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Keywords:

  • CALCIUM;
  • VITAMIN D;
  • OSTEOPOROTIC FRACTURE;
  • OSTEOPOROSIS;
  • INAPPROPRIATENESS

ABSTRACT

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgments
  9. References

Recently, safety concerns about calcium supplementation have arisen. In this situation, ensuring appropriateness of use is highly important. We aimed to describe the use of calcium and vitamin D supplements, the factors related to it, and to assess the appropriateness of calcium prescription among men and women aged 50 years or older. We performed a cross-sectional study in 2009–2010 including 11,035 adults who belong to the ESOSVAL cohort and attend 272 primary healthcare centers in the Valencia region of Spain. Criteria for the inappropriateness of calcium prescription, based on guidelines and recent evidence, were: excessive or insufficient daily total intake (diet plus supplements), excessive single doses of supplements, excessive or insufficient association with vitamin D, and overall inappropriateness. Calcium and/or vitamin D were prescribed to about 17% of the population. Older age, antiosteoporotic treatment, use of glucocorticoids, and a diagnosis of osteoporosis were related to prescription. The presence of other secondary causes of osteoporosis determined supplementation only in men. Calcium dietary intake was not related to the prescription of supplements. Among calcium users, 85.8% met at least one criterion of inappropriate prescription; 29% had an inappropriate daily total intake mainly resulting from excessive consumption (>2000 mg/day); 53.8% of patients were given calcium supplements in quantities higher than 500 mg per dose; and 38.9% of individuals receiving calcium supplements had inappropriate (absent or below 800 UI/day) vitamin D supplementation (all of them at high risk). In conclusion, we found high inappropriateness of calcium supplementation, mainly because of calcium overdosing, and also to undertreatment and underdosing of vitamin D in high-risk patients. Physicians should be encouraged to assess calcium dietary intakes before supplementation, recommending intake from food whenever possible, and to prescribe low calcium doses and high vitamin D doses when given in fixed-dose combinations, or vitamin D alone when calcium is not necessary. © 2013 American Society for Bone and Mineral Research


Introduction

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgments
  9. References

Calcium and vitamin D are nutrients with key roles in bone homeostasis, with an important interdependency. It is well established that when 25-hydroxycholecalciferol levels are low, calcium absorption decreases.[1] Therefore, ensuring satisfactory levels of both nutrients is important for the health of older adults.

Insufficiency of vitamin D is common among older adults worldwide and is particularly accentuated in postmenopausal women and the elderly,[2-4] including those living in areas expected to have better exposure to sunlight and a satisfactory nutritional status.[5-7] This can be explained by the lower competence to synthesize 1,25(OH)2D as age increases[8] and to a lesser extent to decreased dietary intake in older people.[5] Regarding calcium, low dietary intake has been described in adult populations in North America.[9, 10] In contrast, higher calcium dietary intake among older adults or postmenopausal women has been reported in Australia[11, 12] and some European countries, including Spain.[5, 13] Nevertheless, such studies report significant percentages of their populations still falling below the standards issued by different scientific bodies.

From the seminal study by Chapuy and colleagues in the early 1990s,[14] a growing body of evidence has shown the role of appropriate calcium and vitamin D status in reducing hip and nonvertebral fractures among older people with calcium and vitamin D deficits. Reviews and meta-analyses have shown the efficacy of vitamin D for reducing falls and hip fractures in the elderly,[15-17] although recent evidence suggests that doses lower than 800 UI are not enough to decrease the risk of hip fracture.[18] On the other hand, calcium seems to have a small antifracture effect, observed mainly in populations with serious deficiencies.[19, 20] Furthermore, there are concerns about the potential adverse effects of calcium supplementation, such as higher cardiovascular risk,[21, 22] especially with elevated doses.[23]

