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World J Diabetes. Mar 25, 2016; 7(6): 122-133
Published online Mar 25, 2016. doi: 10.4239/wjd.v7.i6.122
Metformin revisited: Does this regulator of AMP-activated protein kinase secondarily affect bone metabolism and prevent diabetic osteopathy
Antonio Desmond McCarthy, Ana María Cortizo, Claudia Sedlinsky
Antonio Desmond McCarthy, Ana María Cortizo, Claudia Sedlinsky, Laboratorio de Investigaciones en Osteopatías y Metabolismo Mineral, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, La Plata 1900, Argentina
Author contributions: All authors contributed equally to the present manuscript.
Supported by MINCyT Argentina, No. PICT-2012-0053.
Conflict-of-interest statement: All authors declare that they have no conflicting interests.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Antonio Desmond McCarthy, Professor, Laboratorio de Investigaciones en Osteopatías y Metabolismo Mineral, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, Calle 50 y 115, La Plata1900, Argentina. mccarthy@biol.unlp.edu.ar
Telephone: +54-221-4512426 Fax: +54-221-4512426
Received: September 27, 2015
Peer-review started: October 3, 2015
First decision: December 4, 2015
Revised: January 21, 2016
Accepted: January 28, 2016
Article in press: January 31, 2016
Published online: March 25, 2016
Processing time: 178 Days and 19.9 Hours
Abstract

Patients with long-term type 1 and type 2 diabetes mellitus (DM) can develop skeletal complications or “diabetic osteopathy”. These include osteopenia, osteoporosis and an increased incidence of low-stress fractures. In this context, it is important to evaluate whether current anti-diabetic treatments can secondarily affect bone metabolism. Adenosine monophosphate-activated protein kinase (AMPK) modulates multiple metabolic pathways and acts as a sensor of the cellular energy status; recent evidence suggests a critical role for AMPK in bone homeostasis. In addition, AMPK activation is believed to mediate most clinical effects of the insulin-sensitizer metformin. Over the past decade, several research groups have investigated the effects of metformin on bone, providing a considerable body of pre-clinical (in vitro, ex vivo and in vivo) as well as clinical evidence for an anabolic action of metformin on bone. However, two caveats should be kept in mind when considering metformin treatment for a patient with type 2 DM at risk for diabetic osteopathy. In the first place, metformin should probably not be considered an anti-osteoporotic drug; it is an insulin sensitizer with proven macrovascular benefits that can secondarily improve bone metabolism in the context of DM. Secondly, we are still awaiting the results of randomized placebo-controlled studies in humans that evaluate the effects of metformin on bone metabolism as a primary endpoint.

Keywords: Diabetes mellitus; Osteoporosis; Bone fractures; Metformin; AMP-activated kinase

Core tip: Patients with long-term type 1 and type 2 diabetes mellitus (DM) can develop skeletal complications. These include osteopenia, osteoporosis and increased incidence of low-stress fractures. In this context, it is important to evaluate whether current anti-diabetic treatments can secondarily affect bone metabolism. Over the past decade, several research groups have investigated the effects of metformin on bone, providing a considerable body of pre-clinical (in vitro, ex vivo and in vivo) as well as clinical evidence for an anabolic action of metformin on bone. This could be particularly relevant when considering treatment options for DM in the context of diabetic osteopathy.