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Calcium and vitamin D for osteoporotic fracture risk COMMENT
 
 
  The Lancet Aug 25, 2007; 370:632-634
 
Jean-Yves Reginster
Bone and Cartilage Metabolism Unit, CHU Centre Ville, 4020 Liege, Belgium
 
Osteoporosis is a chronic progressive bone disease, in which bone resorption exceeds bone formation, leading to a reduction in bone-mineral density and disruption of bone microarchitecture. Calcium and vitamin D deficiency are important factors for bone health, because reduced calcium absorption increases parathyroid hormone concentration and accelerates the rate of bone loss, which raises the number and activity of osteoclasts that release calcium from bone. Although many studies have investigated the effect of supplementation with calcium or calcium with vitamin D on fracture risk in postmenopausal osteoporosis, there are conflicting outcomes.1-3 However, calcium and vitamin D are still widely regarded as essential components in osteoporosis management.4,5
 
In today's Lancet,6 Benjamin Tang and colleagues provide a well-designed systematic review of 29 randomised trials that assessed all fractures and changes in bone-mineral density after individuals aged 50 years or older were supplemented with calcium or calcium plus vitamin D. Unlike previous meta-analyses,7,8 Tang provides clear answers to several questions which could be of immediate practical importance for the daily management of osteoporosis. Their conclusion is that calcium supplementation, or calcium with vitamin D, is effective in the prevention of osteoporotic fractures. This isolated statement, even though supported by a strong method, would probably not be a major contribution to an evidence-based management of patients with osteoporosis. However, the strength and interest of the study come from the large sample size (more than almost 64000 participants), which allows for meaningful and properly powered subgroup analysis for fracture effect.
 
Some recent studies have concluded that calcium supplementation with or without vitamin D should not be systematically recommended for the primary or secondary prevention of fracture in elderly patients.3,9 However, most of these studies had poor long-term adherence to study drug, which is a common feature for many anti-osteoporosis drugs that are given daily. In the main analysis of these studies, 50-60% of the original population were no longer taking their medication properly, which might generate concerns about the overall negative conclusions reported. However, Tang and colleagues showed that, in a subpopulation with a compliance rate of at least 80%, the level of risk reduction was doubled compared with those with poor compliance, which provides robust scientific grounds for a worldwide interaction between drug manufacturers (eg, development of user-friendly formulations), physicians (eg, delivery of positive messages or reinforcement through densitometric and biochemical feedbacks), and patients, to provide optimum adherence to calcium or calcium with vitamin D supplementation.
 
30-100 nmol/L is the estimated concentration of circulating 25-hydroxyvitamin D needed to maintain normal concentrations of parathyroid hormone and prevent bone fragility.10,11 The acceptable threshold for dietary calcium intake, or for calcium pharmacological supplementation, is unclear-recommendations range from 400 to 1500 mg per day. These uncertainties have contributed to a wide range of clinical practices for calcium with or without vitamin D supplementation. The recommended minimum daily doses of 1200 mg of calcium or 800 IU of vitamin D proposed by Tang and co-workers are consistent with previous reports that 400 IU per day of vitamin D is not sufficient for fracture prevention, and that doses of 700-800 IU per day are needed to reduce the risk of hip and non-vertebral fracture in ambulatory or institutionalised women.12 Such guidance seems conservative and appropriate to ensure a positive risk-benefit ratio for people at increased risk of, or who have developed, osteoporosis.
 
However, two major issues remain. First, should calcium be added to vitamin D supplementation or vitamin D to calcium supplementation? Tang and colleagues conclude that addition of vitamin D to calcium does not significantly affect treatment efficacy. Nevertheless, they report an increased treatment effect of calcium or calcium with vitamin D in individuals with low serum 25-hydroxyvitamin D (<25 nmol/L), as well as in elderly and institutionalised patients. This result is surprising since these patients have consistently been reported to have a high prevalence of vitamin D deficiency. Because another meta-analysis13 recently concluded that oral vitamin D reduces the risk of hip fracture only when calcium supplement is added, it might be cautious to concentrate on combined calcium and vitamin D preparations, at least in people at increased risk of osteoporotic fractures, until further studies are done.
 
Second, the cost-conscious use of calcium or calcium with vitamin D supplementation is not fully addressed by Tang and colleagues. Various treatment options have been advocated, including systematic supplementation at the onset of menopause and restriction of calcium with or without vitamin D to patients receiving other anti-osteoporotic drugs. Tang suggests that the number needed to treat (63 patients over 3¥5 years) with calcium or calcium and vitamin D to prevent one osteoporotic fracture compares favourably with similar calculations from the cardiovascular field. They suggest that the cost-effectiveness of calcium supplementation might even be better in high-risk participants or in those with optimum or improved compliance. This assumption, however, should be interpreted carefully.
 
Number needed to treat is highly dependent on the baseline absolute risk of the clinical endpoint under investigation. Tang and co-workers' analysis emphasises the need for extensive and sophisticated health-economic analyses to assess the incremental cost-effectiveness ratio of calcium or calcium with vitamin D supplementation in various doses, regimens, populations, and settings. In conclusion, Tang and colleagues' contribution is important because it paves the way for future research aiming at the best clinical, pharmacological, and economic use of calcium and vitamin D in patients at increased risk of osteoporotic fractures.
 
J-YR has received consulting fees from Servier, Novartis, Negma, Lilly, Wyeth, Amgen, GlaxoSmithKline, Roche, Merckle, Nycomed, NPS, and Theramex; lecture fees from Merck Sharp and Dohme, Lilly, Rottapharm, IBSA, Genevrier, Novartis, Servier, Roche, GlaxoSmithKline, Teijin, Teva, Ebewee Pharma, Zodiac, Analis, Theramex, Nycomed, and Novo-Nordisk; and grant support from Bristol Myers Squibb, Merck Sharp & Dohme, Rottapharm, Teva, Lilly, Novartis, Roche, GlaxoSmithKline, Amgen, and Servier.
 
References
 
1. Dawson-Hughes B, Harris SS, Krall EA, Dallal GE. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. N Engl J Med 1997; 337: 670-676. MEDLINE | CrossRef
 
2. Chapuy MC, Arlot ME, Delmas PD, Meunier PJ. Effect of calcium and cholecalciferol treatment for three years on hip fractures in elderly women. BMJ 1994; 308: 1081-1082.
 
3. Jackson RD, LaCroix AZ, Grass M, et alWomen's Health Initiative Investigators. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006; 354: 669-683. CrossRef
 
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6. Tang BMP, Eslick GD, Nowson C, Smith C, Bensoussan A. Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis. Lancet 2007; 370: 657-666. Abstract | Full Text | Full-Text PDF (351 KB)
 
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9. Grant AM, Avenell A, Campbell MKfor 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: 1621-1628. Abstract | Full Text | Full-Text PDF (200 KB) | CrossRef
 
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12. Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich T, Dawson-Hughes B. Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA 2005; 293: 2257-2264. CrossRef
 
13. Boonen S, Lips P, Bischoff-Ferrari HA, Vanderschueren D, Haentjens P. Need for an additional calcium to reduce the risk of hip fracture with vitamin D supplementation: evidence from a comparative meta-analysis of randomized controlled trials. J Clin Endocrinol Metab 2007; 92: 1415-1423. CrossRef
 
 
 
 
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