Model-Informed Approach to Recommend Burosumab Dosing Regimens for Pediatric and Adult Patients With the Ultrarare Disease Tumor-Induced Osteomalacia.

Burosumab is approved for the treatment of hypophosphatemia in persistent tumor-induced osteomalacia. This work exemplifies a model-informed drug development approach that evaluated burosumab pharmacokinetics and pharmacokinetic/pharmacodynamics in the ultrarare tumor-induced osteomalacia population to support adult and pediatric dosing. Data from tumor-induced osteomalacia participants were combined with data from X-linked hypophosphatemia to understand pharmacokinetic and pharmacokinetic/pharmacodynamic characteristics and covariates specific to tumor-induced osteomalacia. Pharmacokinetic and pharmacokinetic/pharmacodynamic simulations were performed using final models to support dosing recommendations for adults and extrapolation to pediatric patients. Burosumab pharmacokinetics were described using a one-compartment model with first-order absorption and body weight as a significant covariate. Pharmacokinetic/pharmacodynamic relationships were described using a sigmoidal Emax model with significant covariates of baseline fibroblast growth factor 23 on baseline fasting serum phosphate and potency of burosumab response and tumor-induced osteomalacia disease state resulting in a steep slope of response; however, the covariates are not clinically meaningful. Simulations demonstrated that, in pediatric patients, starting doses of burosumab 0.3 and 0.4 mg/kg every 2 weeks at steady state would achieve normal serum phosphate levels in ≥ 30% of patients with relatively low risk of hyperphosphatemia (< 3%). In adults, burosumab 0.3 and 0.5 mg/kg every 4 weeks achieves similar percentages of responders and a relative low risk of hyperphosphatemia (< 7%). Serum phosphate titration-based burosumab dosing increased the probability of achieving normal serum phosphate levels. The models supported a model-informed drug development approach for global approvals of titration-based burosumab dosing, guided by monitoring fasting serum phosphate levels.

Nephrocalcinosis and kidney function in children and adults with X-linked hypophosphatemia: baseline results from a large longitudinal study.

BACKGROUND: In patients with X-linked hypophosphatemia (XLH), conventional therapy with oral phosphate salts and active vitamin D has been associated with nephrocalcinosis. However, the nature of the relationships among XLH, its treatment, nephrocalcinosis, and kidney function remain poorly understood. METHODS: Renal ultrasounds were performed and glomerular filtration rates were estimated (eGFR) at baseline in burosumab-naïve patients with XLH who participated in burosumab clinical trials (NCT02181764, NCT02526160, NCT02537431, NCT02163577, NCT02750618, NCT02915705) or enrolled in the XLH Disease Monitoring Program (XLH-DMP; NCT03651505). In this cross-sectional analysis, patient, disease, and treatment characteristics were described among patients with and without nephrocalcinosis. RESULTS: The analysis included 196 children (mean [SD] age 7.6 [4.0] yr) and 318 adults (40.3 [13.1] yr). Mean (SD) height z-score was -1.9 (1.2) for children and -2.3 (1.7) for adults. Nearly all children (97%) and adults (94%) had previously received conventional therapy. Nephrocalcinosis was detected in 22% of children and 38% of adults. In children, reduced eGFR <90 mL/min/1.73 m2 was more prevalent in those with nephrocalcinosis (25%) than in those without (11%), a finding that was not observed in adults. Children with nephrocalcinosis had lower mean values of TmP/GFR (p<.05), serum 1,25(OH)2D (p<.05), and eGFR (p<.001) and higher mean serum calcium concentrations (p<.05) than did those without nephrocalcinosis. Adults with nephrocalcinosis had lower mean serum phosphorus (p<.01) and 1,25(OH)2D (p<.05) concentrations than those without. Exploratory logistic regression analyses revealed no significant associations between the presence of nephrocalcinosis and other described patient or disease characteristics. CONCLUSIONS: Nephrocalcinosis was observed in nearly one-quarter of children and more than one-third of adults with XLH. Further study is needed to better understand the predictors and long-term consequences of nephrocalcinosis, with surveillance for nephrocalcinosis remaining important in the management of XLH.

