Vitamin D supplementation for prevention of mortality in adults

  • Review
  • Intervention

Authors

  • Goran Bjelakovic,

    Corresponding author
    1. Medical Faculty, University of Nis, Department of Internal Medicine, Nis, Serbia
    2. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, The Cochrane Hepato-Biliary Group, Copenhagen, Denmark
    • Goran Bjelakovic, Department of Internal Medicine, Medical Faculty, University of Nis, Zorana Djindjica 81, Nis, 18000, Serbia. goranb@junis.ni.ac.rs.

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  • Lise Lotte Gluud,

    1. Copenhagen University Hospital Hvidovre, Gastrounit, Medical Division, Hvidovre, Denmark
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  • Dimitrinka Nikolova,

    1. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, The Cochrane Hepato-Biliary Group, Copenhagen, Denmark
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  • Kate Whitfield,

    1. Rigshospitalet, Copenhagen University Hospital, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Copenhagen, Denmark
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  • Jørn Wetterslev,

    1. Rigshospitalet, Copenhagen University Hospital, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Copenhagen, Denmark
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  • Rosa G Simonetti,

    1. Ospedali Riuniti Villa Sofia-Cervello, U.O. di Medicina 2, Palermo, Italy
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  • Marija Bjelakovic,

    1. Medical Faculty, University of Nis, Institute of Anatomy, Nis, Serbia
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  • Christian Gluud

    1. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, The Cochrane Hepato-Biliary Group, Copenhagen, Denmark
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Abstract

Background

Available evidence on the effects of vitamin D on mortality has been inconclusive. In a recent systematic review, we found evidence that vitamin D3 may decrease mortality in mostly elderly women. The present systematic review updates and reassesses the benefits and harms of vitamin D supplementation used in primary and secondary prophylaxis of mortality.

Objectives

To assess the beneficial and harmful effects of vitamin D supplementation for prevention of mortality in healthy adults and adults in a stable phase of disease.

Search methods

We searched The Cochrane Library, MEDLINE, EMBASE, LILACS, the Science Citation Index–Expanded and Conference Proceedings Citation Index–Science (all up to February 2012). We checked references of included trials and pharmaceutical companies for unidentified relevant trials.

Selection criteria

Randomised trials that compared any type of vitamin D in any dose with any duration and route of administration versus placebo or no intervention in adult participants. Participants could have been recruited from the general population or from patients diagnosed with a disease in a stable phase. Vitamin D could have been administered as supplemental vitamin D (vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol)) or as an active form of vitamin D (1α-hydroxyvitamin D (alfacalcidol) or 1,25-dihydroxyvitamin D (calcitriol)).

Data collection and analysis

Six review authors extracted data independently. Random-effects and fixed-effect meta-analyses were conducted. For dichotomous outcomes, we calculated the risk ratios (RRs). To account for trials with zero events, we performed meta-analyses of dichotomous data using risk differences (RDs) and empirical continuity corrections. We used published data and data obtained by contacting trial authors.

To minimise the risk of systematic error, we assessed the risk of bias of the included trials. Trial sequential analyses controlled the risk of random errors possibly caused by cumulative meta-analyses.

Main results

We identified 159 randomised clinical trials. Ninety-four trials reported no mortality, and nine trials reported mortality but did not report in which intervention group the mortality occurred. Accordingly, 56 randomised trials with 95,286 participants provided usable data on mortality. The age of participants ranged from 18 to 107 years. Most trials included women older than 70 years. The mean proportion of women was 77%. Forty-eight of the trials randomly assigned 94,491 healthy participants. Of these, four trials included healthy volunteers, nine trials included postmenopausal women and 35 trials included older people living on their own or in institutional care. The remaining eight trials randomly assigned 795 participants with neurological, cardiovascular, respiratory or rheumatoid diseases. Vitamin D was administered for a weighted mean of 4.4 years. More than half of the trials had a low risk of bias. All trials were conducted in high-income countries. Forty-five trials (80%) reported the baseline vitamin D status of participants based on serum 25-hydroxyvitamin D levels. Participants in 19 trials had vitamin D adequacy (at or above 20 ng/mL). Participants in the remaining 26 trials had vitamin D insufficiency (less than 20 ng/mL).
Vitamin D decreased mortality in all 56 trials analysed together (5,920/47,472 (12.5%) vs 6,077/47,814 (12.7%); RR 0.97 (95% confidence interval (CI) 0.94 to 0.99); P = 0.02; I2 = 0%). More than 8% of participants dropped out. 'Worst-best case' and 'best-worst case' scenario analyses demonstrated that vitamin D could be associated with a dramatic increase or decrease in mortality. When different forms of vitamin D were assessed in separate analyses, only vitamin D3 decreased mortality (4,153/37,817 (11.0%) vs 4,340/38,110 (11.4%); RR 0.94 (95% CI 0.91 to 0.98); P = 0.002; I2 = 0%; 75,927 participants; 38 trials). Vitamin D2, alfacalcidol and calcitriol did not significantly affect mortality. A subgroup analysis of trials at high risk of bias suggested that vitamin D2 may even increase mortality, but this finding could be due to random errors. Trial sequential analysis supported our finding regarding vitamin D3, with the cumulative Z-score breaking the trial sequential monitoring boundary for benefit, corresponding to 150 people treated over five years to prevent one additional death. We did not observe any statistically significant differences in the effect of vitamin D on mortality in subgroup analyses of trials at low risk of bias compared with trials at high risk of bias; of trials using placebo compared with trials using no intervention in the control group; of trials with no risk of industry bias compared with trials with risk of industry bias; of trials assessing primary prevention compared with trials assessing secondary prevention; of trials including participants with vitamin D level below 20 ng/mL at entry compared with trials including participants with vitamin D levels equal to or greater than 20 ng/mL at entry; of trials including ambulatory participants compared with trials including institutionalised participants; of trials using concomitant calcium supplementation compared with trials without calcium; of trials using a dose below 800 IU per day compared with trials using doses above 800 IU per day; and of trials including only women compared with trials including both sexes or only men. Vitamin D3 statistically significantly decreased cancer mortality (RR 0.88 (95% CI 0.78 to 0.98); P = 0.02; I2 = 0%; 44,492 participants; 4 trials). Vitamin D3 combined with calcium increased the risk of nephrolithiasis (RR 1.17 (95% CI 1.02 to 1.34); P = 0.02; I2 = 0%; 42,876 participants; 4 trials). Alfacalcidol and calcitriol increased the risk of hypercalcaemia (RR 3.18 (95% CI 1.17 to 8.68); P = 0.02; I2 = 17%; 710 participants; 3 trials).

Authors' conclusions

Vitamin D3 seemed to decrease mortality in elderly people living independently or in institutional care. Vitamin D2, alfacalcidol and calcitriol had no statistically significant beneficial effects on mortality. Vitamin D3 combined with calcium increased nephrolithiasis. Both alfacalcidol and calcitriol increased hypercalcaemia. Because of risks of attrition bias originating from substantial dropout of participants and of outcome reporting bias due to a number of trials not reporting on mortality, as well as a number of other weaknesses in our evidence, further placebo-controlled randomised trials seem warranted.

摘要

以維生素 D 的補充來預防成人的死亡率

背景

關於維生素 D 對死亡率的影響,現有的證據一直沒有定論。在近期的系統性回顧中,我們發現有證據指出,維生素 D3 可以降低多數年長女性的死亡率。現行的系統性回顧已更新且重新評估了維生素 D 的補充在初級和次級預防死亡率中的好處與壞處。

目的

評估維生素 D 的補充在健康和處於疾病穩定期的成人於死亡率防治的好處和壞處。

搜尋策略

我們檢索 The Cochrane Library, MEDLINE, EMBASE, LILACS, the Science Citation Index–Expanded 以及 Conference Proceedings Citation Index–Science(皆至 2012 年 2 月)。因為有不明確的相關試驗,我們檢查了一些含有試驗在內與製藥公司的參考文獻。

選擇標準

成人受試者以隨機試驗將任何形式的維生素 D 以任何劑量、時間與給藥途徑對安慰劑組或未介入組進行比較。受試者可以從一般群體或從被診斷出處於疾病穩定期的患者中招募而來。維生素 D 的給予可以是補充型的維生素 D(維生素 D3(cholecalciferol)或維生素 D2(ergocalciferol))或活化型的維生素 D(1α 羥基維生素 D(alfacalcidol)或1,25-二羥基維生素 D (calcitriol))。

資料收集與分析

六位審查作者獨自萃取數據。進行隨機效應和固定效應的統合分析。對於二元性的結果測量,我們計算風險比(RR)。為了說明試驗中的零事件,我們使用統合分析得出風險差異(RDS)和連續性更正的二元性的結果。我們使用已公布的數據和與試驗作者聯繫所獲得的資料。

為了盡量減少系統誤差的風險,我們評估所納入試驗的偏差。試驗序列分析控制了可能由累積統合分析所引起的隨機錯誤風險。

主要結果

我們確定了 159 個隨機臨床試驗。94 個試驗無報告死亡率,9 個試驗中有報告死亡率,但是在有死亡發生的介入組中並沒有報告死亡率。因此,有 95,286 受試者的 56 個隨機試驗提供了可使用的死亡率數據。受試者的年齡介於 18 至 107 歲之間。大多數的試驗包括了年齡超過 70 歲的女性。女性的平均比例為 77%。48 個試驗隨機分配 94,491 位健康的受試者。其中,4 個試驗包括健康的志願者,9 個試驗包括停經後婦女和 35 個試驗包括獨自生活或於機構照護的年長者。其餘 8 項試驗隨機分配 795 位有神經系統,心血管,呼吸或類風濕疾病的受試者。維生素 D 的給予時間在加權平均後是 4.4年。超過一半的試驗有低風險的偏差。所有試驗都是在高收入國家進行的。45 個試驗(80%)指出其受試者的維生素D 基準值是根據血清 25-羥基維生素 D 水平而定的。有 19 個試驗,其受試者體內有充足的維生素 D 濃度(達到或超過 20奈克/毫升)。其餘的 26 個試驗中,受試者的維生素 D 濃度有不足的狀況(低於20 奈克/毫升)。
維生素 D 在 56 個一併分析的試驗中,死亡率都有減少(5,920/47,472(12.5%) vs 6,077/47,814(12.7%); RR 0.97(95% confidence interval (CI) 0.94 to 0.99); P = 0.02; I2 = 0%)。有超過 8%的受試者退出試驗。“Worst-best case”和“best-worst case”的情境分析指出,維生素 D 可以和死亡率的顯著增加或減少有關。當不同形式的維生素 D 在不同的分析方法下評估,只有維生素 D3 使死亡率下降(4,153/37,817(11.0 %)與 4,340/38,110(11.4%); RR 0.94(95% CI 為 0.91〜0.98), P = 0.002; I2 = 0%; 75,927 人參與; 38 個試驗)。維生素 D2,alfacalcidol 和 calcitriol 對死亡率的影響並不顯著。在高風險偏差的次群組分析試驗中指出,維生素 D2 甚至可能會增加死亡率,但這一發現可能是由於隨機誤差造成的。試驗序列分析支持我們對維生素 D3 的發現,為了利益而打破試驗連續監測邊界的累積 Z 分數,相當於 150 人給予維生素 D3 五年以上以預防一個額外死亡的案例。我們在很多試驗的次群組分析中並沒有觀察到維生素 D 對死亡率有顯著的影響。這些試驗包含:高風險偏差與低風險偏差的比較;安慰劑組與未介入的控制組比較;有風險的企業偏差試驗與無風險的企業偏差試驗比較;初級預防的評估試驗與次級預防的評估試驗比較;受試者體內的維生素 D 濃度低於 20ng/ml 的試驗與大於(包含)20ng/ml 的試驗進行比較;可步行的受試者與機構照護的受試者試驗進行比較;使用有鈣添加的補充品與無鈣添加的試驗進行比較;使用低於 800 國際單位(IU)的劑量與每天使用超過 800 IU 的試驗進行比較;只有女性與有兩性或只有男性的試驗比較。維生素 D3 顯著降低癌症的死亡率(RR 0.88(95% CI 為 0.78〜0.98),P = 0.02; I2 = 0%; 44,492 人參與; 4 項試驗)。維生素 D3 與鈣一併服用會增加腎結石的風險(RR 1.17(95% CI為 1.02〜1.34),P = 0.02; I2 = 0%; 42,876 人參加; 4 項試驗)。Alfacalcidol 與 calcitriol 會增加高血鈣症的風險(RR 3.18(95% CI 為 1.17〜8.68),P = 0.02; I2 = 17%; 710 人參與; 3 項試驗)。

作者結論

維生素 D3 似乎會降低獨居和於機構中養護的年長者的死亡率。維生素 D2 ,alfacalcidol 及 calcitriol 對死亡率沒有顯著的效益。維生素 D3 與鈣結合會增加腎結石的風險。alfacalcidol 與 calcitriol 會增加高鈣血症的風險。由於受試者大量的減少造成損耗性偏差的風險,以及一些試驗並沒有回報死亡率而造成結果回報的偏差,此外,我們的證據也還有一些缺點,因此,再進行安慰劑對照隨機試驗是必要的。

譯註

翻譯者:廖誼青
服務單位:陽明大學 臨床醫學研究所
職稱:研究生

本翻譯計畫由臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan)、台灣實證醫學學會及東亞考科藍聯盟(EACA)統籌執行
聯絡E-mail:cochranetaiwan@tmu.edu.tw

アブストラクト

ビタミンD補充による成人の死亡予防

背景

死亡率に対するビタミンDの効果について入手可能なエビデンスは決定的ではない。最近のシステマティック・レビューでは、ビタミンD3 が主に高齢女性の死亡率を低下させる可能性があるというエビデンスが得られた。本システマティック・レビューでは、死亡の一次予防および二次予防におけるビタミンD補充の有益性と有害性について更新および再評価を行った。

目的

健康成人および疾患安定期の成人を対象に、死亡予防に対するビタミンD補充の有益性と有害性を評価すること。

検索戦略

The Cochrane Library、MEDLINE、EMBASE、LILACSScience Citation Index-ExpandedおよびConference Proceedings Citation Index-Science(いずれも2012年2月まで)を検索した。未同定の関連試験に関しては、対象とした試験の参考文献を参照するか、または製薬企業に確認した。

選択基準

成人参加者を対象に、あらゆる型および用量のビタミンDをさまざまな期間および経路で投与した場合と、プラセボまたは無介入を比較したランダム化試験。参加者は、一般集団または疾患安定期と診断された患者集団から集められた。ビタミンDは、ビタミンDサプリメント(ビタミンD3 [コレカルシフェロール]もしくはビタミンD2[エルゴカルシフェロール])または活性型ビタミンD(1αヒドロキシビタミンD[アルファカルシドール]もしくは1,25-ジヒドロキシビタミンD[カルシトリオール])として投与した。

データ収集と分析

6名のレビュー著者が独立してデータを抽出した。ランダム効果メタアナリシスおよび固定効果メタアナリシスを実施した。アウトカムが2値変数の場合は、リスク比(RR)を計算した。イベント数が0の試験を説明するために、リスク差(RD)および経験連続補正を用いて2値変数データのメタアナリシスを実施した。出版物に発表されたデータおよび論文の著者に連絡して入手したデータを使用した。

システマティックエラーのリスクを最小限にするため、対象試験のバイアスのリスク評価を行った。試験の逐次解析によって、累積メタアナリシスで生じる可能性があるランダムエラーのリスクを管理した。

主な結果

159件のランダム化臨床試験を同定した。94件の試験では死亡例は認められず、9件の試験では死亡例が認められたが、どの介入群で死亡が発生したかについての記載はなかった。このため、56件のランダム化試験(参加者数95,286例)から死亡率に関する利用可能なデータが得られた。参加者の年齢は18歳から107歳であった。ほとんどの試験では、70歳より高齢の女性が対象に含まれていた。女性が占める割合の平均値は77%であった。48件の試験では、健康な参加者94,491例を無作為に割り付けた。このうち、4件の試験では健常人が、9件の試験では閉経後の女性が、また、35件の試験では独居しているか、または介護施設でケアを受けている高齢者が対象であった。残り8件の試験では、神経疾患、心血管疾患、呼吸器疾患またはリウマチ疾患を有する参加者795例を無作為に割り付けた。。ビタミンD投与期間の加重平均は4.4年であった。バイアスのリスクは、対象試験の半数超で低かった。試験はすべて高所得国で実施された。45件(80%)の試験では、参加者の血清25-ヒドロキシビタミンD濃度をもとにベースライン時のビタミンD濃度を報告していた。19件の試験では、参加者のビタミンDは充足していた(20 ng/mL以上)。残り26件の試験の参加者では、ビタミンD不足(20 ng/mL未満)が認められた。同時解析を行った56件の試験すべてにおいて、ビタミンDは死亡率を低下させた(5,920/47,472(12.5%)対6,077/47,814(12.7%);RR0.97(95%信頼区間(CI)0.94〜0.99);P = 0.02;I2= 0%)。試験から脱落した参加者は8%を上回った。「ワースト・ベストケース」および「ベスト・ワーストケース」シナリオ分析では、ビタミンDが死亡率の顕著な上昇または低下に関与していることが示された。ビタミンDの種類別に異なる分析法を用いて評価した結果、ビタミンD3のみが死亡率を低下させた(4,153/37,817(11.0%)対4,340/38,110(11.4%);RR0.94(95%CI 0.91〜0.98);P = 0.002;I2 = 0%;参加者数75,927例;試験数38件)。ビタミンD2、アルファカルシドールおよびカルシトリオールは、死亡率に有意な影響を及ぼさなかった。バイアスのリスクが高い試験のサブグループ解析では、ビタミンD2 が死亡率をむしろ増加させる可能性が示唆されたが、この知見はランダムエラーが原因の可能性がある。試験の逐次解析では、ビタミンD3 に関する知見を支持する結果が得られ、試験の逐次モニタリングでは累積Zスコアが有益性の境界を超えた。これは、新規死亡1例を予防するために150例が5年超のビタミンD3投与を受ける必要があることを意味する。サブグループ解析では、バイアスのリスクが低い試験とバイアスが高い試験の比較、対照群にプラセボを用いた試験と対照群に無介入を用いた試験の比較、助成金バイアスのリスクが認められない試験と助成金バイアスが認められる試験の比較、一次予防を評価した試験と二次予防を評価した試験の比較、登録時のビタミンD濃度が20 ng/mL未満の参加者を含む試験と登録時の参加者のビタミンD濃度が20 ng/mL以上の試験の比較、日帰り施設利用者を対象とした試験と施設入所者を対象とした試験の比較、カルシウムサプリメント併用試験とカルシウム非併用試験の比較、投与量が800 IU/日未満の試験と投与量が800 IU/日超の試験の比較、女性のみを対象とした試験と男女両方または男性のみを対象とした試験の比較を行った結果、死亡率に対するビタミンDの効果に統計学的有意差は認められなかった。ビタミンD3を投与した場合、癌による死亡率の低下に統計学的有意性が認められた(RR0.88(95%CI 0.78〜0.98);P = 0.02;I2= 0%;参加者数44,492例;試験数4件)。ビタミンD3とカルシウムを併用した場合、腎結石のリスクが上昇した(RR1.17(95%CI 1.02〜1.34);P = 0.02;I2 =0%;参加者数42,876例;試験数4件)。アルファカルシドールおよびカルシトリオールは、高カルシウム血症のリスクを上昇させた(RR3.18(95%CI 1.17〜8.68);P = 0.02;I2 = 17%;参加者数710例;試験数3件)。

著者の結論

ビタミンD3は、独居しているか、または介護施設でケアを受けている高齢者の死亡率を低下させると考えられた。ビタミンD2 、アルファカルシドールおよびカルシトリオール の死亡率に対する利益に、統計学的有意性は認められなかった。ビタミンD3とカルシウムを併用した場合、腎結石の発生率が上昇した。アルファカルシドールおよびカルシトリオールは、いずれも高カルシウム血症の発生率を上昇させた。脱落した参加者数が多いことに起因する症例減少バイアスのリスクや死亡率の報告がない試験が数件存在することに起因するアウトカム報告バイアスのリスクの他にも、複数のエビデンスの弱さが存在するため、さらにプラセボ対照ランダム化試験が必要であると考えられる。

訳注

《実施組織》厚生労働省「「統合医療」に係る情報発信等推進事業」(eJIM:http://www.ejim.ncgg.go.jp/)[2016.7.11]
《注意》この日本語訳は、臨床医、疫学研究者などによる翻訳のチェックを受けて公開していますが、訳語の間違いなどお気づきの点がございましたら、eJIM事務局までご連絡ください。なお、2013年6月からコクラン・ライブラリーのNew review, Updated reviewとも日単位で更新されています。eJIMでは最新版の日本語訳を掲載するよう努めておりますが、タイム・ラグが生じている場合もあります。ご利用に際しては、最新版(英語版)の内容をご確認ください。

Plain language summary

Vitamin D supplementation for prevention of mortality in adults

Review question

To assess the beneficial and harmful effects of vitamin D for prevention of mortality in healthy adults and adults in a stable phase of disease.

Background

Numerous observational studies suggest that optimal vitamin D status may be associated with fewer occurrences of cancer and cardiovascular disease (such as heart attack or stroke). Vitamin D is synthesised in the skin as vitamin D3 (cholecalciferol) or is obtained from dietary sources or supplements as vitamin D3 or vitamin D2 (ergocalciferol). Our Cochrane systematic review from 2011, which analysed the influence of different forms of vitamin D on mortality, showed that vitamin D3 (cholecalciferol) decreased mortality. This systematic review is now updated, and all included trials have been reassessed in accordance with improved Cochrane methodology, developed to enhance the validity of the conclusions.

Study characteristics

In the 56 trials that provided data for the analyses, a total of 95,286 participants were randomly assigned to vitamin D versus no treatment or placebo. More than half of the trials were considered to have low risk of bias. All trials were conducted in high-income countries. The age of participants ranged from 18 to 107 years. The mean proportion of women was 77%. Vitamin D was administered for an average of 4.4 years.

This plain language summary is as current as of February 2012.

Key results

This review suggests that vitamin D3 may reduce mortality, showing that about 150 participants need to be treated over five years for one additional life to be saved. We found comparable effects of vitamin D3 in studies that included only women compared with studies including both women and men. Vitamin D3 also seemed to decrease cancer mortality, showing a reduction in mortality of 4 per 1000 persons treated for five to seven years. We also observed adverse effects to vitamin D such as renal stone formation (seen for vitamin D3 combined with calcium) and elevated blood levels of calcium (seen for both alfacalcidol and calcitriol). In conclusion, we found some evidence that vitamin D3 seems to decrease mortality in elderly people not dependent on help or living in institutional care.

Quality of the evidence

A large number of study participants left the trial before completion, and this raises concerns regarding the validity of the results. More randomised clinical trials are needed on the effects of vitamin D3 on mortality in younger, healthy persons, as well as in elderly community-dwelling and institutionalised persons without apparent vitamin D deficiency.

淺顯易懂的口語結論

以維生素 D 的補充來預防成人死亡率

回顧的問題

評估維生素 D 的補充對健康成人和處於疾病穩定期的成人,其預防死亡率的好處與壞處。

背景

許多觀察性研究指出,最佳的維生素 D狀態可能與癌症和心血管疾病(如心臟病發作或中風)發生較少有關。維生素D 以維生素 D3 的形式在皮膚中合成(cholecalciferol),維生素 D 也可以從飲食獲得或是以維生素 D3 或維生素 D2 的形式(ergocalciferol)補充而得。我們的 Cochrane 系統性回顧自 2011 年以來,分析了不同形式的維生素 D 對死亡率 的 影 響 , 結 果 指 出 維 生 素 D3(cholecalciferol)可以降低死亡率。該系統性回顧現在已經更新,且所有納入的試驗也已根據改進的 cochrane 方法學而被重新評估,進而提高結論的正確性。

研究特點

在 56 個試驗分析所提供的數據中,總共有 95286 位受試者被隨機分配到維生素D 介入組與未治療或安慰劑組中。有一半以上的試驗被認為有低風險的偏差。所有試驗都是在高收入國家中進行的。受試者的年齡介於 18 至 107 歲之間。女性所佔的平均比例為 77%。平均給予維生素 D 4.4 年。

這篇研究的總結資料最新至 2012 年 2 月。

主要成果

本次的回顧指出維生素 D3 可能可以降低死亡率。資料顯示大約每 150 名受試者介入超過五年會有一個人得救。我們發現維生素 D 在只有女性的研究與同時有男性和女性的研究中有可比較的影響。維生素 D3 似乎也會降低癌症死亡率,資料指出在給予維生素 D3,治療 5 到 7 年後,每 1000 人可以減少 4 個案例的死亡。此外,我們也觀察到維生素 D 的不良影響,如腎結石的形成(發生在維生素 D3 與鈣一同服用時)和血鈣濃度的增加(alfacalcidol 和 calcitriol 皆增加)。總而言之,我們發現了一些證據指出,維生素 D3 似乎能降低獨居與住在照護機構的年長者的死亡率。

證據的品質

之前有大量的受試者在完成試驗前退出,這產生了結果有效性的問題。需要更多的隨機臨床試驗來驗證維生素 D3 對那些沒有明顯維生素 D 缺乏症的年輕、健康的人,以及居住在社區和照護機構的年長者的死亡率的影響。

譯註

翻譯者:廖誼青
服務單位:陽明大學 臨床醫學研究所
職稱:研究生

本翻譯計畫由臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan)、台灣實證醫學學會及東亞考科藍聯盟(EACA)統籌執行
聯絡E-mail:cochranetaiwan@tmu.edu.tw

Laički sažetak

Davanje nadomjestaka vitamina D za prevenciju smrtnosti kod odraslih

Istraživačko pitanje

Procijeniti korisne i štetne učinke vitamina D za prevenciju smrtnosti u zdravih odraslih osoba te odraslih osoba u stabilnoj fazi bolesti.

Dosadašnje spoznaje

Brojne opservacijske studije ukazuju da optimalni status vitamina D može biti povezan s rjeđom pojavom raka i srčano-žilnih bolesti (kao što su srčani ili moždani udar). Vitamin D se sintetizira u koži kao vitamin D3 (kolekalciferol) ili se unosi putem hrane ili nadomjestaka kao vitamin D3 ili vitamin D2 (ergokalciferol). Ovaj Cochrane sustavni pregled prvi put je objavljen 2011., pri čemu je analizirao učinak različitih oblika vitamina D na smrtnost, i pokazao da vitamin D3 (kolekalciferol) smanjuje smrtnost. Ovaj sustavni pregled je sada obnovljen, a sva uključena istraživanja ponovno procijenjena u skladu s poboljšanom Cochrane metodologijom, razvijenom kako bi se povećala valjanost zaključaka.

Značajke istraživanja

U 56 istraživanja koja su korištena kao izvor podataka za analizu, ukupno 95.286 sudionika je nasumično raspoređeno u skupinu koja je dobivala vitamin D i skupinu koja nije dobivala terapiju ili je dobivala placebo. Više od polovice istraživanja imalo je nizak rizik od pristranosti. Sva istraživanja su provedena u zemljama s visokim dohotkom. Sudionici su bili u dobi od 18 do 107 godina. Prosječan udio žena je bio 77%. Vitamin D je u prosjeku primjenjivan 4,4 godine.

Ovaj laički sažetak je obnovljen u veljači 2012.

Ključni rezultati

Pregled pokazuje da vitamin D3 može smanjiti smrtnost. Pokazalo se da je potrebno liječiti približno 150 ispitanika, više od 5 godina, kako bi se spasio jedan ljudski život. Sličan učinak vitamina D3 uočen je u studijama koje su uključivale samo žene u usporedbi s onima koje su uključivale i žene i muškarce. Čini se da vitamin D3 također smanjuje smrtnost od raka, za 4 osobe na svakih 1000 liječenih u trajanju od 5 do 7 godina. Opaženi su također i neželjeni učinci vitamina D kao što je nastanak bubrežnih kamenaca (kod kombinacije vitamina D3 s kalcijem) kao i povišeni nivo kalcija u krvi (opažen i za alfakalcidol i kalcitriol). Zaključno, pronađeni su neki dokazi da vitamin D3 smanjuje smrtnost kod starijih ljudi koji nisu ovisni o tuđoj pomoći ili žive u ustanovi za skrb.

Kvaliteta dokaza

Velik broj ispitanika je napustio istraživanje prije njegovog završetka, a ovo izaziva zabrinutost u pogledu valjanosti rezultata. Potrebno je više randomiziranih kliničkih pokusa o učinku vitamina D 3 na smrtnost u mladih, zdravih osoba, kao i u odraslih u stambenim zajednicama i institucijama za skrb, kod kojih ne postoji očiti nedostatak vitamina D.

Bilješke prijevoda

Cochrane Hrvatska
Prevela: Viljemka Bučević Popović
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

平易な要約

ビタミンD補充による成人の死亡予防

レビューの論点

健康成人および疾患安定期の成人の死亡予防に対するビタミンDの有益性および有害性を評価すること。

背景

至適濃度のビタミンDが癌や心血管疾患(心臓発作や脳卒中など)の発生率の低さと関連していることが、多数の観察研究によって示されている。ビタミンDは、ビタミンD3(コレカルシフェロール)として皮膚で合成されるか、または食物やサプリメントからビタミンD3もしくはビタミンD2(エルゴカルシフェロール)の形で摂取される。2011年以降のコクラン・システマティック・レビューでは、種々の型のビタミンDの死亡率に対する影響を分析し、ビタミンD3(コレカルシフェロール)が死亡率を低下させることが示された。現在このシステマティック・レビューは更新され、結論の妥当性(正当性)を強化するために開発された改良版コクラン分析法に従って、すべての対象試験を再評価した。

研究の特性

分析データを入手した56件の試験では、計95,286例の参加者をビタミンD投与群、無治療群、またはプラセボ投与群に無作為に割り付けた。対象試験の半数超で、バイアスのリスクは低いと判断された。試験はすべて高所得国で実施された参加者の年齢は18歳から107歳であった。女性が占める割合の平均値は77%であった。ビタミンD投与期間は平均4.4年であった。

この平易な要約は2012年2月現在のものである。

主な結果

このレビューは、ビタミンD3 が死亡率を低下させる可能性があることを示唆している。これは、新たに1人の生命を救うためには、ビタミンD3を約150人の参加者に5年超投与する必要があることを示している。女性のみを対象とした研究では、男女両方を対象とした研究と同様のビタミンD3 の効果が認められた。また、ビタミンD3は、癌による死亡率も低下させると考えら、5〜7年間投与した場合、1000人あたり4人の死亡率が低下した。また、ビタミンD投与により、腎結石形成(ビタミンD3 をカルシウムと併用した場合)や血中カルシウム濃度の上昇(アルファカルシドールおよびカルシトリオールの両方)などの有害作用が観察された。以上から、ビタミンD3が、介助を必要としないか、または介護施設でケアを受けている高齢者の死亡率を低下させるというエビデンスが得られた。

エビデンスの質

多数の参加者が、試験終了前に試験参加を中止した。このため、結果の妥当性が疑問視される。健康な若年者や、明らかなビタミンD欠乏が認められない地域社会で生活する高齢者および介護施設入所者の死亡率に対するビタミンD3 の効果については、さらにランダム化臨床試験が必要である。

訳注

《実施組織》厚生労働省「「統合医療」に係る情報発信等推進事業」(eJIM:http://www.ejim.ncgg.go.jp/)[2016.7.11]
《注意》この日本語訳は、臨床医、疫学研究者などによる翻訳のチェックを受けて公開していますが、訳語の間違いなどお気づきの点がございましたら、eJIM事務局までご連絡ください。なお、2013年6月からコクラン・ライブラリーのNew review, Updated reviewとも日単位で更新されています。eJIMでは最新版の日本語訳を掲載するよう努めておりますが、タイム・ラグが生じている場合もあります。ご利用に際しては、最新版(英語版)の内容をご確認ください。

Summary of findings(Explanation)

Summary of findings for the main comparison. Vitamin D supplementation for prevention of mortality in adults
  1. aDowngraded by one level because of risk of attrition bias
    bDowngraded by two levels because of risk of attrition bias and imprecision

Vitamin D supplementation for prevention of mortality in adults
Population: adults
Settings: any
Intervention: vitamin D
Comparison: placebo or no intervention
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Placebo or no intervention Vitamin D

All-cause mortality in trials using vitamin D3
(cholecalciferol)

(Follow-up: 0.08 to 7 years)

Study population RR 0.94
(0.91 to 0.98)
75,927
(38)

⊕⊕⊕⊝

moderatea

Trial sequential analysis of all trials irrespective of bias risks showed that the required information size had not yet been reached and that the cumulative Z-curve crossed the trial sequential monitoring boundary for benefit. If this is correct, the intervention effect corresponds to a number needed to treat for a beneficial outcome (NNTB) of 150 participants over five years to save one additional life
114 per 1000 107 per 1000
(104 to 112)
Moderate risk
46 per 1000 43 per 1000
(42 to 45)

Cardiovascular mortality in trials using vitamin D3 (cholecalciferol)

(Follow-up: 0.31 to 6.2 years)

Study population RR 0.98
(0.90 to 1.07)
47,267
(10)

⊕⊕⊝⊝

lowb

Trial sequential analysis showed that the cumulative Z-curve did not cross the conventional monitoring boundary for benefit. The required information size was 2,539,845 participants
42 per 1000 41 per 1000
(38 to 45)
Moderate risk
13 per 1000 11 per 1000
(12 to 15)

Cancer mortality in trials using vitamin D3 (cholecalciferol)

(Follow-up: 5 to 7 years)

Study population RR 0.88
(0.78 to 0.98)
44,492
(4)

⊕⊕⊕⊝

moderatea

Trial sequential analysis showed that the cumulative Z-curve did not cross the conventional monitoring boundary for benefit. The required information size was 66,724 participants
29 per 1000 25 per 1000
(22 to 31)
Moderate risk
21 per 1000 19 per 1000
(16 to 21)

Adverse events: nephrolithiasis in trials using vitamin D3 combined with calcium

(Follow-up: 1.25 to 7 years)

Study population RR 1.17
(1.02 to 1.34)
42,876
(4)
⊕⊕⊕⊝
moderatea
 
18 per 1000 21 per 1000
(18 to 24)
Moderate risk
9 per 1000 11 per 1000
(9 to 12)

Adverse events: hypercalcaemia in trials using the active forms of vitamin D (alfacalcidol and calcitriol)

(Follow-up: 0.75 to 3 years)

Study population RR 3.18
(1.17 to 8.68)
710
(3)
⊕⊕⊝⊝
lowb
 
23 per 1000 72 per 1000
(27 to 197)
Moderate risk
11 per 1000 15 per 1000
(4 to 23)

Health-related quality of life

(Follow-up: 0.38 years)

See commentSee commentNot estimable

105

(1)

See commentInsufficient information: significant worsening in disease-specific quality of life in the vitamin D2 group compared with the placebo group was reported. The between-group difference at 20 weeks was 5.3 (0.5 to 10.2), and the minimally important difference (MID) is estimated to be 5 points in either direction

Health economics

(Follow-up: 4 years)

See commentSee commentNot estimable

3270

(1)

See commentInsufficient information: authors reported that vitamin D3 and calcium supplementation prevented 46 hip fractures in every 1000 women treated
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio; RRR: relative risk reduction
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Description of the condition

Vitamin D is synthesised in the skin as vitamin D3 (cholecalciferol) or is obtained from dietary sources or supplements as vitamin D3 or vitamin D2 (ergocalciferol). Vitamins D3 and D2 are metabolised in the liver to 25-hydroxyvitamin D and in the kidneys to the biologically active 1,25-dihydroxyvitamin D (calcitriol), which functions as a steroid-like hormone (Horst 2005; Lips 2006). The effects of vitamin D are mediated by its binding to vitamin D receptors in the cells (Wesley Pike 2005). Renal production of 1,25-dihydroxyvitamin D is regulated by parathyroid hormone levels, by serum calcium and phosphorus levels and by the phosphaturic hormone fibroblast growth factor-23 (Kovesdy 2013).

