Interrelationships Between Bone Microarchitecture and Strength in Ovariectomized Monkeys Treated With Teriparatide

Hip fracture is the most devastating osteoporotic fracture type with significant morbidity and mortality. Several studies in humans identified chromosomal regions linked to hip size and bone mass. Animal models, particularly the inbred rat, serve as complementary approaches for studying the genetic influence on hip fragility. The purpose of this study is to identify sex-independent and sex-specific quantitative trait loci (QTLs) for femoral neck density, structure, and strength in inbred Copenhagen 2331 (COP) and Dark Agouti (DA) rats. A total of 828 (405 males and 423 females) F(2) progeny derived from the inbred COP and DA strains of rats were phenotyped for femoral neck volumetric BMD (vBMD), cross-sectional area, polar moment of inertia (Ip), neck width, ultimate force, and energy to break. A whole genome screen was performed using 93 microsatellite markers with an average intermarker distance of 20 cM. Recombination-based marker maps were generated using MAPMAKER/EXP from the COP x DA F(2) data and compared with published Rat Genome Database (RGD) maps. These maps were used for genome-wide linkage analyses to detect sex-independent and sex-specific QTLs. Significant evidence of linkage (p < 0.01) for sex-independent QTLs were detected for (1) femoral neck vBMD on chromosomes (Chrs) 1, 6, 10, and 12, (2) femoral neck structure on Chrs 5, 7, 10, and 18, and (3) biomechanical properties on Chrs 1 and 4. Male-specific QTLs were discovered on Chrs 2, 9, and 18 for total vBMD, on Chr 17 for trabecular vBMD, on Chr 9 for total bone area, and on Chr 15 for ultimate force. A female-specific QTL was discovered on Chr 2 for ultimate force. The effect size of the individual QTL varied between 1% and 4%. We detected evidence that sex-independent and sex-specific QTLs contribute to hip fragility in the inbred rat. Several QTLs regions identified in this study are homologous to human chromosomal regions previously linked to QTLs contributing to femoral neck and related phenotypes.

Physical exercise induces spatially heterogeneous adaptation in bone. However, it remains unclear where the changes in BMD and geometry have the greatest impact on femoral neck strength. The aim of this study was to determine the principal BMD-and-geometry changes induced by exercise that have the greatest effect on femoral neck strength. Pre- and post-exercise 3D-DXA images of the proximal femur were collected of male participants from the LIFTMOR-M exercise intervention trial. Meshes with element-by-element correspondence were generated by morphing a template mesh to each bone to calculate changes in BMD and geometry. Finite element (FE) models predicted femoral neck strength changes under single-leg stance and sideways fall load. Partial least squares regression (PLSR) models were developed with BMD-only, geometry-only, and BMD-and-geometry changes to determine the principal modes that explained the greatest variation in neck strength changes. The PLSR models explained over 90% of the strength variation with 3 PLS components using BMD-only (R2 > 0.92, RMSE < 0.06 N) and 8 PLS components with geometry-only (R2 > 0.93, RMSE < 0.06 N). Changes in the superior neck and distal cortex were most important during single-leg stance while the superior neck, medial head, and lateral trochanter were most important during a sideways fall. Local changes in femoral neck and head geometry could differentiate the exercise groups from the control group. Exercise interventions may target BMD changes in the superior neck, inferior neck, and greater trochanter for improved femoral neck strength in single-leg stance and sideways fall.

Despite the general belief that higher protein intake may be helpful for bone homeostasis, its impact on human bone health is still debated. Furthermore, the association of dietary protein intake with femoral neck (FN) strength, which can predict fracture risk independently of bone mineral density (BMD), has not been thoroughly studied. This is a population-based, cross-sectional study from Korea National Health and Nutrition Examination Surveys, including 592 men aged 50years or older and 590 postmenopausal women. The composite indices of FN strength, such as the compression strength index (CSI), bending strength index (BSI), and impact strength index (ISI), were generated by combining BMD, body weight, and height with the femoral axis length and width, which were measured by dual-energy X-ray absorptiometry. After adjustment for confounders, total protein intake (g/kg/day) positively correlated with all three FN composite indices in both genders (P= 0.006 to 0.035), except for BSI showing marginal significance in postmenopausal women (P= 0.093). Consistently, compared with subjects in lowest total protein intake quartile, those in the highest quartile showed markedly higher CSI, BSI, and ISI values (P= 0.043 to < 0.001), with a dose-response manner across increasing total protein intake quartile categories in both men and women (P for trend = 0.028 to < 0.001). These findings provide the clinical evidence that higher dietary protein intake can play a beneficial role on bone health through the increase of FN strength relative to load in adults.

