Background: Understanding X-linked Hypophosphatemia
X-linked hypophosphatemia (XLH) represents the most prevalent form of inherited rickets, affecting approximately 1 in 20,000 to 1 in 60,000 individuals worldwide. This rare genetic disorder stems from loss-of-function mutations in the PHEX gene, resulting in dysregulated phosphate homeostasis and impaired bone mineralization.
The pathophysiology of XLH centers on elevated fibroblast growth factor 23 (FGF23), a hormone produced by osteocytes and osteoblasts. Excess FGF23 suppresses renal phosphate reabsorption by downregulating sodium-phosphate cotransporters (NaPi-2a and NaPi-2c) in the proximal tubule. Additionally, FGF23 inhibits 1α-hydroxylase activity, reducing active vitamin D (1,25-dihydroxyvitamin D) synthesis. The resulting chronic hypophosphatemia leads to defective mineralization of the growth plate and bone matrix, manifesting as rickets in children and osteomalacia in adults.
Patients with XLH present with a constellation of symptoms including skeletal deformities (leg bowing, wrist widening), growth impairment, dental abnormalities (dental abscesses, enamel hypoplasia), hearing difficulties, and chronic bone pain. The disease burden extends beyond physical manifestations, significantly impacting quality of life, functional capacity, and psychosocial well-being.
Prior to the advent of burosumab, conventional therapy comprised oral phosphate supplementation combined with active vitamin D analogs. While this approach provided partial benefit, it required frequent dosing, carried risks of hypercalciuria and nephrocalcinosis, and often proved insufficient to normalize phosphate levels or fully correct skeletal abnormalities.
Study Design and Population
The XLH Disease Monitoring Program represents a prospective, longitudinal, real-world outcomes initiative designed to capture comprehensive data on individuals living with XLH. Unlike the controlled environment of randomized clinical trials, this program reflects everyday clinical practice, incorporating patients who may have been excluded from pivotal studies.
This analysis specifically evaluated participants who were burosumab-naive at baseline and initiated burosumab between baseline and their Year 1 visit. The study population included 139 participants across multiple age strata, notably encompassing groups traditionally excluded from clinical trials: infants under 1 year of age, adolescents aged 13-17 years, and elderly patients aged 65 years or older.
The primary objectives assessed changes from baseline in three domains: (1) biochemical parameters including serum phosphate and alkaline phosphatase, (2) clinical outcomes such as Rickets Severity Scores in pediatric participants, and (3) patient-reported outcomes (PROs) capturing pain, fatigue, physical function, and disease-specific quality of life. Assessments were performed at Year 1 (Y1) and Year 3 (Y3) visits, enabling evaluation of both short-term response and durability of treatment effects.
Key Findings: Biochemical Improvements
The cornerstone biochemical finding demonstrated that burosumab therapy produced significant and sustained improvements in serum phosphate homeostasis. Mean serum phosphate z-scores increased substantially from baseline, with a change of 1.4 (standard deviation 1.1) observed at both Y1 and Y3 timepoints (P < .0001 for each comparison). The consistency of this improvement across both evaluation intervals is particularly noteworthy, as it indicates no evidence of tachyphylaxis or diminishing returns with prolonged treatment.
The statistical significance reached at both timepoints (P < .0001) underscores the robust nature of this biochemical response. Importantly, these improvements occurred in a real-world setting where patient adherence, dosing regimens, and monitoring frequencies may vary from protocol-driven clinical trials.
Pediatric Subgroup Results
Among pediatric participants, treatment with burosumab yielded improvements across multiple clinically relevant endpoints. Serum alkaline phosphatase z-scores, a marker of bone turnover and disease activity in growing children, showed significant declines at both Y1 and Y3 assessments, reflecting reduced disease activity and improved bone mineralization.
The Rickets Severity Score (RSS), a validated radiographic measure of rickets severity, demonstrated significant improvement at both timepoints. This finding carries particular clinical significance, as radiographic evidence of rickets healing directly correlates with functional and cosmetic outcomes for affected children.
Patient-reported pain interference scores improved significantly in pediatric participants at Y1 and Y3, indicating meaningful reduction in the burden of chronic bone pain that profoundly affects these children’s daily activities, school attendance, and psychosocial development.
