X-Linked Hypophosphatemia: A Review of Pathophysiology, Clinical Manifestations, Current Management, and Emerging Therapeutic Strategies

Kevin Tay; Sobrina Mohammed

doi:10.20944/preprints202607.0233.v1

Submitted:

03 July 2026

Posted:

03 July 2026

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Abstract

X-linked hypophosphatemia (XLH) is one of the most common inherited phosphate-wasting disorders, caused by pathogenic variants in the PHEX gene that result in excess fibroblast growth factor 23 (FGF23) and chronic hypophosphatemia. Historically considered a pediatric disease characterized by rickets and growth impairment, XLH is now recognized as a lifelong condition with substantial adult morbidity including osteomalacia, fractures, enthesopathy, osteoarthritis, and reduced quality of life. The discovery of FGF23 as the central mediator of phosphate wasting transformed understanding of disease pathophysiology and enabled development of burosumab, a monoclonal antibody that neutralizes FGF23 and restores phosphate homeostasis. While burosumab represents a paradigm shift in therapy, accumulating evidence indicates that XLH involves FGF23-independent mechanisms, including osteopontin accumulation, ASARM peptide generation, and pyrophosphate dysregulation, which contribute to persistent skeletal abnormalities despite biochemical correction. This review integrates current insights into the molecular genetics, pathophysiology, and lifelong clinical features of XLH, with particular attention to emerging concepts involving local bone matrix abnormalities and their impact on therapeutic innovation. We trace the transition from conventional phosphate and active vitamin D supplementation to targeted FGF23 inhibition, highlight the limitations of existing treatment strategies, and explore future directions such as small‑molecule inhibitors, anti‑sclerostin therapy, gene-based approaches, and ultimately PHEX‑focused repair. A comprehensive understanding of XLH as both a systemic endocrine disorder and an intrinsic defect of osteocyte biology is critical for optimizing patient care and steering the development of curative therapies.

Keywords:

X-linked hypophosphatemia (XLH)

;

PHEX gene

;

fibroblast growth factor 23 (FGF23)

;

osteomalacia

;

burosumab

Subject:

Medicine and Pharmacology - Endocrinology and Metabolism

Introduction

X-linked hypophosphatemia (XLH) is one of the most common inherited phosphate-wasting disorder and the most prevalent genetic form of hypophosphatemic rickets(1). The disease arises from pathogenic variants in the phosphate-regulating endopeptidase homolog X-linked (PHEX) gene and is characterized by chronic renal phosphate wasting, impaired skeletal mineralization, and abnormalities in growth and musculoskeletal development (1). While classically identified in childhood due to rickets and lower extremity deformities, the clinical burden of XLH extends well beyond the pediatric period. Increasing recognition of adult disease has highlighted a spectrum of complications including osteomalacia, fractures, pseudo fractures, enthesopathy, osteoarthritis, chronic pain, and functional impairment that significantly impact quality of life.

The prevalence of XLH has been estimated at approximately 1 in 20,000 to 1 in 60,000 individuals, although increased awareness and broader use of genetic testing suggest that the disease remains underdiagnosed (1). The disorder follows an X-linked dominant inheritance pattern with high penetrance, affecting both males and females, although disease severity varies considerably even within affected families (2). These features contribute to diagnostic delays and clinical heterogeneity that complicate management.

The discovery of fibroblast growth factor 23 (FGF23) as key regulator of phosphate homeostasis represented a major advance in understanding XLH pathophysiology (3,4). In XLH, excess FGF23 activity decreases renal phosphate reabsorption and suppresses 1,25-dihydroxyvitamin D production, resulting in persistent hypophosphatemia and impaired mineralization, Figure 1 (1). This mechanistic framework directly informed the development of targeted therapies such as burosumab, which have transformed contemporary management (5–7).

Reproduced from Dahir et al. (1) under the Creative Commons Attribution 4.0 International License.

While XLH has historically been conceptualized as a disorder of phosphate wasting driven by excess FGF23, emerging evidence supports a more complex model in which XLH represents both a systemic endocrine disorder and an intrinsic disease of osteocyte biology. Clinical observations and experimental data increasingly suggest that correction of phosphate metabolism alone does not fully resolve skeletal abnormalities. Local factors within bone, including osteopontin accumulation, ASARM peptide activity, and altered osteocyte function, appear to contribute independently to impaired mineralization (8). This distinction is clinically important, as it provides a mechanistic explanation for persistent skeletal pathology despite correction of phosphate homeostasis and highlights limitations of current therapies. And so, in this review, we synthesize evidence supporting this dual-pathway model and examine its implications for treatment strategies and future therapeutic development.