Under conditions of hypocalcaemia, synthesis of the biologically active form of vitamin D (1,25-dihydroxyvitamin D or calcitriol) is stimulated. This, in turn, stimulates the transport of calcium out of the intestine, kidneys and bones into the blood (Lips 2006). Therefore, homeostasis of vitamin D and calcium levels is essential for bone health (Holick 2007a; Horst 2005; Lips 2006). Current interest in vitamin D has been provoked by the discovery that most cells and tissues in our body contain vitamin D receptors (Holick 2006). During past decades, observational studies have suggested that vitamin D is effective for prevention of malignant, cardiovascular, autoimmune and infectious diseases (Holick 2007a; Nnoaham 2008; Rosen 2011; Souberbielle 2010).

Vitamin D status

Vitamin D status is determined by measurement of the serum 25-hydroxyvitamin D level, which is a functional indicator of 'vitamin D status' (Bischoff-Ferrari 2009c; Dawson-Hughes 2005; Lips 2004). The US Institute of Medicine recently recommended a target serum 25-hydroxyvitamin D level of 20 ng/mL (50 nmol/L) (IOM 2011). The worldwide prevalence of suboptimal vitamin D status is estimated to be high (Holick 2007a; Mithal 2009). Major causes of vitamin D deficiency include insufficient exposure to sunlight, decreased dietary intake, skin pigmentation, obesity and advanced age (Lips 2006). Vitamin D deficiency in adults precipitates or exacerbates osteopenia and osteoporosis and induces osteomalacia (Holick 2007a). Vitamin D insufficiency is linked to increased risk of malignant, cardiovascular, autoimmune and infectious diseases (Holick 2007a; Rosen 2011; Souberbielle 2010). An opposing hypothesis that vitamin D insufficiency is a consequence of disease but not its cause has been postulated by Marshall et al (Marshall 2008).

How the intervention might work

Vitamin D supplementation (vitamin D3 (cholecalciferol), vitamin D2 (ergocalciferol), 1α-hydroxyvitamin D (alfacalcidol) or 1,25-dihydroxyvitamin D (calcitriol)) seems to prevent osteoporosis, osteomalacia and fractures (Holick 2007a; Lamberg-Allardt 2006). It has been speculated that vitamin D may confer benefits beyond the skeletal system (Davis 2007). Evidence on whether vitamin D may prevent cancer, cardiovascular disease and mortality is contradictory (Bjelakovic 2011; Davis 2007; Giovannucci 2005; Michos 2008; Pittas 2010; Wang 2010; Zittermann 2006).

Adverse effects of the intervention

Excessive vitamin D intake over a prolonged time may lead to vitamin D toxicity. However, evidence that ingestion of high quantities of vitamin D is harmful is sparse. Most trials have reported hypercalcaemia, hypercalciuria or nephrocalcinosis when vitamin D was administered to participants with renal failure (Cranney 2007). Excessive exposure to sunlight does not seem to lead to vitamin D intoxication (Holick 2007b).

Why it is important to do this review

Available evidence on vitamin D and mortality is intriguing and for the most inconclusive. Most observational studies have associated low vitamin D status with increased risk of death (Johansson 2012; Zittermann 2012). Several systematic reviews and meta-analyses found beneficial effects of vitamin D in elderly people with vitamin deficiency or in people who received vitamin D as monotherapy or in combination with calcium for osteoporosis, fractures and falls (Bischoff-Ferrari 2005; Bischoff-Ferrari 2009a; Jackson 2007; Latham 2003b; Richy 2005; Tang 2007). Vitamin D supplementation revealed positive effects in maintaining glucose homeostasis (Pittas 2007a) and in preventing tuberculosis (Nnoaham 2008). However, Izaks et al (Izaks 2007) and Boonen et al (Boonen 2006) found no statistically significant effects of vitamin D supplementation on these outcomes in the general population. A meta-analysis by Autier and Gandini (Autier 2007) of 18 randomised clinical trials found significantly lower mortality among vitamin D–supplemented participants (Autier 2007). A Cochrane systematic review of 16 randomised trials on prevention of fractures found only a non-significant tendency of vitamin D to reduce mortality (Avenell 2009). In our published Cochrane review in 2011, data from 50 randomised clinical trials with 94,148 participants suggested a beneficial effect of vitamin D3 on mortality (Bjelakovic 2011). Since the time of that review (Bjelakovic 2011), the results of several new randomised trials conducted to test the influence of vitamin D supplementation on mortality have become available. Also, we wanted to analyse further the influence of participants' sex on the effects of vitamin D3 and to implement the improved Cochrane methodology in performing data assessment. The present review is an update of the former review (Bjelakovic 2011).

Objectives

To assess the beneficial and harmful effects of vitamin D supplementation for prevention of mortality in healthy adults and adults in a stable phase of disease.

Methods

Criteria for considering studies for this review

Types of studies

Randomised clinical trials, irrespective of blinding, publication status or language, that have assessed supplemental vitamin D (vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol)) or an active form of vitamin D (1α-hydroxyvitamin D (alfacalcidol) or 1,25-dihydroxyvitamin D (calcitriol)). We included primary prevention trials (defined as trials that seek to prevent disease before it occurs) and secondary prevention trials (defined as trials undertaken to prevent recurrences or exacerbations of a disease that has already been diagnosed) (Starfield 2008).

Types of participants

We included adult participants (18 years of age or older) who were.

  • Healthy or were recruited from the general population (primary prevention), irrespective of vitamin D status in the blood.

  • Diagnosed with a specific disease and in a stable phase (secondary prevention), irrespective of vitamin D status in the blood.

  • Diagnosed with vitamin D deficiency (secondary prevention).

We excluded trials that included:

  • Patients with secondary induced osteoporosis (e.g. glucocorticoid-induced osteoporosis, thyroidectomy, primary hyperparathyroidism, chronic kidney disease, liver cirrhosis, Crohn's disease, gastrointestinal bypass surgery).

  • Pregnant or lactating women (as they usually are in need of vitamin D).

  • Patients with cancer.

Types of interventions

Intervention

Vitamin D at any dose and for any duration, administered as monotherapy or in combination with calcium. The route of administration could have been enteral or parenteral.

Vitamin D could have been administered as supplemental vitamin D (vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol)) or as an active form of vitamin D (1α-hydroxyvitamin D (alfacalcidol) or 1,25-dihydroxyvitamin D (calcitriol)).

Control

Identical placebo or no intervention.

Calcium in the control group was allowed if used equally in the vitamin D groups of the trial.

Types of outcome measures

Primary outcomes
  • All-cause mortality.

  • Adverse events: depending on the availability of data, we attempted to classify adverse events as serious and non-serious. A serious adverse event was defined as any untoward medical occurrence that was life threatening; resulted in death, or in persistent or significant disability or incapacity; or was a congenital anomaly/birth defect; or any medical event that might have jeopardised the participant or required intervention to prevent it (ICH-GCP 1997). All other adverse events (i.e. medical occurrences not necessarily having a causal relationship to the treatment but causing a dose reduction or discontinuation of treatment) were considered as non-serious.

Secondary outcomes
  • Cancer-related mortality.

  • Cardiovascular mortality.

  • Fracture-related mortality.

  • Other causes of mortality.

  • Health-related quality of life.

  • Health economics.

Co-variates, effect modifiers and confounders

We recorded any possible co-variates, effect modifiers and confounders such as dosage and form of vitamin D, dosing schedule, duration of supplementation, duration of follow-up, mean age, risk of bias, calcium co-administration, other medications, compliance and attrition.

Timing of outcome measurement

We applied no restrictions regarding duration of the intervention or length of follow-up. We assessed outcome data at the end of the trial follow-up period.

Search methods for identification of studies

Electronic searches

We searched the following sources from inception to the specified date to identify trials that met our criteria.

  • The Cochrane Library (Issue 2, February 2012).

  • MEDLINE (until February 2012).

  • EMBASE (until February 2012).

  • LILACS (until February 2012).

  • Science Citation Index–Expanded (until February 2012).

  • Conference Proceedings Citation Index–Science (until February 2012).

We also searched Clinicaltrials.gov (http://clinicaltrials.gov/) and the World Health Organization International Clinical Trials Registry Platform (ICTRP 2011) to look for ongoing trials.

The search strategies for the databases we have searched are given in Appendix 1.

Searching other resources

We identified additional trials by searching reference lists of included trials and systematic reviews, meta-analyses and health technology assessment reports. We also contacted experts and main manufacturers of vitamin D to ask about unpublished randomised trials.

Data collection and analysis

The present updated review expands on the previously published review in 2011 (Bjelakovic 2011) and the protocol published in 2008 (Bjelakovic 2008a).

Selection of studies

One review author (GB) performed the electronic searches. Six review authors (GB, LLG, DN, KW, RGS and MB) participated in the manual searches, identified trials eligible for inclusion from the search results and extracted data from the included trials. GB listed the excluded studies along with the reasons for exclusion. When a discrepancy occurred in trial selection or data extraction, the review author CG was consulted so consensus could be reached. We contacted authors of the trials to ask for missing information. Interrater agreement for trial selection was measured using the Kappa statistic (Cohen 1960). Agreement between the review authors was very good (Kappa = 0.85). An adapted PRISMA flow diagram of study selection is included in the review (Moher 2009).

Data extraction and management

Six review authors (GB, LLG, DN, KW, RGS and MB) independently extracted data on the relevant population and intervention characteristics, as well as on the risk of bias components, from trials that fulfilled the inclusion criteria of our review protocol. We used standard templates for data extraction. We searched for duplicate publications. Disagreements were resolved by discussion or, when needed, by the review author CG.

Assessment of risk of bias in included studies

Because of the risk of overestimation of beneficial intervention effects in randomised clinical trials with unclear or inadequate methodological quality (Kjaergard 2001; Lundh 2012; Moher 1998; Savovic 2012; Schulz 1995; Wood 2008), we assessed the influence of the risk of bias on our results. We used the following domains: allocation sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, industry bias and other apparent biases (Higgins 2011). The following definitions were used.

Allocation sequence generation 
  • Low risk of bias: sequence generation was achieved using computer random number generation or a random number table. Drawing lots, tossing a coin, shuffling cards and throwing dice are adequate if performed by an independent person not otherwise involved in the trial.

  • Uncertain risk of bias: the method of sequence generation was not specified.

  • High risk of bias: the sequence generation method was not random.

Allocation concealment
  • Low risk of bias: the participant allocations could not have been foreseen in advance of, or during, enrolment. Allocation was controlled by a central and independent randomisation unit. The allocation sequence was unknown to the investigators (e.g. if the allocation sequence was hidden in sequentially numbered, opaque and sealed envelopes).

  • Uncertain risk of bias: the method used to conceal the allocation was not described so that intervention allocations may have been foreseen in advance of, or during, enrolment.

  • High risk of bias: the allocation sequence was likely to be known to the investigators who assigned the participants.

Blinding of participants, personnel and outcome assessors
  • Low risk of bias: blinding was performed adequately, or the assessment of outcomes was not likely to be influenced by lack of blinding.

  • Uncertain risk of bias: information was insufficient to allow assessment of whether blinding was likely to induce bias on the results.

  • High risk of bias: no blinding or incomplete blinding was provided, and assessment of outcomes was likely to be influenced by lack of blinding.

Incomplete outcome data
  • Low risk of bias: missing data were unlikely to make treatment effects depart from plausible values. Sufficient methods, such as multiple imputation, have been employed to handle missing data.

  • Uncertain risk of bias: information was insufficient to allow assessment of whether missing data in combination with the method used to handle missing data were likely to induce bias on the results.

  • High risk of bias: the results were likely to be biased because of missing data.

Selective outcome reporting
  • Low risk of bias: all outcomes were predefined and reported, or all clinically relevant and reasonably expected outcomes were reported.

  • Uncertain risk of bias: it is unclear whether all predefined and clinically relevant and reasonably expected outcomes were reported.

  • High risk of bias: one or more clinically relevant and reasonably expected outcomes were not reported, and data on these outcomes were likely to have been recorded.

To be assessed with low risk of bias in the selective outcome reporting domain, the trial should have been registered on the www.clinicaltrials.gov website or a similar register, or a protocol should exist (e.g. published in a paper journal). In cases where the trial was run and published during the years when trial registration was not required, we tried to carefully scrutinise the publication reporting on the trial to identify the trial objectives and outcomes. If usable data on all outcomes specified in the trial objectives were provided in the publication's results section, the trial was considered to have low risk of bias in the 'Selective outcome reporting' domain.

Industry bias
  • Low risk of bias: the trial is not funded by a manufacturer of vitamin D.

  • Uncertain risk of bias: the source of funding is not clear.

  • High risk of bias: the trial is funded by a manufacturer of vitamin D.

Other bias
  • Low risk of bias: the trial appears to be free of other components that could put it at risk of bias. 

  • Uncertain risk of bias: the trial may or may not be free of other components that could put it at risk of bias.

  • High risk of bias: other factors in the trial could put it at risk of bias (e.g. authors have conducted trials on the same topic, etc).

Trials assessed as having 'low risk of bias' in all of the individual domains specified above were considered 'trials with low risk of bias'. Trials assessed as having 'uncertain risk of bias' or 'high risk of bias' in one or more of the specified individual domains were considered trials with 'high risk of bias' (Gluud 2011).

Dealing with missing data

We tried to obtain relevant missing data from authors of the included trials. We performed an evaluation of important numerical data such as screened, eligible and randomly assigned participants, as well as intention-to-treat (ITT) and per-protocol (PP) populations. We investigated attrition (i.e. dropouts, losses to follow-up, and withdrawals).

Dealing with duplicate publications

In the case of duplicate publications and companion papers of a primary trial, we tried to maximise the yield of information by simultaneously evaluating all available data. When doubts arose, the publication that reported the longest follow-up (usually the most recent publication) was given priority.

Assessment of heterogeneity

We identified heterogeneity through visual inspection of the forest plots by using a standard Chi2 test and a significance level of α = 0.1. In view of the low power of such tests, we also examined heterogeneity by using the I2 statistic (Higgins 2002); I2 values of 50% or more indicate a substantial level of heterogeneity (Higgins 2003). When heterogeneity was found, we attempted to determine potential reasons for it by examining individual trial characteristics and subgroups of the main body of evidence. For heterogeneity adjustment of the required information size, we used diversity, the D2 statistic (Wetterslev 2009).

Assessment of reporting biases

Funnel plots were used to assess the potential existence of bias (Lau 2006). Several explanations can be offered for the asymmetry of a funnel plot, including true heterogeneity of effect with respect to trial size, poor methodological design (and hence bias of small trials) and publication bias. We performed adjusted rank correlation (Begg 1994) and a regression asymmetry test for detection of bias (Egger 1997).

Data synthesis

We performed this review and meta-analyses in accordance with the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

For the statistical analyses, we used Review Manager 5.2 (RevMan 2012), Trial Sequential Analysis version 0.9 beta (TSA 2011), STATA 8.2 (STATA Corp, College Station, Texas) and Sigma Stat 3.0 (SPSS Inc, Chicago, Illinois). For dichotomous outcomes, we calculated the Mantel-Haenszel risk ratios (RRs) (Gluud 2008). For all association measures, 95% confidence intervals (CIs) were used. We analysed the data with both fixed-effect (DeMets 1987) and random-effects (DerSimonian 1986) model meta-analyses. In cases where no difference in statistical significance was observed between the results obtained with the two models, we presented the result of the random-effects model analysis. Otherwise, we presented the results of both analyses.

We calculated weighted averages for factors related to the trials such as duration of the intervention and length of the follow-up period.

Analyses were performed using the intention-to-treat (ITT) principle, including all randomly assigned participants, irrespective of completeness of data. Participants with missing data were included in the analyses using a carry forward of the last observed response. Accordingly, participants who had been lost to follow-up were counted as being alive.

Review Manager 5.2 does not include trials with zero events in both intervention groups when calculating RR (RevMan 2012). To account for trials with zero events, meta-analyses of dichotomous data were repeated using risk differences (RDs) (Friedrich 2007; Keus 2009). The influence of trials with zero events in the treatment, control or both groups was also assessed by recalculating the random-effects model meta-analyses with 0.5, 0.01 and 0.001 as empirical continuity corrections (Bradburn 2007; Sweeting 2004) using Trial Sequential Analysis version 0.9 beta (TSA 2011; www.ctu.dk/tsa).

For trials using a factorial design that tested vitamin D parallel to any other intervention (i.e. hormone replacement therapy, other vitamins, etc), we used 'inside the table' analysis in which we compared only the vitamin D intervention group versus the placebo or no intervention group. Otherwise, we used 'at margins' analysis (McAlister 2003). In trials with parallel-group design with more than two intervention groups and additional therapy, we compared the vitamin D singly administered group versus the placebo or no intervention group.

We included in the analyses individually randomised trials as well as cluster-randomised trials. Data from cluster-randomised trials were incorporated using the generic inverse variance method. We explored the association between intervention effects of vitamin D and the subgrouping of individually randomised and cluster-randomised trials. The influence of cluster-randomised trials on our results was also explored in sensitivity analyses, which either included or excluded them.

We compared the intervention effects in subgroups of trials using the method described by Bornstein et al (Borenstein 2009) and implemented in RevMan 5.2 for all types of meta-analyses.

Trial sequential analysis

A cumulative meta-analysis runs the risk of random errors due to analysis of sparse data and repetitive testing of data (Thorlund 2009; Thorlund 2011a; Thorlund 2011b; Wetterslev 2008). We conducted trial sequential analyses to control the risk of random errors and to prevent premature statements of superiority of the experimental or control intervention or probably falsely declarations of absence of effect in cases for which we have too few data (Thorlund 2011a; Thorlund 2011b; Wetterslev 2008). We performed trial sequential analyses with a type I error of 5%, a type II error of 20% (80% power) and a diversity-adjusted required information size (Brok 2008; Brok 2009; Thorlund 2009; Wetterslev 2008; Wetterslev 2009). We assumed an event proportion of 10% of deaths in the control group (Autier 2007) and an anticipated intervention effect of 5% relative risk reduction or otherwise as stated. Trials were entered into trial sequential analyses according to year of publication, and in cases where more than one trial was published in a year, trial entrance followed alphabetically the family name of the first author.

Subgroup analysis and investigation of heterogeneity

We performed subgroup analyses in cases where one of the primary outcome measures showed statistically significant differences between intervention groups.

We performed the following subgroup analyses.

  • Trials at low risk of bias compared with trials at high risk of bias.

  • Placebo-controlled trials compared with trials with no intervention in the control group.

  • Individually randomised trials compared with cluster-randomised trials.

  • Primary prevention trials compared with secondary prevention trials.

  • Vitamin D3 compared with placebo or no intervention.

  • Trials that administered vitamin D3 singly compared with trials that administered vitamin D3 combined with calcium.

  • Trials that administered low-dose vitamin D3 compared with trials that administered high-dose vitamin D3.

  • Trials that administered vitamin D3 daily compared with trials that administered vitamin D3 intermittently.

  • Trials that administered vitamin D3 to vitamin D–sufficient participants compared with trials that administered vitamin D3 to vitamin D–insufficient participants.

  • Vitamin D2 compared with placebo or no intervention.

  • Trials that administered vitamin D2 singly compared with trials that administered vitamin D2 combined with calcium.

  • Trials that administered low-dose vitamin D2 compared with trials that administered high-dose vitamin D2.

  • Trials that administered vitamin D2 daily compared with trials that administered vitamin D2 intermittently.

  • Trials that administered vitamin D2 to vitamin D–sufficient participants compared with trials that administered vitamin D2 to vitamin D–insufficient participants.

  • Alfacalcidol compared with placebo or no intervention.

  • Trials that administered alfacalcidol to vitamin D–sufficient participants compared with trials that administered alfacalcidol to vitamin D–insufficient participants.

  • Calcitriol compared with placebo or no intervention.

  • Trials that administered calcitriol to vitamin D–sufficient participants compared with trials that administered calcitriol to vitamin D–insufficient participants.

Sensitivity analysis

We performed the following sensitivity analyses to explore the influence of these factors on the intervention effect size.

  • Repeating the analysis while excluding cluster-randomised trials.

  • Repeating the analysis while including trials with zero mortality in both intervention groups.

  • Repeating the analysis while taking attrition bias into consideration.

Results

Description of studies

Results of the search

We identified a total of 5995 references of possible interest by searching The Cochrane Library (n = 1118), MEDLINE (n = 1263), EMBASE (n = 1836), LILACS (n = 505), Science Citation Index–Expanded (n = 1205), Conference Proceedings Citation Index–Science (n = 28) and reference lists (n = 40). We excluded 4802 duplicates and 842 clearly irrelevant references by reading the abstracts. Accordingly, 351 references were retrieved for further assessment. Of these, we excluded 95 references describing 82 studies because they were not randomised clinical trials or did not fulfil our review protocol inclusion criteria. Reasons for exclusion are listed in the table Characteristics of excluded studies.

In total, 159 randomised trials described in 256 publications fulfilled our inclusion criteria (Figure 1). They included a total of 105,992 participants. In total, 94 trials described in 114 publications reported no deaths (Abu-Mouch 2011; Aloia 1988; Aloia 1990; Aloia 2008; Aloia 2010; Andersen 2009; Angeles-Agdeppa 2010; Armas 2004b; Arvold 2009; Bang 2011; Barnes 2006; Barnes 2011; Biancuzzo 2010; Braam 2004; Bunout 2006; Burton 2010; Caniggia 1984; Cashman 2008; Chen 1997; Christiansen 1980; Christiansen 1981; Dawson-Hughes 1991; Deroisy 2002; Dhesi 2004; Di 2004; Domrongkitchaiporn 2000; Ebeling 2001; Fliser 1997; Forsythe 2012; Gallagher 1982; Gorai 1999; Green 2010; Harris 1999; Harris 2002; Himeno 2009; Himmelstein 1990; Holick 2008c; Hulshof 2000; Hunter 2000; Ishida 2004; Islam 2010; Jensen 1982a; Jensen 1982b; Jensen 1985; Johnson 1980; Jorde 2008; Jorde 2009; Jorde 2010a; Jorde 2010b; Jorde 2010c; Jorde 2010d; Jorde 2010e; Kenny 2003; Khaw 1994; Kimball 2011; Kruger 2010; Kuwabara 2009; Laaksi 2010; Lambrinoudaki 2000; Lappe 2008; Li-Ng 2009; Lind 1989; Lind 1992; Lips 1988; Ljunghall 1987; Major 2007; Major 2009; Maki 2011; Malhotra 2009; Martin-Bautista 2010; Menczel 1994; Mitri 2011; Nagpal 2009; Nelson 2009; Nordin 1985; Ongphiphadhanakul 2000; Orimo 1994; Orwoll 1988; Orwoll 1994; Patel 2001; Pfeifer 2000; Pfeifer 2001; Pfeifer 2009; Pignotti 2010; Pilz 2011; Schaafsma 2000; Scragg 1995a; Scragg 1995b; Shiomi 1999a; Shiomi 1999b; Shiraki 1985; Shiraki 1996; Shiraki 2004; Sneve 2008; Son 2001; Songpatanasilp 2009; Sorva 1991; Sugden 2008; Urbain 2011; Ushiroyama 1995; Ushiroyama 2001; Ushiroyama 2002; Van Der Klis 1996; Viljakainen 2006; Viljakainen 2009; von Hurst 2008; von Hurst 2009; von Hurst 2010a; von Hurst 2010b; Weisman 1986; Wicherts 2010; Yusupov 2010; Zittermann 2009b; Zubillaga 2006). We contacted the authors, and the authors of 62 trials confirmed that mortality was indeed zero. For 32 trials, we did not obtain such confirmation. Nine trials reported on deaths (n ≈ 50), but they did not report the trial intervention group in which the deaths occurred (Cashman 2009; Chapuy 1987; Doetsch 2004; Fedirko 2010; Gallagher 1989; Keane 1998; Moreira-Pfrimer 2009; Orwoll 1990; Peacock 2000). The study authors did not reply to our request for additional information.

Figure 1.

Study flow diagram.

In total, 56 trials described in 154 publications, with 95,286 participants, provided data for our analyses of mortality. A further 62 trials with zero mortality in both experimental and control groups were included in our sensitivity analyses.

We contacted 139 study authors to ask for the missing information and received answers from authors of 91 randomised clinical trials (65%).

We identified an additional 11 ongoing randomised clinical trials by searching databases of ongoing trials. Data from these trials will be included in future updates of this review.

Included studies

The included trials are described in detail in the tables Characteristics of included studies; Table 1; Table 2; Table 3; Table 4; Appendix 2; Appendix 3; Appendix 4; Appendix 5; and Appendix 6.

Table 1. Characteristics of included trials (I)
  1. NI: no intervention; NR: not reported; PL: placebo

Characteristic

Study ID

DesignArmsBias
risk
BlindingParticipants
[N]
Women
[%]
Mean
age [years]
Aloia 2005Parallel2LowPL20810060
Avenell 20042 × 24HighNI1348377
Avenell 20122 × 24LowPL52928577
Baeksgaard 1998Parallel3HighPL24010062.5
Bischoff 2003Parallel2HighPL12210085.3
Bjorkman 2007Parallel3LowPL2188284.5
Bolton-Smith 20072 × 24LowPL24410068
Brazier 2005Parallel2HighPL19210074.6
Broe 2007Parallel5LowPL1247389
Brohult 1973Parallel2HighPL506852
Burleigh 2007Parallel2LowPL2055983
Campbell 20052 × 24HighNI3916883.6
Chapuy 1992Parallel2HighPL327010084
Chapuy 2002Parallel3HighPL61010085
Chel 2008Parallel6HighPL3387784
Cherniack 2011Parallel2HighPL46280
Cooper 2003Parallel2LowPL18710056
Corless 1985Parallel2HighPL657882.4
Daly 2008Parallel2HighNI167061.9
Dawson-Hughes 1997Parallel2LowPL3895571
Dukas 2004Parallel2LowPL3785171
Flicker 2005Parallel2LowPL6259583.4
Gallagher 20012 × 24LowPL48910071.5
Glendenning 2012Parallel2LowPL68610076.7
Grady 1991Parallel2HighPL985479.1
Grimnes 2011Parallel2LowPL1044952
Harwood 2004Parallel4HighNI15010081.2
Jackson 2006Parallel2LowPL36,28210062.4
Janssen 2010Parallel2LowPL7010080.8
Komulainen 19992 × 24LowPL46410052.7
Krieg 1999Parallel2HighNI24810084.5
Kärkkäinen 2010Parallel2HighNI313910067
Lappe 2007Parallel3HighPL117910066.7
Larsen 20042 × 24HighNI96056075
Latham 20032 × 24LowPL2435379.5
Law 2006Parallel2HighNI37177685
Lehouck 2012Parallel2LowPL1812068
Lips 1996Parallel2LowPL25787480
Lips 2010Parallel2LowPL226NR78
Lyons 2007Parallel2LowPL34407684
Meier 2004Parallel2HighNI556556.5
Mochonis 2006Parallel3HighNI11210060.3
Ooms 1995Parallel2LowPL34810080.3
Ott 1989Parallel2HighPL8610067.5
Porthouse 2005Parallel2HighNI331410076.8
Prince 2008Parallel2LowPL30210077.2
Sanders 2010Parallel2LowPL225810076.0
Sato 1997Parallel2HighPL644568.5
Sato 1999aParallel2HighPL867870.6
Sato 1999bParallel3HighNI1035670.7
Sato 2005aParallel2LowPL9610074.1
Schleithoff 2006Parallel2LowPL1231751
Smith 2007Parallel2LowPL94405479.1
Trivedi 2003Parallel2LowPL26862474.7
Witham 2010Parallel2LowPL1053479.7
Zhu 2008Parallel3LowPL12010075
Table 2. Characteristics of included trials (II)

Characteristic

Study ID

ParticipantsOutcome MeasuresCountrySponsor
Aloia 2005Black postmenopausal African-American womenBone mineral densityUSANo
Avenell 2004Elderly people with an osteoporotic fracture within the past 10 yearsRecruitment, compliance and retention within a randomised trialUKYes
Avenell 2012Elderly people with low-trauma osteoporotic fracture in the previous 10 yearsFracturesUKYes
Baeksgaard 1998Postmenopausal womenBone mineral densityDenmarkYes
Bischoff 2003Elderly women living in institutional careFallsSwitzerlandYes
Bjorkman 2007Chronically bedridden patientsParathyroid function and bone mineral densityFinlandYes
Bolton-Smith 2007Elderly non-osteoporotic womenBone mineral densityUKYes
Brazier 2005Elderly vitamin D–insufficient womenBone mineral densityFranceYes
Broe 2007Nursing home residentsFallsUSAYes
Brohult 1973Patients with rheumatoid arthritisObjective and subjective improvementSwedenYes
Burleigh 2007Older geriatric inpatientsFallsUKYes
Campbell 2005Elderly people with visual impairmentNumbers of falls and injuries resulting from fallsNew ZealandNo
Chapuy 1992Healthy ambulatory womenFracturesFranceYes
Chapuy 2002Elderly people living in institutional careBiochemical variables of calcium homeostasis, femoral neck bone mineral density and hip
fracture risk
FranceYes
Chel 2008Nursing home residentsVitamin D statusNetherlandsYes
Cherniack 2011Elderly peopleVitamin D statusUSAYes
Cooper 2003Postmenopausal womenBone mineral densityAustraliaYes
Corless 1985Elderly patients from the geriatric wardsAbilities to carry out basic activities of daily lifeUKYes
Daly 2008Healthy ambulatory menBone mineral densityAustraliaYes
Dawson-Hughes 1997Healthy ambulatory participantsBone mineral densityUSAYes
Dukas 2004Elderly peopleFallsSwitzerlandYes
Flicker 2005Elderly people living in institutional careFalls and fracturesAustraliaNo
Gallagher 2001Elderly womenBone mineral densityUSANo
Glendenning 2012Elderly community-dwelling ambulatory womenFalls, muscular strength and mobilityAustraliaNo
Grady 1991Elderly peopleMuscle strengthUSAYes
Grimnes 2011Healthy people with a low vitamin D statusInsulin sensitivity and secretionNorwayNo
Harwood 2004Elderly women following surgery for hip fractureBone mineral density, falls and fracturesUKYes
Jackson 2006Postmenopausal womenFracturesUSAYes
Janssen 2010Elderly vitamin D–insufficient womenMuscle strength, power and functional mobilityNetherlandsYes
Komulainen 1999Postmenopausal womenBone mineral densityFinlandYes
Krieg 1999Elderly institutionalised womenBone mineral densitySwitzerlandYes
Kärkkäinen 2010Postmenopausal womenFallsFinlandYes
Lappe 2007Healthy postmenopausal white womenFracturesUSAYes
Larsen 2004Older community-dwelling residentsFallsDenmarkYes
Latham 2003Frail elderly peopleSelf-rated physical health and fallsNew ZealandNo
Law 2006Nursing home residentsFalls and fracturesUKNo
Lehouck 2012Patients with chronic obstructive pulmonary diseaseTime to first exacerbationBelgiumYes
Lips 1996Elderly peopleFracturesNetherlandsYes
Lips 2010Elderly people with vitamin D insufficiencyPostural stability, muscle strength and safetyNetherlandsNo
Lyons 2007Older people living in institutional careFracturesUKNo
Meier 2004Healthy volunteersBone mineral densityGermanyNo
Mochonis 2006Postmenopausal womenBone mineral densityGreeceYes
Ooms 1995Elderly peopleBone mineral densityNetherlandsYes
Ott 1989Postmenopausal womenBone massUSAYes
Porthouse 2005Elderly women with one or more risk factors for hip fractureFracturesUKYes
Prince 2008Elderly women with a history of falling and vitamin D insufficiencyFallsAustraliaYes
Sanders 2010Elderly women at high risk of fractureFalls and fracturesAustraliaYes
Sato 1997Outpatients with hemiplegia after strokeBone mineral density and fracturesJapanNo
Sato 1999aElderly patients with Parkinson's diseaseFracturesJapanNo
Sato 1999bOutpatients with hemiplegia after strokeBone mineral densityJapan Yes
Sato 2005aHospitalised elderly women with post-stroke hemiplegiaFallsJapanNo
Schleithoff 2006Patients with congestive heart failureMortalityGermanyYes
Smith 2007Elderly peopleFracturesUKNo
Trivedi 2003Elderly peopleMortality, fracturesUKNo
Witham 2010Patients with systolic heart failureExercise capacityUKNo
Zhu 2008Elderly womenBone mineral densityAustraliaNo
Table 3. Characteristics of included trials (III)
  1. aEqual dose of calcium was administered to a control group
    bCalcium was tested singly in one arm of the trial as well as combined with vitamin D; placebo or no intervention group of the trial was not supplemented with calcium

    1α(OH)D: alfacalcidol; 1,25(OH)2D: calcitriol; IU: international units; µg: microgram

