The authors have no conflict of interest.
Vitamin D and Calcium Supplementation Prevents Osteoporotic Fractures in Elderly Community Dwelling Residents: A Pragmatic Population-Based 3-Year Intervention Study†
Version of Record online: 22 DEC 2003
Copyright © 2004 ASBMR
Journal of Bone and Mineral Research
Volume 19, Issue 3, pages 370–378, March 2004
How to Cite
Larsen, E. R., Mosekilde, L. and Foldspang, A. (2004), Vitamin D and Calcium Supplementation Prevents Osteoporotic Fractures in Elderly Community Dwelling Residents: A Pragmatic Population-Based 3-Year Intervention Study. J Bone Miner Res, 19: 370–378. doi: 10.1359/JBMR.0301240
- Issue online: 2 DEC 2009
- Version of Record online: 22 DEC 2003
- Manuscript Accepted: 30 OCT 2003
- Manuscript Revised: 8 SEP 2003
- Manuscript Received: 26 MAY 2003
- accidental falls;
- home safety;
- vitamin D
This study of 9605 community-dwelling residents supports that vitamin D and calcium supplementation may prevent osteoporotic fractures in elderly in a northern European region known to be deficient in vitamin D, especially during winter periods.
Introduction: We evaluated the effect of two programs for the prevention of osteoporotic fractures leading to acute hospital admission in a population of elderly community-dwelling residents.
Materials and Methods: This was a factorial, cluster-randomized, pragmatic, intervention study. We included 9605 community-dwelling residents aged 66+ years. We offered a prevention program of a daily supplement of 1000 mg of elemental calcium as calcium carbonate and 400 IU (10 μg) of vitamin D3 to a total of 4957 participants. Another program with evaluation and suggestions for the improvement of the domestic environment was offered to a total of 5063 participants. Both programs included revision of the resident's current pharmaceutical treatment. We achieved information on osteoporotic fractures in the study population from the Danish Hospital Registration Database. We defined osteoporotic fractures as low energy fractures of the proximal humerus, distal forearm, vertebral column, pelvis, cervical femur, and intertrochanteric femur.
Results: Active participation was 50.3% in the Calcium and Vitamin D Program and 46.4% in the Environmental and Health Program. We observed a 16% reduction in fracture incidence rate (relative risk [RR], 0.84; CI, 0.72–0.98; p < 0.025) among male and female residents offered the Calcium and Vitamin D Program (intention-to-prevent analysis).
Conclusions: This study supports that vitamin D and calcium supplementation may prevent osteoporotic fractures in community-dwelling elderly people in a northern European region known to be deficient in vitamin D, especially during winter periods.
FALLS AND FRACTURES among elderly people living in the community constitute a major public health problem.(1, 2) Twenty percent of the elderly who suffer a hip fracture die within the first year after the fracture.(3, 4) Furthermore, in many geographical regions, the risk of vertebral fracture and hip fracture among elderly people has increased significantly during the last decades.(5, 6)
Osteoporosis is characterized by a reduction in bone mass with age,(7, 8) contributing to a loss in bone strength.(9, 10) It is biologically plausible that slowing the progressive bone loss by use of vitamin D and calcium supplementation(11, 12) may reduce fracture rates. There is some epidemiological evidence for this,(13, 14) but the effectiveness of preventive intervention, including vitamin D and calcium supplementation, needs further documentation, including fracture outcomes.(15) Moreover, osteoporosis is associated with a decrease in muscle mass and muscle strength, suggesting that the loss of bone and muscle tissue may be related.(16–19) Finally, elderly with a low dietary intake of calcium and vitamin D, a low cutaneous production of vitamin D, and/or a decreasing renal production of calcitriol [1,25(OH)2D] may be at risk for falls and fractures owing to myopathy caused by vitamin D deficiency and secondary hyperparathyroidism.(20-25)
In a Dutch study, prevention of osteoporotic fractures by treatment of 400 IU vitamin D3 in one tablet daily showed no protective effect compared with placebo among community-dwelling participants that were, on average, 80 years of age.(26) However, daily treatment with tricalcium phosphate tablets containing 1.2 g of elemental calcium and 800 IU vitamin D3 reduced the number of hip fractures in institutionalized vitamin D-deficient elderly French people after 18 months.(27) Furthermore, in elderly U.S. citizens with a mean age of 71 years, daily treatment with 500 mg calcium and 700 IU vitamin D3 tablets significantly reduced the total number of nonvertebral fractures.(28) Finally, 100,000 IU oral vitamin D3 supplementation given every fourth month over 5 years (15 doses in total) significantly reduced the number of fractures of the hip, wrist, forearm, and spine compared with placebo in elderly British men and women 65–85 years of age.(29)