Conventionally, patients with X-linked hypophosphatemia (XLH) were treated with phosphate and vitamin D taken by mouth. However, this therapy might lead to a buildup of calcium in the kidney, called nephrocalcinosis. Here, we tried to better understand how XLH, conventional therapy, nephrocalcinosis, and kidney function are related. Nephrocalcinosis was detected with kidney ultrasounds. Kidney function, called the estimated glomerular filtration rate (eGFR), was determined using blood levels of creatinine. Patients had been part of burosumab clinical trials or part of the XLH Disease Monitoring Program. Data were collected from patients before they received burosumab. The study included 196 children and 318 adults. Almost all children and adults had received conventional therapy. 22% of children and 38% of adults had nephrocalcinosis. Some lab values were different among patients with vs without nephrocalcinosis. Children with nephrocalcinosis had significantly greater loss of phosphate by the kidneys, lower blood levels of the active form of vitamin D (1,25(OH)2D), lower eGFR, and higher blood levels of calcium than those without nephrocalcinosis. Adults with nephrocalcinosis had significantly lower blood levels of phosphorus and 1,25(OH)2D concentrations than those without. It remains important to monitor patients with XLH for nephrocalcinosis. Further study is needed to better understand nephrocalcinosis.

Goal-directed osteoporosis treatment: ASBMR/BHOF task force position statement 2024.

The overarching goal of osteoporosis management is to prevent fractures. A goal-directed approach to long-term management of fracture risk helps ensure that the most appropriate initial treatment and treatment sequence is selected for individual patients. Goal-directed treatment decisions require assessment of clinical fracture history, vertebral fracture identification (using vertebral imaging as appropriate), measurement of bone mineral density (BMD), and consideration of other major clinical risk factors. Treatment targets should be tailored to each patient's individual risk profile and based on the specific indication for beginning treatment, including recency, site, number and severity of prior fractures, and BMD levels at the total hip, femoral neck, and lumbar spine. Instead of first-line bisphosphonate treatment for all patients, selection of initial treatment should focus on reducing fracture risk rapidly for patients at very high and imminent risk, such as in those with recent fractures. Initial treatment selection should also consider the probability that a BMD treatment target can be attained within a reasonable period of time and the differential magnitude of fracture risk reduction and BMD impact with osteoanabolic versus antiresorptive therapy. This position statement of the ASBMR/BHOF Task Force on Goal-Directed Osteoporosis Treatment provides an overall summary of the major clinical recommendations about treatment targets and strategies to achieve those targets based on the best evidence available, derived primarily from studies in older postmenopausal women of European ancestry.

Goal-directed treatment can help healthcare providers recommend the best treatments for individual patients to prevent fractures. The goal-directed strategy considers the site, number, and recency of prior fractures. This may require imaging for spine fractures, which may not have caused pain. Treatment decisions also require bone mineral density (BMD) measurement and consideration of other major risk factors. In contrast to the standard approach, same first treatment for all, treatment selection is tailored to an individual's risk. In patients with recent fractures of the spine, hip, or pelvis, fracture risk is very high and treatment should rapidly reduce that risk. For others, the target is a specific BMD level and should consider the likelihood that the treatment target can be attained within a reasonable period of time, which differs for osteoporosis medications. After initial therapy, BMD should be assessed to determine if the target has been achieved. If so, strategies should focus on maintaining BMD. If the target is not yet achieved, treatment should be intensified, or continued if it is already the most potent option. This position statement represents a consensus of expert recommendations about treatment targets and strategies to achieve those targets based on the best available evidence.

Healthcare resource use associated with tumor-induced osteomalacia: a literature review.