Although bone mineral density (BMD) is a strong predictor of fracture risk, additional parameters, such as bone strength, are needed to predict future fracture risk because of the low sensitivity of BMD for predicting fracture risk. The objective was to study the association of vitamin D with femoral neck (FN) strength. This was a population-based, cross-sectional study from Korea National Health and Nutrition Examination Surveys. A total of 1209 Koreans (586 men and 623 women) aged ≥50 years participated. We calculated composite indices of FN strength, such as the compression strength index, bending strength index (BSI), and impact strength index, by combining BMD, body weight, and height with the femoral axis length and width, which were measured by dual-energy x-ray absorptiometry. Multiple regression analysis demonstrated that serum 25-hydroxyvitamin D [25(OH)D] levels were associated with compression strength index, BSI, and impact strength index in both genders. When women were categorized into four quartiles of 25(OH)D, FN BMD and composite indices (except for BSI) significantly increased from the lowest (Q1) to the highest quartile (Q4) (P for trend = .001-.004). In contrast, there is no significant association of quartiles with composite indices in men. When women were divided into two groups according to their serum 25(OH)D levels, the composite indices as well as the FN BMD were markedly higher in subjects with higher 25(OH)D levels (≥51.5 nmol/L). These findings provide the first clinical evidence that high serum 25(OH)D levels exhibit higher composite indices of FN strength in a dose-dependent manner, especially in women.

Femoral neck strength of mouse in two loading configurations: method evaluation and fracture characteristics

The effects of physical activity on bone strength acquisition during growth are not well understood. In our cluster randomized trial, we found that participation in a novel school-based physical activity program enhanced bone strength acquisition and bone mass accrual by 2-5% at the femoral neck in girls; however, these benefits depended on teacher compliance with intervention delivery. Our intervention also enhanced bone mass accrual by 2-4% at the lumbar spine and total body in boys. We investigated the effects of a novel school-based physical activity program on femoral neck (FN) bone strength and mass in children aged 9-11 yrs. We used hip structure analysis to compare 16-month changes in FN bone strength, geometry and bone mineral content (BMC) between 293 children who participated in Action Schools! BC (AS! BC) and 117 controls. We assessed proximal femur (PF), lumbar spine (LS) and total body (TB) BMC using DXA. We compared change in bone outcomes between groups using linear regression accounting for the random school effect and select covariates. Change in FN strength (section modulus, Z), cross-sectional area (CSA), subperiosteal width and BMC was similar between control and intervention boys, but intervention boys had greater gains in BMC at the LS (+2.7%, p = 0.05) and TB (+1.7%, p = 0.03) than controls. For girls, change in FN-Z tended to be greater (+3.5%, p = 0.1) for intervention girls than controls. The difference in change increased to 5.4% (p = 0.05) in a per-protocol analysis that included girls whose teachers reported 80% compliance. AS! BC benefits bone strength and mass in school-aged children; however, our findings highlight the importance of accounting for teacher compliance in classroom-based physical activity interventions.

Biomechanical study on femoral neck fracture fixation in relation to bone mineral density