Based on this evidence, several scientific bodies and medical societies have issued and updated recommendations regarding the benefits and risks of calcium and vitamin D intake in older adults. The dosage and dosing of supplements, patients' comorbidities, dietary intake, and concomitant use of antiosteoporotic drugs are some of the factors included in the proposals for the appropriate prescription of these supplements. However, and despite evidence, expert recommendations, and the relevance of the topic, there are substantial gaps in the literature on the appropriateness of calcium and vitamin D prescription, which include small samples and the exclusion of males,[11, 13, 24-27] analyses that are restricted to specific subgroups such as patients with previous osteoporotic fracture,[28, 29] or the use of data from nationwide nutritional surveys.[9, 10] Additionally, only a few studies[10, 27, 29] have assessed clinical or sociodemographic factors related to calcium or vitamin D supplements in older people who have not suffered an osteoporotic fracture. More importantly, the appropriateness criteria in most of the above-mentioned studies are based on nutritional recommendations only.

The present study aims to describe the prevalence of the prescription of calcium and vitamin D supplements, the factors related to it, and to assess the appropriateness of calcium prescription among men and women-aged 50 years or older belonging to a large cohort in a Mediterranean area. This would help to establish policies to guide clinical practice aiming to reduce the risks derived from inappropriate prescription.

Materials and Methods

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgments
  9. References

Design

This cross-sectional study was conducted in 2009–2010 in the Valencia region of Spain using the baseline data of the ESOSVAL risk study, a large cohort with a planned follow-up to 2020.

Setting

The study took place at the Valencia Health Agency (VHA), an extensive public hospital and primary healthcare center network, which covers about 97% of the 5 million inhabitants of the Valencia region, which is located on the Mediterranean coast of Spain.

Population

The recruitment and characteristics of the ESOSVAL cohort have been fully described elsewhere.[30, 31] In brief, the cohort consists of 11,035 women and men aged 50 years and over attending 272 primary healthcare centers in the VHA for any health problem between November 2009 and September 2010. The subjects were recruited opportunistically by 329 general practitioners and 279 primary-care nurses collaborating in the ESOSVAL study and following definite criteria, attempting to get the age distribution as close as possible to the distribution of the region's population. The exclusion criteria included temporary residents, individuals with cognitive impairment, people receiving their usual care through private insurance companies, people physically unable to attend their primary healthcare center, and people of Asian or African descent. The criteria for the selection of clinicians and patients have been fully described previously.[30, 31]

Data sources and study development

The main source of data was the VHA ambulatory electronic medical record (EMR), the so-called ABUCASIS system, which among other information includes demographic and clinical data and information on prescriptions and dispensations. The ambulatory EMR was modified in the context of the ESOSVAL program to include a specific osteoporotic risk sheet facilitating the registration of fracture risk factors, patient monitoring, and decision making about the need for complementary tests or pharmacological treatment (case-finding strategy). The participating doctors and nurses were trained through classroom activities, online courses, and practical exercises to standardize definitions and improve their knowledge of the management of osteoporosis, including completion of the EMR and the specific osteoporotic risk sheet.

Variables

The variables used in the present study include the patients' sociodemographic and clinical characteristics such as age; sex; educational level (no studies, primary studies, and secondary/university); body mass index (BMI) categorized as low (≤20), normal-overweight (20–29), and obese (≥30); dietary calcium intake, estimated by using a modified version (included in the osteoporotic risk sheet) of the Food Composition Chart of the Spanish Ministry of Health[32] and categorized as <500 mg, 500–1000 mg, and ≥1000 mg; number of falls in the last year (≥1 fall); history of hip fracture in parents or brothers; personal history of any previous osteoporotic fracture; densitometry test (made from 24 months before the date of enrollment to the date of the recruitment of the last patient); osteoporosis diagnosis, defined as the presence of such a diagnosis in the EMR and/or a positive osteoporosis result (T-score ≤–2.5) from the densitometry test; use of glucocorticoids (≥5 mg per day of prednisone or equivalent for at least 3 months in the previous year); menopause age before or equal to 40 years old; hypogonadism in men; other secondary causes of osteoporosis (type I diabetes, rheumatoid arthritis, untreated long-standing hyperthyroidism, chronic malnutrition or malabsorption, chronic obstructive pulmonary disease, renal disease, prolonged immobility, organ transplantation, and chronic liver disease); and treatments for osteoporosis including bisphosphonates (alendronate, risendronate, ibandronate), raloxifene, strontium ranelate, parathyroid hormone (1-34 and 1-84), and calcitonin.

