The anti-diabetic drug metformin does not affect bone mass in vivo or fracture healing

Abstract

SummaryThe present study shows no adverse effects of the anti-diabetic drug metformin on bone mass and fracture healing in rodents but demonstrates that metformin is not osteogenic in vivo, as previously proposed.IntroductionIn view of the increased incidence of fractures in patients with type 2 diabetes mellitus (T2DM), we investigated the effects of metformin, a widely used T2DM therapy, on bone mass and fracture healing in vivo using two different rodent models and modes of metformin administration.MethodsWe first subjected 12-week-old female C57BL/6 mice to ovariectomy (OVX). Four weeks after OVX, mice received either saline or metformin administered by gavage (100 mg/kg/daily). After 4 weeks of treatment, bone micro-architecture and cellular activity were determined in tibia by micro-CT and bone histomorphometry. In another experiment, female Wistar rats aged 3 months were given only water or metformin for 8 weeks via the drinking water (2 mg/ml). After 4 weeks of treatment, a mid-diaphyseal osteotomy was performed in the left femur. Rats were sacrificed 4 weeks after osteotomy and bone architecture analysed by micro-CT in the right tibia while fracture healing and callus volume were determined in the left femur by X-ray analysis and micro-CT, respectively.ResultsIn both models, our results show no significant differences in cortical and trabecular bone architecture in metformin-treated rodents compared to saline. Metformin had no effect on bone resorption but reduced bone formation rate in trabecular bone. Mean X-ray scores assessed on control and metformin fractures showed no significant differences of healing between the groups. Fracture callus volume and mineral content after 4 weeks were similar in both groups.ConclusionsOur results indicate that metformin has no effect on bone mass in vivo or fracture healing in rodents.

Metformin Prevents Nonunion after Three-Cannulated-Screw Fixation in Displaced Femoral Neck Fractures: A Retrospective Study

“…Theoretically, metformin could promote bone formation and thus facilitate fracture healing. However, the studies based on animal models have shown controversial effects of metformin on fracture healing [17, 18]. Our study supported the notion that metformin might prevent the nonunion after femoral neck fracture by providing clinical evidences.…”

Low dose of propranolol does not affect rat osteotomy healing and callus strength

“…Left femora (fractured side) were scanned at 14 µm resolution using micro‐computed tomography (micro‐CT, Skyscan 1172, Kontich, Belgium). A length of approximately 15 mm of the callus with the osteotomy in the centre was scanned and histomorphometric analysis in 2‐ and 3‐ dimensions (2D, 3D) performed by Skyscan software (v. 1.11.8.0), as described . Binarization of the reconstructed datasets involved two thresholds, one to delineate the low mineralized callus and the other one to define mineralized callus and cortical bone.…”

Biological Impact of Metformin Versus Thiazolidinedione on Alveolar Bone of Induced Diabetic Rats (A Histological and Immuno-Histomorphometric Study).

“…But were against other studies that indicated that metformin has no effect on bone mass in vivo or fracture healing in rodents. (Jeyabalan et al, 2013) The mechanisms through which metformin regulates bone metabolism are not fully known. Results from in vitro and animal studies have shown that metformin has a positive effect on osteoblast differentiation by activating the osteoblast-specific Runx2 (runt-related transcription factor 2) transcription factor via the AMPK/USF-1/SHP regulatory cascade.…”