Impaired Bone Matrix: The Key to Fragility in Type 2 Diabetes?

Diabetes is a common cause of morbidity. In the United States, 1 in 4 older adults have type 2 diabetes mellitus (T2DM). Individuals with T2DM have twice the risk of fragility fracture of nondiabetics and greater mortality after fracture (1). While risk of fragility fracture is often attributed to low bone mineral density (BMD), individuals with T2DM have normal or high BMD and have a greater risk of fracture at any given BMD compared to nondiabetics. Many skeletal factors have been proposed to explain the increased risk of fracture in T2DM, including changes in bone matrix constituents such as increased advanced glycation end products (2, 3), which may promote matrix fragility, and increased sclerostin, which suppresses bone formation. Difficulties in obtaining bone tissue from patients with T2DM have limited the study of the changes in mechanical properties of bone tissue. In this issue of JCEM, Sihota and colleagues (4) examine the mechanical and chemical properties of bone tissue retrieved after fragility fracture of the hip and show clear impairments of bone tissue material properties in individuals with T2DM.

A novelty of this study is that tissue samples were collected after patients sustained hip fractures. A major limitation of prior studies of bone tissue in diabetes is that bone samples were collected at the time of elective arthroplasty (2, 3, 5) and may therefore have alterations in bone tissue associated with the underlying arthritis. In addition, patients typically undergo intensive glycemic control in the period before elective surgery, so perioperative glycated hemoglobin may not reflect their usual glucose levels. Patients in the Sihota et al cohort presented in the setting of trauma, suggesting their glycated hemoglobin values are more reflective of their steady state. An important limitation of this work (common to other studies) is that the authors could not relate material properties to long-term glycemic control (more than 3 months prior to measurement). Further, information was not reported regarding how diabetes was diagnosed, duration of disease, or the presence of complications. By focusing on hip fractures, the authors enrolled a population with unambiguous fragility. Of note, diabetic and control patients had both osteoporosis at the femoral neck by dual-energy x-ray absorptiometry. The findings of lower bone volume fraction (BV/TV) in the diabetic group, in contrast to most prior reports (2, 3, 5), may relate to the clinically significant fragility that characterized the diabetic and nondiabetic patients in this study. Patient recruitment after fracture is challenging because of pain, disability, and social issues; therefore, the insights gained from the present cohort are particularly valuable because of their rarity.

A strength of the Sihota et al study is the direct examination of the changes in the biomechanical properties of cancellous bone in T2DM. The ability of bone to resist fracture is determined by a combination of bone quantity as well as bone quality. Bone quantity is the primary determinant of bone strength, and is represented in cancellous bone by BV/TV. However, if the material properties of the bone matrix are impaired, the mechanical performance of cancellous bone will be impaired in ways that are not explained by BV/TV. Sihota and colleagues report reduced cancellous bone strength in patients with T2DM as compared to nondiabetics, primarily because the diabetic cohort had reduced BV/TV (the relationships between BV/TV and strength are identical in Fig. 8C). However, 2 distinct biomechanical properties, postyield energy and toughness, were reduced in tissue from diabetic patients in ways that could not be explained by bone quantity (as indicated by differences in regression lines in Fig. 8D and 8E). Strength is the most commonly assessed failure property of bone, but reductions in postyield energy and toughness indicate that the bone matrix is more brittle than healthy bone—a change that can make the bone more susceptible to failure under impact loading or cyclic loading (see [6] for a review accessible to nonengineers). Along with the nanoindentation and biochemical analysis, these findings by Sihota and colleagues demonstrate that bone tissue from patients with T2DM is mechanically impaired.

How important are changes in bone matrix mechanical properties? Clinical studies suggest a nonlinear relationship between computed tomography scan–based estimates of whole bone strength and probability of hip fracture so that small reductions in whole bone strength can cause large increases in probability of fracture, especially in bones that are already osteopenic (7). Such a relationship may explain why increases in fracture risk in diabetes may not be as obvious in other cohorts that are not osteopenic. The majority of pharmaceutical approaches focus on increasing bone quantity by altering the amount of bone resorbed or formed. The focus on bone quantity has been successful at reducing fracture risk because, as mentioned earlier, bone quantity is the single most influential determinant of bone strength. However, as the field seeks to reduce the incidence of fragility fracture beyond what is possible with current interventions, new strategies must be developed that focus on other contributors to mechanical failure. The findings by Sihota and colleagues suggest the potential utility of interventions that address poor bone matrix in some populations.

To be sure, the pathophysiology of bone fragility in T2DM is multifactorial, with other factors (eg, falls, neuropathies) contributing to skeletal fragility in T2DM in addition to impaired bone matrix properties (1). However, the elevated fracture risk in individuals with T2DM persists even after adjusting for many covariates such as age, BMD, body mass index, neuropathies, retinopathies, and falls (8), suggesting that additional factors, including impaired bone tissue properties, contribute to skeletal fragility in T2DM. Additionally, there is evidence that interventions that address bone matrix quality are possible: Anabolic approaches have some potential to improve bone matrix quality by adding layers of freshly made tissue, osteocytes may modulate their local bone matrix, and changes in the gut microbiome may mediate matrix properties (7).

The findings of Sihota et al highlight that diabetic patients who have low BMD may be at particularly high risk of fragility fracture because of compromised bone tissue quality. These results implicate tissue quality as an important mechanism for fragility among diabetics and highlights the potential of interventions that enhance bone matrix quality.