The possible role of environmental hazards is poorly documented.(30, 31) Whether there are beneficial effects of fracture prevention programs among elderly community residents is still a matter of debate, because of conflicting findings in the small number of published studies.(32, 33) Fall prevention programs have effectively reduced falls in elderly people, using multifaceted approaches that include various combinations of education, exercise, medication assessment, risk factor reduction, and environmental modifications.(34–38) However, there is little evidence as yet to what extent interventions to prevent falls will also prevent hip or other fall-associated fractures. The British EPOS study concludes that modification of lifestyle risk factors is unlikely to have a major impact on the population occurrence of vertebral fractures.(39) Hip protectors seem to be effective in preventing hip fractures, but acceptability and compliance in community-dwelling women may be low.(40, 41)
In this factorial study we evaluated the effect of two programs for the prevention of fractures leading to acute hospital admission in a population of elderly community-dwelling Danish residents. One program included the provision of vitamin D and calcium, whereas the other program offered an evaluation of and suggestions for the improvement of the domestic environment. Both programs included revision of the resident's current pharmaceutical treatment.
MATERIALS AND METHODS
Study population and intervention
The study design has been presented previously.(42) In January 1995, we identified, in the Danish Central Population Registry, all 9605 community dwelling residents 66 of age and older (women, 5771; men, 3834; median age, 74.0 years; range, 66–103 years) in the municipality of Randers, Denmark (population, 62,000). We excluded elderly who were living in nursing homes (4.9%) and severely impaired persons living in sheltered homes for the elderly (6.8%), as well as elderly with mental retardation who were unable to give informed consent. We obtained information on the occurrence of osteoporotic fractures in the study population from the Danish Hospital Registration Database. We defined osteoporotic fractures as low-energy fractures including the proximal humerus, distal forearm, vertebral column, pelvis, cervical femur, and intertrochanteric femur.
For the present purpose, we divided the municipality into four comparable blocks, each comprising two to three public social service centers, which collected the data. We allocated the four blocks at random to three different fracture prevention programs and no intervention. We offered a home safety inspection by a community nurse to participants in the first block (N = 2532 residents; median age, 73.0 years; range, 66–98 years; women, 59.8%) to identify and remedy possible hazards (Environment and Health Program). We furthermore offered identification and correction of potential health or dietary problems. Finally, the nurse evaluated the resident's prescribed medication to identify possible errors or necessary dose adjustments. Those who accepted a home visit in this area were given leaflets with information of different ways to avoid falling. We offered participants in the second block (N = 2426 residents; median age, 74.0 years; range, 66-103 years; women, 58.0%) a daily supplement of 1000 mg of elemental calcium as calcium carbonate and 400 IU (10 μg) of vitamin D3 (Calcichew D; Nycomed DAK) (Calcium and Vitamin D Program). The vitamin D and calcium supplementation were delivered free of charge at the local pharmacies by showing a check card every second month. Furthermore, we offered these participants an evaluation of their prescribed medication, as mentioned above. This revision also ensured that the elderly took no other types of calcium and vitamin D products. If the elderly used cardiovascular medicine (digoxin or calcium antagonists) that may interact with calcium, they were referred to their general practitioner. Those who accepted a home visit were given leaflets with information of different ways to avoid osteoporosis. We offered a combination of the two programs (Both Programs) to participants in the third block (N = 2531 residents; median age, 75.0 years; range, 66-103 years; women, 62.3%).
