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Date of release: 22 July, 2009

Prevention of non-vertebral fractures with vitamin D


Antifracture efficacy with supplemental vitamin D has been questioned by several trials published in the last 4 years, leading to uncertainty among patients and physicians regarding recommendations for vitamin D supplementation. A recent meta-analysis confirms the efficacy of oral supplemental vitamin D in preventing non-vertebral and hip fractures among older individuals (≥ 65 years) [1]. The meta-analysis compared oral vitamin D, with or without calcium, with calcium or placebo. To incorporate adherence to treatment, the dose was multiplied by the percentage of adherence to estimate the mean received dose (dose × adherence) for each trial. The primary goal was to determine the antifracture efficacy of oral vitamin D supplementation among individuals aged 65 years or older by performing a systematic review of the literature and meta-analysis of high-quality, double-blinded, randomized, controlled trials (RCTs). Twelve double-blind RCTs for non-vertebral fractures (n = 42,279) and eight RCTs for hip fractures (n = 40,886) were included, among them the data from the Women’s Health Initiative trial. In addition, the analysis specifically addressed the antifracture efficacy by received dose, achieved 25-hydroxyvitamin D levels and in predefined subgroups.


The authors reported the following results. The pooled relative risk (RR) was 0.86 (95% confidence interval (CI) 0.77–0.96) for prevention of non-vertebral fractures and 0.91 (95% CI 0.78–1.05) for the prevention of hip fractures. However, there was a significant heterogeneity for both endpoints. Including all trials, antifracture efficacy increased significantly with a higher dose and higher achieved blood 25-hydroxyvitamin D levels for both endpoints. Consistently, pooling trials with a higher received dose of more than 400 IU/day vitamin D resolved heterogeneity. For the higher dose, the pooled RR was 0.80 (95% CI 0.72–0.89; n = 33,265 subjects from nine trials) for non-vertebral fractures and 0.82 (95% CI 0.69–0.97; n = 31,872 subjects from five trials) for hip fractures. The higher dose reduced non-vertebral fractures in community-dwelling individuals (−29%) and institutionalized older individuals (−15%), and its effect was independent of additional calcium supplementation.


It was concluded that non-vertebral fracture prevention with vitamin D is dose-dependent and that a higher dose should reduce fractures by at least 20% for individuals aged 65 years or older.

