Bouxsein, Mary

Abstract In 2024, the National Academies of Sciences, Engineering, and Medicine (NASEM) published a report entitled Advancing Research on Chronic Conditions in Women. A major purpose of this report was to summarize the current state of research into a series of 21 chronic conditions that affect women differently or that are more common in women. The American Society for Bone and Mineral Research (ASBMR) established a working group to evaluate the NASEM report’s implications for women’s musculoskeletal (MSK) health. This perspective summarizes key research gaps identified in the NASEM report, including the lack of sex-specific data, underrepresentation of women in clinical studies, and minimal integration of MSK health with other chronic conditions. The NASEM report underscores the need for more comprehensive study designs that consider hormonal, genetic, and social determinants of health across the lifespan. In addition to osteoporosis, in this perspective, the ASBMR working group highlights emerging but poorly understood evidence of detrimental effects on musculoskeletal biology in non-MSK, chronic diseases that were identified in the NASEM report to disproportionately affect women. To advance the field, we advocate for better diagnostics, increased investment, and stronger representation of women in research studies. Addressing these gaps is critical for improving prevention, care, and outcomes for chronic conditions that uniquely or disproportionately affect women.

Abstract Context Preclinical studies demonstrate that treatment with calcitriol attenuates skeletal complications in mice with X-linked hypophosphatemia (XLH). Objective This work aimed to assess serum markers of mineral metabolism, nephrocalcinosis, skeletal microarchitecture, growth, and evidence of rickets following calcitriol monotherapy in children and adults with XLH. Methods A 1-year, prospective, single-arm, open-label study was conducted comparing baseline and 12-month outcomes. Participants were recruited from outpatient endocrinology clinics in the United States. Data were collected in a research unit. Eligible participants were aged 4 years or older, not pregnant, with baseline 25-hydroxyvitamin D of 20 ng/mL or greater and normal serum calcium. Participants were treated with calcitriol, with dose based on serum and urinary calcium concentrations, for 1 year. The primary end points were change in serum phosphate and nephrocalcinosis (all participants) and rickets severity score (children). Secondary end points included changes in additional markers of mineral metabolism, skeletal microarchitecture parameters via high-resolution peripheral quantitative computed tomography (all participants), and height z-scores (children). Results Serum phosphate did not change over 12 months of optimized calcitriol treatment. Rickets improved in 2 of 4 children with open epiphyses; height z-scores were unchanged. Nephrocalcinosis scores remained stable. Adults had increased cortical thickness at the radius diaphysis (P = .012). Serum alkaline phosphatase decreased in children (P = .021) and parathyroid hormone trended lower both in children (P = .065) and adults (P = .063). Four participants developed mild hypercalcemia and 2 developed hypercalciuria that resolved with calcitriol titration. Conclusion Calcitriol monotherapy is safe and well-tolerated in XLH, with modest benefits on laboratory indices of mineral metabolism and rickets.

Abstract With the goal of preventing more hip fractures, a next generation of the VirtuOst Biomechanical Computed Tomography (BCT) test was developed that integrates measurements from a clinical CT scan related to fall risk, impact force, and femoral strength, the three main determinants of hip fracture. Here, we introduce the test and validate it against BMD and FRAX. Our source population from a large healthcare system comprised of 341364 patients (≥65 yr) with an abdominal-pelvic CT during care. Using data from 3035 patients (1790 with hip fracture), we developed a “BCT Risk Score” (range: 0-100) having input risk factors of age, femoral strength, ratio of trabecular/cortical BMD, muscle area, intramuscular fat, FN volume, hip width, and posterior fat thickness. In a geographically distinct set of 2124 patients (1293 with hip fracture), we then compared the BCT Risk Score against a DXA-equivalent hip BMD T-score (lowest hip value, measured from the CT scan by VirtuOst) and FRAX hip fracture risk (with BMD but without parental fracture history) for predicting a first incident hip fracture within 5 yr. For the women, the c-statistic for predicting fracture was higher for BCT (0.89, 95% CI: 0.87-0.90) than for BMD (0.81, 0.79-0.84) or FRAX (0.85, 0.83-0.87). Using binary thresholds to identify high-risk patients, sensitivity for BCT (Risk Score ≥ 75) was higher than for BMD (T-score ≤ −2.5) and FRAX (hip risk ≥ 3.0%): 81.4% vs 47.8% vs 75.9%, respectively; positive predictive values confirmed comparable high-risk status (BCT 13.6% vs BMD 15.3% vs FRAX 12.7%). Similar trends were observed for the men, 2-yr outcomes, and identifying very-high-risk patients. We conclude that, compared to both BMD and FRAX, the integrative BCT test better predicted hip fracture and its high sensitivity should improve fracture prevention.