CONTEXT: Tumor-induced osteomalacia (TIO) is an ultra-rare, paraneoplastic syndrome caused by tumors that secrete fibroblast growth factor 23 (FGF23). Initial signs and musculoskeletal symptoms can be non-specific and unrecognized, leading to long delays in diagnosis and treatment, which results in severe and progressive disability in patients with TIO. This review aimed to identify published evidence on healthcare resource use in TIO to better understand the burden of the disease. EVIDENCE ACQUISITION: A targeted literature review was conducted to identify publications reporting on disease characteristics and healthcare resource use associated with TIO. EVIDENCE SYNTHESIS: In total, 414 publications were included in the review, of which 376 were case reports. From the case reports, data on 621 patients were extracted. These patients had a mean (standard deviation) age of 46.3 (15.8) years; 57.6% were male. Mean time from first symptoms to diagnosis of TIO was 4.6 (4.7) years and, in cases where imaging tests were reported, patients underwent a mean of 4.1 (2.7) procedures. Tumor resection was attempted in 81.0% of patients and successful in 67.0%. Fracture was reported in 49.3% of patients. Results from association analyses demonstrated that longer time to diagnosis was associated with poorer tumor resection outcomes and a higher probability of tumor recurrence. Unfavorable tumor resection outcomes were associated with greater use of pharmacologic treatment and a greater likelihood of orthopedic surgery. CONCLUSION: TIO is associated with a substantial healthcare resource burden. Improvements in the diagnostic process could lead to better management of TIO, thereby benefiting patients and reducing that burden.

Burosumab Improves Patient-Reported Outcomes in Adults With Tumor-Induced Osteomalacia: Mixed-Methods Analysis.

Tumor-induced osteomalacia (TIO) is an ultra-rare disease caused by tumors that secrete fibroblast growth factor 23, leading to chronic hypophosphatemia, poor skeletal health, and impaired physical function. In a phase 2 trial (UX023T-CL201; NCT02304367; n = 14), 48 weeks of burosumab treatment restored phosphate homeostasis, with improvements in skeletal health, functional mobility, and patient-reported pain, fatigue, and health-related quality of life (HRQL) (SF-36 v2). Here, we report an exploratory mixed-methods analysis of change from baseline after 144 weeks of burosumab treatment alongside qualitative data from exit interviews with 8 of 14 trial participants to evaluate meaningful treatment effects from a patient perspective. The interview subset (n = 8) reported pain and fatigue and compromised HRQL at baseline. In the interviews, participants reported that compromised HRQL and pain were the most important aspects of the disease to treat; both were considered more bothersome than fatigue and compromised physical function and activities of daily living. Improvements in pain and fatigue after treatment were reported, some of which achieved statistically and/or clinically meaningful thresholds. Furthermore, improvements in SF-36 v2 scores were most pronounced in the Physical Component Score and its Physical Function and Bodily Pain domains. Overall, the interview subset provided descriptions of symptomatic improvement and its clinical meaningfulness, including physical function, participation in activities of daily living, and mental well-being. Thus, this exploratory mixed-methods analysis provides deeper understanding of patients' perception of clinical meaningfulness beyond that articulated in validated patient-reported outcome instruments. © 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).

Global guidance for the recognition, diagnosis, and management of tumor-induced osteomalacia.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by mesenchymal tumors that secrete fibroblast growth factor 23 (FGF23). Patients present with progressive bone pain, muscle weakness, and fragility fractures. TIO is characterized by hypophosphatemia, excess renal phosphate excretion, and low/inappropriately normal 1,25-dihydroxyvitamin D (1,25(OH)2 D) levels. Rarity and enigmatic clinical presentation of TIO contribute to limited awareness among the medical community. Accordingly, appropriate diagnostic tests may not be requested, leading to delayed diagnosis and poorer patient outcomes. We have developed a global guidance document to improve the knowledge of TIO in the medical community, enabling the recognition of patients with TIO and appropriate referral. We provide recommendations aiding diagnosis, referral, and treatment, helping promote a global standard of patient management. We reviewed the literature and conducted a three-round Delphi survey of TIO experts. Statements were drafted based on published evidence and expert opinions (≥70% consensus required for final recommendations). Serum phosphate should be measured in patients presenting with chronic muscle pain or weakness, fragility fractures, or bone pain. Physical examination should establish features of myopathy and identify masses that could be causative tumors. Priority laboratory evaluations should include urine/serum phosphate and creatinine to assess renal tubular reabsorption of phosphate and TmP/GFR, alkaline phosphatase, parathyroid hormone, 25-hydroxyvitamin D, 1,25(OH)2 D, and FGF23. Patients with the clinical/biochemical suspicion of TIO should be referred to a specialist for diagnosis confirmation, and functional imaging should be used to localize causative tumor(s). Recommended treatment is tumor resection or, with unresectable/unidentifiable tumors, phosphate salts plus active vitamin D, or burosumab.

