Metabolic status modifies skeletal response to active vitamin D: A post hoc analysis of the DPVD randomized trial

Active vitamin D analogs increase bone mineral density (BMD), but inter-individual variability in skeletal response remains unexplained. Emerging evidence suggests skeletal remodeling is influenced by systemic metabolic status. Therefore, we examined whether metabolic state, defined by glycemic trajectory, modifies skeletal responsiveness to eldecalcitol.

This post hoc cohort analysis used data from the Diabetes Prevention with Vitamin D (DPVD) randomized, placebo-controlled trial. Among 1,256 individuals with prediabetes, 1,164 participants with longitudinal BMD measurements were included. Longitudinal changes in lumbar spine BMD over three years were analyzed using a linear mixed-effects model including treatment group, glycemic trajectory (incident type 2 diabetes, persistent prediabetes, or regression to normoglycemia), time, and their interaction terms. Multivariable linear regression was used to identify baseline factors associated with the 3-year percentage change in lumbar spine BMD in the eldecalcitol group.

Lumbar spine BMD trajectories differed according to treatment assignment and glycemic trajectory (treatment-by-trajectory-by-time interaction, P=0.0307). Among participants receiving eldecalcitol, 3-year BMD increases were progressively greater with more favorable glycemic trajectories (4.6% in those who progressed to type 2 diabetes, 7.3% in those with persistent prediabetes, and 9.2% in those who regressed to normoglycemia; trajectory-by-time interaction, P=0.0098), whereas no significant differences across glycemic trajectories were observed in the placebo group (P=0.772). In addition, a lower baseline HbA1c was independently associated with a greater 3-year increase in lumbar spine BMD (β = -5.15 percentage points per 1% higher HbA1c; 95% CI, -8.34 to -1.95; P = 0.002).

These findings suggest that metabolic status influences skeletal response to active vitamin D therapy and support the concept of bone-metabolic coupling.