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Vitamin D supplementation and musculoskeletal health

2019; Elsevier BV; Volume: 7; Issue: 2 Linguagem: Inglês

10.1016/s2213-8587(18)30348-6

2213-8595

Roger Bouillon, Paul Lips, John P. Bilezikian,

Vitamin C and Antioxidants Research

Mark Bolland and colleagues1Bolland MJ Grey A Avenell A Effects of vitamin D supplementation on musculoskeletal health: a systematic review, meta-analysis, and trial sequential analysis.Lancet Diabetes Endocrinol. 2018; 6: 847-858Summary Full Text Full Text PDF PubMed Scopus (253) Google Scholar conclude that vitamin D supplementation is futile as a therapeutic agent to prevent falls and fractures. Many physicians and patients might thus conclude that they can stop prescribing or taking vitamin D supplements, which is a potentially dangerous message given the prevalence of vitamin D deficiency worldwide. Bolland and colleagues are experts in meta-analysis, but their analysis falls into a common trap of misleading selection of primary data.1Bolland MJ Grey A Avenell A Effects of vitamin D supplementation on musculoskeletal health: a systematic review, meta-analysis, and trial sequential analysis.Lancet Diabetes Endocrinol. 2018; 6: 847-858Summary Full Text Full Text PDF PubMed Scopus (253) Google Scholar, 2Murad MH Montori VM Ioannidis JP et al.How to read a systematic review and meta-analysis and apply the results to patient care: users' guides to the medical literature.JAMA. 2014; 312: 171-179Crossref PubMed Scopus (302) Google Scholar Several meta-analyses3Boonen S Lips P Bouillon R Bischoff-Ferrari HA Vanderschueren D Haentjens P Need for additional calcium to reduce the risk of hip fracture with vitamin d supplementation: evidence from a comparative metaanalysis of randomized controlled trials.J Clin Endocrinol Metab. 2007; 92: 1415-1423Crossref PubMed Scopus (449) Google Scholar, 4Avenell A Mak JC O'Connell D Vitamin D and vitamin D analogues for preventing fractures in post-menopausal women and older men.Cochrane Database Syst Rev. 2014; 4 (CD000227.)PubMed Google Scholar, 5Bolland MJ Grey A Gamble GD Reid IR The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis.Lancet Diabetes Endocrinol. 2014; 2: 307-320Summary Full Text Full Text PDF PubMed Scopus (337) Google Scholar clearly showed that a supplement of vitamin D combined with calcium, given to older participants with a calcium intake well below the recommended intake for their age and with mild or severe vitamin D deficiency, results in a 15–20% reduction of hip or non-vertebral fractures. Bolland and colleagues recently also corroborated the beneficial effects of combined supplementation,4Avenell A Mak JC O'Connell D Vitamin D and vitamin D analogues for preventing fractures in post-menopausal women and older men.Cochrane Database Syst Rev. 2014; 4 (CD000227.)PubMed Google Scholar, 5Bolland MJ Grey A Gamble GD Reid IR The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis.Lancet Diabetes Endocrinol. 2014; 2: 307-320Summary Full Text Full Text PDF PubMed Scopus (337) Google Scholar in line with most guidelines.6Bouillon R Comparative analysis of nutritional guidelines for vitamin D.Nat Rev Endocrinol. 2017; 13: 466-479Crossref PubMed Scopus (210) Google Scholar However, Bolland and colleagues1Bolland MJ Grey A Avenell A Effects of vitamin D supplementation on musculoskeletal health: a systematic review, meta-analysis, and trial sequential analysis.Lancet Diabetes Endocrinol. 2018; 6: 847-858Summary Full Text Full Text PDF PubMed Scopus (253) Google Scholar excluded all studies using combined vitamin D and calcium supplementation (compared with double placebo), and only assessed the results of vitamin-D-only supplementation (with or without another agent in both arms of the study). Because of this selection bias, the authors conclude what has been already well established for more than a decade.3Boonen S Lips P Bouillon R Bischoff-Ferrari HA Vanderschueren D Haentjens P Need for additional calcium to reduce the risk of hip fracture with vitamin d supplementation: evidence from a comparative metaanalysis of randomized controlled trials.J Clin Endocrinol Metab. 2007; 92: 1415-1423Crossref PubMed Scopus (449) Google Scholar The results of the new meta-analysis do not contradict the beneficial effects of combining vitamin D with calcium supplementation for older patients.3Boonen S Lips P Bouillon R Bischoff-Ferrari HA Vanderschueren D Haentjens P Need for additional calcium to reduce the risk of hip fracture with vitamin d supplementation: evidence from a comparative metaanalysis of randomized controlled trials.J Clin Endocrinol Metab. 2007; 92: 1415-1423Crossref PubMed Scopus (449) Google Scholar, 4Avenell A Mak JC O'Connell D Vitamin D and vitamin D analogues for preventing fractures in post-menopausal women and older men.Cochrane Database Syst Rev. 2014; 4 (CD000227.)PubMed Google Scholar, 5Bolland MJ Grey A Gamble GD Reid IR The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis.Lancet Diabetes Endocrinol. 2014; 2: 307-320Summary Full Text Full Text PDF PubMed Scopus (337) Google Scholar, 6Bouillon R Comparative analysis of nutritional guidelines for vitamin D.Nat Rev Endocrinol. 2017; 13: 466-479Crossref PubMed Scopus (210) Google Scholar Moreover, about two-thirds of included studies lasted less than 1 year; no rational analysis of fracture efficacy should include such short-term studies. Furthermore, Bolland and colleagues included studies that used very high bolus doses of vitamin D, which are known to increase the risk of fractures or falls, also biasing the results. Another major problem is that most of the studies included were done in vitamin D-sufficient participants. Since vitamin D is a threshold nutrient,6Bouillon R Comparative analysis of nutritional guidelines for vitamin D.Nat Rev Endocrinol. 