In the present factorial design, a total of 5063 residents were offered the Environment and Health Program and 4957 residents were offered the Calcium and Vitamin D Program. The last block (N = 2116 residents; median age, 74.0 years; range, 66–98 years; women, 60.2%) was offered no intervention at all and served as a control population.
We informed all municipal residents 66+ years of age by mail that a home visit by a community nurse would be offered during the spring of 1995. One of the authors (ERL) trained the nurses at the eight public social service centers in fracture prevention. All intervention was free of charge. Nonrespondents were recontacted twice by mail or phone. Furthermore, one-fourth of the elderly in the prevention areas consented to participate in meetings, where details of the project were specified.
We followed the total elderly population, participants as well as nonparticipants, from January 1995 to June 1998 (42 months), using the Danish Hospital Registration Database and the Danish Central Population Registry. The Danish Hospital Registration Database is a computer-based register run by the Danish Board of Health including all discharges from Danish hospitals.(43) The register was founded in 1977 and is linked with other registers through the nationwide Danish Central Population Registry. This register assigns each inhabitant in Denmark a unique Civil Registration Number. On admission to a hospital, the dates of admission and discharge are recorded along with a diagnosis (ICD8 or ICD10) for the actual admission. If surgical procedures are performed, codes for these are also entered into the register. We defined osteoporotic fractures as low-energy fractures of the proximal humerus, the distal forearm, the spine, the pelvis, the cervical femur, and the intertrochanteric femur (ICD8 codes: 805.09, 805.10, 805.11, 805.19, 805.99, 808.08, 808.09, 812.00, 812.01, 812.02, 812.08, 812.09, 812.19, 813.20, 813.21, 813.28, 813.29, 813.99, 820.00, 820.01, 820.02, 820.08, 820.09; ICD10 codes: S122A-E, S127, S129, S220, S220A-L, S320, S320A-E, S325, S328A-C, S422, S422A-C, S423, S423A, S429, S525, S525A-C, S526, S528, S529, S720, S721, S721A-B, S728A). We only included the first (incident) osteoporotic fracture in the follow-up-period leading to hospital admission with or without overnight stay in this analysis. We calculated the risk time included in the osteoporotic fracture incidence rate as the time from start of intervention (spring 1995) to a censoring event (death; leaving the city; first admission to a Danish hospital after an osteoporotic fracture). We did not analyze the consequences of residents shifting address within the city during follow-up, because the address at inclusion was used to identify the type of intervention.
We mailed a self-administered questionnaire to the elderly residents in the total area to obtain information on paternal fractures, maternal fractures, present height, and present weight. A checklist filled in by the community nurse yielded information on medication and fractures after the age of 45 years.
We performed blood tests at baseline, after 1 month, and after 2 years in two random subsamples of residents offered the Calcium and Vitamin D Program (n = 67; median age, 73 years; range, 66–88 years) and residents serving as controls (n = 37; median age, 71 years; range, 66-84 years). We measured plasma levels of calcium, creatinine, alkaline phosphatase (ALP), 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)2D], and intact parathyroid hormone (PTH). Total plasma calcium was corrected for individual variations in albumin according to the following formula: adjusted plasma calcium (mM) = plasma calciumtotal (mM) − 0.00086 × [650 − plasma albumin (μM)]. Laboratory 95% reference values were 2.20-2.52 mM. Plasma intact PTH was measured by an IMMULITE automated analyzer (Diagnostic Products Corp., Los Angeles, CA, USA). The inter- and intra-assay CVs were 7%, and 6%, respectively, and reference values were 1.3-7.6 pM. Plasma 25(OH)D was measured by an equilibrium radioimmunoassay (RIA) procedure (DiaSorin, Stillwater, MN, USA). The inter- and intra-assay CVs were 13%, and 10%, respectively. Reference values were 20-80 nM in January and February and 40-160 nM in July and August. We considered a value <50 nM as below the threshold that predisposes to secondary hyperparathyroidism.(44) Quantification of 1,25(OH)2D was achieved by a competitive radioreceptor assay (1,25-Dihydroxyvitamin D kit; Nichols Institute Diagnostics, San Juan Capistrano, CA, USA). The inter- and intra-assay CVs were 13% and 10%, respectively. Reference values were 40-160 pM. ALP was measured spectrophotometrically using an automated instrument (Hitachi 917; Roche Diagnostics). The total CV was less than 8%. Reference range was 80-275 U/liter.
