Introduction
Tumour induced osteomalacia (TIO), previously known as oncogenic osteomalacia, is a rare paraneoplastic metabolic bone disorder characterised by renal phosphate wasting, hypophosphatemia, and osteomalacia (Carpenter, 2003). This complex paraneoplastic syndrome was first described in 1947 by McCance with less than 500 reported cases to date. Lack of awareness amongst clinicians often leads to substantial delays in the diagnosis of this rare condition with significant implications for affected individuals.
The pathogenesis of TIO is related to uncontrolled secretion of fibroblast growth factor 23 (FGF-23) by mesenchymal tumour tissues. FGF23 regulates vitamin D and phosphate metabolism as it inhibits phosphate reabsorption at the proximal tubule, promoting renal phosphate excretion and inhibiting calcitriol production (Perwad et al. 2007). Low serum phosphate is physiologically accompanied by suppressed FGF23; consequently, finding of elevated serum FGF23 in hypophosphatemia strongly suggests either TIO (Chong et al 2011) or a hereditary syndrome such as X-linked hypophosphatemic rickets (XLH), autosomal dominant (ADHR) and autosomal recessive (ARHR) hypophosphatemic rickets (Yamazaki et al. 2002).
We present a patient with TIO in whom the delayed diagnosis was accompanied by serious physical and psychosocial disabilities that have significantly improved after surgical resection of causative tumour.
Case Presentation
A 48-year-old man presented with an acute exacerbation of chronic lower back pain and severe bilateral leg weakness, present for at least 6 years. Pain severely restricted his mobility confining him to life in his apartment. He was of short stature with height of 155 cm, weight of 80kg, and BMI of 33. Neurological examination revealed predominantly proximal muscle weakness in both upper and lower limbs and associated muscle wasting. Whole spine MRI demonstrated mild disc disease without any obvious thoracolumbar spine fractures or enhancing lesions. Nerve conduction studies (2017) showed no evidence of generalised large fibre neuropathy or demyelinating features, and without clear neurogenic or myopathic features in the muscles sampled. Screens for vasculitis and multiple myeloma were negative.
Biochemistry found hypophosphatemia (0.21-0.76 mmol/L, reference range (RR) 0.75-1.50 mmol/L)) and despite intravenous and oral phosphate supplementations (up to 1g/day) his phosphate values did not revert to the normal reference range. Serum calcium level remained within normal range. He had consistently raised alkaline phosphatase (ALP) between 175-347 U/L (RR 30-110 U/L), elevated iPTH up to 27.4 pmol/L (RR 1.6-6.9 pmol/L ) and low 1,25(OH)2D of 42 nmol/L (60-200 nmol/L) which improved over time with calcitriol supplementation (up to 1.25 mcg per day). Estimated maximum tubular resorption of phosphorus corrected for glomerular filtration rate (TmP/GFR) revealed reduced fractional excretion of phosphate of 0.433 mmol/L (RR 0.9-1.35 mmol/L for males aged years 45-55), consistent with renal phosphate wasting. A whole-body bone scan revealed thoracolumbar scoliosis and lower limb arthritis. Bone mineral density (BMD) measured by Dual Energy X-ray Absorptiometry (DXA) was severely low with lumbar spine (LS) T score of -4.6, femoral neck (FN) T score of -2.9, and total hip (TH) T score of -4.1.
The patient continued to experience exacerbations of his back pain, not alleviated by CT guided steroid injections, as well pain radiating to his knees, shoulder, and chest. Pelvic CT, skeletal survey and repeat lumbar spine MRI showed no evidence of any lytic lesions or fractures. Over the next 18 months, the patient suffered from minimal trauma fractures involving his bilateral clavicles, multiple ribs, right humeral neck, and left humeral midshaft. After two years, a repeat DXA scan showed decrease in bone density with lumbar spine (LS) T score of -5.2 and total hip (TH) T score of -3.5 despite calcitriol (0.5 mcg twice daily), cholecalciferol (50 mcg daily) and a trial of denosumab. A review of his hormonal assays revealed hypogonadotrophic hypogonadism without evidence of an additional endocrinopathy. No pituitary pathology was found on MRI. The patient continued to find phosphate replacement challenging, due to ongoing diarrhoea, hence the progressive hypophosphatemia. Finally, his progressive physical disability led to financial crisis when he lost ownership of his home.
68Ga-DOTATATE ([68Ga-DOTA0-Ty3] octreotate) PET CT scan showed a single focus of significant abnormal uptake in the left femoral head (Figure 1). At this time, serum intact FGF 23 was elevated at 205 pg/mL (DiaSorin Liaison, RR <50 pg/ml). MRI revealed bilateral non-acute femoral neck fractures and left sided avascular necrosis, treated subsequently with bilateral total hip replacement. Histological analysis confirmed the presence of a phosphaturic mesenchymal tumour in the left femoral head measuring 27 mm. Post-operative FGF 23 declined to 12.7 pg/mL post-operatively and remained within the normal reference at 43.1 pg/mL at 10 months after the surgery. His recovery was complicated by “Hungry Bone Syndrome” treated successfully with calcium and calcitriol replacement. He reported complete resolution of his chronic pain. He has become more independent with the activities of daily living without falls or fractures, at 10 months post-surgery. He no longer suffers from severe depression and he has actively participated in his rehabilitation program. Mark’s progress was assessed by the 36-Item Short Form Health Survey (SF-36). Postoperative improvement in Mark’s health status (quality of life (QoL) score of 80 out of 100)) was reflected by his highly perceived satisfaction with change in his overall health (QoL score of 100). In particular, Mark reported a major improvement in his social functioning (QoL score of 50) with lesser change (QoL scores of 30) for both physical functioning and emotional well-being.
Discussion and Literature Review
Classic features of osteomalacia of any cause include bone pain, musculoskeletal weakness, and recurrent pathological fractures (Econs at al.1994). Laboratory features of TIO include hypophosphatemia, phosphaturia, normal PTH and serum calcium, decreased 1,25(OH)2D, elevated ALP and raised FGF-23 (Jan de Beur, 2005). TIO tumours are divided into 4 subtypes with phosphaturic mesenchymal tumour being the most common (Econs et al. 1994). They are generally located in bone or soft tissues (Siegel et al. 2002).
Once diagnosed, TIO prognosis is generally good as most FGF23-secreting tumours are benign and rarely metastasise (Edmister et al. 2002). However, diagnosis of these tumours is frequently delayed by many years due to their occult nature, small size, and atypical location (Jagtap et al. 2011). Tumour resection leads to prompt correction of all the clinical and biochemical manifestations of this syndrome (Chong et al. 2011; Ryan et al. 1984), and gradual re-mineralization of the osteoid matrix (Hautmann et al. 2015). Localisation of FGF23 secreting tumours is often challenging as they are often small in size and slow-growing, moreover, they are frequently located in atypical skeletal sites. Various imaging techniques are often used including functional imaging with octreotide scintigraphy, fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography (PET/CT), Ga68 DOTATATE PET/CT, anatomical imaging with MRI and selective venous sampling for FGF-23 levels (Clifton-Bligh et al. 2013; Colt et al. 2005). In our case, Ga68 DOTATATE PET/CT detected the tumour lesion in our patient. The high sensitivity and specificity of Ga68 DOTATATE PET/CT favours its early use in suspected cases of TIO (Clifton-Bligh et al. 2013).
Medical treatment of TIO involves high doses of oral phosphate and calcitriol, as oral phosphate replacement alone is usually insufficient for correcting hypophosphatemia and often poorly tolerated. Prompt diagnosis and tumour excision can result in a dramatic improvement in the quality of life.