Efficacy of Burosumab in Adults with X-linked Hypophosphatemia (XLH): A Post Hoc Subgroup Analysis of a Randomized Double-Blind Placebo-Controlled Phase 3 Study.

The anti-fibroblast growth factor 23 monoclonal antibody burosumab corrects hypophosphatemia in adults with X-linked hypophosphatemia (XLH) and improves pain, stiffness, physical function, and fatigue. This post hoc subgroup analysis used data from the 24-week placebo-controlled period of a phase 3 study in 134 adults with XLH (ClinicalTrials.gov NCT02526160), to assess whether the benefits of burosumab are evident in 14 clinically relevant subgroups defined by baseline demographic and functional criteria, including sex, Brief Pain Inventory-short form (BPI-SF) Average And Worst Pain, region, race, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC®) Stiffness, Physical Function and Pain domains and total score, use of opioid/other pain medication, active fractures/pseudo-fractures, and 6-min walk test distance. There were no statistically significant interactions between any of the subgroups and treatment arm for any endpoint. Higher proportions of subjects achieved mean serum phosphate concentration above the lower limit of normal (the primary endpoint) with burosumab than with placebo in all subgroups. For the key secondary endpoints (WOMAC Stiffness and Physical Function; BPI-SF Worst Pain) individual subgroup categories showed improvements with burosumab relative to placebo. For additional efficacy endpoints, burosumab was favored in some subgroups but differences were not significant and confidence intervals were wide. For some endpoints the treatment effect is small at 24 weeks in all subjects. This subgroup analysis shows that burosumab was largely superior to placebo across endpoints in the 14 clinically relevant subgroup variables at 24 weeks and is likely to benefit all symptomatic adults with active XLH.

Working to Increase Stability through Exercise (WISE): screening, recruitment, and baseline characteristics.

BACKGROUND: The aim of this paper is to describe the utility of various recruitment modalities utilized in the Working to Increase Stability through Exercise (WISE) study. WISE is a pragmatic randomized trial that is testing the impact of a 3-year, multicomponent (strength, balance, aerobic) physical activity program led by trained volunteers or delivered via DVD on the rate of serious fall-related injuries among adults 65 and older with a past history of fragility fractures (e.g., vertebral, fall-related). The modified goal was to recruit 1130 participants over 2 years in three regions of Pennsylvania. METHODS: The at-risk population was identified primarily using letters mailed to patients of three health systems and those over 65 in each region, as well as using provider alerts in the health record, proactive recruitment phone calls, radio advertisements, and presentations at community meetings. RESULTS: Over 24 months of recruitment, 209,301 recruitment letters were mailed, resulting in 6818 telephone interviews. The two most productive recruitment methods were letters (72% of randomized participants) and the research registries at the University of Pittsburgh (11%). An average of 211 letters were required to be mailed for each participant enrolled. Of those interviewed, 2854 were ineligible, 2,825 declined to enroll and 1139 were enrolled and randomized. Most participants were female (84.4%), under age 75 (64.2%), and 50% took an osteoporosis medication. Not having a prior fragility fracture was the most common reason for not being eligible (87.5%). The most common reason provided for declining enrollment was not feeling healthy enough to participate (12.6%). CONCLUSIONS: The WISE study achieved its overall recruitment goal. Bulk mailing was the most productive method for recruiting community-dwelling older adults at risk of serious fall-related injury into this long-term physical activity intervention trial, and electronic registries are important sources and should be considered.