2017; 13: 466-479Crossref PubMed Scopus (210) Google Scholar it would be surprising if a therapeutic benefit was observed in the context of already normal concentrations. However, a third of the world's population have serum concentrations of 25-hydroxyvitamin D (25OHD) that are less than 50 nmol/L, and more than 7% that are less than 30nmol/L. Such low concentrations (ie, <30 nmol/L) are uniformly considered in all guidelines6Bouillon R Comparative analysis of nutritional guidelines for vitamin D.Nat Rev Endocrinol. 2017; 13: 466-479Crossref PubMed Scopus (210) Google Scholar to be a risk factor for rickets and osteomalacia. Additionally, several studies have showed that supplementation in participants with such low 25OHD concentrations results in substantial improvements of multiple outcomes, including fewer respiratory infections,7Martineau AR Jolliffe DA Hooper RL et al.Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data.BMJ. 2017; 356: i6583Crossref PubMed Scopus (1143) Google Scholar reduced loss of bone mass over time, improved lung function of patients with asthma or chronic obstructive pulmonary disease,8Sluyter JD Camargo Jr, CA Waayer D et al.Effect of monthly, high-dose, long-term vitamin D on lung function: a randomised controlled trial.Nutrients. 2017; 9: 12Crossref Scopus (36) Google Scholar and reduced mortality.9Chowdhury R Kunutsor S Vitezova A et al.Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies.BMJ. 2014; 348: g1903Crossref PubMed Scopus (467) Google Scholar Consequently, we believe the conclusion of Bolland and colleagues that vitamin D supplementation is futile is inappropriate. On the contrary, it is important to adopt a public health strategy that eliminates vitamin D deficiency in affected populations. Unnecessary supplementation with high doses of vitamin D might be a relatively common practice, without proven benefit, and even with the risk of harm, but the problem remains that a large proportion of the global population lacks access to the small amounts of vitamin D that are essential to correct deficiency. We have a common duty to identify and implement a suitable solution for vitamin D-deficient populations around the world. RB received lecture fees from L'Oreal, Faes, Frezenius, and Abiogen; and has one patent licensed to Hybrifenix on a vitamin D analogue. PL reports personal fees from Abiogen, outside the submitted work. JPB reports other from Amgen, Abiogen, Radius, Regeneron, Ultragenyx, and Shire, outside the submitted work. Effects of vitamin D supplementation on musculoskeletal health: a systematic review, meta-analysis, and trial sequential analysisOur findings suggest that vitamin D supplementation does not prevent fractures or falls, or have clinically meaningful effects on bone mineral density. There were no differences between the effects of higher and lower doses of vitamin D. There is little justification to use vitamin D supplements to maintain or improve musculoskeletal health. This conclusion should be reflected in clinical guidelines. Full-Text PDF Vitamin D supplementation and musculoskeletal healthMark Bolland and colleagues1 identified 81 open-label and blinded randomised trials with 53 537 adult participants that compared vitamin D with untreated controls, placebo, or another dose of vitamin D. The authors report no effect of vitamin D supplementation on fractures and falls. They also report no benefit for bone mineral density given their subjectively defined futility boundary of 0·5% improvement. Notably, in three of five skeletal locations, the benefits of vitamin D on bone mineral density were significant, with increases of 0·34% (95% CI 0·13–0·55) at the total hip, 0·76% at the femoral neck (0·42–1·09), and 0·25% (0–0·49) at the lumbar spine. Full-Text PDF Vitamin D supplementation and musculoskeletal health – Authors' replyHeike Bischoff-Ferrari and colleagues are concerned that, in our meta-analysis and trial sequential analysis of vitamin D supplementation for musculoskeletal health in adults,1 we concluded that statistically significant effects of vitamin D supplements on bone density were not clinically important. However, differences (compared with controls) of −0·16% to 0·76% that do not progressively increase over 1–5 years are smaller than the average loss of bone density in post-menopausal women of 0·5–1·0% over one year,2 and so are clinically irrelevant. Full-Text PDF Vitamin D supplementation and musculoskeletal healthProtective effects of vitamin D supplementation against non-musculoskeletal outcomes, such as acute respiratory infection, are strongest in people with baseline 25-hydroxyvitamin D (25OHD) concentrations less than 25 nmol/L.1 It would seem reasonable to expect a similar phenomenon to apply to the musculoskeletal outcomes investigated in the meta-analysis of aggregate data by Mark Bolland and colleagues.2 Unfortunately, methodological problems—including a lack of access to individual participant data—limit the ability of this analysis to determine whether effects of vitamin D supplementation vary according to baseline 25OHD concentration. Full-Text PDF Vitamin D supplementation and musculoskeletal healthIn their meta-analysis1 of randomised clinical trials (RCTs) assessing the effects of vitamin D supplementation on fractures, falls, and bone mineral density in people older than 18 years, Mark Bolland and colleagues reported that vitamin D supplementation did not prevent falls or fractures in this age group. However, their approach to evaluating such RCTs might not have been sufficiently comprehensive. Full-Text PDF