Comment
Published online October 11, 2013 dx.doi/10.1016/S0140-6736(13)61721-3 1
Vitamin D supplementation: bones of contention象神
自制懒人沙发The discovery of vitamin D as an esntial nutrient for skeletal development a century ago was a major pub-lic health victory. Supplementation, whether solar or dietary, prevented the devastating eff ects of rickets in chil d ren. Five decades later, the molecular mechanisms of the vitamin’s active form (1,25-dihydroxyvitamin D) and its receptor (vitamin D receptor [VDR]), were elucidated, and subquently clinical investigators linked vitamin D defi ciency or insuffi ciency with osteoporosis. This fi nding emed logical becau osteomalacia (ie, the softening of bone in adults due to impaired mineralisation) can cau fractures and often coexists histologically with osteoporosis. Slowly, vitamin D supplementation became established for prevention of osteoporosis. But, as shown in a meta-analysis in The Lancet,1 the story is more complex, both from an epidemiological and mechanistic perspective.
Ian Reid and colleagues 1 did a systematic review of the eff ects of vitamin D supplements on bone mi
neral density that included 23 randomid controlled trials encompassing more than 4000 participants, with a mean age of 59 years. The authors found that vitamin D supplementation for 2 years resulted in no change in bone mineral density at four major skeletal sites (spine, total hip, radius, and total body), with a signifi cant increa (0·8%, 95% CI 0·2–1·4) only at the femoral neck. Surprisingly, any benefi t reported in bone mineral density was independent of calcium supplementation, baline concentration of 25-hydroxyvitamin D, duration of treatment, or age. The investigators conclude that widespread vitamin D prophylaxis in healthy community dwelling adults to prevent osteoporosis is unwarranted.H ow can the surprising fi ndings be reconciled with clinical practice and public health strategies to prevent osteoporosis? First, bone mineral density was the primary outcome in the prent analysis and is widely ud as a surrogate measure of fracture risk. H owever, changes of bone mineral density in this age group are a modest predictor of subquent fractures.2,3 Even with bisphosphonate treatment in high-risk elderly patients (older than 70 years), the bone mineral density increa with bisphosphonates accounts for less than 50% of the eff ect on fractures.4 Thus, the abnce of a positive relation between vitamin D supplementation and change in bone mineral density
could be dismisd as the fi ndings having few clinical implications. H owever, the results are consist
ent with tho of two recent meta-analys of randomid trials with vitamin D supplementation alone that recorded no effi cacy in fracture prevention, nor in another meta-analysis of vitamin D with an intention-to-treat design.5–7Second, it is diffi cult to distinguish between the eff ects of calcium versus tho of vitamin D on skeletal integrity, becau the main mechanism of action for vitamin D is promotion of calcium absorption in the gut and not direct incorporation of calcium in bone.8 In the prent meta-analysis, only half of the trials ud both calcium and vitamin D supplementation.1 In trials in which vitamin D was given simultaneously with calcium, a signifi cant reduction of 11% in hip fractures and a very modest increa in hip bone mineral density was reported.9,10 This fi nding formed the basis of the recommendation by the US Institute of Medicine that 1200 mg of calcium and 800 IU of vitamin D were optimum intakes for skeletal health in elderly people.10 The inclusion of more studies with calcium plus vitamin D in the prent report could have resulted in greater increas in bone mineral density, but confounding by calcium supplementation would not have clarifi ed the role of vitamin D alone in supporting bone mass.