Burosumab treatment in adults with X-linked hypophosphataemia: 96-week patient-reported outcomes and ambulatory function from a randomised phase 3 trial and open-label extension.

OBJECTIVES: To report the impact of burosumab on patient-reported outcomes (PROs) and ambulatory function in adults with X-linked hypophosphataemia (XLH) through 96 weeks. METHODS: Adults diagnosed with XLH were randomised 1:1 in a double-blinded trial to receive subcutaneous burosumab 1 mg/kg or placebo every 4 weeks for 24 weeks (NCT02526160). Thereafter, all subjects received burosumab every 4 weeks until week 96. PROs were measured using the Western Ontario and the McMaster Universities Osteoarthritis Index (WOMAC), Brief Pain Inventory-Short Form (BPI-SF) and Brief Fatigue Inventory (BFI), and ambulatory function was measured with the 6 min walk test (6MWT). RESULTS: Subjects (N=134) were randomised to burosumab (n=68) or placebo (n=66) for 24 weeks. At baseline, subjects experienced pain, stiffness, and impaired physical and ambulatory function. At week 24, subjects receiving burosumab achieved statistically significant improvement in some BPI-SF scores, BFI worst fatigue (average and greatest) and WOMAC stiffness. At week 48, all WOMAC and BPI-SF scores achieved statistically significant improvement, with some WOMAC and BFI scores achieving meaningful and significant change from baseline. At week 96, all WOMAC, BPI-SF and BFI achieved statistically significant improvement, with selected scores in all measures also achieving meaningful change. Improvement in 6MWT distance and percent predicted were statistically significant at all time points from 24 weeks. CONCLUSIONS: Adults with XLH have substantial burden of disease as assessed by PROs and 6MWT. Burosumab treatment improved phosphate homoeostasis and was associated with a steady and consistent improvement in PROs and ambulatory function. TRIAL REGISTRATION NUMBER: NCT02526160.

High-throughput Molecular Analysis of Pseudohypoparathyroidism 1b Patients Reveals Novel Genetic and Epigenetic Defects.

CONTEXT: Patients with pseudohypoparathyroidism type 1b (PHP1b) show disordered imprinting of the maternal GNAS allele or paternal uniparental disomy (UPD). Genetic deletions in STX16 or in upstream exons of GNAS are present in many familial but not sporadic cases. OBJECTIVE: Characterization of epigenetic and genetic defects in patients with PHP1b. DESIGN AND PATIENTS: DNA from 84 subjects, including 26 subjects with sporadic PHP1b, 27 affected subjects and 17 unaffected and/or obligate gene carriers from 12 PHP1b families, 11 healthy individuals, and 3 subjects with PHP1a was subjected to quantitative pyrosequencing of GNAS differentially methylated regions (DMRs), microarray analysis, and microsatellite haplotype analysis. SETTING: Academic medical center. MAIN OUTCOME MEASUREMENTS: Molecular pathology of PHP1b. RESULTS: Healthy subjects, unaffected family members and obligate carriers of paternal PHP1b alleles, and subjects with PHP1a showed normal methylation of all DMRs. All PHP1b subjects showed loss of methylation (LOM) at the exon A/B DMR. Affected members of 9 PHP1b kindreds showed LOM only at the exon A/B DMR, which was associated with a 3-kb deletion of STX16 exons 4 through 6 in 7 families and a novel deletion of STX16 and adjacent NEPEPL1 in 1 family. A novel NESP deletion was found in 1 of 2 other families with more extensive methylation defects. One sporadic PHP1b had UPD of 20q, 2 had 3-kb STX16 deletions, and 5 had apparent epigenetic mosaicism. CONCLUSIONS: We found diverse patterns of defective methylation and identified novel or previously known mutations in 9 of 12 PHP1b families.

Challenges in the management of tumor-induced osteomalacia (TIO).

