Conditions resulting in elevated fibroblast growth factor 23 (FGF23) cause hypophosphatemic rickets and osteomalacia. The most common of these is X-linked hypophosphatemia. In this review we will broadly discuss the other less common and clinically distinct forms of renal hypophosphatemia, with a focus on the autosomal dominant and autosomal recessive types. Variants in multiple genes cause dominant (FGF23, SGK3, FGFR1), recessive (DMP1, ENPP1, FAM20C, INPPL1) or even somatic (NRAS, HRAS, GNAS, gene fusions) conditions of FGF23 excess, with important phenotypic differences. For example, in autosomal dominant hypophosphatemic rickets due to FGF23 variants, iron deficiency drives the phenotype, while ENPP1 variants cause phenotypes ranging from severe neonatal vascular calcifications to rickets or osteoporosis. Other gene abnormalities cause FGF23-independent hypophosphatemia, often involving kidney disease. Recognizing the different mechanisms and phenotypes of hypophosphatemic conditions is critical to prognosis, management and to developing more effective therapies.

Accurate fracture risk prediction is important for osteoporosis management, but commonly used clinical tools may not fully use information available in electronic health records (EHRs) and dual-energy X-ray absorptiometry (DXA) reports. We developed and externally validated time-to-event fracture prediction models among adults aged 50 years or older with clinically obtained DXA reports in 2 US health care systems. The development cohort was derived from NewYork-Presbyterian/Weill Cornell Medical Center and the external validation cohort from the Indiana Network for Patient Care. Predictors included demographics, lifestyle factors, prior fracture, comorbidities, medication exposures, osteoporosis treatment history, and DXA-derived T-scores extracted from radiology reports. The outcome was time from index DXA to first incident fragility fracture identified from structured diagnosis codes. We evaluated penalized Cox regression, random survival forest, gradient-boosting survival, and XGBoost survival models using 2 prespecified predictor settings and compared discrimination with clinically reported FRAX major osteoporotic fracture probabilities. The development cohort included 11,510 adults, of whom 858 sustained incident fragility fractures; the external validation cohort included 1,932 adults, of whom 180 sustained fractures. In internal validation, the expanded Cox model achieved a mean Harrell C-index of 0.779, compared with 0.653 for FRAX. In external validation, the corresponding Cox model achieved a Harrell C-index of 0.714, compared with 0.590 for FRAX; gradient-boosting survival had the highest external discrimination (0.725). EHR- and DXA-enhanced models showed better discrimination than clinically reported FRAX scores in this DXA-tested population, but calibration assessment, prospective evaluation, and implementation workflow assessment are needed before clinical use.

CONTEXT:X-linked hypophosphatemia (XLH) is a rare, genetic, progressive, lifelong disorder manifest by impaired growth and disproportionate short stature. Burosumab, a monoclonal antibody against fibroblast growth factor 23, is approved for treating patients with XLH. OBJECTIVE:To understand the impact of burosumab treatment on growth in a real-world setting. DESIGN:Interim data from 3 ongoing, real-world observational studies (NCT03651505, NCT03193476, and NCT03745521), were unified into a single study (APEX). SETTING:Outpatient clinics. PATIENTS:Children aged 2-17 years with XLH. INTERVENTION(S):Subcutaneous burosumab vs oral phosphate salts and active vitamin D or no treatment. MAIN OUTCOME MEASURE(S):Retrospective and prospective height data from children enrolled in APEX were analyzed to provide long-term estimation of the impact of treatment on growth. Growth and height were estimated by a mixed regression model with separate models for children and adolescents. RESULTS:In total, 641 participants were analyzed (402 female) with 498 burosumab-treated and 143 burosumab naïve. Median (interquartile range [IQR]) enrollment ages were 8 (5-12) years for burosumab-treated and 10 (4-14) years for burosumab-naïve participants. Burosumab-treated participants experienced improved growth over burosumab-naïve participants (additional growth velocity: 0.085 Z-score/year for children [P < .0001]; 0.121 Z-score/year for adolescents [P < .0001]). Modeling predicted greater adult height among burosumab-treated participants. CONCLUSION:Burosumab had a robust, positive association with improved growth outcomes in male and female children and adolescents with XLH. Modeling based on a median of 3.3 years of follow-up predicted burosumab can support improvement of growth that will likely result in greater adult height.

