Effects of Diabetes on Bone Homeostasis, Regeneration, and the Role of Insulin in Bone

David N Paglia, Kristen Mason, Eric A Breitbart, Swaroopa Vaidya, Dana Graves, J Patrick O’Connor, Sheldon S Lin
US Musculoskeletal Review, 2011;6(1):50-5
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Abstract

With over 6 million fractures occurring annually in the US, approximately 600,000 of which result in non-union, a fracture healing adjunct that can be used to manage effectively the high-risk patient (those with diabetes mellitus, steroid use, smoking and/or maturity of age) has become a necessity. Among these high-risk patients, those with diabetes mellitus have a significant risk of a non-union, resulting from local growth factor deficiencies, accumulation of advanced glycation end-products, and altered osteoblast and osteoclast formation or activity. Recent research has suggested that exogenous insulin treatment, in addition to regulating glucose control in diabetics, could help ameliorate these adverse effects associated with diabetes mellitus. Several investigators have postulated the mechanism of action of insulin in vivo and its potential for regulating diabetic bone homeostasis, managing the diabetic osteopathology and accelerating diabetic fracture healing. Further research to investigate the potential of local insulin delivery using higher-order animal and human models will elucidate both the mechanism and efficacy of local insulin administration at the fracture site, to accelerate diabetic bone fracture healing.
Keywords
Fracture, diabetes, insulin, homeostasis, bone
Disclosure The authors have no conflicts of interest to declare.
Received: April 13, 2011 Accepted May 18, 2011
Correspondence: David N Paglia, MS, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Department of Orthopaedics, 185 South Orange Avenue, Newark, NJ 07103. E: dnp6@njit.edu

Orthopaedic care relies on the timely principles of restoration of anatomy, appropriate osseous stabilization, and subsequent restoration of bone function. Of the 6.2 million fractures sustained in the US annually, 10% are subject to either delayed union or non-union.1 As such, potential adjuncts that might enhance fracture healing are sorely needed. Several of these adjuncts, commonly considered for their therapeutic potential, include biomechanical means, such as low-intensity pulse ultrasound (LIPUS), and biological factors, such as the bone morphogenic proteins (BMP), particularly BMP2. Although these and other currently available agents hold promise in accelerating fracture healing, they have limited usefulness or efficacy.

The rate of delayed fracture healing or non-unions is highest among sub-populations with specific risk factors. Risk factors for impaired fracture healing include smoking, old age, steroid use, use of certain pharmaceuticals (i.e. anticancer drugs), and metabolic diseases, such as diabetes mellitus (DM).2

An increased mechanistic understanding of impaired osseous healing associated with any one specific high-risk population, could provide information that might help to accelerate fracture healing in the general population, or among those with various risk factors. The association between DM and impaired osseous healing has been thoroughly examined in both clinical and experimental settings.3–8 Three retrospective studies have evaluated complications following elective arthrodesis in patients with DM. Although the patients in these studies represent a subpopulation of diabetics with neuropathy, the investigators noted that increased incidence of delayed union, non-union, and pseudarthrosis was significant in patients with DM.6,7,9 Animal experiments with mechanical studies have shown similar findings, documenting an impaired biomechanical strength of the DM fracture callus.3,5,8,10,11 Macey et al. hypothesized that the decreased mechanical parameters of the DM fracture callus during the early stages of repair results from decreased synthesis of collagen secondary to impaired cellular proliferation and/or migration.5 Between days four and 11 of healing, investigators observed a significant decrease (50–55%) in the collagen content of untreated DM fracture callus compared with controls. The DNA content, an indicator of callus cellularity, decreased by 40% in the untreated DM group, suggesting retarded cellular proliferation. Moreover, a decreased collagen:DNA ratio (representative of collagen synthesis) was documented during the 14-day healing period in animals with DM. The correlation of decreased mechanical strength and decreased or abnormal collagen synthesis suggests that early events have an important, persistent and deleterious role in DM fracture healing.5

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