J Endocrinol Invest (2015) 38:91–94 DOI 10.1007/s40618-014-0127-0
OPINION
Effects of vitamin D supplements on bone density Ian R. Reid
Received: 19 June 2014 / Accepted: 21 June 2014 / Published online: 20 July 2014 Ó Italian Society of Endocrinology (SIE) 2014
Keywords Vitamin D Osteoporosis Osteomalacia Bone density Vitamin D was originally identified as a factor which cured rickets in children and osteomalacia in adults. It was misnamed, since it is not an essential dietary constituent, but a hormonal precursor made in the skin following exposure to ultraviolet light. It plays a pivotal role in bone health, and the osteomalacia seen in vitamin D-deficient humans is recapitulated in animals lacking the vitamin D receptor (VDR). The VDR is present in bone cells, in the gut, and in a number of other tissues, though there is ongoing controversy with respect to its expression in muscle [1]. Elegant experiments have demonstrated that the osteomalacia of the VDR knockout mouse can be completely corrected by the selective expression of VDR in the enterocytes of the gut [2]. Conversely, selective knockout of the VDR in the gut reproduces the osteomalacic phenotype, indicating that it is the effect of VDR to facilitate calcium absorption that is critical to its effect on bone health [3]. In fact, selective knockout of VDR from bone is associated with an increase in bone mass, suggesting that the direct effects of the vitamin D endocrine system on bone are negative [3, 4]. The direct actions of VDR on bone are mediated via the osteoblast, and result in increased expression of the osteoclastogenic factor, RANKL, and suppression of its antagonist, I. R. Reid Department of Endocrinology, Auckland District Health Board, University of Auckland, Auckland, New Zealand I. R. Reid (&) Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand e-mail: [email protected]
osteoprotegerin. There is also recent evidence that activation of VDR in bone increases bone pyrophosphate levels, resulting in decreased bone mineralisation [3]. These findings clarify the biological role of VDR, which is primarily to maintain extracellular fluid calcium concentrations, rather than to maintain bone health. In times of calcium privation, the vitamin D/endocrine system will deplete the skeleton of calcium, such that serum calcium can be maintained, since this is critical to the normal function of the nervous system, the heart, muscle and blood coagulation. Thus, vitamin D is not a tonic for bone, but its adequate provision is necessary for bone health [5]. In recent decades, vitamin D supplements have come to be a common component of the management of osteoporosis. This practice has become established based on the misconception that vitamin D exerts major positive effects on the skeleton, and in the hope that if some vitamin D is good for bone, then more will be better. The randomised controlled trial of Chapuy [6] in the early 1990s, provided a major boost to this belief by demonstrating an 43 % reduction in hip fractures and a 32 % reduction in total fractures in frail elderly women administered a combination of calcium plus vitamin D. However, subsequent studies have not produced such positive results, particularly when vitamin D is administered on its own. Thus, recent meta-analyses have shown no effect of vitamin D alone on total fracture [7–9], a trend towards an adverse effect of vitamin D monotherapy on hip fracture [7, 9], and a beneficial trend of calcium plus vitamin D on hip fracture, which is in fact confined to studies in institutionalised patients (Fig. 1). The latter is an important qualification, since a substantial reduction in fracture risk will only be realised in individuals who have very low baseline vitamin D and/or calcium status. For instance, the placebo group in
123
92
J Endocrinol Invest (2015) 38:91–94
Study
Calcium/ Vitamin D Control n/N n/N
Relative Risk/ Hazard Ratio [95% confidence interval]
Weight (%)
Calcium/ Vitamin D- community Dawson-Hughes, 1997 Avenell CaD, 2004 Harwood CaD, 2004 Porthouse, 2005 RECORD CaD, 2005 OSTPRE, 2010 WHI 2013
0/187 1/35 1/75 8/1321 46/1306 4/1718 70/4015 130/8657
1/202 1/35 1/37 17/1993 41/1332 2/1714 61/3957 124/9270
0.36 [0.02, 8.78] 0.6 1.00 [0.07, 15.4] 0.8 0.49 [0.03, 7.67] 0.8 0.71 [0.31, 1.64] 9 1.14 [0.76, 1.73] 35 2.00 [0.37, 10.9] 2 1.20 [0.85, 1.69] 52 1.12 [0.88, 1.44] P=0.36