Comment

The necessity for vitamin D supplementation in elderly people has been a highly debated subject for many years. Some specialists favored a general vitamin D supplementation after the age of 65 years; others felt that such a measure is not necessary for elderly individuals having regular outdoor activity. In 1992, two independent groups published data showing a decreased risk of hip fractures as well as other non-vertebral fractures in healthy ambulatory women (mean ± SD age, 84 ± 6 years) [2], and a positive correlation between bone density at the lumbar spine, neck and trochanteric regions of the femur and serum 25-hydroxyvitamin [3]. The prolongation of the Chapuy study [2] to 36 months confirmed the significant decrease of hip and other non-vertebral fractures in vitamin D-supplemented women [4].
In 2002, an international Position Paper on Women’s Health [5] was in favor of vitamin D supplementation in elderly women, in addition to regular physical activity and a sufficient calcium intake. It recommended supplements of vitamin D for at-risk populations, especially those 65 years of age and older [5]. The dose needed for at-risk populations was estimated at 700–800 IU vitamin D per day, provided that the daily calcium intake was sufficient. 
Recent trials, mostly using significantly lower doses (≤ 400 IU vitamin D), questioned such recommendations. The recent meta-analysis presented above [1] confirms the efficacy of the prevention of non-vertebral fracture with vitamin D, but shows that the preventive effect is dose-dependent: a higher dose (482–770 IU vitamin D per day) should reduce fractures by at least 20% and hip fractures by at least 18% for individuals aged 65 years or older. It is suggested that greater benefits may be achieved with earlier initiation of vitamin D supplementation and longer duration of use.
There is as yet no common definition of ‘optimum’ vitamin D status, although there is emerging evidence that the minimum blood level of 25-hydroxyvitamin D that would be optimal for fracture prevention is 70–80 nmol/l [6]. To achieve this, an average older individual, man or woman, would need a vitamin D intake of at least 800–1000 IU/day (20–25 µg/day), which is approximately double the intake recommended in most countries. Although there is ongoing debate as to what constitutes the optimal level of vitamin D, the recent IOF report [7] shows that, regardless of whether it is defined at 50 nmol/l or 75 nmol/l, vitamin D status is seriously inadequate in large proportions of the population across the globe.
Dosages of 25-hydroxyvitamin D higher than the recommended 800–1000 IU/day have been used for several months (up to 5000 units/day), particularly in rickets. However, most trials of higher doses of vitamin D were not adequately designed to assess long-term harms. It has to be noted that, in some individuals taking high doses of 25-hydroxyvitamin D, there might be an increased risk of hypercalcemia and renal stones.
Because of the higher costs and higher risk profile, 1α-hydroxylated vitamin D offers no advantage compared with an adequate dose of supplemental vitamin D except in individuals with specific indications.
Finally, it has to be stressed that vitamin D deficiency is associated with death from heart failure and sudden cardiac death and that the 25-hydroxyvitamin D level is positively related to muscle power, force, velocity and jump height, suggesting that muscle contractility may be affected by vitamin D status [8, 9]. 
In conclusion, reports from across the world indicate that hypovitaminosis D is widespread and is re-emerging as a major health problem globally [9]. Higher than traditionally recommended vitamin D supplementation (dose recommended by IOF: 800–1000 IU vitamin D per day [9]) remains an inexpensive and efficient tool for fracture prevention in the elderly. Vitamin D has additional extra-skeletal benefits. The recent data do not support use of low-dose vitamin D, with or without calcium, in the prevention of fractures among older individuals.

Comentario

Martin Birkhäuser
Professor Emeritus, Division of Gynecological Endocrinology and Reproductive Medicine, Department of Obstetrics & Gynecology, University of Berne, Switzerland

    References

  1. Bischoff-Ferrari HA, Willett WC, Wong JB, et al. Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials. Arch Intern Med 2009;169:551-61. Published March 23, 2009.
    http://www.ncbi.nlm.nih.gov/pubmed/19307517

  2. 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.
    http://www.ncbi.nlm.nih.gov/pubmed/1331788

  3. Khaw KT, Sneyd MJ, Compston J. Bone density, parathyroid hormone and 25-hydroxyvitamin D concentrations in middle aged women. BMJ 1992;305:273-7.
    http://www.ncbi.nlm.nih.gov/pubmed/1392857

  4. 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;308:1081-2.
    http://www.ncbi.nlm.nih.gov/pubmed/8173430

  5. International Position Paper on Womens Health and Menopause: a comprehensive approach. National Heart, Lung and Blood Institute, Office of Research on Womens Health, National Institute of Health, and Giovanni Lorenzini Medical Science Foundation. NIH publication no. 02-3284, July 2002.
    http://www.nhlbi.nih.gov/health/prof/heart/other/menopaus/menopaus.pdf

  6. Dawson-Hughes B, Heaney RP, Holick MF, et al. Estimates of optimal vitamin D status. Osteoporos Int 2005;16:713-16.
    http://www.ncbi.nlm.nih.gov/pubmed/15776217

  7. Mithal A, Wahl DA, Bonjour J-P, et al. on behalf of the IOF Committee of Scientific Advisors, Nutrition Working Group. Global vitamin D status and determinants of hypovitaminosis D. Osteoporos Int 2009 Jun 19. [Epub ahead of print].
    http://www.ncbi.nlm.nih.gov/pubmed/19543765

  8. Giovannucci E. Expanding roles of vitamin D. J Clin Endocrinol Metab 2009;94:418-20.
    http://www.ncbi.nlm.nih.gov/pubmed/19193916