Molecular Genetics and Pathophysiology

The PHEX Gene

Registry data from the International XLH Registry demonstrated that approximately 89% of genetically tested individuals harbor a confirmed pathogenic PHEX variant (9). More than 900 pathogenic variants have been identified, including missense, nonsense, splice-site, insertion, deletion, and duplication variants (10). Although disease severity varies considerably, penetrance approaches 100%, and both sexes are affected. Several studies have attempted to establish genotype–phenotype correlations. Early reports suggested that truncating mutations may be associated with more severe skeletal disease and a greater need for orthopedic intervention (11). However, larger contemporary studies have produced inconsistent findings (12), suggesting that modifier genes, environmental factors, and downstream signaling pathways contribute substantially to phenotypic variability. A notable exception is the North American founder variant involving c.*231A>G with duplication of exons 13–15, which may present with relatively mild hypophosphatemia and be misdiagnosed as ankylosing spondylitis because of prominent enthesopathy (13).

The PHEX gene is located on chromosome Xp22.1 and encodes a membrane-bound zinc-dependent endopeptidase that participates in regulation of extracellular matrix proteins involved in skeletal mineralization(14). Among its known substrates are members of the Small Integrin-Binding Ligand N-linked Glycoprotein (SIBLING) family, a group of five non-collagenous bone matrix proteins that includes matrix extracellular phosphoglycoprotein (MEPE), osteopontin (OPN), dentin matrix protein 1 (DMP1), bone sialoprotein (BSP), and dentin sialophosphoprotein (DSPP). These proteins share a conserved acidic serine- and aspartate-rich motif known as the ASARM motif, which plays an important role in regulating mineralization (8,9,15). Among the SIBLING proteins, osteopontin appears particularly relevant to XLH pathogenesis.

Physiologic Role of FGF23

FGF23 is a 251-amino acid phosphaturic hormone produced primarily by osteocytes and osteoblasts. Under normal physiologic conditions, secretion of FGF23 increases in response to elevations in serum phosphate, 1,25-dihydroxyvitamin D, and other mineral regulatory signals (3,4).

FGF23 exerts its biologic effects through binding to the FGFR1–α-Klotho receptor complex located predominantly within the kidney. Activation of this receptor suppresses expression of sodium-phosphate cotransporters NaPi-IIa and NaPi-IIc in the proximal tubule, thereby reducing phosphate reabsorption. Simultaneously, FGF23 suppresses CYP27B1 expression and increases CYP24A1 activity, resulting in lower concentrations of active vitamin D and reduced intestinal phosphate absorption, Figure 2.

Post-Translational Regulation of FGF23

FGF23 activity is regulated not only through transcription but also through post-translational modification. Intact biologically active FGF23 undergoes proteolytic cleavage between Arg179 and Ser180, producing inactive N-terminal and C-terminal fragments (16).

O-glycosylation by GALNT3 protects FGF23 from cleavage and increases concentrations of biologically active hormone (17). Conversely, phosphorylation by FAM20C promotes degradation of intact FGF23 and limits hormone activity (16). These regulatory mechanisms play an important role in several inherited phosphate disorders and provide additional control over phosphate homeostasis, Figure 3.

The PHEX–FGF23 Axis

Although XLH is characterized by elevated circulating FGF23 concentrations, accumulating evidence indicates that FGF23 is not directly degraded by PHEX. Rather, PHEX appears to regulate FGF23 expression through complex interactions within the osteocyte extracellular matrix and local mineralization pathways, Figure 4 (9). Understanding this relationship has been central to unraveling the pathophysiology of XLH and remains an active area of investigation.

Reproduced from Ariceta et al (9) under the Creative Commons Attribution 4.0 International License.

Loss of PHEX activity in Hyp mice results in accumulation of osteopontin fragments within the bone matrix (8). This accumulation contributes directly to impaired mineralization and osteomalacia independent of systemic phosphate concentrations, supporting an important local skeletal role for PHEX beyond regulation of phosphate homeostasis. The persistence of osteomalacia despite correction of serum phosphate further suggests that abnormalities in extracellular matrix composition are central to disease pathogenesis.

Although PHEX is an endopeptidase, it does not directly cleave FGF23. Experimental studies demonstrated that PHEX regulates FGF23 expression rather than its degradation, indicating that the relationship between PHEX deficiency and elevated FGF23 concentrations is indirect (18). Restoration of PHEX expression alters FGF23 production without affecting degradation of existing hormone, implicating upstream regulatory pathways controlling FGF23 transcription and secretion. This concept is reinforced by evidence that FGF23 is processed by subtilisin-like proprotein convertases rather than PHEX (19). In vitro studies using, Human Embryonic Kidney 293 (HEK293) cells, showed that inhibition of proprotein convertases prevents FGF23 cleavage, whereas co-incubation experiments using a secreted form of PHEX failed to demonstrate any direct enzyme–substrate interaction between PHEX and intact FGF23. Together, these findings establish that elevated circulating FGF23 concentrations in XLH arises through increased production rather than impaired proteolytic degradation (19).

Current models propose that loss of PHEX activity alters osteocyte signaling and extracellular matrix biology, ultimately promoting excess FGF23 production. One proposed mechanism involves accumulation of ASARM-containing peptides and osteopontin fragments within the bone microenvironment, which are thought to disrupt normal osteocyte maturation and phosphate sensing, thereby stimulating FGF23 expression. Although the precise molecular pathway remains incompletely defined, the cumulative evidence supports a regulatory role for PHEX in controlling FGF23 production rather than hormone degradation (8,14).

