Skeletal fragility is a major complication of type 2 diabetes mellitus (T2D), but there is a poor understanding of mechanisms underlying T2D skeletal fragility. The increased fracture risk has been suggested to result from deteriorated bone microarchitecture or poor bone quality due to accumulation of advanced glycation end-products (AGEs). We conducted a clinical study to determine whether: 1) bone microarchitecture, AGEs, and bone biomechanical properties are altered in T2D bone, 2) bone AGEs are related to bone biomechanical properties, and 3) serum AGE levels reflect those in bone. To do so, we collected serum and proximal femur specimens from T2D (n = 20) and non-diabetic (n = 33) subjects undergoing total hip replacement surgery. A section from the femoral neck was imaged by microcomputed tomography (microCT), tested by cyclic reference point indentation, and quantified for AGE content. A trabecular core taken from the femoral head was imaged by microCT and subjected to uniaxial unconfined compression tests. T2D subjects had greater HbAc (+23%, p ≤ 0.0001), but no difference in cortical tissue mineral density, cortical porosity, or trabecular microarchitecture compared to non-diabetics. Cyclic reference point indentation revealed that creep indentation distance (+18%, p ≤ 0.05) and indentation distance increase (+20%, p ≤ 0.05) were greater in cortical bone from T2D than in non-diabetics, but no other indentation variables differed. Trabecular bone mechanical properties were similar in both groups, except for yield stress, which tended to be lower in T2D than in non-diabetics. Neither serum pentosidine nor serum total AGEs were different between groups. Cortical, but not trabecular, bone AGEs tended to be higher in T2D subjects (21%, p = 0.09). Serum AGEs and pentosidine were positively correlated with cortical and trabecular bone AGEs. Our study presents new data on biomechanical properties and AGEs in adults with T2D, which are needed to better understand mechanisms contributing to diabetic skeletal fragility.
Sclerostin, a product of the SOST gene produced mainly by osteocytes, is a potent negative regulator of bone formation that appears to be responsive to mechanical loading, with SOST expression increasing following mechanical unloading. We tested the ability of a murine sclerostin antibody (SclAbII) to prevent bone loss in adult mice subjected to hindlimb unloading (HLU) via tail suspension for 21 days. Mice (n = 11–17/group) were assigned to control (CON, normal weight bearing) or HLU and injected with either SclAbII (subcutaneously, 25 mg/kg) or vehicle (VEH) twice weekly. SclAbII completely inhibited the bone deterioration due to disuse, and induced bone formation such that bone properties in HLU-SclAbII were at or above values of CON-VEH mice. For example, hindlimb bone mineral density (BMD) decreased –9.2%±1.0% in HLU-VEH, whereas it increased 4.2%±0.7%, 13.1%±1.0%, and 30.6%±3.0% in CON-VEH, HLU-SclAbII, and CON-SclAbII, respectively (p < 0.0001). Trabecular bone volume, assessed by micro–computed tomography (μCT) imaging of the distal femur, was lower in HLU-VEH versus CON-VEH (p < 0.05), and was 2- to 3-fold higher in SclAbII groups versus VEH (p < 0.001). Midshaft femoral strength, assessed by three-point bending, and distal femoral strength, assessed by micro–finite element analysis (μFEA), were significantly higher in SclAbII versus VEH-groups in both loading conditions. Serum sclerostin was higher in HLU-VEH (134±5 pg/mL) compared to CON-VEH (116±6 pg/mL, p < 0.05). Serum osteocalcin was decreased by hindlimb suspension and increased by SclAbII treatment. Interestingly, the anabolic effects of sclerostin inhibition on some bone outcomes appeared to be enhanced by normal mechanical loading. Altogether, these results confirm the ability of SclAbII to abrogate disuse-induced bone loss and demonstrate that sclerostin antibody treatment increases bone mass by increasing bone formation in both normally loaded and underloaded environments.
