Literature search

The literature search initially identified 555 potentially eligible records. After removal of duplicates, 416 records were examined by title and abstract and, of these, 17 were examined in full text to evaluate their inclusion. The analysis of the full text studies led to the inclusion of a total of 7 studies: 1 guideline [6], 5 consensus [7, 8, 13,14,15] and 1 clinical pathway of an Italian local health unit [16].

The main characteristics of the included studies are described in Table 2, while the studies evaluated in full-text and excluded are described in Online Resource 3. Remarkably, only one [6] among the included studies, was structured as a guidelines document and had the focus on XLH.

Table 2 Main characteristics of included studiesIdentification of the hypophosphatemic patient

The following clinical signs and symptoms are commonly recognized as associated with hypophosphatemia [6,7,8, 14]: history of rickets, growth retardation or deformity of the lower limbs, cranial deformities or other physical deformities, clinical and/or radiological signs of osteomalacia (including pseudo-fractures, early arthrosis and enthesopathies), serum phosphate levels below the age-related reference range, renal phosphate depletion, dental abscesses, periodontal disease, fatigue/weakness/asthenia and/or muscle pain, osteo-articular pain, crooked gait and/or other gait disorders, joint stiffness.

To define the diagnosis, after the medical history and clinical examination, it appears necessary to exclude causes related to blood dilution (e.g. due to massive fluid resuscitation, dialysis, plasmapheresis), spurious hypophosphatemia (e.g. interference of drugs such as amphotericin B, interference by bilirubin or specific paraproteins), effects of drugs (e.g. phosphate binders, niacin) or alcohol abuse [7]. From a diagnostic point of view, it is also essential to discriminate between renal and non-renal causes of hypophosphatemia, measuring the ratio between the maximum tubular reabsorption of phosphate and the glomerular filtration rate (TmPO4/GFR) which must be calculated from fasting plasma samples and fasting spot urine from the second morning void (obtained 2 h after the first voided urine) for measurement of phosphate and creatinine. Recently, Arcidiacono and colleagues demonstrated that TmP/GFR must be effectively calculated also using 24 h urine collection in adult patients with FGF23-dependent renal phosphate leak [17]. This parameter can be obtained using the Walton and Bijvoet nomogram or using the Kenny and Glen algorithm [8]. If renal phosphate wasting is documented, a distinction must be made between hereditary and acquired FGF23-dependent or FGF23-independent conditions. Regarding family history, international guidelines [6] recommend that any first-degree family member of a patient with XLH should be investigated for XLH, even though sons of the males affected by XLH are not at risk. If the PHEX gene analysis produces a negative result for XLH, it is recommended to also evaluate other causes of hereditary or acquired hypophosphatemia. Furthermore, genetic counselling is recommended for patients with XLH, particularly in the transition from paediatric to adult age and for families planning a pregnancy. If genetic analysis is not available, elevated or inappropriately normal plasma levels of intact FGF23 and/or a positive family history of XLH support the diagnosis.

Diagnostic workout

The following laboratory tests are indicated for the diagnostic evaluation of the XLH patient [6,7,8, 14]: serum phosphate, serum calcium, bone-specific alkaline phosphatase (ALP), parathyroid hormone (PTH), 25(OH) vitamin D, 1,25(OH)2 vitamin D, FGF23, serum creatinine, urinary calcium: creatinine ratio, urinary phosphate and creatinine levels to be used for the calculation of TmPO4/GFR.

The presence of hypophosphatemia and loss of phosphate through the urine, in the absence of Fanconi syndrome and hereditary hypophosphatemic rickets, suggests the need to look for a neoplasm in the context of oncogenic osteomalacia. Since these mesenchymal tumours usually express somatostatin receptors, their presence can be ascertained by Indium-111-labeled octreotide scintigraphy (Octreoscan™), although 68Gallium DOTATOC positron emission tomography/computed tomography and technetium-99 m HYNIC-TOC single-photon emission computed tomography showed the highest sensitivity [18]. All diagnostic images must be total body (i.e., from head to toe). The differential diagnosis includes other forms of hypophosphatemic osteomalacia (e.g. XLH, autosomal dominant or recessive) and primary or acquired Fanconi renal syndrome. Primary Fanconi syndrome is usually sustained by inherited diseases (cystinosis, Wilson disease, tyrosinemia, galactosemia) and, being typical of the childhood, its main clinical manifestations are related to rachitis and growth defects. On the contrary, the acquired form of Fanconi regards the adults and its main skeletal manifestation is osteomalacia. Both the forms may be associated with asthenia, polyuria, polydipsia and hypovolemia (following ions losses), constipation and muscle weakness (due to hypokalaemia) and sings of hyperchloremic metabolic acidosis in case of rapid onset (headache, lack of energy, nausea, and vomiting).

A series of additional tests can be considered for differential diagnosis [6, 7], including urinary pH, plasma bicarbonate, urinary amino acids, urinary glucose, uric acid in urine, and low molecular weight proteinuria.