137/1634 27/389 164/2023
178/1636 21/194 199/1830
0.77 [0.62, 0.95] 87 0.64 [0.37, 1.10] 13 0.75 [0.62, 0.92] P=0.005
Calcium/ Vitamin D- institution Chapuy 1994 Chapuy 2002
0.1 0.2 0.5 1 2 5 10 Favours treatment Favours control
Fig. 1 Meta-analysis of the effects of vitamin D with calcium, on hip fracture risk in randomised controlled trials. Studies have been divided according to the residential status of their participants. The classification of the Harwood study is debatable since subjects were in hospital following fractures at trial entry, though most had been
community dwelling previously. The WHI data are for those women not randomised to oestrogen, since a significant interaction was found between oestrogen and randomization to calcium plus vitamin D [20]. More details have been published previously [21]. Copyright MJ Bolland 2013, used with permission
the Chapuy study [6] had circulating 25-hydroxyvitamin D [25(OH)D] levels of 14 nmol/L, so much of the dividend in terms of both bone density and fracture prevention is likely to have arisen from the treatment of osteomalacia. What the meta-analyses demonstrate is that comparable dividends are not forthcoming in the more robust, communitydwelling individuals, most of whom are starting with much higher 25(OH)D levels. Meta-analyses also demonstrate that the anti-fracture efficacy of calcium plus vitamin D is very comparable to that of calcium alone [10], questioning the contribution of the vitamin D component of the combined intervention. The disappointing results from the meta-analyses of fracture outcomes prompted us to systematically review studies of vitamin D supplementation on bone density [11]. This review identified 23 studies in which adults had been randomised into groups that allowed comparison of vitamin D supplementation with control. There were [4,000 people in these studies and baseline 25(OH)D levels covered a wide range, with a mean value of 53 nmol/L. The mean duration of the studies was 2 years. Five of these studies identified positive change in bone density at a single anatomical site, not confirmed at the other site(s) measured. These studies had baseline 25(OH)D levels \40 nmol/L. Two studies found significant decreases in bone density in the supplemented groups. Metaanalysis demonstrated no significant change in bone density at the spine, total hip, total body or forearm. There was a 0.8 % benefit at the femoral neck (p = 0.05) but this was not seen in the total hip (Fig. 2) suggesting it might represent a chance finding. There was a significant interaction between supplement dose and the effect on bone density,
with doses \800 U/day showing significantly greater benefits, and no effect whatsoever from doses of 800 U/day and greater. These results could be interpreted as indicating that vitamin D has no influence on bone density. However, we know that very low levels of vitamin D cause osteomalacia, and there is clear documentation of bone density increases of up to 50 % in the 12 months after vitamin D treatment of patients with osteomalacia [12]. Indeed, in some of the studies where there have been substantial increases in bone density following the use of calcium plus vitamin D, such as the Chapuy study, it is likely that some of this increase represents healing of osteomalacia. Thus, our recent metaanalysis does not say that vitamin D has no effect on bone density, but that levels [40 nmol/L are quite adequate for optimal bone density and increases above this level are without effect. The role of vitamin D is primarily in osteomalacia prevention rather than as a tonic for bone. In fact, some studies of high-dose calciferol or 1a-hydroxylated vitamin D metabolites show increased bone loss [13] and fractures [14–16], which is consistent with high levels of vitamin D having adverse effects on bone resorption and skeletal mass. The clinical implications of the biphasic nature of vitamin D effects on bone are that we should intervene to prevent severe deficiency, but that we should not waste resources through supplementing where it is unneeded, nor impair skeletal health through pushing 25(OH)D levels above the physiological range. Also, we need to bear in mind the substantial costs of 25(OH)D measurement and the low accuracy of many of the available assays. The recognition that it is only levels of 25(OH)D \40 nmol/L