Abstract Identifying individuals at risk for short-term fracture is essential to offer prompt beneficial treatment, especially since many fractures occur in those without osteoporosis by DXA-aBMD. We evaluated whether deficits in bone microarchitecture and density predict short-term fracture risk independent of the clinical predictors, DXA-BMD and FRAX. We combined data from eight cohorts to conduct a prospective study of bone microarchitecture at the distal radius and tibia (by HR-pQCT) and 2-year incidence of fracture (non-traumatic and traumatic) in 7327 individuals (4824 women, 2503 men, mean 69 ± 9 years). We estimated sex-specific hazard ratios (HR) for associations between bone measures and 2-year fracture incidence, adjusted for age, cohort, height, and weight, and then additionally adjusted for FN aBMD or FRAX for major osteoporotic fracture. Only 7% of study participants had FN T-score ≤ −2.5, whereas 53% had T-scores between −1.0 and −2.5 and 37% had T-scores ≥−1.0. Two-year cumulative fracture incidence was 4% (296/7327). Each SD decrease in radius cortical bone measures increased fracture risk by 38%-76% for women and men. After additional adjustment for FN-aBMD, risks remained increased by 28%-61%. Radius trabecular measures were also associated with 2-year fracture risk independently of FN-aBMD in women (HRs range: 1.21 per SD for trabecular separation to 1.55 for total vBMD). Decreased failure load (FL) was associated with increased fracture risk in both women and men (FN-aBMD ranges of adjusted HR = 1.47-2.42). Tibia measurement results were similar to radius results. Findings were also similar when models were adjusted for FRAX. In older adults, FL and HR-pQCT measures of cortical and trabecular bone microarchitecture and density with strong associations to short-term fractures improved fracture prediction beyond aBMD and FRAX. Thus, HR-pQCT may be a useful adjunct to traditional assessment of short-term fracture risk in older adults, including those with T-scores above the osteoporosis range.

Abstract Randomized trials have not been performed, and may never be, to determine if osteoporosis treatment prevents hip fracture in men. Addressing that evidence gap, we analyzed data from an observational study of new hip fractures in a large integrated healthcare system to compare the reduction in hip fractures associated with standard-of-care osteoporosis treatment in men versus women. Sampling from 271,389 patients aged ≥ 65 who had a hip-containing CT scan during care between 2005 and 2018, we selected all who subsequently had a first hip fracture (cases) after the CT scan (start of observation) and a sex-matched equal number of randomly selected patients. From those, we analyzed all who tested positive for osteoporosis (DXA-equivalent hip BMD T-score ≤ −2.5, measured from the CT scan using VirtuOst). We defined “treated” as at least six months of any osteoporosis medication by prescription fill data during follow-up; “not-treated” was no prescription fill. Sex-specific odds ratios of hip fracture for treated vs not-treated patients were calculated by logistic regression; adjustments included age, BMD T-score, BMD-treatment interaction, BMD, race/ethnicity, and seven baseline clinical risk factors. At two-year follow-up, 33.9% of the women (750/2,211 patients) and 24.0% of the men (175/728 patients) were treated primarily with alendronate; 51.3% and 66.3%, respectively, were not-treated; and 721 and 269, respectively, had a first hip fracture since the CT scan. Odds ratio of hip fracture for treated vs not-treated was 0.26 (95% confidence interval: 0.21–0.33) for women and 0.21 (0.13–0.34) for men; the ratio of these odds ratios (men:women) was 0.81 (0.47–1.37), indicating no significant sex effect. Various sensitivity and stratified analyses confirmed these trends, including results at five-year follow-up. Given these results and considering the relevant literature, we conclude that osteoporosis treatment prevents hip fracture similarly in both sexes.

Abstract Fracture risk increases with lower areal bone mineral density (aBMD); however, aBMD-related estimate of risk may decrease with age. This may depend on technical limitations of 2-dimensional (2D) dual energy X-ray absorptiometry (DXA) which are reduced with 3D high-resolution peripheral quantitative computed tomography (HR-pQCT). Our aim was to examine whether the predictive utility of HR-pQCT measures with fracture varies with age. We analyzed associations of HR-pQCT measures at the distal radius and distal tibia with two outcomes: incident fractures and major osteoporotic fractures. We censored follow-up time at first fracture, death, last contact or 8 years after baseline. We estimated hazard ratios (HR) and 95%CI for the association between bone traits and fracture incidence across age quintiles. Among 6835 men and women (ages 40–96) with at least one valid baseline HR-pQCT scan who were followed prospectively for a median of 48.3 months, 681 sustained fractures. After adjustment for confounders, bone parameters at both the radius and tibia were associated with higher fracture risk. The estimated HRs for fracture did not vary significantly across age quintiles for any HR-pQCT parameter measured at either the radius or tibia. In this large cohort, the homogeneity of the associations between the HR-pQCT measures and fracture risk across age groups persisted for all fractures and for major osteoporotic fractures. The patterns were similar regardless of the HR-pQCT measure, the type of fracture, or the statistical models. The stability of the associations between HR-pQCT measures and fracture over a broad age range shows that bone deficits or low volumetric density remain major determinants of fracture risk regardless of age group. The lower risk for fractures across measures of aBMD in older adults in other studies may be related to factors which interfere with DXA but not with HR-pQCT measures.