Characteristic

Study ID

D3
[IU]
D2
[IU]
1α(OH)D
[µg]
1,25(OH)2D
[µg]
Ca
[mg]
Regimen RouteTreatment
[years]
Follow-up
[years]
Aloia 2005800
2000
   1200-1500aDailyOral33
Avenell 2004800   1000bDailyOral11
Avenell 2012800   500bDailyOral3.756.2
Baeksgaard 1998560   1000DailyOral22
Bischoff 2003800   1200aDailyOral0.250.25
Bjorkman 2007400
1200
   500aDailyOral0.50.5
Bolton-Smith 2007400   1000DailyOral22
Brazier 2005800   1000DailyOral11
Broe 2007 200
400
600
800
   DailyOral0.420.42
Brohult 1973100,000    DailyOral11
Burleigh 2007800   1200aDailyOral0.080.08
Campbell 2005

50,000

100,000

    MonthlyOral11
Chapuy 1992800   1200DailyOral1.54
Chapuy 2002800   1200DailyOral22
Chel 2008600
4200
18.000
   800
1600
Daily
Weekly
Monthly
Oral0.330.33
Cherniack 20112000   1200aDailyOral0.50.5
Cooper 2003 10,000  1000aWeeklyOral22
Corless 1985 9000   DailyOral0.750.75
Daly 2008800   1000DailyOral23.5
Dawson-Hughes 1997700   500DailyOral33
Dukas 2004  1  DailyOral0.750.75
Flicker 2005 1000
10,000
  600aDaily
Weekly
Oral22
Gallagher 2001   0.5 DailyOral35
Glendenning 2012150,000    Three-monthlyOral0.50.75
Grady 1991   0.5 DailyOral0.50.5
Grimnes 201120,000    Twice weeklyOral0.50.5
Harwood 2004800300,000  1000Single dose
daily

Intramuscular

Oral

11
Jackson 2006400   1000DailyOral77
Janssen 2010400   500aDailyOral0.50.5
Komulainen 1999300   500DailyOral55
Krieg 1999880   1000DailyOral22
Kärkkäinen 2010800   1000DailyOral33
Lappe 20071000   1400-1500bDailyOral44
Larsen 2004400   1000DailyOral3.53.5
Latham 2003300,000    Single doseOral0.0030.5
Law 2006 100,000   Four-monthlyOral0.830.83
Lehouck 2012100,000    MonthlyOral11
Lips 1996400    DailyOral3.53.5
Lips 20108400   500aweeklyOral0.310.31
Lyons 2007 100,000   Four-monthlyOral33
Meier 2004500   500DailyOral0.51
Mochonis 2006300   1200bDailyOral11
Ooms 1995400    DailyOral22
Ott 1989   0.5
2
1000aDailyOral22
Porthouse 2005800   1000DailyOral22
Prince 2008 1000  1000aDailyOral11
Sanders 2010500,000    YearlyOral2.962.96
Sato 1997  1 300aDailyOral0.50.5
Sato 1999a  1  DailyOral1.51.5
Sato 1999b  1  DailyOral11
Sato 2005a 1000   DailyOral22
Schleithoff 20062000   500aDailyOral0.751.25
Smith 2007 300,000   YearlyIntramuscular33
Trivedi 2003100,000    Four-monthlyOral55
Witham 2010 100,000    10-weeklyOral0.380.38
Zhu 2008 1000  1200bDailyOral55
Table 4. Overview of study populations
  1. "-" denotes not reported

    aNumbers not available for all studies

    C: control; I: intervention; ITT: intention-to-treat

Characteristic

Study ID

Intervention(s) and control(s)[N] screened / eligible[N] randomised[N] ITT[N] finishing study[%] of randomised participants
finishing study
1. Aloia 2005I: vitamin D3 plus calcium3221041047471
C: placebo1041047471
total:20820814871
2. Avenell 2004I: vitamin D31807070--
C: no intervention6464--
total:134134--
3. Avenell 2012I: vitamin D315,02426492649181368
C: matched placebo tablets26432643176267
total:52925292357568
4. Baeksgaard 1998I: vitamin D3 plus calcium-80806581
C: matched placebo tablets80806480
total:16016012980
5. Bischoff 2003I: vitamin D3 plus calcium1306262--
C: calcium6060--
total:1221228973
6. Bjorkman 2007I: vitamin D3 plus calcium121515015012382
C: calcium68685987
total:21821818283
7. Bolton-Smith 2007I: vitamin D3 plus calcium-62625081
C: matched placebo61615692
total:12312310686
8. Brazier 2005I: vitamin D3 plus calcium36095957478
C: matched placebo tablets97976870
total:19219214274
9. Broe 2007I: vitamin D212699999697
C: matched placebo tablets252525100
total:12412412198
10. Brohult 1973I: vitamin D3-25252496
C: placebo252525100
total:50504998
11. Burleigh 2007I: vitamin D3 plus calcium5151011019897
C: placebo10410410197
total:20520519997
12. Campbell 2005I: home safety assessment and modification programme39119519517791
C: social visits19619618494
total:39139136192
13. Chapuy 1992I: vitamin D3 plus calcium-16341634159097
C: double placebo16361636157396
total:32703270316396
14. Chapuy 2002I: vitamin D3 plus calcium639393393--
C: double placebo190190--
total:583583--
15. Chel 2008I: vitamin D3100616616613984
C: matched placebo tablets17217213780
total:33833827682
16. Cherniack 2011I: vitamin D3 plus calcium5223231774
C: matched placebo plus calcium23231774
total:46463474
17. Cooper 2003I: vitamin D2 plus calcium-93937378
C: calcium94948085
total:18718715382
18. Coreless 1985I: vitamin D23203232825
C: placebo33331751
total:65652538
19. Daly 2006I: calcium-vitamin D3–fortified milk plus calcium42285857689
C: no intervention82827389
total:16716714989
20. Dawson-Hughes 1997I: vitamin D3 plus calcium54518718714879
C: placebo20220217084
total:38938931882
21. Dukas 2004I: alfacalcidol410192192--
C: placebo186186--
total:378378--
22. Flicker 2005I: vitamin D3 plus calcium176731331326986
C: calcium31231227187
total:62562554086
23. Gallagher 2001I: calcitriol190512312310182
C: matched placebo12312311291
total:24624621387
24. Glendenning 2012I: cholecalciferol 150,000 three-monthly211035335333194
C: placebo vitamin D 33333330792
total:68668663893
25. Grady 1991I: calcitriol9850504998
C: placebo vitamin D48484798
total:98989698
26. Grimnes 2011I: vitamin D310851514996
C: placebo53534585
total:1041049490
27. Harwood 004I: vitamin D plus calcium208113113--
C: no intervention3737--
total:150150--
28. Jackson 2006I: vitamin D3 plus calcium68,13218,17618,17616,93693
C: matched placebo18,10618,10616,81593
total:36,28236,28233,75193
29. Janssen 2010I: vitamin D3 plus calcium9136361850
C: matched placebo vitamin D3 plus calcium34343191
total:70704970
30. Komulainen 1999I: oestradiol valerate and cyproterone acetate13,100116116--
C: placebo116116--
total:232232--
31. Krieg 1999I: vitamin D3 plus calcium-1241245040
C: no treatment1241245343
total:24824810341
32. Kärkkäinen 2010I: vitamin D3 plus calcium540717181718156691
C: no treatment 17141714157392
total:34323432313991
33. Lappe 2007I: vitamin D3 plus calcium1180446446--
C: calcium plus placebo tablets 733733--
total:11791179--
34. Larsen 2004I: home safety inspection, vitamin D3 plus calcium62,00049574957--
C: no intervention46484648--
total:96059605--
35. Latham 2003I: vitamin D33,02812112110889
C: matched placebo tablets12212211493
total:24324322291
36. Law 2006I: vitamin D2-17621762136677
C: no intervention19551955156980
total:37173717293579
37. Lehouck 2012I: vitamin D341991917279
C: matched placebo91917886
total:18218215082
38. Lips 1996I: vitamin D3-12911291106182
C: matched placebo12871287102980
total:25782578209081
39. Lips 2010I: vitamin D359311411410592
C: matched placebo1121129787
total:22622620289
40. Lyons 2007I: vitamin D257451725172577845
C: matched placebo tablets1715171576244
total:34403440154044
41. Meier 2004I: vitamin D3-30302790
C: no intervention25251664
total:55554378
42. Mochonis 2006I: vitamin D3 plus calcium-72726590
C: no intervention40403690
total:11211210190
43. Ooms 1995I: vitamin D3-17717712671
C: matched placebo17117111869
total:34834824470
44. Ott 1989I: vitamin D3 plus calcium-43433991
C: matched placebo vitamin D plus calcium43433786
total:86867688
45. Porthouse 2005I: vitamin D3 plus calcium11,02213211321121292
C: no intervention19931993186293
total:34543454307492
46. Prince 2008I: vitamin D2 plus calcium82715115114495
C: matched placebo tablets of vitamin D plus calcium15115114596
total:30230228995
47. Sanders 2010I: vitamin D3720411311131101590
C: matched placebo tablets 11271127101790
total:22582258103290
48. Sato 1997I: vitamin D (alfacalcidol) plus calcium-45453067
C: matched placebo tablets of vitamin D and calcium 39393487
total:84846476
49. Sato 1999aI: vitamin D (alfacalcidol)-43434093
C: matched placebo tablets of vitamin D43434093
total:86868093
50. Sato 1999bI: vitamin D (alfacalcidol)-34343294
C: matched placebo tablet of vitamin D35353291
total:69696493
51. Sato 2005aI: vitamin D2-48484390
C: matched placebo tablets of vitamin D48484287
total:96968588
52. Schleithoff 2006I: vitamin D3 plus calcium-61614269
C: matched placebo vitamin D plus calcium62625182
total:1031039390
53. Smith 2007I: vitamin D213,48747274727230449
C: matched placebo intramuscular injection47134713226648
total:94409440457048
54. Trivedi 2003I: vitamin D3-13451345126294
C: matched placebo vitamin D13411341126494
total:26962696252694
55. Witham 2010I: vitamin D217353534891
C: matched placebo tablets52524891
total:1051059691
56. Zhu 2008I: vitamin D2 plus calcium-39393385
C: matched placebo vitamin D and calcium81817491
total:12012010789
Grand total All interventions   47,472  45,351 
All controls 47,814 45,278
All interventions and controls 95,286 90,629a
Trial characteristics

Of the 56 trials reporting mortality, 54 trials randomly assigned participants individually and two trials as clusters (Larsen 2004; Law 2006). Forty-eight trials used a parallel-group design, and eight trials (Avenell 2004; Avenell 2012; Bolton-Smith 2007; Campbell 2005; Gallagher 2001; Komulainen 1999; Larsen 2004; Latham 2003) used the 2 × 2 factorial design (Pocock 2004). The 56 trials were published from 1973 to 2012.

The trials were conducted in Europe (n = 34), North America (n = 9), Oceania (n = 9) and Asia (n = 4). All 56 trials came from high-income countries.

In 38 trials (69%), vitamin D was provided free of charge by pharmaceutical companies. In the other 18 trials, funding was not reported.

The 62 trials reporting no mortality included a total of 10,723 participants. These trials were mostly phase I or phase II short-term clinical trials assessing the pharmacokinetic or pharmacodynamic properties of vitamin D. These trials had typical outcome measures that are non-validated potential surrogates for participant-relevant outcomes (Gluud 2006).

Participants

A total of 95,286 participants were randomly assigned in the 56 trials reporting mortality (Table 4). The number of participants in each trial ranged from 46 to 36,282 participants (median 226). The age range of participants was from 18 to 107 years. The mean proportion of women was 77% (Table 1).

Forty-eight trials were primary prevention trials that included 94,491 apparently healthy participants. Of these 48 trials, four trials included healthy volunteers, nine trials postmenopausal women and 35 trials older people living independently or in institutional care.

Eight trials with 795 participants were secondary prevention trials that included participants with neurological (Sato 1997; Sato 1999a; Sato 1999b; Sato 2005a), cardiovascular (Schleithoff 2006; Witham 2010), respiratory (Lehouck 2012) or rheumatoid disease (Brohult 1973) (Table 2).

Of the 56 trials reporting mortality, 45 trials (80%) reported the baseline vitamin D status of participants based on serum 25-hydroxyvitamin D levels. Participants in 19 trials (Bjorkman 2007; Bolton-Smith 2007; Broe 2007; Burleigh 2007; Chel 2008; Cooper 2003; Daly 2008; Dawson-Hughes 1997; Dukas 2004; Flicker 2005; Gallagher 2001; Glendenning 2012; Grady 1991; Meier 2004; Moschonis 2006; Ott 1989; Smith 2007; Trivedi 2003; Zhu 2008) had baseline 25-hydroxyvitamin D levels at or above vitamin D adequacy (20 ng/mL). Participants in the remaining 26 trials had baseline 25-hydroxyvitamin D levels within a range of vitamin D insufficiency (less than 20 ng/mL). Eleven trials did not report the baseline vitamin D status of participants (Avenell 2004; Baeksgaard 1998; Brohult 1973; Campbell 2005; Komulainen 1999; Lappe 2007; Larsen 2004; Law 2006; Lyons 2007; Porthouse 2005; Sato 1997).

The main outcomes in the trials were bone mineral density, numbers of falls and fractures and mortality (Table 2).

Experimental interventions
Vitamin D3 (cholecalciferol)

Vitamin D was administered as vitamin D3 (cholecalciferol) in 38 trials (75,927 participants; 76.8% women; age range 51 to 85 years). Vitamin D3 was tested singly in 11 trials and combined with calcium in 25 trials. An additional two trials tested vitamin D3 both singly and combined with calcium (Avenell 2004; Avenell 2012). Vitamin D3 was tested orally in all trials. Vitamin D3 was administered daily in 30 trials and intermittently in eight trials (daily, weekly or monthly (Chel 2008); twice weekly (Grimnes 2011); weekly (Lips 2010); monthly (Campbell 2005; Lehouck 2012); three-monthly (Glendenning 2012); four-monthly (Trivedi 2003); or yearly (Sanders 2010)). The dose of vitamin D3 was 300 IU to 500,000 IU (mean daily dose 3650 IU; median daily dose 800 IU). The duration of supplementation in trials using vitamin D3 was one day to seven years (weighted mean 4.9 years), and the length of the follow-up period was one month to seven years (weighted mean 5.2 years) (Table 3).

Vitamin D2 (ergocalciferol)

Vitamin D was administered as vitamin D2 (ergocalciferol) in 12 trials (18,349 participants; 82% women; age range 56 to 89 years). Vitamin D2 was tested singly in seven trials and combined with calcium in four trials. An additional one trial tested vitamin D2 both singly and combined with calcium (Harwood 2004). Vitamin D2 was administered orally in 10 trials. One trial administered vitamin D2 orally and parenterally (single intramuscular injection) (Harwood 2004), and one trial administered vitamin D2 parenterally (single intramuscular injection yearly) (Smith 2007). The dosing schedule for vitamin D2 was daily in five trials (Broe 2007; Corless 1985; Prince 2008; Sato 2005a; Zhu 2008) and intermittently in five trials (weekly (Cooper 2003), 10-weekly (Witham 2010), three-monthly (Law 2006), four-monthly (Lyons 2007) or yearly (Smith 2007)). One trial tested vitamin D2 first weekly and then daily (Flicker 2005). The dose of vitamin D2 was 200 IU to 300,000 IU (mean daily dose 1661 IU; median daily dose 1000 IU). The duration of supplementation and follow-up in trials using vitamin D2 was one day to seven years (weighted mean 2.4 years) (Table 3).

Alfacalcidol (1α-hydroxyvitamin D)

Vitamin D was administered as alfacalcidol in four trials (617 participants; 57% women; age range 68 to 71 years). Alfacalcidol was tested singly in three trials and combined with calcium in one trial (Sato 1997). Alfacalcidol was administered orally and daily in all trials. The dose of alfacalcidol was 1 μg in all four trials. The duration of supplementation and follow-up in trials using alfacalcidol was six months to one year (weighted mean 0.9 years) (Table 3).

Calcitriol (1,25-dihydroxyvitamin D)

Vitamin D was administered as calcitriol in three trials (430 participants; 85% women; age range 67 to 79 years). Calcitriol was tested singly in two trials and combined with calcium in one trial (Ott 1989). Calcitriol was administered orally and daily in all trials. The dose of calcitriol was 0.5 μg in two trials (Gallagher 2001; Grady 1991), and one trial tested two doses of calcitriol 0.5 μg and 2 μg (Ott 1989). The duration of supplementation in trials using calcitriol was two to five years (weighted mean 2.2 years) and the follow-up period lasted two to five years (weighted mean four years) (Table 3).

Control interventions

A total of 44 trials used placebo vitamin D and 12 trials used no intervention in the control group (Table 1).

Co-interventions

Thirty-four trials used vitamin D in combination with calcium in the experimental intervention groups. Calcium was administered orally and daily in all 34 trials. The dose of calcium was 300 mg to 1600 mg (mean 920 mg; median 1000 mg) (Table 3).

Thirteen trials used calcium combined with vitamin D placebo in the control group. The dose of calcium was 300 mg to 1500 mg (mean 835 mg; median 1000 mg). These trials used an equal dose of calcium in the experimental intervention groups (Table 3).

One trial with a 2 × 2 factorial design tested a combination of vitamin D3, vitamin K1 and calcium in one of the intervention groups (Bolton-Smith 2007). The factorial design of this trial allowed us to compare only the vitamin D3 plus calcium group versus the placebo group of this trial. Another two trials with parallel-group designs and three intervention groups tested in one of the groups the combination of calcium and multivitamins (Baeksgaard 1998) or ipriflavone (Sato 1999b). The parallel-group design of these trials allowed us to compare the vitamin D group versus the placebo group. Two trials with a 2 × 2 factorial design tested vitamin D and hormone replacement (Gallagher 2001; Komulainen 1999). We have compared only the vitamin D group with the placebo group of these trials.

Risk of bias in included studies

Thirty trials reporting mortality (54% of the trials; 71% of the participants) were considered as having low risk of bias. The remaining 26 trials had unclear bias control in one or more of the components assessed (Table 1; Figure 2; Figure 3). Inspection of the funnel plot does not suggest potential bias (asymmetry) (Figure w7, http://ctu.dk/publications/supplementary-material.aspx). The adjusted-rank correlation test (P = 0.44) and the regression asymmetry test (P = 0.08) found no statistically significant evidence of bias.

Figure 2.

Risk of bias according to bias domains in the 56 randomised clinical trials on vitamin D and mortality.

Figure 3.

Risk of bias in the included 56 randomised clinical trials on vitamin D and mortality.

Allocation

The generation of the allocation sequence was adequately described in 43 trials. The remaining 13 trials were described as randomised, but the method used for sequence generation was not described (Baeksgaard 1998; Bischoff 2003; Brohult 1973; Chapuy 1992; Chapuy 2002; Chel 2008; Grady 1991; Krieg 1999; Larsen 2004; Meier 2004; Ott 1989; Sato 1997; Sato 1999b).

The method used to conceal allocation was adequately described in 37 trials. The method used for allocation concealment was judged as unclear in 12 trials (Baeksgaard 1998; Bischoff 2003; Brohult 1973; Chapuy 1992; Chapuy 2002; Chel 2008; Corless 1985; Grady 1991; Meier 2004; Ott 1989; Sato 1997; Sato 1999a) and inadequate in seven trials (Avenell 2004; Daly 2008; Krieg 1999; Moschonis 2006; Larsen 2004; Law 2006; Sato 1999b).

Blinding

The method of blinding was adequately described in 34 trials. The method of blinding was unclear in 10 trials (Brazier 2005; Brohult 1973; Chapuy 1992; Chapuy 2002; Chel 2008; Corless 1985; Grady 1991; Ott 1989; Sato 1997; Sato 1999a). Twelve trials were not blinded (Avenell 2004; Campbell 2005; Daly 2008; Harwood 2004; Krieg 1999; Kärkkäinen 2010; Larsen 2004; Law 2006; Meier 2004; Moschonis 2006; Porthouse 2005; Sato 1999b).

Incomplete outcome data

Incomplete data were addressed adequately in 54 trials. In two trials, information is insufficient to allow assessment of whether the missing data mechanism in combination with the method used to handle missing data is likely to induce bias on the estimate of effect (Lappe 2007; Larsen 2004).

Selective reporting

Predefined primary and secondary outcomes were reported in 51 trials. Five trials did not report all predefined or clinically relevant and reasonably expected outcomes (Baeksgaard 1998; Brohult 1973; Larsen 2004; Porthouse 2005; Sato 1997). The 103 randomised clinical trials that could not provide data for mortality analyses represent an unknown reservoir of outcome reporting bias.

Industry bias

Seven trials were not funded by industry (Campbell 2005; Flicker 2005; Janssen 2010; Lyons 2007; Meier 2004; Trivedi 2003; Witham 2010). Ten trials were funded by industry (Bischoff 2003; Brazier 2005; Brohult 1973; Chapuy 2002; Harwood 2004; Komulainen 1999; Lips 2010; Moschonis 2006; Porthouse 2005; Smith 2007) and 32 trials reported that trial medications were funded by industry (Aloia 2005; Avenell 2004; Avenell 2012; Baeksgaard 1998; Bjorkman 2007; Bolton-Smith 2007; Broe 2007; Burleigh 2007; Chapuy 1992; Chel 2008; Cherniack 2011; Cooper 2003; Daly 2008; Dawson-Hughes 1997; Dukas 2004; Gallagher 2001; Grady 1991; Grimnes 2011; Jackson 2006; Kärkkäinen 2010; Krieg 1999; Lappe 2007; Larsen 2004; Latham 2003; Lehouck 2012; Lips 1996; Ooms 1995; Ott 1989; Prince 2008; Sanders 2010; Schleithoff 2006; Zhu 2008). The source of funding is not clear for seven trials (Corless 1985; Glendenning 2012; Law 2006; Sato 1997; Sato 1999a; Sato 1999b; Sato 2005a).

Other potential sources of bias

Two trials had other factors that could put the trials at risk of bias, such as recruitment bias (Larsen 2004; Law 2006). The remaining 54 trials appeared to be free of other components that could put them at risk of bias.

Effects of interventions

See: Summary of findings for the main comparison Vitamin D supplementation for prevention of mortality in adults

All-cause mortality in all trials

Overall, vitamin D significantly decreased all-cause mortality (RR 0.97 (95% CI 0.94 to 0.99); P = 0.02; I2 = 0%; 95,286 participants; 56 trials; Analysis 1.1). A total of 5920 of 47,472 participants (12.5%) randomly assigned to the vitamin D group versus 6077 of 47,814 participants (12.7%) randomly assigned to the placebo or no intervention group died. A sensitivity analysis excluding the cluster-randomised trials had no noticeable effect on the result (RR 0.96 (95% CI 0.93 to 0.99); P = 0.01; I2 = 0%; 81,964 participants; 54 trials; Analysis 1.2). The difference between the estimate of the effect of vitamin D on mortality in individually randomised and cluster-randomised trials was not statistically significant by the test of interaction (Chi2 = 0.48; P = 0.49; Analysis 1.2).

Intervention effects according to bias risk of trials

In the trials with low risk of bias, mortality was significantly decreased in the vitamin D group (RR 0.96 (95% CI 0.92 to 0.99); P = 0.02; I2 = 0%; 67,516 participants; 30 trials; Analysis 1.1). In the trials with high risk of bias, vitamin D did not significantly affect all-cause mortality (RR 0.99 (95% CI 0.92 to 1.06); P = 0.71; I2 = 10%; 27,770 participants; 26 trials; Analysis 1.1). The difference between the estimate of the effect of vitamin D on mortality in low- and high-bias risk trials was not statistically significant by the test of interaction (Chi2 = 0.56; P = 0.46; Analysis 1.1).

Placebo-controlled trials compared with trials with no intervention in the control group

Vitamin D significantly decreased mortality in the placebo-controlled trials (RR 0.96 (95% CI 0.93 to 0.99); P = 0.009; I2 = 0%; 73,892 participants; 44 trials; Analysis 1.3). Vitamin D had no statistically significant effect on mortality in the trials with no intervention in the control group (RR 1.05 (95% CI 0.91 to 1.21); P = 0.51; I2 = 29%; 21,394 participants; 12 trials; Analysis 1.3.2). The difference between the estimate of the effect of vitamin D on mortality in the placebo-controlled trials and in trials with no intervention in the control group was not statistically significant by the test of interaction (Chi2 = 1.50; P = 0.22; Analysis 1.3).

Trials without risk of industry bias compared to trials with risk of industry bias

Vitamin D had no significant effect on mortality in the trials without risk of industry bias (RR 0.97, 95% CI 0.92 to 1.03; P = 0.32; I2 = 0%; 7,372 participants; 7 trials; Analysis 1.4). Vitamin D significantly decreased mortality in the trials with risk of industry bias (RR 0.96 (95% CI 0.93 to 1.00); P = 0.003; I2 = 0%; 87,914 participants; 49 trials; Analysis 1.4). The difference between the estimate of the effect of vitamin D on mortality in the trials without risk of industry bias and the trials with risk of industry bias was not statistically significant by the test of interaction (Chi2 = 0.07; P = 0.80; Analysis 1.4).

Primary prevention compared with secondary prevention

Vitamin D significantly decreased mortality in the primary prevention trials (RR 0.97 (95% CI 0.94 to 0.99); P = 0.02; I2 = 0%; 94,491 participants; 48 trials; Analysis 1.5). Vitamin D had no statistically significant effect on mortality in the secondary prevention trials (RR 1.31 (95% CI 0.73 to 2.35); P = 0.37; I2 = 0%; 795 participants; 8 trials; Analysis 1.5). The difference between the estimates of the effect of vitamin D on mortality in the primary prevention and the secondary prevention trials was not statistically significant by the test of interaction (Chi2 = 1.04; P = 0.31; Analysis 1.5).

Intervention effects according to vitamin D status at entry

Vitamin D significantly decreased mortality in participants with vitamin D insufficiency at entry (RR 0.95 (95% CI 0.91 to 0.99); P = 0.01; I2 = 0%; 56,697 participants; 26 trials; Analysis 1.6). Vitamin D had no statistically significant effect on mortality in the trials including participants with vitamin D adequacy (RR 0.95 (95% CI 0.87 to 1.05); P = 0.30; I2 = 0%; 16,283 participants; 19 trials; Analysis 1.6). A similar finding was obtained in the trials including participants with unknown vitamin D status (Analysis 1.6). The difference between the estimates of the effect of vitamin D on mortality in the trials including participants with vitamin D insufficiency and the trials including participants with vitamin D adequacy was not statistically significant by the test of interaction (Chi2 = 1.59; P = 0.45; Analysis 1.6).

Trials including participants living independently compared with trials including participants living in care institutions

Vitamin D significantly decreased mortality in ambulatory participants (RR 0.95 (95% CI 0.92 to 0.98); P = 0.0003; I2 = 0%; 86,071 participants; 45 trials; Analysis 1.7). Vitamin D had no statistically significant effect on mortality in the trials including institutionalised participants (RR 1.02 (95% CI 0.92 to 1.13); P = 0.74; I2 = 21%; 9215 participants; 11 trials; Analysis 1.7). The difference between the estimates of the effect of vitamin D on mortality in the trials including ambulatory participants and the trials including institutionalised participants was not statistically significant by the test of interaction (Chi2 = 1.60; P = 0.21; Analysis 1.7).

Sensitivity analyses taking attrition into consideration

Of the 56 trials reporting mortality, 53 trials reported the exact numbers of participants with missing outcomes in the intervention and control groups. Two trials did not report losses to follow-up (Larsen 2004; Sato 1997), and one trial did not report losses to follow-up for the intervention groups separately (Lappe 2007). A total of 3634 of 42,024 participants (8.6%) had missing outcomes in the vitamin D group versus 3523 of 42,394 participants (8.3%) in the control group.

'Best-worst case' scenario

If we assume that all participants lost to follow-up in the experimental intervention group survived and all those with missing outcomes in the control intervention group died, vitamin D significantly decreased mortality (RR 0.40 (95% CI 0.32 to 0.51); P < 0.00001; I2 = 96%; 84,418 participants; 53 trials; Analysis 1.8).

'Worst-best case' scenario

If we assume that all participants lost to follow-up in the experimental intervention group died and all those lost to follow-up in the control intervention group survived, vitamin D significantly increased mortality (RR 2.78 (95% CI 2.13 to 3.63); P < 0.00001; I2 = 97%; 84,418 participants; 53 trials; Analysis 1.8).

Sensitivity analyses taking zero event trials into account

In addition to the 56 trials reporting mortality, 62 trials with 10,804 participants had zero mortality in both experimental and control groups. We assessed the influence of these trials by recalculating the RR with 0.5, 0.01 and 0.001 as empirical continuity corrections. The random-effects model RR for the three continuity corrections was not noticeably influenced (RR 0.97 (95% CI 0.94 to 0.99); P = 0.020; RR 0.97 (95% CI 0.94 to 1.00); P = 0.022; RR 0.97 (95% CI 0.94 to 1.00); P = 0.023; respectively). We also tested the influence of zero event trials using risk difference as the measure of association. Vitamin D significantly decreased all-cause mortality using the fixed-effect model meta-analysis (RD -0.004 (95% CI -0.016 to -0.008); P = 0.015). Heterogeneity was substantial (I2 = 64%). The random-effects model revealed no statistically significant effect of vitamin D on all-cause mortality (RD -0.002 (95% CI -0.005 to 0.002); P = 0.30).

Vitamin D3 (cholecalciferol)

Vitamin D3 was tested in 38 trials (75,927 participants). Inspection of the funnel plot did not suggest potential bias (asymmetry) (Figure w8, http://ctu.dk/publications/supplementary-material.aspx). The adjusted-rank correlation test (P = 0.79) and the regression asymmetry test (P = 0.97) found no statistically significant evidence of bias. Overall, vitamin D3 significantly decreased mortality (RR 0.94 (95% CI 0.91 to 0.98); P = 0.002; I2 = 0; 75,927 participants; 38 trials; Analysis 1.9). Vitamin D3 significantly decreased mortality in the trials with low risk of bias (RR 0.93 (95% CI 0.89 to 0.98); P = 0.009; I2 = 0%; 52,645 participants; 20 trials; Analysis 1.9). Vitamin D3 had no statistically significant effect on mortality in the trials with high risk of bias (RR 0.95 (95% CI 0.91 to 1.00); P = 0.06; I2 = 0%; 23,282 participants; 18 trials; Analysis 1.7.2). The difference between estimates of the effect of vitamin D3 on mortality in the trials with low risk of bias and the trials with high risk of bias was not statistically significant by the test of interaction (Chi2 = 0.39; P = 0.53; Analysis 1.9).

Trial sequential analysis of all 38 vitamin D3 trials was constructed on the basis of diversity-adjusted required information size calculated using mortality of 10% in the control group, a relative risk reduction of 5% with vitamin D3, a type I error of 5% and a type II error of 20% (80% power). No diversity was noted. The trial sequential analysis showed that the required information size had not yet been reached and that the cumulative Z-curve crossed the trial sequential monitoring boundary for benefit in 2006 during the 22nd trial. The trial sequential analysis excludes risk of random errors (Figure 4). The intervention effect corresponds to the number needed to treat for an additional beneficial outcome (NNTB) of 150 participants treated over five years to save one additional life.

Figure 4.

Trial sequential analysis on mortality in 38 vitamin D3 trials
The diversity-adjusted required information size (RIS) was calculated based on mortality in the control group of 10%; relative risk reduction of 5% in the experimental group; type I error of 5%; and type II error of 20% (80% power). No diversity was noted. The required information size was 110,505 participants. The cumulative Z-curve (blue line) crossed the trial sequential monitoring boundaries for benefit (red inward sloping line) after the 22nd trial. Accordingly, the risk of random error in the finding seems acceptable according to the O'Brien Fleming stopping rule for an individual trial interim analysis. Subsequently, 16 trials have been published.

Vitamin D3 and calcium

Vitamin D3 administered singly versus placebo or no intervention had no statistically significant effect on mortality (RR 0.92 (95% CI 0.85 to 1.00); P = 0.06; I2 = 5%; 12,609 participants; 13 trials; Analysis 1.10). Vitamin D3 combined with calcium versus placebo or no intervention significantly decreased mortality (RR 0.96 (95% CI 0.92 to 0.99); P = 0.03; I2 = 0%; 63,051 participants; 27 trials; Analysis 1.10). The difference between the estimate of the effect of vitamin D3 on mortality in the trials using vitamin D3 singly and the trials using vitamin D3 combined with calcium was not statistically significant by the test of interaction (Chi2 = 0.49; P = 0.49; Analysis 1.10).

The trial sequential analysis on mortality in the 27 trials that administered vitamin D3 combined with calcium showed that the cumulative Z-curve did not cross the trial sequential monitoring boundary for benefit (Figure w9, http://ctu.dk/publications/supplementary-material.aspx).

Dose of vitamin D3

A dose of vitamin D3 less than 800 IU a day significantly decreased mortality (RR 0.92 (95% CI 0.87 to 0.97); P = 0.005; I2 = 0%; 50,437 participants; 13 trials; Analysis 1.11). A dose of vitamin D3 equal to or greater than 800 IU a day had no statistically significant effect on mortality (RR 0.96 (95% CI 0.92 to 1.00); P = 0.07; I2 = 0%; 25,558 participants; 26 trials; Analysis 1.11). The difference between the estimate of the effect of vitamin D3 on mortality in the trials using a low dose of vitamin D3 and the trials using a high dose of vitamin D3 was not statistically significant by the test of interaction (Chi2 = 1.37; P = 0.24; Analysis 1.11).

The trial sequential analysis on mortality in the 13 trials that administered a low dose of vitamin D3 showed that the cumulative Z-curve did not cross the trial sequential monitoring boundary for benefit (Figure 5).

Figure 5.

Trial sequential analysis on mortality in the 13 trials that administered low dose of vitamin D3 (i.e. a dose less than 800 IU per day)
The diversity-adjusted required information size (RIS) was calculated based on mortality in the control group of 10%; relative risk reduction of 5% in the experimental group; type I error of 5%; and type II error of 20% (80% power). No diversity was noted. The required information size was 110,505 participants. The cumulative Z-curve (blue line) did not cross the trial sequential monitoring boundaries for benefit (red line) at any time. Accordingly, the crossing of the conventional statistical 5% boundary (the horizontal brown line) may be due to random errors.

Dosing schedule of vitamin D3

Vitamin D3 administered daily significantly decreased mortality (RR 0.95 (95% CI 0.91 to 0.98); P = 0.004; I2 = 0%; 69,168 participants; 31 trials; Analysis 1.12). Vitamin D3 administered intermittently had no statistically significant effect on mortality (RR 0.89 (95% CI 0.77 to 1.03); P = 0.11; I2 = 0%; 6871 participants; 8 trials; Analysis 1.12). The difference between the estimate of the effect of vitamin D3 on mortality in the trials that administered vitamin D3 daily and the trials that administered vitamin D3 intermittently was not statistically significant by the test of interaction (Chi2 = 0.66; P = 0.41; Analysis 1.12).

