Following confirmation of the diagnosis of TIO, medical therapy should be initiated as soon as possible to reduce symptoms and strengthen bones in preparation for surgery [16]. Chronic medical treatment is necessary in cases where a PMT is either non-localizable or inoperable, or a patient is a poor surgical candidate [51].

Until recently, the primary medical approach to managing TIO involved using phosphate salts and activated vitamin D (calcitriol, alfacalcidol) to increase phosphate levels and relieve clinical symptoms. The required dose of these medications can vary widely and should be adjusted based on the individual’s symptoms and laboratory values [3, 31]. Frequent, smaller doses of phosphate are preferred to minimize gastrointestinal side effects, although this can be burdensome and challenging for patients. Phosphate monotherapy should be avoided, as it frequently leads to secondary hyperparathyroidism, exacerbating hyperphosphaturia and worsening hypophosphatemia [16]. Furthermore, chronic secondary hyperparathyroidism may progress to tertiary hyperparathyroidism [52]. To prevent secondary hyperparathyroidism, it is essential to combine phosphate with calcitriol or alfacalcidol, although excessive activated vitamin D supplementation can cause hypercalciuria, increasing the risk for nephrolithiasis, nephrocalcinosis, and renal impairment [52]. Oral calcium supplementation may also be required to allow for bone remineralization but must be taken separately from phosphate supplementation, further complicating therapy. This regimen requires close monitoring, targeting low or low-normal blood phosphate levels, and both intact parathyroid hormone (PTH) and 24-h urine calcium excretion levels within the normal range. The goal of treatment is improvement in bone quality which is reflected by normalization of alkaline phosphatase [3].

The calcimimetic cinacalcet, an agonist of the calcium-sensing receptor, may be used as an adjuvant treatment along with calcitriol and phosphate in select cases. This approach takes advantage of the finding that FGF23’s action on renal phosphate excretion is PTH-dependent [53]. By decreasing PTH, cinacalcet decreases the effect of FGF23 on the renal tubule, resulting in decreased renal phosphate losses. Two patients with TIO were successfully treated with cinacalcet, as evidenced by increased blood phosphate and decreased calcitriol and phosphate supplement requirements [54]. Based on similar reasoning, a patient with TIO and tertiary hyperparathyroidism underwent a deliberate total parathyroidectomy, resulting in improved blood phosphate levels and decreased phosphate requirements despite persistently elevated FGF23 [55]. With both approaches, the reduction in PTH has the potential of increasing the risk of hypercalciuria and hypocalcemia, necessitating careful monitoring [54]. More studies are needed to establish the optimal use of these options in TIO.

Burosumab, a human monoclonal antibody against FGF23, has emerged as a promising new treatment option for patients with unresectable or non-localizable disease. It has been approved for the treatment of TIO in the USA, EU, China, and Japan [16, 56,57,58]. In two open-label phase 2 studies, a total of 27 adults with TIO were effectively treated with burosumab, showing improvements in phosphate levels, fracture healing, and quality of life [57]. Average serum phosphate increased and was maintained in the normal range up to 144 weeks [56, 57]. At week 144, 33% of 249 fractures and pseudofractures in 14 patients were fully healed and 13% were partially healed [57]. Within the confines of the trials, blood phosphate was maintained in the low-normal range, so fracture healing may be more substantial at higher dosages in clinical practice [59]. After 96 weeks, bone mineral density was improved at the lumbar spine and total hip in 12 subjects [56]. While on burosumab, the bone turnover markers type 1 collagen C-telopeptides (CTX), procollagen 1 N-terminal propeptide (P1NP), bone specific alkaline phosphatase (BALP), and osteocalcin (OC) increased initially, peaked at week 16 or 24 and then started to trend down [56, 57]. In a subset of 8 patients who participated in exit interviews, patients reported symptomatic improvements including in physical functioning and mental well-being [60]. Additional trials and case reports have supported the ability of burosumab to improve serum phosphate levels, pain, and physical performance in patients with TIO [56, 61, 62]. Data regarding the long-term safety and impacts of burosumab are needed.

Burosumab is given as a subcutaneous injection which is administered every 2 to 4 weeks up to a maximum of 2 mg/kg/dose. Adjustments are made based on the peak fasting serum phosphate level obtained midway between doses. Blood phosphate, creatinine, alkaline phosphatase, intact PTH, and blood and urinary calcium should be monitored while on therapy [16]. Due to limitations of existing FGF23 assays, which cannot differentiate between burosumab-bound and free FGF23, FGF23 levels are uninterpretable while on burosumab [63]. Given the long half-life of burosumab of 16.4 days [64], it may thus be advisable to delay burosumab initiation until there is a confirmed diagnosis of TIO and it is certain that venous sampling will not be needed. This limitation also prevents FGF23 from being used as a reliable marker of disease progression or tumor growth while a patient is taking burosumab.

It is important to note that treatment with either burosumab or the combination of phosphate and activated vitamin D does not remove the underlying causative tumor, and local expansion or metastatic extension is still possible [3]. Thus, attempts to localize the tumor or monitor growth should continue with imaging every 1–2 years even while patients are on medical therapy [16].

Despite the presence of somatostatin receptors on most PMTs, octreotide therapy did not result in meaningful changes in blood phosphate, FGF23, or TRP levels in five patients with TIO [65].

To molecularly target tumors directly, infigratinib, an orally bioavailable FGFR1-3 tyrosine kinase inhibitor, has been investigated for treatment of TIO. The rational for using infigratinib arises from the frequent occurrence of a presumptively causative gene fusion of fibronectin 1 and FGFR1 (FN1-FGFR1) which has been identified in over 40% of cases of resectable PMTs [66]. When used in a patient with metastatic TIO harboring a FN1-FGFR1 fusion, infigratinib was shown to profoundly lower FGF23 levels and reduce tumor burden, although the biochemical response reversed after drug discontinuation [67]. Intriguingly, evidence of apparent metaplastic differentiation into mature lamellar bone was observed in the patient’s tumors. These findings prompted a follow up study in four patients with benign TIO in which infigratinib effectively reversed the biochemical abnormalities of TIO, including normalization of phosphate, intact FGF23, and 1,25(OH)2-Vitamin D levels. Upon cessation of the drug after up to 24 weeks of therapy, however, biochemical parameters returned to baseline, and no patients experienced prolonged remission. Further enrollment was halted due to a high incidence of ocular AE’s, including corneal keratitis and scarring [68, 69]. While effective in correcting the biochemical abnormalities of TIO and possibly also impacting tumor growth, a short course of infigratinib failed to induce a lasting remission, and long-term therapy is limited by serious ocular side effects. Still, it may be an option to consider in the treatment of rare, life-limiting, metastatic disease. Advances in targeted treatments that more selectively block FGFR1 may permit the use of higher doses and more sustained treatment without side effects.

In cases of CAO, in which FGF23 excess is caused by non-PMT solid or hematologic malignancies, the treatment approach involves targeting the underlying malignancy, while using medical therapies to manage the hypophosphatemia and symptoms. The use of burosumab in treating CAO is likely beneficial in select cases, but its efficacy has not been confirmed.