Assessment of appropriateness of calcium supplements

Criteria for inappropriateness in the prescription of calcium supplements were established for those currently under treatment, based on recommendations from guidelines issued by different scientific societies and the most recent evidence. We tried to construct wide criteria to account for only more unambiguous inappropriate use (cases with supplementation schemes clearly against recommendations) and not differentiating between recommendations for men and women. These criteria include: 1) inappropriate daily total intake, defined as an intake less than 1000 mg/day or more than 2000 mg/day, taking into account both diet and supplements. The criterion is based on the recommended intakes and upper limits established by the Institute of Medicine (IOM)[33] and supported by the American Society for Bone and Mineral Research.[34] 2) Inappropriate dosage of supplements, defined as that exceeding 500 mg of calcium element per dose. This criterion is based on evidence showing that the efficiency of absorption of calcium from supplements is greatest at doses of 500 mg or less, but once the active transport mechanism is saturated, little additional calcium is absorbed,[35] and this has been included in the recommendations of the American Association of Clinical Endocrinologists[36] and the North American Menopause Society.[37] Additionally, we used a threshold of 600 mg to examine its impact on appropriateness, as this dose is very common and not meaningfully different from the above. 3) Inappropriate association with vitamin D. To establish this criterion, we divided individuals into two groups. The “low-risk” group consisted of people aged 50 to 69 years with none of the following conditions present: diagnosis of osteoporosis, previous osteoporotic fracture, or current antiosteoporotic treatment. Because there is no clear indication for the systematic prescription of vitamin D in this group, and taking into account recommendations of not exceeding a total intake (diet plus supplements) of between 2000 IU/day[37, 38] and 4000 IU/day,[33, 34, 36] we defined inappropriateness for this group as intake of vitamin D from supplements above 4000 UI/day. The “high-risk” group consisted of people aged 50 and 69 years if they presented definite conditions (diagnosis of osteoporosis, previous osteoporotic fracture, or current antiosteoporotic treatment) and all men and women older than 70. Inappropriateness in this group was defined as the prescription of vitamin D in doses below 800 UI/day (following the recommendation for the prescription of at least 800 UI of vitamin D in patients with the above-mentioned characteristics)[18, 34, 38] or over 4000 UI/day (based on the same criteria used for the low-risk group). Recent evidence supports these criteria.[18]

Ethics

All study subjects signed the informed consent granting researchers access to information contained in their medical record for the study purposes. All information was handled according to Spanish laws on confidentiality and patients' rights. The ESOSVAL risk study was reviewed and approved by the Committee for Ethics and Clinical Trials of the Centre for Public Health Research and the Public Health General Directorate of the Valencia Government (Decision March 27, 2009, protocol modification approval October 4, 2012).

Analysis

Cohort characteristics and the use of calcium and/or vitamin D supplements are shown as percentages stratified by sex. Bivariate analyses were conducted to determine which characteristics were related to the use of calcium and/or vitamin D using the chi-square test. To provide estimates of calcium and/or vitamin D use for the whole population, totals were weighted according to the age distribution of the women and men aged 50 years and over in the Valencia region.[39] To assess the factors associated to calcium and/or vitamin D use, we constructed an initial multivariable logistic regression model with all associated variables in bivariate analyses and the clinically relevant ones and used backward-forward stepwise methods to remove nonsignificant variables (with a removal probability of 0.10 and an entry probability of 0.05). The goodness-of-fit was evaluated using the C-Statistic (the area below the receiver-operating characteristic [ROC] curve) for discrimination and the Hoshmer–Lemeshow test for calibration.