Intervention effect of vitamin D3 according to vitamin D status at entry

Vitamin D3 significantly decreased mortality in the trials including participants with vitamin D insufficiency (RR 0.95 (95% CI 0.91 to 0.99); P = 0.009; I2 = 0%; 55,883 participants; 20 trials; Analysis 1.13). Vitamin D3 had no statistically significant effect on mortality in the trials including participants with vitamin D adequacy (RR 0.92 (95% CI 0.80 to 1.07); P = 0.29; I2 = 0%; 4979 participants; 10 trials; Analysis 1.13). The difference between the estimate of the effect of vitamin D3 on mortality in the trials including participants with vitamin D insufficiency and the trials including participants with vitamin D adequacy was not statistically significant by the test of interaction (Chi2= 0.1; P = 0.75; Analysis 1.13).

Intervention effect of vitamin D3 according to the sex of the trial participants

Vitamin D3 had no statistically significant effect on mortality in the trials that exclusively included women (RR 0.93 (95% CI 0.84 to 1.03); P = 0.16; I2 = 22%; 53,062 participants; 19 trials; Analysis 1.14). Vitamin D3 significantly decreased mortality in the trials including both men and women, or including only men (one trial by Daly 2008) (RR 0.94 (95% CI 0.89 to 0.99); P = 0.01; I2 = 0%; 22,865 participants; 19 trials; Analysis 1.14). The difference between the estimate of the effect of vitamin D3 on mortality in the trials including only women and the trials including both men and women or only men was not statistically significant by the test of interaction (Chi2 = 0.03; P = 0.87; Analysis 1.14).

Vitamin D2 (ergocalciferol)

Vitamin D2 was tested in 12 trials (18,349 participants). Inspection of the funnel plot did not suggest potential bias (asymmetry) (Figure w10, http://ctu.dk/publications/supplementary-material.aspx). The adjusted-rank correlation test (P = 0.60) and the regression asymmetry test (P = 0.55) found no statistically significant evidence of bias. Overall, vitamin D2 had no statistically significant effect on mortality (RR 1.02 (95% CI 0.96 to 1.08); P = 0.54; I2 = 4%; Analysis 1.15). Vitamin D2 had no statistically significant effect on mortality in the trials with low risk of bias (RR 0.98 (95% CI 0.93 to 1.04); P = 0.57; I2 = 0%; 14,439 participants; 9 trials; Analysis 1.15). Vitamin D2 significantly increased mortality in the trials with high risk of bias (RR 1.20 (95% CI 1.05 to 1.37); P = 0.007; I2 = 0%; 3910 participants; 3 trials; Analysis 1.15). The difference between the estimate of effect of vitamin D2 on mortality in the trials with low risk of bias and the trials with high risk of bias was statistically significant by the test of interaction (Chi2 = 7.28; P = 0.007; Analysis 1.15).

The trial sequential analysis of all vitamin D2 trials suggests that we reached the futility area after the eighth trial, allowing us to conclude that any possible intervention effect, if present, is lower than a 5% relative risk reduction, or that the number needed to treat for an additional beneficial outcome (NNTB) is greater than 150 (Figure 6).

Figure 6.

Trial sequential analysis of mortality in 12 vitamin D2 trials
The diversity-adjusted required information size (RIS) was conducted based on 10% mortality in the control group; relative risk reduction of 10% in the experimental group; type I error of 5%; and type II error of 20% (80% power). No diversity was noted. The required information size was 27,585 participants. The cumulative Z-curve (blue line) crossed the trial sequential monitoring boundaries for futility (red outward sloping line) after the eighth trial.

Vitamin D2 and calcium

Vitamin D2 administered singly had no statistically significant effect on mortality (RR 1.03 (95% CI 0.96 to 1.12); P = 0.37; I2 = 14%; 17,079 participants; 8 trials; Analysis 1.16). Vitamin D2 combined with calcium had no statistically significant effect on mortality (RR 1.00 (95% CI 0.64 to 1.57); P = 1.00; I2 = 11%; 1307 participants; 5 trials; Analysis 1.16). The difference between the estimates of effect of vitamin D2 on mortality in the trials using vitamin D2 singly and the trials using vitamin D2 combined with calcium was not statistically significant by the test of interaction (Chi2 = 0.02; P = 0.88; Analysis 1.16).

Dose of vitamin D2

A dose of vitamin D2 less than 800 IU a day, tested in one trial, had no statistically significant effect on mortality (RR 0.82 (95% CI 0.17 to 3.98); P = 0.81; 101 participants; Analysis 1.17). A dose of vitamin D2 equal to or greater than 800 IU a day had no statistically significant effect on mortality (RR 1.02 (95% CI 0.95 to 1.10); P = 0.51; I2 = 9%; 18,273 participants; 12 trials; Analysis 1.17). The difference between the estimate of effect of vitamin D2 on mortality in the trials using a high dose of vitamin D2 and the trial using low-dose vitamin D2 was not statistically significant by the test of interaction (Chi2 = 0.07; P = 0.79; Analysis 1.17).

Dosing schedule of vitamin D2

Vitamin D2 administered daily had no statistically significant effect on mortality (RR 0.88 (95% CI 0.68 to 1.12); P = 0.30; I2 = 0%; 1349 participants; 6 trials; Analysis 1.18). Vitamin D2 administered intermittently had no statistically significant effect on mortality (RR 1.06 (95% CI 0.95 to 1.18); P = 0.33; I2 = 46%; 17,000 participants; 6 trials; Analysis 1.18). The difference between the estimates of effect of vitamin D2 on mortality in the trials that administered vitamin D2 daily and the trials that administered vitamin D2 intermittently was not statistically significant by the test of interaction (Chi2 = 1.81; P = 0.18; Analysis 1.18).

Intervention effect of vitamin D2 according to vitamin D status

Vitamin D2 significantly increased mortality in the trials including participants with vitamin D insufficiency (RR 1.20 (95% CI 1.05 to 1.37); P = 0.008; I2 = 0%; 4413 participants; 6 trials; Analysis 1.19). Vitamin D2 had no statistically significant effect on mortality in the trials including participants with vitamin D adequacy (RR 0.97 (95% CI 0.86 to 1.10); P = 0.62; I2 = 0%; 10,496 participants; 5 trials; Analysis 1.19). The difference between the estimates of effect of vitamin D2 on mortality in the trials including participants with vitamin D insufficiency and the trials including participants with vitamin D adequacy was statistically significant by the test of interaction (Chi2 = 5.23; P = 0.02; Analysis 1.19).

Alfacalcidol (1α-hydroxyvitamin D)

Alfacalcidol was tested in four trials (617 participants). Inspection of the funnel plot did not suggest potential bias (asymmetry) (Figure w11, http://ctu.dk/publications/supplementary-material.aspx). The adjusted-rank correlation test (P = 1.00) found no significant evidence of bias. Alfacalcidol had no statistically significant effect on mortality (RR 0.96 (95% CI 0.22 to 4.15); P = 0.95; I2 = 0%; Analysis 1.20). The effect of alfacalcidol on mortality was not dependent on vitamin D status (Analysis 1.21).

Calcitriol (1,25-dihydroxyvitamin D)

Calcitriol was tested in three trials (430 participants). Inspection of the funnel plot did not suggest potential bias (asymmetry) (Figure w12, http://ctu.dk/publications/supplementary-material.aspx). Calcitriol had no statistically significant effect on mortality (RR 1.37 (95% CI 0.27 to 7.03); P = 0.71; I2 = 0%; Analysis 1.22). The effect of calcitriol on mortality was not dependent on vitamin D status (Analysis 1.23).

Cause-specific mortality

Vitamin D3 statistically significantly decreased cancer mortality (RR 0.88 (95% CI 0.78 to 0.98); P = 0.02; I2 = 0%; 44,492 participants; 4 trials; Analysis 1.24).

Trial sequential analysis on cancer mortality in the four trials that administered vitamin D3 was performed on the basis of mortality in the control group of 2.85%; relative risk reduction (based on trials with low risk of bias) of 12.28% in the experimental group; type I error of 5%; and type II error of 20% (80% power). No diversity was noted. The required information size was 66,724 participants. The cumulative Z-curve (blue line) did not cross the trial sequential monitoring boundary for benefit (red line) (Figure w13, http://ctu.dk/publications/supplementary-material.aspx).

Vitamin D3 had no significant effect on cardiovascular mortality (RR 0.98 (95% CI 0.90 to 1.07); P = 0.68; I2 = 0%; 47,267 participants; 10 trials; Analysis 1.25).

The trial sequential analysis on cardiovascular mortality in the 10 trials that administered vitamin D3 was performed on the basis of mortality in the control group of 4.17%; relative risk reduction (based on trials with low risk of bias) of 1.68% in the experimental group; type I error of 5%; and type II error of 20% (80% power). No diversity was noted. The required information size was 2,539,845 participants. The cumulative Z-curve (blue line) did not cross the conventional monitoring boundary for benefit (red line) (Figure w14, http://ctu.dk/publications/supplementary-material.aspx).

We were not able to extract from the included trials relevant data on fracture-related mortality and other causes of mortality.

Adverse events

Several adverse events were reported (e.g. hypercalcaemia, nephrolithiasis, hypercalciuria, renal insufficiency, gastrointestinal disorders, cardiovascular disorders, psychiatric disorders, skin disorders, cancer).

The supplemental forms of vitamin D (D3 and D2) had no statistically significant effect on the risk of hypercalcaemia (RR 1.36 (95% CI 0.85 to 2.18); P = 0.21; I2 = 0%; 11,323 participants; 15 trials; Analysis 1.26).

The active forms of vitamin D (alfacalcidol and calcitriol) statistically significantly increased the risk of hypercalcaemia (RR 3.18 (95% CI 1.17 to 8.68); P = 0.02; I2 = 17%; 710 participants; 3 trials; Analysis 1.26). The difference between the estimate of effect of vitamin D on hypercalcaemia in the trials that administered supplemental forms of vitamin D (D3 and D2) and the trials that administered active forms of vitamin D (alfacalcidol or calcitriol) was not statistically significant by the test of interaction (Chi2 = 2.27; P = 0.13; Analysis 1.26).

Vitamin D3 combined with calcium significantly increased nephrolithiasis (RR 1.17 (95% CI 1.02 to 1.34); P = 0.02; I2 = 0%; 42,876 participants; 4 trials; Analysis 1.26).

The effect of vitamin D on the other adverse events was not statistically significant (hypercalciuria: RR 4.64 (95% CI 0.99 to 21.76; P = 0.05; I2 = 0%; 695 participants; 3 trials; Analysis 1.26 renal insufficiency: RR 1.70 (95% CI 0.27 to 10.70); P = 0.57; I2 = 53%; 5495 participants; 3 trials; Analysis 1.26; cardiovascular disorders: RR 0.95 (95% CI 0.86 to 1.05); P = 0.29; I2 = 0%; 4495 participants; 8 trials; Analysis 1.26; gastrointestinal disorders: RR 1.36 (95% CI 0.87 to 2.13); P = 0.17; I2 = 57%; 9702 participants; 16 trials; Analysis 1.26; psychiatric disorders: RR 1.44 (95% CI 0.56 to 3.73); P = 0.45; I2 = 0%; 580 participants; 3 trials; Analysis 1.26; skin disorders: RR 3.27 (95% CI 0.17 to 62.47); P = 0.43; I2 = 77%; 3810 participants; 2 trials; Analysis 1.26; cancer: RR 0.99 (95% CI 0.94 to 1.06); P = 0.85; I2 = 0%; 49,707 participants; 14 trials; Analysis 1.26).

Health-related quality of life

Only one trial published data on health-related quality of life (Witham 2010). Authors reported significant worsening in disease-specific quality of life (MLWHF, Minnesota Living With Heart Failure score) in the vitamin D2 group compared with the placebo group (Witham 2010). The between-group difference at 20 weeks was 5.3 (0.5 to 10.2), and the minimally important difference (MID) was estimated to be 5 points in either direction.

Health economics

We found only one randomised clinical trial (Chapuy 1992) that reported a cost-effectiveness analysis (Lilliu 2003). The authors found that vitamin D3 and calcium supplementation prevented 46 hip fractures in every 1000 women treated and concluded that vitamin D3 with calcium supplementation is cost-effective (Lilliu 2003). Mortality was not addressed.

Discussion

Summary of main results

Our systematic review contains a number of important findings. We found evidence suggesting that vitamin D3 may significantly benefit survival of elderly ambulatory participants living in institutional care who were likely to be vitamin D deficient with significant risk of falls and fractures, when we disregard the risks of attrition bias and outcome reporting bias. However, if these bias risks are considered, we do not yet know whether vitamin D3 affects mortality. Vitamin D2, alfacalcidol and calcitriol had no statistically significant effect on mortality, but these estimates are at risk of type II errors because of the fact that much smaller groups of participants were examined compared with the trials assessing vitamin D3.

A subgroup analysis of trials with high risk of bias suggests that vitamin D2 may increase mortality, but a trial sequential analysis opens the possibility that this could be a random error. Alfacalcidol and calcitriol significantly increased the risk of hypercalcaemia, and vitamin D3 combined with calcium significantly increased nephrolithiasis. Vitamin D had no clear effect on other adverse events, including cancer.

Compared with our previous version of this systematic review (Bjelakovic 2011), the number of included trials in the present review has increased, with six new trials (12%) adding another 1,138 participants (1.2%). In addition, we have obtained updated results of a longer follow-up from one large-scale randomised trial (Avenell 2012). In spite of these additional amounts of information, our results remain largely the same, but our assessment of the robustness of our findings has weakened.

Overall completeness and applicability of evidence

Our published protocol described our plan to analyse the effect of vitamin D on mortality in primary and secondary prevention randomised clinical trials in adults. All eligible randomised clinical trials up to February 2012 were included. All trials were conducted in high-income countries. Both sexes were included. Most of the participants were elderly persons, They were living alone or were living in institutions. A vast majority of the participants came from primary prevention trials, and we assume that they were apparently healthy when included in the trials. Few trials with very few participants were included in the secondary prevention trials, so our ability to say anything about such patients is week to absent. We included randomised trials with both vitamin D–deficient participants and persons who seemed to have adequate vitamin D levels at entry. We were unable to detect significant differences regarding these variables on the estimated intervention effect on mortality. Surprisingly little heterogeneity was found in all of our analyses. Most trials assessed vitamin D3, and our major conclusions are related to this intervention. Although more than half of the trials were considered of low risk of bias, our analyses revealed that outcome reporting on more than 8% of participants was lacking. This number is too high when mortality is about 12% to 13% in the placebo or no intervention group. Accordingly, our 'best-worst case' and 'worst-best case' analyses revealed that our results were compatible with both a very large beneficial effect and a very large detrimental effect of vitamin D3 on mortality. Although these extreme sensitivity analyses are unlikely, they reveal how few unaccounted for patients should have died to substantially change our findings of modest benefit into nil effect or maybe even harm. Therefore, we warn against uncritical application of our findings.

Quality of the evidence

Our review follows the overall plan of a published, peer-reviewed Cochrane protocol (Bjelakovic 2008a). It represents a comprehensive review of the topic, including 159 randomised trials with more than 105,000 participants. A total of 56 trials including more than 94,000 participants reported on mortality. This increases the precision and power of our analyses (Higgins 2011). Previous meta-analyses of preventive trials of vitamin D supplements have included substantially less information and have not examined the separate influence of different forms of vitamin D on mortality. We conducted a thorough review in accordance with The Cochrane Collaboration methodology (Higgins 2011) while implementing findings of methodological studies (Kjaergard 2001; Lundh 2012; Moher 1998; Savovic 2012; Schulz 1995; Wood 2008). Between-trial heterogeneity is almost absent in our meta-analyses. This may emphasise the consistency of our findings but should also raise concern (Ioannidis 2006). Furthermore, all-cause mortality should generally be connected with unbiased estimates (Savovic 2012; Wood 2008). We also performed trial sequential analyses to control the risk of random errors in a cumulative meta-analysis and to prevent premature statements of superiority of vitamin D based on estimation of the diversity-adjusted required information size (Brok 2008; Brok 2009; Thorlund 2009; Thorlund 2011a; Thorlund 2011b; Wetterslev 2008; Wetterslev 2009).

A major drawback in most of the included trials is the relatively large proportion of more than 8% of participants who dropped out. This opens up for attrition bias, and our 'best-worst' and 'worst-best' intention-to-treat analyses demonstrate that the intervention effect of vitamin D may be either beneficial or harmful. Although both of the two extreme scenarios are unlikely, they demonstrate that we cannot depend fully on the estimates we arrive at. The percentage of participants lost to follow-up in both experimental and control groups was about 8.5%. Our 'best-worst case' and 'worst-best case' scenario analyses revealed much more extreme confidence limits (95% CI 0.32 to 3.63) compared with our 'complete-case' scenario analysis (95% CI 0.93 to 0.99), and they convey a message of a noticeable degree of uncertainty regarding our results. This observation calls for more comprehensive meta-analyses of individual participant data plus further large randomised clinical trials. We have abstained from conducting 'uncertainty' analyses (Gamble 2005). The latter analyses accept the point estimate from the complete-participant analysis, assuming that the distribution of deaths among the participants lost to follow-up is equal to the distribution of deaths among all participants. But the distribution of dead participants among the lost to follow-up participants may indeed be different from the distribution of dead participants among participants actually followed through the whole observation period, making the 'uncertainty' analyses themselves uncertain.

We conducted a number of subgroup analyses. We observed no statistically significant different effects of the intervention effect of vitamin D on mortality in subgroup analyses of trials with low risk of bias compared with trials with high risk of bias; of trials using placebo compared with trials using no intervention in the control group; of trials with no risk of industry bias compared with trials with risk of industry bias; of trials assessing primary prevention compared with trials assessing secondary prevention; of trials including participants with vitamin D level below 20 mg/mL at entry compared with trials including participants with normal vitamin D levels at entry; of trials including ambulatory participants compared with trials including institutionalised participants; of vitamin D3 trials using concomitant calcium supplementation compared with vitamin D3 trials without calcium; of trials using a dose of vitamin D3 less than 800 IU per day compared with trials using doses greater than 800 IU per day; of vitamin D3 trials including only women compared with vitamin D3 trials including both sexes or only men.

In addition to the 56 trials reporting mortality, 62 trials with 10,804 participants had zero mortality in both the experimental and control groups. These trials were mostly phase I and phase II randomised clinical trials assessing the effects of short-term vitamin D administration on surrogate outcomes. These trials were excluded from the meta-analyses by using RR as the association measure. We assessed the influence of these trials by recalculating the RR with 0.5, 0.01 and 0.001 as empirical continuity corrections. The random-effects model RR for the three continuity corrections was not noticeably influenced. We also tested the influence of zero event trials using a risk difference as the measure of association. Vitamin D significantly decreased all-cause mortality using the fixed-effect model meta-analysis. Heterogeneity was substantial. The random-effects model revealed no statistically significant effect of vitamin D on all-cause mortality. Accordingly, the decreased mortality could be an artefact created by exclusion of trials with zero events in both intervention groups (Bradburn 2007; Sweeting 2004).

Two trials had other factors that could put them at risk of bias (i.e. recruitment bias) (Larsen 2004; Law 2006). These trials were cluster-randomised. We explored the association between intervention effects of vitamin D and the subgrouping of individually randomised and cluster-randomised trials. The influence of cluster-randomised trials on our results was also explored in sensitivity analyses, which included or excluded them. The difference between the estimate of the effect of vitamin D on mortality in individually randomised compared with cluster-randomised trials was not statistically significant. Our sensitivity analyses by including or excluding cluster-randomised trials revealed no noticeable effect on our results.

We conducted trial sequential analyses to control the risk of random errors and to prevent premature statements of superiority of the experimental or control intervention or probably false declarations of absence of effect in the cases for which we had too few data (Thorlund 2011a; Thorlund 2011b; Wetterslev 2008). The finding of significantly decreased mortality with vitamin D3 (cholecalciferol) did not seem to be due to a random error. The cumulative Z-curve crossed the trial sequential monitoring boundary for benefit after the 22nd trial. However, such an analysis cannot remove risks of bias-detected or undetected. The trial sequential analysis for vitamin D2 (ergocalciferol) suggests that we reached the futility area after the eighth trial, allowing us to conclude that any possible intervention effect, if present, is lower than a 5% relative risk reduction. One should discuss, however, how much evidence one would require when dealing with potential benefit or harm. On the one hand, beneficial or harmful effects can occur as the result of random errors; therefore, sufficient information needs to be assessed to demonstrate benefit or harm beyond reasonable doubt.

Potential biases in the review process

We repeatedly searched several databases and contacted authors of trials and industry producing vitamin D supplements. Therefore, we believe that we have not overlooked important randomised clinical trials. On the other hand, only about every second trial is reported (Gluud 2008), so we cannot exclude reporting biases, although our funnel plots did not suggest publication bias. On the positive side, we managed to obtain much more information on a number of trials from this update. However, this does not detract from the fact that we did not have access to individual participant data. Accordingly, we have no chance of analysing the effect of vitamin D in only women or in only men. When we separate trials with only women from trials with men and women combined, we see no significant difference in the intervention effect of vitamin D.

We selected all trials and extracted all data in duplicate, and we reached a high level of agreement. We did not conduct the quality assessments or data extractions blinded for authors and bias risks.

In this review update, we have now presented a more conservative and, we believe, a more correct interpretation of our findings compared with interpretations in the first version of this review.

Agreements and disagreements with other studies or reviews

In our present systematic review, we found no significant effects of bias on our estimates of intervention of vitamin D in general or of vitamin D3 specifically.

On the other hand, most of the trials were conducted with some type of support from the industry, and in general, the risk of potential industry bias was poorly described or accounted for. However, the difference in the estimates of vitamin D effect on mortality in the trials sponsored by industry compared with trials that were not sponsored by industry was not statistically significant. Accordingly, we could not confirm results from a recently published Cochrane review (Lundh 2012), which found that sponsorship of a trial by the manufacturing company leads to more favourable results and conclusions compared with trials having no sponsors.

No difference in the estimates of vitamin D effect on mortality was evident in the primary and secondary prevention trials. The number of trials with secondary prevention was low, and these trials included very few participants. Our findings may seem to contrast with earlier claims in the literature that vitamin D might be beneficial for patients with cardiovascular, malignant, infectious or autoimmune diseases (Holick 2007a; Rosen 2011; Souberbielle 2010). Assessment of vitamin D supplementation for participant groups with active disease was outside the scope of the present systematic review.

We found no statistically significant difference regarding the effect of vitamin D on mortality in trials including participants with vitamin D insufficiency (25-hydroxyvitamin D level less than 20 ng/mL) compared with trials including participants with optimal vitamin D status. The optimal vitamin D status, reached by using the blood level of 25-hydroxyvitamin D that maximally suppresses serum parathyroid hormone, varies widely (8 ng/mL to 44 ng/mL) (Dawson-Hughes 2005; Lips 2004; Vieth 2006). The level of 25-hydroxyvitamin D in the blood also depends much on the laboratory methods used for assessment of vitamin D concentration (Binkley 2009; Holick 2009; Lips 1999). Many external factors (latitude, season, time of the day, air pollution) and internal factors (skin colour, age, clothing, use of sunscreen) influence the cutaneous synthesis of vitamin D, and consequently the 25-hydroxyvitamin D levels (Webb 2006). According to a recent report of the Institute of Medicine (IOM 2011), a serum 25-hydroxyvitamin D level of 20 ng/mL (50 nmol/L) meets the vitamin D requirements of at least 97.5% of the population. Our results do not support earlier claims that participants with insufficient vitamin D status may benefit from vitamin D supplementation (Bischoff-Ferrari 2009c; Holick 2008a; Zittermann 2009a).

No difference was noted in the estimates of vitamin D effect on mortality in trials including ambulatory participants compared with trials including institutionalised participants. This could be due to random error associated with the fact that a much smaller number of institutionalised participants were analysed.

Our review identified a possible difference between the two forms of supplemental vitamin D, that is, vitamin D3 and vitamin D2. Vitamin D3 seemed to significantly decrease mortality, while the effect of vitamin D2 may be neutral or even detrimental. The World Health Organization officially regards these two forms as equivalent, based on the results of quite old studies on rickets prevention (World Health Organization 1950). Biological differences between vitamins D3 and D2 are found in some species such as birds and monkeys (Hoy 1988; Marx 1989). Evidence on biological differences between the two vitamins in humans has been sparse and contradictory. A number of recently published clinical trials found evidence that vitamin D3 increases serum 25-hydroxyvitamin D more efficiently than vitamin D2 (Armas 2004; Heaney 2011; Leventis 2009; Romagnoli 2008; Trang 1998). However, a randomised clinical trial found that vitamin D3 and vitamin D2 were comparable in maintaining serum 25-hydroxyvitamin D levels (Holick 2008b). A recently published systematic review and meta-analysis indicated that vitamin D3 is more efficacious than vitamin D2 in raising serum 25-hydroxyvitamin D concentrations (Tripkovic 2012). An emerging body of evidence suggests several plausible explanations for this observation. The plasma half-life of vitamin D3 is longer, and it has higher affinity to the vitamin D binding protein, hepatic vitamin D hydroxylase, and the vitamin D receptor (Holmberg 1986; Houghton 2006; Mistretta 2008). Vitamin D3 is the only naturally occurring form of vitamin D produced endogenously in our body, while vitamin D2 can be obtained only through the diet (Norman 2008). Vitamin D2 seems to upregulate several enzymes that degrade administered vitamin D2 and endogenous D3 (Heaney 2008). Our result could be of interest to health policy makers in different countries. The predominant supplemental form of vitamin D in the United States is vitamin D2 (Houghton 2006). In Europe, Japan and Canada, vitamin D supplements principally contain vitamin D3 (Holick 2008a), although in some European countries, like France and Great Britain, vitamin D2 is also available on the market.

Furthermore, we found no statistically significant difference between the intervention effects of vitamin D3 on mortality in trials using vitamin D3 singly and trials using vitamin D3 combined with calcium. Vitamin D3 was tested in combination with calcium in 27 trials and alone in 13 trials. Because of the small number of included trials assessing vitamin D3 alone, the findings could be due to a type II error. Our finding seems consistent with the result obtained by Autier et al, who found that calcium supplements did not affect mortality (Autier 2007), but opposite to the results of recent meta-analyses examining the influence of vitamin D on mortality (Rejnmark 2012) or bone health (DIPART 2010). These meta-analyses concluded that vitamin D is effective in preventing mortality (Rejnmark 2012) and hip fractures (DIPART 2010) only when combined with calcium. The complex interactions between vitamin D and calcium make it difficult to separate their effects. More research seems needed.

The current recommendation for adequate intake of calcium for adults is in the range of 1000 mg to 1200 mg. The tolerable upper limit is 2,000 mg (IOM 2011). The dosages used in the trials included in our meta-analysis are in accordance with recommended intakes. In most of the included trials, the primary outcome measure was bone health. Vitamin D and calcium are well-recognised nutritional factors related to bone health. Fractures, especially in elderly people, are associated with increased mortality risk (Haentjens 2010). We speculate that by preventing fractures, especially in elderly people, vitamin D combined with calcium can indirectly decrease mortality. Our results concur with the results of a recently published Cochrane review, which found that vitamin D singly could not prevent hip fracture but combined with calcium had a significant beneficial effect (Avenell 2009). However, Avenell et al found no statistically significant effect of vitamin D on mortality (Avenell 2009), although the review authors assessed a much more limited number of trials. A number of meta-analyses of randomised trials found that vitamin D combined with calcium could prevent falls and fractures (Bischoff-Ferrari 2005; Bischoff-Ferrari 2009a; Bischoff-Ferrari 2009b; Tang 2007). A recent meta-analysis observed that calcium supplementation (with or without co-administration of vitamin D) is associated with increased risk of cardiovascular events, especially myocardial infarction (Bolland 2010; Bolland 2011). Another review of prospective studies and randomised clinical trials found neutral effects of calcium (Patel 2012). A US Preventive Services Task Force recently recommended against daily supplementation with 400 IU or less of vitamin D3 and 1000 mg or less of calcium for the primary prevention of fractures in noninstitutionalised postmenopausal women (Moyer 2013).

A further important outcome of our review is that we found no significant differences in the effect of vitamin D3 on mortality in trials assessing doses less than 800 IU a day compared with trials assessing doses equal to or greater than 800 IU a day. The cutoff value for dividing trials was the median daily dose of vitamin D3 in the included trials (800 IU). The trial sequential analysis revealed that we may need more randomised trials assessing the influence of low doses of vitamin D3 (less than 800 IU) on mortality if we are to obtain the required information size. Controversy persists about the optimal dosage of vitamin D. Recommended daily intakes of vitamin D proposed by the Institute of Medicine are 600 IU per day for adults up to 70 years of age and 800 IU per day for those 70 years of age and older (IOM 2011). Recent randomised trials and meta-analyses of randomised trials that have falls and fractures as the primary outcome have concluded that the reduction in risk for falls and hip and non-vertebral fractures is dose dependent (Bischoff-Ferrari 2009a; Bischoff-Ferrari 2009b; Bischoff-Ferrari 2009c; Bischoff-Ferrari 2012). Conversely, two recent randomised clinical trials (Sanders 2010; Smith 2007) identified a potential harm associated with high doses of vitamin D. Furthermore, recent studies undertaken to examine how vitamin D status in the blood relates to all-cause mortality found a U- or J-shaped association between vitamin D status and all-cause mortality (Durup 2012; Michaëlsson 2010), as well as cancer mortality (Michaëlsson 2010). Both high and low concentrations of plasma 25-hydroxyvitamin D were associated with elevated risks of mortality (Durup 2012; Michaëlsson 2010). Amer et al evaluated the association of 25-hydroxyvitamin D with all-cause and cardiovascular mortality using National Health and Nutrition Examination Survey data (2001 to 2004) (Amer 2013). They found an inverse association between 25-hydroxyvitamin D and all-cause mortality in healthy adults with serum 25-hydroxyvitamin D levels equal to or less than 21 ng/mL (Amer 2013). These results should warn us to be very cautious about the changes in recommended daily intakes of vitamin D (Bischoff-Ferrari 2010b; Holick 2011; Sanders 2013).

It still is not known which dosing schedules are optimal for vitamin D3 supplementation. We found no significant differences in the effects of vitamin D3 on mortality in trials that administered vitamin D3 orally and daily compared with trials that applied vitamin D3 orally and intermittently. This could be due to type II errors. The randomised trial by Chel et al comparing daily, weekly and monthly dosing of vitamin D3 found that daily dosing was more effective than weekly and monthly dosing for preventing fractures (Chel 2008). A recently completed randomised clinical trial that assessed annual high-dose vitamin D3 reported an increase in the primary outcome of fractures compared with placebo (Sanders 2010).

Most of the trial participants were women. However, when we compared the effect of vitamin D3 on all-cause mortality in trials including participants of both sexes or only men versus the effect of vitamin D3 on all-cause mortality in trials including only women, no statistically significant difference was noted. Therefore, our results are compatible with vitamin D3 having similar effects in men and women. Obviously, further randomised trials stratifying for sex and reporting effects according to the sex of the participants are needed.

We observed that vitamin D2 may increase mortality in trials with high risk of bias, as well as in vitamin D–insufficient participants. These subgroup findings may be due to random errors, and our trial sequential analysis supports this assessment. Until more data become available, regulatory authorities need to consider how this information should be handled.

We lack evidence for drawing any firm conclusions about the influence of the active forms of vitamin D (alfacalcidol and calcitriol) on mortality. Available evidence suggests that alfacalcidol and calcitriol have no statistically significant effect on mortality risk. However, only a few trials were conducted, and the risk of type II errors is high. We were not able to identify other meta-analyses or systematic reviews assessing the influence of alfacalcidol and calcitriol on mortality. A recent systematic review that examined the influence of alfacalcidol and calcitriol on falls and fractures found no significant effect on vertebral fractures, a beneficial effect on non-vertebral fractures and falls and increased risk of hypercalcaemia (O'Donnell 2008). Occurrences of hypercalcaemia due to the active forms of vitamin D were increased significantly in our review.

Vitamin D had no significant effect on cardiovascular mortality. Much debate in the literature has surrounded the possible beneficial effect of vitamin D on cardiovascular disease (Holick 2004; Scragg 2010; Zittermann 2006; Zittermann 2010). Results of recently published population-based cohort studies are inconsistent (Schottker 2013; Skaaby 2012). Four recently published systematic reviews summarised the role of vitamin D in cardiovascular disease (Elamin 2011; Myung 2013; Pittas 2010; Wang 2010). These review authors found no evidence to support the use of vitamin D for prevention or treatment of cardiovascular disease (Elamin 2011; Myung 2013; Pittas 2010; Wang 2010).

Vitamin D seems to decrease cancer mortality. However, data were sparse, and selective outcome reporting bias is likely. Furthermore, the cumulative Z-curve did not cross the trial sequential monitoring boundary in our analysis of cancer mortality, and additional evidence seems needed. Pilz and coworkers recently reviewed the evidence on vitamin D status and cancer mortality (Pilz 2009b). They concluded that epidemiological data were inconsistent in favour of the hypothesis that optimal vitamin D status was related to decreased cancer mortality. However, they lacked evidence from randomised clinical trials on intervention with vitamin D to strengthen their conclusion (Pilz 2009b). Although our present data are encouraging, we need more trials to exclude risks of systematic errors and risks of random errors.

We found that vitamin D had no significant effect on cancer occurrence (Bjelakovic 2008b). A large number of observational studies have provided evidence suggesting that vitamin D may have a role in cancer prevention (Garland 2007; Gorham 2007; Schwartz 2007). The first evidence came from ecological studies that found an inverse relationship between exposure to sunlight and cancer risk (Apperly 1941; Garland 1980). Several mechanisms have been proposed to explain how vitamin D may modify cancer risk. Experimental studies revealed that vitamin D inhibits cellular proliferation and stimulates apoptosis (Artaza 2010; Pan 2010). However, some observational studies found that high vitamin D status was connected with increased oesophageal (Chen 2007), pancreatic (Stolzenberg 2006), breast (Goodwin 2009) and prostate cancer risks (Ahn 2008). One should consider the possibility of a U-shaped relation between vitamin D status and cancer risk (Toner 2010). Our results are in accordance with the conclusions of the recently published International Agency for Research on Cancer and Institute of Medicine reports stating that vitamin D status is not correlated with cancer occurrence (IARC 2008; IOM 2011). Recently, an updated meta-analysis prepared for the US Preventive Services Task Force found inconclusive evidence regarding vitamin D supplementation for the prevention of cancer (Chung 2011). We still lack evidence; therefore, we need additional randomised clinical trials if we are to better understand the potential effect of vitamin D on cancer.