Tumor-induced osteomalacia (TIO), also known as oncogenic osteomalacia, is a rare acquired paraneoplastic disease, which is challenging to diagnose and treat. TIO is characterized by hypophosphatemia resulting from excess levels of tumor-secreted fibroblast growth factor 23 (FGF23), one of the key physiological regulators of phosphate metabolism. Elevated FGF23 results in renal phosphate wasting and compromised vitamin D activation, ultimately resulting in osteomalacia. Patients typically present with progressive and non-specific symptoms, including bone pain, multiple pathological fractures, and progressive muscle weakness. Diagnosis is often delayed or missed due to the non-specific nature of complaints and lack of disease awareness. Additionally, the disease-causing tumour is often difficult to detect and localize because they are often small, lack localizing symptoms and signs, and dwell in widely variable anatomical locations. Measuring serum/urine phosphate should be an inherent diagnostic component when assessing otherwise unexplained osteomalacia, fractures and weakness. In cases of hypophosphatemia with inappropriate (sustained) phosphaturia and inappropriately normal or frankly low 1,25-dihydroxy vitamin D, differentiation of the potential causes of renal phosphate wasting should include measurement of FGF23, and TIO should be considered. While patients experience severe disability without treatment, complete excision of the tumour is typically curative and results in a dramatic reversal of symptoms. Two additional key current unmet needs in optimizing TIO management are: (1 and 2) the considerable delay in diagnosis and consequent delay between the onset of symptoms and surgical resection; and (2) alternative management. These may be addressed by raising awareness of TIO, and taking into consideration the accessibility and variability of different healthcare infrastructures. By recognizing the challenges associated with the diagnosis and treatment of TIO and by applying a stepwise approach with clear clinical practice guidelines, patient care and outcomes will be improved in the future.

Vaccination for Coronavirus Disease 2019 (COVID-19) and Relationship to Osteoporosis Care: Current Evidence and Suggested Approaches.

The development of coronavirus disease 2019 (COVID-19) vaccines has proceeded at an unprecedented pace, with numerous trials conducted simultaneously across the world as a result of massive technological and financial resource expenditures. With multiple vaccines having now received regulatory approval, public health efforts to promote widespread vaccine dissemination are currently underway. There has been particular emphasis placed on vaccination of older populations, the age group in which COVID-19 infection has been most lethal. However, such widespread vaccination approaches have necessarily raised important questions related to potential interactions with underlying diseases and concomitant treatments among persons to be vaccinated. Osteoporosis is a chronic condition marked by reduced bone strength and an associated increased risk for fracture that generally requires sustained medical intervention(s). Osteoporosis is neither associated with a higher risk of COVID-19 infection nor by more pronounced disease severity following infection, such that individuals with osteoporosis need not be more highly prioritized for COVID-19 vaccination. Osteoporosis therapies do not interfere with the efficacy or side effect profiles of COVID-19 vaccines and should not be stopped or indefinitely delayed because of vaccination. Depending on the specific drug profile within an anti-osteoporosis medication category, minor adjustments to the timing of drug administration may be considered with respect to the patient's COVID-19 vaccination schedule. Herein we provide practical recommendations for the care of patients requiring treatment for osteoporosis in the setting of COVID-19 vaccination. © 2021 American Society for Bone and Mineral Research (ASBMR).

Burosumab for the Treatment of Tumor-Induced Osteomalacia.

