Correspondence

University of Macau, Faculty of Social Sciences, Department of Psychology, Taipa, Macau, China (BJH); Faculty of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, China (WC, LL); Sun Yatsen Center for Migrant Health Policy, Guangzhou, China (BJH, WC, LL, JDT); Department of Health Behavior and Society and Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA (CL); University of North Carolina Chapel Hill Project-China, Guangzhou, China (JDT); and University of North Carolina Chapel Hill, Institute of Global Health and Infectious Diseases, Chapel Hill, NC, USA (JDT) 1

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Mathews G, Yang Y. How Africans pursue lowend globalization in Hong Kong and Mainland China. J Curr Chin Aff 2012; 41: 95–120. Bodomo AB. Africans in China: a sociocultural study and its implications on Africa-China relations. New York: Cambria Press; 2012. Haugen H. Chinese exports to Africa: competition, complementarity and cooperation between micro-level actors. Forum Devel Stud 2011; 38: 157–76. Link BG, Phelan JC. Stigma and its public health implications. Lancet 2006; 367: 528–29. Cheng Y. From campus racism to cyber racism: discourse of race and Chinese nationalism. China Q 2011; 207: 561–79. Yip WC-M, Hsiao WC, Chen W, Hu S, Ma J, Maynard A. Early appraisal of China’s huge and complex health-care reforms. Lancet 2012; 379: 833–42.

Vitamin D supplements and bone mineral density The meta-analysis by Ian Reid and colleagues (Jan 11, p 146)1 concluded that treatment with vitamin D did not improve bone mineral density (BMD), although femoral neck BMD was 0·8% greater compared with placebo (13 trials: all women, n=2201). The VICtORy study was not included in their analysis.2 This 12-month placebocontrolled trial, designed to eliminate seasonal effects in 300 older women, found that 1000 IU per day of vitamin D

significantly increased BMD at the total hip compared with placebo (+0·6%, equivalent to +1·2% in 24 months) with no concomitant change in bone turnover markers.2 Supplementary data by region of the hip are presented in the table. The on-going VDOP trial will also determine the effects of vitamin D dose on BMD in 375 older men and women.3 We hypothesise that vitamin D might only improve BMD in individuals with marginally under-mineralised bone, for which higher doses than 400 IU daily might be required. Chapuy and colleagues4 showed a clear fracture risk reduction with vitamin D combined with calcium supplementation. Their study included a population older than 60 years at risk with low vitamin D status,4 whereas more than half the participants in the meta-analysis1 were younger than 60 years. We believe that individuals with poor bone health who are deficient in vitamin D will benefit most from vitamin D supplementation. HM is the principal investigator for the VICtORy study.2 TJA is s the principal investigator for the VDOP study.3 We declare that we have no competing interests.

*Helen Macdonald, Terence J Aspray

400 IU vitamin D3

Femoral neck

+0·5 (0·0 to +0·9)

+0·1 (–0·4 to +0·6)

Greater trochanter

+0·7 (–0·1 to +1·5)

–0·2 (–0·9 to +0·5)

Ward’s triangle

+0·6 (–0·2 to +1·4)

–0·2 (–1·0 to +0·6)

Total hip2

+0·6 (+0·1 to +1·0)

+0·1 (–0·4 to +0·5)

BMD=bone mineral density.

Table: Effect of vitamin D3 on BMD according to region of the hip (VICtORy trial)

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I declare that I have no competing interests.

Colin Robert Dunstan [email protected] University of Sydney, Sydney, NSW 2006, Australia 1

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Reid IR, Bolland MJ, Grey A. Effects of vitamin D supplements on bone mineral density: a systematic review and meta-analysis. Lancet 2014; 383: 146–55. Zhai G, Hart DJ, Valdes AM, et al. Natural history and risk factors for bone loss in postmenopausal Caucasian women: a 15-year follow-up population-based study. Osteoporos Int 2008; 19: 1211–17.

