Personalised medicine for hypophosphataemic rickets – a new era

Rickets results from impaired mineralisation of the growth plate. Hypophosphataemia is common to all forms of rickets as hypophosphataemia impairs both hydroxyapatite formation and failure of apoptosis of the hypertrophied chondrocytes1. Hypophosphataemic rickets (HR) is rare and has several causes, many with an underlying genetic basis (Table). It is necessary to establish the cause of hypophosphataemia to enable institution of targeted therapy. This mini review focuses on the commonest cause of HR, X-linked hypophosphataemia (XLH).

XLH affects approximately one in 20,000 individuals and is caused by loss of function of the PHEX gene, mainly expressed by osteocytes. The PHEX gene is located on the X chromosome; thus an affected mother will have a 50% chance of passing the condition on to her child and an affected father will have affected daughters but no affected sons. The genotype–phenotype relationship is highly variable even within affected families2.

Loss of PHEX function leads to increased secretion of fibroblast growth factor (FGF)23. Elevated FGF23 levels cause hypophosphataemia by enhanced renal phosphate excretion (by inhibition of the sodium-phosphate co-transporters NaPi2a and NaPi2c) in the proximal renal tubule, and by inhibiting 1,25-dihydroxyvitamin D3 synthesis resulting in reduced dietary phosphate absorption1.

XLH is diagnosed because of a family history (present in 60%) or as a de novo case presenting with clinical features, usually in the first 2 years of life. Early recognition is essential to optimise outcomes. The diagnosis of XLH is based on a combination of clinical, biochemical and radiographical features. Typical clinical features at presentation are lower limb deformity, wrist and ankle swelling, delayed motor development, waddling gait, dental abscesses, short stature and bone/joint pain. Rarer associations include craniosynostosis and Chiari malformation.

Serum phosphate is usually low and must be interpreted in the context of an age-specific reference range. Key investigations include serum phosphate, creatinine, calcium, alkaline phosphatase, parathyroid hormone (PTH), and 25-hydroxyvitamin D, and urine phosphate and creatinine. Renal phosphate wasting should be assessed by calculating the tubular maximum reabsorption of phosphate per glomerular filtration rate (TmP/GFR), and a wider tubulopathy secondary to Fanconi syndrome must be excluded. Measurement of FGF23 may be helpful to distinguish FGF23-mediated causes and FGF23-independent causes2 (Table). The biochemical characteristics of XLH are renal phosphate wasting, elevated alkaline phosphatase, elevated FGF23 and inappropriately low or normal 1,25-dihydroxyvitamin D3. Mutation analysis of the PHEX gene is recommended to confirm a clinical diagnosis of XLH.

The goals of therapy are to correct lower limb deformities to reduce the requirement for surgery, optimise linear growth, minimise pain and improve dental health, necessitating a multidisciplinary approach. A current focus has been to improve the recognition of the XLH, as the earlier therapy is instituted the better the long-term outcomes. There are currently two medical treatment strategies, conventional therapy or anti-FGF23 monoclonal antibody.

Conventional therapy

Conventional therapy consists of multiple doses of oral phosphate (4–6 times per day) and an activated vitamin D analogue (calcitriol or alphacalcidol once a day). Higher doses are needed during phases of rapid linear growth. Medicine nonadherence and intolerance are frequent. Adverse effects include secondary hyperparathyroidism, nephrocalcinosis and cardiovascular abnormalities. Treatment monitoring is with serum alkaline phosphatase (ALP), PTH, severity of rickets assessed by X-ray (hand or knee) and intercondylar and/or intermalleolar distance, and growth. Treatment is continued until cessation of linear growth.

Conventional therapy does not fully correct the biochemical derangement nor symptoms of XLH. A limitation is that as serum phosphate levels are increased, FGF23 levels are further increased with consequent increased renal phosphate wasting, potentially reducing treatment efficacy.

Anti-FGF23 monoclonal antibody (burosumab)

Burosumab, a recombinant IgG1 monoclonal antibody, directly inhibits FGF23 activity and thus increases TmP/GFR and indirectly enhances intestinal phosphate and calcium absorption. The EMA granted marketing authorisation in 2018 for treatment for children older than 1 year with XLH and radiographical evidence of rickets; the FDA approved usage in children and adults. Burosumab is given subcutaneously every 2 weeks and is well tolerated with a reassuring safety profile. Side effects include a mild reaction at the site of injection, headache and cough. Fasting serum phosphate should be monitored regularly to achieve a phosphate in the lower end of the age-specific reference range. The monitoring required includes serum ALP, TmP/GFR and wrist X-ray, annual renal ultrasound and urine calcium: creatinine ratio3.

Compared to conventional therapy, burosumab resulted in superior improvements in radiological rickets healing, serum phosphate, growth, pain, reduction in renal phosphate wasting and functional outcomes4,5.

Early diagnosis of XLH is a key management step to enable access to targeted therapy to reduce long-term morbidity. Anti-FGF23 therapy is a preferable treatment compared to conventional therapy.

Consultant Paediatric Endocrinologist & Hon. Associate Professor, Southampton Children’s Hospital; Faculty of Medicine, University of Southampton, UK
  1. Beck-Nielsen SS, Mughal Z, Haffner D, Nilsson O, Levtchenko E, Ariceta G, et al. FGF23 and its role in X-linked hypophosphatemia-related morbidity. Orphanet J Rare Dis 2019; 14: 58 doi: 10.1186/s13023-019-1014-8
  2. Haffner D, Emma F, Eastwood DM, Duplan MB, Bacchetta J, Schnabel D, et al. Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia. Nat Rev Nephrol 2019; 15: 435–455
  3. Padidela R, Cheung MS, Saraff V, Dharmaraj P. Clinical guidelines for burosumab in the treatment of XLH in children and adolescents: British paediatric and adolescent bone group recommendations Endocr Connect 2020; 9: 1051–1056
  4. Imel EA, Glorieux FH, Whyte MP, Munns CF, Ward LM, Nilsson O, et al. Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial. Lancet 2019; 393: 2416–2427
  5. Linglart A, Imel EA, Whyte MP, Portale AA, Högler W, Boot AM, et al. Sustained efficacy and safety of burosumab, a monoclonal antibody to FGF23, in children With X-linked hypophosphatemia. J Clin Endocrinol Metab 2022; 107: 813–824

Table. Causes of hypophosphataemia (Genetic basis)

  • FGF23-mediated
    • X-linked hypophosphataemia (PHEX)
    • Autosomal dominant HR (DMP1)
    • Autosomal recessive HR types 1, 2, 3 (FGF23ENPP1FAM20C)
    • Fibrous dysplasia (GNAS)
    • Tumour induced osteomalacia
    • Iron polymaltose infusions
  • Non-FGF23-mediated
    • Primary hyperparathyroidism
    • Hereditary hypophosphataemic rickets with hypercalciuria (SLC34A3)
    • Vitamin D dependent rickets (type 1A, 1B, 2A, 3)
    • Causes of Fanconi syndrome
Martin Savage
Programme Director

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