Vitamin D3 combined with calcium significantly increased nephrolithiasis. Active forms of vitamin D significantly increased hypercalcaemia. Other adverse events such as elevated urinary calcium excretion, renal insufficiency, cancer and cardiovascular, gastrointestinal, psychiatric or skin disorders were not statistically significantly influenced by vitamin D supplementation.

We lack sufficient evidence on the effect of vitamin D supplementation on health-related quality of life and on the cost-effectiveness of vitamin D supplementation. However, vitamin D3 products and calcium are relatively cheap, so these interventions are likely to be cost-effective if they work sufficiently well.

In conclusion, we see a potentially positive effect of vitamin D3 on mortality, but we caution against thinking that now we know what to do in clinical practice because of the following. Our collection of trials showed a large dropout rate, which could seriously influence our results. The 'worst-best case' scenario analysis does not exclude a risk of increased mortality associated with vitamin D. We found no significant difference in mortality between vitamin D3 given singly compared with combined with calcium, or vitamin D3 given in doses greater than compared with less than 800 IU/d. Vitamin D3 in doses less than 800 IU did not cross the trial sequential monitoring boundary for benefit, so random errors cannot be excluded. The effect of vitamin D3 on participants with adequate vitamin D status is unknown. Furthermore, we do not know the harm-to-benefit ratio when the intervention is used over a longer time. Moreover, we lack information on the effect in men and in younger persons of both sexes. All these reservations lead us to conclude that more research is urgently needed.

A great debate has been documented in the literature about the possible beneficial health effects of vitamin D supplementation. A lot of evidence indicates that vitamin D has beneficial effects, in addition to its effects on bones (Cavalier 2009; Stechschulte 2009; Wang 2009). It has been speculated that optimal vitamin D status is related to prevention of a spectrum of chronic diseases, including malignant and cardiovascular diseases (Fleet 2008; Ingraham 2008; Judd 2009; Zittermann 2010). Vitamin D insufficiency has been associated with increased mortality (Hutchinson 2010; Melamed 2008; Pilz 2009a; Pilz 2012; Zittermann 2009a). Two recently published evidence reports prepared for The Agency for Healthcare Research and Quality have assessed the influence of vitamin D and calcium on different health outcomes (Chung 2009; Cranney 2007). Most of the findings on bone health and different health outcomes were inconsistent (Chung 2009; Cranney 2007). The Institute of Medicine recently reported that available evidence supports a role of vitamin D and calcium in skeletal health (IOM 2011). However, the evidence was considered insufficient and inconclusive for extraskeletal outcomes, including mortality (IOM 2011). A recent meta-analysis on the effects of vitamin D supplements on bone mineral density concluded that vitamin D supplementation for osteoporosis prevention in community-dwelling adults without specific risk factors for vitamin D deficiency seems inappropriate (Reid 2013; Rosen 2013).

Authors' conclusions

Implications for practice

We found some evidence that vitamin D3 may decrease all-cause mortality and cancer mortality in predominantly elderly participants living independently or in institutional care. Vitamin D3 combined with calcium increased nephrolithiasis. Vitamin D2, alfacalcidol and calcitriol had no statistically significant effect on mortality. Alfacalcidol and calcitriol increased hypercalcaemia. Elevated urinary calcium excretion, renal insufficiency, cancer and cardiovascular, gastrointestinal, psychiatric or skin disorders were not statistically significantly influenced by vitamin D supplementation. However, because of risks of attrition bias, of outcome reporting bias and other biases, we cannot yet recommend or refute the use of vitamin D for preventing all-cause mortality or cancer mortality.

Implications for research

More randomised clinical trials are needed on the effects of vitamin D3 on mortality in younger, healthy persons and in elderly community-dwelling and institutionalised persons without apparent vitamin D deficiency. Before drawing conclusions, we need more evidence on the effect of vitamin D on cancer and cardiovascular disease, especially when we consider the different forms of vitamin D used for supplementation. More randomised clinical trials are needed to test the efficacy of vitamin D3 applied singly or in combination with calcium and to compare different doses of vitamin D3. The effects of vitamin D on health-related quality of life and cost-effectiveness deserve further investigation. A number of issues are still insufficiently addressed. We do not know the importance of daily doses of vitamin D3, the influence of vitamin D insufficiency, the influence of dietary habits, the influence of sun exposure, the influence of latitude on the globe, the influence of sex of the participants and the influence of age. Future randomised clinical trials ought to be conducted without influence of industry on the design and reporting and ought to stratify participants for age and sex. Future trials ought to be designed according to the SPIRIT guidelines (Chan 2013) and reported according to the CONSORT guidelines (www.consort-statement.org). Future trials ought to report individual participant data, so that proper individual participant data meta-analyses of the effects of vitamin D in subgroups can be conducted.

Acknowledgements

We extend our gratitude to all participants and investigators in the randomised clinical trials. We are grateful to the many authors of publications who kindly responded to our requests for further information on the trials in which they were involved.

Data and analyses

Download statistical data

Comparison 1. Vitamin D versus placebo or no intervention
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 All-cause mortality in trials with low or high risk of bias5695286Risk Ratio (M-H, Random, 95% CI)0.97 [0.94, 0.99]
1.1 Trials with low risk of bias3067516Risk Ratio (M-H, Random, 95% CI)0.96 [0.92, 0.99]
1.2 Trials with high risk of bias2627770Risk Ratio (M-H, Random, 95% CI)0.99 [0.92, 1.06]
2 All-cause mortality in individually randomised and cluster-randomised trials5695286Risk Ratio (M-H, Random, 95% CI)0.97 [0.94, 0.99]
2.1 Individually randomised trials5481964Risk Ratio (M-H, Random, 95% CI)0.96 [0.93, 0.99]
2.2 Cluster-randomised trials213322Risk Ratio (M-H, Random, 95% CI)1.05 [0.82, 1.34]
3 All-cause mortality in placebo-controlled and no intervention trials5695286Risk Ratio (M-H, Random, 95% CI)0.97 [0.94, 0.99]
3.1 Placebo in the control group4473892Risk Ratio (M-H, Random, 95% CI)0.96 [0.93, 0.99]
3.2 No intervention in the control group1221394Risk Ratio (M-H, Random, 95% CI)1.05 [0.91, 1.21]
4 All-cause mortality and risk of industry bias5695286Risk Ratio (M-H, Random, 95% CI)0.97 [0.94, 0.99]
4.1 Trials without risk of industry bias77372Risk Ratio (M-H, Random, 95% CI)0.97 [0.92, 1.03]
4.2 Trials with risk of industry bias4987914Risk Ratio (M-H, Random, 95% CI)0.96 [0.93, 1.00]
5 All-cause mortality in primary and secondary prevention trials5695286Risk Ratio (M-H, Random, 95% CI)0.97 [0.94, 0.99]
5.1 Primary prevention trials4894491Risk Ratio (M-H, Random, 95% CI)0.97 [0.94, 0.99]
5.2 Secondary prevention trials8795Risk Ratio (M-H, Random, 95% CI)1.31 [0.73, 2.35]
6 All-cause mortality and vitamin D status5695286Risk Ratio (M-H, Random, 95% CI)0.97 [0.94, 0.99]
6.1 Vitamin D insufficiency2656697Risk Ratio (M-H, Random, 95% CI)0.95 [0.91, 0.99]
6.2 Vitamin D adequacy1916283Risk Ratio (M-H, Random, 95% CI)0.95 [0.87, 1.05]
6.3 Unknown vitamin D status1122306Risk Ratio (M-H, Random, 95% CI)1.02 [0.92, 1.13]
7 All-cause mortality in ambulatory and institutionalised participants5695286Risk Ratio (M-H, Random, 95% CI)0.97 [0.94, 0.99]
7.1 Ambulatory participants4586071Risk Ratio (M-H, Random, 95% CI)0.95 [0.92, 0.98]
7.2 Institutionalised participants119215Risk Ratio (M-H, Random, 95% CI)1.02 [0.92, 1.13]
8 All-cause mortality ('best-worst case' and 'worst-best case' scenario)53 Risk Ratio (M-H, Random, 95% CI)Subtotals only
8.1 'Best-worst' case scenario5384418Risk Ratio (M-H, Random, 95% CI)0.40 [0.32, 0.51]
8.2 'Worst-best' case scenario5384418Risk Ratio (M-H, Random, 95% CI)2.78 [2.13, 3.63]
9 All-cause mortality in trials using vitamin D3 (cholecalciferol)3875927Risk Ratio (M-H, Random, 95% CI)0.94 [0.91, 0.98]
9.1 Vitamin D3 trials with low risk of bias2052645Risk Ratio (M-H, Random, 95% CI)0.93 [0.89, 0.98]
9.2 Vitamin D3 trials with high risk of bias1823282Risk Ratio (M-H, Random, 95% CI)0.95 [0.91, 1.00]
10 All-cause mortality in trials using vitamin D3 singly or combined with calcium38 Risk Ratio (M-H, Random, 95% CI)Subtotals only
10.1 Vitamin D3 singly1312609Risk Ratio (M-H, Random, 95% CI)0.92 [0.85, 1.00]
10.2 Vitamin D3 combined with calcium2763051Risk Ratio (M-H, Random, 95% CI)0.96 [0.92, 0.99]
11 All-cause mortality in trials using low or high dose of vitamin D338 Risk Ratio (M-H, Random, 95% CI)Subtotals only
11.1 Low dose of vitamin D3 (< 800 IU a day)1350437Risk Ratio (M-H, Random, 95% CI)0.92 [0.87, 0.97]
11.2 High dose of vitamin D3 (≥ 800 IU a day)2625558Risk Ratio (M-H, Random, 95% CI)0.96 [0.92, 1.00]
12 All-cause mortality in trials applying vitamin D3 daily or intermittently38 Risk Ratio (M-H, Random, 95% CI)Subtotals only
12.1 Vitamin D3 daily3169168Risk Ratio (M-H, Random, 95% CI)0.95 [0.91, 0.98]
12.2 Vitamin D3 intermittently86871Risk Ratio (M-H, Random, 95% CI)0.89 [0.77, 1.03]
13 All-cause mortality in trials using vitamin D3 and vitamin D status3875927Risk Ratio (M-H, Random, 95% CI)0.94 [0.91, 0.98]
13.1 Vitamin D insufficiency2055883Risk Ratio (M-H, Random, 95% CI)0.95 [0.91, 0.99]
13.2 Vitamin D adequacy104979Risk Ratio (M-H, Random, 95% CI)0.92 [0.80, 1.07]
13.3 Unknown vitamin D status815065Risk Ratio (M-H, Random, 95% CI)0.95 [0.78, 1.16]
14 All-cause mortality in trials using vitamin D3 according to the participant's sex3875927Risk Ratio (M-H, Random, 95% CI)0.94 [0.91, 0.98]
14.1 Vitamin D3 trialsincluding only women1953062Risk Ratio (M-H, Random, 95% CI)0.93 [0.84, 1.03]
14.2 Vitamin D3 trials including men and women1922865Risk Ratio (M-H, Random, 95% CI)0.94 [0.89, 0.98]
15 All-cause mortality in trials using vitamin D2 (ergocalciferol)1218349Risk Ratio (M-H, Random, 95% CI)1.02 [0.96, 1.08]
15.1 Vitamin D2 trials with low risk of bias914439Risk Ratio (M-H, Random, 95% CI)0.98 [0.93, 1.04]
15.2 Vitamin D2 trials with high risk of bias33910Risk Ratio (M-H, Random, 95% CI)1.20 [1.05, 1.37]
16 All-cause mortality in trials using vitamin D2 singly or combined with calcium12 Risk Ratio (M-H, Random, 95% CI)Subtotals only
16.1 Vitamin D2 singly817079Risk Ratio (M-H, Random, 95% CI)1.03 [0.96, 1.12]
16.2 Vitamin D2 combined with calcium51307Risk Ratio (M-H, Random, 95% CI)1.00 [0.64, 1.57]
17 All-cause mortality in trials using low or high dose of vitamin D212 Risk Ratio (M-H, Random, 95% CI)Subtotals only
17.1 Low dose of vitamin D21101Risk Ratio (M-H, Random, 95% CI)0.82 [0.17, 3.98]
17.2 High dose of vitamin D21218273Risk Ratio (M-H, Random, 95% CI)1.02 [0.95, 1.10]
18 All-cause mortality in trials applying vitamin D2 daily or intermittently12 Risk Ratio (M-H, Random, 95% CI)Subtotals only
18.1 Vitamin D2 daily61349Risk Ratio (M-H, Random, 95% CI)0.88 [0.68, 1.12]
18.2 Vitamin D2 intermittently617000Risk Ratio (M-H, Random, 95% CI)1.06 [0.95, 1.18]
19 All-cause mortality in trials using vitamin D2 and vitamin D status1218349Risk Ratio (M-H, Random, 95% CI)1.02 [0.96, 1.08]
19.1 Vitamin D insufficiency64413Risk Ratio (M-H, Random, 95% CI)1.20 [1.05, 1.37]
19.2 Vitamin D adequacy510496Risk Ratio (M-H, Random, 95% CI)0.97 [0.86, 1.10]
19.3 Unknown vitamin D status13440Risk Ratio (M-H, Random, 95% CI)0.99 [0.93, 1.05]
20 All-cause mortality in trials using alfacalcidol (1α-hydroxyvitamin D)4617Risk Ratio (M-H, Random, 95% CI)0.96 [0.22, 4.15]
21 All-cause mortality in trials using alfacalcidol and vitamin D status4617Risk Ratio (M-H, Random, 95% CI)0.96 [0.22, 4.15]
21.1 Vitamin D insufficiency2155Risk Ratio (M-H, Random, 95% CI)1.01 [0.11, 9.52]
21.2 Vitamin D adequacy1378Risk Ratio (M-H, Random, 95% CI)0.97 [0.06, 15.37]
21.3 Unknown vitamin D status184Risk Ratio (M-H, Random, 95% CI)0.87 [0.06, 13.40]
22 All-cause mortality in trials using calcitriol (1,25-dihydroxyvitamin D)3430Risk Ratio (M-H, Random, 95% CI)1.37 [0.27, 7.03]
23 All-cause mortality in trials using calcitriol and vitamin D status3430Risk Ratio (M-H, Random, 95% CI)1.37 [0.27, 7.03]
23.1 Vitamin D insufficiency186Risk Ratio (M-H, Random, 95% CI)0.33 [0.01, 7.96]
23.2 Vitamin D adequacy2344Risk Ratio (M-H, Random, 95% CI)2.28 [0.34, 15.39]
24 Cancer mortality444492Risk Ratio (M-H, Random, 95% CI)0.88 [0.78, 0.98]
25 Cardiovascular mortality1047267Risk Ratio (M-H, Random, 95% CI)0.98 [0.90, 1.07]
26 Adverse events35 Risk Ratio (M-H, Random, 95% CI)Subtotals only
26.1 Hypercalcemia in trials using supplemental forms of vitamin D1511323Risk Ratio (M-H, Random, 95% CI)1.36 [0.85, 2.18]
26.2 Hypercalcemia in trials using active forms of vitamin D3710Risk Ratio (M-H, Random, 95% CI)3.18 [1.17, 8.68]
26.3 Nephrolithiasis in trials using vitamin D3 combined with calcium442876Risk Ratio (M-H, Random, 95% CI)1.17 [1.02, 1.34]
26.4 Nephrolithiasis in trials using calcitriol1246Risk Ratio (M-H, Random, 95% CI)0.33 [0.01, 8.10]
26.5 Hypercalciuria3695Risk Ratio (M-H, Random, 95% CI)4.64 [0.99, 21.76]
26.6 Renal insufficiency35495Risk Ratio (M-H, Random, 95% CI)1.70 [0.27, 10.70]
26.7 Cardiovascular disorders84495Risk Ratio (M-H, Random, 95% CI)0.95 [0.86, 1.05]
26.8 Gastrointestinal disorders169702Risk Ratio (M-H, Random, 95% CI)1.36 [0.87, 2.13]
26.9 Psychiatric disorders3580Risk Ratio (M-H, Random, 95% CI)1.44 [0.56, 3.73]
26.10 Skin disorders23810Risk Ratio (M-H, Random, 95% CI)3.27 [0.17, 62.47]
26.11 Cancer1449707Risk Ratio (M-H, Random, 95% CI)0.99 [0.94, 1.06]
Analysis 1.1.

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 1 All-cause mortality in trials with low or high risk of bias.

Analysis 1.2.

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 2 All-cause mortality in individually randomised and cluster-randomised trials.

Analysis 1.3.

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 3 All-cause mortality in placebo-controlled and no intervention trials.

Analysis 1.4.

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 4 All-cause mortality and risk of industry bias.

Analysis 1.5.

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 5 All-cause mortality in primary and secondary prevention trials.

Analysis 1.6.

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 6 All-cause mortality and vitamin D status.

Analysis 1.7.

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 7 All-cause mortality in ambulatory and institutionalised participants.

Analysis 1.8.

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 8 All-cause mortality ('best-worst case' and 'worst-best case' scenario).

Analysis 1.9.

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 9 All-cause mortality in trials using vitamin D3 (cholecalciferol).

Analysis 1.10.

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 10 All-cause mortality in trials using vitamin D3 singly or combined with calcium.

Analysis 1.11.

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 11 All-cause mortality in trials using low or high dose of vitamin D3.

Analysis 1.12.

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 12 All-cause mortality in trials applying vitamin D3 daily or intermittently.

Analysis 1.13.

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 13 All-cause mortality in trials using vitamin D3 and vitamin D status.

Analysis 1.14.

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 14 All-cause mortality in trials using vitamin D3 according to the participant's sex.

Analysis 1.15.

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 15 All-cause mortality in trials using vitamin D2 (ergocalciferol).

Analysis 1.16.

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 16 All-cause mortality in trials using vitamin D2 singly or combined with calcium.

Analysis 1.17.

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 17 All-cause mortality in trials using low or high dose of vitamin D2.

Analysis 1.18.

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 18 All-cause mortality in trials applying vitamin D2 daily or intermittently.

Analysis 1.19.

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 19 All-cause mortality in trials using vitamin D2 and vitamin D status.

Analysis 1.20.

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 20 All-cause mortality in trials using alfacalcidol (1α-hydroxyvitamin D).

Analysis 1.21.

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 21 All-cause mortality in trials using alfacalcidol and vitamin D status.

Analysis 1.22.

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 22 All-cause mortality in trials using calcitriol (1,25-dihydroxyvitamin D).

Analysis 1.23.

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 23 All-cause mortality in trials using calcitriol and vitamin D status.

Analysis 1.24.

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 24 Cancer mortality.

Analysis 1.25.

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 25 Cardiovascular mortality.

Analysis 1.26.

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 26 Adverse events.

Appendices

Appendix 1. Search strategies

Search terms for various databases

Unless otherwise stated, search terms are free-text terms.

Abbreviations:

'$': stands for any character; '?': substitutes one or no character; adj: adjacent (i.e. number of words within range of search term); exp: exploded MeSH; MeSH: medical subject heading (MEDLINE medical index term); pt: publication type; sh: MeSH; tw: text word.

The Cochrane Library
1. MeSH descriptor Vitamin D explode all trees
2. MeSH descriptor Cholecalciferol explode all trees
3. MeSH descriptor Ergocalciferols explode all trees
4. MeSH descriptor Dihydrotachysterol explode all trees
5. MeSH descriptor 25-hydroxyvitamin D 2 explode all trees
6. MeSH descriptor Hydroxycholecalciferols explode all trees
7. ( (vitamin* in All Text and d in All Text and 2 in All Text) or (vitamin* in All Text and d2 in All Text) )
8. (cholecalciferol* in All Text or calciferol* in All Text or calcitriol* in All Text or dihydrotachysterol* in All Text or (hydroxyvitamin* in All Text and d* in All Text) )
9. (alfacalcidol* in All Text or alphacalcidol* in All Text or cholecalciferol* in All Text)
10. (#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9)
11. MeSH descriptor Mortality explode all trees
12. (mortality in All Text or mortaliti* in All Text)
13. (#11 or #12)
14. MeSH descriptor Primary Prevention explode all trees
15. prevent* in All Text
16. MeSH descriptor Neoplasms explode all trees
17. (cancer* in All Text or neoplasm* in All Text or tumo?r* in All Text)
18. (#14 or #15 or #16 or #17)
19. (#10 and #13)
20. (#10 and #18)
21. (#19 or #20)
MEDLINE
1. exp Vitamin D/
2. exp Cholecalciferol/
3. exp ergocalciferols/ or exp dihydrotachysterol/ or exp 25-hydroxyvitamin d 2/
4. exp Hydroxycholecalciferols/
5. vitamin D?.tw,ot.
6. (cholecalciferol$ or calcifediol$ or calcitriol$ or dihydrotachysterol$ or hydroxyvitamin$ d?).tw,ot.
7. (alfacalcidol$ or alphacalcidol$ or colecalciferol$).tw,ot.
8. or/1-7
9. exp Mortality/
10. mortality.tw,ot.
11. mortaliti$.tw,ot.
12. or/9-11
13. exp Primary Prevention/
14. (prevention$ or prevent$).tw,ot.
15. exp Neoplasm/
16. (cancer$ or neoplasm$ or tumo?r$).tw,ot.
17. or/13-16
18. exp Randomized Controlled Trials as topic/
19. Randomized Controlled Trial.pt.
20. exp Controlled Clinical Trials as topic/
21. Controlled Clinical Trial.pt.
22. exp Random Allocation/
23. exp Double-Blind Method/
24. exp Single-Blind Method/
25. or/18-24
26. exp "Review Literature as topic"/
27. exp Technology Assessment, Biomedical/
28. exp Meta-analysis as topic/
29. Meta-analysis.pt.
30. hta.tw,ot.
31. (health technology adj6 assessment$).tw,ot.
32. (meta analy$ or metaanaly$ or meta?analy$).tw,ot.
33. ((review$ or search$) adj10 (literature$ or medical database$ or medline or pubmed or embase or cochrane or cinahl or psycinfo or psyclit or healthstar or biosis or current
content$ or systemat$)).tw,ot.
34. or/26-33
35. 25 or 34
36. 8 and 17 and 35
37. 8 and 12 and 35
38 36 or 37
39. limit 38 to animals
40. limit 38 to humans
41. 39 not 40
42 38 not 41
EMBASE
1. exp ergocalciferol/ or exp vitamin D/
2. exp colecalciferol/
3. exp dihydrotachysterol/
4. exp 25 hydroxyvitamin D/
5. exp hydroxycolecalciferol/
6. (vitamin* D? or vitamin*D?).tw,ot.
7. (cholecalciferol* or colecalciferol* or calcifediol* or calcitriol* or dihydrotachysterol* or hydroxyvitamin* d?).tw,ot.
8. exp alfacalcidol/
9. (alfacalcidol* or alphacalcidol*).tw,ot.
10. or/1-9
11. exp mortality/
12. (mortality or mortaliti*).tw,ot.
13. 11 or 12
14. exp prevention/
15. prevent*.tw,ot.
16. exp neoplasm/
17. or/14-16
18. randomized controlled trial/
19. double blind procedure/
20. single blind procedure/
21. exp randomization/
22. exp controlled clinical trial/
23. or/18-22
24. exp meta analysis/
25. (metaanaly$ or meta analy$ or meta?analy$).ab,ti,ot.
26. ((review$ or search$) adj10 (literature$ or medical database$ or medline or pubmed or embase or cochrane or cinahl or psycinfo or psyclit or healthstar or biosis or current content$ or systematic$)).ab,ti,ot.
27. exp Literature/
28. exp Biomedical Technology Assessment/
29. hta.tw,ot.
30. (health technology adj6 assessment$).tw,ot.
31. or/24-30
32. (comment or editorial or historical-article).pt.
33. 31 not 32
34. 23 or 33
35. 10 and 13 and 34
36. 10 and 17 and 34
37. 35 or 36
38. limit 37 to human
LILACS
1. Vitamin D
2. Cholecalciferol
3. Ergocalciferol
4. Alfacalcidol
5. Calcitriol
ISI Web of Science
1. TS=(vitamin d2 OR vitamin d 2 OR hydroxyvitamin* OR cholecalciferol* OR calciferol* OR calcitriol* OR calcifediol* OR dihydrotachysterol* OR alfacalcidol* OR alphacalcidol* OR colecalciferol*)
2. TS=(mortalit* OR prevent* OR cancer* OR neoplasm* OR tumor* OR tumour*)
3. #2 AND #1
4. TS=(random* OR blind* OR placebo* OR meta-analys*)
5. #4 AND #3

Appendix 2. Description of interventions

Characteristic

Study ID

Intervention(s)
[route, frequency, total dose/day]
Control(s)
[route, frequency, total dose/day]
Aloia 2005Vitamin D3 (800 IU) plus calcium (1200 to 1500 mg) orally, dailyMatched placebo tablets plus calcium (1200 to 1500 mg) orally, daily
Avenell 2004Vitamin D3 (800 IU) orally, dailyNo intervention
Calcium (1000 mg) orally, daily
Vitamin D3 (800 IU) plus calcium (1000 mg) orally, daily
Avenell 2012Vitamin D3 (800 IU) orally, dailyMatched placebo tablets orally, daily
Calcium (1000 mg) orally, daily
Vitamin D3 (800 IU) plus calcium (1000 mg) orally, daily
Baeksgaard 1998Vitamin D3 (560 IU) plus calcium (1000 mg) orally, dailyMatched placebo tablets orally, daily
Vitamin D3 (560 IU) plus calcium (1000 mg) plus multivitamin orally, daily
Bischoff 2003Vitamin D3 (800 IU) plus calcium 1200 mg orally, dailyCalcium 1200 mg orally, daily
Bjorkman 2007Vitamin D3 (1200 IU) plus calcium (500 mg) orally, dailyCalcium (500 mg) orally, daily
Vitamin D3 (400 IU) plus calcium (500 mg) orally, daily
Bolton-Smith 2007Vitamin D3 (400 IU) plus calcium 1000 mg orally, dailyMatched placebo orally, daily
Vitamin D3 (400 IU) plus calcium 1000 mg plus vitamin K1 200 μg orally, daily
Vitamin K1 200 μg orally, daily
Brazier 2005Vitamin D3 (800 IU) plus calcium (1000 mg) orally, dailyMatched placebo tablets orally, daily
Broe 2007Vitamin D2 (800 IU) orally, dailyMatched placebo tablets orally, daily
Vitamin D2 (600 IU) orally, daily
Vitamin D2 (400 IU) orally, daily
Vitamin D2 (200 IU) orally, daily
Brohult 1973Vitamin D3 (100,000 IU) dailyPlacebo daily
Burleigh 2007Vitamin D3 (800 IU) plus calcium (1200 mg) orally, dailyCalcium (1200 mg) orally, daily
Campbell 2005Home safety assessment and modification programmeSocial visits
Exercise programme plus vitamin D3 100,000 IU initially and then 50,000 IU orally, monthly
Both interventions
Chapuy 1992Vitamin D3 (800 IU) plus calcium (1200 mg) orally, dailyDouble placebo orally, daily
Chapuy 2002Vitamin D3 (800 IU) plus calcium (1200 mg) (fixed combination) orally, dailyDouble placebo orally, daily
Vitamin D3 (800 IU) plus calcium (1200 mg), (separate combination) orally, daily
Chel 2008Vitamin D3 (600 IU) orally, dailyMatched placebo tablets orally, daily
Vitamin D3 (4200 IU) orally, weeklyMatched placebo tablets orally, weekly
Vitamin D3 (18,000 IU) orally, monthlyMatched placebo powder orally, monthly
Cherniack 2011Vitamin D3 2000 IU plus calcium 1200 mg orally, dailyMatched placebo plus calcium 1200 mg orally, daily
Cooper 2003Vitamin D2 (10,000 IU) orally, weekly plus calcium (1000 mg) orally, dailyCalcium (1000 mg) orally, daily
Coreless 1985Vitamin D2 (9000 IU) orally, dailyPlacebo orally, daily
Daly 2006Calcium-vitamin D3–fortified milk containing vitamin D3 (800 IU) plus calcium (1000 mg) dailyNo intervention
Dawson-Hughes 1997Vitamin D3 (700 IU) plus calcium (500 mg) orally, dailyDouble placebo orally, daily
Dukas 2004Alfacalcidol (1 μg) orally, dailyPlacebo orally, daily
Flicker 2005Vitamin D3 (10,000 IU) weekly and thereafter vitamin D31000 IU daily plus calcium (600 mg) orally, dailyCalcium (600 mg) orally, daily
Gallagher 2001Calcitriol (0.5 μg) dailyMatched placebo pills orally, daily
Conjugated oestrogens 0.625 mg/daily plus medroxyprogesterone acetate 2.5 mg orally, daily
Calcitriol (0.5 μg daily) plus conjugated oestrogens 0.625 mg/daily plus medroxyprogesterone acetate 2.5 mg orally, daily
Glendenning 2012Cholecalciferol 150,000 three-monthlyPlacebo vitamin D three-monthly
Grady 1991Calcitriol (0.5 μg) orally, dailyPlacebo vitamin D orally, daily
Grimnes 2011Vitamin D3 (20,000 IU) orally, twice weeklyPlacebo orally, twice weekly.
Harwood 2004Single injection of 300,000 IU of vitamin D2No intervention
Single injection of 300,000 IU of vitamin D2 plus oral calcium (1000 mg) daily
Oral vitamin D3 (800 IU) plus calcium (1000 mg) daily
Jackson 2006Vitamin D3 (400 IU) plus calcium (1000 mg) orally, dailyMatched placebo orally, daily
Janssen 2010Vitamin D3 (400 IU) plus calcium (500 mg) orally, dailyMatched placebo vitamin D3 plus calcium (500 mg) orally, daily
Komulainen 1999Sequential combination of 2 mg oestradiol valerate (days 1 to 21) and 1 mg cyproterone acetate (days 12 to 21) and a treatment-free interval (days 22 to 28)Placebo
Vitamin D3 (300 IU) plus calcium (500 mg) dailya
Sequential combination of 2 mg oestradiol valerate (days 1 to 21) and 1 mg cyproterone acetate (days 12 to 21) and a treatment-free interval (days 22 to 28) plus vitamin D3 (300 IU) and calcium (500 mg) orally, daily
Krieg 1999Vitamin D3 (880 IU) plus calcium (1000 mg) orally, dailyNo treatment
Kärkkäinen 2010Vitamin D3 800 IU plus calcium 1000 mg orally, dailyNo intervention
Lappe 2007Vitamin D3 (1000 IU) plus calcium (1400 to 1500 mg) orally, dailyDouble placebo tablets, orally, daily
Calcium (1400 to 1500 mg) plus a vitamin D placebo orally, daily
Larsen 2004Home safety inspectionNo intervention
Vitamin D3 (400 IU) plus calcium (1000 mg) orally, daily
Both interventions
Latham 2003Resistance exerciseMatched placebo tablets, orally
Attention control
Vitamin D3 (300,000 IU) single dose, orally
Law 2006Vitamin D2 100,000 IU every three months, orallyNo intervention
Lehouck 2012Vitamin D3 100,000 IU monthly, orallyMatched placebo orally, monthly
Lips 1996Vitamin D3 400 IU orally, dailyMatched placebo orally, daily
Lips 2010Vitamin D3 8400 IU orally, weeklyMatched placebo orally, weekly.
Lyons 2007Vitamin D2 100,000 IU four-monthly, orallyMatched placebo tablets four-monthly, orally
Meier 2004Vitamin D3 (500 IU) orally, dailyNo intervention
Mochonis 2006Vitamin D3 300 IU plus calcium 1200 mg orally, dailyNo intervention
Calcium 1200 mg, orally, daily
Ooms 1995Vitamin D3 400 IU orally, dailyMatched placebo orally, daily
Ott 1989Vitamin D3 17.2 IU plus calcium 1000 mgMatched placebo vitamin D plus calcium 1000 mg orally, daily
Porthouse 2005Vitamin D3 (800 IU) plus calcium (1000 mg), orally, dailyNo interventionb
Prince 2008Vitamin D2 1000 IU plus calcium 1000 mg orally, dailyMatched placebo tablets of vitamin D plus calcium 1000 mg orally, daily
Sanders 2010Vitamin D3 500,000 IU orally, yearlyMatched placebo tablets of vitamin D orally, yearly
Sato 1997Vitamin D (alfacalcidol) (1 μg) plus calcium 300 mg orally, dailyMatched placebo tablets of vitamin D and calcium orally, daily
Sato 1999aVitamin D (alfacalcidol) (1 μg) orally, dailyMatched placebo tablets of vitamin D orally, daily
Sato 1999bVitamin D (alfacalcidol) (1 μg) orally, dailyNo treatment
Ipriflavone 600 mg orally, daily
Sato 2005aVitamin D2 (1000 IU) orally, dailyMatched placebo tablets of vitamin D daily
Schleithoff 2006Vitamin D3 2000 IU plus calcium 500 mg orally, dailyMatched placebo vitamin D plus calcium 500 mg orally, daily
Smith 2007Vitamin D2 300,000 IU intramuscular injection, yearlyMatched placebo intramuscular injection yearly
Trivedi 2003Vitamin D3 100,000 IU every four months orallyMatched placebo vitamin D every four months orally
Witham 2010Vitamin D2 (10,000 IU) orally, dailyMatched placebo tablets orally, daily
Zhu 2008Vitamin D2 (1000 IU) plus calcium (1200 mg) orally, dailyMatched placebo vitamin D and placebo calcium orally, daily
Calcium 1200 mg plus placebo vitamin D orally, daily

Footnotes

aNo intake during June to August; the vitamin D3 dosage was lowered to 100 IU/d after four years of treatment
bInformation leaflet on dietary calcium intake and prevention of falls

Appendix 3. Baseline characteristics (I)

Characteristic

Study ID

Duration of interv

ention
[years]

Duration of follow-up
[years]
Participating
population
CountrySettingEthnic groups
Aloia 200533Postmenopausal African-American womenUSAOutpatientsAll black
Avenell 200411Elderly people with an osteoporotic fracture within the past 10 yearsUKOutpatients-
Avenell 20123.756.2Elderly people with low-trauma, osteoporotic fracture in the previous 10 yearsUKOutpatients-
Baeksgaard 199822Postmenopausal womenDemarkOutpatients-
Bischoff 20030.250.25Elderly women living in institutional careSwitzerlandInpatients-
Bjorkman 20070.50.5Chronically bedridden patientsFinland--
Bolton-Smith 200722Elderly non-osteoporotic womenUKOutpatients-
Brazier 200511Elderly vitamin D–insufficient womenFranceOutpatients-
Broe 20070.420.42Nursing home residentsUSAInpatients-
Brohult 197311Patients with rheumatoid arthritisSwedenOutpatients-
Burleigh 20070.080.08Elderly peopleUKInpatients-
Campbell 200511Elderly people with visual impairmentNew ZealandOutpatients-
Chapuy 19921.54Healthy ambulatory womenFranceOutpatients-
Chapuy 200222Elderly people living in institutional careFranceOutpatients-
Chel 20080.330.33Nursing home residentsNetherlandsInpatients-
Cherniack 20110.50.5Elderly peopleUSAOutpatients-
Cooper 200322Postmenopausal womenAustraliaOutpatientsAll white
Coreless 19850.750.75Elderly patients from geriatric wardsUKInpatients-
Daly 200623.5Healthy ambulatory menAustraliaOutpatients-
Dawson-Hughes 199733Healthy ambulatory participantsUSAOutpatients-
Dukas 20040.750.75Elderly peopleSwitzerlandOutpatients-
Flicker 200522Elderly people living in institutional careAustraliaInpatients-
Gallagher 200135Elderly womenUSAOutpatients-
Grady 19910.50.5Elderly peopleUSAOutpatients-
Glendenning 20120.50.75Elderly womenAustraliaOutpatients-
Grimnes 20110.50.5Healthy people with low vitamin D statusNorwayOutpatients-
Harwood 00411Elderly womenUKOutpatients-
Jackson 200677Postmenopausal womenUSAOutpatients-
Janssen 201011Elderly vitamin D–insufficient womenNetherlandsOutpatients-
Komulainen 199955Postmenopausal womenFinlandOutpatients-
Krieg 199922Elderly institutionalised womenSwitzerlandOutpatients-
Kärkkäinen 201033Postmenopausal womenFinlandOutpatients-
Lappe 200744Postmenopausal womenUSAOutpatientsAll white
Larsen 20043.53.5Elderly peopleDenmarkOutpatients-
Latham 20030.0030.5Elderly peopleNew ZealandOutpatients-
Law 20060.830.83Elderly peopleUKInpatients-
Lehouck 201211Patients with chronic obstructive pulmonary diseaseBelgiumOutpatients-
Lips 19963.53.5Elderly peopleNetherlandsOutpatients-
Lips 20100.310.31Elderly people with vitamin D insufficiencyNetherlandsOutpatients-
Lyons 200733Elderly people living in institutional careUKInpatients-
Meier 20040.51Healthy volunteersGermanyOutpatients-
Mochonis 200611Postmenopausal womenGreeceOutpatients-
Ooms 199522Elderly peopleNetherlandsOutpatients-
Ott 198922Postmenopausal womenUSAOutpatients-
Porthouse 200522Elderly womenUKOutpatients-
Prince 200811Elderly women with vitamin D insufficiencyAustraliaOutpatients-
Sanders 20102.962.96Elderly womenAustraliaOutpatients-
Sato 19970.50.5Patients with hemiplegia after strokeJapanOutpatients-
Sato 1999a1.51.5Elderly patients with Parkinson's diseaseJapanOutpatients-
Sato 1999b11Patients with hemiplegia after strokeJapanOutpatients-
Sato 2005a22Elderly women with hemiplegia after strokeJapanOutpatients-
Schleithoff 20060.751.25Patients with congestive heart failureGermanyInpatients-
Smith 200733Elderly peopleUKOutpatients-
Trivedi 200355Elderly peopleUKOutpatients-
Witham 20100.380.38Patients with systolic heart failureUKOutpatients-
Zhu 200855Elderly womenAustraliaOutpatients-

Footnotes

"-" denotes not reported.