123
J Endocrinol Invest (2015) 38:91–94 Weighted mean difference in total hip/ Weight trochanter BMD (%) [95% CI] (%) Ooms, 1995 -0.2 [-1.9, 1.5] 2 Hunter, 2000 4 0.7 [-0.5, 1.9] Patel, 2001 -0.1 [-0.8, 0.6] 8 Cooper, 2003 3 0.3 [-1.0, 1.6] Harwood, 2004 3 2.0 [0.5, 3.5] Aloia, 2005 0.0 [-0.4, 0.4] 14 Zhu, 2008a 2 1.1 [-0.9, 3.2] Zhu, 2008b 9 0.3 [-0.4, 1.0] Islam, 2010 2 3.0 [1.2, 4.8] Jorde 2010 0.1 [-0.3, 0.4] 16 Grimnes, 2011 -0.3 [-0.6, 0.1] 15 Rastelli, 2011 2 0.0 [-1.9, 1.8] Steffensen, 2011 3 0.7 [-0.6, 2.0] Verschueren 2011 -0.1 [-0.9, 0.8] 7 Nieves, 2012 0.2 [-0.4, 0.7] 11 0.2 [-0.1, 0.4] P = 0.17 Total Study
Test for heterogeneity: I² = 39%, P = 0.06
-3 -2 -1 0 Favours decreased BMD with vitamin D
1 2 3 Favours increased BMD with vitamin D
Fig. 2 Meta-analysis of the effects of vitamin D supplementation on bone mineral density at the total hip or trochanter, as described by Reid [11]. Reprinted from The Lancet, Copyright (2013), with permission from Elsevier
that are a threat to skeletal health is important in reconciling these various considerations. Individuals with such low levels can usually be identified from clinical risk factors alone, such as dark skin, marked frailty, permanent veiling, or seldom venturing outdoors. If low doses of calciferol (e.g. 400–800 U/day) are provided to these individuals, osteomalacia will be averted [17]. In general, individuals living independently in the community and not dark skinned or veiled will not need supplements at all. Higher doses of vitamin D do not produce greater effects on bone density, if anything they may be less effective [11]. Thus, a review suggesting that achieved levels of 25(OH)D are directly related to anti-fracture efficacy is likely to be flawed [18], because it compared compliant individuals with non-compliant. Fracture outcomes are different in individuals who are compliant or non-compliant with placebo [19], suggesting that compliance is itself a marker for fracture risk. In summary, vitamin D is critically important for the maintenance of normocalcaemia and normophosphataemia, and, through these intermediates, for the prevention of osteomalacia. A daily vitamin D dose of 400–800 IU can achieve this goal without need for monitoring of serum 25(OH)D concentrations. Dose escalation beyond these levels is unnecessary in most subjects, and possibly dangerous. Monitoring of serum 25(OH)D, except in the context of specific diseases or risk factors, is unlikely to be helpful and incurs a cost much larger than that of the vitamin D supplements themselves.
93 Acknowledgement This work was supported by the Health Research Council of New Zealand. Conflict of interest
None.
References 1. Wang YJ, DeLuca HF (2011) Is the vitamin D receptor found in muscle? Endocrinology 152:354–363 2. Xue Y, Fleet JC (2009) Intestinal vitamin D receptor is required for normal calcium and bone metabolism in mice. Gastroenterology 136:1317–1327 3. Lieben L, Masuyama R, Torrekens S et al (2012) Normocalcemia is maintained in mice under conditions of calcium malabsorption by vitamin D-induced inhibition of bone mineralization. J Clin Invest 122:1803–1815 4. Yamamoto Y, Yoshizawa T, Fukuda T et al (2013) Vitamin D receptor in osteoblasts is a negative regulator of bone mass control. Endocrinology 154:1008–1020 5. Reid IR, Bolland MJ (2014) Skeletal and nonskeletal effects of vitamin D: is vitamin D a tonic for bone and other tissues? Osteoporos Int. (in press) 6. Chapuy MC, Arlot ME, Duboeuf F et al (1992) Vitamin-D3 and calcium to prevent hip fractures in elderly women. N Engl J Med 327:1637–1642 7. Avenell A, Gillespie WJ, Gillespie LD et al (2009) Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis. Cochrane Database Syst Rev. doi:10.1002/14651858.CD000227.pub3 8. Abrahamsen B, Masud T, Avenell A et al (2010) Patient level pooled analysis of 68,500 patients from seven major vitamin D fracture trials in US and Europe. BMJ 340:B5463 9. Bolland MJ, Grey A, Gamble GD et al (2014) Are more trials of vitamin D supplementation needed for skeletal, vascular or cancer outcomes? A trial sequential meta-analysis. Lancet Diab Endocrinol. doi:10.1016/S2213-8587(13)70212-2 10. Tang BMP, Eslick GD, Nowson C et al (2007) 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 370:657–666 11. Reid IR, Bolland MJ, Grey A (2014) Effects of vitamin D supplements on