Radiological examinations and other tests may be considered as well. It is advisable to perform X-rays of the lower limbs and wrist (including the assessment of bone age) using low radiation dose investigation techniques. DXA is generally not recommended in patients with XLH [7, 14]. International guidelines [6] also recommend carrying out renal ultrasonography, to evaluate the possible presence of stones, and a neurological examination, to evaluate the consequences of craniosynostosis and spinal stenosis.

TreatmentConventional pharmacological treatment

In symptomatic adults with XLH, international guidelines and consensus [6, 7, 13] recommend treatment with active vitamin D (calcitriol or alfacalcidol) together with oral phosphorus (phosphate salts) to reduce osteomalacia and its consequences and to improve oral health. The recommended dosage is 750–1,600 mg per day (based on elemental phosphorus) for phosphate and 0.50–0.75 and 0.75–1.5 µg per day for calcitriol and alfacalcidol, respectively [6].

However, routine treatment of asymptomatic hypophosphatemic adults, including XLH adult patients, is not recommended [6]. Phosphate supplements should not be prescribed without vitamin D analogues, as phosphate alone promotes secondary hyperparathyroidism and thus renal phosphate wasting [7].

It is recommended to treat pregnant and breastfeeding women with active vitamin D in combination with phosphate supplements [6, 8].

Doses of active vitamin D should be reduced in patients who develop hypercalciuria and hypercalcemia [6]. Phosphate supplements should be discontinued in patients with significantly increased parathyroid hormone levels [6].

Active vitamin D can be administered without phosphate supplements to adult patients with secondary hyperparathyroidism if close follow-up is performed [6].

It is suggested to supplement patients with native vitamin D (cholecalciferol or ergocalciferol) in case of vitamin D deficiency and to ensure normal calcium intake [6].

In patients undergoing medical therapy, monitoring and adjustment of treatment doses should be based on measurements of plasma and urine calcium and phosphate, creatinine, ALP, PTH and 25(OH) vitamin D at each visit [6, 7].

Treatment with burosumab

In 2018, the European Medicines Agency (EMA) granted conditional marketing authorization to the anti-FGF23 monoclonal antibody burosumab for the treatment of XLH in children aged ≥ 1 year with a growing skeleton and evidence radiography of bone diseases [19]. In late 2020, authorization was extended to adolescents and adults with XLH and radiographic evidence of bone disease, regardless of growth status. In March 2023, Italian Medicines Agency (AIFA) approved the indication of burosumab for adolescent and adult patients with XLH under the reimbursement regime by the National Health Service [20]. Based on the AIFA statement of March 13, 2023, the drug Crysvita® (burosumab) is indicated for the treatment of XLH in patients over 12 years of age, with evidence of active disease (Rickets Severity Score ≥ 1.5 and until skeletal maturity is reached in subjects in whom epiphyseal welding has not already occurred; skeletal pain attributable to XLH and at least one active fracture/pseudofracture in adult subjects) and already subjected to conventional therapy with phosphate and/or analogues of vitamin D.

Already in 2019, international guidelines recommended considering treatment with burosumab in adults with XLH with the following characteristics: persistent bone and/or joint pain due to XLH and/or osteomalacia that limits daily activities; pseudo-fractures or fractures related to osteomalacia; insufficient or refractory response to conventional therapy [6]. Treatment with burosumab was also recommended if patients experience complications related to conventional therapy [6, 8].

The starting dose of burosumab is 1.0 mg/kg body weight (maximum dose of 90 mg), administered subcutaneously every 4 weeks [6, 21].

The dose should be discontinued if the fasting serum phosphate level increases above the upper limit of normal for age. Then, burosumab can be restarted at approximately half the previous dose when the serum phosphate concentration is below the normal range [6, 21].

It is recommended to avoid administering burosumab concomitantly with conventional therapy, when serum phosphate levels are within the normal range for age and in the presence of severe renal insufficiency [6].

Recommendations for musculoskeletal treatment

Interventions aimed at reducing bone and joint pain, deformity, stiffness, muscle weakness and improving walking distance and physical function are recommended. These interventions include the use of analgesics (for example, short periods of use of non-steroidal anti-inflammatory drugs), intra-articular infiltrations (in the presence of degenerative changes), physiotherapy, rehabilitation, physical activity, and non-pharmacological treatment of pain [6].

FGF23-independent hypophosphatemia

In addition to the FGF23-dependent forms of hypophosphatemia, there are other FGF23-independent forms, for example those linked to malabsorption or primary tubular hyporeabsorption of phosphate. The therapy to be used for these forms is different from that used for FGF23-dependent hypophosphatemia. For example, treatment for hereditary hypophosphatemic rickets with hypercalciuria (HHRH; OMIM: 241530) and hypophosphatemia secondary to Fanconi and Dent syndrome consists of long-term medical therapy with phosphate supplements, without vitamin D supplementation [22].