Oral Presentation 29th Australian and New Zealand Bone and Mineral Society Annual Scientific Meeting 2019

Bone appetite (#42)

Shejil Kumar 1 , Terry Diamond 2
  1. Basic Physician Training Network, Royal North Shore Hospital, Sydney, New South Wales, Australia
  2. Endocrinology Department, St George Public Hospital, SYDNEY, New South Wales, Australia

Case summary

Tumour-induced osteomalacia (TIO) is a rare paraneoplastic syndrome usually caused by a fibroblast-growth-factor-23 (FGF-23)-secreting phosphaturic mesenchymal tumour (PMT)1 2. These tumours predominantly occur in bone (40%) or soft tissue (55%) anywhere from head-to-toe1-3. TIO is characterised by hypophosphataemic osteomalacia, impaired renal proximal tubular phosphate reabsorption, suppressed vitamin D synthesis, and elevated circulating FGF-23 concentrations2 3. Although studies have been limited by small sample size, the Gallium-68 (68Ga)-DOTATATE PET/CT scan has demonstrated superior sensitivity and specificity in detecting PMTs over other somatostatin receptor-based studies and the FDG-PET/CT scan4-10. Complete tumour resection is the only established definitive cure2. However, patients with TIO suffer a mean 5.7 years with progressive, debilitating symptoms before receiving definitive treatment2 11 12. Contributing factors include delayed recognition of hypophosphataemia, misdiagnosis or inability to recognise TIO as the cause for symptoms, and difficulty in locating the culprit tumour2 11. Diagnostic difficulty arises due to diffuse and non-specific symptoms of TIO including widespread bone and joint pain and generalised weakness which relate to the paraneoplastic syndrome of hypophosphataemic osteomalacia rather than localised pain from the slow-growing tumours themselves2 4.

Hungry bone syndrome (HBS) is a phenomenon that occurs post-parathyroidectomy in some patients with severe hyperparathyroidism13 14. Accelerated influx of circulating calcium and phosphate into bone to facilitate rapid remineralisation and bone formation results in severe (<2.1 mmol/L) and prolonged (>4 days) post-operative hypocalcaemia13-15. Treatment involves high-dose calcium and vitamin D supplementation13 14. Burosumab, a human monoclonal antibody that neutralises FGF-23, is a potential future therapy for patients with inoperative TIO or prior to resection and may theoretically reduce the risk of HBS16 17. HBS has very rarely been reported in patients with TIO post-tumour resection15.

We present a 36-year-old man who presented with diffuse progressively worsening bone and joint pain and stiffness and muscle weakness. He was incorrectly diagnosed with ankylosing spondylitis and was managed ineffectively for 2 years with NSAIDs, prednisone, etanercept and adalimumab, resulting in symptom progression and severe restriction in his mobility. Whole-body bone scan showed features of metabolic bone disease prompting referral to our endocrine service.

He was found to have persistent hypophosphataemia (0.30-0.43 mmol/L) with inappropriately low renal tubular phosphate reabsorption (80.86%). Corrected calcium (2.23 mmol/L) and 25-hydroxyvitamin D3 levels (57 nmol/L) were normal. Elevated bone-specific ALP levels (106 µg/L) and urine DPD/creatinine ratio (15.8 µmol/mmol) indicated increased bone turnover. PTH level was inappropriately normal (5.8 pmol/L) and 1,25-dihydroxyvitamin D3 level was suppressed (27 pmol/L), suggesting secondary hyperparathyroidism. DEXA BMD scan demonstrated severe osteoporosis at the lumbar spine (0.68 g/cm2, T-score -4.7) and left femoral neck (0.53 g/cm2, T-score -4.1) but not the distal radius (0.96 g/cm2, T-score -0.3). CT-guided bone biopsy was performed on the right iliac crest, indicating severe osteomalacia.

Elevated FGF-23 concentrations (140 ng/L) raised suspicion for TIO. Initial 68Ga-DOTATATE PET/CT scan including the standard field from mid-brain to proximal femora showed no evidence of an underlying neuroendocrine, somatostatin receptor-expressing tumour. Repeat 68Ga-DOTATATE PET/CT scan of the whole body (from vertex to feet) revealed focally increased tracer uptake (SUVmax 38.3) in the proximal left fibula. MRI scan confirmed a well-marginated 17-18mm lesion in the left fibular head demonstrating diffuse contrast enhancement.

Prior to tumour resection, he was commenced on high-dose phosphate (1000mg TDS) and calcitriol (0.5µg TDS). He then underwent en-bloc tumour resection which yielded an astronomically high FGF-23 concentration in the ex-vivo tumour aspiration (16,600 ng/L). Histopathological examination demonstrated complete resection of an intraosseous tumour classified as PMT-mixed connective tissue variant (PMT-MCT). Immunohistochemistry showed diffuse strongly positive staining for FGF-23 and SSTR2A.

Within 2 days post-operatively, FGF-23 concentrations (<10 ng/L) declined below the normal-range. After 2 weeks, serum phosphate normalised and remained stable between 1.09 and 1.29 mmol/L. Bone-specific ALP and urine DPD/creatinine ratio also decreased within 1 month. Three weeks post-operatively, he developed muscle cramps associated with profound hypocalcaemia to 1.77 mmol/L and urinary calcium excretion decreased to 0.7 mmol/day, suggestive of HBS. Therapy was adjusted to provide high-dose caltrate (1200mg QID) and calcitriol (0.5µg QID) and low-dose phosphate (500mg BD). His serum calcium (2.38 mmol/L) and urinary calcium excretion (5.8 mmol/day) subsequently normalised. Repeat DEXA studies 6 months post-resection showed significant improvement in BMD of 95.4% at the lumbar spine (1.32 g/cm2, T-score +0.7) and 89.8% at the left femoral neck (1.01 g/cm2, T-score -0.5), which were sustained at 18-months follow-up. After 1 year post-operatively, his skeletal pain and stiffness and muscle weakness resolved, and he returned to his pre-morbid level of functioning and mobility. Fifteen months after surgery he maintained normal phosphate (1.21 mmol/L), calcium (2.24 mmol/L) and PTH (4.0 pmol/L) concentrations on minimal therapy. Iliac crest bone biopsy performed 18-months post-tumour resection showed resolution of osteomalacia. His calcium and vitamin D therapy was subsequently ceased.

This case report and discussion of the literature highlights the issues contributing to delayed diagnosis and treatment of TIO and helps alert clinicians to the rare complication of post-operative HBS and available and emerging therapies. We believe this case would be suitable for presentation at ‘Clinical Cases in Metabolic Bone Disease Seminar’ given the key clinical focus on dysregulated (and subsequent restoration to normal) bone and mineral metabolism as well as helping clinicians avoid delayed diagnosis and treatment of this debilitating but potentially treatable paraneoplastic syndrome.

Take-home messages

  • When patients present with diffuse skeletal and muscle pain, serum hypophosphataemia can be a simple, sensitive and important clue to the diagnosis of hypophosphataemic TIO.
  • PMTs rarely cause localised symptoms and can occur anywhere from head-to-toe. Therefore, when utilising the 68Ga DOTATATE PET/CT scan to help diagnose FGF-23-producing TIO, we must include the whole body from vertex to feet and not just the standard oncological field from midbrain to proximal femora, to prevent missed diagnosis or inability to locate the tumour.
  • TIOs can be a debilitating condition, especially when undiagnosed or misdiagnosed for several years. However if the syndrome of TIO is recognised and the culprit tumour localised and completely resected, patients can benefit from sustained improvement and resolution of symptoms, mobility, biochemistry, bone mineral density and bone mineralisation.
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