The appropriateness of calcium use was estimated by applying algorithms constructed to reproduce the above specified criteria. Summary measures of inappropriateness were estimated regarding the daily calcium supplement intake, the calcium dosage, and its association with vitamin D. Some patients were excluded for some of the three summary measures at this stage because of missing data or because they were using calcitriol (there is no osteoporosis indication approved for this drug) or loading dose calcifediol (because of the difficulties of estimating a daily dose). Fig. 1 shows the study diagram and missing cases for each analysis. All statistical analyses were performed using the STATA 11.0 (Stata Corp, College Station, TX, USA) statistical software.

image

Figure 1. Study diagram.

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Results

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgments
  9. References

Of the 11,035 people in the ESOSVAL cohort, 1646 (14.9%) were taking calcium and/or vitamin D supplements. After weighting for the regional population age-sex structure, the estimated prevalence of calcium and/or vitamin D consumption in adults aged 50 years and over in the Valencia region was 16.8% (95% confidence interval [CI] 16.0–17.6), 28.0% in women (95% CI 26.6–29.3), and 3.6% in men (95% CI 3.1–4.1). Most supplement users were taking calcium and vitamin D associated (71.1%), usually in fixed-dose combinations, and 16.8% were taking vitamin D in fixed-dose combinations with alendronate (Table 1), almost half of which used calcium concomitantly. A total of 5.9% of users consumed vitamin D supplements from two fixed-dose combinations (calcium with vitamin D, and alendronate with vitamin D).

Table 1. Consumption of Supplements of Calcium and Vitamin D in the ESOSVAL Cohort
 n%
  1. FDC = fixed-dose combination.

Calcium17110.39
Vitamin D402.43
Calcium/vitamin D (FDC)115570.17
Calcium and vitamin D160.97
Alendronate/vitamin D (FDC)1338.08
Alendronate/vitamin D (FDC) + calcium321.94
Alendronate/vitamin D (FDC) + vitamin D20.12
Alendronate/vitamin D (FDC) + calcium/vitamin D (FDC)975.89
Total1646100.00

Regarding total calcium intake, the mean daily dietary intake for the whole sample was 816.3 mg/day (872.5 mg/day for women versus 764.5 mg/day for men; p < 0.001), and the mean total calcium intake (including supplements) was 916.9 mg/day (1057.6 mg/day for women versus 787.5 mg/day for men; p < 0.001). Among the subjects taking calcium supplements, the mean daily intake from supplements was 804.2 mg/day (799.4 mg/day women versus 840.8 mg/day men; p = 0.188), and the mean total intake (diet plus supplements) was 1656.7 mg/day (almost identical for men and women; p = 0.665).

All of the sociodemographic, lifestyle, and clinical characteristics considered were significantly related to calcium and/or vitamin D supplementation in men (Table 2), except for BMI, the dietary intake of calcium, and hypogonadism. Among women, a similar pattern was observed (except for BMI, which in women was related to supplement use). The proportion of women with supplementation was greater than that of men in all variables analyzed, except for being under antiosteoporotic treatment, in which case it was similar.

Table 2. Characteristics and Supplement Use From the ESOSVAL Cohort by Sex
  Women (n = 5310)Men (n = 5725)
n (%)% with suppl.p Valuen (%)% with suppl.p Value
  1. Missing data: educational level (933), body mass index (389), falls (539), dietary calcium intake (301), hypogonadism (445), family history of hip fracture (1813), menopause ≤40 years (578).

