Morgan W. Bolger

Age-related changes to BMD, morphometry, and microarchitecture do not occur uniformly across the population and the common skeletal phenotypes beyond BMD are not well defined. Additionally, the associations between bone and muscle are critical to understanding fall and fracture risk. We hypothesized that unsupervised clustering of HR-pQCT measures at the distal tibia (DT) and radius (DR), separately, would reveal unique skeletal phenotypes; and certain phenotypes would be associated with worse muscle function. In the Study of Muscle, Mobility and Aging (SOMMA; first annual follow-up visit), a cohort of community-dwelling older women and men (61% women; 87% White), HR-pQCT parameters acquired at the DT (N = 321; 76.3 ± 4.6 yr) and DR (N = 295; 76.1 ± 4.5 yr) were standardized within-sex then combined to form clusters. This resulted in 3 phenotypic clusters, (C1) high total BMD (Tt.BMD) and cortical area (Ct.Ar); (C2) medium Tt.BMD, Ct.Ar, and low trabecular BMD (Tb.BMD); and (C3) low Tt.BMD, and Ct.Ar. DT C2 and C3 exhibited lower micro-finite element analysis failure loads, with the cortical load fraction higher in C2 and lower in C3. C2 and C3 both had a similar proportion of osteoporotic and osteopenic/low bone density individuals, highlighting the novel granularity of HR-pQCT clusters vs aBMD clinical cutoffs. In linear regression models for women, DT C3 was associated with lower leg power (p < .05). For men, DT C3 was associated with lower stair climb and leg power (p < .05). No significant difference was found in grip strength between DT clusters. For DR, no significant difference or association was found between muscle function and clusters for women and men. These findings suggest the concept of bone phenotypic-specific associations with lower but not upper extremity muscle function and have possible implications for the interaction between skeletal phenotypes and muscle function as potential contributory factors to fracture risk.

Osteocytes are the most abundant cell type in bone and remodel their local perilacunar matrix in response to a variety of stimuli and diseases. How the perilacunar composition and mechanical properties are affected by type 1 diabetes (T1D), and the contribution of these local changes to the decline in whole-bone functional properties that occurs with diabetes remains unclear. 12–14 week old C57/BL6 male mice were administered a series of low-dose streptozotocin injections and sacrificed at baseline (BL), 3 (D3) and 7 weeks (D7) following confirmation of diabetes, along with age-matched controls (C3, C7). Femora were then subjected to a thorough morphological (μCT), mechanical (four-point bending, nanoindentation), and compositional (HPLC for collagen cross-links, Raman spectroscopy) analysis at the whole-bone and local (perilacunar and intracortical) levels. At the whole-bone level, D7 mice exhibited 10.7% lower ultimate load and 26.4% lower post-yield work relative to C7. These mechanical changes coincided with 52.2% higher levels of pentosidine at D7 compared to C7. At the local level, the creep distance increased, while modulus and hardness decreased in the perilacunar region relative to the intracortical for D7 mice, suggesting a spatial uncoupling in skeletal adaptation. D7 mice also exhibited increased matrix maturity in the 1660/1690 cm⁻¹ ratio at both regions relative to C7. The perilacunar matrix maturity was predictive of post-yield work (46%), but perilacunar measures were not predictive of ultimate load, which was better explained by cortical area (26%). These results show that diabetes causes local perilacunar composition perturbations that affect whole-bone level mechanical properties, implicating osteocyte maintenance of its local matrix in the progression of diabetic skeletal fragility.