Use of noninvasive imaging to identify causes of skeletal fragility in adults with diabetes: a review.

Diabetes, a disease marked by consistent high blood glucose levels, is associated with various complications such as neuropathy, nephropathy, retinopathy, and cardiovascular disease. Notably, skeletal fragility has emerged as a significant complication in both type 1 (T1D) and type 2 (T2D) diabetic patients. This review examines noninvasive imaging studies that evaluate skeletal outcomes in adults with T1D and T2D, emphasizing distinct skeletal phenotypes linked with each condition and pinpointing gaps in understanding bone health in diabetes. Although traditional DXA-BMD does not fully capture the increased fracture risk in diabetes, recent techniques such as quantitative computed tomography, peripheral quantitative computed tomography, high-resolution quantitative computed tomography, and MRI provide insights into 3D bone density, microstructure, and strength. Notably, existing studies present heterogeneous results possibly due to variations in design, outcome measures, and potential misclassification between T1D and T2D. Thus, the true nature of diabetic skeletal fragility is yet to be fully understood. As T1D and T2D are diverse conditions with heterogeneous subtypes, future research should delve deeper into skeletal fragility by diabetic phenotypes and focus on longitudinal studies in larger, diverse cohorts to elucidate the complex influence of T1D and T2D on bone health and fracture outcomes.

Relative Effects of Radiation-Induced Changes in Bone Mass, Structure, and Tissue Material on Vertebral Strength in a Rat Model.

The observed increased risk of fracture after cancer radiation therapy is presumably due to a radiation-induced reduction in whole-bone strength. However, the mechanisms for impaired strength remain unclear, as the increased fracture risk is not fully explained by changes in bone mass. To provide insight, a small animal model was used to determine how much of this whole-bone weakening effect for the spine is attributable to changes in bone mass, structure, and material properties of the bone tissue and their relative effects. Further, because women have a greater risk of fracture after radiation therapy than men, we investigated if sex had a significant influence on bone's response to irradiation. Fractionated in vivo irradiation (10 × 3 Gy) or sham irradiation (0 Gy) was administered daily to the lumbar spine in twenty-seven 17-week-old Sprague-Dawley rats (n = 6-7/sex/group). Twelve weeks after final treatment, animals were euthanized, and lumbar vertebrae (L4 and L5 ) were isolated. Using a combination of biomechanical testing, micro-CT-based finite element analysis, and statistical regression analysis, we separated out the effect of mass, structural, and tissue material changes on vertebral strength. Compared with the sham group (mean ± SD strength = 420 ± 88 N), the mean strength of the irradiated group was lower by 28% (117 N/420 N, p < 0.0001). Overall, the response of treatment did not differ with sex. By combining results from both general linear regression and finite element analyses, we calculated that mean changes in bone mass, structure, and material properties of the bone tissue accounted for 56% (66 N/117 N), 20% (23 N/117 N), and 24% (28 N/117 N), respectively, of the overall change in strength. As such, these results provide insight into why an elevated clinical fracture risk for patients undergoing radiation therapy is not well explained by changes in bone mass alone. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Radiation-induced changes in load-sharing and structure-function behavior in murine lumbar vertebrae.

In this study, we used micro-CT-based finite element analysis to investigate the biomechanical effects of radiation on the microstructure and mechanical function of murine lumbar vertebrae. Specifically, we evaluated vertebral microstructure, whole-bone stiffness, and cortical-trabecular load sharing in the L5 vertebral body of mice exposed to ionizing radiation 11 days post exposure (5 Gy total dose; n = 13) and controls (n = 14). Our findings revealed the irradiated group exhibited reduced trabecular bone volume and microstructure (p < 0.001) compared to controls, while cortical bone volume remained unchanged (p = 0.91). Axially compressive loads in the irradiated group were diverted from the trabecular centrum and into the vertebral cortex, as evidenced by a higher cortical load-fraction (p = 0.02) and a higher proportion of cortical tissue at risk of initial failure (p < 0.01). Whole-bone stiffness was lower in the irradiated group compared to the controls, though the difference was small and non-significant (2045 ± 142 vs. 2185 ± 225 vs. N/mm, irradiated vs. control, p = 0.07). Additionally, the structure-function relationship between trabecular bone volume and trabecular load fraction differed between groups (p = 0.03), indicating a less biomechanically efficient trabecular network in the irradiated group. We conclude that radiation can decrease trabecular bone volume and result in a less biomechanically efficient trabecular structure, leading to increased reliance on the vertebral cortex to resist axially compressive loads. These findings offer biomechanical insight into the effects of radiation on structure-function behavior in murine lumbar vertebrae independent of possible tissue-level material effects.

