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Sexual dimorphism in the material properties of bone extracellular matrix (ECM) and geometry, which are parameters of bone quality have been recognized (Alswat, 2017; Nieves et al., 2005). However, the molecular mechanisms responsible for dimorphic bone quality remain unclear, limiting our ability to therapeutically target fragility, which is determined by bone quality. Recently, using male mice, we found that systemic or osteocyte-intrinsic inhibition of TGFβ signaling (TβRIIocy-/-), suppresses perilacunar/canalicular remodeling (PLR) and compromises bone quality (Dole et al., 2017). Since we previously demonstrated that female bone mass is more sensitive to TGFβ (Mohammad et al., 2009), we hypothesized that loss of osteocytic TGFβ in females will lead to more severe deterioration of PLR and bone quality. Analysis of female bones, however, surprisingly revealed sexual dimorphism in the TGFβ regulation of osteocyte function. While the male TβRIIocy-/- mice demonstrated reduced trabecular bone mass and repression in expression of requisite PLR genes, including matrix metalloproteinases (Mmp2, Mmp13, and Mmp14), cathepsin K (Ctsk), and tartrate-resistant acid phosphatase (Acp5/TRAP) (Qing et al., 2012), the female TβRIIocy-/- bones were intact. With absence of osteocytic TGFβ signaling, the canaliculi of male TβRIIocy-/- osteocytes were truncated and a severe deterioration of lacuno-canalicular network (LCN) was observed. Unlike the male TβRIIocy-/- mice that exhibited poor bone quality, female TβRIIocy-/- bones were completely protected from bone quality defects and macromechanical bone fragility. Thus, TGFβ-dependent regulation PLR and bone quality is sexually dimorphic. Since, lactation is a potent PLR agonist, we also evaluated the lactation-induced PLR response of TβRIIocy-/- female mice. Compared to WT, lactation-induced bone loss and upregulation of PLR genes was significantly attenuated in the TβRIIocy-/- female mice. Lactation-mediated increases in osteocyte lacunar volume were suppressed in TβRIIocy-/- bones as well. This mitigation in PLR of lactating TβRIIocy-/- mice was analogous to that observed in mice with osteocyte-specific ablation of parathyroid hormone type I receptor (PTHR1) (Qing et al., 2012). Remarkably, lactation-inducible PTHR1 expression was also diminished in TβRIIocy-/- osteocytes. Therefore, osteocyte-intrinsic TGFβ signaling is critical for the maximal induction of PLR during lactation, and TGFβ is an upstream regulator of PTHR1-dependent activation of osteocytic PLR. Indeed, we also found sexual dimorphism in the regulation of osteocytic PTHR1 expression by TGFβ, such that male, but not female, TβRIIocy-/- mice had reduced PTHR1 compared to WT. In summary, we identify a novel PTH-dependent mechanism that protects female bone against the severe bone fragility that results from suppressed TGFβ signaling in osteocytes.

Background: With increasing survival rates after hematopoietic stem cell transplantation (HSCT), it has become important to evaluate methods of improving patients’ quality of life. Most female patients of childbearing age experience premature ovarian failure after transplantation, which results in decreased quality of life and an increase in fracture risk due to rapid bone loss. We analyzed the effects of hormone therapy (HT) on serum follicle stimulating hormone (FSH), serum estradiol, and bone mineral density (BMD) in young female HSCT recipients. Methods: This retrospective cohort study included 234 female patients who underwent allogenic HSCT between April 2009 and April 2018 at our center. The maximum age at the time of transplantation was 40 years, and patients were followed up for at least 3 years. Of the 734 patients who were initially screened, 360 patients aged