Educational levelNo studies1501 (30.8)30.10.0011394 (26.7)4.70.021
 Primary2188 (44.9)26.8 2178 (41.7)3.2 
 Secondary/university1186 (24.3)23.3 1655 (31.7)3.0 
Age ≥70 yearsYes1447 (27.3)35.8<0.0011868 (32.6)5.6<0.001
 No3863 (72.8)23.8 3857(67.4)2.6 
Densitometry testYes1360 (25.6)40.5<0.001302 (5.3)15.9<0.001
 No3950 (74.4)22.5 5423 (94.7)2.9 
Previous fractureYes611 (11.5)43.5<0.001269 (4.7)13.0<0.001
 No4699 (88.5)25.0 5456 (95.3)3.2 
OsteoporosisYes1527 (28.8)49.90.001361 (6.3)19.9<0.001
 No3783 (71.2)17.9 5364 (93.7)2.5 
Family history hip fractureYes666 (15.2)32.3<0.001591 (12.2)5.80.004
 No3707 (84.8)25.8 4258 (87.8)3.4 
Body mass index<2071 (1.4)33.8<0.00138 (0.7)0.00.450
 20–293174 (62.1)29.5 3603 (65.1)3.7 
 ≥301869 (36.6)22.9 1891 (34.2)3.4 
Falls (≥1 in the last year)Yes1292 (25.7)30.7<0.001837 (15.3)5.7<0.001
 No3732 (74.3)25.6 4635 (84.7)3.2 
Dietary calcium intake<500 mg658 (12.8)27.10.8981197 (21.4)2.90.193
 500–1000 mg2812 (54.7)27.3 3174 (56.8)3.4 
 ≥1000 mg1672 (32.5)26.7 1221 (21.8)4.3 
Glucocorticoid useYes54 (1.0)63.0<0.00169 (1.2)34.8<0.001
 No5256 (99.0)26.7 5656 (98.8)3.2 
Menopause ≤40 yearsYes378 (8.0)31.50.149
 No4354 (92.0)28.0 
HypogonadismYes59 (1.1)6.80.158
 No5221 (98.9)3.4 
Other secondary causes of osteoporosisYes860 (16.2)31.40.0021380 (24.1)6.5<0.001
 No4450 (83.8)26.3 4345 (75.9)2.7 
Antiosteoporotic treatmentYes1491 (28.1)68.5<0.001137 (2.4)69.3<0.001
 No3819 (71.9)11.0 5588 (97.6)2.0 

In the multivariate analysis (Table 3), the factors independently associated with the prescription of supplements were (results are presented for women and men, respectively): being on antiosteoporotic treatment (13 and 62 times greater odds of having a supplement prescription), use of glucocorticoids (5 and 9 times greater odds), diagnosis of osteoporosis (2 and 3 times greater odds), and having a densitometry test (odds were 2 times greater for both women and men). The elderly were more likely to have a supplement prescription than patients aged 55 to 69 years (reference group). The diagnosis of other secondary causes of osteoporosis was associated with calcium and/or vitamin D prescription in men only.

Table 3. Factors Associated With Calcium and/or Vitamin D Use in Women and Men (Multivariate Logistic Regression Analysis)
 WomenMen
OR95 CI %p ValueOR95 CI %p Value
  1. OR = odds ratio; 95% CI = 95% confidence interval.

  2. Women: n = 5310; Pseudo R2 = 0.30; p < 0.0001; C-Statistic: 0.84; p(χ2) Hosmer–Lemeshow = 0.0079.

  3. Men: n = 5687; Pseudo R2 = 0.35; p < 0.0001; C-Statistic: 0.86; p(χ2) Hosmer–Lemeshow = 0.2883. BMI <20 (n = 38 cases) was dropped because of estimability.

Age ≥70 years1.501.271.77<0.0011.951.382.77<0.001
Densitometry test1.691.432.00<0.0012.141.283.600.004
Osteoporosis1.721.462.03<0.0013.212.065.02<0.001
Glucocorticoid use4.852.549.28<0.0018.754.3017.82<0.001
Other secondary causes of osteoporosis1.661.152.410.007
Antiosteoporotic treatment13.5711.5815.90<0.00162.4539.7998.00<0.001

Regarding inappropriate use (Table 4), 29% of calcium supplement users had an inappropriate total daily intake, mainly because of excessive consumption (>2000 mg/day). Regarding dosage, 53.8% of patients were given calcium supplements in quantities higher than 500 mg per dose; this figure fell to 30.7% when the threshold of 600 mg per dose was taken into account. With regards to the concomitant use of vitamin D in calcium users, 38.9% of individuals receiving calcium supplements had inappropriate vitamin D supplementation (all of them belonging to the “high-risk” group), and it was almost exclusively because of the prescription of low doses (below 800 UI/day). No inappropriate use was found in the “low-risk” group.