bone mineral density: A systematic review and metaAnalysis. Lancet 383:146–155 12. El-Desouki MI, Othman SM, Fouda MA (2004) Bone mineral density and bone scintigraphy in adult Saudi female patients with osteomalacia. Saudi Med J 25:355–358 13. Ott SM, Chesnut CH (1989) Calcitriol treatment is not effective in postmenopausal osteoporosis. Ann Intern Med 110:267–274 14. Sanders KM, Stuart AL, Williamson EJ et al (2010) Annual highdose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA 303:1815–1822 15. Smith H, Anderson F, Raphael H et al (2007) Effect of annual intramuscular vitamin D on fracture risk in elderly men and women. A population-based, randomized, double-blind, placebocontrolled trial. Rheumatology 46:1852–1857 16. Ebeling PR, Wark JD, Yeung S et al (2001) Effects of calcitriol or calcium on bone mineral density, bone turnover, and fractures in men with primary osteoporosis: A two-year randomized, double blind, double placebo study. J Clin Endocrinol Metab 86:4098–4103 17. Gallagher JC, Sai A, Templin T et al (2012) Dose Response to vitamin D supplementation in postmenopausal women a randomized trial. Ann Intern Med 156:425–437
123
94 18. Bischoff-Ferrari HA, Willett WC, Orav EJ et al (2012) A pooled analysis of vitamin D dose requirements for fracture prevention. N Engl J Med 367:40–49 19. Curtis JR, Delzell E, Chen L et al (2011) The relationship between bisphosphonate adherence and fracture: is it the behavior or the medication? results from the placebo arm of the fracture intervention trial. J Bone Miner Res 26:683–688
123
J Endocrinol Invest (2015) 38:91–94 20. Robbins JA, Aragaki A, Crandall CJ et al (2013) Women’s Health Initiative clinical trials: interaction of calcium and vitamin D with hormone therapy. Menopause 21:116–123 21. Reid IR, Bolland MJ (2014) Calcium risk-benefit updated-New WHI analyses. Maturitas 77:1–3
OPINION
Effects of vitamin D supplements on bone density Ian R. Reid
Received: 19 June 2014 / Accepted: 21 June 2014 / Published online: 20 July 2014 Ó Italian Society of Endocrinology (SIE) 2014
Keywords Vitamin D Osteoporosis Osteomalacia Bone density Vitamin D was originally identified as a factor which cured rickets in children and osteomalacia in adults. It was misnamed, since it is not an essential dietary constituent, but a hormonal precursor made in the skin following exposure to ultraviolet light. It plays a pivotal role in bone health, and the osteomalacia seen in vitamin D-deficient humans is recapitulated in animals lacking the vitamin D receptor (VDR). The VDR is present in bone cells, in the gut, and in a number of other tissues, though there is ongoing controversy with respect to its expression in muscle [1]. Elegant experiments have demonstrated that the osteomalacia of the VDR knockout mouse can be completely corrected by the selective expression of VDR in the enterocytes of the gut [2]. Conversely, selective knockout of the VDR in the gut reproduces the osteomalacic phenotype, indicating that it is the effect of VDR to facilitate calcium absorption that is critical to its effect on bone health [3]. In fact, selective knockout of VDR from bone is associated with an increase in bone mass, suggesting that the direct effects of the vitamin D endocrine system on bone are negative [3, 4]. The direct actions of VDR on bone are mediated via the osteoblast, and result in increased expression of the osteoclastogenic factor, RANKL, and suppression of its antagonist, I. R. Reid Department of Endocrinology, Auckland District Health Board, University of Auckland, Auckland, New Zealand I. R. Reid (&) Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand e-mail: [email protected]
osteoprotegerin. There is also recent evidence that activation of VDR in bone increases bone pyrophosphate levels, resulting in decreased bone mineralisation [3]. These findings clarify the biological role of VDR, which is primarily to maintain extracellular fluid calcium concentrations, rather than to maintain bone health. In times of calcium privation, the vitamin D/endocrine system will deplete the skeleton of calcium, such that serum calcium can be maintained, since this is critical to the normal function of the nervous system, the heart, muscle and blood coagulation. Thus, vitamin D is not a tonic for bone, but its adequate provision is necessary for bone health [5]. In recent