Vitamin D and vitamin D analogues with or without calcium supplement for preventing fractures in post-menopausal women and older men

Vitamin D plus calcium can help prevent hip fracture or any type of fracture. Vitamin D alone, in the doses and formulations that have been used, appears unlikely to be effective in fracture prevention in older people.

Summary

• A Cochrane review included 53 studies with a total of 91 791 subjects. Thirty-one trials, with sample sizes ranging from 70 to 36 282 participants, examined vitamin D (including 25-hydroxy vitamin D) with or without calcium in the prevention of fractures in community, nursing home or hospital inpatient populations. Twelve of these 31 trials had participants with a mean or median age of 80 years or over. 22 smaller trials examined calcitriol or alfacalcidol (1-alphahydroxyvitamin D3), mostly with participants who had established osteoporosis. These trials were carried out in the setting of institutional referral clinics or hospitals.
• Vitamin D alone, in the formats and doses tested, did not prevent hip fracture (11 trials, 27 693 participants; RR 1.12, 95% CI 0.98 to 1.29)or any new fracture (15 trials, 28 271 participants; RR 1.03, 95% CI 0.96 to 1.11).
• Vitamin D plus calcium resulted in a small reduction in hip fracture risk (9 trials, 49 853 participants; RR 0.84, 95% CI 0.74 to 0.96. In low-risk populations (residents in the community: with an estimated eight hip fractures per 1000 per year), this equates to one fewer hip fracture per 1000 older adults per year (95% CI 0 to 2). In high risk populations (residents in institutions: with an estimated 54 hip fractures per 1000 per year), this equates to nine fewer hip fractures per 1000 older adults per year (95% CI 2 to 14). Vitamin D plus calcium reduced the risk of any type of fracture (10 trials, 49 976 participants; RR 0.95, 95% CI 0.90 to 0.99).
• Two trials of alfacalcidol suggested that vertebral fractures may be prevented by taking alfacalcidol (two trials, 872 participants, RR 0.57, 95% CI 0.49 to 0.65), although the evidence did not suggest prevention of hip or non-vertebral fractures. The effect of calcitriol in fracture prevention was unclear, but it was associated with a statistically significant increase in risk of hypercalcaemia (4 trials, 988 participants, RR 4.41, 95% CI 2.14 to 9.09).