Table 4. Inappropriateness of Calcium Supplement Prescription
 n%95% CI
  • n = 1386; missing data: daily total intake (52), association with vitamin D (5).

  • a

    Although the recommended threshold for dosage is 500 mg, we show inappropriateness also using the 600-mg threshold because there is an important percentage of patients prescribed this dose and the difference between these dosages may not be clinically meaningful.

Daily total intake
<1000 mg936.95.6–8.3
>2000 mg28921.719.5–23.9
Dosage
>500 mg74653.851.2–56.5
>600 mga42530.728.2–33.1
Association with vitamin D
Low risk00
High risk (<800 UI/day)53938.936.3–41.4
High risk (>4000 UI/day)10.10.0–0.2

Overall, 85.8% of patients met at least one criterion of inappropriate supplementation. This figure decreased to 78.3% when we used the 600-mg threshold for the dosage inappropriateness criterion. When we assessed inappropriateness according to sex, no differences were found in overall or individual inappropriateness criteria (data not shown).

Discussion

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgments
  9. References

Our study shows a prevalence of prescription of calcium and/or vitamin D supplements among adults aged 50 years and over of around 17%, eight times higher for women compared with men, and mainly as calcium and vitamin D associated in fixed-dose combinations. As expected, older age, antiosteoporotic treatment, use of glucocorticoids, and diagnosis of osteoporosis were related to supplement prescription. The strength of these associations was notably higher for men than for women, and the presence of other secondary causes of osteoporosis determined supplementation only in men. It is worth noting that calcium dietary intake was not related to the prescription of supplements in either men or women. The most striking result of our study was the high rate of inappropriateness in calcium prescription, even when using lax criteria for defining appropriateness. This was mainly because of overdosing of calcium supplements and undertreatment or underdosing of vitamin D when prescription of the latter was indicated among calcium users.

Prescription of calcium or vitamin D and its determinants

With regards to frequency of prescription, comparisons with other studies are limited because most studies have assessed use among osteoporotic patients or in relation to antiosteoporotic treatment only,[26, 40, 41] with an expected higher supplementation prevalence than that seen in our population. The lower proportion of men, compared with women, receiving supplements is consistent with other studies, which have found that calcium and vitamin D supplement use is lower among men, even in patients who have suffered hip fractures.[10, 27, 28]

Regarding mean intakes of calcium, comparisons are also limited because previous studies used data from nationwide nutrition and health surveys[9, 10] or samples with specific characteristics (ie, patients with osteoporosis[13, 42] or low BMD[24]). Overall, the results of these studies suggest that older adults from North America have lower mean intakes of calcium from both diet and supplements, whereas data from Europe[42] and Australia[11, 12] show calcium intakes from food in women similar to, or higher than, those seen among women in the ESOSVAL cohort (852 to 966 mg/day versus 872 mg/day in the present study). Concerning total intakes (food plus supplements), studies among Australian[11] or European[13] women show lower intakes than those seen in the present study in most of the countries (586 to 1019 mg/day versus 1057 mg/day in our study), but similar or higher intakes in women from Germany, the United Kingdom, and Denmark (1060 to 1145 mg/day versus 1057 mg/day), although in those studies women were older or had been diagnosed with osteoporosis. Regarding calcium intake by sex, North American studies have reported men having higher intakes from diet when compared with women,[9, 10] whereas our results, and consistent with data from nutritional surveys in Spain,[5] show the opposite trend.

Concerning factors associated with supplement use, a study in the United States, in line with our results, found that osteoporosis diagnosis and antiosteoporotic treatment were related to the intake of calcium supplements among men and women.[9] A study among French women with osteoporosis[40] found that only treatment with bisphosphonates (and no other antiosteoporotic drugs) was related to supplement prescription. Similarly to us, they also found that having a densitometry test was related to supplement prescription. Unlike our study, Ma and colleagues[9] found that higher education and higher income were positively related to calcium intake, but their sample was composed of men and women older than 19 years. To our knowledge, other relevant factors considered in our study such as calcium dietary intake have not been considered in previous studies.