Tumor-induced osteomalacia (TIO) is caused by phosphaturic mesenchymal tumors producing fibroblast growth factor 23 (FGF23) and is characterized by impaired phosphate metabolism, skeletal health, and quality of life. UX023T-CL201 is an ongoing, open-label, phase 2 study investigating the safety and efficacy of burosumab, a fully human monoclonal antibody that inhibits FGF23, in adults with TIO or cutaneous skeletal hypophosphatemia syndrome (CSHS). Key endpoints were changes in serum phosphorus and osteomalacia assessed by transiliac bone biopsies at week 48. This report focuses on 14 patients with TIO, excluding two diagnosed with X-linked hypophosphatemia post-enrollment and one with CSHS. Serum phosphorus increased from baseline (0.52 mmol/L) and was maintained after dose titration from week 22 (0.91 mmol/L) to week 144 (0.82 mmol/L, p < 0.0001). Most measures of osteomalacia were improved at week 48: osteoid volume/bone, osteoid thickness, and mineralization lag time decreased; osteoid surface/bone surface showed no change. Of 249 fractures/pseudofractures detected across 14 patients at baseline, 33% were fully healed and 13% were partially healed at week 144. Patients reported a reduction in pain and fatigue and an increase in physical health. Two patients discontinued: one to treat an adverse event (AE) of neoplasm progression and one failed to meet dosing criteria (receiving minimal burosumab). Sixteen serious AEs occurred in seven patients, and there was one death; all serious AEs were considered unrelated to treatment. Nine patients had 16 treatment-related AEs; all were mild to moderate in severity. In adults with TIO, burosumab exhibited an acceptable safety profile and was associated with improvements in phosphate metabolism and osteomalacia. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research..

Continued Beneficial Effects of Burosumab in Adults with X-Linked Hypophosphatemia: Results from a 24-Week Treatment Continuation Period After a 24-Week Double-Blind Placebo-Controlled Period.

Burosumab, a fully human monoclonal antibody to FGF23, is the only approved treatment for X-linked hypophosphatemia (XLH), a rare genetic disorder characterized by renal phosphate wasting and substantial cumulative musculoskeletal morbidity. During an initial 24-week randomized, controlled trial, 134 adults with XLH received burosumab 1 mg/kg (n = 68) or placebo (n = 66) every 4 weeks. After 24 weeks, all subjects received open-label burosumab until week 48. This report describes the efficacy and safety of burosumab during the open-label treatment period. From weeks 24-48, serum phosphorus concentrations remained normal in 83.8% of participants who received burosumab throughout and were normalized in 89.4% who received burosumab after placebo. By week 48, 63.1% of baseline fractures/pseudofractures healed fully with burosumab, compared with 35.2% with burosumab after placebo. In both groups, burosumab was associated with clinically significant and sustained improvement from baseline to week 48 in scores for patient-reported outcomes of stiffness, pain, physical function, and total distance walked in 6 min. Rates of adverse events were similar for burosumab and placebo. There were no fatal adverse events or treatment-related serious adverse events. Nephrocalcinosis scores did not change from baseline by more than one grade at either week 24 or 48. These data demonstrate that in participants with XLH, continued treatment with burosumab is well tolerated and leads to sustained correction of serum phosphorus levels, continued healing of fractures and pseudofractures, and sustained improvement in key musculoskeletal impairments.

Working to Increase Stability through Exercise (WISE): Study protocol for a pragmatic randomized controlled trial of a coached exercise program to reduce serious fall-related injuries.

Approximately one-third of older adults fall each year and fall-related injuries are a leading cause of death and disability among this rapidly expanding age group. Despite the availability of bisphosphonates to reduce fractures, concerns over side effects have dramatically reduced use, suggesting that other treatment options are needed. Though many smaller studies have shown that physical activity programs can reduce falls, no study has been adequately powered to detect a reduction in fall-related injuries. We present the design of a three-year randomized controlled clinical trial of 1130 adults age 65 and older with a past history of fragility fractures (e.g., vertebral, fall-related). The main aim is to determine the impact of a community-based multicomponent (strength, balance, aerobic) physical activity program led by trained volunteers (or delivered via DVD) and accompanied by coaching and oversight, by telephone and in-person, by a fitness professional. The main outcome measure is serious fall-related injuries. Secondary outcomes include health care utilization, bone and muscle mass, loneliness, health-related quality of life and mood. The study represents the first large clinical trial of a comprehensive physical activity program to reduce secondary injuries among patients with a history of fragility fracture.