Beyond its systemic endocrine effects on renal phosphate handling, emerging evidence indicates that FGF23 also exerts direct local actions within bone. Studies in Hyp mice have identified previously unrecognized autocrine/paracrine mechanism by which osteocyte-derived FGF23 contributes directly to defective mineralization (8). Hyp mice osteocytes were found to express approximately 70-fold higher levels of fibroblast growth factor receptor 3 (FGFR3) compared with osteoblasts, rendering them highly responsive to locally produced FGF23 (8). Activation of FGFR3 signaling suppresses transcription of tissue nonspecific alkaline phosphatase (TNAP), a key enzyme required for degradation of pyrophosphate, leading to accumulation of pyrophosphate within the bone microenvironment (8). Because pyrophosphate is a potent inhibitor of hydroxyapatite crystal formation, this pathway directly impairs mineralization independent of systemic phosphate concentrations (8).

The significance of this pathway was confirmed through multiple complementary experiments. Pharmacologic blockade of FGF23 or FGFR3 restored TNAP expression, phosphate production, reduced pyrophosphate accumulation, and improves mineralization in cultured osteocyte-like cells derived from Hyp mice (8). Similarly, bone-specific deletion of FGF23 rescues TNAP activity in vivo, whereas administration of recombinant FGF23 reproduces the mineralization defect in wild-type models (8). These findings demonstrate that FGF23 contributes to osteomalacia not only through systemic phosphate wasting but also via direct local effects within bone. Targeting downstream pathways such as FGFR3 signaling or pyrophosphate metabolism may therefore represent therapeutic strategies independent of phosphate correction.

These insights have important implications for understanding disease persistence despite treatment. While therapies such as burosumab effectively correct phosphate wasting and improve serum phosphate concentrations, local abnormalities in extracellular matrix composition, osteocyte signaling, and mineralization pathways may continue to drive skeletal pathology. XLH is therefore best understood as both an endocrine disorder of phosphate homeostasis and an intrinsic osteocyte disease characterized by dysregulated matrix biology and impaired mineralization.

FGF23-Independent Mechanisms of Disease

While FGF23 excess governs systemic phosphate regulation, complementary mechanisms within bone contribute to the mineralization defect in XLH. These processes reflect intrinsic alterations in extracellular matrix composition and osteocyte function arising from loss of PHEX activity, and act in parallel with endocrine disturbances to shape the skeletal phenotype (8,15).

A central feature of this local pathology is the accumulation of mineralization inhibitors within the bone matrix. Osteopontin is among the best-characterized contributors. In Hyp mice, impaired PHEX activity leads to increased osteopontin fragments within bone tissue, where they interfere with hydroxyapatite deposition and compromise mineralization (8). This mechanism highlights the direct impact of altered matrix composition on skeletal integrity.

Another important mechanism involves acidic serine-aspartate-rich MEPE-associated (ASARM) peptides. In the absence of functional PHEX, excessive ASARM peptides accumulate within the extracellular matrix and bind directly to hydroxyapatite crystals, inhibiting crystal growth and mineralization (20). This effect reflects disruption of matrix–mineral interactions at the tissue level rather than a consequence of systemic phosphate handling.

Additional evidence implicates abnormalities in pyrophosphate metabolism. Studies by Murali and colleagues demonstrated that Hyp mice exhibit increased pyrophosphate accumulation as a consequence of excessive osteocytic FGF23 signaling and suppression of tissue nonspecific alkaline phosphatase activity (8). In this setting, pyrophosphate acts alongside osteopontin and ASARM peptides to constrain hydroxyapatite formation through distinct but convergent mechanisms.

Collectively, these findings challenge the traditional FGF23-centric paradigm and support a model in which local matrix abnormalities and osteocyte dysfunction contribute independently to disease progression. While elevated FGF23 remains the principal mediator of renal phosphate wasting, these processes operate at the tissue level to shape disease expression. Recognition of these pathways has important therapeutic implications, as they provide a mechanistic explanation for persistent skeletal disease despite normalization of phosphate homeostasis and highlight the limitations of therapies that target FGF23 alone.

Clinical Manifestations Across the Lifespan

The clinical manifestations of XLH evolve throughout life and reflect the cumulative consequences of chronic hypophosphatemia, impaired mineralization, skeletal deformity, and degenerative joint disease. Registry studies demonstrate that disease burden remains substantial despite treatment and includes orthopedic, dental, neurologic, renal, and quality-of-life complications (11).

In childhood, manifestations typically become apparent after the onset of weight-bearing. Progressive bowing of the lower extremities, particularly genu varum and genu valgum, represents the most common presenting feature. Skeletal abnormalities affect more than 90% of pediatric patients and are frequently accompanied by delayed walking, waddling gait, rachitic rosary formation, and growth impairment (9). Height trajectories remain consistently below population norms, and short stature persists into adulthood in many patients.

