Poster Presentation 29th Australian and New Zealand Bone and Mineral Society Annual Scientific Meeting 2019
Osteomalacia due to a phosphaturic mesenchymal tumour of the lateral glenoid (#111)
CASE
A 55 year old woman presented in 2002 with rapidly progressive osteoporosis, multiple fractures and myopathy. She had a 12month history of generalised bony pain associated with 5cm loss of height.
She entered menopause at 42 years old and received hormone-replacement therapy until 54 years old. She had no family history of osteoporosis, osteomalacia or malignancy. She was a lifelong non-smoker and non-drinker.
Regular medications included perindopril 5mg daily and alendronate 70mg weekly (commenced 3 months previously).
Examination revealed marked kyphosis of the thoracic spine and a non-tender pectus deformity. BMI was 20kg/m2. She was not Cushingoid. Blood pressure was 145/125mmHg. Thyroid, breast and abdominal examinations were normal.
Imaging of her spine revealed multiple compression fractures affecting T6-T10. DEXA imaging showed left femoral neck BMD 0.81g/cm2 (T -1.4) and lumbar spine BMD 0.95g/cm2 (T -2.1).
The BMD appeared out of keeping with the degree of fracture, and further investigations (table 1) revealed: hypophosphataemia, normocalcaemia, normal 25-hydroxyvitamin D, low 1,25-dihydroxyvitamin D and normal PTH. Elevated ALP with otherwise normal liver enzymes suggested osteomalacia. Urine biochemistry indicated urinary phosphate wasting.
Tumour-induced osteomalacia (TIO) was suspected, and later confirmed by an FGF23 level 15 times the upper limit of normal (Table 2). Whole body MRI did not reveal an oncogenic focus.
Treatment was commenced with oral phosphate replacement and calcitriol. This rapidly alleviated musculoskeletal symptoms, normalised serum phosphate and suppressed PTH (Table 2, 2002-2004), however renal dysfunction emerged due to nephrocalcinosis.
By 2010, her BMD had deteriorated (lumbar spine BMD 0.83 g/cm2; T – 2.9), and was now in the osteoporotic range (Table 2). Moreover, PTH was rising despite calcitriol treatment.
A parathyroid sestamibi scan demonstrated a small focus of activity adjacent to the medial aspect of the left upper pole, corresponding with an 8x9x7mm hypoechoic region on contemporaneous ultrasound. Minimally-invasive parathyroidectomy was performed, with histopathology favouring parathyroid hyperplasia. PTH-dependent hypercalcaemia persisted, and cinacalcet was commenced in 2012.
In 2011, newly available Ga68-Octreotide PET imaging revealed a solitary octreotide-avid abnormality in the lateral glenoid, corresponding to an abnormal area on CT imaging (Figure 1). Marginal resection was performed, with histopathology consistent with a phosphaturic mesenchymal tumor. There were no cytological atypia to suggest malignancy. FGF23 levels declined from 1910pg/mL (reference <5 pg/mL) preoperatively to 427pg/mL postoperatively. However, serum phosphate remained low and repeat Ga68-Octreotide PET imaging confirmed residual disease (Figure 2). This was treated with radiofrequency ablation, which proved curative.
In 2014, cinacalcet was continued to control hyperparathyroidism and there was no evidence of recurrent FGF23-mediated hypophosphataemia. However, BMD continued to deteriorate (Table 2, 2014). Denosumab 60mg was commenced with subsequent improvement in BMD (Table 2, 2015).
LITERATURE REVIEW
This case is noteworthy for several reasons. Firstly, the unusual presentation of what appeared to be rapidly progressive osteoporosis despite antiresportive therapy in the setting of normal serum 25-hydroxy vitamin D, calcium, and PTH concentrations. Secondly, the protracted time period between presentation and curative treatment, during which the natural history and complications TIO were demonstrated. Finally, the presence of coexisting osteoporosis that became apparent after treatment of osteomalacia.
Osteomalacia is a disorder of impaired bone mineralisation and reduced BMD. It occurs when vitamin D or phosphate deficiency are present after completion of skeletal growth (1, 2). It has has been estimated to affect up to 4% of hospitalised elderly patients and up to 24% of those with hip fracture (2).
Osteomalacia most commonly presents with polyarthralgias, bone pain, and fractures, the latter being the most common reason for referral (3). Inadequate sun exposure and malabsorption syndromes are the most common causes of vitamin D deficient osteomalacia, whereas hereditary disorders and renal tubulopathy are the most common causes of phosphate deficient osteomalacia (3). Serum alkaline phosphatase (ALKP) and parathyroid hormone (PTH) are typically elevated (4).
TIO is a rare paraneoplastic syndrome in which secretion of fibroblast growth factor 23 (FGF23) by tumour cells results in hypophosphataemic osteomalacia (5). FGF23 reduces expression of sodium-phosphate cotransporters in the proximal renal tubule thereby impairing urinary phosphate reabsorption (5). FGF23 also inhibits 1-alpha hydroxylation of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D (5). This results in a syndrome of elevated FGF23, PTH-independent renal phosphate wasting, hypophosphataemia, and inappropriately low/normal serum 1,25-dihydroxy vitamin D (5). The majority of implicated tumours are benign and histologically classified as ‘phosphaturic mesenchymal tumours’ (6). Such tumours are typically small, found in the craniofacial bones or extremities, and are difficult to localise with traditional imaging modalities (7). The average time from biochemical diagnosis to treatment has been reported as five years (7).
Ga68-DOTATATE PET/CT imaging, has proven successful in localising phosphaturic mesenchymal tumours, and can now be considered as first-line functional imaging in suspected cases (5, 8). Following localisation, complete surgical resection is curative. When surgery is not feasible, radiofrequency ablation has been effective in selected cases (9).
If localisation is not possible, symptomatic therapy involves phosphate and calcitriol replacement to achieve a low-normal serum phosphate and normal alkaline phosphatase, PTH, and calcium (7). Chronic oral phosphate replacement may contribute to hyperparathyroidism, which further deteriorates bone density. Hyperparathyroidism may be mitigated in the short-term by calcitriol administration, however in this case prolonged treatment resulted in hypercalcaemia, nephrocalcinosis, and kidney injury.
Serial BMD measurements are helpful in monitoring response to treatment. Typically, gains of 50-60% in BMD at the lumbar spine and hip can be seen within six months after successful treatment (4). This is compared with 2-10% change in BMD seen within 1-7 years after antiresportive treatment for osteoporosis (4). Slowly recovering or plateauing BMD despite treatment of osteomalacia may suggest incorrect or inadequate treatment, or coexisting osteoporosis.
LEARNING POINTS
1. FGF23-secreting tumours are a rare cause of osteomalacia, characterised by renal phosphate wasting, low (or inappropriately normal) 1,25-dihydroxyvitamin D, and elevated FGF23 levels.
2. If TIO is suspected, Ga68-DOTATATE PET/CT is the most appropriate initial imaging modality.
3. Complications of TIO include fracture and hyperparathyroidism, with resultant hypercalciuria, nephrocalcinosis, and renal impairment.
4. Failure to achieve a rapid recovery in BMD following treatment of osteomalacia should raise suspicion for coexisting osteoporosis.
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