Autosomal dominant osteopetrosis (ADO) is a rare bone disorder caused by impaired osteoclastic resorption. Despite high bone mass, ADO is paradoxically associated with increased fracture risk. High-resolution peripheral quantitative computed tomography (HR-pQCT) provides unique, low-radiation assessments of bone, but prior studies in ADO are limited to small case series. Using baseline cross-sectional data from an ongoing natural history study, we characterized HR-pQCT phenotypes in adults with ADO and explored associations with self-reported fracture history and bone turnover markers. HR-pQCT outcomes at the distal ends and shafts of the radius and tibia in 48 adults with ADO were compared to 144 matched controls (1, 3 ratio). In addition, z-scores for outcomes in ADO were calculated using established reference data. At trabecular-rich distal sites, ADO demonstrated markedly elevated total volumetric bone mineral density (vBMD), trabecular vBMD, trabecular bone volume fraction, trabecular thickness, and estimated failure load (all p<0.001), with values often approaching or exceeding twice those in controls. At cortical-rich shaft sites, total vBMD, bone area, bone area fraction, and cortical thickness were greater in ADO (all p<0.05). However, there was considerable interindividual variability, with some individuals having normal z-scores while others exhibited z-scores exceeding +20. The phenotype reflected increased bone mass rather than mineralization-cortical vBMD was normal and tissue mineral density was normal-to-lower in ADO. Outcomes at both distal and shaft sites were strongly correlated with lifetime fracture number (Spearman ρ=0.64-0.75, p<0.001), indicating ADO individuals with the "strongest" bones (via micro-finite element modeling) reported most fractures. The outcomes were correlated inversely with serum C-telopeptide and positively with serum tartrate resistant acid phosphatase 5b, consistent with ADO being rich with dysfunctional osteoclasts. Overall, the data reveal the profound, yet variable, phenotype in ADO and indicate that HR-pQCT measures correlate with disease severity and represent potential surrogate endpoints for future therapeutic trials.

Autosomal dominant osteopetrosis (ADO) is a rare osteosclerotic disorder usually caused by missense variants in the CLCN7 gene, which results in impaired osteoclastic bone resorption. Penetrance is incomplete, and disease severity varies widely, even among relatives within the same family. Although ADO can cause visual loss, osteonecrosis, osteomyelitis, and bone marrow failure, the most common complication of ADO is fracture. We are conducting a natural history study to characterize disease progression and determinants of disease severity. We hypothesized that baseline BMD and bone turnover markers would correlate with self-reported fracture history. We report cross-sectional analysis of baseline data from the natural history study in 54 individuals (42 adults, 12 children). In adults, Z-scores for both volumetric (r = 0.87, p < .001) and areal BMD (aBMD) of the LS, and Z-scores for FN, and TH aBMD (r = 0.77 to 0.78; p < .001) were correlated with lifetime fracture number. Tartrate resistant acid phosphatase, a marker of osteoclast number, correlated positively with fracture (r = 0.52, p = .004) consistent with an adaptive response of higher numbers of osteoclasts among more severely affected individuals. However, fracture number correlated inversely with the bone resorption markers serum C-telopeptide (r = -0.60, p < .001) and urine N-telopeptide/creatinine ratio (r = -0.35, p = .047), suggesting that ADO subjects who have the most reduced osteoclast activity have a greater tendency to fracture. Correlation coefficients between fractures, BMD, and bone turnover markers were similar when limited to the 37 adults with disease-causing CLCN7 variants. There were no statistically significant differences between subjects with the most common CLCN7 variant (G215R), the most common variant in our cohort, compared to other CLCN7 variants with respect to fracture, bone density measures, or biochemical markers of bone turnover. These data demonstrate that bone density and biochemical bone turnover markers are indicators of ADO severity as defined by fracture number.