Dental disease is another hallmark manifestation of XLH. Spontaneous dental abscesses are particularly characteristic and result from defective dentin mineralization. Registry analyses have demonstrated dental disease in approximately 40% of pediatric patients, with abscesses representing the most common complication (9).

Neurologic complications are increasingly recognized. Craniosynostosis affects approximately 20% of affected children and may be associated with elevated intracranial pressure, headaches, visual symptoms, developmental concerns, or Chiari malformation (9).

The clinical picture changes substantially during adulthood. Persistent osteomalacia contributes to diffuse bone pain, muscle weakness, fatigue, and impaired physical function. Fractures and pseudofractures become increasingly common and may occur despite treatment. Registry data have demonstrated fractures in more than one-third of adults with available data (9).

Enthesopathy represents one of the most disabling adult manifestations and is characterized by calcification and ossification at tendon and ligament insertion sites. Radiographic studies first demonstrated the high prevalence of enthesopathy in adults with XLH and established it as a hallmark of long-term disease burden (21). Osteoarthritis similarly develops at younger ages than expected and frequently affects the knees, hips, and shoulders. Registry data confirm that degenerative joint disease becomes increasingly prevalent with advancing age and contributes substantially to impaired mobility and quality of life (9).

The cumulative burden of skeletal disease frequently necessitates orthopedic intervention. Guided growth procedures, osteotomies, fracture fixation, and joint replacement surgeries are common throughout life, and nearly half of adult registry participants have undergone at least one orthopedic procedure (9).

Diagnostic Evaluation

Diagnosis of XLH requires integration of clinical findings, biochemical abnormalities, radiographic features, and molecular confirmation. Clinical suspicion should arise in children presenting with lower extremity deformities, growth impairment, dental abscesses, or a family history of hypophosphatemia. In adults, diagnosis may be delayed because manifestations are often attributed to more common orthopedic disorders.

Biochemically, patients typically exhibit hypophosphatemia resulting from renal phosphate wasting. Characteristic findings include reduced tubular maximum phosphate reabsorption per glomerular filtration rate (TmP/GFR), elevated alkaline phosphatase concentrations, normal serum calcium levels, and inappropriately low-normal concentrations of 1,25-dihydroxyvitamin D (2).

Radiographic findings differ according to age. In children, radiographs typically demonstrate metaphyseal widening, fraying, cupping, and bowing deformities consistent with rickets. Adults more commonly exhibit osteomalacia, pseudofractures, enthesopathy, and degenerative joint disease (2,21).

Current consensus recommendations support molecular confirmation whenever possible. Diagnostic approaches include targeted PHEX sequencing, deletion/duplication analysis, multigene panels, exome sequencing, and genome sequencing (2). Genetic confirmation facilitates diagnosis, family screening, genetic counseling, and therapeutic decision-making.

As awareness of XLH continues to increase, earlier diagnosis and intervention may help reduce long-term skeletal complications and improve quality of life. Nevertheless, diagnostic delays remain common, particularly among adults presenting with nonspecific musculoskeletal symptoms or atypical phenotypes.

Current Management of XLH: Conventional Therapy and Burosumab

The goals of treatment in XLH are to improve skeletal mineralization, promote normal growth and development in children, reduce symptoms, prevent complications, and optimize quality of life across the lifespan. Historically, management focused on correction of the biochemical consequences of phosphate wasting through administration of oral phosphate and active vitamin D analogues. Although this approach improved rickets and osteomalacia, treatment remained burdensome and failed to fully address many long-term complications of the disease. The development of burosumab, a monoclonal antibody directed against FGF23, represented a paradigm shift in treatment by targeting the underlying hormonal abnormality responsible for phosphate wasting (1).

Conventional Therapy

Before the availability of burosumab, treatment of XLH relied on frequent oral phosphate supplementation combined with active vitamin D analogues such as calcitriol or alfacalcidol. This approach was developed based on the understanding that hypophosphatemia and relative deficiency of 1,25-dihydroxyvitamin D contribute to defective mineralization. Administration of phosphate increases phosphate availability for skeletal mineralization, while active vitamin D enhances intestinal absorption of calcium and phosphate and helps suppress secondary hyperparathyroidism (1,2).

Clinical studies demonstrated that conventional therapy improves radiographic evidence of rickets, reduces bone pain, and promotes healing of osteomalacia. However, outcomes remain incomplete. Growth impairment often persists despite treatment, and many patients continue to develop skeletal deformities requiring orthopedic intervention. Furthermore, the need for phosphate administration several times daily creates a substantial treatment burden and contributes to poor adherence, particularly during adolescence and adulthood (1).

Long-term conventional therapy is also associated with significant adverse effects. Oral phosphate stimulates parathyroid hormone secretion, increasing the risk of secondary and tertiary hyperparathyroidism. Hypercalciuria, nephrocalcinosis, and nephrolithiasis may occur as a consequence of treatment, particularly when high doses of phosphate and active vitamin D are required(1). Gastrointestinal side effects including abdominal pain and diarrhea further complicate therapy. These limitations highlighted the need for more targeted approaches capable of correcting the underlying pathophysiology of XLH rather than simply replacing phosphate losses (1).

