Journal of Diabetes & Metabolic Disorders https://doi.org/10.1007/s40200-019-00398-y CASE REPORT Oncogenic osteomalacia and metastatic breast cancer: a case report and review of the literature Constantinos Savva1,2 & Jason Adhikaree2,3 & Srinivasan Madhusudan2,3 & Kamal Chokkalingam4 Received: 19 December 2018 /Accepted: 14 March 2019 # Springer Nature Switzerland AG 2019 Abstract Objectives Oncogenic osteomalacia is a rare paraneoplastic metabolic syndrome that is characterised by severe hypophosphataemia, hyperphosphaturia and osteomalacia secondary to renal loss of phosphate. It is commonly caused by overproduction of fibroblast growth factor-23 (FGF23) from benign tumours of mesenchymal origin. Currently, there is no clear evidence on the management of oncogenic osteomalacia in patients with metastatic solid tumours. Methods We report a case of breast cancer-induced oncogenic osteomalacia and discuss its diagnosis and management. Results A 71-year-old woman with advanced breast cancer developed symptomatic oncogenic osteomalacia with raised FGF23, severe hypophosphataemia and hypocalcaemia. The electrolytic disturbances were exacerbated after the administration of bisphosphonates in the context of her oncological treatment. Systemic chemotherapy and maintenance endocrine treatment along with phosphate and calcium supplementation reduced the activity of oncogenic osteomalacia and resolved the electrolytic imbalances. Conclusions To our knowledge, this is the first reported case of oncogenic osteomalacia in a patient with breast cancer. Oncogenic osteomalacia constitutes a diagnostic and therapeutic challenge. Pre-clinical and clinical evidence suggest that a possible underlying mechanism is the presence of molecular alterations in the FGF/FGFR signalling pathway leading to over- expression of FGF23. In metastatic setting, anticancer treatment can potentially lead to the normalisation of the electrolytic disturbances and reduction of the activity of oncogenic osteomalacia. The use of antiresorptive therapy in patients with bone metastases can potentially trigger FGF23 overexpression. Its use should be guided by the patients’ risk of skeletal-related events and electrolytic disturbances as well as the degree of activity of oncogenic osteomalacia. Keywords Tumour-induced osteomalacia . Breast cancer . Hypocalcaemia . Hypophosphataemia Introduction Oncogenic osteomalacia is a rare paraneoplastic metabolic bone disease, which is characterised by renal loss of phos- * Constantinos Savva phate [1, 2]. The incidence is largely unknown but more than [email protected] 300 cases have been reported in the literature [3]. Oncogenic osteomalacia is commonly associated with tumours of mesen- 1 Cancer Sciences Unit, Centre for Cancer Immunology, Faculty of chymal origin that secrete the fibroblast growth factor-23 Medicine, University Of Southampton, Tremona Road, (FGF23), a vitamin D- and phosphate-regulating hormone Southampton SO16 6YD, UK [4]. This is the first reported case of breast cancer-induced 2 Translational Oncology, Nottingham Breast Cancer Research Centre, oncogenic osteomalacia. This case constitutes a diagnostic Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG51 PB, UK and therapeutic challenge since the oncological management of metastatic breast cancer involves not only chemotherapy 3 Department of Oncology, Nottingham University Hospitals NHS Trust, Nottingham NG5 1PB, UK and/or endocrine therapy but also bone protection, such as zoledronic acid or denosumab, which can exacerbate the elec- 4 Department of Endocrinology and Metabolic Medicine, Nottingham University Hospitals NHS Trust, Nottingham NG5 1PB, UK trolytic abnormalities caused by oncogenic osteomalacia. J Diabetes Metab Disord Case presentation adenocarcinoma. All the relevant investigations through- out her oncological management are summarised in A 71-year-old woman presented 2 years ago with recurrent Table 1. metastatic oestrogen receptor (ER) positive and human epi- The electrolytic disturbances were managed by dermal growth factor receptor 2 (HER2) negative breast can- discontinuing the zoledronic acid infusions and by initially cer with bone metastases and bone marrow infiltration. She administrating calcium and phosphate infusions. After the received 3 cycles of weekly paclitaxel chemotherapy as well phosphate and calcium were normalised the patient was com- as two cycles of zoledronic acid as a part of her oncological menced on oral calcium and phosphate supplements. She re- treatment. The patient developed symptomatic electrolytic ceived weekly paclitaxel chemotherapy (80 mg/m2 IV infu- disturbances with severe hypophosphataemia and sion, Day 1, 8 & 15), an antimitotic agent which promotes hypocalcaemia after she