Poster Presentation 33rd ASM of the Australian & New Zealand Bone & Mineral Society 2023

Broken bones, miserable moans, and unfortunate unknowns (#246)

Tomasz J Block 1 2 , Michael JW Thompson 1
  1. Department of Diabetes and Endocrinology, Royal Hobart Hospital, Hobart, TAS, Australia
  2. Department of Diabetes, Monash University, Melbourne, VIC, Australia

Case-Summary

A 62-year-old female presented to a new specialist for review of profound skeletal fragility with numerous fractures despite 5 years of potent antiresorptive and osteoanabolic treatment. She was initially diagnosed with severe osteoporosis at age 58, when she presented with 12-months of persistent lumbar, hip, and bilateral foot pains associated with prominent myalgias.  Whole body bone scan with SPECT CT demonstrated several minimal trauma vertebral, rib, pelvic and metatarsal fractures. Initial BMD demonstrated a T-score of -3.3 at the lumbar spine (0.779 g/cm2) and -2.9 at the femoral neck (0.655 g/cm2). She was an ex-smoker with a 40 pack-year history and had a BMI of 14.6 kg/m2. There were no syndromic features, nor any history of early onset skeletal fragility or family history of minimal trauma fractures. There were no other significant risk factors for osteoporosis.

Investigation for secondary causes of skeletal fragility included a normal FBC, tryptase, TFT, PTH, HbA1c, corrected calcium and renal function. ALP was 133 U/L (N 30-115). Other LFTs were normal and 25-hydroxyvitamin D was 68 nmol/L. Myeloma assessment, inflammatory & autoimmune markers and 24-hour urinary free cortisol were normal.

Initial treatment comprised optimising dietary calcium, vitamin D supplementation and denosumab 60 mg 6-monthly. However, over the next 12-months her myalgias continued and resulted in progressive disability. Repeat bone scan demonstrated new focal lesions in the left clavicle, left rib cage, bilateral ulnar and right radius, with progressive uptake in bilateral femoral heads. Oncologist review and staging CT of the chest, abdomen, and pelvis, 18FDG-PET, bilateral mammography, pap smear, skin check and colonoscopy did not reveal any signs of malignancy. Bilateral hip MRI demonstrated a 12-mm lesion in the right acetabulum of indeterminate appearance, lacking FDG or scintigraphic uptake. She was subsequently treated with 18-months of teriparatide and then continued regular denosumab. Despite an improvement in BMD with a lumbar spine T-score of -1.7 (+0.22 g/cm2, +28%) and -2.4 at the hip (+0.065 g/cm2, +10%) within 4 years, she continued to experience numerous minimal/no trauma fractures, one of which required a right dynamic hip screw.

Upon referral to an endocrinologist, it was noted she had an acquired and persistent moderate to severe hypophosphatemia (~0.40 mmol/L) over the last 5 years, with a normal serum phosphate 10 years prior. Renal phosphate wasting was demonstrated by a markedly reduced tubular maximum reabsorption of phosphate to glomerular filtration rate (TmP/GFR) of 0.29 (N >0.84) without evidence of a proximal tubulopathy with normal urine glucose and plasma bicarbonate. 1,25 dihydroxyvitamin D was 74 (N 50-190), and IGF-1 and iron studies were normal. FGF23 was elevated at 310 ng/L (N 23.2 - 95.4). A subsequent 68Ga-DOTA PET/CT demonstrated an avid focus in the right acetabulum, corresponding to a 13mm well-circumscribed lucent and stable lesion on CT, present on previous MRI studies. A diagnosis of tumour-induced osteomalacia (TIO) due to a presumed benign FGF-23 producing phosphaturic mesenchymal tumour was made.

She was commenced on phosphate and calcitriol with rapid improvements in muscle strength and reduced myalgias. Serum phosphate increased from 0.37 to 0.78 mmol/L (N 0.8-1.5) within 4 weeks. Currently, she is awaiting an orthopaedic opinion regarding potential resection of the lesion, which may be complicated due to existing metalware in the affected joint. Burosumab via compassionate access is being arranged if definitive treatment is not viable.

 

Tumour-Induced-Osteomalacia

TIO is a rare acquired paraneoplastic syndrome characterised by overproduction of FGF23 by ectopic phosphaturic mesenchymal tumours of the mixed connective tissue type.(1) FGF23 is produced by osteocytes and is the principal regulator of phosphate homeostasis. It acts at the proximal renal tubule to reduce expression of the sodium phosphate cotransporters NaPi-2a/2c causing decreased tubular phosphate reabsorption. FGF23 also inhibits expression of 1-alpha-hydroxylase in the proximal tubules, leading to reduced concentration of calcitriol and subsequent decreased intestinal phosphate and calcium absorption.(2) The resulting hypophosphatemia, phosphaturia, and low or inappropriately normal concentration of calcitriol, lead to muscle weakness, bone pain, osteomalacia, and ultimately fragility fractures.(3) The occult nature, small size, slow growth, and often obscure anatomical location of an underlying tumour leads to an average delay from symptom onset to diagnosis of 2.9 ± 2.3 years, resulting in skeletal deformities and severe disability.(4)