Consensus recommendations published before the introduction of burosumab emphasized careful monitoring of serum phosphate, calcium, parathyroid hormone, alkaline phosphatase, urinary calcium excretion, and renal ultrasonography in patients receiving conventional therapy (2). Such monitoring remains important for patients who continue to receive phosphate and active vitamin D because of limited access to burosumab, contraindications, or individual treatment considerations.

Burosumab: A New Era in XLH Management

The identification of excess FGF23 as the central mediator of phosphate wasting in XLH provided the rationale for development of targeted therapies. Burosumab is a fully human monoclonal antibody that binds circulating FGF23 and prevents interaction with the FGFR1–α-Klotho receptor complex. By inhibiting FGF23 signaling, burosumab restores renal phosphate reabsorption, increases circulating concentrations of 1,25-dihydroxyvitamin D, and improves phosphate availability for skeletal mineralization (1).

The mechanism of burosumab differs fundamentally from conventional therapy because it addresses the primary endocrine abnormality rather than compensating for downstream consequences. This distinction has important implications because it allows restoration of physiologic phosphate homeostasis without exposing patients to many of the adverse effects associated with conventional therapy.

The approval of burosumab represented the first disease-specific treatment for XLH and fundamentally altered the therapeutic landscape.

Burosumab in Children

The pivotal phase 2 and phase 3 pediatric trials established the efficacy of burosumab in children with XLH (5). Treatment significantly increased serum phosphate concentrations, improved radiographic evidence of rickets, reduced alkaline phosphatase levels, and enhanced growth parameters compared with conventional therapy (5).

Subsequent longer-term follow-up studies confirmed sustained efficacy and safety. Improvements in serum phosphate concentrations, rickets severity scores, and biochemical markers of mineral metabolism have been maintained through more than three years of treatment (6). These findings provide important reassurance regarding durability of response and support long-term use in pediatric populations.

Growth outcomes have been particularly encouraging. Although complete normalization of adult height has not yet been established, burosumab consistently improves growth velocity and height Z-scores compared with conventional treatment. Enhanced lower-extremity alignment has also been reported, suggesting that earlier correction of phosphate metabolism may reduce the severity of skeletal deformities (6).

More recently, children transitioning from conventional therapy to burosumab experienced significant correction of lower-limb malalignment, further supporting the superiority of targeted FGF23 inhibition in managing skeletal manifestations (5).

Burosumab in Adults

Adult XLH presents unique challenges because many complications reflect decades of cumulative skeletal damage. Osteomalacia, fractures, pseudofractures, enthesopathy, and osteoarthritis may persist despite treatment. Nevertheless, clinical trials have demonstrated meaningful benefits of burosumab in adult populations.

Long-term administration of burosumab safely maintains serum phosphate concentrations within the normal range while improving biochemical markers of mineral metabolism (7). These benefits have been sustained through extended follow-up periods and are accompanied by improvements in patient-reported outcomes.

Similarly, significant improvements in pain, stiffness, physical function, fatigue, and ambulatory performance have been demonstrated in adults receiving burosumab (22). Fracture and pseudofracture healing are also enhanced, supporting the role of FGF23 inhibition in improving skeletal health beyond simple biochemical correction.

Longer-term follow-up studies have further demonstrated that the benefits of burosumab are maintained during ongoing treatment. Importantly, treatment interruption is associated with deterioration in serum phosphate concentrations and clinical outcomes, suggesting that continued therapy is necessary to preserve therapeutic benefits (23).

Although established osteoarthritis and enthesopathy often persist, improvements in pain, mobility, and quality of life remain clinically meaningful. These findings emphasize that treatment initiation earlier in the disease course may ultimately provide greater long-term benefits by preventing irreversible structural complications.

Despite these advances, several limitations warrant consideration. Much of the adult evidence base relies on relatively small randomized trials and open-label extension studies, with limited long-term data on hard clinical outcomes such as fracture reduction, prevention of enthesopathy, or progression of osteoarthritis. In addition, improvements are often assessed using surrogate biochemical or patient-reported outcomes, and direct comparisons with optimized conventional therapy remain limited. These gaps highlight the need for longer-term, real-world, and comparative effectiveness data.

Real-World Effectiveness

Data from the XLH Disease Monitoring Program demonstrated sustained improvements in phosphate homeostasis and patient-reported outcomes across age groups (24). These findings are particularly important because XLH is considered a rare disease and long-term randomized controlled trials are inherently difficult to conduct.

Real-world studies also provide insight into treatment patterns, adherence, and outcomes outside of highly controlled clinical trial settings. Collectively, available evidence supports burosumab as the most effective currently available therapy for most patients with XLH.

Safety of Burosumab

Long-term safety data have remained favorable. Injection-site reactions are the most commonly reported adverse events and are generally mild. Hyperphosphatemia occurs infrequently and is typically managed through dose adjustment. Unlike conventional therapy, burosumab does not require high-dose phosphate administration and may therefore reduce the risk of nephrocalcinosis and treatment-related hyperparathyroidism (7).

