X-linked hypophosphataemia: Multidisciplinary care needed, targeted therapy effectively normalizes phosphate homeostasis

Management of X-linked hypophosphataemia (XLH) has evolved in the past few years following the availability of burosumab, a fully humanized monoclonal antibody targeting circulating fibroblast growth factor 23 (FGF23), which has changed the landscape of XLH management, a panel of experts who spoke at EDM HK 2025 concurred.

XLH is a rare metabolic bone disorder caused by loss-of-function mutation in the phosphate-regulating endopeptidase homolog X-linked (PHEX) gene, which results in inappropriately increased production of FGF23 by the bone (mainly osteocytes, osteoblasts) and, to a lesser extent, by the teeth (odontoblasts). Increased FGF23 in the circulation causes decreased production of 1,25-dihydroxy vitamin D and, as a result, decreased gut absorption of phosphate as well as decreased phosphate reabsorption in the renal tubules, causing renal phosphate wasting. All these abnormalities contribute to decreases in serum phosphate level. XLH resulting from excess circulating FGF23 is the most common form of inheritable hypophosphataemic rickets and affects one in 20,000–60,000 people. [Eur J Pediatr 2008;167:493; Nat Rev Nephrol 2025;21:330-354]

Clinical manifestations of XLH include leg deformities (eg, bowlegs), short stature, dental disease (eg, abscesses), maxillofacial cellulitis and hearing impairment starting from childhood, as well as skeletal pain, insufficiency fractures and degenerative joint disease in adulthood. [J Endocr Soc 2020;4:1-15]

“XLH is a lifelong, progressive multisystem condition and requires multidisciplinary management to optimize outcomes,” said Dr Joanna Yuet-Ling Tung, a paediatric endocrinologist from Hong Kong Children’s Hospital. “In Hong Kong, a total of 46 XLH cases had been identified up to the year 2023 under the Hospital Authority, of which nine were children.”

Conventional treatment: Limitations

Conventional treatment of XLH involves frequent doses of phosphate supplements (200–1,600 mg daily) and active vitamin D (calcitriol, 0.25–0.75 µg daily) (Pi/D).  “This treatment can ameliorate rickets and osteomalacia, improve pain symptoms and oral health [reduce frequency of periodontitis and dental abscesses], and partially restore growth in children with XLH,” said Dr Risa Ozaki, an adult endocrinologist from Prince of Wales Hospital.

“However, the efficacy of conventional treatment is limited. Pi/D does not prevent or improve hearing loss, osteoarthritis or enthesopathies, and evidence of benefit in asymptomatic adults is limited, as it is just treating the downstream abnormalities rather than the actual pathology,” noted Ozaki. “Moreover, frequent dosing of phosphate supplements is needed to maintain sufficiently high serum phosphate levels, which quickly return to trough levels 1–2 hours after intake. This may be burdensome for many, and some patients may experience gastrointestinal side effects.” [J Endocrinol Invest 2025;48:2199-2228]

“The limited efficacy of conventional treatment could also be attributed in part to both phosphate and active vitamin D further stimulating FGF23 secretion, resulting in a vicious cycle of renal phosphate wasting,” she added. “Hyperparathyroidism and nephrocalcinosis are also common and challenging complications associated with conventional treatment.”

Burosumab targets underlying XLH pathology

“The launch of burosumab in 2018 for XLH treatment marked a turning point for many of our patients,” said Ozaki.

Burosumab, a fully humanized antibody against FGF23, works by binding to and inhibiting excess FGF23, thereby increasing active vitamin D production and decreasing phosphate loss. This results in restoration of phosphate homeostasis, and improvements in skeletal mineralization and symptoms. “However, these levels or effects revert to pretreatment ranges after treatment cessation, making long-term treatment with burosumab necessary for sustained effect,” noted Ozaki. [Crysvita Prescribing Information, January 2020; Lancet 2019;393:2416-2427; Drugs 2018;78:707-714]

The landmark 48-week CL303 trial that led to the approval of burosumab for XLH treatment demonstrated the safety, tolerability and sustained efficacy of continued exposure to burosumab. Serum phosphate concentrations remained normal during weeks 24–48 in 84 percent of participants who received burosumab from the beginning of the study, and were normalized in 89 percent of those who received burosumab only after week 24. Continued exposure to burosumab also resulted in increasing proportions of fully healed osteomalacia-related fractures and pseudofractures, and improved pain, stiffness, physical function and functional exercise capacity scores. Despite long-standing physical impairments from a lifetime of XLH, the study’s participants experienced clinically meaningful benefits that began to manifest shortly after burosumab was initiated. These benefits persisted with continued treatment, with an overall positive benefit-risk profile through at least 48 weeks of treatment. [Calcif Tissue Int 2019;105:271-284]

“Although no head-to-head randomized control trial data comparing the effectiveness of burosumab vs conventional treatment are available to date, there are some real-world prospective observational data,” said Ozaki.

A study utilizing real-world data from the prospective Americas-based XLH Disease Monitoring Program found that compared with Pi/D, burosumab treatment was associated with improvements in biochemical parameters (normalized serum phosphate concentrations, 66 vs 30 percent), pain (Pi/D cohort showed an increase from baseline), physical function, and mobility. Despite study limitations due to the real-world nature of the programme (eg, different intervals between programme enrolment and burosumab treatment initiation, leading to varying treatment durations), the results concur with those of the CL303 trial. [J Bone Miner Res 2025;40:973-986]

“Burosumab is currently available in public hospitals for children with confirmed XLH, but there is currently little guidance for adult patients, as cost is a limiting factor,” said Ozaki.

Multidisciplinary management

The surgeon, who is a part of the XLH multidisciplinary team, plays a role in helping to manage severe deformities or inserting plates to guide bone growth and minimize limb malalignments. “I look forward to seeing a diminishing role of the orthopaedic surgeon in XLH management, as agents such as burosumab can improve lower limb malalignment without requiring surgical intervention [as demonstrated in the CL205 and CL301 studies],” said Dr Evelyn Kuong, a paediatric orthopaedic surgeon from Queen Mary Hospital. [J Pediatr Soc North Am 2024;6:100012]