Journal of Bone and Mineral Research最新文献

Bariatric surgery induces a decrease in areal BMD (aBMD), but the long-term effect on trabecular and cortical volumetric BMD (vBMD) has not been well assessed. The main aim of this 5-yr longitudinal study was to investigate the changes following sleeve gastrectomy (SG) in aBMD, bone turnover markers, and trabecular and cortical vBMD. Forty-five patients with obesity were assessed before and 1, 2, and 5 yr after SG. Trabecular and cortical vBMD, cortical thickness, and structural parameters were assessed by 3D-Shaper software at the hip. Values of bone turnover markers peaked after 1 yr and decreased after 2 and 5 yr, but without returning to baseline values. aBMD decreased mostly at the femoral neck (-9.7%) and total hip (-10.7%) over the 5 yr, with the greatest loss occurring at 1 yr (-5.9% and -6.3%, respectively). A similar profile of decrease was observed for integral hip vBMD with significant decreases of 6.6%, 7.7%, and 10.7% after 1, 2, and 5 yr, mainly due to a reduction in the trabecular (10.5%, 12.0%, and 17.2%, respectively) rather than cortical (1.4%, 1.9%, and 2.9%, respectively) component. A modest decrease in mean cortical thickness (2.5%, 2.8%, and 3.9%, respectively) and an alteration in the structural parameters were concomitantly observed. Older age and greater body weight loss were the factors most associated with an increased loss of aBMD and vBMD. In conclusion, the study demonstrates that SG induces not only an alteration in bone turnover and aBMD, but also a reduction in vBMD at the hip, predominantly due to trabecular component deterioration as determined by 3D-Shaper software. The maintenance of bone deterioration for at least 5 yr-ie, after 4 yr of relative body weight stabilization or minimal weight regain-suggests the need for a therapeutic approach to preserve bone health in patients who undergo SG.

Bone mineral density (BMD) is only one of several bone strength determinants affected by osteoporosis therapies. Trabecular Bone Score (TBS), a gray-level texture index determined from lumbar spine (LS) dual-X-ray absorptiometry scans, is an indirect measure of bone microarchitecture independent of and complementary to BMD and clinical risk factors. In the Active-Controlled Fracture Study in Postmenopausal Women with Osteoporosis at High Risk (ARCH), monthly subcutaneous romosozumab 210 mg for 12 mo followed by 24-mo open-label weekly oral alendronate 70 mg (romosozumab-to-alendronate) significantly reduced fracture risk compared to 36-mo alendronate alone in postmenopausal women with osteoporosis and prior fracture. This analysis evaluated tissue thickness-adjusted TBS (TBSTT) in a subgroup of patients from ARCH who had post-hoc TBS measurements at baseline and at least one post-baseline visit at months 12, 24, and 36. Baseline characteristics were similar between romosozumab-to-alendronate (n = 190) and alendronate alone (n = 188). Romosozumab led to significantly greater gains in TBSTT vs alendronate at month 12 (least squares mean difference, 3.6%), with greater gains maintained after transition to alendronate and persisting at months 24 (2.9%) and 36 (2.3%; all p<.001). Romosozumab-to-alendronate increased the percentage of individual patients with "normal" TBSTT from 28.9% at baseline to 48.1%, 43.9%, and 45.4% at months 12, 24, and 36, respectively, and decreased the percentage of individual patients with degraded TBSTT from 52.6% to 33.3%, 36.0%, and 33.5%, respectively (all p<.001). A similar but smaller trend was observed with alendronate alone from baseline through month 36 (p ≤.012). Changes in TBSTT and LS BMD were largely unrelated from baseline to month 12 (romosozumab-to-alendronate, r2 = 0.065; alendronate alone, r2 = 0.021) and month 36 (r2 = 0.058; r2 = 0.057, respectively). In postmenopausal women with osteoporosis and prior fracture, 12-mo romosozumab followed by 24-mo alendronate significantly improved bone microarchitecture estimated by TBSTT more than 36-mo alendronate alone.