decades, vitamin D supplements have come to be a common component of the management of osteoporosis. This practice has become established based on the misconception that vitamin D exerts major positive effects on the skeleton, and in the hope that if some vitamin D is good for bone, then more will be better. The randomised controlled trial of Chapuy [6] in the early 1990s, provided a major boost to this belief by demonstrating an 43 % reduction in hip fractures and a 32 % reduction in total fractures in frail elderly women administered a combination of calcium plus vitamin D. However, subsequent studies have not produced such positive results, particularly when vitamin D is administered on its own. Thus, recent meta-analyses have shown no effect of vitamin D alone on total fracture [7–9], a trend towards an adverse effect of vitamin D monotherapy on hip fracture [7, 9], and a beneficial trend of calcium plus vitamin D on hip fracture, which is in fact confined to studies in institutionalised patients (Fig. 1). The latter is an important qualification, since a substantial reduction in fracture risk will only be realised in individuals who have very low baseline vitamin D and/or calcium status. For instance, the placebo group in
123
92
J Endocrinol Invest (2015) 38:91–94
Study
Calcium/ Vitamin D Control n/N n/N
Relative Risk/ Hazard Ratio [95% confidence interval]
Weight (%)
Calcium/ Vitamin D- community Dawson-Hughes, 1997 Avenell CaD, 2004 Harwood CaD, 2004 Porthouse, 2005 RECORD CaD, 2005 OSTPRE, 2010 WHI 2013
0/187 1/35 1/75 8/1321 46/1306 4/1718 70/4015 130/8657
1/202 1/35 1/37 17/1993 41/1332 2/1714 61/3957 124/9270
0.36 [0.02, 8.78] 0.6 1.00 [0.07, 15.4] 0.8 0.49 [0.03, 7.67] 0.8 0.71 [0.31, 1.64] 9 1.14 [0.76, 1.73] 35 2.00 [0.37, 10.9] 2 1.20 [0.85, 1.69] 52 1.12 [0.88, 1.44] P=0.36
137/1634 27/389 164/2023
178/1636 21/194 199/1830
0.77 [0.62, 0.95] 87 0.64 [0.37, 1.10] 13 0.75 [0.62, 0.92] P=0.005
Calcium/ Vitamin D- institution Chapuy 1994 Chapuy 2002
0.1 0.2 0.5 1 2 5 10 Favours treatment Favours control
Fig. 1 Meta-analysis of the effects of vitamin D with calcium, on hip fracture risk in randomised controlled trials. Studies have been divided according to the residential status of their participants. The classification of the Harwood study is debatable since subjects were in hospital following fractures at trial entry, though most had been
community dwelling previously. The WHI data are for those women not randomised to oestrogen, since a significant interaction was found between oestrogen and randomization to calcium plus vitamin D [20]. More details have been published previously [21]. Copyright MJ Bolland 2013, used with permission
the Chapuy study [6] had circulating 25-hydroxyvitamin D [25(OH)D] levels of 14 nmol/L, so much of the dividend in terms of both bone density and fracture prevention is likely to have arisen from the treatment of osteomalacia. What the meta-analyses demonstrate is that comparable dividends are not forthcoming in the more robust, communitydwelling individuals, most of whom are starting with much higher 25(OH)D levels. Meta-analyses also demonstrate that the anti-fracture efficacy of calcium plus vitamin D is very comparable to that of calcium alone [10], questioning the contribution of the vitamin D component of the combined intervention. The disappointing results from the meta-analyses of fracture outcomes prompted us to systematically review studies of vitamin D supplementation on bone density [11]. This review identified 23 studies in which adults had been randomised into groups that allowed comparison of vitamin D supplementation with control. There were [4,000 people in these studies and baseline 25(OH)D levels covered a wide range, with a mean value of 53 nmol/L. The mean duration of the studies was 2 years. Five of these studies identified positive change in bone density at a single anatomical site, not confirmed at the other site(s) measured. These studies had baseline 25(OH)D levels \40 nmol/L. Two studies found significant decreases in bone density in the supplemented groups. Metaanalysis demonstrated no significant change in bone density at the spine, total hip, total body or forearm. There was a 0.8 % benefit at the femoral neck (p = 0.05) but this was not seen in the total hip (Fig. 2) suggesting it might represent a chance finding. There was a significant interaction between supplement dose and the effect on bone density,