Context:Tumor-induced osteomalacia (TIO) is an ultra-rare condition caused by tumors secreting fibroblast growth factor-23, leading to chronic hypophosphatemia, pain, muscle weakness, fractures, and impaired physical function. Burosumab is a monoclonal antibody indicated for treatment of TIO when tumors cannot be curatively resected. Objective:This study compares clinical and patient-reported outcomes in patients with TIO treated vs not treated with burosumab in a real-world setting. Design:This interim analysis reports outcomes at enrollment in the prospective, observational Tumor-Induced Osteomalacia Disease Monitoring Program (NCT04783428), stratified by burosumab treatment status at enrollment. Setting:Tertiary care centers in the United States and Argentina. Patients:Patients with TIO from the Disease Monitoring Program. Exposure:Burosumab treatment. Main outcome measures:Biochemistry measurements and patient-reported health-related quality of life (pain, fatigue, and physical function). Results:21 patients with TIO (61.9% female, median [Q1, Q3] age 49.7 years [41.6, 57.3]) were included. At enrollment, 11 (52.4%) patients were treated with burosumab, for a median (Q1, Q3) duration of 4.1 years (0.8, 7.0). Burosumab-treated patients had significantly higher serum phosphate and 1,25-dihydroxyvitamin D levels, and nonsignificantly lower alkaline phosphatase levels, compared with patients not treated with burosumab. Patients treated with burosumab reported significantly lower median Brief Pain Inventory scores, nonsignificantly lower Brief Fatigue Inventory scores, and nonsignificantly higher Patient-Reported Outcomes Measurement Information System Physical Function and Short-Form-36 scores, indicating lower symptom severity and better health-related quality of life. Conclusion:This study suggests favorable biochemical and patient-reported outcomes in patients with TIO treated with burosumab.

CONTEXT:X-linked hypophosphatemia (XLH) is a rare disorder characterized by excess fibroblast growth factor 23 (FGF23), leading to chronic hypophosphatemia, osteomalacia, and rickets. OBJECTIVE:To evaluate outcomes up to 3 years following initiation of treatment with anti-FGF23 antibody (burosumab) in a real-world setting among individuals with XLH, stratified by age group, including those excluded from clinical trials (<1, 13-17, and ≥65 years). METHODS:The XLH Disease Monitoring Program is a prospective, longitudinal, long-term-outcomes program for individuals with XLH. This analysis included participants who were burosumab-naive at baseline and who had initiated burosumab between baseline and the Year 1 visit. Changes from baseline in biochemistry, clinical outcomes, and patient-reported outcomes (PROs) were assessed at Year 1 (Y1) and Year 3 (Y3) visits. RESULTS:Among participants (n = 139), burosumab led to significant and sustained improvements in mean (SD) serum phosphate z-scores at Y1 and Y3 (change from baseline: 1.4 [1.1]; P < .0001 for each timepoint). Among pediatric participants, serum alkaline phosphatase z-scores, Rickets Severity Scores, and patient-reported pain interference declined significantly at Y1 and Y3; non-significant changes were observed in fatigue and physical function mobility. Adults showed significant improvements in PRO measures of pain, stiffness, and physical function, with higher proportions of participants achieving minimal clinically important differences at Y3 vs Y1. Trends observed in overall cohorts were generally consistent across age sub-groups, with statistical significance reached for many endpoints. CONCLUSION:This analysis demonstrated the real-world effectiveness of burosumab for XLH, which appears evident across age groups.

Tumor-induced osteomalacia (TIO) is an ultra-rare, paraneoplastic syndrome caused by tumors secreting fibroblast growth factor 23 (FGF23). In children, TIO may be mistaken for more common causes of rickets and osteomalacia, including monogenic forms, leading to long diagnostic delays. This review aimed to identify evidence on the diagnostic journey and burden of TIO in pediatric patients. A literature review was conducted to identify publications reporting disease characteristics, investigations, treatments, and clinical outcomes in pediatric patients diagnosed with TIO. In total, 41 studies were included in the review, reporting on 46 pediatric patients. Mean age at presentation was 11.2 years (standard deviation [SD]: 4.6). The majority of individuals (60.9

