Long-term effects of lifestyle and metformin interventions in DPP on bone density

Abstract

In the Diabetes Prevention Program Outcome Study (DPPOS), a cohort at high risk of diabetes, randomization to intensive lifestyle intervention or metformin, both associated with weight loss, did not have long-term negative effects on BMD compared with the placebo group. Potential positive effects of metformin on bone warrant further investigation.

Introduction: Randomization to lifestyle intervention (ILS) or metformin in the Diabetes Prevention Program (DPP) resulted in weight loss and reduced progression to diabetes. Weight loss is associated with reduced bone mineral density (BMD), but the long-term effects of these interventions on BMD are unknown. In the DPP Outcome Study (DPPOS), we determined if randomization to ILS or metformin, compared with placebo, was associated with differences in BMD approximately 16 years later.

Methods: Of 3234 DPP participants, 2779 continued in DPPOS and were offered ILS in group format. Those randomized to metformin were offered unmasked metformin. At DPPOS year 12, 1367 participants had dual-energy X-ray absorptiometry scans. BMD in metformin and ILS groups was compared to placebo using sex-specific linear regression models, adjusted for age, race/ethnicity, and weight and weight-bearing activity at DPP baseline.

Results: At DPPOS year 12, mean age was 66.5 (±9.5) years. Femoral neck BMD was similar in the ILS and placebo groups in men (difference = -0.021 g/cm², 95%CI (-0.063, 0.021)) and in women (+0.014 g/cm², 95%CI (-0.014, 0.042)). Femoral neck BMD was higher in the metformin compared to placebo group although not statistically different in men (+0.017 g/cm², 95% CI (-0.023, 0.058)) and in women (+0.019 g/cm², 95% CI (-0.009, 0.047)). Prevalence of osteoporosis was low and similar across treatment groups in men (0.9%; p=0.745) and women (2.4%; p=0.466).

Conclusion: In a cohort at high risk of diabetes, lifestyle intervention or metformin did not appear to have long-term negative effects on BMD. Potential positive effects of metformin on bone warrant further research.

Keywords: Bone mineral density; Metformin; Prediabetes; Weight loss.

Fig. 1

Timeline for the Diabetes Prevention Program (DPP) and DPP Observational Study (DPPOS), including DXA visits

Fig. 2

Mean weight at each annual visit in DPP and DPPOS for men and women who completed DXA visit. Mean weight loss from DPP baseline to DPPOS Y12 (about 16 years later) differed across treatment groups in men (−5.9 kg ILS, −3.2 kg metformin, −1.7 kg placebo; p=0.002), but not in women (−3.7 kg for all groups, p=0.891)

Fig. 3

Mean weight-bearing physical activity at each annual visit in DPP and DPPOS for men and women who completed DXA visit. Mean change in weight-bearing physical activity from DPP baseline to DPPOS Y12 (about 16 years) was not statistically different in men (+0.6 met-h/week ILS; −2.3 met-h/week metformin; −2.4 met-h/week placebo; p=0.458) but was different across treatment groups in women (+0.7 met-h/week ILS; −1.9 met-h/week metformin; −2.0 met-h/week placebo; p= 0.036)