Adolescent growth provides a unique opportunity for the growing body to adapt to external stimuli. A positive association between site-specific mechanical loading and increases in regional bone mineral content (BMC) during adolescence is established. Mechanical loads associated with middle-distance running expose the skeleton to a combination of compressive ground reaction forces and muscular contraction. Previous studies concerning musculoskeletal health in active adolescents are largely limited to planar, two-dimensional measures of bone mineral status, using Dual X-ray Absorptiometry (DXA). Intrinsic bone material properties are accurately measured using DXA. However, the interaction between bone material and structural properties that reflects the mechanical integrity of bone require a combination of imaging modalities. Magnetic Resonance Imaging (MRI) provides a three-dimensional geometric and biomechanical assessment of bone. When MRI is integrated with DXA technology, an effective non-invasive method of assessing in vivo bone strength is achieved. The impact of high training volumes on musculoskeletal development of male and female adolescent athletes engaged in repetitive, high magnitude mechanical loading has not been investigated. Specifically, differences in total body and regional bone mineral, bone and muscle geometry, bone biomechanical indices and bone strength at differentially-loaded skeletal sites have not been compared between adolescent middle-distance runners and age- and gender-matched non-athletic controls.;Objectives: (i) to investigate the effects of intense sports participation involving mechanical loading patterns on bone mineral, bone and muscle geometry, biomechanical indices and estimated regional bone strength between elite adolescent male and female middle-distance runners and age- and gender-matched controls (ii) to examine factors predictive of total body BMC, distal tibial bone geometry, distal tibial bone strength, and Hip Strength Analysis (HSA)- derived indicators of bone strength at the femoral neck. Methods: Four groups of 20 adolescents were comprised of male (mean (SD) age 16.8 REPLACE2 0.6 yr, physical activity 14.1 REPLACE2 5.7 hr.wk-1) and female (age 16 REPLACE2 1.7 yr, physical activity 8.9 REPLACE2 2.1 hr.wk-1) middle-distance runners, and male (16.4 REPLACE2 0.7 yr, physical activity 2.2 REPLACE2 0.7 hr.wk-1) and female (age 16 REPLACE2 1.8 yr, physical activity 2.0 REPLACE2 0.07 hr.wk-1) controls. Total body and regional BMC were calculated using DXA. Distal tibial bone and muscle cross-sectional areas (CSA) were assessed using MRI. To calculate distal tibial bone strength index (BSI), a region of interest representing 10% of the mid distal tibia was analysed for DXA-derived bone mineral and was combined with bone geometry and biomechanical properties from MRI assessments. Calculations for femoral neck strength were acquired from DXA-derived HSA software. Results: No differences were found between male athletes and controls for unadjusted BMC at total body or regional sites. After covarying for fat mass (kg), male athletes displayed greater BMC at the lumbar spine (p = 0.001), dominant proximal femur (p = 0.001) and dominant leg (p = 0.03) than male controls. No differences were found in distal tibial bone geometry, bone strength at the distal tibia or HSA-derived indicators of bone strength at the femoral neck between male athletes and controls.;Lean tissue mass and fat mass were the strongest predictors of total body BMC (R2 = 0.71), total muscle CSA explained 43.5% of variance in BSI at the distal tibia, and femur length and neck of femur CSA explained 33.4% of variance at the femoral neck. In females, athletes displayed greater unadjusted BMC at the proximal femur (+3.9 REPLACE21.4 g, p = 0.01), dominant femoral neck (+0.5 REPLACE2 0.12 g, p = 0.01) and dominant tibia (+4.1 REPLACE2 2.1 g, p = 0.05) than female controls. After covarying for fat mass (kg), female athletes displayed greater (p = 0.001) total body, dominant proximal femur and dominant leg BMC than female controls. Female athletes also showed greater distal tibial cortical CSA (+30.9 REPLACE2 9.5 mm2, p = 0.003), total muscle (+240.2 REPLACE2 86.4 mm2, p = 0.03) and extensor muscle (+46.9 REPLACE219.5 mm2, p = 0.02) CSA, smaller medullary cavity (-32.3 REPLACE2 14.7 mm2, p = 0.03) CSA and greater BSI at the distal tibia (+28037 REPLACE2 8214.7 g/cm3.mm4, p = 0.002) than female controls. Lean tissue mass and fat mass were the strongest predictors of total body BMC (R2 = 65), hours of physical weekly activity and total muscle CSA explained 58.3% of the variance of distal tibial BSI, and neck of femur CSA accounted for 64.6% of the variance in a marker of femoral neck HSA. Conclusion: High training loads are associated with positive musculoskeletal outcomes in adolescent middle-distance runners compared to non-athletic controls. Exposure to similar high training loads may advantage female adolescent athletes, more than male adolescent athletes compared with less active peers in bone strength at the distal tibia.

