The Paradox of Fragile but Dense Bones in Type 2 Diabetes

Abstract

Epidemiologic evidence from the past decade has demonstrated that increased bone fracture risk is one of the myriad clinical complications of type 2 diabetes mellitus (T2DM). Counterintuitively, the increased fracture risk in T2DM occurs despite greater bone mineral density, and persists after accounting for potential confounders like body mass index, neuropathies, and falls. Therefore, T2DM may alter aspects of bone’s intrinsic resistance to fracture beyond bone mineral density, such as material properties or microarchitecture, thereby increasing bone fragility independently of bone mass. Although the mechanisms that underlie bone fragility in T2DM are not yet well established, a multiplicity of factors, including hyperglycemia, altered bone remodeling, and non‐enzymatic collagen crosslinking in the bone matrix are implicated. In this work we elucidate the factors that influence fragility in T2DM by characterizing the biochemical, material, microarchitectural, and mechanical properties of bone from a clinical population of men with and without T2DM. The cancellous bone from patients with T2DM had greater concentrations of the advanced glycation endproduct pentosidine and sugars bound to the collagen matrix, had greater mineral content, and trended toward a greater bone volume fraction than the non‐DM specimens. Surprisingly, the T2DM specimens had similar strength and toughness as those from non‐DM controls. Regression modeling of the mechanical outcomes revealed competing effects of T2DM on bone mechanical behavior. The trend toward greater bone volume fraction and greater mineral content of the T2DM specimens increased strength, while the greater concentrations of pentosidine in the T2DM group increased brittleness. These data suggest that high concentrations of AGEs can increase fragility by reducing the ability of bone to absorb energy prior to failure, especially for the subset of T2DM patients with low bone volume fraction. Further, our model shows that an increase in bone volume fraction offers a protective effect for T2DM patients, even with the inferior intrinsic quality of the T2DM bone, whereas loss of bone volume fraction substantially increases risk of bone fragility for T2DM patients. The primary clinical implications of these findings are that preservation of bone volume fraction is critical in patients with T2DM.Support or Funding InformationSupported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (K01 AR064314)