with doses \800 U/day showing significantly greater benefits, and no effect whatsoever from doses of 800 U/day and greater. These results could be interpreted as indicating that vitamin D has no influence on bone density. However, we know that very low levels of vitamin D cause osteomalacia, and there is clear documentation of bone density increases of up to 50 % in the 12 months after vitamin D treatment of patients with osteomalacia [12]. Indeed, in some of the studies where there have been substantial increases in bone density following the use of calcium plus vitamin D, such as the Chapuy study, it is likely that some of this increase represents healing of osteomalacia. Thus, our recent metaanalysis does not say that vitamin D has no effect on bone density, but that levels [40 nmol/L are quite adequate for optimal bone density and increases above this level are without effect. The role of vitamin D is primarily in osteomalacia prevention rather than as a tonic for bone. In fact, some studies of high-dose calciferol or 1a-hydroxylated vitamin D metabolites show increased bone loss [13] and fractures [14–16], which is consistent with high levels of vitamin D having adverse effects on bone resorption and skeletal mass. The clinical implications of the biphasic nature of vitamin D effects on bone are that we should intervene to prevent severe deficiency, but that we should not waste resources through supplementing where it is unneeded, nor impair skeletal health through pushing 25(OH)D levels above the physiological range. Also, we need to bear in mind the substantial costs of 25(OH)D measurement and the low accuracy of many of the available assays. The recognition that it is only levels of 25(OH)D \40 nmol/L
123
J Endocrinol Invest (2015) 38:91–94 Weighted mean difference in total hip/ Weight trochanter BMD (%) [95% CI] (%) Ooms, 1995 -0.2 [-1.9, 1.5] 2 Hunter, 2000 4 0.7 [-0.5, 1.9] Patel, 2001 -0.1 [-0.8, 0.6] 8 Cooper, 2003 3 0.3 [-1.0, 1.6] Harwood, 2004 3 2.0 [0.5, 3.5] Aloia, 2005 0.0 [-0.4, 0.4] 14 Zhu, 2008a 2 1.1 [-0.9, 3.2] Zhu, 2008b 9 0.3 [-0.4, 1.0] Islam, 2010 2 3.0 [1.2, 4.8] Jorde 2010 0.1 [-0.3, 0.4] 16 Grimnes, 2011 -0.3 [-0.6, 0.1] 15 Rastelli, 2011 2 0.0 [-1.9, 1.8] Steffensen, 2011 3 0.7 [-0.6, 2.0] Verschueren 2011 -0.1 [-0.9, 0.8] 7 Nieves, 2012 0.2 [-0.4, 0.7] 11 0.2 [-0.1, 0.4] P = 0.17 Total Study
Test for heterogeneity: I² = 39%, P = 0.06
-3 -2 -1 0 Favours decreased BMD with vitamin D
1 2 3 Favours increased BMD with vitamin D
Fig. 2 Meta-analysis of the effects of vitamin D supplementation on bone mineral density at the total hip or trochanter, as described by Reid [11]. Reprinted from The Lancet, Copyright (2013), with permission from Elsevier
that are a threat to skeletal health is important in reconciling these various considerations. Individuals with such low levels can usually be identified from clinical risk factors alone, such as dark skin, marked frailty, permanent veiling, or seldom venturing outdoors. If low doses of calciferol (e.g. 400–800 U/day) are provided to these individuals, osteomalacia will be averted [17]. In general, individuals living independently in the community and not dark skinned or veiled will not need supplements at all. Higher doses of vitamin D do not produce greater effects on bone density, if anything they may be less effective [11]. Thus, a review suggesting that achieved levels of 25(OH)D are directly related to anti-fracture efficacy is likely to be flawed [18], because it compared compliant individuals with non-compliant. Fracture outcomes are different in individuals who are compliant or non-compliant with placebo [19], suggesting that compliance is itself a marker for fracture risk. In summary, vitamin D is critically important for the maintenance of normocalcaemia and normophosphataemia, and, through these intermediates, for the prevention of osteomalacia. A daily vitamin D dose of 400–800 IU can achieve this goal without need for monitoring of serum 25(OH)D concentrations. Dose escalation beyond these levels is unnecessary in most subjects, and possibly dangerous. Monitoring of serum 25(OH)D, except in the context of specific diseases or risk factors, is unlikely to be helpful and incurs a cost much larger than that of the vitamin D supplements themselves.
