Publications

Current fracture risk assessment does not directly include fall probability, despite most hip fractures resulting from falls. Additionally, the role of trochanteric soft tissue thickness (TST) in hip fracture risk remains unclear. This study aimed to develop a subject-specific fall risk tool and test whether incorporating fall probability and TST improves hip fracture prediction beyond FRAX alone in older adults from the AGES-Reykjavik study. Baseline data from 3242 individuals (58% women) were used to predict repeated falls (≥2 in 12 months) at follow-up ( 5 years later) via multivariate logistic regression, considering age, sex, fall history, neuromuscular function, dynamic balance, and medication use. In a case-cohort study (698 hip fractures, 1348 controls; median follow-up 10 years), Cox proportional hazards models assessed hip fracture risk. We compared the predictive value of fall probability and TST combined with FRAX against FRAX alone using time-dependent AUC at 5-, 10-, and 16-year follow-up. At follow-up, 295 individuals had ≥2 falls in the past year. The best model for future falls included a timed up-and-go test, fall history, and grip strength. The probability of falling predicted incident hip fracture and improved hip fracture prediction beyond FRAX, in both men and women. The improved predictive value of fall risk was greater among men than women (e.g. AUC for predicting 10 yrs hip fracture risk, 0.83 (95%CI 0.79-0.87) in men vs 0.75 (95%CI 0.72-0.78) in women). Lower TST was linked to higher hip fracture risk in women but not men. However, adding TST to a model with fall probability and FRAX among women did not enhance time-dependent AUC (p>0.10). In conclusion, fall probability significantly improves hip fracture prediction beyond FRAX, particularly in men. Thus, subject-specific fall risk assessment may enhance clinical evaluation of hip fracture risk in older adults.

CONTEXT: Preclinical studies demonstrate that treatment with calcitriol attenuates skeletal complications in mice with X-linked hypophosphatemia (XLH).

OBJECTIVE: To assess serum markers of mineral metabolism, nephrocalcinosis, skeletal microarchitecture, growth, and evidence of rickets following calcitriol monotherapy in children and adults with XLH.

DESIGN: A 1-year prospective single-arm open-label study comparing baseline and 12-month outcomes.

SETTING: Participants were recruited from outpatient endocrinology clinics in the United States. Data were collected in a research unit.

PARTICIPANTS: Eligible participants were ≥ 4 years old, not pregnant, with baseline 25-hydroxyvitamin D ≥20 ng/mL and normal serum calcium.

INTERVENTION: Participants were treated with calcitriol, with dose based on serum and urinary calcium concentrations, for 1 year.

MAIN OUTCOME MEASURES: The primary endpoints were change in serum phosphate and nephrocalcinosis (all participants) and rickets severity score (children). Secondary endpoints 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=0.012). Serum alkaline phosphatase decreased in children (p=0.021) and parathyroid hormone trended lower in both children (p=0.065) and adults (p=0.063). 4 participants developed mild hypercalcemia and 2 developed hypercalciuria which resolved with calcitriol titration.

CONCLUSIONS: Calcitriol monotherapy is safe and well-tolerated in XLH, with modest benefits on laboratory indices of mineral metabolism and rickets.

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 bone mineral density (BMD) and FRAX®. Our source population from a large healthcare system comprised of 341,364 patients (≥ 65 years) with an abdominal-pelvic CT during care. Using data from 3,035 patients (1,790 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, femoral neck volume, hip width, and posterior fat thickness. In a geographically distinct set of 2,124 patients (1,293 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 five years. For the women, the c-statistic for predicting fracture was higher for BCT (0.89, 95% confidence interval 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, two-year 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.

Emerging anti-osteoporosis therapies might present varied mechanisms of action and demand active control groups or sequential therapies due to ethical or mechanistic reasons. We previously showed a strong association between treatment-induced changes in total hip bone mineral density(THBMD) at 12 and 24 mo and reduced fracture risk in placebo-controlled trials. We determined the surrogate threshold effect(STE): the minimum THBMD difference (active-placebo) in a trial that would predict a significant reduction in fracture risk in trials. In this analysis, we investigated whether these associations are influenced by drug mechanism of action or trial design, including treatment with an anabolic followed by an anti-resorptive compared to active control or placebo. We analyzed individual patient data from 22 randomized, placebo-controlled trials (17 anti-resorptive, 3 PTH analogues, 1 odanacatib, and 1 romosozumab placebo-controlled phase), and three trials of an anabolic followed by an anti-resorptive(1 PTH analogue and 2 romosozumab). We established treatment-related differences in THBMD changes, calculated fracture risk reductions for radiologic vertebral and all clinical fractures, and estimated study-level associations between these features via meta-regression. We found consistent associations between treatment-related THBMD changes and fracture risk reduction across different drug mechanisms and trial designs. Among placebo-controlled trials, the r2 values for vertebral fractures were 0.73(p = .0001) and 0.78(p = .0002) at 24 mo, and 0.59(p = .0003) and 0.70(p = .0007) at 12 mo for all drugs versus only anti-resorptive drugs, respectively. Similarly, for all clinical fractures, the r2 were 0.71(p < .0001) and 0.65(p = .0009) at 24 mo and 0.46(p = .0007) and 0.51(p = .002) at 12 mo for all drugs versus only anti-resorptive drugs. For trials of an anabolic followed by an anti-resorptive, the association between THBMD change and fracture risk reduction was similar to that for the placebo-controlled monotherapy trials. Our analyses indicate robust associations between treatment-induced THBMD changes and fracture risk reduction across various anti-osteoporosis therapies and trial designs, suggesting that treatment-induced changes in THBMD predict anti-fracture efficacy regardless of drug mechanism or trial design.

Osteogenesis imperfecta (OI) is a group of diseases caused by defects in type I collagen processing which result in skeletal fragility. While these disorders have been regarded as defects in osteoblast function, the role of matrix-embedded osteocytes in OI pathogenesis remains largely unknown. Homozygous human SP7 (c.946 C > T, R316C) mutation results in a recessive form of OI characterized by fragility fractures, low bone mineral density and osteocyte dendrite defects. To better understand how the OI-causing R316C mutation affects the function of SP7, we generated Sp7R342C knock-in mice. Consistent with patient phenotypes, Sp7R342C/R342C mice demonstrate increased cortical porosity and reduced cortical bone mineral density. Sp7R342C/R342C mice show osteocyte dendrite defects, increased osteocyte apoptosis, and intracortical bone remodeling with ectopic intracortical osteoclasts and elevated osteocyte Tnfsf11 expression. Remarkably, these defects in osteocyte function contrast to only mild changes in mature osteoblast function, suggesting that this Sp7 mutation selectively interferes with the function of Sp7 in osteocytes and mature osteoblasts, but not during early stages of osteoblast differentiation. Osteocyte morphology changes in Sp7R342C/R342C mice were not restored by inhibiting osteoclast formation, indicating that dendrite defects lie upstream of high intracortical osteoclast activity in this model. Moreover, transcriptomic profiling reveals that the expression of a core set osteocyte-enriched genes is highly dysregulated by the R342C mutation. Thus, this supports a model in which osteocyte dysfunction can drive OI pathogenesis and provides a valuable resource to test novel therapeutic approaches and to understand the osteocyte-specific role of SP7 in bone remodeling.