X-linked hypophosphatemia (XLH) is caused by PHEX gene variants that result in increased circulating levels of fibroblast growth factor 23 (FGF23). FGF23 in turn decreases renal reabsorption of phosphate and suppresses renal production of 1,25(OH)2D, leading to rickets and growth impairment in children and osteomalacia in children and adults. Burosumab is a fully human FGF23-blocking monoclonal antibody approved for treating XLH. Limited data are available on the impact of phosphorus-containing meals or supplements or diurnal variation on serum phosphorus levels, with increases observed in some, but not all studies. It is recommended that serum phosphorus be measured in the morning fasted state when monitoring treatment in patients with XLH. The present substudy of the pivotal pediatric and adult phase 3 clinical trials of burosumab examined the impact of meal consumption and timing around meals on serum phosphorus and calcium levels in children and adults with XLH during burosumab treatment. Thirty-nine participants (pediatric, n = 13; adult, n = 26) were included. The mean (SD) duration of burosumab treatment prior to the substudy was 15.4 (6.6) mo for pediatric and 24.2 (3.7) mo for adult participants. Serum phosphorus and calcium levels were measured before and after breakfast in children, and before and after both breakfast and lunch in adults. In both age groups, there was no clinically meaningful difference in mean levels of serum phosphorus measured at 1 and 2 h after meals compared to fasted levels, and serum calcium levels remained within the normal range for all pediatric participants and most adults, although interpatient variation was observed. These results suggest that, when fasting is not possible, nonfasting serum phosphorus levels may be a suitable alternative in patients with XLH receiving a stable dose of burosumab.

X-linked hypophosphatemia (XLH) is a phosphate-wasting disorder mediated by increased fibroblast growth factor 23 (FGF23) activity. Typical clinical features are skeletal deformities, muscle weakness, stiffness, and impaired physical function. Using real-world data from the XLH Disease Monitoring Program (XLH-DMP) and the International XLH Registry, this study sought to determine whether the age at which XLH is diagnosed differs between children with and without a family history of the disease. In both real-world studies, children with a family history of XLH were diagnosed at a younger age than those without a family history (XLH-DMP [n = 347]: mean age at diagnosis 1.6 [standard error (SE) 0.2] vs 2.7 [SE 0.2] years [p < .001]; International XLH Registry [n = 360]: mean age at diagnosis 1.8 [SE 0.2] vs 4.1 [SE 0.3] years [p < .001]). After controlling for sex, race, ethnicity, and country of residence (Cox proportional hazards model), children with a family history of XLH received a diagnosis of XLH at a younger age than those without a family history (XLH-DMP: hazard ratio 1.69, 95% confidence interval [CI] 1.33-2.16; International XLH Registry: hazard ratio 2.47, 95% CI 1.88-3.24). This study demonstrates that children without a family history of XLH are diagnosed at a significantly older age than those from families known to be affected, and that diagnosis may also be delayed despite a family history of XLH. A greater awareness of XLH and its early symptoms among pediatric healthcare professionals is required to avoid delays in diagnosis and treatment initiation.

BACKGROUND:There is increasing awareness of a role for muscle composition in sarcopenia and cachexia. Computed tomography (CT)-based measures of muscle density (MusD) are commonly used to indicate composition, with a decrease in MusD reflecting an increase in muscle fat infiltration. The current study explored predictors of MusD acquired using high-resolution peripheral quantitative computed tomography (HR-pQCT) and whether MusD predicted physical performance. In addition, reference data for MusD were generated and applied. METHODS:HR-pQCT scans performed in 1662 adults (aged 18-80 years) at 30% of bone length proximal from the distal end of the radius and tibia were analysed for forearm and leg MusD, respectively. Predictors of MusD were explored, and it was investigated whether MusD predicted physical performance. Centile curves were fit to the MusD data using the LMS approach to generate reference data, and a calculator was developed to enable computation of subject-specific standardised outcomes. The utility of the calculator was explored in validation cohorts of female collegiate-level athletes (n = 50) and individuals with chronic kidney disease (CKD) (n = 50). RESULTS:Forearm and leg MusD were predicted by whole-body percent fat, sex and age. Forearm and leg MusD were 0.46 (~1.9%) and 0.60 mgHA/cm3 (~2.6%) lower in females than in males, respectively (all p ≤ 0.002). For every decade of greater age, forearm and leg MusD were 0.28 (~1.2%) and 0.75 mgHA/cm3 (~3.3%) lower, respectively (all p < 0.001). These observations were independent of whole-body percent fat and appendicular lean mass (ALM)/height2. MusD predicted grip strength, fast gait speed and self-reported physical function independent of ALM/height2, body mass index and whole-body percent fat. Grip strength was 0.756 kg (~2.4%) greater for every 1 mgHA/cm3 (~4.2%) greater forearm MusD (p < 0.001). Reference data were generated. Compared to the reference data, female athletes had above-average leg MusD (z-score = 0.20; 95% CI, 0.01-0.39), whereas those with CKD had z-scores for forearm and leg MusD of -1.51 (95% CI, -1.95 to -1.08) and -1.70 (95% CI, -2.04 to -1.36), respectively. CONCLUSIONS:HR-pQCT acquired MusD provides a novel indicator of muscle composition which predicts physical function independent of muscle quantity (i.e., ALM/height2). Whether the unique information provided by MusD has a role in quantifying health and the consequences of disease and illness (including sarcopenia and cachexia) requires further exploration. Studies in this area may be facilitated by the reference data generated which enable MusD in an individual or population of interest to be expressed relative to sex- and age-matched norms.