[email protected] Musculoskeleal Research, University of Aberdeen, Aberdeen AB25 2ZD, UK (HM); and Musculoskeletal Unit, Freeman Hospital, Newcastle upon Tyne, UK (TJA) 1

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BMD difference from placebo Mean % per year (95% CI ) 1000 IU vitamin D3

assessed by comparing baseline bone density to bone density changes with vitamin D treatment. No consideration was given by the authors to the natural history of bone density in this patient population. One could well expect that the population in this study would show a reduction of about 3% in bone density over the mean 2 years’ duration of treatment if vitamin D was ineffective.2 The fact that there is no significant increase at measured sites, apart from the clinically important femoral neck, is not necessarily a negative finding. Perhaps more remarkable is that there was no significant decrease in bone density at any site in older patients receiving vitamin D.

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Reid IR, Bolland MJ, Grey A. Effects of vitamin D supplements on bone mineral density: a systematic review and meta-analysis. Lancet 2014; 383: 146–55. Macdonald HM, Wood AD, Aucott LS, et al. Hip bone loss is attenuated with 1000 IU but not 400 IU daily vitamin D3: a 1-year double-blind RCT in postmenopausal women. J Bone Miner Res 2013; 28: 2202–13. Schoenmakers I, Francis RM, McColl E, et al. Vitamin D supplementation in older people (VDOP): study protocol for a randomised controlled intervention trial with monthly oral dosing with 12,000 IU, 24,000 IU or 48,000 IU of vitamin D3. Trials 2013; 14: 299. 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: 1081–82.

The recent article by Ian Reid and colleagues1 contains a basic flaw in interpretation. The population, primarily of post-menopausal women, was

We are intrigued by the meta-analysis by Ian Reid and colleagues1 reporting no beneficial effect of vitamin D supplementation on bone mineral density (BMD). These findings, allying with recent data for maternal vitamin D status and offspring bone development,2 are likely to restrain the prevailing view of vitamin D panacea in the clinical community worldwide. However, there is a need for a balanced view based on representative populations. Reid and colleagues’ meta-analysis1 included mainly white populations with adequate vitamin D status and calcium intake. A mean level of less than 30 nmol/L was noted in only five studies (among 24 included), which is certainly not representative of the world population. We assume that this recruitment bias favoured the high heterogeneity in both femoral neck (I²=67%) and total body BMD (I²=85%) favouring beneficial www.thelancet.com Vol 383 April 12, 2014

Correspondence

We declare that we have no competing interests.

Spyridon N Karras, Panagiotis Anagnostis, Olivier Beauchet, Dimitrios G Goulis, *Cedric Annweiler [email protected] Unit of Reproductive Endocrinology, First Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece (SNK, PA, DGG); Department of Neuroscience, Angers University Hospital, 49933 Angers, France (OB, CA); and Robarts Research Institute, Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada (CA) 1

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Reid IR, Bolland MJ, Grey A. Effects of vitamin D supplements on bone mineral density: a systematic review and meta-analysis. Lancet 2014; 383: 146–55. Lawlor DA, Wills AK, Fraser A, Sayers A, Fraser WD, Tobias JH. Association of maternal vitamin D status during pregnancy with bonemineral content in offspring: a prospective cohort study. Lancet 2013; 381: 2176–83. Bischoff-Ferrari HA, Kiel DP, Dawson-Hughes B, et al. Dietary calcium and serum 25-hydroxyvitamin D status in relation to BMD among U.S. adults. J Bone Miner Res 2009; 24: 935–42. Bischoff-Ferrari HA, Willett WC, Wong JB, et al. Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a metaanalysis of randomized controlled trials. Arch Intern Med 2009; 169: 551–61. Anderson PH, Turner AG, Morris HA. Vitamin D actions to regulate calcium and skeletal homeostasis. Clin Biochem 2012; 45: 880–86.