Epidural steroid injections (ESIs) are a common and often effective treatment for radicular back pain. While oral glucocorticoids increase fracture incidence, little is known regarding fracture risk after ESI. This study investigated the incidence of fractures among individuals who received ESI and those who did not. We hypothesized that ESI exposure would be associated with an increased incidence of osteoporotic fractures and specifically vertebral fractures. Using 2005-2018 5% Medicare data, individuals with radicular pain who had ≥1 ESI and those who did not (non-ESI) were matched 1:10 by age, sex, and month of radicular pain diagnosis using exposure density sampling (EDS). Using a high-dimensional propensity score (HDPS) calculated based on the top 500 covariates across multiple data dimensions, ESI and non-ESI individuals were matched 1:1. Fractures were identified using validated ICD-9/10 diagnosis codes. Fracture incidence rate (IR) was calculated by group, and hazard ratios (HR) compared using Cox regression. 25 062 ESI patients and 221 735 non-ESI patients who met eligibility criteria were identified using EDS. Mean age was 76 yr (74% female). Among ESI-treated individuals, there were 2296 fractures, IR 49.1 (95% CI: 47.2-51.2) per 1000 person yr. For non-ESI individuals, there were 11 917 fractures, IR 35.2 (95% CI: 34.5-35.8). Individuals who received ESI had a greater hazard of fracture at typical osteoporotic sites, HR 1.39 (95% CI 1.33-1.46) by EDS and 1.32 (1.12-1.54) by HDPS, and a greater hazard of vertebral fracture, 1.54 (1.45-1.64) by EDS and 1.69 (1.38-2.07) by HDPS. Patients who received greater cumulative ESI doses (≥3 in 1 yr) had a higher risk of fractures within the first 6 mo of follow-up. ESI exposure in older individuals is associated with an increased risk of fracture, suggesting there may be lasting detrimental skeletal effects of ESI. Further research into strategies to reduce fracture risk in this population is warranted.

Growth-plate (GP) injures in limbs and other sites can impair GP function and cause deceleration of bone growth, leading to progressive bone lengthening imbalance, deformities and/or physical discomfort, decreased motion and pain. At present, surgical interventions are the only means available to correct these conditions by suppressing the GP activity in the unaffected limb and/or other bones in the ipsilateral region. Here, we aimed to develop a pharmacologic treatment of GP growth imbalance that involves local application of nanoparticles-based controlled release of a selective retinoic acid nuclear receptor gamma (RARγ) agonist drug. When RARγ agonist-loaded nanoparticles were implanted near the medial and lateral sides of proximal tibial growth plate in juvenile C57BL/6j mice, the GP underwent involution and closure. Overall tibia length was shortened compared to the contralateral element implanted with drug-free control nanoparticles. Importantly, when the RARγ agonist nanoparticles were implanted on the lateral side only, the adjacent epiphysis tilted toward the lateral site, leading to apical angulation of the tibia. In contrast to the local selectivity of these responses, systemic administration of RARγ agonists led to GP closure at many sites, inhibiting skeletal growth over time. Agonists for RARα and RARβ elicited no obvious responses over parallel regimens. Our findings provide novel evidence that RARγ agonist-loaded nanoparticles can control activity, function and directionality of a targeted GP, offering a potential and clinically-relevant alternative or supplementation to surgical correction of limb length discrepancy and angular deformities.

Fracture risk calculators, such as the Fracture Risk Assessment Tool (FRAX), calculate the risk of major osteoporotic (MOF) and hip fracture, but do not account for the excess risk of fracture in people with diabetes. We examined the predictive performance of FRAX without BMD in ethnically diverse, older patients with diabetes. Patients included were between ages 65-89 from the Kaiser Permanente Northern California Diabetes Registry and not already taking osteoporosis medications. Race and ethnicity were self-identified. We calculated FRAX without BMD based on baseline characteristics and assessed how well FRAX predicted MOF and hip fracture over follow-up. Predictive performance was based on measures of discrimination (area under the receiver operator curve, AUC) and calibration (observed-to-predicted ratio, O/P). We identified 96 914 patients (47.0% female), of whom 5383 (5.6%) and 1767 (1.8%) had MOF and hip fracture, respectively, over a mean follow-up of 4.3 years. The AUC for MOF and hip fracture were 0.72 and 0.77, respectively. FRAX mildly underestimated MOF and hip fracture rates (O/P 1.2 for both) overall. Discrimination was similar by race and ethnicity and diabetes duration but was worse in those over age 75 (AUC < 0.7). In some groups, there were substantial calibration errors, such as Hispanic women (O/P: 1.8 and 1.5), Black men (O/P: 1.5 and 1.8), those with duration of diabetes ≥20 years (O/P: 1.6 and 1.5), and those over the age of 80 (O/P: 1.4 and 1.2) for MOF and hip fracture, respectively. While the discriminatory performance of FRAX without BMD was good overall in patients with diabetes, it underestimated risk in Hispanic women, Black men, those with long duration of diabetes, and in the oldest patients with diabetes. These algorithmic biases suggest that diabetes-specific tools may be needed to stratify fracture risk in patients with diabetes.