The effects of dietary protein on bone structure and metabolism have been controversial, with evidence for and against beneficial effects. Because no long-term randomized, controlled studies have been performed, a two-year study of protein supplementation in 219 healthy ambulant women aged 70 to 80 years was undertaken. Participants were randomized to either a high-protein drink containing 30 g of whey protein (n = 109) or a placebo drink identical in energy content, appearance, and taste containing 2.1 g of protein (n = 110). Both drinks provided 600 mg of calcium. Dual-energy X-ray absorptiometric (DXA) hip areal bone mineral density (aBMD), 24-hour urinary calcium excretion, and serum insulin-like growth factor 1 (IGF-1) were measured at baseline and at 1 and 2 years. Quantitative computed tomographic (QCT) hip volumetric bone mineral density (vBMD) and a femoral neck engineering strength analysis were undertaken at baseline and at 2 years. Baseline average protein intake was 1.1 g/kg of body weight per day. There was a significant decrease in hip DXA aBMD and QCT vBMD over 2 years with no between-group differences. Femoral neck strength was unchanged in either group over time. The 24-hour urinary calcium excretion increased significantly from baseline in both groups at 1 year but returned to baseline in the placebo group at 2 years, at which time the protein group had a marginally higher value. Compared with the placebo group, the protein group had significantly higher serum IGF-1 level at 1 and 2 years (7.3% to 8.0%, p < .05). Our study showed that in protein-replete healthy ambulant women, 30 g of extra protein increased IGF-1 but did not have beneficial or deleterious effects on bone mass or strength. The effect of protein supplementation in populations with low dietary protein intake requires urgent attention.

Background/Objectives: Central bone mineral density (cBMD) is widely utilized for assessing bone quality, but its reliability as a predictor of knee bone strength for cementless total knee arthroplasty (TKA) remains unclear. This study aimed to determine whether cBMD reliably estimates bone strength suitable for cementless fixation. Methods: 188 patients scheduled for TKA underwent preoperative cBMD assessment of the lumbar spine and femoral neck. During surgery, femoral bone specimens were collected for indentation tests. We compared distal femoral bone strength among osteoporosis classification groups (normal, osteopenia, osteoporosis) and examined the distribution of cementless suitable versus cemented mandatory cases with chi-square tests. ROC analysis evaluated cBMD’s diagnostic performance in predicting cementless TKA suitability, with AUC, sensitivity, and specificity calculated for both measurement sites. Results: No significant differences in distal femoral bone strength existed between osteopenia and osteoporosis groups (p = 0.845 for lumbar spine, p = 0.857 for femoral neck). Among patients with normal cBMD, 35.4% (lumbar spine) and 30.7% (femoral neck) were unsuitable for cementless TKA, whereas 30.8% and 45.0% of osteoporotic patients, respectively, had adequate bone strength for cementless fixation. The AUC values for predicting cementless suitability were 0.656 (lumbar spine) and 0.669 (femoral neck), with sensitivity and specificity below 0.75 for both measurements. Conclusions: Central BMD does not reliably represent distal femoral bone strength and demonstrates inadequate predictive capability for identifying appropriate candidates for cementless TKA in this predominantly Asian female cohort. Future multi-center, multi-ethnic studies are needed to enhance generalizability.

Parity, lactation, bone strength, and 16-year fracture risk in adult women: Findings from the Study of Women's Health Across the Nation (SWAN)

ObjectiveThe objective of this paper was to present the results of our study of the utility of bone mineral density (BMD) measurements at various segments of distal forearm in predicting central‐site osteoporosis and deteriorated trabecular microarchitecture.MethodsThis was a cross‐sectional study and BMD at the femoral neck, lumbar spine, and distal forearm were assessed using the dual‐energy X‐ray absorptiometry (DXA) scanner and bone microarchitecture at lumbar spine by trabecular bone score (TBS). The utility of forearm BMD in predicting osteoporosis as well as the deteriorated TBS was assessed by a receiver operating characteristic analysis.ResultsA total of 352 postmenopausal women with mean (SD) age of 60.7 (6.8) years were included. The odds of having osteoporosis at femoral neck [odds ratio (OR) = 14.1, 95% confidence interval (CI): 7.8–25.2] and lumbar spine (OR = 7.5, 95% CI: 4.6–12.1) was highest with the mid‐distal radius. A derived T‐score cut off ≤ −1.6, −1.9, and −1.7 at any segment of the forearm was elucidated to predict osteoporosis at the central‐site, femoral neck, and lumbar spine, respectively, with sensitivity of 80%–88% and specificity of 60%–70%. The T‐scores at all three forearm segments ≤ −1.2 showed fair performance in predicting degraded trabecular microarchitecture. The T‐scores thus derived were further validated in cohort of 360 Bengali postmenopausal women.ConclusionBMD assessment at the forearm may be utilized in prediction of trabecular microarchitecture and central site osteoporosis at the femoral neck and lumbar spine in postmenopausal women.

