Estimating the causal effect of milk powder supplementation on bone mineral density: a randomized controlled trial with both non-compliance and loss to follow-up

Abstract

Background/objectives: Although previous studies reported that calcium supplementation can effectively improve bone mineral density in postmenopausal women, some studies showed the reverse conclusion. One of the reasons was that most of the studies did not take into full consideration the information of noncompliers, which seriously influenced the precision of conclusion. The aim of this paper was to investigate the effect of calcium supplementation on bone mineral density with correcting impact of noncompliance using the complier average causal effect (CACE).

Subjects/methods: A randomized controlled trial was designed to investigate the effect of high-calcium milk powder on bone mineral density. One hundred and forty-one postmenopausal women were randomly assigned to either a control group (n=72) or a milk powder supplementation group (n=69). The participants in the intervention group took 50 g of high-calcium milk powder containing 450 mg of elemental calcium and 400 IU vitamin D every morning and evening, respectively. The effects of the intervention on the primary outcome, bone mineral density, were assessed using the CACE model and intention-to-treat (ITT) and per-protocol (PP) analyses.

Results: Using the CACE model, the calcium supplementation was found to significantly reduce the bone loss at the lumbar spine compared with the control group at 24 months when adjusting the covariates (effect size 1.170, 95% confidence interval (CI) 0.376~1.964, P=0.0040). At the hip site, there was no significant difference between the calcium group and the control group. Compared with the control group, no significant weight gain was found in the calcium group over 24 months. However, the calcium group had less height loss at 24 months (effect size 1.040, 95% CI 0.012~2.066, P=0.0470) than the control group. High-density lipoprotein was significantly increased in the calcium group at 12 months (effect size 0.120, 95% CI 0.009~0.232, P=0.0340). Serum total cholesterol, triglyceride and low-density lipoprotein were not affected over 24 months. The estimates of complier average causal effect of latent ignorability model with missing data assumption of latent ignorability were consistent with the CACE estimates.

Conclusion: Consumption of high-calcium milk powder is effective in reducing the bone loss at the lumbar spine among healthy postmenopausal women. Supplementing with high-calcium milk powder had additional benefits of reducing height loss.