Author
BISCHOFF-FERRARI, HEIKE - University Hospital Zurich | |
DAWSON-HUGHES, BESS - Jean Mayer Human Nutrition Research Center On Aging At Tufts University | |
WILLETT, WALTER - Harvard University |
Submitted to: Osteoporosis International
Publication Type: Other Publication Acceptance Date: 5/22/2018 Publication Date: 6/12/2018 Citation: Bischoff-Ferrari, H., Dawson-Hughes, B., Willett, W.C. 2018. Issues of trial selection and subgroup considerations in the recent meta-analysis of Zhao and colleagues on fracture reduction by calcium and vitamin D supplementation in community-dwelling older adults. Osteoporosis International. 29(9):2151-2152. https://doi.org/10.1007/s00198-018-4587-5. DOI: https://doi.org/10.1007/s00198-018-4587-5 Interpretive Summary: Technical Abstract: Title Response: Issues of trial selection and subgroup considerations by dosing regimens and application. Zhao and colleagues are addressing an important question about the efficacy of calcium and vitamin D as well as their combination among community-dwelling adults age 50+. However, we are concerned about four aspects of their approach, which may affect the validity of their conclusions and implications for public health. First, with the inclusion of trials among middle-aged adults age 50+ and exclusion of seniors living in institutions, the authors selected a target population less vulnerable to low calcium intake, vitamin D deficiency and fracture risk. While the authors were fairly clear that they are limiting their analysis to community-dwelling participants, they ignore that results were previously found to be similar in community-dwelling and institutionalized persons, and this led to exclusion of much relevant data on the overall efficacy of calcium and vitamin D. Second, the authors included many studies that had little chance to demonstrate a benefit of the interventions: In one third of the trials follow-up was too short to demonstrate a benefit on fracture risk by the interventions as skeletal benefits cannot be expected to occur immediately (11 of 33 with follow-up of = 12 months); 4 trials had an open study design without a treatment in the control group, and the authors used an incorrect fracture report for one larger trial on calcium supplementation versus placebo (the fracture data of the original Baron trial was published in 2006). Third, a serious limitation of this meta-analysis is that adherence to supplements was not addressed. While the authors acknowledged this limitation with their argument that assessment of adherence substantially differed between included trials, this was achieved in two prior meta-analyses demonstrating its significance. Notably, in the heavily weighted Record trial, only about half of the participants were taking any of their vitamin D or calcium supplements at the halfway point in the 5 year trial. Fourth, for vitamin D alone, 8 of the 12 trials gave vitamin D in bolus doses (orally or intra-muscular application), which has repeatedly raised concerns in the literature about promoting both falls and fractures. While it may be hard to make an a priori case to exclude all bolus studies of vitamin D, the Sanders trial made a fairly convincing case that high dose bolus supplementation annually is bad, and so it is very possible that high monthly boluses are also bad. However, the authors have failed to address this concern in a subgroup analysis. Based on these limitations and the fact that there will be a many-fold increase in the data on vitamin D supplementation among community-dwelling adults within a few months from two large double-blind randomized controlled trials (VITAL and DO-HEALTH), both testing 2000 IU daily vitamin D against placebo, we believe that it is too early to recommend the cessation of vitamin D with or without calcium for the prevention of fractures among community-dwelling adults. |