Tumour-Induced Osteomalacia

Tumour induced osteomalacia is an acquired paraneoplastic disorder in which a small mesenchymal tumour secretes fibroblast growth factor 23 (FGF23), causing renal phosphate wasting, hypophosphataemia, low calcitriol and osteomalacia.

It is rare and typically presents in middle aged adults. The tumour is usually a phosphaturic mesenchymal tumour, often small, slow growing and hard to find, in bone or soft tissue (limbs, head and neck).

Diagnosis is delayed by several years in many patients, who are first treated for muscle or bone disease. Resection cures the disease.

Pathophysiology.

FGF23 reduces sodium phosphate cotransporter expression in the proximal tubule, causing phosphaturia, and suppresses 1-alpha hydroxylase, lowering calcitriol. Reduced intestinal phosphate absorption adds to the loss. Low phosphate impairs bone mineralisation.

• Progressive bone pain, proximal muscle weakness, fatigue, difficulty walking and fragility fractures (ribs, pelvis, femoral neck).
• Height loss and deformity. A palpable lump is sometimes present, and hypophosphataemia may have been recorded for years.

Red flags.

• Multiple fractures and loss of mobility.
• A rapidly enlarging mass or known tumour.

• Fasting serum phosphate low, with normal or low calcium, normal or mildly raised parathyroid hormone, raised alkaline phosphatase, and low or inappropriately normal calcitriol.
• Renal phosphate wasting: tubular maximum reabsorption of phosphate to glomerular filtration rate (TmP/GFR) under 0.8 mmol/L, or tubular reabsorption of phosphate under 82%.
• FGF23 raised or inappropriately normal (assay dependent).
• Exclude other causes: vitamin D deficiency, Fanconi syndrome (glycosuria, aminoaciduria, bicarbonaturia), drug effects (tenofovir, ifosfamide, iron infusions), X-linked hypophosphataemia and other inherited forms.
• Localisation: somatostatin receptor PET-CT first, then whole body MRI, fluorodeoxyglucose PET-CT or selective venous sampling for FGF23. Confirm by biopsy.

Differential diagnosis.

• X-linked and other inherited hypophosphataemic rickets.
• Fanconi syndrome and drug induced renal phosphate wasting.
• Vitamin D deficiency osteomalacia and hyperparathyroidism.
• Fibrous dysplasia and McCune-Albright syndrome.

• Complete resection with wide margins is curative; phosphate usually normalises within days to weeks. After surgery give calcium and calcitriol for hungry bone and stop phosphate when the level normalises.
• Before surgery, or if the tumour cannot be found or resected: elemental phosphorus 1 to 3 g daily in 3 to 5 divided doses, with calcitriol 0.5 to 1.5 micrograms daily (or alfacalcidol), titrated to phosphate, calcium and parathyroid hormone. Side effects are diarrhoea and secondary hyperparathyroidism.
• Burosumab for unresectable or unlocalised disease: start 0.5 mg/kg subcutaneously every 4 weeks (rounded to the nearest 10 mg), titrated by 0.5 mg/kg to a maximum of 2 mg/kg (180 mg) every 4 weeks, with fasting phosphate. Stop oral phosphate and calcitriol before starting, and avoid if fasting phosphate is over the normal range.
• Radiofrequency or cryoablation, or radiotherapy, for tumours that cannot be resected.
• Analgesia and physiotherapy.

Monitoring. Phosphate, calcium, parathyroid hormone, alkaline phosphatase and urine calcium every 3 months during treatment, then every 6 to 12 months. Renal ultrasound for nephrocalcinosis. Imaging yearly for recurrence for at least 5 years.

Referral and escalation. Endocrinology with an orthopaedic oncologist and nuclear medicine; tertiary centre for localisation.