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


Therapeutics

Vitamin D3, calcium, or both did not prevent secondary fractures in elderly people

PDF

ACP J Club. 2005 Nov-Dec;143:74. doi:10.7326/ACPJC-2005-143-3-074

Related Content in this Issue
• Companion Abstract and Commentary: Review: 700 to 800 IU/d of vitamin D reduces hip and nonvertebral fractures in older persons and Calcium and vitamin D supplementation did not reduce fractures in women ≥ 70 years of age


Clinical Impact Ratings

GIM/FP/GP: 5 stars

Emergency Med: 3 stars

Geriatrics: 7 stars

Phys Med & Rehab: 6 stars

Rheumatology: 5 stars


Source Citation

The RECORD Trial Group. Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial. Lancet. 2005;365:1621−8. [PubMed ID: 15885294]


Abstract

Question

In older persons with a previous low-trauma fracture, how do vitamin D3, calcium, or both compare for preventing secondary fractures?

Methods

Design: Randomized placebo-controlled trial (Randomized Evaluation of Calcium Or Vitamin D [RECORD]).

Allocation: Concealed.*

Blinding: Blinded ({patients, clinicians, data collectors}†, and outcome assessors).*

Follow-up period: 24 to 62 months.

Setting: 21 hospitals in the United Kingdom.

Patients: 5292 patients ≥ 70 years of age (mean age 77 y, 85% women) who had a low-trauma, osteoporotic fracture (a fracture due to a fall from no more than standing height, or radiologist-confirmed vertebral fracture) in the previous 10 years. Exclusion criteria included bed or chair-bound before the fracture; cognitive impairment; cancer in the past 10 years that could metastasize to bone; fracture associated with preexisting local bone abnormality; hypercalcemia; renal stone in the past 10 years; life expectancy < 6 months; daily intake of > 200 IU vitamin D or > 500 mg calcium; intake in the previous 5 years of fluoride, bisphosphonates, calcitonin, tibolone, hormone replacement therapy, selective estrogen-receptor modulators, or any vitamin D3 metabolite; and vitamin D3 by injection in the past year.

Intervention: Vitamin D3, 800 IU taken as 2 tablets with meals (n = 1343); calcium, 1000 mg given as a carbonate (n = 1311); vitamin D3 plus calcium (COMBO) (n = 1306); or placebo (n = 1332). Groups were combined to allow comparisons between calcium and non–calcium-containing regimens (COMBO + calcium vs vitamin D3 + placebo), vitamin D3 and non–vitamin D3-containing regimens (COMBO + vitamin D3 vs calcium + placebo), or COMBO and placebo.

Outcomes: All new low-trauma fractures. Secondary outcomes were all new fractures, radiographically confirmed fractures, hip fractures, death, number of falls, and quality of life.

Patient follow-up: 90% (intention-to-treat analysis)

Main results

Of 698 patients (13%) who had a new low-trauma fracture, 183 (4%) had a hip fracture. New low-trauma fractures did not differ between calcium and non–calcium-containing regimens (Table). Results were similar between vitamin D3 and non–vitamin D3-containing regimens (Table). COMBO and placebo groups did not differ for new low-trauma fractures (Table). Secondary outcomes did not differ among any group comparisons.

Conclusion

In older persons with a previous low-trauma fracture, calcium, vitamin D3, or both did not prevent secondary fractures.

*See Glossary.

†Information provided by author.

Sources of funding: Chief Scientist Office, Scottish Executive Health Department; Medical Research Council; Shire Pharmaceuticals; Nycomed.

For correspondence: Professor A.M. Grant, Health Services Research Unit, University of Aberdeen, Aberdeen, Scotland, UK. E-mail a.grant@abdn.ac.uk.


Table. Calcium (Ca) and vitamin D3 (VitD3) regimens for new low-trauma fracture at 24 months†

Comparisons Event rates RRR (95% CI) NNT
Ca regimen (COMBO + Ca) vs no Ca regimen (VitD3 + placebo) 13% vs 14% 8% (−6 to 20) Not significant
VitD3 regimen (COMBO + VitD3) vs no VitD3 regimen (Ca + placebo) 13% vs 13% 2% (−11 to 17) Not significant
COMBO vs placebo 13% vs 13% 6% (−14 to 23) Not significant

†COMBO = VitD3 + Ca. Other abbreviations defined in Glossary; RRR, NNT, and CI calculated from data in article.


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 osteoporosistreated 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 withexisting 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]