Despite reassuring safety data, continued surveillance remains necessary because many patients will require decades of treatment. Important unanswered questions include long-term cardiovascular effects, renal outcomes, and potential influences on ectopic calcification.

Current Guideline Recommendations

The publication of international clinical practice guidelines in 2025 marked an important milestone in XLH management. Pediatric guidelines recommend burosumab as first-line therapy for most children and adolescents with XLH because of superior efficacy and safety compared with conventional treatment (23).

Similarly, adult guidelines recommend burosumab for symptomatic adults, particularly those with active fractures, pseudofractures, bone pain, impaired mobility, or evidence of osteomalacia (24). Conventional therapy remains an option when burosumab is unavailable or contraindicated, but targeted FGF23 inhibition is now considered the preferred treatment strategy for most patients.

Remaining Challenges

Despite substantial advances, several important challenges remain. Burosumab does not fully reverse established enthesopathy or osteoarthritis, likely because these manifestations reflect irreversible structural changes and FGF23-independent disease mechanisms. In addition, uncertainties remain regarding final adult height, long-term renal outcomes, hearing impairment, dental disease, and pregnancy.

These limitations highlight the need for continued investigation into disease-modifying therapies capable of addressing both FGF23-dependent and FGF23-independent mechanisms.

Table 1. Major Clinical Outcomes Associated with Burosumab Therapy.

Outcome	Children	Adults
Serum phosphate	Improved	Improved
TmP/GFR	Improved	Improved
Rickets severity	Improved	Not applicable
Growth velocity	Improved	Not applicable
Fracture healing	Limited data	Improved
Pain	Improved	Improved
Physical function	Improved	Improved
Quality of life	Improved	Improved

Pregnancy and X-Linked Hypophosphatemia

The management of XLH during pregnancy remains one of the least studied areas in the field. Evidence guiding management during pregnancy is limited largely to case reports, expert opinion, and consensus recommendations. Consequently, clinical decision-making often relies on pathophysiologic principles, individualized risk assessment, and multidisciplinary collaboration among endocrinologists, maternal–fetal medicine specialists, nephrologists, and pediatric specialists.

Pregnancy is associated with profound physiologic changes in mineral metabolism. Approximately 20 g of phosphorus are transferred from the maternal circulation to the developing fetus by the end of gestation, most of which occurs during the third trimester. To accommodate these increased mineral requirements, intestinal absorption of calcium and phosphate increases substantially, largely driven by elevations in circulating 1,25-dihydroxyvitamin D concentrations. Interestingly, despite persistently elevated FGF23 concentrations, women with XLH appear capable of mounting the physiologic increase in calcitriol that normally occurs during pregnancy. This observation suggests that pregnancy-associated factors, including parathyroid hormone-related peptide, prolactin, placental lactogen, and estrogen, may override the suppressive effects of FGF23 on vitamin D metabolism (25).

Because evidence-based recommendations are lacking, management strategies vary considerably. Current international guidance recommends that all women of childbearing age with XLH receive genetic counseling regarding inheritance patterns, reproductive risks, and available treatment options. Since XLH is inherited in an X-linked dominant fashion, affected women have a 50% probability of transmitting the disease-causing variant to each offspring. Counseling should therefore include discussion of disease manifestations, expected outcomes, and reproductive planning (23,24).

Biochemical monitoring during pregnancy is particularly important because physiologic changes may alter phosphate requirements and treatment responses. Expert recommendations suggest assessment of serum calcium at least once each trimester and periodic evaluation of serum phosphate concentrations throughout pregnancy. Women receiving active treatment should also undergo monitoring of renal function, urinary calcium excretion, and parathyroid hormone concentrations (25).

Management of medical therapy during pregnancy remains controversial. Conventional treatment with phosphate supplementation and active vitamin D analogues has historically been used when clinically indicated, particularly in women with significant hypophosphatemia, pseudofractures, severe bone pain, or evidence of ongoing skeletal fragility. Available case reports suggest that successful pregnancies can occur both with and without continuation of conventional therapy, although concerns remain regarding maternal complications such as worsening osteomalacia, fracture risk, hyperparathyroidism, nephrocalcinosis, and hypercalciuria (25).

The role of burosumab during pregnancy remains uncertain. Clinical trials excluded pregnant women, and robust safety data are unavailable. Consequently, current guidelines generally recommend discontinuation of burosumab before conception whenever possible (23,24). However, increasing recognition of symptom recurrence and biochemical deterioration following treatment withdrawal has raised important questions regarding management of women with severe disease. Additional studies are needed to determine whether continuation of FGF23 inhibition may be appropriate in selected high-risk situations.