Third, mechanisms of vitamin D action on the skeleton have recently been re-examined leading to a new appre-ciation of the vitamin’s biological role; the fi ndings also
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3 dx.doi/10.1016/S0140-6736(13)61721-3
lend further support to the prent meta-analysis. For example, 1,25 dihydroxyvitamin D has been shown to inhibit mineralisation in bone cell cultures. To reconcile this paradoxical fi nding, Lieben and colleagues 11 ud mice in which the VDR in intestine or bone was deleted. In mice with the intestine-specifi c knockout of VDR, condary increas in 1,25-dihydroxyvitamin D concentrations stimu l ated bone resorption while simultaneously inhibit-ing mineralisation in vivo. By contrast, VDR ablation in bone cells only resulted in incread bone mass and enhanced mineralisation.11 Lieben
and coworkers surmid that, over the long run, maintenance of normocalcaemia takes precedence over skeletal integrity, hence bone is lost and mineralisation is suppresd at the expen of circulating concentrations until calcium suffi ciency is restored.If correct, the fi ndings support the data prented by Reid and colleagues.1 During states of adequate calcium intake and normal skeletal homoeostasis, vitamin D supplementation might have little or no role in strengthening bone mass since calcium status is adequate. H owever, with vere vitamin D defi ciency (eg, 25-hydroxyvitamin D concentrations <40 nmol/L) or low calcium intake or both, skeletal micro-architecture (but not necessarily areal bone mineral density) is disrupted leading to micro-cracks, skeletal fragility, defects in mineralisation, and incread bone resorption from high concentrations of 1,25-dihydroxyvitamin D.12 Replacement with vitamin D and calcium would restore skeletal homoeostasis. In Reid and coworkers’ analysis,1 the predominantly female population in middle age is almost certain to be in a state of calcium suffi ciency.
Reid and colleagues’ meta-analysis is consistent with our understanding of vitamin D: supplementation to prevent osteoporosis in healthy adults is not warranted.
H owever, maintenance of vitamin D stores in the elderly combined with suffi cient dietary calcium intake (800–1200 mg per day) remains an eff ective approach for prevention of hip fractures.Cliff ord
J Ron
Maine Medical Rearch Institute, Scarborough, Maine 04074, USA ronc@mmc
I declare that I have no confl icts of interest. 1
Reid IR, Bolland MJ, Grey A. Eff ects of vitamin D supplements on bone
mineral density: a systematic review and meta-analysis. Lancet 2013; published online Oct 11. dx.doi/10.1016/S0140-6736(13)61647-5.
2 Leslie W, Tsang JF, Caetona PA, Lix LM. Eff ectiveness of bone density for
predicting osteoporotic fractures in clinical practice. J Clin Endocrinol Metab 2007; 92: 77–81.
3 Leslie W, Morin SN, Lix L. Rate of bone density change does not enhance
fracture prediction in routine clinical practice. J Clin Endocrinol Metab 2012; 97: 1211–18.
4 Jacques RM, Boonen S, Cosman F, et al. Relationship of changes in total hip
bone mineral density to vertebral and nonvertebral fracture risk in women with postmenopausal osteoporosis treated with once-yearly zoledronic acid 5 mg: the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res 2012; 27: 1627–34.
5 Avenell A, Gillespie WJ, Gillespie LD, O’Connell D. Vitamin D and vitamin D
analogues for preventing fractures associated with involutional and post menopausal osteoporosis. Cochrane Databa Syst Rev 2005; 3: CD000227.6 Abrahamn B, Masud T, Avenell A, et al. Patient level pooled analysis of
68 500 patients from ven major vitamin D fracture trials in US and Europe. BMJ 2010; 340: B5463.7 Bischoff -Ferrari HA, Willett WC, Orav EJ, et al. A pooled analysis of
字母练习vitamin D do requirements for fracture prevention. N Engl J Med 2012; 367: 40–49.
朱自清散文背影8 Xue Y, Fleet JC. Intestinal vitamin D receptor is required for normal calcium
and bone metabolism in mice. Gastroenterology 2009; 136: 1317–27.
9 Tang BMP, Eslick GD, Nowson C, Smith C, Bensoussan A. U of calcium or
calcium in combination with vitamin D supplementation to prevent
海上日落fractures and bone loss in people aged 50 years and older: a meta-analysis. Lancet 2007; 370: 657–66.
猫咪拉血10 Institute of Medicine, Committee to Review Dietary Reference Intakes for
职业证书查询Vitamin D and Calcium. Dietary reference intakes for calcium and vitamin D. Washington, DC: National Academies Press, 2011.
11 Lieben L, Masuyama R, Torrekens S, et al. Normocalcemia is maintained in
mice under conditions of calcium malabsorption by vitamin D-induced inhibition of bone mineralization. J Clin Invest 2012; 122: 1803–15.12 Bus B, Bale HA, Zimmermann EA, et al. Vitamin D defi ciency induces
early signs of aging in human bone increasing the risk of fracture. Sci Transl Med 2013; 5: 193ra88.