We included bi- and multivariate Cox regression analyses in the statistical analysis.(45, 46) We reduced regression models by use of forward selection of variables, applying the χ2 distributed −2 ln (likelihood ratio) as a significance test. We used p < 0.10 as a general level of significance and log-minus-log survival plots to confirm the proportional hazards model. We analyzed intervention effect by use of the intention to prevent principle. We used Student's t-test for paired data to compare means of biochemical values, which were approximately normally distributed. All p values were two-tailed.
Ethics and permissions
The study is in agreement with the Helsinki declarations, and the regional committee for ethics in science approved the study. The Danish National Registry Inspectorate permitted the development of the data project's database.
Background profile and mortality
The median age of the 9605 community residents was 74.0 years (range, 65–103 years). There were 5771 (60.1%) women and 3834 (39.9%) men. A total of 5.7% had never been married; 49.1% were married; 7.7% were divorced, and 37.5% were widowed. During follow-up, a total of 1671 (17.4%) of the subjects died (14.8% among women versus 21.4% among men; p < 0.001). The difference in mortality did not result in any substantial difference in mean risk time between the two genders (women: mean risk time, 3.10 years; total observed no. of years, 17,910; men: mean risk time, 3.08 years; total observed no. of years, 11,821). Four women and two men left the city during follow-up.
Table 1 compares register-based baseline characteristics for all residents offered calcium and vitamin D intervention and all residents not offered calcium and vitamin D. Elderly offered calcium and vitamin D were significantly older than the rest, but the mean difference was only 0.5 years. A subanalysis disclosed that in the 80- to 89-year group, a significantly higher percentage was offered calcium and vitamin D than no treatment. The two groups were comparable with respect to gender, and there were only minor differences in marital status. It should be noted that there was no difference between the two groups in fracture occurrence before intervention, despite the slightly higher age in the calcium and vitamin D group.
A total of 51.6% of the women versus 46.1% of the men accepted to participate in the programs (p < 0.001). Participation was 47.8% among the 2532 residents who were offered the pure Environment and Health Program, 55.7% among the 2426 residents offered the pure Calcium and Vitamin D Program, and 45.0% among the 2531 residents offered both programs. Consequently, 46.4% of all 5063 residents who were offered the Environment and Health Program and 50.3% of all 4957 residents offered the Calcium and Vitamin D Program participated in the study. Table 2 compares questionnaire-based baseline characteristics for residents actually participating in the study. There was no difference in the occurrence of paternal and maternal fractures between the two groups. Furthermore, there was no difference in percentage of fractures after the age of 45 years until inclusion or in percentage of fractures during the years 1990–1994 immediately before study start. The questionnaire-based background characteristics among those without calcium and vitamin D supplementation (n = 2178) showed a higher proportion of bronchitis (19.3% versus 15.9% among elderly offered calcium and vitamin D (n = 2895; p < 0.001). No differences in the proportion of other diseases were found. However, we found a difference in the use of medication among the two intervention groups. A higher proportion of elderly without calcium and vitamin D supplementation used cardiovascular medicine (28.8% versus 25.1% among elderly accepting calcium and vitamin D supplementation, p < 0.05); sedatives (12.1% versus 8.8%, p < 0.005); analgesics (30.2% versus 24.5%, p < 0.001); nonsteroidal anti-inflammatory drugs (NSAIDs; 12.1% versus 10.0%, p < 0.001); estrogen (13.0% versus 9.2%, p < 0.001), and calcium (7.2% versus 5.3%, p < 0.05).
