Phosphaturic Mesenchymal Tumour and Tumour-Induced Osteomalacia

Fibroblast growth factor 23 (FGF23) is a bone-derived hormone whose physiological job is to lower serum phosphate. A phosphaturic mesenchymal tumour secretes it autonomously and in excess.

Two coordinated effects, both of which are on the exam:

1. Renal phosphate wasting. FGF23 acting through FGF receptor 1 with the co-receptor alpha-Klotho in the proximal tubule downregulates the sodium-phosphate co-transporters NaPi-IIa and NaPi-IIc in the brush border. Tubular reabsorption of phosphate falls, urinary phosphate loss rises, serum phosphate falls.
2. Suppression of active vitamin D. FGF23 inhibits renal 1-alpha-hydroxylase and stimulates 24-hydroxylase. So 1,25-dihydroxyvitamin D is low or inappropriately normal. Normally, hypophosphataemia is a powerful stimulus to 1-alpha-hydroxylase, so a "normal" active vitamin D in the face of a low phosphate is pathological.

Because gut calcium absorption is not driven up, serum calcium stays normal and PTH stays normal (or is only mildly raised late, or after phosphate supplementation). Chronic hypophosphataemia impairs mineralisation of newly formed osteoid — osteomalacia, not osteoporosis. Unmineralised osteoid seams accumulate, bone becomes mechanically incompetent and painful, and insufficiency fractures and Looser zones appear.

How to prove renal phosphate wasting. Take a fasting morning serum phosphate and creatinine with a paired second-void urine phosphate and creatinine. Calculate the tubular reabsorption of phosphate (TRP):

TRP = 1 minus (urine phosphate multiplied by serum creatinine) divided by (serum phosphate multiplied by urine creatinine).

Then derive TmP/GFR from the Walton–Bijvoet nomogram or standard formula. In hypophosphataemia the kidney should reabsorb almost all filtered phosphate (TRP greater than 95 percent). A TRP that is not maximally raised, and a low TmP/GFR, prove inappropriate renal loss. If phosphate is being lost in the gut or shifted into cells instead, TRP will be appropriately high — that excludes TIO.

FGF23 assays. Intact and C-terminal assays exist and are not interchangeable; both are affected by iron deficiency and by iron carboxymaltose. A value that is raised, or simply not suppressed, in the presence of hypophosphataemia is supportive. A normal FGF23 does not exclude TIO if the clinical and TmP/GFR picture fits — a minority of tumours secrete other phosphatonins (secreted frizzled-related protein 4, MEPE, FGF7).

The tumour may be anywhere: bone or soft tissue, head and neck sinuses, femur, tibia, foot, hand, groin, thigh, or the nasal cavity. It is often 1 to 2 cm and has usually been present, asymptomatic and unnoticed, for years.

Cinacalcet has been used adjunctively to blunt the compensatory rise in PTH and reduce phosphaturia, at the cost of hypocalcaemia risk and close monitoring. It is a specialist manoeuvre, not routine.

Indication. A localised, resectable PMT in a patient with biochemically confirmed TIO. There is no role for watchful waiting once the tumour is found and resectable.

Contraindications. Unlocalised tumour; unresectable site with unacceptable functional cost where medical therapy is a reasonable alternative; disseminated malignant PMT (then treat as sarcoma with systemic and local strategies plus burosumab).

Why excision over anything else. It is the only treatment that returns FGF23, phosphate, vitamin D metabolism and bone mineralisation to normal and abolishes lifelong drug therapy and its renal risks.

This is where the orthopaedic surgeon most often meets the disease, and where the most damage is done.

Principles:

1. Do not fix a fracture in undiagnosed osteomalacia. If the biochemistry is not yet done, do it before or at the time of surgery. Fixation into unmineralised bone gives poor screw purchase, cut-out, non-union and periprosthetic fracture.
2. Suspect the pattern. Bilateral or multiple insufficiency fractures, especially symmetrical rib, pubic ramus and femoral neck lesions, in a patient with raised alkaline phosphatase.
3. Undisplaced femoral neck insufficiency fracture in a metabolically untreated patient: protected weight-bearing and metabolic correction alone can achieve union, because these are metabolic pseudofractures rather than traumatic fractures. Displaced or progressive fractures need fixation, but with metabolic therapy running concurrently.
4. Avoid arthroplasty as a reflex. Osteomalacic bone gives poor cement interdigitation and a high early periprosthetic fracture risk. Where arthroplasty is unavoidable, defer until the phosphate is corrected if the clinical situation allows.
5. Antiresorptives are the wrong drug. Bisphosphonates and denosumab do not treat osteomalacia; they may worsen the mineralisation defect and cause severe hypocalcaemia in a mineral-deficient patient. Withdraw them once TIO is recognised.
6. Rehabilitation. Proximal myopathy needs a graded strengthening and gait programme; falls prevention while bone quality is recovering.

Global epidemiology. TIO is rare, reported worldwide with no clear ethnic predilection, affecting men and women roughly equally, most often presenting between the third and sixth decades. Reported case numbers have risen steeply since somatostatin receptor PET became widely available and since serum phosphate became a more frequently requested test — the true incidence is almost certainly higher than historical figures because of under-diagnosis. Paediatric cases occur but are distinctly uncommon and must be separated from inherited rickets.

Society and organisational guidance, where it genuinely applies:

• Endocrine and metabolic bone societies (including the American Society for Bone and Mineral Research and European endocrine bodies) provide the most directly applicable consensus: confirm FGF23-mediated hypophosphataemia biochemically, localise with functional then anatomical imaging, resect completely where possible, and use conventional or anti-FGF23 therapy when resection is not achievable.
• Sarcoma and musculoskeletal tumour guidance (ESMO soft tissue and bone sarcoma guidance, and national sarcoma network standards) applies to the surgical component: biopsy through a planned, excisable tract, referral to a specialist musculoskeletal tumour unit, and margin-directed excision with multidisciplinary review.
• WHO Classification of Soft Tissue and Bone Tumours lists phosphaturic mesenchymal tumour as a distinct entity of uncertain differentiation, most cases benign with a rare malignant variant.
• NICE and equivalent health technology bodies have appraised anti-FGF23 antibody therapy principally in the context of X-linked hypophosphataemia, with variable extension to TIO by jurisdiction — access remains the dominant determinant of practice.
• AAOS and BOA/BOAST documents do not address PMT specifically; their relevance is indirect, through fragility and insufficiency fracture pathways which should prompt metabolic bone screening.

Registries. There is no implant registry relevance here. Instead, the useful data sources are rare disease and metabolic bone registries and multicentre international case series, which have been the mechanism by which localisation strategies and outcomes have been defined. Contributing cases to such registries is the practical way a unit adds to the evidence base.

Practice variation by resource setting.

Across all settings the single highest-value intervention is the cheapest: measuring serum phosphate in an adult with unexplained bone pain and fragility fractures.

• How hard, and how long, to hunt. There is no consensus on the optimal re-imaging interval in occult TIO. Practice ranges from annual to every three years. The argument for persistence is that cure remains available; the argument against is cost and radiation.
• Which functional tracer. Somatostatin receptor PET is first line, but head-to-head data with newer tracers are limited and FDG PET retains advocates for the minority of tumours with low receptor expression.
• Value of selective venous sampling. Some centres regard it as essential when multiple candidates exist; others consider it obsolete given modern PET resolution and the technical failure rate.
• Margin width. Whether a truly wide sarcoma-style margin is needed for a histologically benign tumour, or whether a marginal excision with a thin cuff suffices, is unresolved. The pragmatic position is that recurrence follows enucleation, so aim for a clear cuff without sacrificing critical structures.
• Ablation versus resection. Image-guided thermal ablation avoids morbid open surgery at difficult sites, but leaves no margin assessment and no specimen; persistence rates appear higher.
• Burosumab in localised disease. Whether anti-FGF23 therapy should be used to optimise bone quality before excision or before fracture fixation, and for how long, is an active question without trial data.
• Duration and endpoint of therapy in occult disease. No agreed target phosphate; most aim for the low-normal range to limit hyperparathyroidism and nephrocalcinosis rather than full normalisation.
• Follow-up after cure. Late recurrence is described, but the optimal duration of biochemical surveillance after apparently complete excision of a benign PMT is undefined; annual serum phosphate for at least five years is a common pragmatic compromise.