DPP-4i Treatment Significantly Reduces Osteoporosis Risk in Patients with Type 2 Diabetes

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Results showed treatment with dipeptidyl peptidase-4 inhibitors (DPP-4i) improved bone mineral density and reduced osteoporosis risk in patients with type 2 diabetes.

In patients with type 2 diabetes mellitus (T2DM), treatment with Dipeptidyl peptidase-4 inhibitors (DPP-4i) increased bone mineral density and decreased the risk of osteoporosis, according to a study published in Journal of Clinical Densitometry.1

DPP-4i is commonly used in the treatment and management of T2DM, offering a low risk of hypoglycemia, a solid safety profile, and neutral effects on weight. However, there have been conflicting data on the impact of this drug on bone metabolism, with some studies reporting beneficial effects while others have shown neutral or even adverse effects.2

“T2DM frequently coexists with osteoporosis and reduced bone mineral density,” wrote a group of Chinese investigators. “DPP-4i, a class of antihyperglycemic agents, are commonly employed in T2DM treatment. However, the influence of DPP-4i on bone health remains unclear and debated. This meta-analysis is conducted to explore the relationship between the use of DPP-4i and changes in bone mineral density, as well as the prevalence of osteoporosis among T2DM patients.”

A comprehensive search was performed using PubMed, Cochrane Library, Embase, and Web of Science to identify relevant studies from inception to June 2023. The meta-analysis included research evaluating patients with T2DM receiving DPP-4i treatment and analyzing the effects on bone mineral density and osteoporosis.

Eligible studies were randomized controlled trials (RCTs), cohort studies, or case-control studies, involved patients with T2DM treated with DPP-4i, provided outcomes regarding osteoporosis incidence or changes in bone mineral density, and reported enough data to be able to calculate effect sizes. Heterogeneity was assessed and pooled effects were determined using fixed-effect and random-effects models.

Out of an initial total of 453 records, 10 studies, comprised of a combined population of 214,541 patients, were identified for inclusion. These studies varied in trial design, age ranged from 54 to 68 years, and the duration of DPP-4i treatment ranged from 6 months to 5 years. Of the included studies, 6 provided information on the incidence of osteoporosis and 4 focused on the effect of DPP-4i on bone mineral density.

Findings revealed an increase in bone mineral density following DPP-4i treatment (standardized mean difference [SMD] .15, 95 % confidence interval [CI] .03 ­—.26). These results were similar between patients receiving DPP-4i treatment short-term (defined as <2 years) and long-term (≥2 years). The analysis also demonstrated a significant reduction in the risk of developing osteoporosis (odds ratio [OR] .90, 95 % confidence interval .86 — .94) in this patient population with very low heterogeneity. According to the funnel plot, there was no publication bias, and the robustness of the findings were confirmed in the sensitivity analyses.

Investigators noted the comprehensive search and thorough statistical methods to confirm the consistency of the results, which were not dependent on any single study, as strengths of the analysis. Another asset was the use of random-effect models to account for any variations between studies.

However, they mentioned findings may be subject to unaccounted confounding factors, such disease duration, concomitant medications, patient age, and lifestyle, and urged future research to control for these possible confounders. Additionally, the inclusion of a variety of study designs may have created inherent biases, although the sensitivity analysis indicated otherwise.

“These findings carry important clinical implications, offering a new perspective on the comprehensive management of T2DM,” investigators concluded. “Incorporating considerations of bone health into the selection of antihyperglycemic therapy, particularly in patients at an increased risk of osteoporosis, could optimize patient outcomes and reduce healthcare burdens.”


  1. Huang L, Zhong W, Liang X, Wang H, Fu SE, Luo Z. Meta-Analysis on the Association Between DPP-4 Inhibitors and Bone Mineral Density and Osteoporosis. J Clin Densitom. Published online November 28, 2023. doi:10.1016/j.jocd.2023.101455
  2. Monami M, Dicembrini I, Antenore A, Mannucci E. Dipeptidyl peptidase-4 inhibitors and bone fractures: a meta-analysis of randomized clinical trials [published correction appears in Diabetes Care. 2014 Jan;37(1):312]. Diabetes Care. 2011;34(11):2474-2476. doi:10.2337/dc11-1099