93 Acknowledgement This work was supported by the Health Research Council of New Zealand. Conflict of interest
None.
References 1. Wang YJ, DeLuca HF (2011) Is the vitamin D receptor found in muscle? Endocrinology 152:354–363 2. Xue Y, Fleet JC (2009) Intestinal vitamin D receptor is required for normal calcium and bone metabolism in mice. Gastroenterology 136:1317–1327 3. Lieben L, Masuyama R, Torrekens S et al (2012) Normocalcemia is maintained in mice under conditions of calcium malabsorption by vitamin D-induced inhibition of bone mineralization. J Clin Invest 122:1803–1815 4. Yamamoto Y, Yoshizawa T, Fukuda T et al (2013) Vitamin D receptor in osteoblasts is a negative regulator of bone mass control. Endocrinology 154:1008–1020 5. Reid IR, Bolland MJ (2014) Skeletal and nonskeletal effects of vitamin D: is vitamin D a tonic for bone and other tissues? Osteoporos Int. (in press) 6. Chapuy MC, Arlot ME, Duboeuf F et al (1992) Vitamin-D3 and calcium to prevent hip fractures in elderly women. N Engl J Med 327:1637–1642 7. Avenell A, Gillespie WJ, Gillespie LD et al (2009) Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis. Cochrane Database Syst Rev. doi:10.1002/14651858.CD000227.pub3 8. Abrahamsen B, Masud T, Avenell A et al (2010) Patient level pooled analysis of 68,500 patients from seven major vitamin D fracture trials in US and Europe. BMJ 340:B5463 9. Bolland MJ, Grey A, Gamble GD et al (2014) Are more trials of vitamin D supplementation needed for skeletal, vascular or cancer outcomes? A trial sequential meta-analysis. Lancet Diab Endocrinol. doi:10.1016/S2213-8587(13)70212-2 10. Tang BMP, Eslick GD, Nowson C et al (2007) 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 370:657–666 11. Reid IR, Bolland MJ, Grey A (2014) Effects of vitamin D supplements on bone mineral density: A systematic review and metaAnalysis. Lancet 383:146–155 12. El-Desouki MI, Othman SM, Fouda MA (2004) Bone mineral density and bone scintigraphy in adult Saudi female patients with osteomalacia. Saudi Med J 25:355–358 13. Ott SM, Chesnut CH (1989) Calcitriol treatment is not effective in postmenopausal osteoporosis. Ann Intern Med 110:267–274 14. Sanders KM, Stuart AL, Williamson EJ et al (2010) Annual highdose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA 303:1815–1822 15. Smith H, Anderson F, Raphael H et al (2007) Effect of annual intramuscular vitamin D on fracture risk in elderly men and women. A population-based, randomized, double-blind, placebocontrolled trial. Rheumatology 46:1852–1857 16. Ebeling PR, Wark JD, Yeung S et al (2001) Effects of calcitriol or calcium on bone mineral density, bone turnover, and fractures in men with primary osteoporosis: A two-year randomized, double blind, double placebo study. J Clin Endocrinol Metab 86:4098–4103 17. Gallagher JC, Sai A, Templin T et al (2012) Dose Response to vitamin D supplementation in postmenopausal women a randomized trial. Ann Intern Med 156:425–437
123
94 18. Bischoff-Ferrari HA, Willett WC, Orav EJ et al (2012) A pooled analysis of vitamin D dose requirements for fracture prevention. N Engl J Med 367:40–49 19. Curtis JR, Delzell E, Chen L et al (2011) The relationship between bisphosphonate adherence and fracture: is it the behavior or the medication? results from the placebo arm of the fracture intervention trial. J Bone Miner Res 26:683–688
123
J Endocrinol Invest (2015) 38:91–94 20. Robbins JA, Aragaki A, Crandall CJ et al (2013) Women’s Health Initiative clinical trials: interaction of calcium and vitamin D with hormone therapy. Menopause 21:116–123 21. Reid IR, Bolland MJ (2014) Calcium risk-benefit updated-New WHI analyses. Maturitas 77:1–3