Context: Autosomal dominant osteopetrosis (ADO) is a rare sclerotic bone disease characterized by impaired osteoclast activity, resulting in high bone mineral density and skeletal fragility. The full phenotype and disease burden on patients' daily lives has not been systematically measured. Objective: We developed an online registry to ascertain population-based data on the spectrum and rate of progression of disease and to identify relevant patient-centered outcomes that could be used to measure treatment effects and guide the design of future clinical trials. Methods: Cross-sectional data from participants with osteopetrosis were collected using an online REDCap-based database. Thirty-four participants with a confirmed diagnosis of ADO, aged 4-84 years were included. Participants aged 18 years and older completed the PROMIS 57, participants aged 8-17 years completed the PROMIS Pediatric 49, and parents of participants aged <18 years completed the PROMIS Parent Proxy 49. Results: Based on the PROMIS 57, relative to the general population, adults with ADO reported low physical function and low ability to participate in social roles and activities, and high levels of anxiety, fatigue, sleep problems, and pain interference. Daily pain medications were reported by 24% of the adult population. In contrast, neither pediatric participants nor their parent proxy reported a negative impact on health-related quality of life. Conclusion: Data from this registry demonstrate the broad spectrum of ADO disease severity and high impact on health-related quality of life in adults with ADO.

X-linked hypophosphatemia (XLH) is a rare disorder of renal phosphate wasting and dysregulated active vitamin D metabolism, ultimately presenting as rickets and osteomalacia, among other manifestations. Lower extremity deformity (genu valgum and/or varum) is frequent in this pediatric population. Despite prompt active vitamin D and phosphate supplementation (active D/Pi), many patients require corrective surgery for lower limb malformation. Burosumab has demonstrated improvements in lower limb malalignment in children with XLH in several studies. We expand on those reports by assessing mechanical femoral tibial angle (mFTA) change in patients enrolled in the XLH Disease Monitoring Program (DMP), (NCT03651505) to determine the impact of initiating burosumab treatment after a history of active D/Pi. Included patients had either switched from active D/Pi to burosumab treatment at the discretion of their treating physician or as part of a burosumab clinical trial, or remained on active D/Pi through Year 3 of the DMP. Year 3 radiographs were compared with baseline to assess mFTA change and gauge improvement. Additional multivariate factor analysis examined 24 attributes to determine which had the greatest association with mFTA change. Change in mFTA was assessed for each limb independently. A greater proportion of limbs of patients switching from active D/Pi to burosumab had improved mFTA compared with those remaining on active D/Pi (p < .023). Odds ratios comparing limbs that improved to those that did not showed that switching to burosumab yields a significantly greater chance of improvement than continuing active D/Pi (OR [95% CI]: 4.38 [1.09-17.50]; p = .0469). Factor analysis identified younger age at burosumab initiation (p = .001) and lower baseline height Z-score (p = .006) as being significantly associated with greater change in mFTA Z-score. This study shows that switching to burosumab significantly improves lower limb malalignment in children with XLH over benefits conferred by active D/Pi, with early burosumab initiation providing the greatest benefit.