Delivery planning should be individualized. Some women with XLH experience pelvic deformities, short stature, or significant skeletal abnormalities that may increase the risk of obstructed labor. As a result, cesarean delivery rates appear higher than those observed in the general population. Nevertheless, successful vaginal deliveries have also been reported. Decisions regarding mode of delivery should therefore be based on obstetric indications and maternal anatomy rather than the diagnosis of XLH alone (25)

Postpartum management requires reassessment of maternal symptoms, biochemical parameters, and treatment needs. Conventional therapy may be continued during lactation when clinically indicated. The optimal timing of burosumab reinitiation following delivery remains unclear, although many experts recommend resumption after completion of breastfeeding if significant disease activity persists. Further research is urgently needed to establish evidence-based recommendations for pregnancy and lactation in women with XLH.

Emerging Therapeutic Strategies

Although burosumab has transformed management of XLH, several important limitations remain. Many patients continue to experience enthesopathy, osteoarthritis, chronic pain, dental disease, and other complications despite normalization of phosphate metabolism. These observations have stimulated interest in next-generation therapies that target broader aspects of disease pathogenesis.

Small-Molecule FGF23 Inhibitors

One promising area of investigation involves development of small-molecule inhibitors capable of disrupting FGF23 signaling.

Preclinical structural studies have established α-Klotho as a non-enzymatic molecular scaffold required for high-affinity binding of FGF23 to FGFR1, enabling downstream signaling (26). Leveraging this insight, in silico hot spot prediction and high-throughput docking of approximately 5.5 million compounds identified candidate small molecules targeting the FGF23:α-Klotho interface. In a study done by Liu et al, the lead compound, ZINC12409120, binds the KL1 domain of α-Klotho at Tyr433 and produces approximately 70% inhibition of FGF23-mediated ERK phosphorylation in vitro(26) . By disrupting the scaffold function of α-Klotho rather than inhibiting FGFR kinase activity, this approach may allow selective blockade of FGF23 signaling while preserving other FGF pathways.

Despite these advances, small-molecule FGF23 inhibitors remain in early-stage development. In addition, the multi-domain binding profile of α-Klotho–targeting compounds raises potential concerns regarding selectivity, particularly for other endocrine FGFs such as FGF19 and FGF21. No human clinical trials have yet been completed. Nonetheless, ongoing in silico and preclinical efforts highlight the potential for orally available therapies that may complement or eventually provide an alternative to biologic treatments in XLH and related disorders.

FGFR Inhibition

Because FGF23 exerts its biologic effects through activation of fibroblast growth factor receptors, inhibition of downstream receptor signaling has also been explored. The key reference supporting FGFR inhibition in XLH is the 2013 study by Wöhrle et al. demonstrating that pharmacological FGFR inhibition with NVP-BGJ398 normalized phosphate metabolism and improved skeletal outcomes in Hyp mice(27). Burosumab, the current standard of care, blocks this interaction at the ligand level. The theoretical advantage of FGFR inhibition is downstream blockade of all FGF23-mediated signaling, potentially addressing pathways not fully inhibited by antibody-based approaches. However, the pan-FGFR inhibitor strategy carries significant off-target risks given the physiological roles of FGFR signaling in multiple tissues (28). The enthusiasm for systemic FGFR inhibition has been tempered by class-wide toxicities observed in oncology trials, including hyperphosphatemia, stomatitis, nail events, and fatigue (28). These adverse effects arise from blockade of physiological FGF/FGFR signaling beyond the FGF23 pathway(28). The 2025 international working group guidelines for adult XLH management do not include FGFR inhibitors as treatment options, reflecting their lack of clinical availability for this indication (2,24)

Future efforts may focus on developing more selective inhibitors capable of targeting specific signaling pathways while minimizing toxicity.

Anti-Sclerostin Therapy

Sclerostin is an osteocyte-derived protein that suppresses bone formation through inhibition of Wnt signaling. The foundational preclinical evidence comes from studies in Hyp mice, the murine model of XLH, where sclerostin antibody treatment not only increased bone mass and improved skeletal parameters but also normalized circulating phosphate levels and suppressed intact FGF23 concentrations(29). This dual mechanism direct anabolic effects on bone plus indirect reduction of the pathogenic phosphaturic hormone differentiates anti-sclerostin therapy from conventional phosphate replacement and offers a potential complementary approach to burosumab, which targets FGF23 directly. In addition given the established efficacy of sclerostin inhibitors in osteoporosis, this strategy represents an intriguing potential adjunctive therapy for XLH. However, clinical data remain limited, and further investigation is required before such therapies can be incorporated into routine management.

Gene Therapeutic Strategies

Gene therapy and gene repair approaches represents one of the most exciting areas of future research in XLH. These strategies fall into two conceptual categories: compensatory approaches that neutralize pathologic FGF23 signaling, and curative approaches that restore normal PHEX function.

Pre-clinical proof-of-concept studies have demonstrated efficacy using a liver-targeted adeno-associated viral vector expressing the C-terminal fragment of FGF23. This strategy functions as a competitive antagonist of intact FGF23 and successfully corrected phosphate metabolism, improved mineralization, and reduced skeletal abnormalities in Hyp mice(30).

Gene therapy offers the possibility of long-term or even permanent correction of disease manifestations following a single intervention. However, significant challenges remain, including optimization of delivery systems, durability of expression, immune responses, and long-term safety. Importantly, strategies focused exclusively on FGF23 inhibition may not fully address FGF23-independent disease mechanisms.