Pregnancy- and lactation-associated osteoporosis (PLO) is an uncommon disease. The majority of cases are seen in the third trimester or early post-partum in primagravid women and the prominent clinical feature of PLO is severe and prolonged back pain and height loss. The prevalence and aetiology of this disorder are as yet unclear and there are no guidelines for its treatment. We report the outcomes of teriparatide (TRP) treatment in a woman suffering from severe PLO with 6 vertebral fragility fractures, severe back pain and very low BMD. Thirteen months after the initiation of therapy, the patient was almost free of back pain. There was no new clinical vertebral fracture. Her laboratory tests were all normal. BMD increased by 24.4% at the lumbar spine, 9.9% and 4.6% at the left and the right total hip and 12.6% and 7.8% at the left and right femur neck, respectively. TRP treatment simultaneously with weaning and calcium and vitamin D supplementation seems to considerably increase BMD, improve severe back pain and quality of life and prevent further occurrence of vertebral fractures, making TRP a helpful tool in restoring bone strength in PLO patients.

BackgroundMuscle strength has been shown to exert positive effects on bone health. The causal relationship between hand grip strength and osteoporosis is an important public health issue but is not fully revealed. The goal of this study was to investigate whether and to what extent hand grip strength affects bone mineral density (BMD) and fracture risk.MethodsWe conducted a state-of-the-art two-sample Mendelian randomization analysis. Genomewide significant (P<5×10-8) single nucleotide polymorphisms associated with hand grip strength were obtained. Summary level data of BMD and fractures at different body sites (lumbar spine, heel, forearm and femoral neck) was obtained from a large-scale osteoporosis database. The inverse variance weighted method was the primary method used for analysis, and the weighted-median, MR-Egger were utilized for sensitivity analyses.ResultsThe results provided strong evidence that hand grip strength trait was causally and positively associated with lumbar spine BMD (β: 0.288, 95% CI: 0.079 to 0.497; P=0.007), while no causal relationship was found between hand grip strength and BMD at heel (β: -0.081, 95% CI: -0.232 to 0.070; P=0.295), forearm (β: 0.-0.101, 95% CI: -0.451 to 0.248; P=0.571) or femoral neck (β: 0.054, 95% CI: -0.171 to 0.278; P=0.639). In addition, no statistically significant effects were observed for hand grip strength on fracture risks (β: -0.004, 95% CI: -0.019 to 0.012; P=0.662).ConclusionsThis study showed a positive causal relationship between hand grip strength and lumbar BMD, which is the most common site of osteoporotic fracture, but did not find a causal relationship between hand grip strength and BMD of heel, forearm, or femoral neck. No statistically significant effect of hand grip strength on fracture risk was observed. This study indicates variations in the abilities of hand grip strength trait to causally influence BMD at different skeleton sites. These results should be considered in further studies and public health measures on osteoporosis prevention strategies.

Bone mineral density (BMD) and mechanical strength generally show strong positive correlations. However, osteopetrosis is a metabolic bone disease with increased skeletal density radiographically and increased risk of fracture. We have evaluated mechanical strength and mineral density in three osteopetrotic mutations in the rat (incisors-absent [ia/ia], osteopetrosis [op/op], and toothless [tl/tl]) to test the hypothesis that reduced bone resorption in one or more of these mutations results in weaker bones in the presence of greater mineral density and skeletal mass. Peripheral quantitative computed tomography (pQCT) was used to analyze BMD and cross-sectional geometry in the tibial diaphysis and metaphysis as well as the femoral diaphysis and femoral neck. The bending breaking force of tibial and femoral midshafts was obtained using the three-point bending test and femoral neck strength was tested by axial loading. Osteopetrotic mutants were significantly smaller than their normal littermates (NLMs) in each stock. The pQCT analysis showed that BMD and bone mineral content (BMC) were higher than or equal to NLMs in all skeletal sites measured in the osteopetrotic mutants. However, the mechanical breaking force was equal to or lower than their NLMs in all sites. The cross-sectional structure of long bone shafts was markedly different in osteopetrotic mutants, having a thin cortex and a medullary area filled with primary trabecular bone. These results indicate that osteopetrotic mutations in the rat increase bone density and decrease bone strength. The tibial diaphysis was significantly weaker in tl/tl and ia/ia mutants and the tibial metaphysis showed the greatest increase in BMD in all mutants. These data are another illustration that an increased BMD does not necessarily lead to stronger bones.