X-linked hypophosphatemia (XLH) is a rare, genetic, progressive, lifelong disorder caused by pathogenic variants in the phosphate-regulating endopeptidase homolog, X-linked (PHEX) gene, resulting in excess fibroblast growth factor 23 (FGF23) and consequent renal phosphate wasting. Chronic hypophosphatemia leads to deficits of the musculoskeletal system affecting bone, muscle, joint, and dental health. XLH treatments include oral phosphate and active vitamin D—which are associated with a burdensome dosing regimen, gastrointestinal disturbances, hyperparathyroidism, and nephrocalcinosis—or burosumab, a fully human anti-FGF23 antibody. Randomized clinical trials (RCTs) demonstrated burosumab to be well tolerated and efficacious in improving serum phosphate, rickets, bone turnover, and patient-reported outcomes. However, there are limited data on the natural history of XLH or real-world comparisons of the safety, effectiveness, and long-term outcomes of XLH treatments. Advancing Patient Evidence in XLH (APEX) is a global data unification project aiming to describe the burden and lifelong progression of XLH, collect real-world data on treatment effectiveness and safety, and investigate regional differences in treatment outcomes. Participants from three observational, noninterventional, retrospective and prospective, multicenter, longitudinal (10-year) studies of patients with XLH will be included: XLH Disease Monitoring Program (NCT03651505), International XLH Registry (NCT03193476), and SUNFLOWER (NCT03745521). Data collected in the Americas, Europe, Israel, Japan, and South Korea will be processed to unify identical and similar data elements. Data unification will be an iterative process with a clinical and programming review, ensuring validity and accuracy. In this observational study, unified data involving approximately 2000 pediatric and adult participants with XLH will be analyzed to address research questions in an exploratory manner. Long-term observational studies and patient registries provide opportunities to generate real-world data and address knowledge gaps in rare diseases. APEX aims to improve clinical decision-making and practice by bridging evidence gaps that cannot be addressed by RCTs or regional registries.

PURPOSE:X-linked hypophosphatemia (XLH) is a rare, genetic, progressive, lifelong disorder caused by pathogenic variants in the PHEX gene, leading to excess fibroblast growth factor 23 (FGF23) and renal phosphate wasting. Advancing Patient Evidence in XLH (APEX) is a 10-year global data unification project that combines 3 regional observational studies (XLH Disease Monitoring Program [DMP], International XLH Registry [IXLHR], and SUNFLOWER). APEX aims to describe the burden and lifelong progression of XLH, to collect real-world data on treatment effectiveness and safety, and to investigate regional differences in treatment outcomes. METHODS:This was a baseline analysis of the characteristics and disease burden of a global group of patients with XLH. RESULTS:This analysis included 1556 participants (XLH DMP n = 598; IXLHR n = 736; SUNFLOWER n = 222), with 590 participants aged 0-12 years, 193 aged 13-17 years, and 773 aged ≥18 years. Overall, 66 % of participants were female. Family history of XLH and of a PHEX variant were reported for 55 % and 47 % of participants, respectively; 71 % of participants had a confirmed PHEX variant. Participants had reduced height, normal weight, and elevated body mass index compared with a reference population. Clinical histories demonstrated increasing prevalence of dental complications, fractures, and osteoarthritis with age. Median Z-scores for phosphate, tubular maximum reabsorption of phosphate to glomerular filtration rate, and urine calcium/creatinine ratio were below the scores for the reference population. CONCLUSION:This baseline analysis provides substantial information on the global characteristics and natural history of patients with XLH in the APEX program. REGISTRATION:ClinicalTrials.govNCT03651505 (registered August 24, 2018), NCT03193476 (registered June 13, 2017), NCT03745521 (registered November 6, 2018).

The guideline panel, comprising international experts in X-linked hypophosphatemia (XLH), patient partners from the XLH patient population, and guideline methodologists, held 18 teleconferences between January 2023 and July 2024 to develop comprehensive guidelines for the diagnosis and management of XLH in children and adults. For a subset of our questions, we utilized the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology, assessed the certainty of evidence and formulated GRADEd recommendations. For these questions, the panelists and methodologists collaboratively framed PICO (Population, Intervention, Control, and Outcomes) questions and conducted four systematic reviews assessing the impact of medical therapy—using either burosumab or phosphate and active vitamin D—on patient-important outcomes in the XLH population as well as the impact of medical intervention compared to no treatment. We assessed the risk of bias and transparently generated summary of findings tables using MAGICApp. The panel developed three GRADEd treatment recommendations for adults and two for children. Each GRADEd recommendation was linked to an underlying body of evidence, reflecting judgments on the certainty of evidence, recommendation strength, values, preferences, and considerations of costs, feasibility, acceptability, and equity. Due to the paucity of evidence, the panel developed very low-quality GRADEd recommendations on monitoring patients with XLH based on an expert clinical practice survey. Using a rigorous narrative literature review, the panel developed non-GRADEd recommendations including guidance for pregnant women, patients with dental complications, and other areas where evidence is limited. This article summarizes the methodology utilized for the development of both GRADEd and non-GRADEd recommendations for patients with XLH.

