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
2
3
4
5
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.
2 3 4
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
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
2
3
4
5
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.
2 3 4
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
