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



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.


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.


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.


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).


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.

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Availability of data and material

Some or all data generated or analyzed during this study are available in the NIDDK data repository.


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The Research Group gratefully acknowledges the commitment and dedication of the participants of the DPP and DPPOS.


Research reported in this publication was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) under Award Number U01 DK048489, by providing funding during DPP and DPPOS to the clinical centers and the Coordinating Center for the design and conduct of the study, and collection, management, analysis, and interpretation of the data. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The Southwestern American Indian Centers were supported directly by the NIDDK, including its Intramural Research Program, and the Indian Health Service. The General Clinical Research Center Program, National Center for Research Resources, and the Department of Veterans Affairs supported data collection at many of the clinical centers. Funding was also provided by the National Institute of Child Health and Human Development, the National Institute on Aging, the National Eye Institute, the National Heart Lung and Blood Institute, the National Cancer Institute, the Office of Research on Women’s Health, the National Institute on Minority Health and Health Disparities, the Centers for Disease Control and Prevention, and the American Diabetes Association. Merck KGaA provides medication for DPPOS. DPP/DPPOS have also received donated materials from Bristol-Myers Squibb, Parke-Davis, and LifeScan Inc. LifeScan Inc., Health O Meter, Hoechst Marion Roussel, Inc., Merck-Medco Managed Care, Inc., Merck and Co., Nike Sports Marketing, Slim Fast Foods Co., and Quaker Oats Co. donated materials, equipment, or medicines for concomitant conditions. McKesson BioServices Corp., Matthews Media Group, Inc., and the Henry M. Jackson Foundation provided support services under subcontract with the Coordinating Center. The sponsor of this study was represented on the Steering Committee and played a part in study design, how the study was done, and publication. The opinions expressed are those of the study group and do not necessarily reflect the views of the funding agencies.

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Correspondence to A. V. Schwartz.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Institutional review boards at all sites approved the DPP and DPPOS protocols and informed consent procedures.

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Written informed consent was obtained from all individual participants included in the study.

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A complete list of the DPPOS Centers, investigators, and staff can be found in the Appendix ESM.

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Schwartz, A.V., Pan, Q., Aroda, V.R. et al. Long-term effects of lifestyle and metformin interventions in DPP on bone density. Osteoporos Int (2021). https://doi.org/10.1007/s00198-021-05989-1

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  • Bone mineral density
  • Metformin
  • Prediabetes
  • Weight loss