could free up substantial resources that could be better used elsewhere in health care”.1 Vitamin D supplementation is not the core treatment in the prevention of osteoporosis, but a supportive one, essential to reduce the incidence of falls, which cause fractures.2,3 Levis and Theodore’s summary4 of the Agency for Healthcare Research and Quality systematic review report that vitamin D treatment reduced vertebral fractures among primary osteoporosis, and calcium and vitamin D decreased the risk of fracture in elderly women. Reid and colleagues pointed out in their analysis of 23 studies that in ten studies vitamin D supplementation was less than 800 IU per day, this dose might not be sufficient to make any difference in the bone mineral density. Also, six studies showed benefit of vitamin D supplementation. The authors have not taken into consideration the non-compliance of vitamin D intake by patients. The cost of a year’s supply of vitamin D is less than US$35 per patient in western countries and much less in Asian countries. Vitamin D might not increase bone mineral density in 100% of the patients but it reduces falls and thereby reduces the incidence of fractures—this should not be ignored. Without a large randomised controlled study with full compliance of vitamin D use showing no benefit, it is inaccurate to state that it is inappropriate to give vitamin D while vitamin D deficiency is rampant worldwide. Understanding the bias and limitations of the studies analysed is crucial if we do not want many physicians to stop prescribing vitamin D supplementation, which could have serious consequences. We declare that we have no competing interests.

*Mir Sadat-Ali, Haifa A Al-Turki [email protected]

We read with interest and dismay Ian Reid and colleagues’ study. 1 They state that “targeting of lowdose vitamin D supplements only to individuals who are likely to be deficient www.thelancet.com Vol 383 April 12, 2014

College of Medicine University of Dammam and King Fahd Hospital of the University, Al-Khobar 31952, Saudi Arabia 1

Reid IR, Bolland MJ, Grey A. Effects of vitamin D supplements on bone mineral density: a systematic review and meta-analysis. Lancet 2014; 383: 146–55.

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Vieth R. The role of vitamin D in the prevention of osteoporosis. Ann Med 2005; 37: 278–85. Kozaki K. Fall risk and fracture. Aging and fall/ fracture. Clin Calcium 2013; 23: 653–60. Levis S, Theodore G. Summary of AHRQ’s comparative effectiveness review of treatment to prevent fractures in men and women with low bone density or osteoporosis: update of the 2007 report. J Manag Care Pharm 2012; 18: S1–15.

Saturn Stills/Science Photo Library

and detrimental effects on BMD, respectively. Therefore, we propose that potential effects of vitamin D supplements on BMD could have been missed. BMD increases with serum 25-hydroxyvitamin D concentration reaching a plateau at about 75–85 nmol/L.3,4 Beyond this threshold, it is difficult to observe increased bone formation despite increasing vitamin D activity within osteoblast cells through expression of vitamin D receptor transgene.5 The results of this metaanalysis1 urge for further randomised controlled trials investigating vitamin D supplementation in representative populations, in which hypovitaminosis D is common.

Authors’ reply Helen Macdonald and Terence Aspray’s data should be interpreted in the context of existing evidence, and their addition to our meta-analysis does not alter the results.1 We further note the minimal effect of vitamin D on bone mineral density (BMD) in the other two studies published since our meta-analysis. 2,3 These studies are consistent with the findings of our review, small effects on BMD at some sites are seen in patients with baseline concentrations of vitamin D below 40 nmol/L. We agree that those who are deficient will benefit most from supplementation, but better defining deficiency remains a priority. Studies in groups with hypovitaminosis D will aid this, as noted by Spiros Karras and colleagues, although we do not accept that correlations between vitamin D and BMD reflect causation, or that vitamin D acts directly on osteoblasts to increase bone formation, an issue discussed in our paper.1 There was no heterogeneity between the pooled results of trials using D2 or D3 at any skeletal site. With regards to Colin Dunstan’s comments, our data are differences between the vitamin D and placebo groups. Thus, a zero difference does not imply the absence of bone loss but the absence of a therapeutic effect of vitamin D. In response to Mir Sadat-Ali and Haifa Al-Turki’s comments, we reiterate that vitamin D supplementation should be targeted to those likely to be deficient, not that vitamin D supplementation should be abandoned. As discussed in our paper,1 there is little evidence for the anti-fracture efficacy of vitamin D monotherapy, evidence 1293

Vitamin D supplements and bone mineral density.

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