Vitamin D supplementation and musculoskeletal health

Protective 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.1Martineau 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 (1123) Google Scholar 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.2Bolland 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 (247) Google Scholar 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. The authors did prespecified subgroup analyses to test for interactions between the effects of vitamin D supplementation on fractures, falls, and bone mineral density for, among others, baseline 25OHD concentrations less than 25 nmol/L versus 25 nmol/L or more. However, participants were not assigned to subgroups according to their individual baseline 25OHD concentration; instead, classification was apparently done according to the mean (or sometimes the median) baseline 25OHD concentration in a given study population as a whole, or a subset thereof. This approach introduces the potential for misclassification bias in the meta-analysis. The authors classified four trials, with a total of 831 participants, as having a study population with mean baseline 25OHD concentrations less than 25 nmol/L.3Ooms ME Roos JC Bezemer PD van der Vijgh WJ Bouter LM Lips P Prevention of bone loss by vitamin D supplementation in elderly women: a randomized double-blind trial.J Clin Endocrinol Metab. 1995; 80: 1052-1058Crossref PubMed Scopus (0) Google Scholar, 4Andersen R Molgaard C Skovgaard LT et al.Effect of vitamin D supplementation on bone and vitamin D status among Pakistani immigrants in Denmark: a randomised double-blinded placebo-controlled intervention study.Br J Nutr. 2008; 100: 197-207Crossref PubMed Scopus (60) Google Scholar, 5Burleigh E McColl J Potter J Does vitamin D stop inpatients falling? A randomised controlled trial.Age Ageing. 2007; 36: 507-513Crossref PubMed Scopus (50) Google Scholar, 6Witham MD Crighton LJ Gillespie ND Struthers AD McMurdo ME The effects of vitamin D supplementation on physical function and quality of life in older patients with heart failure: a randomized controlled trial.Circ Heart Fail. 2010; 3: 195-201Crossref PubMed Scopus (185) Google Scholar One of these studies does not appear to fulfil this criterion, since median 25OHD concentrations were 25 nmol/L or higher at baseline for participants in both intervention and control groups.3Ooms ME Roos JC Bezemer PD van der Vijgh WJ Bouter LM Lips P Prevention of bone loss by vitamin D supplementation in elderly women: a randomized double-blind trial.J Clin Endocrinol Metab. 1995; 80: 1052-1058Crossref PubMed Scopus (0) Google Scholar For the other three studies, mean or median baseline 25OHD concentrations were only just below the 25 nmol/L threshold, with SDs or IQRs indicating that a substantial proportion of participants will have had baseline 25OHD concentrations greater than 25 nmol/L.4Andersen R Molgaard C Skovgaard LT et al.Effect of vitamin D supplementation on bone and vitamin D status among Pakistani immigrants in Denmark: a randomised double-blinded placebo-controlled intervention study.Br J Nutr. 2008; 100: 197-207Crossref PubMed Scopus (60) Google Scholar, 5Burleigh E McColl J Potter J Does vitamin D stop inpatients falling? A randomised controlled trial.Age Ageing. 2007; 36: 507-513Crossref PubMed Scopus (50) Google Scholar, 6Witham MD Crighton LJ Gillespie ND Struthers AD McMurdo ME The effects of vitamin D supplementation on physical function and quality of life in older patients with heart failure: a randomized controlled trial.Circ Heart Fail. 2010; 3: 195-201Crossref PubMed Scopus (185) Google Scholar Such participants will therefore have been inappropriately classified as having 25OHD concentrations less than 25 nmol/L in subgroup analyses done by Bolland and colleagues. Contamination of the sub-25 nmol/L subgroup with participants having higher baseline 25OHD concentrations could obscure protective effects of the intervention in the profoundly deficient subgroup. Conversely, for studies in which the mean or median 25OHD concentration at baseline was just above the 25 nmol/L threshold,7Lips P Graafmans WC Ooms ME Bezemer PD Bouter LM Vitamin D supplementation and fracture incidence in elderly persons. A randomized, placebo-controlled clinical trial.Ann Intern Med. 1996; 124: 400-406Crossref PubMed Scopus (590) Google Scholar a large proportion of deficient participants will have been misclassified as having 25OHD levels greater than or equal to 25 nmol/L for the purposes of the subgroup analysis. This misclassification constrains the power of the analysis to detect an effect of supplementation in the sub-25 nmol/L subgroup, potentially introducing type 2 error. Misclassification on this scale—inherent in the aggregate data meta-analysis approach—effectively prevents the meta-analysis by Bolland and colleagues from providing any meaningful insight into effects of vitamin D supplementation in individuals with baseline 25OHD concentrations less than 25 nmol/L. It therefore seems inappropriate to conclude that there is little justification in using vitamin D supplements to maintain or improve musculoskeletal health, since the effect of the intervention in profoundly vitamin D-deficient individuals (who account for more than one in five of the UK population, and who potentially stand to gain the most from supplementation) has not been effectively tested. Meta-analysis of individual participant data could have overcome this issue, by allowing accurate categorisation of individuals according to their baseline 25OHD concentration.1Martineau 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 (1123) Google Scholar I am the Principal Investigator for ongoing randomised clinical trials of vitamin D supplementation to improve musculoskeletal health in children. 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 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 Vitamin D supplementation and musculoskeletal healthMark Bolland and colleagues1 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. Full-Text PDF