ABSTRACT Most fracture risk assessment tools use clinical risk factors combined with bone mineral density (BMD) to improve assessment of osteoporosis; however, stratifying fracture risk remains challenging. This study developed a fracture risk assessment tool that uses information about volumetric bone density and three‐dimensional structure, obtained using high‐resolution peripheral quantitative compute tomography (HR‐pQCT), to provide an alternative approach for patient‐specific assessment of fracture risk. Using an international prospective cohort of older adults ( n = 6802) we developed a tool to predict osteoporotic fracture risk, called μFRAC. The model was constructed using random survival forests, and input predictors included HR‐pQCT parameters summarizing BMD and microarchitecture alongside clinical risk factors (sex, age, height, weight, and prior adulthood fracture) and femoral neck areal BMD (FN aBMD). The performance of μFRAC was compared to the Fracture Risk Assessment Tool (FRAX) and a reference model built using FN aBMD and clinical covariates. μFRAC was predictive of osteoporotic fracture (c‐index = 0.673, p < 0.001), modestly outperforming FRAX and FN aBMD models (c‐index = 0.617 and 0.636, respectively). Removal of FN aBMD and all clinical risk factors, except age, from μFRAC did not significantly impact its performance when estimating 5‐year and 10‐year fracture risk. The performance of μFRAC improved when only major osteoporotic fractures were considered (c‐index = 0.733, p < 0.001). We developed a personalized fracture risk assessment tool based on HR‐pQCT that may provide an alternative approach to current clinical methods by leveraging direct measures of bone density and structure. © 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).

ABSTRACT Prevalence of osteoporosis is more than 50% in older adults, yet current clinical methods for diagnosis that rely on areal bone mineral density (aBMD) fail to detect most individuals who have a fragility fracture. Bone fragility can manifest in different forms, and a “one-size-fits-all” approach to diagnosis and management of osteoporosis may not be suitable. High-resolution peripheral quantitative computed tomography (HR-pQCT) provides additive information by capturing information about volumetric density and microarchitecture, but interpretation is challenging because of the complex interactions between the numerous properties measured. In this study, we propose that there are common combinations of bone properties, referred to as phenotypes, that are predisposed to different levels of fracture risk. Using HR-pQCT data from a multinational cohort (n = 5873, 71% female) between 40 and 96 years of age, we employed fuzzy c-means clustering, an unsupervised machine-learning method, to identify phenotypes of bone microarchitecture. Three clusters were identified, and using partial correlation analysis of HR-pQCT parameters, we characterized the clusters as low density, low volume, and healthy bone phenotypes. Most males were associated with the healthy bone phenotype, whereas females were more often associated with the low volume or low density bone phenotypes. Each phenotype had a significantly different cumulative hazard of major osteoporotic fracture (MOF) and of any incident osteoporotic fracture (p &lt; 0.05). After adjustment for covariates (cohort, sex, and age), the low density followed by the low volume phenotype had the highest association with MOF (hazard ratio = 2.96 and 2.35, respectively), and significant associations were maintained when additionally adjusted for femoral neck aBMD (hazard ratio = 1.69 and 1.90, respectively). Further, within each phenotype, different imaging biomarkers of fracture were identified. These findings suggest that osteoporotic fracture risk is associated with bone phenotypes that capture key features of bone deterioration that are not distinguishable by aBMD. © 2021 American Society for Bone and Mineral Research (ASBMR).

ABSTRACT The surrogate threshold effect (STE) is defined as the minimum treatment effect on a surrogate that is reliably predictive of a treatment effect on the clinical outcome. It provides a framework for implementing a clinical trial with a surrogate endpoint. The aim of this study was to update our previous analysis by validating the STE for change in total hip (TH) BMD as a surrogate for fracture risk reduction; the novelty of this study was this validation. To do so, we used individual patient data from 61,415 participants in 16 RCTs that evaluated bisphosphonates (nine trials), selective estrogen receptor modulators (four trials), denosumab (one trial), odanacatib (one trial), and teriparatide (one trial) to estimate trial-specific treatment effects on TH BMD and all, vertebral, hip, and nonvertebral fractures. We then conducted a random effects meta-regression of the log relative fracture risk reduction against 24-month change in TH BMD, and computed the STE as the intersection of the upper 95% prediction limit of this regression with the line of no fracture reduction. We validated the STE by checking whether the number of fractures in each trial provided 80% power and determining what proportion of trials with BMD changes ≥ STE reported significant reductions in fracture risk. We applied this analysis to (i) the trials on which we estimated the STE; and (ii) trials on which we did not estimate the STE. We found that the STEs for all, vertebral, hip, and nonvertebral fractures were 1.83%, 1.42%, 3.18%, and 2.13%, respectively. Among trials used to estimate STE, 27 of 28 were adequately powered, showed BMD effects exceeding the STE, and showed significant reductions in fracture risk. Among the validation set of 11 trials, 10 met these criteria. Thus STE differs by fracture type and has been validated in trials not used to develop the approach. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).