Appendix 4. Baseline characteristics (II)

Characteristic

Study ID

Duration of disease
[mean years (SD) /
range]
Sex
[female %]
Age
[mean years (SD) /
range]
Co-medications/
Co-interventions
Co-morbidities
Aloia 2005-10060 (50 to 75)--
Avenell 2004-8377--
Avenell 2012-8577-Low-trauma osteoporotic fracture
in the previous 10 years
Baeksgaard 1998-10062.5 (58 to 67)--
Bischoff 2003-10085.3--
Bjorkman 2007-8284.5 (65 to 104)--
Bolton-Smith 2007-10068  
Brazier 2005-10074.6--
Broe 2007 7389  
Brohult 19732 (2 to 7)6852 (18 to 69)-Rheumatoid arthritis
Burleigh 2007-5983--
Campbell 2005-6883.6 (75 to 96)--
Chapuy 1992-10084 (69 to 106)--
Chapuy 2002-10085 (64 to 99)--
Chel 2008-7784--
Cherniack 2011-280--
Cooper 2003-10056--
Coreless 1985-7882.4--
Daly 2006-061.9--
Dawson-Hughes 1997 5571--
Dukas 2004-5171--
Flicker 2005-9583.4--
Gallagher 2001-10071.5--
Glendenning 2012-10076.7--
Grady 1991-5479.1 (70 to 97)--
Grimnes 2011-4952--
Harwood 2004-10081.2 (67 to 91)--
Jackson 2006-10062.4 (50 to 79)  
Janssen 2010-10080.8--
Komulainen 1999-10052.7 (47 to 56)--
Krieg 1999-10084.5 (62 to 98)--
Kärkkäinen 2010-10067 (65 to 71)--
Lappe 2007-10066.7--
Larsen 2004-6075 (66 to 103)--
Latham 2003-5385 (64 to 99)--
Law 2006-7685--
Lehouck 2012-2068-Chronic obstructive pulmonary
disease
Lips 1996-7480 (70 to 97)--
Lips 2010--78--
Lyons 2007-7684 (62 to 107)--
Meier 2004-6556.5 (33 to 78)--
Mochonis 2006-10060.3 (55 to 65)--
Ooms 1995-10080.3--
Ott 1989-10067.5--
Porthouse 2005-10076.8--
Prince 2008-10077.2 (70 to 90)--
Sanders 2010-10076.0--
Sato 1997-4568.5-Hemiplegia after stroke
Sato 1999a-7870.6 (65 to 88)-Parkinson's disease
Sato 1999b-5670.7IpriflavoneHemiplegia after stroke
Sato 2005a-10074.1-Hemiplegia after stroke
Schleithoff 2006-1751 (50 to 63)-Congestive heart failure
Smith 2007-5479.1--
Trivedi 2003-2474.7 (65 to 85)--
Witham 2010-3479.7-Systolic heart failure
Zhu 2008-10075 (70 to 80)--

Footnotes

"-" denotes not reported

SD: standard deviation

Appendix 5. Matrix of study endpoints

Characteristic

Study ID

Primary endpoint(s)
[time of measurement]
Secondary endpoint(s)
[time of measurement]
Other endpoint(s)
[time of measurement]
Aloia 2005Bone mineral density (6, 12, 18, 24 mo)-Overall mortality (24 mo)
Avenell 2004Recruitment, compliance and retention within a randomised trial (12 mo)-Overall mortality (12 mo)
Avenell 2012FracturesOverall mortality, vascular disease mortality, cancer mortality and cancer occurrence (3.75, 6.2 yr)-
Baeksgaard 1998Bone mineral density (0, 12, 24 moSerum calcium, serum phosphate and serum intact parathyroid hormone (0, 24 mo)Overall mortality (24 mo)
Bischoff 2003FallsMusculoskeletal function and bone remodeling (3 mo)Overall mortality (3 mo)
Bjorkman 2007Parathyroid function and bone mineral density (0, 6 mo)-Overall mortality (6 mo)
Bolton-Smith 2007Bone mineral density (6, 12, 18, 24 mo)Markers of bone turnover and vitamin status (0, 24 mo)Overall mortality (24 mo)
Brazier 2005Bone mineral density (0, 12 mo)Clinical and laboratory safety of treatment (0, 12 mo)Overall mortality (12 mo)
Broe 2007Falls (5 mo)-Overall mortality (5 mo)
Brohult 1973Objective and subjective improvement (12 mo)-Overall mortality (12 mo)
Burleigh 2007Falls (1 mo)-Overall mortality (1 mo)
Campbell 2005Numbers of falls, injuries resulting from falls (3, 6, 12 mo)Costs of implementing the home safety
programme
Overall mortality (3, 6, 12 mo)
Chapuy 1992Fractures (6, 12, 18 mo)Adverse events (6, 12, 18 mo)Overall mortality (18 mo)
Chapuy 2002Biochemical variables of calcium homeostasis, femoral neck bone mineral density and hip fracture risk (3, 6, 9, 12, 15, 18, 21, 24 mo)-Overall mortality (24 mo)
Chel 2008Efficacy of different doses and intervals of oral vitamin D3 supplementation with the same total dose (4 mo)Effect of calcium supplementation following vitamin D supplementation on serum PTH and markers of bone turnover (4 mo)Overall mortality (4 mo)
Cherniack 2011

Serum calcium, 25-hydroxyvitamin D, parathyroid hormone

and 24-hour urinary calcium (6, 12 mo)

-Overall mortality (18 mo)
Cooper 2003Bone mineral density (0, 6, 12, 18, 24 mo)-Overall mortality (24 mo)
Coreless 1985Abilities to carry out basic activities of daily life (2, 9 mo)-Overall mortality (9 mo)
Daly 2006Bone mineral density-Overall mortality (24 mo)
Dawson-Hughes 1997Bone mineral density, biochemical measures of bone metabolism and the incidence of nonvertebral fractures (1, 6, 18, 24, 30, 36 mo)-Overall mortality (36 mo)
Dukas 2004Falls (9 mo)Serum concentrations of 25-hydroxyvitamin D, 1,25
dihydroxyvitamin D and intact parathormone (0, 3, 6 mo)
Overall mortality (9 mo)
Flicker 2005Falls and fractures (24 mo)-Overall mortality (24 mo)
Gallagher 2001Bone mineral density (1.5, 3, 6, 12, 18, 24, 30, 36 mo)-Overall mortality (24 mo)
Glendenning 2012Falls, muscle strength and mobility (0, 3, 6, 9 mo)Serum 25-hydroxyvitamin D levels and adverse events (0, 3, 6, 9 mo)Overall mortality (9 mo)
Grady 1991Muscle strength (1, 2, 4, 8, 12, 18, 24 wk)-Overall mortality (24 mo)
Grimnes 2011Insulin sensitivity and secretion (6 mo)Blood lipid levels (6 mo)Adverse events (6 mo), overall mortality (6 mo)
Harwood 2004Bone biochemical markers, bone mineral density and rate of falls (3, 6, 12 mo)-Overall mortality (12 mo)
Jackson 2006Fractures, cancer occurrence, mortality (3, 7 yr)--
Janssen 2010Muscle strength, power and functional mobility (0, 6 mo)-Overall mortality (6 mo)
Komulainen 1999Bone mineral density (0, 1, 2, 3, 4, 5 yr)-Adverse events (5 yr), overall mortality (5 yr)
Krieg 1999Quantitative ultrasound parameters of bones and metabolic disturbances (0, 12, 24 mo)-Overall mortality (24 mo)
Kärkkäinen 2010Bone mineral density (0, 3 yr)Vitamin D status (0, 3 yr)Overall mortality (0, 3 yr)
Lappe 2007FracturesCancer occurrence (0, 6, 12, 18, 24, 30, 36, 42, 48 mo), vitamin D status (0, 12 mo)Overall mortality (48 mo)
Larsen 2004Falls (3.5 yr)-Overall mortality (3.5 yr)
Latham 2003Physical health (3 mo), falls (6 mo)Physical performance (6 mo), self-rated function (6 mo)Overall mortality (6 mo)
Law 2006Non-vertebral fractures (10 mo), falls (10 mo)-Overall mortality (10 mo)
Lehouck 2012Time to first exacerbation

Exacerbation rate, time to first hospitalisation,

time to second exacerbation, quality of life, overall mortality

-
Lips 1996Fractures (1, 2, 3.5 yr)Overall mortality (3.5 yr)-
Lips 2010Mediolateral body sway with eyes open (4 mo)

Short physical performance battery (4 mo), vitamin D status (4 mo), calcium concentration (4 mo),

phosphate concentration (4 mo), adverse events (4 mo)

-
Lyons 2007Incidence of first fractureHip fractures, fractures at common osteoporotic sites (hip, wrist, forearm, vertebrae) (3 yr), overall mortality (3 yr)-
Meier 2004

Circannual changes in bone turnover and bone mass

(1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 mo)

-Overall mortality (12 mo)
Mochonis 2006Bone mineral density (0, 6, 12 mo)-Overall mortality (12 mo)
Ooms 1995Bone mineral density (0, 6, 12, 18, 24 mo), biochemical markers of bone turnover (0, 6, 12, 18, 24 mo)-Overall mortality (24 mo)
Ott 1989Bone mass (0, 6, 12, 18, 24 mo)Adverse events (24 mo)Overall mortality (24 mo)
Porthouse 2005Fractures (excluding those of the digits, rib, face and skull) (0, 6, 12, 18, 25 mo)Hip fracture; quality of life, visits to the doctor, hospital admissions, falls, fear of falling (0, 6, 12, 18, 25 mo), overall mortality (25 mo)-
Prince 2008Falls (12 mo)Adverse events (12 mo)Overall mortality (12 mo)
Sanders 2010Falls and fractures (3, 9, 15, 24, 27, 36 mo)Adverse events (36 mo)Overall mortality (36 mo)
Sato 1997Bone mineral density, hip fractures (6 mo)-Overall mortality (6 mo)
Sato 1999aNon-vertebral fractures (18 mo)Progression of osteopenia (0, 18 mo)Overall mortality (0, 18 mo)
Sato 1999bBone mineral density (0, 12 mo)-Overall mortality (12 mo)
Sato 2005aFalls (24 mo)Muscular strength, morphological changes of muscle (0, 24 mo)Overall mortality (24 mo)
Schleithoff 2006Overall mortality (15 mo], biochemical variables (15 mo)Left ventricular ejection fraction (15 mo], left ventricular end-diastolic diameter (15 mo), the cardiothoracic ratio (15 mo), maximal oxygen intake (15 mo) and blood pressure (15 mo)Vitamin D status (15 mo)
Smith 2007Non-vertebral fractures (0, 6, 12, 18, 24, 30, 36 mo)Fractures of the hip or wrist, falls (0, 6, 12, 18, 24, 30, 36 mo)Overall mortality (36 mo)
Trivedi 2003Fractures (5 yr], cause-specific mortality (5 yr)Cancer occurrence (5 yr), cardiovascular disease (5 yr)Overall mortality (5 yr)
Witham 2010Six-minute walk test (0, 10, 20 wk)Timed get-up-and-go test (0, 10, 20 wk), daily physical activity levels (0, 10, 20 wk), health status (0, 10, 20 wk), cardiovascular and inflammatory markers (0, 10, 20 wk), adverse events (20 wk)Overall mortality (20 wk)
Zhu 2008Bone mineral density (0, 1, 3, 5 yr], plasma 25-hydroxyvitamin D (0, 1, 3, 5 yr), biomarkers of bone turnover (0, 1, 3, 5 yr), parathyroid hormone (0, 1, 3, 5 yr), intestinal calcium absorption (0, 1, 3, 5 yr)Adverse events (5 yr)Overall mortality (5 yr)

Footnotes

Primary or secondary endpoint(s) refer to verbatim statements in the publication; other endpoints relate to outcomes that were not specified as 'primary' or 'secondary' outcomes in the publication

"-" denotes not reporte

mo: month; wk: weeks; yr: year

Appendix 6. Adverse events

Characteristic

Study ID

Intervention(s) and control(s)Deaths
[n/N]
All adverse events
[n/N (%)]
Severe/serious adverse events
[n/N (%)]
Left study because of adverse events
[n/N (%)]
Aloia 2005I: vitamin D3, calcium1/104-8/104 (7.7)-
C: placebo2/104-7/104 (6.7)-
total: 222  
Avenell 2004I: vitamin D34/70---
C: no intervention3/64---
total: 8 (6)- 
Avenell 2012I: vitamin D3836/2649363/2649 (13.7)--
C: matched placebo881/2643386/2643 (14.6)--
total:  33 (0.6)-
Baeksgaard 1998I: vitamin D3 plus calcium0/802/80 (2.5)--
C: matched placebo1/802/80 (2.5)--
Bischoff 2003I: vitamin D3 plus calcium1/622/62 (3.2)--
C: matched placebo plus calcium4/600/60 (0.0)--
Bjorkman 2007I: vitamin D3 plus calcium27/150---
C: calcium9/68---
Bolton-Smith 2007I: vitamin D3 plus calcium0/62---
C: matched placebo1/60---
Brazier 2005I: vitamin D3 plus calcium3/9515/95 (15.8)8/95 (8.4)8/95 (8.4)
C: matched placebo1/9717/97 (17.5)10/97 (10.3)10/97 (10.3)
Broe 2007I: vitamin D25/99---
C: matched placebo2/25---
Brohult 1973I: vitamin D31/253/25 (12.0)1/25 (4.0)0/25 (0.0)
C: placebo0/250/25 (0)0/25 (0)0/25 (0.0)
Burleigh 2007I: vitamin D3 plus calcium16/1044/101 (4.0)0/101 (0.0)1/101 (1.0)
C: matched placebo vitamin D3 plus calcium13/1043/104 (2.9)0/104 (0.0)0/104 (0.0)
Campbell 2005I: home safety programme6/195---
C: social visits10/196---
Chapuy 1992I: vitamin D3 plus calcium893/163440/1634 (2.4)40/1634 (2.4)40/1634 (2.4)
C: double placebo917/163628/1636 (1.7)28/1636 (1.7)28/1636 (1.7)
Chapuy 2002I1: vitamin D3 plus calcium70/38927/389 (6.9)3/389 (0.8)-
I2: vitamin D3 plus calcium46/19416/194 (8.2)0/194 (8.2)-
C: double placebo  6/583 (1.0)6/583 (1.0)
Chel 2008I: vitamin D3----
C: matched placebo----
Cherniack 2011I: vitamin D3 plus calcium1/234/23 (17.4)3/23 (13.0)3/23 (13.0)
C: matched placebo plus calcium0/234/23 (17.4)4/23 (17.4)4/23 (17.4)
Cooper 2003I: vitamin D2 plus calcium0/938/93 (8.6)-8/93 (8.6)
C: calcium1/941/94 (1.1)-1/94 (1.1)
total:  6/187 (3.2) 
Coreless 1985I: vitamin D28/413/41 (7.3)1/41 (2.4)1/41 (2.4)
C: matched placebo8/410/41 (0.0)0/41 (0.0)0/41 (0.0)
Daly 2006I: calcium-vitamin D3–fortified milk plus calcium1/859/85 (10.6)9/85 (10.6)9/85 (10.6)
C: no intervention0/822/82 (2.4)2/82 (2.4)2/82 (2.4)
Dawson-Hughes 1997I: vitamin D3 plus calcium2/1876/187 (3.2)6/187 (3.2)6/187 (3.2)
C: placebo2/2023/202 (1.5)3/202 (1.5)3/202 (1.5)
Dukas 2004I: alfacalcidol1/19275/192 (39.0)0/192 (0.0)0/192 (0.0)
C: placebo1/18682/186 (44.1)0/186 (0.0)0/186 (0.0)
Flicker 2005I: vitamin D3 plus calcium----
C: calcium----
Gallagher 2001I: calcitriol2/12387/123 (71.0)55/123 (45.0)-
C: matched placebo1/12356/123 (45.5)46/123 (37.0)-
Glendenning 2012I: cholecalciferol 150,000 three-monthly2/35324/353 (6.8)19/353 (5.4)-
C: placebo vitamin D three-monthly0/33321/333 (6.3)15/333 (4.5)-
Grady 1991I: calcitriol1/507/50 (14.0)7/50 (14.0)-
C: placebo vitamin D0/482/48 (4.2)2/48 (4.2)-
Grimnes 2011I: vitamin D30/5145/51 (88.0)--
C: placebo1/5346/53 (87.0)--
Harwood 2004I: vitamin D2 plus calcium24/113--0/113 (0.0)
C: no intervention5/37--0/37 (0.0)
Jackson 2006I: vitamin D3 plus calcium744/18176449/18,176 (2.5)449/18,176 (2.5)-
C: matched placebo807/18106381/18,106 (2.1)381/18,106 (2.1)-
Janssen 2010I: vitamin D3 plus calcium0/36---
C: matched placebo vitamin D3 plus calcium0/34---
Komulainen 1999I: vitamin D3 plus calcium0/116-5/116 (4.3)-
C: placebo1/116-4/116 (3.4)-
Krieg 1999I: vitamin D3 plus calcium21/12421/12410/124 (8.1)-
C: no treatment26/12426/1242/124 (1.6)-
Kärkkäinen 2010I: vitamin D3 plus calcium15/171817/1718 (0.99)--
C: no intervention13/17140/1714 (0.0)--
Lappe 2007I: vitamin D3 plus calcium4/4461/446 (0.2)13/446 (2.9)-
C: calcium plus vitamin D placebo18/7334/733 (0.5)20/733 (2.7)-
Larsen 2004I: home safety inspection832/4957---
C: vitamin D3 plus calcium839/4648---
Latham 2003I: vitamin D311/121---
C: matched placebo3/122---
Law 2006I: vitamin D2347/1762-28/1762 (1.6)28/1762 (1.6)
C: no intervention322/1955-1955 (0.0)1955 (0.0)
Lehouck 2012I: vitamin D39/914/91 (4.4)--
C: matched placebo6/910/91 (0.0)--
Lips 1996I: vitamin D3282/1291---
C: matched placebo306/1287---
Lips 2010I: vitamin D31/11424/114 (21.0)3/114 (2.6)3/114 (2.6)
C: matched placebo0/11226/112 (23.2)2/112 (2.7)2/112 (2.7)
Lyons 2007I: vitamin D2947/1725---
C: matched placebo953/1715---
Meier 2004I: vitamin D3 (500 IU) orally, daily0/30---
C: no intervention1/25---
Mochonis 2006I: vitamin D3 plus calcium0/420/42 (0.0)-0/42 (0.0)
C: no intervention1/704/70 (5.7)-4/70 (5.7)
Ooms 1995I: vitamin D311/1772/177 (1.1)--
C: matched placebo21/1710/171 (0.0)--
Ott 1989I: vitamin D3 plus calcium0/4311/43 (25.6)--
C: matched placebo vitamin D plus calcium1/431/43 (2.3)--
Porthouse 2005I: vitamin D3 plus calcium57/1321---
C: no intervention68/1993---
Prince 2008I: vitamin D2 plus calcium0/151---
C: matched placebo tablet of vitamin D plus calcium1/151---
Sanders 2010I: vitamin D340/1131223/1131 (19.7)244/1131 (19.7)-
C: matched placebo tablet47/1127201/1127 (17.8)207/1127 (17.8)-
Sato 1997I: vitamin D (alfacalcidol) plus calcium1/45---
C: matched placebo tablets of vitamin D and calcium1/39---
Sato 1999aI: vitamin D (alfacalcidol)1/43---
C: matched placebo tablet of vitamin D0/43---
Sato 1999bI: vitamin D (alfacalcidol)0/34---
C: matched placebo tablet of vitamin D1/35---
Sato 2005aI: vitamin D21/48---
C: matched placebo tablet of vitamin D2/48---
Schleithoff 2006I: vitamin D3 2000 IU plus calcium 500 mg orally, daily7/61---
C: matched placebo vitamin D plus calcium6/62---
Smith 2007I: vitamin D2355/4727---
C: matched placebo intramuscular injection354/4713---
Trivedi 2003I: vitamin D3224/1345---
C: matched placebo vitamin D247/1341---
Witham 2010I: vitamin D2 (10,000 IU) orally, daily4/5320/53 (37.7)--
C: matched placebo tablet2/5225/52 (48.1)--
Zhu 2008I: vitamin D2 plus calcium0/39---
C: calcium plus placebo vitamin D2/81---

Footnotes

"-" denotes not reported

C: control; I: intervention

What's new

DateEventDescription
5 April 2012New search has been performedThe present review version is an update of the review published in 2011 (Bjelakovic 2011).
4 April 2012New citation required but conclusions have not changedNew searches were performed in February 2012. We found and included six new randomised clinical trials with 1138 participants.

Contributions of authors

Goran Bjelakovic (GB): performed the literature search, data extraction and statistical analyses and drafted the review.
Lise Lotte Gluud (LLG): performed data extraction and revised the review.
Dimitrinka Nikolova (DN): performed data extraction and revised the review.
Kate Whitfield (KW): developed the search strategy, performed data extraction and revised the review.
Jørn Wetterslev (JW): performed data extraction and revised the review.
Rosa G Simonetti (RGS): performed data extraction and revised the review.
Marija Bjelakovic (MB) performed data extraction and revised the review.
Christian Gluud (CG): initiated the systematic review, acted as arbiter for disagreements and revised the review.

Declarations of interest

None known.

Sources of support

Internal sources

  • The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Denmark.

External sources

  • Ministry of Science Republic of Serbia, Serbia.

Differences between protocol and review

Difference between the last published review version and the present review version

We interpreted our results much more conservatively as the result of extensive discussion of the validity of our results among the review authors.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Aloia 2005

MethodsRandomised, double-blind, placebo-controlled trial using parallel group design (two intervention groups).
Participants

Country: United States.

Number of participants randomised: 208 healthy calcium-replete, black postmenopausal African American women, 50 to 75 (mean 60) years of age. African American ancestry of the participants was assessed by self-declaration that both parents and at least three of four grandparents were African American.

Inclusion criteria: ambulatory postmenopausal African American women not receiving hormone therapy.

Exclusion criteria: previous treatment with bone active agents and any medication or illness that affects skeletal metabolism.

Interventions

Participants were randomly assigned to receive:

Intervention group: vitamin D3 (800 IU) plus calcium (1200 to 1500 mg) daily, (n = 104);

Control group: matched placebo plus calcium (1200 to 1500 mg) daily, (n = 104);

for a two-year period.

After two years, the vitamin D3 dose was increased to 2000 IU daily in the intervention group, and the trial continued for an additional year. The calcium supplements were provided as calcium carbonate.

OutcomesThe primary outcome measure was the bone mineral density of the total hip.
Stated aim of study"To examine the effect of vitamin D3 supplementation on bone loss in African American women."
Notes

"81 participants from the intervention group and 78 participants form the control group completed two years in the trial.

81 participants from the intervention group switched to vitamin D3 2000 IU daily plus 1200 to 1500 mg of calcium daily after two years.

78 participants from the control group switched to matched placebo plus 1200 to 1500 mg of calcium daily after two years.

74 participants from the intervention group completed 36 months of trial.

74 participants from the control group completed 36 months of the trial.

A total of 222 adverse events were reported in the trial over three years. There were 15 serious adverse events, eight in the intervention group and seven in the control group.

Mean pill count compliance was 87% ± 8% of vitamin D3 pills consumed after the randomisation visit."

Vitamin D3 capsules and matched placebo capsules were custom manufactured for the trial (Tishcon Corp, Westbury, NY). Vitamin D3 content was also analysed in an independent laboratory (Vitamin D, Skin, and Bone Research Laboratory, Department of Medicine, Boston University School of Medicine, Boston, Mass). The calcium supplements were provided as calcium carbonate."

Additional information on the risk of bias domains was received through personal communication with Dr John F Aloia (30.01.2009; 03.02.2009).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSequence generation was achieved using computer random number generation.
Allocation concealment (selection bias)Low riskAllocation was controlled by a central and independent randomisation unit so that intervention allocations could not have been foreseen in advance of, or during, enrolment.
Blinding (performance bias and detection bias)
All outcomes
Low riskThe trial was described as blinded, the parties that were blinded, and the method of blinding was described, so that knowledge of allocation was adequately prevented during the trial.
Incomplete outcome data (attrition bias)
All outcomes
Low riskThe numbers and reasons for dropouts and withdrawals in all intervention groups were described.
Selective reporting (reporting bias)Low riskPre-defined, or clinically relevant and reasonably expected outcomes are reported on.
Industry biasUnclear riskVitamin D3 capsules and matched placebo capsules were custom manufactured for the trial (Tishcon Corp, Westbury, NY).
Other biasLow riskThe trial appears to be free of other components that could put it at risk of bias.

Avenell 2004

MethodsRandomised clinical trial using 2 x 2 factorial design.
Participants

Country: United Kingdom.

Number of participants randomised: 134, aged 70 years or over (mean age 77), 83% women.

Inclusion criteria: people aged 70 years or over with an osteoporotic fracture within the last 10 years.

Exclusion criteria: daily oral treatment with more than 200 IU (5 µg) vitamin D or more than 500 mg calcium or other bone active medications.

Interventions

Participants were randomly assigned to receive:

Intervention group 1: vitamin D3 (800 IU) daily (n = 35);

Intervention group 2: calcium (1000 mg) daily (n = 29);

Intervention group 3: vitamin D3 (800 IU) plus calcium (1000 mg) daily (n = 35);

Intervention group 4 (Control group): no tablets daily (n = 35);

for a one-year period.

The calcium supplements were provided as calcium carbonate.

OutcomesPrimary outcomes were recruitment, compliance, and retention within a randomised trial.
Stated aim of study"To assess the effects of an open trial design (without placebo and participants knowing what tablets they were given) when compared with a blinded, placebo-controlled design on recruitment, compliance, and retention within a randomised trial of secondary osteoporotic fracture prevention."
Notes

"All participants were asked to return unconsumed tablets for a tablet count compliance. Compliance amongst those who returned their tablet containers was similar (overall 85% versus 84.5% of tablet takers took their tablets on more than 80% of days). The same pattern was observed for self-reported tablet consumption at four, eight or 12 months during the trial."

"Shire Pharmaceuticals funded the capsules, which were co-funded and manufactured by Nycomed."

Additional information on mortality was received through personal communication with Dr Alison Avenell (28.01.2009).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSequence generation was achieved using computer random number generation.
Allocation concealment (selection bias)High riskParticipants were told to which compound they had been allocated.
Blinding (performance bias and detection bias)
All outcomes
High riskTrial was not blinded, so that the allocation was known during the trial. Participants were told to which compound they had been allocated. Placebo was not used.
Incomplete outcome data (attrition bias)
All outcomes
Low riskThe numbers and reasons for dropouts and withdrawals in all intervention groups were described.
Selective reporting (reporting bias)Low riskPre-defined, or clinically relevant and reasonably expected outcomes are reported on.
Industry biasUnclear risk"Shire Pharmaceuticals funded the capsules, which were co-funded and manufactured by Nycomed."
Other biasLow riskThe trial appears to be free of other components that could put it at risk of bias.

Avenell 2012

Methods

Randomised Evaluation of Calcium Or vitamin D (RECORD).

Multicentre, randomised, double-blind, placebo-controlled trial using 2 x 2 factorial design.

Participants

Country: United Kingdom.

Number of participants randomised: 5292 people (85% women) aged 70 and over (mean 77 years) with low-trauma, osteoporotic fracture in the previous 10 years.

Inclusion criteria: elderly people aged 70 years or older, who were mobile before developing a low-trauma fracture.

Exclusion criteria: bed or chair bound before fracture; cognitive impairment indicated by an abbreviated mental test score of less than seven; cancer in the past 10 years that was likely to metastasise to bone; fracture associated with pre-existing local bone abnormality; those known to have hypercalcaemia; renal stone in the past 10 years; life expectancy of less than 6 months; individuals known to be leaving the United Kingdom; daily intake of more than 200 IU vitamin D or more than 500 mg calcium supplements; intake in the past 5 years of fluoride, bisphosphonates, calcitonin, tibolone, hormone-replacement therapy, selective oestrogen-receptor modulators, or any vitamin D metabolite (e.g., calcitriol); and vitamin D by injection in the past year.

Interventions

Participants were randomly assigned to receive:

Intervention group 1: vitamin D3 (800 IU) daily (n = 1343);

Intervention group 2: calcium (500 mg) daily (n = 1311);

Intervention group 3: vitamin D3 (800 IU) plus calcium (500 mg) daily (n = 1306);

Intervention group 4 (Control group): matched placebo tablets (n = 1332);

for a 45 month period.

Participants were followed for a period of 6.2 years.

Tablets varied in size and taste, and thus each had matching placebos.

OutcomesThe primary outcome measure was all-new low-energy fractures including clinical, radiologically confirmed vertebral fractures, but not those of the face or skull.
Stated aim of study"To assess whether vitamin D3 and calcium, either alone or in combination, were effective in prevention of secondary fractures."
Notes

"Compliance was measured by a postal questionnaire sent every four months, in which participants were asked how many days of the past seven days they had taken tablets. A randomly selected 10% sample was asked to return unused tablets for pill counting.

Based on questionnaire responses at 24 months, 2886 (54,5%) of 5292 were still taking tablets. Throughout the trial about 80% of those taking tablets did so on more than 80% of days, which is consistent with pill counts in the subsample (data not shown). However, the number who were taking any tablets fell over time. At 24 months, 2268 of 4841 (46,8%), who returned questionnaires, had taken pills on more than 80% of days."

Shire Pharmaceuticals co-funded the drugs, with Nycomed, who also manufactured the drugs.

Additional information received through personal communication with Dr Alison Avenell (02.02.2009).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSequence generation was achieved using computer random number generation.
Allocation concealment (selection bias)Low riskAllocation was controlled by a central and independent randomisation unit so that intervention allocations could not have been foreseen in advance of, or during, enrolment. "Allocation was controlled by a central and independent randomisation unit. The allocation programme was written by the trial programmer and the allocation remained concealed until the final analyses (other than for confidential reports to the data monitoring committee)."
Blinding (performance bias and detection bias)
All outcomes
Low riskThe trial was described as blinded, the parties that were blinded, and the method of blinding was described, so that knowledge of allocation was adequately prevented during the trial.
Incomplete outcome data (attrition bias)
All outcomes
Low riskThe numbers and reasons for dropouts and withdrawals in all intervention groups were described.
Selective reporting (reporting bias)Low riskPre-defined, or clinically relevant and reasonably expected outcomes are reported on.
Industry biasUnclear riskShire Pharmaceuticals co-funded the drugs, with Nycomed, who also manufactured the drugs.
Other biasLow riskThe trial appears to be free of other components that could put it at risk of bias.

Baeksgaard 1998

MethodsRandomised, double-blind, placebo-controlled trial using parallel group design (three intervention groups).
Participants

Country: Denmark.

Number of participants randomised: 240 healthy postmenopausal women, 58 to 67 (mean 62.5) years of age.

Inclusion criteria: Caucasian background, age 58 to 67 years, good general health and postmenopausal status defined as cessation of menstrual bleeding for at least six months.