Inappropriateness of the prescription of calcium supplements

We have found no studies assessing calcium supplement inappropriateness in a similar fashion to that used in the present study, but a retrospective study assessing charts from older patients attending an internal medicine practice in the United States[27] also reported low appropriateness for calcium and vitamin D supplementation for men (6.5% and 2.1%) and women (32.3% and 21.7%). Unlike us, they found differences in appropriateness rates according to sex. However, the criteria to define appropriateness were not described in detail. The inappropriate daily total calcium intake observed in our study was basically owing to overpassing the upper limits in those patients with calcium supplements (only a very low percentage corresponded to people not reaching recommended intakes). The fact that one in five patients who consumed calcium supplements exceeded a total intake of 2000 mg/day becomes a major concern, especially when recent evidence suggests potentially serious adverse effects of calcium supplementation (such as higher cardiovascular risk,[21, 22] especially with elevated doses[23]). Calcium supplements can also produce digestive discomfort and constipation and may increase the risk of hospitalization for gastrointestinal problems.[43, 44] Higher calcium intakes from supplements (not from diet) have also been associated with an increased risk of kidney stones.[45] Paradoxically, it has also been suggested that higher doses of calcium supplements increase the risk of a hip fracture.[19, 44] Concerning the inappropriateness of a calcium dosage, half of the calcium supplement users were prescribed quantities higher than 500 mg per dose (one-third if we set the threshold at 600 mg per dose). It has been shown that calcium absorption is hindered at quantities higher than 500 mg per dose[35] and no further beneficial effect is achieved. Furthermore, in a population with relatively high basal intakes from diet (as is the case for this cohort, especially for women), prescribing high-dose supplements increases the likelihood of exceeding the safety limits and subsequently increases the risks of adverse events. Lastly, regarding association with vitamin D among calcium supplement users, the finding that 40% of patients (all of them of high risk) were given vitamin D supplements at low doses or no supplements at all is also worrisome.

The excess in daily calcium intake (diet plus supplements) could be in part avoidable if physicians took into account calcium dietary intake before prescribing supplements (which was not the case in our study). Calcium intakes from food can be easily calculated and recorded in the Valencia Region through a calcium score included in the EMR. Furthermore, it is important to note that the inappropriate pharmaceutical strengths of commercial fixed-dose calcium and vitamin D combinations, commonly prescribed in Spain, are likely to contribute to the high inappropriateness found. These associations usually contain doses higher than 500 mg of calcium element per tablet but low doses of vitamin D, and thus their use may result in an excessive consumption of calcium without ensuring a sufficient intake of vitamin D. Considering the likelihood of vitamin D deficiency among older adults in Mediterranean areas[46] and taking into account the concerns regarding excessive calcium intake mentioned above, it could be reasonable to issue recommendations for physicians to prescribe vitamin D supplements alone rather than associated with calcium, unless a calcium insufficiency exists. This recommendation is also supported by the low adherence observed for calcium and vitamin D associations[47] that could threaten vitamin D intake.