Relations Between Bone Quantity, Microarchitecture, and Collagen Cross-links on Mechanics Following In Vivo Irradiation in Mice.

Humans are exposed to ionizing radiation via spaceflight or cancer radiotherapy, and exposure from radiotherapy is known to increase risk of skeletal fractures. Although irradiation can reduce trabecular bone mass, alter trabecular microarchitecture, and increase collagen cross-linking, the relative contributions of these effects to any loss of mechanical integrity remain unclear. To provide insight, while addressing both the monotonic strength and cyclic-loading fatigue life, we conducted total-body, acute, gamma-irradiation experiments on skeletally mature (17-week-old) C57BL/6J male mice (n = 84). Mice were administered doses of either 0 Gy (sham), 1 Gy (motivated by cumulative exposures from a Mars mission), or 5 Gy (motivated by clinical therapy regimens) with retrieval of the lumbar vertebrae at either a short-term (11-day) or long-term (12-week) time point after exposure. Micro-computed tomography was used to assess trabecular and cortical quantity and architecture, biochemical composition assays were used to assess collagen quality, and mechanical testing was performed to evaluate vertebral compressive strength and fatigue life. At 11 days post-exposure, 5 Gy irradiation significantly reduced trabecular mass (p < 0.001), altered microarchitecture (eg, connectivity density p < 0.001), and increased collagen cross-links (p < 0.001). Despite these changes, vertebral strength (p = 0.745) and fatigue life (p = 0.332) remained unaltered. At 12 weeks after 5 Gy exposure, the trends in trabecular bone persisted; in addition, regardless of irradiation, cortical thickness (p < 0.01) and fatigue life (p < 0.01) decreased. These results demonstrate that the highly significant effects of 5 Gy total-body irradiation on the trabecular bone morphology and collagen cross-links did not translate into detectable effects on vertebral mechanics. The only mechanical deficits observed were associated with aging. Together, these vertebral results suggest that for spaceflight, irradiation alone will likely not alter failure properties, and for radiotherapy, more investigations that include post-exposure time as a positive control and testing of both failure modalities are needed to determine the cause of increased fracture risk. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Effects of ex vivo ionizing radiation on collagen structure and whole-bone mechanical properties of mouse vertebrae.

Bone can become brittle when exposed to ionizing radiation across a wide range of clinically relevant doses that span from radiotherapy (accumulative 50 Gy) to sterilization (~35,000 Gy). While irradiation-induced embrittlement has been attributed to changes in the collagen molecular structure, the relative role of collagen fragmentation versus non-enzymatic collagen crosslinking remains unclear. To better understand the effects of radiation on the bone material without cellular activity, we conducted an ex vivo x-ray radiation experiment on excised mouse lumbar vertebrae. Spinal tissue from twenty-week old, female, C57BL/6J mice were randomly assigned to a single x-ray radiation dose of either 0 (control), 50, 1000, 17,000, or 35,000 Gy. Measurements were made for collagen fragmentation, non-enzymatic collagen crosslinking, and both monotonic and cyclic-loading compressive mechanical properties. We found that the group differences for mechanical properties were more consistent with those for collagen fragmentation than for non-enzymatic collagen crosslinking. Monotonic strength at 17,000 and 35,000 Gy was lower than that of the control by 50% and 73% respectively, (p < 0.001) but at 50 and 1000 Gy was not different than the control. Consistent with those trends, collagen fragmentation only occurred at 17,000 and 35,000 Gy. By contrast, non-enzymatic collagen crosslinking was greater than control for all radiation doses (p < 0.001). All results were consistent both for monotonic and cyclic loading conditions. We conclude that the reductions in bone compressive monotonic strength and fatigue life due to ex vivo ionizing radiation are more likely caused by fragmentation of the collagen backbone than any increases in non-enzymatic collagen crosslinks.