had received zoledronic acid infu- microtubule stabilisation, thereby inhibiting disassembly re- sion. She had a previous history of early primary breast cancer quired for mitosis. After completing 3 cycles of paclitaxel in 2004 that was treated with wide local excision followed by chemotherapy she was commenced on maintenance endocrine mastectomy and breast reconstruction. She received adjuvant therapy fulvestrant, a subcutaneous oestrogen receptor antag- anastrozole for 5 years. Her medications included ranitidine, onist that is administered 500 mg intramuscularly (IM) 4- amitriptyline and solifenacin. She is a non-smoker and does weekly after an initial loading dose of 500 mg IM 2-weekly not consume alcohol. There was no family history of for three doses. malignancy. Chemotherapy, the subsequent maintenance endocrine The initial laboratory investigations after her first cycle therapy and oral phosphate and calcium supplements, resulted of zoledronic acid showed hypophosphataemia at in the normalisation of the serum electrolytes and an improve- <0.32 mmol/l (0.80–1.45 mmol/l), hypocalcaemia at ment of the FGF23, ALP and PTH (Table 1). The tumour 1.93 mmol/l (2.20–2.60 mmol/l), elevated alkaline phos- markers Ca-153 and CEA improved significantly and the phatase (ALP) at 250 U/l (40–130 U/l), increased parathy- three monthly restaging CT thorax, abdomen and pelvis scans roid hormone (PTH) at 343 ng/l (18–80 ng/l), normal 25 showed stable disease. Nevertheless, 18 months later, a grad- Hydroxyvitamin D (25-HD) at 84 nmol/l (24–167 nmol/l) ual increase in the tumour markers was observed with stable and normal 25-dihydroxyvitamin D (1,25-DHD) at disease in the restaging CT thorax abdomen and pelvis. 57 pmol/l (20–120 pmol/l). The complete blood count, Otherwise, she was asymptomatic with no history of bone liver and renal function tests were all normal. Serum pain or any other cancer-related symptoms. Although the lat- FGF23 was raised at 311 u/ml (normal 0–100 u/ml) which est FGF23 was improving at the value of 121, it was still was consistent with oncogenic osteomalacia. The tumour raised indicating that the patient still has had active oncogenic markers were Ca-153 at 4235 ku/l (normal 0–35 ku/l) and osteomalacia. The rest of the bone profile was normal. At this carcinoembryonic antigen (CEA) was 115 μg/l (normal 0– stage, we considered denosumab, a monoclonal antibody, 3 μg/l) at diagnosis. The baseline staging CT thorax ab- which inhibits the human receptor activator of nuclear factor domen and pelvis showed extensive bone metastases and kappa-B ligand (RANKL). Nonetheless, denosumab was the bone marrow trephine biopsy revealed metastatic withheld because it could potentially cause severe Table 1 Oncological management and laboratory investigations 06/2016 07/2016§ 08/2016 09/2016¶ 11/2016 02/2017 05/2017 01/2018 03/2018 Oncological treatment CT CT & Z CT CT & Z CT ET ET ET ET FGF23 (u/ml) –– –– 311 146 146 121 – ALP (U/L) 138 250 353 144 136 173 105 96 108 PTH (ng/l) 343 – 176 322 406 59 61 52 – 25-HD (nmol/l) 52 – 66 84 57 – 69 79 – Calcium (mmol/l) 1.85 1.93 2.11 1.91 2.11 2.17 2.24 2.34 2.20 Phosphate (mmol/l) 0.60 <0.32 0.41 0.49 0.70 1.27 1.29 1.02 1.03 Ca153 (ku/l) 4235 – 4019 – 2632 1524 1220 1430 1531 CEA (μg/l) 115 – 117 – 76 80 87 123 134 Abbreviations: CT chemotherapy, Z zoledronic acid, ET endocrine treatment, FGF23 fibroblast growth factor 23, ALP alkaline phosphatase, PTH parathyroid hormone, 25-HD 25-hydroxyvitamin D, CEA carcinoembryonic antigen § results obtained 6 days after the administration of zoledronic acid; ¶ results obtained 3 weeks after the administration of zoledronic acid J Diabetes Metab Disord hypocalcaemia and hypophosphataemia on the background of carcinoma [18], small cell lung cancer [19], prostate cancer active oncogenic osteomalacia [5]. [20] and adenocarcinoma of the colon [21]. In cancer, abnormal FGF signalling has been shown to induce cell proliferation, enhance motility, invasiveness and Discussion angiogenesis, evade apoptosis, promote metastasis and resis- tance to anticancer treatment [22]. Impairment of this signal- Oncogenic osteomalacia is a rare paraneoplastic syndrome ling pathway can occur via different pathophysiological that causes severe hypophosphataemia, hyperphosphaturia mechanisms such as amplification of FGFs/FGFRs, mutations and osteomalacia secondary to renal loss of phosphate [6]. in FGFRs, translocations and loss of feedback control [22]. In Secondary hyperparathyroidism may also occur as a normal breast cancer, amplification of FGFR1 and FGFR2 receptors feedback response to low 1, 25-DHD levels [1]. Furthermore, are the most commonly seen molecular alterations with a fre- ALP is elevated due to increased osteoblastic activity.