Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Review: 700 to 800 IU/d of vitamin D reduces hip and nonvertebral fractures in older persons

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ACP J Club. 2005 Nov-Dec;143:72. doi:10.7326/ACPJC-2005-143-3-072

Related Content in this Issue
• Companion Abstract and Commentary: Calcium and vitamin D supplementation did not reduce fractures in women ≥ 70 years of age and Vitamin D3, calcium, or both did not prevent secondary fractures in elderly people


Clinical Impact Ratings

GIM/FP/GP: 6 stars

Geriatrics: 6 stars

Rheumatology: 6 stars


Source Citation

Bischoff-Ferrari HA, Willett WC, Wong JB, et al. Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA. 2005;293:2257-64. [PubMed ID: 15886381]


Abstract

Question

Does oral vitamin D supplementation prevent hip and any nonvertebral fractures in older persons?

Methods

Data sources: MEDLINE and the Cochrane Controlled Trials Register (January 1960 to January 2005), EMBASE/Excerpta Medica (January 1991 to January 2005), experts in the field, reference lists of relevant studies, and abstracts presented at the American Society for Bone and Mineral Research (1995 to 2004).

Study selection and assessment: Blinded randomized controlled trials (RCTs) of oral vitamin D supplementation (cholecalciferol or ergocalciferol) alone or combined with calcium supplementation compared with placebo or calcium supplementation alone in participants ≥ 60 years of age, ≥ 1 fracture occurred in each trial, and follow-up was ≥ 1 year. Individual studies were assessed for randomization procedure, concealment, blinding, and withdrawals.

Outcomes: First hip or nonvertebral fracture.

Main results

7 RCTs (n = 9820, mean age 79 y, 68% women) met the selection criteria. 2 RCTs evaluated 400 IU/d of vitamin D, and 5 RCTs evaluated 700 to 800 IU/d. 4 RCTs included 500 to 1200 mg/d of calcium in the vitamin D intervention; in 2 RCTs the mean calcium intake was 450 to 742 mg/d, and 1 RCT recommended a calcium intake of 800 mg/d through dairy products. Treatment duration ranged from 12 to 60 months. Using random effects, pooling 3 RCTs of vitamin D at higher doses showed reduced hip fracture, while pooling 2 RCTs using lower doses did not (Table). Pooling of 5 RCTs with high doses of vitamin D showed a reduction in any nonvertebral fracture, but not for 2 RCTs with low doses (Table).

Conclusions

Vitamin D at doses of 700 to 800 IU/d reduces hip and nonvertebral fractures in older persons. 400 IU/d of vitamin D does not reduce fractures.

Sources of funding: Medical Foundation (Charles H. Farnsworth Trust; U.S. Trust Company; Trustee and Charles A. King Trust; Fleet National Bank) and James Knox Memorial Foundation.

For correspondence: Dr. H.A. Bischoff-Ferrari, Harvard School of Public Health, Boston, MA, USA. E-mail hbischof@hsph.harvard.edu.


Table. Vitamin D supplementation alone or with calcium vs placebo or calcium alone (control) to prevent fracture in older persons at 12 to 60 months*

Outcomes Vitamin D dose (IU/d) Number of trials (n) Weighted event rates RRR (95% CI) NNT (CI)
Vitamin D Control
Hip fracture 700 to 800 3 (5572) 6.0% 8.4% 26% (12 to 39) 46 (31 to 100)†
RRI (CI) NNH
400 2 (3722) 4.2% 3.5% 14% (−13 to 49) Not significant
RRR (CI) NNT (CI)
Any nonvertebral fracture 700 to 800 5 (6098) 11% 16% 25% (11 to 37) 24 (14 to 80)
RRI (CI) NNH
400 2 (3722) 11% 10.6% 3% (−14 to 24) Not significant

*Abbreviations defined in Glossary; weighted event rates, RRR, RRI, NNT, NNH, and CI calculated from data in article using a random-effects model.
†Calculated using relative risk and control event rate.


Commentary

The review by Bischoff-Ferrari and colleagues, the study by Porthouse and colleagues, and the RECORD trial examined calcium and vitamin D supplementation for the prevention of fractures in older persons. The systematic review by Bischoff-Ferrari and coworkers found that high-dose vitamin D (700 to 800 IU/d) combined with calcium (500 to 1200 mg/d) reduced the risk for hip fractures by 26% (CI 12 to 39) and all nonvertebral fractures by 23% (CI 13 to 32). However, the RECORD and Porthouse studies (which were not included in the Bischoff-Ferrari review) reported no benefit of high-dose vitamin D and calcium for either secondary prevention of fractures or prevention of fractures in high-risk patients of whom over half had previous fractures. Could differences in patient populations, study power, or adherence to study drugs explain these seemingly discordant results?