Fracture liaison services (FLS) address the treatment gap for those with osteoporosis (OP) who fracture and are not treated. Given the limited human resources in FLS, screening high volumes of radiology reports for fractures with Natural Language Processing (NLP) could identify patients that have not been recognized or treated. This study is an analytical and clinical validation of X-Ray Artificial Intelligence Tool software (XRAIT) at its development site (a tertiary hospital) and external validation in an adjudicated cohort from the Dubbo Osteoporosis Epidemiology Study (DOES).Methods: XRAIT uses NLP to perform a Boolean search of radiology reports for fracture and related terms. It can be trained for site-specific reporting styles and use rules to refine identification (e.g. age>50y; bone involved; etc). At the development site, XRAIT was used to search the emergency patient presentations of people over 50 years of age and compared to referrals to FLS (usual care) during the same 3-month period. XRAIT analyzed all plain radiographs and CT scans (n = 5089) while n = 224 were referred to FLS for usual care. External validation: XRAIT was used to analyze digitally readable radiology reports in an untrained cohort from DOES (n = 327) to calculate sensitivity and specificity.Results: XRAIT identified a 5-fold higher number of potential significant fractures (349/5089) compared to manual case finding (70/224). 339/349 were confirmed fractures (97.1%). Only 29% of those eligible were started or recommended anti-resorptive therapy, including those seen by the fracture liaison service. XRAIT unadjusted for the local radiology reporting styles in DOES had a sensitivity of 69.6% and specificity of 95%. Conclusion: XRAIT identifies clinically significant fractures efficiently with minimal additional human resources. Its high specificity in an untrained cohort suggests it could be used at other sites. Automated methods of patient identification may assist fracture liaison services to identify fractures that still remain largely untreated.

24-hour urine collections are used to assess excretion of various analytes. Although concomitant measurement of creatinine excretion adjusted for body weight (BW) is utilized to determine adequacy of collection, no gold standard exists for determining completeness of a collection. Use of current reference ranges for daily creatinine excretion/BW of 15–20 mg creatinine/kg BW/day in women and 20–25 mg creatinine/kg/d in men established prior to the rising prevalence of obesity has resulted in a large proportion of contemporary individuals appearing to have “incomplete” urine collections. Our objective was to evaluate the range of creatinine excretion in accurately collected urine specimen from adults with a wide spread of age and BW, and to generate an equation that accurately predicts 24-hour urine creatinine excretion rate from readily available clinical parameters to aid in assessing adequacy of a 24-hour urine collection. We analyzed data from participants who completed two consecutive 24-hour urine collections while consuming a fixed metabolic diet during inpatient research admissions. Results from participants with 24-hour urine creatinine excretion rate differing by >10% between the two consecutive collections were excluded. In the initial 115 pairs of inpatient 24-hour urine collections (50 female, 65 male) participants, creatinine excretion/BW fell outside the currently accepted reference ranges in >50% of collections. The proportion below the reference range increased with higher BMI. In this derivation dataset, linear regression models were then constructed to predict 24-hr urine creatinine excretion from race, sex, age, weight and height. Reliable prediction of observed 24-hr urine creatinine excretion was confirmed in a validation dataset that included 50 pairs of 24-hour urine samples similarly collected in an inpatient research setting. This new prediction model performed significantly better than the currently used reference ranges in a large outpatient dataset including 1,399 pairs of 24-hour urine collections. In women, actual creatinine excretion fell within the 95% prediction intervals for our derived equation in 90% of cases using the new interval vs 46% using the current reference range. The corresponding values were 90% and 33% in men. In both genders, the superiority of the new prediction over the current reference range was more pronounced at higher BMI. We therefore propose revision of currently used criteria to define adequacy of 24-hour urine collection to account for the impact of obesity. The proposed equation incorporates readily available demographic parameters to predict urine creatinine excretion. These findings have wide implications on patient care and research studies, and future studies should test this equation in different settings, diets, and populations.

Burosumab, a fully human IgG1 monoclonal antibody to FGF23, is approved in Canada and Brazil to treat XLH in patients ≥1 year of age and in the US to treat XLH in patients ≥6 months of age. Burosumab has also received conditional marketing authorization in Europe to treat XLH with radiographic evidence of bone disease in children ≥1 year of age and in adolescents with growing skeletons. Burosumab significantly improved serum phosphorus, fracture/pseudofracture healing, stiffness, and physical functioning in a phase 3, double-blind, multicenter study (CL303, NCT02526160). In this trial, subjects were randomized 1:1 to receive burosumab or placebo subcutaneously every 4 weeks. At Week 24, subjects in the placebo group crossed over to receive burosumab (total duration ≥96 weeks). Here, we report final long-term safety results from this trial. Most (119/134, 89%) subjects completed 96 weeks and received 1 mg/kg burosumab; protocol-specified dose reductions were required for 11/134 (8.2%) subjects to effectively manage hyperphosphatemia (all mild [Grade 1]). Mean (±SE) baseline serum phosphorus was 1.98 (±0.03) mg/dL and was 2.97 (±0.05) mg/dL at Week 94 (midpoint of dose interval). Mean (±SE) iPTH level was 96 (±3.8) pg/mL at baseline and progressively declined to 79 (±3.3) pg/mL at Week 96. Nephrocalcinosis score at Week 96 changed by 0 in 101 subjects, -1 in 9 subjects, +1 in 10 subjects (14 subjects not available). There were no meaningful changes in ectopic mineralization. There were no neutralizing antibodies. No treatment-emergent adverse events led to study or treatment withdrawal. Serum phosphorus was maintained with long-term burosumab treatment, with no evidence of loss of effect in adults with XLH. Burosumab dose reductions effectively managed mild hyperphosphatemia. Frequency, severity, and types of AEs reported were consistent with previous burosumab trials.

