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

Brittle bones in a big man (#105)

Lisa M Raven 1 2
  1. Macarthur Diabetes Service, Campbelltown Hospital, Campbelltown, NSW, Australia
  2. School of Medicine, Western Sydney University, Campbelltown, NSW, Australia

Tumour induced osteomalacia (TIO), also known as oncogenic osteomalacia, is a rare paraneoplastic syndrome where defective mineralisation of the osteoid occurs secondary to urinary phosphate wasting driven by fibroblast growth factor 23 (FGF-23) secreting mesenchymal tumours (1). The first case was described in 1947 and there have since been over 400 reported cases (2). The culprit mesenchymal tumours are often small and located in a diverse range of locations (2-4).This report highlights the challenges in diagnosing TIO in a young patient with multiple minimal trauma fractures and a history of longstanding hypophosphataemia.

 

A 34 year old male rugby player of Samoan background was admitted to hospital with gradual onset reduced mobility, bilateral hip pain, leg weakness, and low mood. He had been bed ridden for 14 days due to the hip pain. He had a four year history of back pain, reduced mobility and myalgia. There were two prior admissions to hospital in the previous 6 months. The first presentation was with acute on chronic back pain and reduced mobility after a minimal trauma fall, during the admission he received physiotherapy and was discharged home on crutches for further outpatient physiotherapy. The second admission was following a fall, when his legs gave way and he lost balance whilst using the crutches on stairs. During that second admission he underwent C4/5 anterior cervical discectomy and fusion for C4/5 disc protrusion secondary to an osteophyte complex indenting the thecal sac and compressing the spinal cord predominantly on the left side. Other past medical history included asthma since childhood on inhaled corticosteroids, type 2 diabetes for 5 years on metformin, and obesity with BMI 38kg/m2. He had previously had a right radial shaft fracture following injury during a rugby game 12 years prior. There was no family history of osteoporosis, osteomalacia or electrolyte derangement.

 

One week after this presentation to hospital, thoracolumbar spine x-ray showed vertebral body height loss of T6-L4 vertebrae with generalised osteopenia. There was a previous computed tomography (CT) scan of the lumbar spine performed six months prior for investigation of back pain following a fall; this showed vertebral body height loss of 20-30% at all lumbar and visualised thoracic vertebrae, maximal at the T11 level, where there was up to 55% anterior height loss. At this time the patient was planned for outpatient bone mineral density and Endocrine clinic referral, however these did not occur. An MRI scan 2 years earlier demonstrated similar changes and the patient was referred to a physiotherapist for back pain exercises.

 

Pathology results showed persistent hypophosphataemia 0.40-0.61 mmol/L which dated back three years, with previously recorded normal phosphate levels 1.14 mmol/L six years prior. 25-Hydroxy Vitamin D levels had previously been low at 16 nmol/L but replaced with oral cholecalciferol with repeat levels 72 nmol/L. However, 1,25-Dihydroxy Vitamin D was low at 25 pmol/L (RR 60-200) despite normalisation of 25-Hydroxy Vitamin D. Renal function was normal with creatinine 55 umol/L. Corrected calcium was persistently normal at 2.10-2.30 mmol/L with normal PTH 5.6 pmol/L. Bone turnover markers were elevated with C-terminal Collagen Type 1 Telopeptide 1262 ng/L (RR 100-600) and Procollagen Type 1 N-Terminal Propeptide 145 ug/L (RR 15-80). Alkaline Phosphatase was elevated at 381 U/L with other liver function tests within normal limits. In the context of a low 1,25-Dihydroxy Vitamin D and normal PTH, hypophosphatemic osteomalacia from renal phosphate wasting was considered. Early morning spot urine phosphate was elevated at 16.5 mmol/L with paired urine creatinine 15.0 mmol/L. Calculated renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP-GFR) ratio was 0.53 (RR 1.00 - 1.35) demonstrating urinary phosphate wasting. FGF-23 level was elevated at 268ng/L (reference range 23.2 – 95.4). There was a lack of aciduria to suggest Fanconi syndrome, while the absence of childhood fractures or bony deformities made genetic causes of hypophosphataemic osteomalacia unlikely, hence leading to a high index of suspicion for a tumour secreting FGF-23 as the source of the phosphaturia.

 

Nuclear medicine technetium-99m whole body bone scan and SPECT/CT showed prominent diffusely increased uptake in bone with decreased soft tissue uptake and low renal uptake suggestive of metabolic bone disease. There was also focal uptake at the femoral necks bilaterally, inferior/posterior aspect of both sacral alae, throughout the spine and in the left 10th rib and right 12th rib suggestive of pseudofractures or insufficiency fractures.  CT scan of bilateral hips confirmed bilateral subacute fractures of the necks of femur.

 

Ga68 DOTATATE PET-CT scan showed focal intensely increased DOTATATE accumulation (SUV max 35.2) localising to a lobulated subcutaneous soft tissue nodule which measured 20 mm x 11mm in the right mid-thigh medially, lying immediately medial to the adductor muscle and situated between the sartorius anteriorly and gracilis posteriorly.

 

Surgical excision of the soft tissue lesion is currently being planned. In the meantime, medical therapy with Calcitriol and oral phosphate supplementation was commenced.

 

Key learning points:

  1. A chronically low serum phosphate should not be ignored or considered benign.
  2. Osteomalacia should be considered as a diagnosis in young people with minimal trauma fractures.
  3. FGF-23 is an important paraneoplastic cause of renal phosphate wasting.
  4. The tumours that secrete FGF-23 are often small and located in unusual places but may be localised with PET-Dotatate scanning as they express somatastatin receptors.
  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. Qian Y, Dai Z, Zhu C, Ruan L, Thapa S, Wu C. Tumor-induced osteomalacia with the culprit lesion located in the palm: a case report. J Int Med Res. 2019;47(5):2240-7.
  3. El-Maouche D, Sadowski SM, Papadakis GZ, Guthrie L, Cottle-Delisle C, Merkel R, et al. (68)Ga-DOTATATE for Tumor Localization in Tumor-Induced Osteomalacia. J Clin Endocrinol Metab. 2016;101(10):3575-81.
  4. Jadhav S, Kasaliwal R, Lele V, Rangarajan V, Chandra P, Shah H, et al. Functional imaging in primary tumour-induced osteomalacia: relative performance of FDG PET/CT vs somatostatin receptor-based functional scans: a series of nine patients. Clin Endocrinol (Oxf). 2014;81(1):31-7.