Type 2 diabetes (T2D) incidence in adolescents is rising and may interfere with peak bone mass acquisition. We tested the effects of early-onset T2D on bone mass, microarchitecture, and strength in the TALLYHO/JngJ mouse, which develops T2D by 8 weeks of age. We assessed metabolism and skeletal acquisition in male TALLYHO/JngJ and SWR/J controls (n = 8-10/group) from 4 weeks to 8 and 17 weeks of age. Tallyho mice were obese; had an approximately 2-fold higher leptin and percentage body fat; and had lower bone mineral density vs SWR at all time points (P < .03 for all). Tallyho had severe deficits in distal femur trabecular bone volume fraction (-54%), trabecular number (-27%), and connectivity density (-82%) (P < .01 for all). Bone formation was higher in Tallyho mice at 8 weeks but lower by 17 weeks of age vs SWR despite similar numbers of osteoblasts. Bone marrow adiposity was 7- to 50-fold higher in Tallyho vs SWR. In vitro, primary bone marrow stromal cell differentiation into osteoblast and adipocyte lineages was similar in SWR and Tallyho, suggesting skeletal deficits were not due to intrinsic defects in Tallyho bone-forming cells. These data suggest the Tallyho mouse might be a useful model to study the skeletal effects of adolescent T2D.
This study investigated the effect of a macrobiotic (vegan-type) diet, low in calcium and vitamin D, consumed in early life, on bone mineral during adolescence. Bone mineral content (BMC) and bone area were measured in 195 adolescents (103 girls, 92 boys) aged 9 -15 years, using dual-energy X-ray absorptiometry. Ninety-three adolescents (43 girls, 50 boys) had followed a macrobiotic diet in childhood, and 102 (60 girls, 42 boys) were control subjects. After adjustment for bone area, weight, height, percent body lean, age, and puberty, BMC was significantly lower in macrobiotic subjects, in boys and girls, respectively, at the whole body, ؊3.4% and ؊2.5%, spine, ؊8.5% and ؊5.0%, femoral neck, ؊8.0% and ؊8.2%, midshaft radius, ؊6.8% and ؊5.6%, and also in girls, at the trochanter, ؊5.8% ( p < 0.05). No group differences were observed at the wrist. Group differences were not explained by current calcium intake or physical activity. We conclude that the use of a macrobiotic diet in early childhood negatively influences adjusted bone mass at age 9 -15 years, observations which may hold important implications for fracture risk in later
The effects of obesity on bone metabolism are complex, and may be mediated by consumption of a high fat diet and/or by obesity-induced metabolic dysregulation. To test the hypothesis that both high fat (HF) diet and diet-induced metabolic disease independently decrease skeletal acquisition, we compared effects of HF diet on bone mass and microarchitecture in two mouse strains: diet-induced obesity (DIO)-susceptible C57BL/6J (B6) and DIO-resistant FVB/NJ (FVB). At 3 wks of age we weaned 120 female FVB and B6 mice onto normal (N, 10% Kcal/fat) or HF diet (45% Kcal/fat) and euthanized them at 6, 12 and 20 weeks of age (N = 10/grp). Outcomes included body mass; percent fat and whole-body bone mineral density (WBBMD, g/cm2) via DXA; cortical and trabecular bone architecture at the midshaft and distal femur via μCT; and marrow adiposity via histomorphometry. In FVB HF, body mass, percent body fat, WBBMD and marrow adiposity did not differ vs. N, but trabecular bone mass was lower at 6 wks of age only (p < 0.05), cortical bone geometric properties were lower at 12 wks only, and bone strength was lower at 20 wks of age only in HF vs. N (p < 0.05). In contrast, B6 HF had higher body mass, percent body fat, and leptin vs. N. B6 HF also had higher WBBMD (p < 0.05) at 9 and 12 wks of age but lower distal femur trabecular bone mass at 12 wks of age, and lower body mass-adjusted cortical bone properties at 20 wks of age compared to N (p < 0.05). Marrow adiposity was also markedly higher in B6 HF vs. N. Overall, HF diet negatively affected bone mass in both strains, but was more deleterious to trabecular bone microarchitecture and marrow adiposity in B6 than in FVB mice. These data suggest that in addition to fat consumption itself, the metabolic response to high fat diet independently alters skeletal acquisition in obesity.
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