Tumor-induced Osteomalacia (TIO) is a rare condition in which excess FGF23 produced by a tumor leads to renal phosphate wasting, impaired 1,25(OH)2D synthesis, osteomalacia, fractures, weakness, fatigue, and decreased mobility. In an ongoing open-label Phase 2 study (NCT02304367), 17 adults with TIO or cutaneous skeletal hypophosphatemia syndrome (CSHS) were enrolled and received burosumab, a fully human monoclonal antibody against FGF23. Key endpoints were changes in serum phosphorus and osteomalacia as assessed from trans-iliac crest bone biopsies. This report excludes 3/17 subjects who did not have TIO: 2 subjects diagnosed with X-linked hypophosphatemia post-enrollment and 1 subject with CSHS. Serum phosphorus increased from baseline (BL; 1.60 mg/dL) and was maintained after titration, from Week (W) 22 (2.85 mg/dL, dosing cycle midpoint) to W144 (2.56 mg/dL, dosing cycle endpoint, p

Background: FOP is an ultra-rare, severely disabling genetic disorder characterized by episodic flare-ups and heterotopic ossification (HO) leading to restricted movement, physical disability, and early death. FOP may initially be misdiagnosed in ~90% of individuals leading to unnecessary and often harmful interventions. Patients with FOP are diagnosed and managed by multiple specialties, including endocrinologists. Data from an ongoing, prospective, longitudinal, global, natural history study (NCT02322255) were used to investigate the progression of FOP, HO formation, and impact on physical functioning over time. We present results from the first 12 months of the 3-year study. Methods: Males and females with FOP and a documented ACVR1 R206H mutation participated. HO volume was assessed by low-dose whole body computed tomography (WBCT) scan, excluding the head. All imaging was interpreted at a blinded, central laboratory using pre-specified procedures. Functional outcomes were evaluated using the Cumulative Analogue Joint Involvement Scale (CAJIS; for each joint: score=0 represents 90% ankylosed across 15 major joints; total score range 0 to 30 [higher scores indicate more severe mobility limitations]) and the FOP Physical Function Questionnaire (FOP-PFQ; percent total score). Changes from Baseline at Month 12 were evaluated for new HO volume, CAJIS, and FOP-PFQ. Results: Of 114 participants (pts) with Baseline data, 99 (4 to 56 years at enrollment; mean 17 years of age; 56% male) also had a Month 12 assessment. A total of 93 pts had evaluable WBCT scans at Baseline and Month 12 and were included in the HO analysis. In total, 40% (37/93) of pts had new HO over 12 months; the mean volume of new HO in these pts was 57,706 mm3 (SD=100,079 mm3; median=20,753 mm3; range: 522 to 438,826 mm3). Of the pts with new HO, 65% (24/37) reported at least one flare-up (mean rate of 2.3 flare-ups/year). Over 12 months, 60% (56/93) of pts did not have new HO; 43% (24/56) of them reported at least one flare-up (mean rate of 1.8 flare-ups/year). Mean changes from Baseline in CAJIS and FOP-PFQ were minimal: CAJIS: 0.6 (SD=2.4; median=1.0; n=99) and FOP-PFQ: 4.4% (SD=11.2; median=3.7%; n=90); and were similar across pts with or without new HO. Conclusions: In participants with FOP, although deterioration of physical function is expected over a patient’s lifetime, CAJIS and FOP-PFQ scores did not worsen significantly in the relative short-term of this study. However, HO volume, quantified by WBCT, increased over the course of 12 months. These results show that measuring HO may be a viable way to monitor changes in FOP over short periods of time.