Once TIO is suspected on biochemical and clinical abnormalities, successful tumour localisation is best performed utilising whole-body 68Ga-DOTA PET/CT imaging, which demonstrates the highest sensitivity and specificity.(5) After successful detection of neoplastic lesions with functional imaging, precise localisation is performed using anatomical imaging typically involving CT or MRI.  Complete tumour resection is the only curative treatment for TIO. This results in prompt reversal of the biochemical abnormalities over days and remineralisation of affected bone over 12 months.(6) In cases of incompletely resected tumours, adjuvant radiotherapy has been successfully used in a few patients(7). If tumour localisation or resection is not possible, conventional medical treatment is with oral phosphate and calcitriol supplementation. The aim is to increase serum phosphate to the lower limit of the age-appropriate normal range, normalise ALP, and maintain PTH within the normal range. However, sustained adherence to this therapy is often poor due to treatment burden and gastrointestinal side effects. Major long-term complications include nephrocalcinosis, nephrolithiasis, and secondary/tertiary hyperparathyroidism.(8)

Burosumab is a novel humanised monoclonal antibody against FGF23. It has demonstrated efficacy in two small trials and corrects the biochemical and radiological abnormalities, and physical symptoms associated with osteomalacia in TIO.(9, 10) It is currently PBS listed for X-linked hypophosphataemia, but not for TIO, making access difficult.

  

Take-Home-Points

  • In a patient with multiple/unusual minimal trauma fractures despite potent osteoporosis therapy, it is imperative to consider rarer causes.
  • Persistently low serum phosphate concentration in a patient with fragility fractures should prompt investigation for osteomalacia, FGF-23 excess, and renal phosphate wasting.
  • The diagnosis of tumour-induced osteomalacia is often delayed by several years resulting in significant skeletal deformities and severe disability.
  • 68Ga-DOTA PET/CT is the most sensitive and specific imaging modality to detect mesenchymal tumours hypersecreting FGF23.
  • Tumour resection affords curative treatment, however burosumab has demonstrated effectiveness in small trials and avoids the problems with phosphate and calcitriol supplementation.

 

  1. Folpe AL, Fanburg-Smith JC, Billings SD, Bisceglia M, Bertoni F, Cho JY, et al. Most osteomalacia-associated mesenchymal tumors are a single histopathologic entity: an analysis of 32 cases and a comprehensive review of the literature. Am J Surg Pathol. 2004;28(1):1-30.
  2. Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y, et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res. 2004;19(3):429-35.
  3. Jonsson KB, Zahradnik R, Larsson T, White KE, Sugimoto T, Imanishi Y, et al. Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. N Engl J Med. 2003;348(17):1656-63.
  4. Florenzano P, Hartley IR, Jimenez M, Roszko K, Gafni RI, Collins MT. Tumor-Induced Osteomalacia. Calcif Tissue Int. 2021;108(1):128-42.
  5. Zhang J, Zhu Z, Zhong D, Dang Y, Xing H, Du Y, et al. 68Ga DOTATATE PET/CT is an Accurate Imaging Modality in the Detection of Culprit Tumors Causing Osteomalacia. Clin Nucl Med. 2015;40(8):642-6.
  6. Chong WH, Andreopoulou P, Chen CC, Reynolds J, Guthrie L, Kelly M, et al. Tumor localization and biochemical response to cure in tumor-induced osteomalacia. J Bone Miner Res. 2013;28(6):1386-98.
  7. Mishra SK, Kuchay MS, Sen IB, Garg A, Baijal SS, Mithal A. Successful Management Of Tumor-Induced Osteomalacia with Radiofrequency Ablation: A Case Series. JBMR Plus. 2019;3(7):e10178.
  8. Huang QL, Feig DS, Blackstein ME. Development of tertiary hyperparathyroidism after phosphate supplementation in oncogenic osteomalacia. J Endocrinol Invest. 2000;23(4):263-7.
  9. Jan de Beur SM, Miller PD, Weber TJ, Peacock M, Insogna K, Kumar R, et al. Burosumab for the Treatment of Tumor-Induced Osteomalacia. J Bone Miner Res. 2021;36(4):627-35.
  10. Imanishi Y, Ito N, Rhee Y, Takeuchi Y, Shin CS, Takahashi Y, et al. Interim Analysis of a Phase 2 Open-Label Trial Assessing Burosumab Efficacy and Safety in Patients With Tumor-Induced Osteomalacia. J Bone Miner Res. 2021;36(2):262-70.