Osteoporotic fractures and correlates of fractures
We found an overall increase in the incidence of fractures of all types among both genders during 1995–1998 (Table 3). The total number of osteoporotic fractures leading to acute hospital admission in the entire follow-up period was 1084. Six hundred fifty-six individuals experienced at least one osteoporotic fracture (women, 543 fractures; fracture incidence rate, 30.3 per 1000 years versus men, 113 fractures; fracture incidence rate, 9.6 per 1000 years; relative risk [RR], 3.1; p < 0.0001) The fracture incidence rate increased substantially with age in both genders (women: age 66-69 years, 16.9 per 1000 years; age 90+ years, 76.1 per 1000 years; RR, 4.3; p < 0.001; men: age 66-69 years, 4.5 per 1000 years; age 85+ years, 28.7 per 1000 years; RR, 6.2; p < 0.001). Widows and widowers sustained fractures relatively often (widows, fracture incidence rate 35.9 per 1000 years, versus 25.0 per 1000 years among all other women; RR, 1.4; p < 0.001; widowers, 16.1 per 1000 years, versus 8.1 per 1000 years among all other men; RR, 2.0; p < 0.001).
Table 4 shows the risk of osteoporotic fractures in the different treatment groups compared with controls and analyzed according to the intention to prevent principle. The risk estimate given is based on bivariate, multivariate mutually balancing programs, and multivariate, mutually balancing programs corrected for age (years) and marital status, respectively. Based on the last principle fracture, risk was significantly reduced among women offered the Calcium and Vitamin D Program (RR, 0.78; 95% CI, 0.63–0.96), among women offered the Environmental and Health Program (RR, 0.82; 95% CI, 0.67-1.00), and among women offered both programs (RR, 0.73; 95% CI, 0.58-0.93) compared with no treatment. Fractures were relatively rare in the elderly men, and no significant intervention effect was observed in this gender. An analysis based on those participating in the programs (per protocol analysis) disclosed the same tendencies (Table 5).
In the final multivariate analyses (Table 6), both genders analyzed together had a decreased fracture risk when offered the Calcium and Vitamin D Program (RR, 0.84; 95% CI, 0.72–0.98; p < 0.025) compared with those not receiving calcium and vitamin D (Table 6; Fig. 1). Female residents offered the Calcium and Vitamin D Program also had a decreased risk (Table 6) when analyzed separately (RR, 081; 95% CI, 0.68-0.95; p < 0.01). Furthermore, women were found to have a relatively high risk of fractures, and the tendency of sustaining a fracture increased with each year of age. This increase was also found in the men 80 of age and older. Male widowers had a relatively high risk of sustaining a fracture.
Forty-six elderly sustained multiple fractures during the intervention period (40 women and 6 men). No association of the intervention programs and multiple fractures were found, probably because of the small number. Two hundred ninety-three elderly experienced an osteoporotic cervical fracture or an intertrochanteric hip fracture (221 women and 72 men). In the multivariate analyses, both genders analyzed together had a marginally significant decreased fracture risk when offered the Calcium and Vitamin D Program (RR, 0.82; 95% CI, 0.65–1.04; p < 0.10).
No significant difference was found in baseline 25(OH)D and PTH between those who were offered the Calcium and Vitamin D Program and control residents (Table 7). On average, 80% had a baseline serum 25(OH)D below 50 nM. One month after initiation of treatment with calcium and vitamin D, the mean 25(OH)D had increased significantly (p < 0.001), and the mean PTH had decreased (p < 0.001) in the Calcium and Vitamin D group compared with baseline levels. This difference was maintained after 24 months. Furthermore, plasma levels of ALP decreased (p < 0.01). In the control group, no significant changes in serum values were found during the intervention period. After 1 and 24 months, respectively, 66% in the Calcium and Vitamin D group and 80% of the controls still had plasma 25(OH)D levels below 50 nM.
The essential finding of this study was a reduced risk of fractures among elderly community-dwelling residents who were offered vitamin D and calcium supplementation compared with the control group and those not receiving calcium and vitamin D. The study was not randomized at the individual level, because this would have introduced a Hawthorne effect,(47) in particular, compromising the health and environmental intervention because of interaction and discussion between experiment and control participants. The study was not planned to test the biological effects of vitamin D and calcium or the causal associations between health education and fall prevention and fracture risk. The aim of this study was to monitor and compare the overall effect of two types of realizable preventive programs in a pragmatic study design imitating normal daily conditions.