This report provides recommendations for X-linked hypophosphatemia (XLH) monitoring based on current monitoring practices of experts in the management of XLH in children (<18 years) and adults. We surveyed 43 international experts in XLH to determine their monitoring practices for children and adults with XLH, including pregnant and lactating women. In the initial evaluation of children and adults with XLH, experts consistently obtain a family history of XLH or hypophosphatemia, a history of fractures and dental infections, and assess pain through age-appropriate clinical interviews or caregiver reports. They measure height, weight, and blood pressure and conduct DNA analysis of multiple genes associated with hypophosphatemia including the PHEX gene. For children follow-up, experts arrange follow-up every 3 to 6 months assessing height, weight, and blood pressure and examining for skeletal deformities. Laboratory tests in children include serum phosphorus, corrected total/ionized calcium, alkaline phosphatase, renal function, and PTH and spot morning urine for calcium, creatinine, and phosphorus. During adult follow-up, experts assess patients every 6 to 12 months, with a clinical examination focused on skeletal deformities and joint involvement. The laboratory profile is completed at least once a year. In the presence of bone pain, experts conduct X-rays both in children and adults to evaluate for fractures or joint damage. With respect to nephrocalcinosis, renal ultrasound is suggested on an annual basis or less frequently when monitoring children and adults with XLH. Experts conduct a dental assessment at baseline and then every 6 to 12 months for all patients with XLH. The findings of the survey inform practice for assessing new patients with XLH, monitoring existing patients, and identifying areas for future research. All recommendations based on these practices are weak with very low-quality evidence.

In X-linked hypophosphatemia (XLH), PHEX gene variants lead to elevated FGF23 production, resulting in hypophosphatemia, osteomalacia, osteomalacia-related fractures, osteoarthritis, enthesopathy, spinal stenosis, and symptoms of pain, stiffness, and decreased physical function. Burosumab is an anti-FGF23 monoclonal Ab approved for XLH treatment. Randomized studies comparing oral phosphate/active vitamin D (Pi/D) to burosumab in adults are lacking. This analysis, which utilized real-world data from the prospective, Americas-based XLH Disease Monitoring Program (NCT03651505), evaluated the effectiveness of burosumab vs Pi/D, based on changes from baseline to the year 1 visit in serum phosphate, 1,25(OH)2D, PTH, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores, Patient-Reported Outcomes Measurement Information System Physical Function (PROMIS PF), and Timed Up and Go performance outcome. Two cohorts of adults with XLH who either began burosumab between baseline and the year 1 visit (n = 65) or were on Pi/D (n = 74) at study entry and did not receive burosumab were included. Inverse probability of treatment weighting was employed to adjust for potential confounding due to baseline cohort differences. At the year 1 visit, mean (SE) change from baseline was significant for burosumab vs Pi/D in serum phosphate (0.78 [0.08] vs 0.15 [0.14] mg/dL; p < .001), 1,25(OH)2D (19.41 [3.39] vs 5.49 [3.43] pg/mL; p = .011), PTH (−13.82 [5.00] vs 11.79 [8.10] pg/mL; p = .006), WOMAC pain (−7.50 [2.34] vs 4.47 [3.23]; p = .004), WOMAC physical function (−5.68 [1.96] vs 6.77 [4.85]; p = .006), and WOMAC total (−7.78 [2.06] vs 3.15 [3.37]; p = .005) scores, PROMIS PF (1.51 [0.73] vs −1.64 [1.11], p = .018), and TUG (−1.19 [0.42] vs 0.55 [0.43] s, p = .011). A trend towards improved WOMAC stiffness was observed for burosumab (−10.16 [2.85] vs −1.79 [3.68]; p = .086). In this real-world analysis of adults with XLH, burosumab treatment was associated with improved biochemical parameters, pain, physical function, and mobility compared with Pi/D.