The socioeconomic burden of hip fractures, the most severe osteoporotic fracture outcome, is increasing and the current clinical risk assessment lacks sensitivity. This study aimed to develop a method for improved prediction of hip fracture by incorporating measurements of bone microstructure and composition derived from high-resolution peripheral quantitative computed tomography (HR-pQCT). In a prospective cohort study of 3028 community-dwelling women aged 75 to 80, all participants answered questionnaires and underwent baseline examinations of anthropometrics and bone by dual x-ray absorptiometry (DXA) and HR-pQCT. Medical records, a regional x-ray archive, and registers were used to identify incident fractures and death. Prediction models for hip, major osteoporotic fracture (MOF), and any fracture were developed using Cox proportional hazards regression and machine learning algorithms (neural network, random forest, ensemble, and XGBoost). In the 2856 (94.3%) women with complete HR-pQCT data at 2 tibia sites (distal and ultra-distal), the median follow-up period was 8.0 years, and 217 hip, 746 MOF, and 1008 any type of incident fracture occurred. In Cox regression models adjusted for age, BMI, clinical risk factors (CRF), and femoral neck bone mineral density (FN BMD) the strongest predictors of hip fracture were tibia total volumetric BMD and cortical thickness. The performance of the Cox regression-based prediction models for hip fracture was significantly improved by HR-pQCT (time-dependent AUC; area under receiver operating characteristic curve at 5 years of follow-up 0.75 [0.64-0.85]), compared to a reference model including CRFs and FN BMD (AUC = 0.71 [0.58-0.81], p<.001) and a FRAX risk score model (AUC = 0.70 [0.60-0.80], p<.001). The Cox regression model for hip fracture had a significantly higher accuracy than the neural network-based model, the best-performing machine learning algorithm, at clinically relevant sensitivity levels. We conclude that the addition of HR-pQCT parameters improves the prediction of hip fractures in a cohort of older Swedish women.

Bone mineral density (BMD) measured with dual-energy X-ray absorptiometry (DXA) is widely used in clinical practice to assess fracture risk and guide management. DXA can also assess hip geometry, including femoral neck width (FNW) and hip axis length (HAL), which have both been associated with increased risk for hip fracture independently from BMD. Our objective was to assess if FNW predicts hip fracture independently from other factors including HAL. We performed a retrospective cohort study using the Province of Manitoba BMD registry. The study population comprised 75 095 individuals (90.8% women), mean age 64.7 years, with baseline hip BMD and hip geometry parameters. Linked health records were used to ascertain subsequent hospitalization with hip fracture as a primary diagnosis. During a mean follow up of 8.3 (SD 5.1) years, 2341 incident hip fractures were recorded. Each SD increase in age- and sex-adjusted FNW was associated with incident hip fracture (HR 1.15, 95% CI 1.10-1.19) which was unchanged after adjustment for height, weight, femoral neck BMD and clinical risk factors. However, FNW showed a significant positive correlation with HAL (r = 0.68). When further adjusted for HAL, FNW was no longer associated with increased risk for hip fracture (HR 0.98, 95% CI 0.94-1.03). A similar pattern was seen for femoral neck, intertrochanteric and non hip fractures. In contrast, increased risk of hip fracture was consistently seen with each SD increase in HAL even after adjustment for all covariates including FNW (HR 1.35, 95% CI 1.28-1.42). In conclusion, FNW is a risk factor for hip fracture before but not after adjustment for HAL. HAL, on the other hand, robustly and independently predicts hip fracture, including both femoral neck and trochanteric fractures.

Bone mineral density (BMD) levels achieved on osteoporosis treatment are predictive of subsequent fracture risk, and T-score > -2.5 has been proposed as a minimum treatment target for women with osteoporosis. Knowing the likelihood of attaining target T-scores with different medications for different baseline BMD levels can help determine appropriate initial treatment for individual patients. In this post hoc analysis, we estimated the probability of achieving a non-osteoporotic T-score (> -2.5 or ≥ -2.0) at the total hip (TH) or lumbar spine (LS) in postmenopausal women >60 years old treated with denosumab for either 3 or 10 years in the FREEDOM trial and its long-term extension. In women with baseline TH T-scores of -2.7, -3.0, and -3.5, the probabilities of achieving target T-scores > -2.5 with 3 years of denosumab were 71%, 12%, and 0.1%, respectively. At LS, for baseline T-scores of -2.7, -3.0, and -3.5, the probabilities were 86%, 59%, and 11%, respectively. Longer treatment duration of up to 10 years increased the probability of achieving target T-scores. The baseline T-scores that permitted at least 50% of women to achieve a target T-score > -2.5 was -2.8 at TH and -3.1 at LS after 3 years and -3.0 at TH and -3.7 at LS after 10 years of treatment. To achieve higher treatment targets (T-scores ≥ -2.0), overall probabilities were lower at both skeletal sites, particularly for TH, even with longer treatment duration. Our results demonstrate that the probability of achieving T-score targets with denosumab is dependent on baseline BMD, skeletal site, and treatment duration. Knowing the probability of achieving treatment targets for different baseline TH and LS T-scores can help determine whether denosumab is an appropriate first choice of treatment in individual patients.