Restoration of normal PHEX function whether through gene addition, gene editing, or repair of the defective allele, represents the most comprehensive therapeutic goal. Unlike FGF23-directed therapies, PHEX repair would be expected to correct both systemic phosphate abnormalities and local mineralization defects. Advances in gene-editing technologies, including CRISPR/Cas9-based approaches, have generated considerable optimism regarding future therapeutic possibilities. CRISPR/Cas9-based approaches have been used to generate knock-in XLH mouse models with patient-specific Phex variants, demonstrating that precise genetic manipulation is technically achievable (31).

However, substantial barriers remain. Effective targeting of osteocytes and osteoblasts presents a significant technical challenge, and long-term safety of gene-editing approaches must be carefully established. Despite these obstacles, PHEX-directed therapy remains the ultimate therapeutic goal because it addresses the primary molecular defect responsible for disease.

Future Directions and Knowledge Gaps

Despite remarkable progress, numerous questions remain unanswered. It is not yet known whether early initiation of burosumab can normalize final adult height or prevent development of enthesopathy and osteoarthritis. Similarly, the long-term effects of FGF23 inhibition on hearing impairment, cardiovascular health, pregnancy outcomes, and renal function remain uncertain.

Additional investigation is needed to better define the contribution of FGF23-independent mechanisms to disease progression. Understanding the relative importance of osteopontin accumulation, ASARM peptide activity, pyrophosphate dysregulation, and osteocyte dysfunction may reveal novel therapeutic targets and explain persistent skeletal abnormalities despite treatment.

Long-term observational studies and registry analyses will be essential for evaluating outcomes across the lifespan. These efforts will provide important information regarding durability of treatment response, safety of prolonged FGF23 inhibition, and optimal approaches for transitioning care from childhood to adulthood.

Conclusions

X-linked hypophosphatemia is a complex inherited disorder characterized by chronic renal phosphate wasting, impaired skeletal mineralization, and lifelong musculoskeletal morbidity. Advances in understanding osteocyte biology and phosphate regulation have transformed perceptions of XLH from a simple phosphate-wasting disorder to a multifaceted disease involving both systemic endocrine abnormalities and intrinsic defects in bone mineralization.

The discovery of FGF23 as the principal mediator of phosphate wasting led directly to development of burosumab, the first disease-specific therapy for XLH. Clinical trials and real-world studies have demonstrated substantial improvements in phosphate homeostasis, skeletal health, pain, mobility, and quality of life in both children and adults (5,7,23,24). Nevertheless, important disease manifestations persist despite treatment, highlighting the role of FGF23-independent mechanisms in disease pathogenesis.

Future therapeutic advances are likely to extend beyond correction of hypophosphatemia and focus increasingly on disease modification. Emerging strategies including small-molecule FGF23 inhibitors, anti-sclerostin therapies, gene transfer approaches, and ultimately PHEX-directed repair offer the potential for more complete correction of disease biology. Continued investigation into osteocyte function, extracellular matrix regulation, and mineralization pathways will be essential for achieving the long-term goal of curative therapy.

Author Contributions

Conceptualization: S.M. Writing, original draft: S.M., K.T. Writing review & editing: all authors.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

XLH	X-linked hypophosphatemia
FGF23	Fibroblast growth factor 23
PHEX	Phosphate-regulating endopeptidase homolog X-linked

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Figure 1. Mechanism of FGF23-mediated hypophosphatemia in X-linked hypophosphatemia. Excess circulating FGF23 decreases renal phosphate reabsorption by suppressing NaPi-2a and NaPi-2c expression while simultaneously reducing 1,25-dihydroxyvitamin D production. The combined effects reduce intestinal phosphate absorption and lower serum phosphate concentrations.

Figure 2. Actions of FGF23 on phosphate homeostasis. FGF23 is produced by osteoblasts/osteocytes. FGF23 binds to Klotho/FGF receptor 1 complex and activates several intracellular signaling pathways including extracellular signal-regulated kinase (ERK). FGF23 suppresses proximal tubular phosphate reabsorption by reducing expression levels of type 2a and 2c sodium–phosphate cotransporters. FGF23 also decreases 1,25(OH)2D by modifying the expression of vitamin D-metabolizing enzyme. From these effects, FGF23 reduces serum phosphate.

Figure 3. Post-translational processing of FGF23. FGF23 is synthesized as a 251-amino acid peptide, undergoes cleavage of a 24-amino acid signal peptide, and may be proteolytically cleaved at the R-X-X-R motif into inactive N-terminal and C-terminal fragments, while intact FGF23 signals through the Klotho–FGFR1 receptor complex.

Figure 4. Regulation of FGF23 expression and secretion in XLH. Multiple interacting pathways regulate FGF23 expression and release in X-linked hypophosphatemia, including PHEX, DMP1, ASARM peptides, FAM20C, phosphate sensing, iron metabolism, Klotho signaling, and vitamin D pathways.

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