A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial Evaluating the Efficacy of Burosumab, an Anti-FGF23 Antibody, in Adults With X-Linked Hypophosphatemia: Week 24 Primary Analysis.

In X-linked hypophosphatemia (XLH), inherited loss-of-function mutations in the PHEX gene cause excess circulating levels of fibroblast growth factor 23 (FGF23), leading to lifelong renal phosphate wasting and hypophosphatemia. Adults with XLH present with chronic musculoskeletal pain and stiffness, short stature, lower limb deformities, fractures, and pseudofractures due to osteomalacia, accelerated osteoarthritis, dental abscesses, and enthesopathy. Burosumab, a fully human monoclonal antibody, binds and inhibits FGF23 to correct hypophosphatemia. This report summarizes results from a double-blind, placebo-controlled, phase 3 trial of burosumab in symptomatic adults with XLH. Participants with hypophosphatemia and pain were assigned 1:1 to burosumab 1 mg/kg (n = 68) or placebo (n = 66) subcutaneously every 4 weeks (Q4W) and were comparable at baseline. Across midpoints of dosing intervals, 94.1% of burosumab-treated participants attained mean serum phosphate concentration above the lower limit of normal compared with 7.6% of those receiving placebo (p < 0.001). Burosumab significantly reduced the Western Ontario and the McMaster Universities Osteoarthritis Index (WOMAC) stiffness subscale compared with placebo (least squares [LS] mean ± standard error [SE] difference, -8.1 ± 3.24; p = 0.012). Reductions in WOMAC physical function subscale (-4.9 ± 2.48; p = 0.048) and Brief Pain Inventory worst pain (-0.5 ± 0.28; p = 0.092) did not achieve statistical significance after Hochberg multiplicity adjustment. At week 24, 43.1% (burosumab) and 7.7% (placebo) of baseline active fractures were fully healed; the odds of healed fracture in the burosumab group was 16.8-fold greater than that in the placebo group (p < 0.001). Biochemical markers of bone formation and resorption increased significantly from baseline with burosumab treatment compared with placebo. The safety profile of burosumab was similar to placebo. There were no treatment-related serious adverse events or meaningful changes from baseline in serum or urine calcium, intact parathyroid hormone, or nephrocalcinosis. These data support the conclusion that burosumab is a novel therapeutic addressing an important medical need in adults with XLH.© 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

Diabetic serum from older women increases adipogenic differentiation in mesenchymal stem cells.

BACKGROUND: Paradoxically, elderly persons with type 2 diabetes mellitus (T2DM) fracture despite having higher bone density than nondiabetics. Systemic factors associated with aging and T2DM may have detrimental, local effects on the skeleton. One such factor could be by altering the microenvironment of the mesenchymal stem cells (MSCs), multipotent progenitors capable of differentiating into adipocytes or osteoblasts. METHODS: Sera were obtained from four participant groups (n = 40 total, 10 per group): (1) young women with normal glucose tolerance (NGTY), (2) postmenopausal women with NGT), (3) postmenopausal women with impaired glucose tolerance (IGT), and (4) postmenopausal women with T2DM. Sera were incubated with human MSCs for 14 days. Cell proliferation and apoptosis were measured using EdU and TUNEL labeling assays, respectively. MSC differentiation for each group was determined using osteogenic and adipogenic gene expression markers quantified by qRT-PCR, as well as Alizarin Red and Oil Red O staining. RESULTS: Expression of adipogenic genes was greater than twofold higher (P < 0.05) in MSCs cultured with T2DM sera compared to those incubated with NGTY, NGT, or IGT sera. The increase in adipogenic gene expression corresponded with increased Oil Red O staining. Despite the increased adipogenic differentiation of MSCs exposed to T2DM sera, cell proliferation and apoptosis rates as well as osteoblastic activity were not significantly different among the four conditions. CONCLUSIONS: Systemic, circulating factors in the serum of older women with T2DM may promote MSC differentiation into adipocytes versus osteoblasts. Increased differentiation of MSCs into adipocytes is one possible mechanism by which T2DM increases fracture risk.