The effect of vitamin D with or without calcium on fracture prevention may vary in different populations. Frail, elderly persons and nursing home patients are at greater risk for falls and fractures than community-dwelling elderly persons. This difference may in part be explained by vitamin D deficiency in persons who are often sunlight-deprived. Many of the patients in the Bischoff-Ferrari meta-analysis were nursing-home residents. A Cochrane review that included 4 recent studies (including the RECORD and Porthouse studies) found that vitamin D alone did not reduce fractures (1). However, when vitamin D was given in combination with calcium, reductions occurred in hip and nonvertebral fractures but not in vertebral fractures. Subgroup analysis suggested that this effect was restricted to elderly patients living in institutions, with a reduction in fractures of 13% (CI 5 to 28). In both the RECORD and Porthouse studies, patients were community-dwelling.

In the Porthouse and RECORD studies, power may not have been sufficient to show a clinically important difference, especially between the vitamin D plus calcium and placebo groups. The RECORD trial was designed to have 80% power to detect an absolute difference in fracture rates of 3% between treatment groups. The intervention groups were formed by collapsing the 2 groups that received the specific intervention (calcium or vitamin D), and the control groups were formed from the 2 groups that did not receive the intervention. The groups that received calcium with vitamin D only or placebo were smaller and had only about 62% power to detect a 3% difference in fracture rate between these 2 groups. In the study by Porthouse and colleagues, the authors could not exclude a reduction in risk < 30% for fractures with vitamin D plus calcium. Meta-analyses in a Cochrane study (1) and the study by Bischoff-Ferrari and colleagues both found reductions in risk for fractures < 30%.

Adherence to therapy and consequent vitamin D levels may have varied in these trials, resulting in differences in biological effects. A meta-regression analysis in Bischoff-Ferrari showed a greater reduction in hip and nonvertebral fractures with higher serum levels of 25-hydroxyvitamin D. 2 hip fracture studies that were included in the Bischoff-Ferrari meta-analysis (Decalyos II 2 and Decalyos I 3) reported exceptionally high rates of compliance with treatment and placebo (95% in Decalyos II and 83% in Decalyos I). In contrast, compliance rates were 60% in the RECORD trial, and 56.6% in the study by Porthouse and colleagues. For a subset of patients in the RECORD and Decalyos I studies, baseline 25-hydroxyvitamin D levels were similar (15.2 ng/mL and 16 ng/mL, respectively). However, after 1 year of treatment, the mean 25-hydroxyvitamin D levels in the Decalyos I treatment group increased to 42 ng/mL (3), while levels in the RECORD study only increased to 24.8 ng/mL.

The review by Bischoff-Ferrari and colleagues and the Porthouse and RECORD studies suggest that calcium plus high-dose vitamin D is effective for the prevention of hip and nonvertebral fractures in older persons, particularly those in institutions. It is important to note that in the secondary prevention trials, which showed the effectiveness of bisphosphonates, calcium and vitamin D were given to all participants (4-6). For patients with a previous low-impact fracture, prevention should include a bisphosphonate in addition to calcium and vitamin D.

Michael Bogaisky, MD
Rosanne M. Leipzig, MD, PhD
Mount Sinai Medical Center
New York, New York, USA


References

1. Avenell A, Gillespie W, Gillespie L, O’Connell D. Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis. Cochrane Database Syst Rev. 2005;3:CD000227. [PubMed ID: 16034849]

2. Chapuy MC, Pamphile R, Paris E, et al. Combined calcium and vitamin D3 supplementation in elderly women: confirmation of reversal of secondary hyperparathyroidism and hip fracture risk: the Decalyos II study. Osteoporos Int. 2002;13:257-64. [PubMed ID: 11991447]

3. Chapuy MC, Arlot ME, Duboeuf F, et al. Vitamin D3 and calcium to prevent hip fractures in the elderly women. N Engl J Med. 1992;327:1637-42. [PubMed ID: 1331788]

4. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA. 1999;282:637-45. [PubMed ID: 10517716]

5. Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet. 1996;348:1535-41. [PubMed ID: 8950879]

6. Kanis JA, Barton IP, Johnell O. Risedronate decreases fracture risk in patients selected solely on the basis of prior vertebral fracture. Osteoporos Int. 2005;16:475-82. [PubMed ID: 15875093]