Notably, non-significant changes were observed in fatigue and physical function mobility domains among pediatric participants. This apparent discrepancy may reflect several factors: the complex multidimensional nature of these outcomes, potential ceiling effects in milder cases, or the influence of developmental and contextual factors on symptom reporting in children.
Adult Subgroup Results
Adult participants with XLH experienced significant improvements across several patient-reported outcome measures. Pain, stiffness, and physical function domains all demonstrated meaningful gains following burosumab initiation. These findings address a significant unmet need, as adults with XLH have historically had limited therapeutic options beyond conventional phosphate and vitamin D supplementation.
Perhaps most compelling was the observation that a higher proportion of participants achieved minimal clinically important differences (MCIDs) at Y3 compared to Y1. This temporal trend suggests that continued treatment yields accumulating benefits, with more patients crossing clinically meaningful thresholds as therapy progresses.
The adult data are particularly valuable given that osteomalacia and its sequelae—including bone pain, fractures, and functional impairment—represent lifelong complications for XLH survivors of childhood-onset disease.
Consistency Across Age Subgroups
A particularly encouraging finding was the consistency of observed trends across all age subgroups. While statistical significance was not uniformly achieved for every endpoint in every subgroup (reflecting both the inherent heterogeneity of XLH and sample size considerations in a rare disease), the overall direction of effect remained positive across age strata.
This consistency extends the generalizability of clinical trial findings to populations previously underrepresented in research. Infants, adolescents, and elderly patients demonstrated biochemical and clinical responses comparable to the broader cohort, supporting the rationale for burosumab use across the lifespan in appropriately selected patients.
Expert Commentary and Clinical Implications
The publication of real-world evidence confirming burosumab’s effectiveness across diverse age groups represents an important milestone in XLH management. Traditional clinical trial populations often exclude the very young, very old, and those with significant comorbidities, creating evidence gaps that complicate clinical decision-making for these patients.
This analysis addresses a critical gap by demonstrating that benefits observed in pivotal trials translate meaningfully to routine clinical practice and to patient populations who would not have qualified for those studies. The durability of response at 3 years provides reassurance regarding long-term efficacy, though continued monitoring for very long-term outcomes remains warranted.
Several limitations merit consideration when interpreting these findings. As an observational study without a control arm, attribution of observed improvements solely to burosumab must be made cautiously. Concurrent supportive care, regression to the mean, and secular trends may contribute to apparent treatment effects. Additionally, the heterogeneous nature of real-world data collection may introduce variability in outcome assessment.
Nevertheless, the consistency of findings across multiple domains—biochemical, radiographic, and patient-reported—provides convergent evidence supporting the effectiveness of burosumab in clinical practice.
Conclusion
The XLH Disease Monitoring Program provides valuable real-world evidence demonstrating that burosumab therapy leads to significant and sustained improvements in phosphate homeostasis, skeletal outcomes, and patient-reported symptoms across diverse age groups. These findings support the integration of burosumab into comprehensive XLH management strategies spanning from infancy through older adulthood.
The achievement of minimal clinically important differences in increasing proportions of adult participants at 3 years suggests that earlier initiation and prolonged treatment may optimize outcomes. For pediatric patients, the improvements in rickets severity and pain interference translate to meaningful benefits in growth, function, and quality of life during critical developmental periods.
Future directions should include longer-term follow-up to assess effects on final adult height, fracture incidence, and hearing outcomes, as well as comparative effectiveness studies versus conventional therapy. The continued accumulation of real-world evidence will further refine our understanding of optimal burosumab use across the heterogeneous spectrum of XLH.
Funding and Disclosures
The XLH Disease Monitoring Program was supported by Kyowa Kirin, Inc. Medical writing assistance was provided by BioScience Communications, Inc.
References
Ward LM, Carpenter TO, Cassinelli H, et al. Real-world Effectiveness of Burosumab Across Age Groups: X-linked Hypophosphatemia (XLH) Disease Monitoring Program. J Clin Endocrinol Metab. 2026. PMID: 41934635.
Haffner D, Emma F, Eastwood DM, et al. Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia. Nat Rev Nephrol. 2019;15(7):435-455.
Rathbun JC, Love J, Bhaumik S, et al. Serum fibroblast growth factor 23 in healthy children and in hypophosphatemic rickets. J Bone Miner Res. 2022;37(11):2190-2200.
Imel EA, Glorieux FH, Whyte MP, et al. Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial. Lancet. 2019;393(10189):2416-2427.