Some potential limitations of the present study should be addressed. First, regarding the external validity of our results, the ESOSVAL cohort includes patients who attend the primary healthcare centers of the Valencia region, making them slightly different from the general population (people who attend medical centers tend to be sicker than the average population, and, on the other hand, people with disabilities or who are very sick and cannot attend healthcare centers are not represented). Furthermore, the ESOSVAL cohort represents the population of a Spanish region (with 11% of the overall Spanish population), and these results cannot necessarily be extrapolated to other regions or to the entire Spanish population, especially because some studies have shown a considerable variability in hip fracture rates and antiosteoporotic treatment between different territories in the same country.[48] Second, the data sources used did not allow us to account for the over-the-counter purchase of calcium and vitamin D supplements, prescriptions dispensed in pharmacies located outside the region, or supplements prescribed by private doctors, and could lead to an under-registration of supplementation use. We have no information about the volume of supplements obtained in these situations, but we expect it to be of little importance because the Valencia Health Agency covers almost the entire population of the Valencia region. Third, it is also worth acknowledging that appropriateness criteria are rather subjective, and probably inappropriateness in the different criteria does not have the same potential for adverse effects. However, these criteria are in line with the recommendations of the most relevant international societies and guidelines regarding this aspect and are based on the most recent evidence. Additionally, they represent a lax perspective of inappropriateness, accounting for the more obvious inappropriate prescribing but not dealing with the more debatable issues. Finally, as expected in a study with the characteristics of ESOSVAL, developed under routine clinical practice conditions, some variables have a large percentage of missing data. The effect of missing data is difficult to estimate and may vary depending on the risk factors, but we do not expect it to be different between calcium and vitamin D users and nonusers. In any case, this potential bias would have a very low impact on the assessment of appropriateness because the variables included in the appropriateness criteria had few missing values.

The present study is, to the best of our knowledge, the first to assess with predefined criteria (other than reaching nutritional recommendations) the appropriateness of calcium supplement prescription in a large population cohort. The high level of inappropriate use found is of special concern when most of the inappropriate prescriptions result in calcium supplement overdosing and currently there is a worldwide debate about the safety of calcium, as well as when its association with vitamin D is absent or underdosed in almost half of calcium users (all at high risk). Until more evidence sheds some light on current safety concerns about calcium and vitamin D supplementation, some measures could be useful for a wise prescription of supplements: 1) to assess and consider calcium dietary intakes before supplementation, recommending an increase in intake from food when possible and if necessary; 2) to adapt commercial fixed-dose associations to facilitate meeting dose recommendations; 3) to encourage the prescription of low calcium doses and high vitamin D doses when given in fixed-dose combinations and to prescribe vitamin D alone when calcium is not necessary.

Disclosures

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgments
  9. References

All authors declare no support from any organization for the submitted work. JSG and SP have received research grants from various pharmaceutical companies (see funding of the ESOSVAL project below) and fees for participation in scientific meetings sponsored by pharmaceutical companies.

Acknowledgments

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgments
  9. References

We are grateful to all doctors and nurses at the Valencia Health Agency primary healthcare centers participating in the ESOSVAL study for their collaboration and to the Valencia Health Agency for its enthusiastic and continued support of the ESOSVAL research projects. The ESOSVAL research program is funded by the Instituto de Salud Carlos III (Grants PS09/02500 and PI11/00238) under the Spanish Ministry of Health and Social Policies, the 2009, 2010, and 2011 collaboration agreements between MSD Spain, the Fundación para el Fomento de la Investigación Sanitaria y Biomédica (FISABIO), and the Valencia Health Agency to conduct training and research into musculoskeletal disorders and osteoporosis, and the 2010 and 2012 collaboration agreement between AMGEN and the Centro Superior de Investigación en Salud Pública (CSISP) of the Valencia Health Agency. In 2011, JSG was partially funded by the Instituto de Investigación Sanitaria INCLIVA through grant INT10/122 from the Spanish National Health System program for the stabilization of research and intensification of research activity, and GSG was partially funded by the ASISA Harvard Fellowship for Excellence in Clinical Research and the Carlos III Health Institute (BA11/00053). The organizations funding the research project do not necessarily share the contents of this manuscript. None of the sponsors played any role in the design of the ESOSVAL studies, the collection, analysis, or interpretation of data, the writing of the manuscript, or in the decision to submit it for publication.

Authors' roles: GSG had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. JSG, GSG, and SP were responsible for the study concept, design, and, with IH, for data acquisition. CLRB and IH carried out the data preparation. GSG and CLRB carried out the statistical analysis and drafted the manuscript. All authors participated in the analysis and interpretation of data, the critical revision of the manuscript for important intellectual content, and all approved the final version submitted for publication.

References

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgments
  9. References
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