Treatment meta-analyses

• A Cochrane review included 45 studies with a total of over 50.000 subjects. The studies compared vitamin D or an analogue, alone or with calcium, against placebo, no intervention, or calcium, reporting fracture outcomes in older people. Vitamin D alone showed no statistically significant effect on hip fracture (RR 1.15, 95% CI 0.99 to 1.33; 9 trials, n=24 749), vertebral fracture (RR 0.90, 95% CI 0.42 to 1.95; 5 trials, n=9 138) or any new fracture (RR 1.01, 95% CI 0.93 to 1.09; 10 trials, n=25 016). Hypercalcaemia was more common when vitamin D or its analogues was given compared with placebo or calcium (RR 2.35, 95% CI 1.59 to 3.47; 18 trials, n=11 346).
• In a patient level analysis seven major randomised trials of vitamin D with calcium or vitamin D alone were pooled, yielding a total of 68 517 participants (mean age 69.9 years, range 47-107 years, 14.7% men). Trials using vitamin D with calcium showed a reduced overall risk of fracture (hazard ratio 0.92, 95% confidence interval 0.86 to 0.99, P=0.025) and hip fracture (all studies: 0.84, 0.70 to 1.01, P=0.07; studies using 10 microg of vitamin D given with calcium: 0.74, 0.60 to 0.91, P=0.005). For vitamin D alone in daily doses of 10 microg or 20 microg, no significant effects were found.
• A pooled meta-analysis on vitamin D dose requirements for fracture prevention included 11 studies with a total of 31.022 participants. Participants who were randomly assigned to receive vitamin D, as compared with those assigned to control groups, had a nonsignificant 10% reduction in the risk of hip fracture (RR 0.90; 95% CI 0.80 to 1.01) and a 7% reduction in the risk of nonvertebral fracture (RR, 0.93; 95% CI, 0.87 to 0.99). By quartiles of actual intake, reduction in the risk of fracture was shown only at the highest intake level (median, 800 IU daily; range, 792 to 2000), with a 30% reduction in the risk of hip fracture (RR 0.70; 95% CI 0.58 to 0.86) and a 14% reduction in the risk of any nonvertebral fracture (RR 0.86; 95% CI 0.76 to 0.96). Benefits at the highest level of vitamin D intake were fairly consistent across subgroups defined by age group, type of dwelling, baseline 25-hydroxyvitamin D level, and additional calcium intake. However, in 5 of the included studies D-vitamin was used in combination with calcium. In the remaining 6 studies with vitamin D as monotherapy, 4 gave negative and 2 gave positive results for fracture prevention.
• In a meta-analysis on effects of vitamin D supplements on bone mineral density, 23 studies with 4082 participants, 92% women, average age 59 years met the inclusion criteria. 8 studies were from Scandinavian countries. Mean baseline serum 25-hydroxyvitamin D concentration was less than 50 nmol/L in eight studies (n=1791). In ten studies (n=2294), individuals were given vitamin D doses less than 800 IU per day. Bone mineral density was measured at one to five sites (lumbar spine, femoral neck, total hip, trochanter, total body, or forearm) in each study, so 70 tests of statistical significance were done across the studies. There were six findings of significant benefit, two of significant detriment, and the rest were non-significant. Only one study showed benefit at more than one site. Results of the meta-analysis showed a small clinically nonsignificant benefit at the femoral neck (WMD 0,8%, 95% CI 0,2 to 1,4). No effect at any other site was reported, including the total hip.

Clinical comments

Note

Date of latest search: 2014-01-14

Ədəbiyyat

1. Avenell A, Mak JC, O'Connell D. Vitamin D and vitamin D analogues for preventing fractures in post-menopausal women and older men. Cochrane Database Syst Rev 2014;4():CD000227. DIPART (Vitamin D Individual Patient Analysis of Randomized Trials) Group. Patient level pooled analysis of 68 500 patients from seven major vitamin D fracture trials in US and Europe. BMJ 2010;340():b5463. Bischoff-Ferrari HA, Willett WC, Orav EJ et al. A pooled analysis of vitamin D dose requirements for fracture prevention. N Engl J Med 2012;367(1):40-9. Reid IR, Bolland MJ, Grey A. Effects of vitamin D supplements on bone mineral density: a systematic review and meta-analysis. Lancet 2014;383(9912):146-55. Wang S. Epidemiology of vitamin D in health and disease. Nutr Res Rev 2009;22(2):188-203. Ebeling R. Vitamin D and bone health: Epidemiologic studies. BoneKEyReports 3 , Article number: 511 published online 5 March 2014 Cauley JA, Lacroix AZ, Wu L et al. Serum 25-hydroxyvitamin D concentrations and risk for hip fractures. Ann Intern Med 2008;149(4):242-50. vvan Schoor NM, Visser M, Pluijm SM et al. Vitamin D deficiency as a risk factor for osteoporotic fractures. Bone 2008;42(2):260-6. . Saquib N, von Mühlen D, Garland CF et al. Serum 25-hydroxyvitamin D, parathyroid hormone, and bone mineral density in men: the Rancho Bernardo study. Osteoporos Int 2006;17(12):1734-41. Michaëlsson K, Melhus H, Bellocco R et al. Dietary calcium and vitamin D intake in relation to osteoporotic fracture risk. Bone 2003;32(6):694-703. 'Roddam AW, Neale R, Appleby P et al. Association between plasma 25-hydroxyvitamin D levels and fracture risk: the EPIC-Oxford study. Am J Epidemiol 2007;166(11):1327-36.