The reason why previous studies of the effect of vitamin D and calcium may have been in conflict with this study(26) may be that only a limited group of the elderly actually is at increased risk, defined by a 25(OH)D plasma level below a certain cut-off value. In our study, we excluded elderly who lived in nursing homes, who were severely impaired persons living in sheltered homes for the elderly, and who had dementia. These groups may have an even higher risk of vitamin D deficiency than the general elderly population,(27, 48–49) and consequently, experience a greater effect of treatment.(27, 50)
The statistical analysis was performed according to the intention-to-prevent principle and included fractures among all individuals, irrespective of whether they took active part in the intervention program or not and of their compliance. Acceptance of the offered preventive program depended on gender, age, marital status, and the motivation and attitude of the health workers.(42) There may have been a health selective preference of participation in the two preventive programs. Relatively healthy subjects may have consented to participate in the Calcium and Vitamin D Program, whereas the relatively impaired elderly may have agreed to participate in the Environment and Health Program. This could also explain why some, elderly men in particular, who participated in the Environment and Health Program, had an increased risk compared with the other intervention blocks. Another possible explanation may be a reduced fear of falling and a higher confidence and thus higher risk taking among those participating in the program.
To improve the effect of the Environmental and Health Program, it seems relevant to consider a physiotherapist for exercise training, an occupational therapist for assessing environmental hazards, and supervising modifications or a home visit by a nurse with several follow-up visits or phone calls to maintain knowledge and motivation among the elderly.(34–38)
The reduced fracture risk among the elderly who were offered the Calcium and Vitamin D Program may have several biological explanations. This finding has to be interpreted in relation to the expected vitamin D status in the population, the biological effects of vitamin D and its active metabolites on bone strength and muscle function, and other known physiological conditions that may affect the fracture risk. In this study, about 80% of the subpopulation who had blood samples drawn at baseline had plasma 25(OH)D levels below 50 nM. Furthermore, calcium and vitamin D supplementation resulted in a significant increase in mean plasma 25(OH)D and a significant reduction in mean plasma PTH compared with controls. This supports the concept of vitamin D deficiency in a proportion of the population.
In 3270 elderly French women living in nursing homes, a daily supplementation of 800 IU vitamin D and 1200 mg calcium after 3 years reduced plasma PTH by 28% compared with placebo.(50) The treatment also normalized plasma 25OH vitamin D levels and reduced the number of hip fractures by 23%. In elderly British men and women who participated in a randomized double-blind placebo-controlled trial with 100,000 IU oral vitamin D3 supplementation every fourth month over 5 years, the total fracture incidence was reduced by 22%, and fractures in major osteoporotic sites were reduced by 33%. The mean vitamin D concentrations were 40% higher in the active treatment group than in the placebo group. Mean parathyroid concentrations were 6% lower, but this difference was not significant.(29) This study indicates that vitamin D alone without calcium supplementation seems to have fracture prevention potential. Studies of vitamin D status among elderly 65 years of age and older in Denmark, who do not take supplementary vitamin D, have shown average plasma levels of 25(OH)D of 50 nM (range, 27–73 nM).(48) In a Norwegian study, the levels were found to be below 50 nM in 40% of community female residents.(49) The deficiency of vitamin D and calcium among elderly Danes has been shown to some extent to be caused by low intake of vitamin D (2-3 μg/day; recommended intake, 5 μg/day) and of calcium (<700 mg/day in 10% of women; recommended intake, 1000 mg/day).(51) In contrast to most other developed countries, the diet is not fortified with vitamin D in Denmark.(52) Furthermore, the cutaneous production of vitamin D is discontinued during low wintertime sun exposure caused by the relatively high latitude (56° N).(53)
In conclusion, the findings in this factorial study of two preventive programs support that vitamin D and calcium supplementation may prevent osteoporotic fractures in community-dwelling elderly people. Further support for the findings should be sought based on large-scale preventive trials randomized at the individual level.
This study was supported by The Danish Osteoporosis Association; The Local Health Service in Randers, Randers Central Hospital, Aarhus County; The Pharmacy Association of 1991; The Danish Health Foundation; and Nycomed DAK. Furthermore, Nycomed DAK supplied the free calcium and vitamin D tablets (Calcichew).
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