Exclusion criteria: treatment with oestrogen or calcitonin during the previous 12 months or with bisphosphonates in the previous 24 months, presence of diseases known to affect bone metabolism, renal disease with serum creatinine above 120 mmol/L, and hepatic disease with increased alanine aminotransferase and/or decreased extrinsic coagulation factors II, VII and X.

Interventions

Participants were randomly assigned to receive:

Intervention group 1: vitamin D3 (560 IU) plus calcium 1000 mg daily, (n = 80);

Intervention group 2: vitamin D3 (560 IU) plus calcium (1000 mg) plus multivitamin containing retinol 800 μg; thiamine 1.4 mg; riboflavine 1.6 mg; pyridoxine 2 mg; cyanocobalamin 1 μg; folic acid 100 μg; niacin 18 mg; pantothenic acid 6 mg; biotin 150 μg; ascorbic acid 60 mg; D-alpha tocopherol 10 mg; and phylloquinone 70 μg; daily, (n = 80);

Intervention group 3 (Control group): matched placebo in a similar combination daily (n = 80);

for a two-year period.

Participants were asked to take no calcium or vitamin D supplement other than the supplement supplied for the trial.

Calcium was in the form of calcium carbonate.

OutcomesThe primary outcome was changes from baseline in the bone mineral density (BMD) in the lumbar spine (L2–4). Secondary outcome measures were hip BMD, forearm BMD, serum calcium, serum phosphate and serum intact parathyroid hormone.
Stated aim of study"To evaluate the effect of vitamin D supplement and a calcium supplement plus or minus multivitamins on bone loss at the hip, spine, and forearm."
Notes

"For all variables measured, authors observed no significant differences between the two experimental intervention groups. In presenting the results, authors, therefore, considered the two groups as one group. During the trial, 41 of the 240 women dropped out. No significant difference in drop-out rate was found between the groups. One hundred and ninety-nine women completed all visits. In the analysis, an additional two women were excluded due to development of radiologically verified vertebral fractures in the lumbar spine.

No formal assessment of compliance, such as tablet counting, was made. At each visit, the participants were questioned about their compliance with the trial medication and encouraged to comply."

All placebo and active treatment tablets were provided by Lube Ltd.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThe trial is described as randomised but the method of sequence generation was not specified.
Allocation concealment (selection bias)Unclear riskThe trial was described as randomised but the method used to conceal the allocation was not described, so that intervention allocations may have been foreseen in advance of, or during, enrolment.
Blinding (performance bias and detection bias)
All outcomes
Low riskThe trial was described as blinded, the parties that were blinded, and the method of blinding was described, so that knowledge of allocation was adequately prevented during the trial. 
Incomplete outcome data (attrition bias)
All outcomes
Low riskThe numbers and reasons for dropouts and withdrawals in all intervention groups were described
Selective reporting (reporting bias)Unclear riskNot all pre-defined or clinically relevant and reasonably expected outcomes are reported on.
Industry biasUnclear riskAll placebo and active treatment tablets were provided by Lube Ltd.
Other biasLow riskThe trial appears to be free of other components that could put it at risk of bias.

Bischoff 2003

MethodsRandomised, double-blind, controlled trial using parallel group design (two intervention groups).
Participants

Country: Switzerland.

Number of participants randomised: 122 elderly women in long-stay geriatric care, aged 60 years or older (mean age 85.3 years).

Inclusion criteria: age 60 or older and the ability to walk three meters with or without a walking aid.

Exclusion criteria: primary hyperparathyroidism, hypocalcaemia, hypercalciuria, renal insufficiency, and fracture or stroke within the last three months, any treatment with hormone replacement therapy, calcitonin, fluoride, or bisphosphonates during the previous 24 months.

Interventions

Participants were randomly assigned to receive:

Intervention group 1: vitamin D3 (800 IU) plus calcium 1200 mg daily (n = 62);

Intervention group 2 (Control group): calcium 1200 mg daily (n = 60);

for a three-month period.

OutcomesThe primary outcome measure was number of falls per person. Secondary outcome measures were musculoskeletal function and bone remodeling.
Stated aim of study"To evaluate hypothesis that higher vitamin D serum levels may increase muscle strength and reduce the number of falls."
Notes

"Tablets containing vitamin D and calcium or calcium alone were taken in the presence of the trial nurse to ensure compliance."

The trial was supported by Strathmann AG, Germany.

Authors reported deaths but not according to intervention group of the trial. All-cause mortality data was taken from a Cochrane systematic review prepared by Avenell et al (Avenell 2009) who obtained mortality data by personal communication with Bischoff trial authors.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThe trial is described as randomised but the method of sequence generation was not specified.
Allocation concealment (selection bias)Low riskAllocation was controlled by sealed envelopes so that intervention allocations could not have been foreseen in advance of, or during, enrolment.
Blinding (performance bias and detection bias)
All outcomes
Low riskThe trial was described as blinded, the parties that were blinded, and the method of blinding was described, so that knowledge of allocation was adequately prevented during the trial. "Tablets in both groups had an identical appearance. Participants, nurses, and all investigators were blinded to the intervention assignment throughout the trial."
Incomplete outcome data (attrition bias)
All outcomes
Low riskThe numbers and reasons for dropouts and withdrawals in all intervention groups were described.
Selective reporting (reporting bias)Low riskPre-defined, or clinically relevant and reasonably expected outcomes are reported on.
Industry biasHigh riskThe trial was supported by Strathmann AG, Germany.
Other biasLow riskThe trial appears to be free of other components that could put it at risk of bias.

Bjorkman 2007

MethodsRandomised, double-blind, placebo-controlled trial using parallel group design (three intervention groups).
Participants

Country: Finland.

Number of participants randomised: 218 chronically bedridden patients (81.7 % women), 65 to 104 (mean 84.5) years of age.

Inclusion criteria: age over 65 years, chronically impaired mobility, stable general condition, and no known present disease (except osteoporosis) or medication (vitamin D supplements, glucocorticoids, antiepileptics, etc.) affecting calcium or bone metabolism.

Exclusion criteria: markedly elevated creatinine levels (> 125 µmol/L) hypercalcaemia (ionised calcium > 1.32 mmol/L), hypothyroidism (thyrotropin > 5.3 mU/L) or hyperthyroidism (thyrotropin < 0.2 mU/L).

Interventions

Participants were randomly assigned to receive:

Intervention group 1: vitamin D3 (1200 IU) daily, (n = 73); 17 participants from this group received calcium 500 mg daily;

Intervention group 2: vitamin D3 (400 IU) daily, (n = 77); 11 participants from this group received calcium 500 mg daily;

Intervention group 3 (Control group): matched placebo vitamin D3 (0 IU) daily (n = 68), 15 participants from this group received calcium 500 mg daily;

for a six-month period.

"Participants received vitamin D3 (Vigantol, Merck KGaA, Darmstadt, Germany 20,000 IU/ml in Migliol oil) in doses of 0 µg, 140 µg, or 420 µg (groups 1, 2, 3) every 2 weeks, equivalent with average daily intakes of 0 IU, 400 IU, or 1200 IU. To ensure that all three groups received identical volumes (26 drops = 0.84 ml), medication oil was diluted three-fold with Migliol oil in group 2, and group 1 received plain Migliol oil. Furthermore, the oil was swallowed entirely in the presence of the nurse and given with a small amount of food or drink, if necessary."

"Before the start of the intervention, the use of dairy products was roughly evaluated to be insufficient among 40 patients, who received a daily calcium carbonate substitution of 500 mg during the intervention. Three other patients also received a previous daily medication of 500 mg calcium carbonate at entry, which they continued to receive through the intervention."

OutcomesThe primary outcome measures were parathyroid function and bone turnover.
Stated aim of study"To evaluate the effects of vitamin D supplementation on parathyroid function and bone turnover in aged, chronically immobile patients."
Notes

"Vitamin D supplementation was well tolerated. One patient, however, developed a mild hypercalcaemia (ionised calcium from 1.24 to 1.40 mmol/L) in group 3."

Treatment agents were produced by Vigantol, Merck KGaA, Darmstadt, Germany.

Authors did not provide data about compliance.

Additional information on the risk of bias domains was received through personal communication with Dr Mikko Björkman (31.01.2009).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSequence generation was achieved using computer random number generation.
Allocation concealment (selection bias)Low risk"Allocation was controlled by coded bottles. Each bottle was individually coded to blind the participants and the ward nurses of not only the content of the bottles but also of the group labels (1, 2, 3)."
Blinding (performance bias and detection bias)
All outcomes
Low riskThe trial was described as blinded, the parties that were blinded, and the method of blinding was described, so that knowledge of allocation was adequately prevented during the trial. 
Incomplete outcome data (attrition bias)
All outcomes
Low riskThe numbers and reasons for dropouts and withdrawals in all intervention groups were described.
Selective reporting (reporting bias)Low riskPre-defined, or clinically relevant and reasonably expected outcomes are reported on.
Industry biasUnclear riskTreatment agents were produced by Vigantol, Merck KGaA, Darmstadt, Germany.
Other biasLow riskThe trial appears to be free of other components that could put it at risk of bias.

Bolton-Smith 2007

MethodsRandomised, double-blind, placebo controlled trial using 2 x 2 factorial design.
Participants

Country: United Kingdom.

Number of participants randomised: 244 healthy, non-osteoporotic women, aged 60 years or over (mean 68).

Inclusion criteria: healthy, non-osteoporotic women, aged 60 years or over.

Exclusion criteria: clinical osteoporosis or chronic disease (e.g., diabetes mellitus, cardiovascular disease, cancer, fat malabsorption syndromes), routine medication that interferes with vitamin K, vitamin D, or bone metabolism (notably warfarin and steroids), and consumption of nutrient supplements that provided in excess of 30 µg vitamin K, 400 IU vitamin D, or 500 mg calcium daily.

Interventions

Participants were randomly assigned to receive:

Intervention group 1: vitamin D3 (400 IU) plus calcium 1000 mg daily, (n = 62);

Intervention group 2: vitamin D3 (400 IU) plus calcium 1000 mg plus vitamin K1 200 μg daily, (n = 61);

Intervention group 3: vitamin K1 200 μg daily (n = 60);

Intervention group 4 (Control group): matched placebo daily (n = 61);

for a two-year period.

OutcomesThe primary outcome measure was bone mineral density. Secondary outcome measure was possible interaction with vitamin K, of vitamin D and calcium.
Stated aim of study"The putative beneficial role of high dietary vitamin K1 (phylloquinone) on bone mineral density and the possibility of interactive benefits with vitamin D were studied."
Notes

"Of the 244 eligible women randomised in the trial, 209 (85.6%) completed the two-year trial. Compliance with the trial intervention was good based on pill count (median, 99; interquartile range, 97.3 to 99.8%)."

Hoffmann-La Roche (Basel, Switzerland) provided the supplementation tablets.

Additional information on mortality, adverse events, and risk of bias domains was received through personal communication with Dr Martin J Shearer (03.02.2009; 05.02.2010).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSequence generation was achieved using computer random number generation.
Allocation concealment (selection bias)Low riskAllocation was controlled by a central and independent randomisation unit so that intervention allocations could not have been foreseen in advance of, or during, enrolment. "An independent statistician at Hoffmann-La Roche, who had no other connection to the trial, provided a randomisation list to the researchers."
Blinding (performance bias and detection bias)
All outcomes
Low riskThe trial was described as blinded, the parties that were blinded, and the method of blinding was described, so that knowledge of allocation was adequately prevented during the trial.
Incomplete outcome data (attrition bias)
All outcomes
Low riskThe numbers and reasons for dropouts and withdrawals in all intervention groups were described.
Selective reporting (reporting bias)Low riskPre-defined, or clinically relevant and reasonably expected outcomes are reported on.
Industry biasUnclear riskHoffmann-La Roche (Basel, Switzerland) provided the supplementation tablets.
Other biasLow riskThe trial appears to be free of other components that could put it at risk of bias.

Brazier 2005

MethodsMulticentre, randomised, double-blind, placebo-controlled trial using parallel group design (two intervention groups).
Participants

Country: France.

Number of participants randomised: 192 women with a 25-hydroxyvitamin D level ≤ 12 ng/mL, mean age 74.6 years.

Inclusion criteria: community-dwelling ambulatory women aged > 65 years who spontaneously consulted a practitioner and presented with vitamin D insufficiency (i.e., serum 25-hydroxy vitamin D ≤ 12 ng/mL).

Exclusion criteria: hypercalcaemia (serum calcium > 2.62 mmol/L), primary hyperparathyroidism, renal insufficiency (serum creatinine >130 pmol/L), hepatic insufficiency, treatment with a bisphosphonate, calcitonin, vitamin D or its metabolites, oestrogen, raloxifene, fluoride, anticonvulsives, or any other drug acting on bone metabolism (e.g., glucocorticoids) in the past six months.

Interventions

Participants were randomly assigned to receive:

Intervention group 1: vitamin D3 (800 IU) plus calcium (1000 mg) daily (n = 95);

Intervention group 2 (Control group): matched placebo tablets (n = 97);

for a one-year period.

OutcomesThe primary outcome was to assess the effects of vitamin D3 plus calcium on bone mineral density and biochemical markers of bone formation and resorption. Secondary outcome was to evaluate the clinical and laboratory safety of treatment.
Stated aim of study"An evaluation of the clinical and laboratory safety of a one-year course of treatment with a combination vitamin D and calcium tablets in ambulatory women aged > 65 years with vitamin D insufficiency."
Notes

Fifty women (21/95 vitamin D plus calcium, 29/97 placebo) were prematurely withdrawn from the trial for various reasons. Treatment-related adverse events were reported in 21 and 23 women in the respective intervention groups. These events consisted mainly of metabolic disorders (9 and 10), particularly hypercalcaemia (6 and 8) and gastrointestinal disorders (9 and 8).

"Treatment compliance was assessed at each visit based on counts of the number of tablets taken compared with the number that was to be taken. Compliance at each visit ranged from a median of 93% to 94% in the vitamin D plus calcium group and from 93% to 96.5% in the placebo group. Global compliance was 92% in the vitamin D plus calcium group and 92.5% in the placebo group. No significant difference in compliance was observed between the two groups at any visit."

This trial was supported by Innothera Laboratories, Arcueil, France.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSequence generation was achieved using computer random number generation.
Allocation concealment (selection bias)Unclear riskThe trial was described as randomised but the method used to conceal the allocation was not described, so that intervention allocations may have been foreseen in advance of, or during, enrolment.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskThe trial was described as double blind, but the method of blinding was not described, so that knowledge of allocation was possible during the trial.
Incomplete outcome data (attrition bias)
All outcomes
Low riskThe numbers and reasons for dropouts and withdrawals in all intervention groups were described.
Selective reporting (reporting bias)Low riskPre-defined, or clinically relevant and reasonably expected outcomes are reported on.
Industry biasHigh riskThis trial was supported by Innothera Laboratories, Arcueil, France.
Other biasLow riskThe trial appears to be free of other components that could put it at risk of bias.

Broe 2007

MethodsRandomised, double-blind, placebo-controlled trial using parallel group design (five intervention groups).
Participants

Country: United States.

Number of participants randomised: 124 nursing home residents (73% women), mean 89 years of age.

Inclusion criteria: a life expectancy of at least six months, the ability to swallow medication, and three months residency at Hebrew Rehabilitation Center for the Aged.

Exclusion criteria: use of glucocorticoids, anti-seizure medication, or pharmacological doses of vitamin D; calcium metabolism disorders; severe mobility limitations; or fracture within the previous six months.

Interventions

Participants were randomly assigned to receive:

Intervention group 1: vitamin D2 (800 IU) daily (n = 23);

Intervention group 2: vitamin D2 (600 IU) daily (n = 25);

Intervention group 3: vitamin D2 (400 IU) daily (n = 25);

Intervention group 4: vitamin D2 (200 IU) daily (n = 26);

Intervention group 5 (Control group): matched placebo tablets daily (n = 25);

for a five-month period.

OutcomesThe primary outcome measure was effect of the vitamin D doses on falls over the trial period.
Stated aim of study"To determine the effect of four vitamin D supplement doses on the risk of falls in elderly nursing home residents."
Notes

"Over the 5-month trial period, 114 completed the trial. Of the 10 participants who did not complete the trial, seven died and three withdrew. There were no significant differences between the intervention groups in the number who did not complete the 5-month trial period with a loss of one to three participants from each intervention group."

"Compliance was calculated as the number of pills taken, as determined according to blister pack counts after the completion of the trial divided by the total days a participant was actively participating (alive, living at Hebrew Rehabilitation Center for Aged, not withdrawn from the trial)."

"Average compliance was 97.6%, with only two participants having a compliance level of less than 50%. Compliance did not differ between the intervention groups."

The vitamin D2 tablets were purchased from Tishcon Corporation (Westbury, NY). Vitamin D content of the supplements was verified at the BU Vitamin D Laboratory.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSequence generation was achieved using computer random number generation.
Allocation concealment (selection bias)Low riskAllocation was controlled by a central and independent randomisation unit so that intervention allocations could not have been foreseen in advance of, or during, enrolment. "The pharmacy of The Hebrew Rehabilitation Center for the Aged randomised participants in blocks of 15 to one of the five intervention groups."
Blinding (performance bias and detection bias)
All outcomes
Low riskThe trial was described as blinded, the parties that were blinded, and the method of blinding was described, so that knowledge of allocation was adequately prevented during the trial. "The pharmacy labelled pill blister packs with names and patient identification numbers only. Blister packs and tablets from all five groups were identical in appearance and taste, so nursing staff, participants, and the trial team were unaware of the group assignment."
Incomplete outcome data (attrition bias)
All outcomes
Low riskThe numbers and reasons for dropouts and withdrawals in all intervention groups were described.
Selective reporting (reporting bias)Low riskPre-defined, or clinically relevant and reasonably expected outcomes are reported on.
Industry biasUnclear riskThe vitamin D2 tablets were purchased from Tishcon Corporation (Westbury, NY).
Other biasLow riskThe trial appears to be free of other components that could put it at risk of bias.

Brohult 1973

MethodsRandomised, double-blind, controlled trial using parallel group design (two intervention groups).
Participants

Country: Sweden.

Number of participants randomised: 100 (68 % women), aged 18 to 69 years (mean age 52).

Inclusion criteria: ambulatory patients with rheumatoid arthritis of at least two years duration.

Exclusion criteria: patients with steroid, gold, or antimalaria therapy.

Interventions

Participants were randomly assigned to receive:

Intervention group 1: vitamin D3 (100,000 IU) daily (n = 25);

Intervention group 2 (Control group): placebo daily (n = 25);

for a one year period.

OutcomesThe primary outcomes were subjective an objective improvement.
Stated aim of studyTo determine the effect of vitamin D supplementation on objective and subjective improvement of patients with rheumatoid arthritis.
NotesThe trial was supported financially by a grant from Ekhagastiftelsen.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThe trial is described as randomised, but the method of sequence generation was not specified.
Allocation concealment (selection bias)Unclear riskThe trial was described as randomised, but the method used to conceal the allocation was not described so that intervention allocations may have been foreseen in advance of, or during, enrolment.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskThere is insufficient information to assess whether the type of blinding used is likely to induce bias on the estimate of effect.
Incomplete outcome data (attrition bias)
All outcomes
Low riskThe underlying reasons for missing data are unlikely to make treatment effects depart from plausible values.
Selective reporting (reporting bias)Unclear riskPre-defined, or clinically relevant and reasonably expected outcomes are reported on.
Industry biasHigh riskThe trial was supported financially by a grant from Ekhagastiftelsen.
Other biasLow riskThe trial appears to be free of other components that could put it at risk of bias.

Burleigh 2007

MethodsRandomised, double-blind, controlled trial using parallel group design (two intervention groups).
Participants

Country: United Kingdom.

Number of participants randomised: 205 (59 % women), aged 65 years or over (mean age 83), acute admissions to a geriatric medical unit.

Inclusion criteria: patients newly transferred or admitted into the general assessment and rehabilitation wards in an acute geriatric unit aged 65 years or over.

Exclusion criteria: known hypercalcaemia, urolithiasis or renal dialysis therapy, terminal or bed-bound patients with a reduced Glasgow Coma Scale, those already prescribed vitamin D supplements and calcium, and those who were deemed 'nil by mouth'.

Interventions

Participants were randomly assigned to receive:

Intervention group 1: vitamin D3 (800 IU) plus calcium (1200 mg) daily (n = 101);

Intervention group 2 (Control group): calcium (1200 mg) daily (n = 104);

for a 30-day period.

OutcomesThe primary outcomes were numbers of fallers and falls.
Stated aim of study"To determine whether routine supplementation with vitamin D plus calcium reduces numbers of fallers and falls in a cohort of hospital admissions while they are inpatients."
Notes

"Vitamin D and calcium were well tolerated in the total trial cohort with a median compliance level of 88%."

Strakan Pharmaceuticals supplied all trial drugs free of charge.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSequence generation was achieved using a random number table.
Allocation concealment (selection bias)Low riskAllocation was controlled by a central and independent randomisation unit so that intervention allocations could not have been foreseen in advance of, or during, enrolment. Randomisation was known only to the statistician and pharmacist.
Blinding (performance bias and detection bias)
All outcomes
Low riskThe trial was described as blinded, the parties that were blinded, and the method of blinding was described, so that knowledge of allocation was adequately prevented during the trial. "Statistician and pharmacist subsequently issued an appropriate uniquely numbered drug blister pack to each patient's ward. Thereafter, trained staff nurses administered trial drugs as part of routine drug rounds. The researchers, therapists, and patients remained blinded to trial drug allocation."
Incomplete outcome data (attrition bias)
All outcomes
Low riskThe numbers and reasons for dropouts and withdrawals in all intervention groups were described.
Selective reporting (reporting bias)Low riskPre-defined, or clinically relevant and reasonably expected outcomes are reported on.
Industry biasUnclear riskStrakan Pharmaceuticals supplied all trial drugs free of charge.
Other biasLow riskThe trial appears to be free of other components that could put it at risk of bias.

Campbell 2005

Methods

Randomised controlled trial using 2 x 2 factorial design.

The VIP (visual impairment) trial.

Participants

Country: New Zealand.

Number of participants randomised: 391 elderly people (68 % women) aged 75 to 96 (mean 83.6) years, with visual acuity of 6/24 or worse, who were living in the community.

Inclusion criteria: elderly people aged 75 years or over with visual acuity of 6/24 or worse who were living in the community.

Exclusion criteria: those who could not walk around their own residence, who were receiving physiotherapy at the time of recruitment, or could not understand the trial requirements.

Interventions

Participants were randomly assigned to receive:

Intervention group 1: home safety assessment and modification programme delivered by an occupational therapist (n = 100);

Intervention group 2: an exercise programme prescribed at home by a physiotherapist plus vitamin D3 100,000 IU initially and then 50,000 IU monthly (n = 97);

Intervention group 3: both interventions (intervention 1 plus intervention 2) (n = 98);

Intervention group 4 (Control group): social visits (n = 96);

for a one-year period.

The one-year exercise intervention consisted of the specific muscle strengthening and balance retraining exercises that progress in difficulty and a walking plan, modified for those with severe visual acuity loss, with vitamin D supplementation.

The home safety assessment and modification programme was specifically designed for people with severe visual impairments. The occupational therapist visited the person at home and used a home safety assessment checklist to identify hazards and to initiate discussion with the participant about any items, behaviour, or lack of equipment that could lead to falls.

Research staff made two home visits lasting an hour each during the first six months of the trial to participants in intervention group four.

OutcomesThe primary outcome measures were number of falls and number of injuries resulting from falls. Secondary outcome measure was costs of implementing the home safety programme.
Stated aim of study"To assess the efficacy and cost effectiveness of a home safety programme and a home exercise programme to reduce falls and injuries in older people with poor vision."
NotesAdditional information received through personal communication with Professor John Campbell (19.02.2010).
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSequence generation was achieved using a random number table.
Allocation concealment (selection bias)Low riskAllocation was controlled by a central and independent randomisation unit so that intervention allocations could not have been foreseen in advance of, or during, enrolment. "The schedule was held by an independent person at a separate site and was accessed by a research administrator for the trial, who telephoned after each baseline assessment was completed. The administrator then informed the occupational therapist, physiotherapist, or social visitor, who delivered the assigned intervention to that participant where possible within the next two weeks."
Blinding (performance bias and detection bias)
All outcomes
High riskTrial was not blinded, so that the allocation was known during the trial. Placebo was not used.
Incomplete outcome data (attrition bias)
All outcomes
Low riskThe numbers and reasons for dropouts and withdrawals in all intervention groups were described.
Selective reporting (reporting bias)Low riskPre-defined, or clinically relevant and reasonably expected outcomes are reported on.
Industry biasLow riskThe trial is not funded by a manufacturer of vitamin D.
Other biasLow riskThe trial appears to be free of other components that could put it at risk of bias.

Chapuy 1992

Methods

Vitamin D, Calcium, Lyon Study I (DECALYOS I).

Randomised, double-blind, placebo controlled trial using parallel group design (two intervention groups).

Participants

Country: France.

Number of participants randomised: 3270, 69 to 106 (mean 84) years of age, healthy ambulatory women.

Inclusion criteria: ambulatory woman (with activity levels ranging from going outdoors easily to walk indoors with a cane or a walker), with no serious medical conditions, and with a life expectancy of at least 18 months.

Exclusion criteria: receiving drugs known to alter bone metabolism, such as corticosteroids, thyroxine, or anticonvulsant drugs within the past year, women who had been treated with fluoride salts for more than three months, or with vitamin D or calcium during the previous six months or for more than one year within the past five years.

Interventions

Participants were randomly assigned to receive:

Intervention group 1: vitamin D3 (800 IU) plus calcium (1200 mg) daily (n = 1634);

Intervention group 2 (Control group): double placebo daily (n = 1636);

for a 18 month period. Participants were followed for four years.

Calcium was in a form of tricalcium phosphate powder in an aqueous suspension.

Placebo pills contained lactose and suspension of lactose, kaolin, and starch.

The supplements were taken in the presence of a nurse to ensure compliance.

OutcomesThe primary outcome was frequency of hip fractures and other nonvertebral fractures, identified radiologically.
Stated aim of study"To evaluate if vitamin D and calcium supplements reduce the risk of hip fractures and other nonvertebral fractures identified radiologically."
Notes

Duphar and Company Laboratories provided the vitamin D3 (Devaron), and Merck-Clevenot Laboratories provided the tricalcium phosphate (Ostram).

Additional information on mortality was received through personal communication with Professor Pierre Meunier (27.02.2010).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThe trial is described as randomised but the method of sequence generation was not specified.
Allocation concealment (selection bias)Unclear riskThe trial was described as randomised but the method used to conceal the allocation was not described, so that intervention allocations may have been foreseen in advance of, or during, enrolment.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskThe trial was described as double blind, but the method of blinding was not described, so that knowledge of allocation was possible during the trial.
Incomplete outcome data (attrition bias)
All outcomes
Low riskThe numbers and reasons for dropouts and withdrawals in all intervention groups were described.
Selective reporting (reporting bias)Low riskPre-defined, or clinically relevant and reasonably expected outcomes are reported on.
Industry biasUnclear riskDuphar and Company Laboratories provided the vitamin D3 (Devaron), and Merck-Clevenot Laboratories provided the tricalcium phosphate (Ostram).
Other biasLow riskThe trial appears to be free of other components that could put it at risk of bias.

Chapuy 2002

Methods

Vitamin D, Calcium, Lyon Study II (DECALYOS II).

Multicenter, randomised, double-blind, placebo controlled trial using parallel group design (three intervention groups).

Participants

Country: France.

Number of participants randomised: 610, 64 to 99 (mean 85) years of age, healthy ambulatory women.

Inclusion criteria: ambulatory woman (able to walk indoors with a cane or a walker) and life expectancy of at least 24 months.

Exclusion criteria: intestinal malabsorption, hypercalcaemia (serum calcium 42.63 mmol/L) or chronic renal failure (serum creatinine 4150 mmol/L), receiving drugs known to alter bone metabolism, such as corticosteroids, anticonvulsants, or a high dose of thyroxine within the past year, treatments with fluoride salts (43 months), bisphosphonates, calcitonin (41 month), calcium (4500 mg/day), and vitamin D (4100 IU/day) during the last 12 months.

Interventions

Participants were randomly assigned to receive:

Intervention group 1: vitamin D3 (800 IU) plus calcium (1200 mg) daily (fixed combination) (n = 199);

Intervention group 2: vitamin D3 (800 IU) plus calcium (1200 mg) daily (separate combination) (n = 194);

Intervention group 3 (Control group): double placebo daily (n = 190);

for a two-year period.

"The sachet of the calcium–vitamin D3 fixed combination (Ostram–vitamin D3, Merck KGaA) contains a fixed combination of 1200 mg elemental calcium in the form of tricalcium phosphate and 800 IU of vitamin D3. The calcium (Ostram, Merck KGaA) contains 1200 mg of elemental calcium in the form of tricalcium phosphate. Vitamin D3 (Devaron, i.e., cholecalciferol, Duphar Solvay) was given in two pills of 400 IU each. Each day women in intervention groups one and two received 1200 mg of elemental calcium and 800 IU of vitamin D3 given either by a sachet of calcium–vitamin D3 fixed combination (Ca–D3 group) or as a sachet of calcium and two tablets of vitamin D3 (Ca+D3 group). The other women received a placebo of vitamin D3 and calcium (one sachet containing lactose, microcrystalline cellulose and the same excipient as the active treatment and two tablets of vitamin D3 placebo)."

OutcomesThe primary outcomes were biochemical variables of calcium homeostasis, femoral neck bone mineral density, and hip fracture risk.
Stated aim of study"To confirm the effects of combined vitamin D supplementation and calcium on biochemical variables of calcium homeostasis, femoral neck bone mineral density, and hip fracture risk."
Notes

"The supplements were taken in the presence of a nurse to ensure compliance.

The mean compliance was more than 95% for both sachets and tablets in each treatment group."

The trial was sponsored by MERCK KGaA, Darmstadt, Germany.

Additional information on mortality was received through personal communication with Professor Pierre Meunier (27.02.2010).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThe trial is described as randomised but the method of sequence generation was not specified.
Allocation concealment (selection bias)Unclear riskThe trial was described as randomised but the method used to conceal the allocation was not described, so that intervention allocations may have been foreseen in advance of, or during, enrolment.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskThe trial was described as double blind, but the method of blinding was not described, so that knowledge of allocation was possible during the trial.
Incomplete outcome data (attrition bias)
All outcomes
Low riskThe numbers and reasons for dropouts and withdrawals in all intervention groups were described
Selective reporting (reporting bias)Low riskPre-defined, or clinically relevant and reasonably expected outcomes are reported on.
Industry biasHigh riskThe trial was sponsored by MERCK KGaA, Darmstadt, Germany.
Other biasLow riskThe trial appears to be free of other components that could put it at risk of bias.

Chel 2008

MethodsRandomised, double-blind, placebo-controlled trial using parallel group design (six intervention groups).
Participants

Country: the Netherlands.

Number of participants randomised: 338 (77% women), aged 70 years or over (mean age 84), nursing home residents.

Inclusion criteria: nursing home residents aged 70 years or over.

Exclusion criteria: going outside in the sunshine more than once a week, the use of vitamin D or calcium supplementation, the use of more than one vitamin D fortified food or drink per day, complete immobilisation and a very poor life expectancy.

Interventions

Participants were randomly assigned to receive:

Intervention group 1: vitamin D3 (600 IU) daily (n = 55);

Intervention group 2 (control group): matched placebo tablet daily (n = 57);

Intervention group 3: vitamin D3 (4200 IU) weekly (n = 54);

Intervention group 4 (Control group): matched placebo tablets weekly (n = 58);

Intervention group 5: vitamin D3 (18,000 IU) powder monthly (n = 57);

Intervention group 6 (Control group): matched placebo powder monthly (n = 57);

for a four and a half month period.

The treatment period of four and a half months was completed by 276 out of 338 participants.

The 276 participants who completed the vitamin D intervention trial were randomly assigned to receive:

Intervention group: calcium 800 mg or 1600 mg daily (n = 138);

Control group: matched placebo tablet daily (n = 138);

for the period of 4 months.

The treatment was completed by 269 participants.

The first 156 randomised participants received 800 mg calcium carbonate or placebo; the subsequent 120 participants received 1600 mg calcium carbonate or placebo.

Outcomes

The primary outcome was to assess efficacy of different doses and intervals of oral vitamin D3 supplementation with the same total dose.

Secondary outcome measure was to assess the additional effect of calcium supplementation following vitamin D supplementation on serum parathyroid hormone and markers of bone turnover.

Stated aim of study"To investigate, in a Dutch nursing home population, whether there is a difference in efficacy of different doses and intervals of oral vitamin D3 supplementation with the same total dose compared with placebo. A second aim was to assess the additional effect of calcium supplementation following vitamin D supplementation on serum parathyroid hormone and markers of bone turnover."
Notes

"The trial medication was centrally distributed to ensure compliance. Random samples of the returned medication were counted in order to verify compliance."

"The compliance assessed within 96 random samples of the returned medication was good. In the daily administration group, all 33 participants were compliant, used at least 80% of the tablets. For weekly administration, 80% of the 35 participants were compliant, used at least 80% of the tablets. For monthly administration, 93% of the 28 participants were compliant, used at least four out of five powders."

Solvay Pharmaceuticals supplied the research medication.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThe trial is described as randomised but the method of sequence generation was not specified.
Allocation concealment (selection bias)Unclear riskThe trial was described as randomised but the method used to conceal the allocation was not described, so that intervention allocations may have been foreseen in advance of, or during, enrolment.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskThe trial was described as double blind, but the method of blinding was not described so that knowledge of allocation was possible during the trial.
Incomplete outcome data (attrition bias)
All outcomes
Low riskThe numbers and reasons for dropouts and withdrawals in all intervention groups were described.
Selective reporting (reporting bias)Low riskPre-defined, or clinically relevant and reasonably expected outcomes are reported on.
Industry biasUnclear riskSolvay Pharmaceuticals supplied the research medication.
Other biasLow riskThe trial appears to be free of other components that could put it at risk of bias.

Cherniack 2011

MethodsRandomised, double-blind, controlled trial using parallel group design (two intervention groups).
Participants

Country: United States.

Number of participants randomised: 46 (2% women), aged 70 years an older (mean age 80).

Inclusion criteria: community-dwelling elderly veterans living in south Florida who were aged 70 and older.

Exclusion criteria: current users of vitamin D or corticosteroids; or had hypo- or hypercalcaemia, hypercalciuria, hyperparathyroidism, chronic serum creatinine greater than 2.0 mg/dL, or cholestatic liver disease; or were unable to take medication daily.

Interventions

Participants were randomly assigned to receive:

Intervention group 1: vitamin D3 (2000 IU) daily (n = 23);

Intervention group 2 (Control group): placebo daily (n = 23);

for a one year period.

The 41 participants found to have inadequate calcium intake (< 1200 mg/d) according to dietary questionnaire were also dispensed a calcium supplement to provide adequate daily intake.

OutcomesThe primary outcomes were serum calcium, 25-hydroxyvitamin D, parathyroid hormone, and 24-hour urinary calcium.
Stated aim of study"To determine the prevalence of hypovitaminosis D (serum 25-hydroxyvitamin D < 32 ng/mL; HVD) in a population of elderly veterans and conduct a preliminary assessment of the efficacy of supplementation with cholecalciferol in correcting HVD".
NotesCarlson Laboratories donated the cholecalciferol and placebo capsules.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSequence generation was achieved using computer random number generation
Allocation concealment (selection bias)Low riskAllocation was controlled by a central and independent randomisation unit so that intervention allocations could not have been foreseen in advance of, or during, enrolment.
Blinding (performance bias and detection bias)
All outcomes
Low riskThe outcome measurement is not likely to be influenced by lack of blinding.
Incomplete outcome data (attrition bias)
All outcomes
Low riskThere is insufficient information to assess whether the missing data mechanism in combination with the method used to handle missing data are likely to induce bias on the estimate of effect.
Selective reporting (reporting bias)Low riskPre-defined, or clinically relevant and reasonably expected outcomes are reported on.
Industry biasUnclear riskCarlson Laboratories donated the cholecalciferol and placebo capsules.
Other biasLow riskThe trial appears to be free of other components that could put it at risk of bias.

Cooper 2003

MethodsRandomised, double-blind, placebo controlled trial using parallel group design (two intervention groups).
Participants

Country: Australia.

Number of participants randomised: 187 healthy, white, postmenopausal women, mean age 56 years.

Inclusion criteria: healthy, white women who were postmenopausal for one to ten years, and who were not receiving hormone replacement therapy.

Exclusion criteria: malignant disease, renal, hepatic, endocrine, or gastrointestinal disorder associated with abnormal calcium metabolism, use of oestrogen, progesterone, glucocorticoids, anticonvulsants, thiazide diuretics, vitamin D supplements, or other medications known to affect calcium or bone metabolism in the previous 12 months. Participants with laboratory evidence of renal, hepatic, or endocrine disorder; a serum follicle-stimulating hormone concentration < 40 mIU/mL, or bone mineral density at any site ± two standard deviation from the mean for potential participant matched for age were also excluded.

Interventions

Participants were randomly assigned to receive:

Intervention group 1: vitamin D2 (10,000 IU) weekly plus calcium (1000 mg) daily (n = 93);

Intervention group 2 (Control group): calcium (1000 mg) daily (n = 94);

for a two-year period.

Calcium was in a form of tricalcium phosphate powder in an aqueous suspension.

OutcomesThe primary outcome was bone mineral density.
Stated aim of study"To examine the effects of vitamin D2 supplementation on changes in bone mineral density in younger (age: 56 years) postmenopausal women who were also given 1000 mg calcium daily and to compare those changes with the changes in bone mineral density in women given 1000 mg calcium daily only."
Notes

"Compliance was assessed by tablet counts and diary review. Compliance with treatment was 98.2 ± 6.1% for the calcium plus vitamin D group and 97.7 ± 5.4% for the calcium group."

Vitamin D2 was provided by Ostelin; Boots Healthcare Pharmaceuticals, Sydney, Australia. Calcium carbonate was provided by Cal-Sup; 3M Pharmaceutical, Sydney, Australia.

Additional information on mortality and risk of bias domains was received through personal communication with Professor Philip Clifton-Bligh (12.11.2007; 08.02.2010).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSequence generation was achieved using computer random number generation.
Allocation concealment (selection bias)Low riskThe trial was described as randomised but the method used to conceal the allocation was not described, so that intervention allocations may have been foreseen in advance of, or during, enrolment.
Blinding (performance bias and detection bias)
All outcomes
Low riskAllocation was controlled by a central and independent randomisation unit so that intervention allocations could not have been foreseen in advance of, or during, enrolment.
Incomplete outcome data (attrition bias)
All outcomes
Low riskThe numbers and reasons for dropouts and withdrawals in all intervention groups were described.
Selective reporting (reporting bias)Low riskPre-defined, or clinically relevant and reasonably expected outcomes are reported on.
Industry biasUnclear riskVitamin D2 was provided by Ostelin; Boots Healthcare Pharmaceuticals, Sydney, Australia. Calcium carbonate was provided by Cal-Sup; 3M Pharmaceutical, Sydney, Australia.
Other biasLow riskThe trial appears to be free of other components that could put it at risk of bias.

Corless 1985

MethodsRandomised double-blind placebo controlled trial using parallel group design (two intervention groups).
Participants

Country: United Kingdom.

Number of participants randomised: 82, elderly hospital patients (78% women), mean age 82.4 years.

Inclusion criteria: elderly hospital patients.

Exclusion criteria: overt clinical osteomalacia, either plasma calcium less than 1.95 mmol/L or Looser's zones, or on calciferol therapy; a judgement that he or she was unlikely to be able to co-operate in the trial; plasma creatinine more than 150/mmol/L, potassium less than 3.3 mmol/L; plasma 25(OH)D more than 40nmol/L (16ng/ml); refused consent or unable to give informed consent.

Interventions

Participants were randomly assigned to receive:

Intervention group 1: vitamin D2 (9000 IU) daily (n = 32);

Intervention group 2 (Control group): matching placebo tablets daily (n = 33);

for a nine-month period.

Placebo tablets were identical in appearance to the vitamin D2 tablets containing lactose.

OutcomesThe primary outcome measure was abilities of elderly hospital patients to carry out basic activities of daily life.
Stated aim of study"To evaluate the effect of oral vitamin D supplements on the ability of elderly hospital patients with low or low normal plasma 25(OH)D to perform basic activities of daily living."
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSequence generation was achieved using computer random number generation.
Allocation concealment (selection bias)Unclear riskThe trial was described as randomised but the method used to conceal the allocation was not described, so that intervention allocations may have been foreseen in advance of, or during, enrolment.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskThe trial was described as double blind, but the method of blinding was not described, so that knowledge of allocation was possible during the trial.
Incomplete outcome data (attrition bias)
All outcomes
Low riskThe numbers and reasons for dropouts and withdrawals in all intervention groups were described.
Selective reporting (reporting bias)Low riskPre-defined, or clinically relevant and reasonably expected outcomes are reported on.
Industry biasUnclear riskThe source of funding is not clear.
Other biasLow riskThe trial appears to be free of other components that could put it at risk of bias.

Daly 2008

MethodsRandomised controlled trial using parallel group design (two intervention groups).
Participants

Country: Australia.

Number of participants randomised: 167 ambulatory community living men 50 to 87 (mean 61.9) years of age.

Inclusion criteria: ambulatory community living men aged 50 years or over.

Exclusion criteria: taking calcium and/or vitamin D supplements in the preceding 12 months, participating in regular high-intensity resistance training in the previous six months or more, then 150 minutes a week of moderate- to high-impact weight-bearing exercise, had a body mass index > 35 kg/m2, lactose intolerance, consuming more than four alcoholic beverages per day, a history of osteoporotic fracture or medical disease, or medication use that is known to affect metabolism of bones.

Interventions

Participants were randomly assigned to receive:

Intervention group 1: calcium-vitamin D3-fortified milk containing vitamin D3 (800 IU) plus calcium (1000 mg) daily (n = 85);

Intervention group 2 (Control group): usual diet (n = 82);

for a two-year period. Participants were followed for additional a year and a half.

OutcomesThe primary outcome measure was bone mineral density.
Stated aim of study"To assess the effects of calcium and vitamin D3 fortified milk on bone mineral density in community living men > 50 years of age."
Notes

"To monitor milk compliance, participants were asked to record the number of tetra packs consumed per day on a compliance calendar, which was collected and checked every three months. Compliance proportion (expressed as a percentage) was calculated as the actual number of tetra packs consumed, divided by the expected consumption each month. The overall mean reported milk compliance, calculated as the percentage of the tetra packs consumed and based on daily diaries was 85.1%.

Milk was specifically formulated by Murray Goulburn Cooperative Co. (Brunswick, Australia). The added milk calcium salt (Natra-Cal) was prepared by Murray Goulburn Cooperative Co. The vitamin D (Vitamin D3) used to fortify the milk was obtained from DSM Nutritional Products Pty (NSW, Australia)."

Additional information on mortality was received through personal communication with Professor Robin Daly (04.02.2009).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSequence generation was achieved using a random number table.
Allocation concealment (selection bias)High riskThe allocation sequence was known to the investigators who assigned participants.
Blinding (performance bias and detection bias)
All outcomes
High riskTrial was not blinded, so that the allocation was known during the trial. Placebo was not used.
Incomplete outcome data (attrition bias)
All outcomes
Low riskThe numbers and reasons for dropouts and withdrawals in all intervention groups were described.
Selective reporting (reporting bias)Low riskPre-defined, or clinically relevant and reasonably expected outcomes are reported on.
Industry biasUnclear riskThe vitamin D (Vitamin D3) used to fortify the milk was obtained from DSM Nutritional Products Pty (NSW, Australia).
Other biasLow riskThe trial appears to be free of other components that could put it at risk of bias.

Dawson-Hughes 1997

Methods

Boston STOP IT (Sites Testing Osteoporosis Prevention Intervention Treatment).

Randomised, double-blind, placebo controlled trial using parallel group design (two intervention groups).

Participants

Country: United States.

Number of participants randomised: 389, healthy, ambulatory participants (55% women), aged 65 years or older (mean 71).

Inclusion criteria: healthy, ambulatory men and women 65 years of age or older.

Exclusion criteria: current cancer or hyperparathyroidism; a kidney stone in the past five years; renal disease; bilateral hip surgery; therapy with a bisphosphonate, calcitonin, oestrogen, tamoxifen, or testosterone in the past six months or fluoride in the past two years; femoral-neck bone mineral density more than 2 SD below the mean for participants of the same age and sex; dietary calcium intake exceeding 1500 mg per day; and laboratory evidence of kidney or liver disease.

Interventions

Participants were randomly assigned to receive:

Intervention group 1: vitamin D3 (700 IU) plus calcium (500 mg) daily (n = 187);

Intervention group 2 (Control group): matched placebo tablets daily (n = 202);

for a three-year period.

Calcium was in the form of calcium citrate malate. Placebo pills contained microcrystalline cellulose.

OutcomesThe primary outcome measures were bone mineral density, biochemical measures of bone metabolism, and the incidence of nonvertebral fractures.
Stated aim of study"To examine the effects of combined vitamin D supplementation and calcium on bone loss, biochemical measures of bone metabolism, and the incidence of nonvertebral fractures in men and women 65 years of age or older who were living in the community."
Notes

Procter & Gamble, Cincinnati manufactured calcium tablets.

Additional information on mortality was received through personal communication with Professor Bess Dawson-Hughes (04.02.2009).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSequence generation was achieved using computer random number generation.
Allocation concealment (selection bias)Low riskAllocation was controlled by a central and independent randomisation unit so that intervention allocations could not have been foreseen in advance of, or during, enrolment.
Blinding (performance bias and detection bias)
All outcomes
Low riskThe trial was described as blinded, the parties that were blinded, and the method of blinding was described, so that knowledge of allocation was adequately prevented during the trial.
Incomplete outcome data (attrition bias)
All outcomes
Low riskThe numbers and reasons for dropouts and withdrawals in all intervention groups were described.
Selective reporting (reporting bias)Low riskPre-defined or clinically relevant and reasonably expected outcomes are reported on.
Industry biasUnclear riskProcter & Gamble, Cincinnati manufactured calcium tablets.
Other biasLow riskThe trial appears to be free of other components that could put it at risk of bias.

Dukas 2004

MethodsRandomised, double-blind, placebo-controlled trial using parallel group design (two intervention groups).
Participants

Country: Switzerland.

Number of participants randomised: 378 (51% women), mean age 71 years, community-dwelling elderly people.

Inclusion criteria: community-dwelling elderly people who are mobile and have an independent life style.

Exclusion criteria: primary hyperparathyroidism, polyarthritis or inability to walk, calcium intake by supplement of more than 500 mg daily, vitamin D intake of more than 200 IU daily, active kidney stone disease, history of hypercalcuria or cancer or other incurable diseases, dementia, elective surgery within the next three months, severe renal insufficiency (creatinine clearance < 20 mL/min, and fracture or stroke within the last 3 months. Calcium supplementation of 500 mg/d or less was accepted.

Interventions

Participants were randomly assigned to receive:

Intervention group 1: 1 α(OH)D3 (alfacalcidol), (1 μg) daily (n = 192);

Intervention group 2 (Control group): placebo (n = 186);

for a nine-month period.

OutcomesThe primary outcome measure was number of fallers. Secondary outcome measures were muscle strength, balance, blood pressure, and bone quality.
Stated aim of study"To evaluate whether treatment with alfacalcidol, a precursor of the D hormone calcitriol, reduces the number of fallers and falls in community-dwelling men and women."
Notes

Trial medication was provided by TEVA Pharmaceuticals Industries Ltd, Israel.

Additional information on the risk of bias domains was received through personal communication with Dr Laurent C Dukas (28.01.2010).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSequence generation was achieved using computer random number generation.
Allocation concealment (selection bias)Low riskAllocation was controlled by a central and independent randomisation unit so that intervention allocations could not have been foreseen in advance of, or during, enrolment. "An independent statistical group performed the blinding and randomisation. All investigators and staff conducting the trial remained blinded throughout the intervention period."
Blinding (performance bias and detection bias)
All outcomes
Low riskThe trial was described as blinded, the parties that were blinded, and the method of blinding was described, so that knowledge of allocation was adequately prevented during the trial.
Incomplete outcome data (attrition bias)
All outcomes
Low riskThe numbers and reasons for dropouts and withdrawals in all intervention groups were described.
Selective reporting (reporting bias)Low riskPre-defined, or clinically relevant and reasonably expected outcomes are reported on.
Industry biasUnclear riskTrial medication was provided by TEVA Pharmaceuticals Industries Ltd, Israel.
Other biasLow riskThe trial appears to be free of other components that could put it at risk of bias.

Flicker 2005

MethodsRandomised, double-blind, placebo-controlled trial using parallel group design (two intervention groups).
Participants

Country: Australia.

Number of participants randomised: 625, older residents (mean age 83.4), 95% females, with serum 25-hydroxyvitamin D levels between 25 and 90 nmol/L.

Inclusion criteria: older people resident in hostels and nursing homes with serum 25-hydroxyvitamin D levels between 25 and 90 nmol/L.

Exclusion criteria: use of agents that could affect bone and mineral metabolism, such as warfarin, chronic heparin therapy, vitamin D therapy within the previous three months, glucocorticoids at an average daily dose of greater than 5 mg prednisolone (or equivalent) for more than one month within the preceding year, current use of bisphosphonates, and hormone replacement therapy, thyrotoxicosis within the previous three years, primary hyperparathyroidism treated within the previous three years, multiple myeloma, Paget’s disease of bone, history of malabsorption, intercurrent active malignancy, and other disorders affecting bone and mineral metabolism.

Interventions

Participants were randomly assigned to receive:

Intervention group: vitamin D3 (10000 IU) weekly until November 1998 and thereafter vitamin D31000 IU daily plus calcium (600 mg) daily (n = 313);

Control group: calcium (600 mg) (n = 312);

for a two-year period.

OutcomesThe primary outcomes were falls and fractures.
Stated aim of study"To test whether administration of vitamin D could reduce the incidence of falls and fractures in nursing home residents."
Notes"Supplements and placebos were purchased commercially, and the suppliers played no role in the trial design or in the collection, analysis, or interpretation of data."
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSequence generation was achieved using computer random number generation.
Allocation concealment (selection bias)Low riskAllocation was controlled by a central and independent randomisation unit so that intervention allocations could not have been foreseen in advance of, or during, enrolment. An individual who was not involved in contact with the participants or the residential care institutions performed randomisation.
Blinding (performance bias and detection bias)
All outcomes
Low riskThe trial was described as blinded, the parties that were blinded, and the method of blinding was described, so that knowledge of allocation was adequately prevented during the trial. "Participants were randomised to receive sequentially numbered bottles containing vitamin D or placebo. Both interventions had matching placebo preparations given in identical fashion, and residents, institutional staff, and trial staff were blinded to treatment allocation."
Incomplete outcome data (attrition bias)
All outcomes
Low riskThe numbers and reasons for dropouts and withdrawals in all intervention groups were described.
Selective reporting (reporting bias)Low riskPre-defined, or clinically relevant and reasonably expected outcomes are reported on.
Industry biasLow riskThe trial is not funded by a manufacturer of vitamin D.
Other biasLow riskThe trial appears to be free of other components that could put it at risk of bias.

Gallagher 2001

Methods

Sites Testing Osteoporosis Prevention / Intervention Treatment (STOP IT).

Randomised, double-blind, placebo-controlled trial using 2 x 2 factorial design.

Participants

Country: United States.

Number of participants randomised: 489 healthy elderly women 65 to 77 (mean 71.5) years of age.

Inclusion criteria: healthy elderly women 65 to 77 years of age and femoral neck density within the normal range for their age.

Exclusion criteria: severe chronic illness, primary hyperparathyroidism or active renal stone disease, and were on certain medications, such as bisphosphonates, anticonvulsants, oestrogen, fluoride, or thiazide diuretics in the previous 6 months.

Interventions

Participants were randomly assigned to receive:

Intervention group 1: calcitriol (0.5 μg) daily (n = 123);

Intervention group 2: conjugated oestrogens (Premarin) 0.625 mg/daily plus medroxyprogesterone acetate (Provera) 2.5 mg daily (n = 121);

Intervention group 3: calcitriol (0.5 μg) plus conjugated oestrogens daily; (Premarin) 0.625 mg/daily plus medroxyprogesterone acetate (Provera) 2.5 mg daily (n = 122);

Intervention group 4 (Control group): matched placebo daily (n = 123);

for a three-year period.

OutcomesThe primary outcome measure was the change in bone mineral density of the femoral neck and spine. Secondary outcome measure was incidence of nonvertebral fractures.
Stated aim of study"To examine the effect of oestrogen and 1,25-dihydroxyvitamin D therapy given individually or in combination on bone loss in elderly women."
Notes

"Compliance to trial medication was evaluated by pill counts. At 36 months, treatment group differences in adherence to assigned therapy were evident, with 78% of those assigned to placebo, 70% of those assigned to calcitriol, 65% of those assigned to HRT/ERT and 62% of those assigned to HRT/ERT calcitriol still adherent to their assigned medication. Among those still on medication the compliance for the groups calculated at six months and compared with 36 months, respectively, was: conjugated estrogens, 86% and 92%; medroxyprogesterone acetate, 91% and 94%; calcitriol, 87% and 93%; placebos, 94% and 92%."

The active trial drug and placebo were supplied by Wyeth-Ayerst Laboratories, Inc Pharm, Hoffman-LaRoche Inc and Pharmacia & Upjohn, Inc.

Additional information on mortality and risk of bias domains was received through personal communication with Dr John Gallagher (09.02.2009; 11.03.2010).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSequence generation was achieved using computer random number generation.
Allocation concealment (selection bias)Low riskAllocation was controlled by a central and independent randomisation unit so that intervention allocations could not have been foreseen in advance of, or during, enrolment. An independent statistical group performed the blinding and randomisation.
Blinding (performance bias and detection bias)
All outcomes
Low riskThe trial was described as blinded, the parties that were blinded, and the method of blinding was described, so that knowledge of allocation was adequately prevented during the trial.
Incomplete outcome data (attrition bias)
All outcomes
Low riskThe numbers and reasons for dropouts and withdrawals in all intervention groups were described.
Selective reporting (reporting bias)Low riskPre-defined, or clinically relevant and reasonably expected outcomes are reported on.
Industry biasUnclear riskThe active trial drug and placebo were supplied by Wyeth-Ayerst Laboratories, Inc Pharm, Hoffman-LaRoche Inc and Pharmacia & Upjohn, Inc.
Other biasLow riskThe trial appears to be free of other components that could put it at risk of bias.

Glendenning 2012

MethodsRandomised, double-blind, placebo-controlled trial using parallel group design (two intervention groups).
Participants

Country: Australia.

Number of participants randomised: 686 community-dwelling ambulant women aged over 70 years (mean 76.7).

Inclusion criteria: age over 70 years, registration with a general practitioner, and likelihood, in the investigators’ opinion, of attending four study visits over 9 months.

Exclusion criteria: consumption of vitamin D supplementation either in isolation or as part of a combination treatment; e.g., Actonel combi +D or Fosamax plus, cognitive impairment (Mini Mental State Score < 24), and individuals who in the investigators’ opinion would not be
suitable for the study.

Interventions

Participants were randomly assigned to receive:

Intervention group 1: cholecalciferol 150,000 three-monthly (n = 353);

Intervention group 2 (Control group): placebo vitamin D three-monthly (n = 333);

for a nine-month period.

OutcomesThe primary outcome measures were falls, muscle strength, and mobility. Secondary outcome measures were serum 25-hidrohyvitamin D levels, and adverse events.
Stated aim of study"to evaluate the effects of cholecalciferol treatment and lifestyle advice compared to lifestyle advice alone on falls, serum 25OHD levels, physical function, and adverse events in 686 women aged over 70 years"
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSequence generation was achieved using computer random number generation
Allocation concealment (selection bias)Low riskAllocation was controlled by a central and independent randomisation unit so that intervention allocations could not have been foreseen in advance of, or during, enrolment.
Blinding (performance bias and detection bias)
All outcomes
Low riskThe outcome measurement is not likely to be influenced by lack of blinding.
Incomplete outcome data (attrition bias)
All outcomes
Low riskThe underlying reasons for missing data are unlikely to make treatment effects depart from plausible values.
Selective reporting (reporting bias)Low riskPre-defined, or clinically relevant and reasonably expected outcomes are reported on.
Industry biasUnclear riskThe source of funding is not clear.
Other biasLow riskThe trial appears to be free of other components that could put it at risk of bias.

Grady 1991

MethodsRandomised, double-blind, placebo-controlled trial using parallel group design (two intervention groups).
Participants

Country: United States.

Number of participants randomised: 98 elderly ambulatory men and women (54%) women, aged 70 to 97 (mean 79.1) years of age.

Inclusion criteria: elderly ambulatory men and women.

Exclusion criteria: serum calcium levels of 2.57 mmol/L or more, urinary calcium levels of 7.28 mmol/day or more, creatinine clearance less than 0.42 mmol/s, history of hypercalcaemia, nephrolithiasis, seizure disorder, hyperparathyroidism, treatment with calcium, vitamin D or thiazide diuretics, and average calcium intake greater than 1000 mg/day.

Interventions

Participants were randomly assigned to receive:

Intervention group 1: calcitriol (0.5 μg) daily (n = 50);

Intervention group 2 (Control group): placebo vitamin D (n = 48);

for a six-month period.

OutcomesThe primary outcome measure was muscle strength.
Stated aim of study"To test the hypothesis that the weakness associated with aging is in part due to inadequate serum concentrations of 1,25-(OH2)D3."
Notes

"Participants were evaluated at 1, 2, 4, 8, 12, 18, and 24 weeks of intervention regimen to maintain compliance. Participants in both groups took more than 95% of the assigned medication."

Calcitriol and placebo capsules were provided by Hoffman-LaRoche (Nutley, NJ).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThe trial is described as randomised but the method of sequence generation was not specified.
Allocation concealment (selection bias)Unclear riskThe trial was described as randomised but the method used to conceal the allocation was not described, so that intervention allocations may have been foreseen in advance of, or during, enrolment.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskThe trial was described as double blind, but the method of blinding was not described, so that knowledge of allocation was possible during the trial.
Incomplete outcome data (attrition bias)
All outcomes
Low riskThe numbers and reasons for dropouts and withdrawals in all intervention groups were described.
Selective reporting (reporting bias)Low riskPre-defined, or clinically relevant and reasonably expected outcomes are reported on.
Industry biasUnclear riskCalcitriol and placebo capsules were provided by Hoffman-LaRoche (Nutley, NJ).
Other biasLow riskThe trial appears to be free of other components that could put it at risk of bias.

Grimnes 2011

MethodsRandomised, double-blind, placebo-controlled trial using parallel group design (two intervention groups).
Participants

Country: Norway.

Number of participants randomised: 104 (45% women), mean age 51.5 years.

Inclusion criteria: participants with low serum 25-hydroxyvitamin D levels.

Exclusion criteria: diabetes, acute myocardial infarction or stroke during the past 12 months, cancer during the past 5 years, steroid use, serum creatinine ≥130 μmol/L (males) ≥ 110 μmol/L (females), possible primary hyperparathyroidism (plasma parathyroid hormone [PTH] > 5.0 pmol/L combined with serum calcium > 2.50 mmol/L), sarcoidosis, systolic blood pressure > 175 mmHg or diastolic blood pressure > 105 mmHg, and specifically for women, pregnancy, lactation, or fertile age and no contraception use.

Interventions

Participants were randomly assigned to receive:

Intervention group 1: vitamin D3 (20,000 IU) twice weekly (n = 51);

Intervention group 2 (Control group): placebo twice weekly (n = 53);

for a six months period.

OutcomesThe primary outcomes were insulin sensitivity and secretion. Secondary outcome measure was blood lipid level.
Stated aim of study"to compare insulin sensitivity (the primary end point) and secretion and lipids in subjects with low and high serum 25(OH)D (25-hydroxyvitamin D) levels and to assess the effect of vitamin D supplementation on the same outcomes among the participants with low serum 25(OH)D levels."
NotesVitamin D3 was manufactured by Dekristol; Mibe, Brehna, Germany.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSequence generation was achieved using computer random number generation
Allocation concealment (selection bias)Low riskAllocation was controlled by a central and independent randomisation unit so that intervention allocations could not have been foreseen in advance of, or during, enrolment.
Blinding (performance bias and detection bias)
All outcomes
Low riskThe outcome measurement is not likely to be influenced by lack of blinding.
Incomplete outcome data (attrition bias)
All outcomes
Low riskThe underlying reasons for missing data are unlikely to make treatment effects depart from plausible values.
Selective reporting (reporting bias)Low riskPre-defined, or clinically relevant and reasonably expected outcomes are reported on.
Industry biasUnclear riskVitamin D3 was manufactured by Dekristol; Mibe, Brehna, Germany.
Other biasLow riskThe trial appears to be free of other components that could put it at risk of bias.

Harwood 2004

Methods

The Nottingham Neck of Femur Study (NONOF).

Randomised controlled trial, using parallel group design (four intervention groups).

Participants

Country: United Kingdom.

Number of participants randomised: 150 previously independent elderly women, 67 to 92 (mean 81.2) years of age, recruited following surgery for hip fracture.

Inclusion criteria: elderly women post-hip fracture, previous community residence, independence in activities of daily living.

Exclusion criteria: institutionalised patients, diseases or medication known to affect bone metabolism, and those with a 10-point abbreviated mental test score less than seven at the time of recruitment.

Interventions

Participants were randomly assigned to receive:

Intervention group 1: single injection of 300,000 IU of vitamin D2 (n = 38);

Intervention group 2: single injection of 300,000 IU of vitamin D2 plus oral calcium (1000 mg) daily (n = 36);

Intervention group 3: oral vitamin D3 (800 IU) plus calcium (1000 mg) daily (n = 39);

Intervention group 4 (Control group): no treatment (n = 37);

for a one-year period.

OutcomesThe primary outcomes were bone biochemical markers, bone mineral density, and rate of falls and new fractures.
Stated aim of study"To compare the effects of different calcium and vitamin D supplementation regimens on bone biochemical markers, bone mineral density, and rate of falls in elderly women post-hip fracture."
Notes

"There were no cases of hypercalcaemia, and no participants were withdrawn because of adverse effects of trial medication."

The trial was supported by Provalis Healthcare Ltd.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSequence generation was achieved using computer random number generation.
Allocation concealment (selection bias)Low riskAllocation was controlled by a opaque and sealed envelopes.
Blinding (performance bias and detection bias)
All outcomes
High riskTrial was not blinded, so that the allocation was known during the trial. Placebo was not used.
Incomplete outcome data (attrition bias)
All outcomes
Low riskThe numbers and reasons for dropouts and withdrawals in all intervention groups were described.
Selective reporting (reporting bias)Low riskPre-defined, or clinically relevant and reasonably expected outcomes are reported on.
Industry biasHigh riskThe trial was supported by Provalis Healthcare Ltd.
Other biasLow riskThe trial appears to be free of other components that could put it at risk of bias.

Jackson 2006

Methods

Women’s Health Initiative (WHI).

Multicentre, randomised, double-blind, placebo controlled trial using parallel group design (two intervention groups).

Participants

Country: United States.

Number of participants randomised: 36,282 50 to 79 (mean 62) years of age, healthy postmenopausal women.

Inclusion criteria: postmenopausal women 50 to 79 years of age at the initial screening without evidence of a medical condition associated with a predicted survival of less than three years and no safety, adherence, or retention risks.

Exclusion criteria: hypercalcaemia, renal calculi, corticosteroid use, and calcitriol use.

Personal supplemental calcium (up to 1000 mg per day) and vitamin D (up to 600 IU per day) were allowed. In 1999, the upper limit of personal vitamin D intake was raised to 1000 IU. The calcium with vitamin D trial permitted the use of bisphosphonates and calcitonin. Use of oestrogen (with or without a progestin) was according to randomisation among women in the Hormone Therapy trial. Independent use of hormone therapy or selective oestrogen-receptor modulators was permitted for women in the Dietary Modification trial.

Interventions

Participants were randomly assigned to receive:

Intervention group 1: vitamin D3 (400 IU) plus calcium (1000 mg) daily (n = 18176);

Intervention group 2 (Control group): matched placebo daily (n = 18106);

for a seven-year period.

OutcomesThe primary outcome measure was hip fracture. The secondary outcomes were other fractures and colorectal cancer.
Stated aim of study"To test the primary hypothesis that postmenopausal women randomly assigned to vitamin D supplementation plus calcium would have a lower risk of hip fracture, and, secondarily, of all fractures than women assigned to placebo. Another secondary hypothesis was that women receiving calcium with vitamin D supplementation would have a lower rate of colorectal cancer than those receiving placebo."
Notes

"The Women’s Health Initiative was clinical investigation of strategies for the prevention of some of the most common causes of morbidity and mortality among postmenopausal women. It consisted of two components, the randomised controlled clinical trial and observational study. Randomised controlled trial tested two interventions (hormone therapy and dietary modification. Women who were ineligible or unwilling to enrol in randomised trial were invited to participate in the observational study. One year later participants enrolled in the dietary modification trial, hormone therapy trials, or both were invited to join the Women Health Initiative calcium-vitamin D trial."

"Adherence to the trial medication was established by weighing returned pill bottles during clinic visits. The rate of adherence (defined as use of 80% or more of the assigned trial medication) ranged from 60% to 63% during the first three years of follow-up, with an additional 13% to 21% of the participants taking at least half of their trial pills. At the end of the trial, 76% were still taking the trial medication, and 59% were taking 80% or more of it."

The active trial drug and placebo were supplied by GlaxoSmithKline Consumer Healthcare (Pittsburgh).

We extracted data about cancer occurrence and cancer mortality from the article: Brunner RL, Wactawski-Wende J, Caan BJ, Cochrane BB, Chlebowski RT, Gass ML, et al. The effect of calcium plus vitamin D on risk for invasive cancer: results of the Women's Health Initiative (WHI) calcium plus vitamin D randomised clinical trial. Nutrition an Cancer 2011;63(6):827-41.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSequence generation was achieved using computer random number generation.
Allocation concealment (selection bias)Low riskAllocation was controlled by a central and independent randomisation unit so that intervention allocations could not have been foreseen in advance of, or during, enrolment.
Blinding (performance bias and detection bias)
All outcomes
Low riskThe trial was described as blinded, the parties that were blinded, and the method of blinding was described, so that knowledge of allocation was adequately prevented during the trial.
Incomplete outcome data (attrition bias)
All outcomes
Low riskThe numbers and reasons for dropouts and withdrawals in all intervention groups were described.
Selective reporting (reporting bias)Low riskPre-defined, or clinically relevant and reasonably expected outcomes are reported on.
Industry biasUnclear riskThe active trial drug and placebo were supplied by GlaxoSmithKline Consumer Healthcare (Pittsburgh).
Other biasLow riskThe trial appears to be free of other components that could put it at risk of bias.

Janssen 2010

MethodsRandomised, double-blind, placebo-controlled trial using parallel group design (two intervention groups).
Participants

Country: Netherlands.

Number of participants randomised: 70 female geriatric patients older than 65 years with serum 25 hydroxyvitamin D concentrations between 20 and 50 nmol/L.

Inclusion criteria: vitamin D insufficient geriatric patients able to walk and follow simple instructions.

Exclusion criteria: treatment with vitamin D or steroids in the previous six months, a history of hypercalcaemia or renal stones, liver cirrhosis, serum creatinine > 200 μmol/L, malabsorptive bowel syndrome, primary hyperparathyroidism, uncontrolled thyroid disease, anticonvulsant drug therapy, and/or presence of any other condition that would probably interfere with the patients compliance (i.e., surgery planned).

Interventions

Participants were randomly assigned to receive:

Intervention group 1: vitamin D3 (400 IU) plus calcium (500 mg) daily (n = 36);

Intervention group 2 (Control group): placebo vitamin D3 plus calcium (500 mg) daily (n = 34);

for a six months period.

OutcomesThe primary outcomes were muscle strength, power and functional mobility.
Stated aim of study"To test the hypothesis that vitamin D plus calcium supplementation improves muscle strength and mobility, compared with calcium monotherapy in vitamin D insufficient female geriatric patients."
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSequence generation was achieved using computer random number generation
Allocation concealment (selection bias)Low riskAllocation was controlled by a central and independent randomisation unit.
Blinding (performance bias and detection bias)
All outcomes
Low riskThe outcome measurement is not likely to be influenced by lack of blinding.
Incomplete outcome data (attrition bias)
All outcomes
Low riskThe underlying reasons for missing data are unlikely to make treatment effects depart from plausible values.
Selective reporting (reporting bias)Low riskPre-defined, or clinically relevant and reasonably expected outcomes are reported on.
Industry biasLow riskThe trial is not funded by a manufacturer of vitamin D.
Other biasLow risk