Oncogenic osteomalacia and metastatic breast cancer: a case report and review of the literature.

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 overexpression 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.

Independent and combined effects of acute physiological hyperglycaemia and hyperinsulinaemia on metabolic gene expression in human skeletal muscle.

Physiological hyperglycaemia and hyperinsulinaemia are strong modulators of gene expression, which underpins some of their well-known effects on insulin action and energy metabolism. The aim of the present study was to examine whether acute in vivo exposure of healthy humans to hyperinsulinaemia and hyperglycaemia have independent or additive effects on expression of key metabolic genes in skeletal muscle. On three randomized occasions, seven young subjects underwent a 4 h (i) hyperinsulinaemic (50 m-units·m⁻²·min⁻¹) hyperglycaemic (10 mmol/l) clamp (HIHG), (ii) hyperglycaemic (10 mmol/l) euinsulinaemic (5 m-units·m⁻²·min⁻¹) clamp (LIHG) and (iii) hyperinsulinaemic (50 m-units·m⁻²·min⁻¹) euglycaemic (4.5 mmol/l) clamp (HING). Muscle biopsies were obtained before and after each clamp for the determination of expression of genes involved in energy metabolism, and phosphorylation of key insulin signalling proteins. Hyperinsulinaemia and hyperglycaemia exerted independent effects with similar direction of modulation on PI3KR1 (phosphatidylinositol 3-kinase, regulatory 1), LXRα (liver X receptor α), PDK4 (pyruvate dehydrogenase kinase 4) and FOXO1 (forkhead box O1A) and produced an additive effect on PI3KR1, the gene that encodes the p85α subunit of PI3K in human skeletal muscle. Acute hyperglycaemia itself altered the expression of genes involved in fatty acid transport and oxidation [fatty acid transporter (CD36), LCAD (long-chain acyl-CoA dehydrogenase) and FOXO1], and lipogenesis [LXRα, ChREBP (carbohydrate-responseelement-binding protein), ABCA1 (ATP-binding cassette transporter A1) and G6PD (glucose-6-phosphate dehydrogenase). Surperimposing hyperinsulinaemia on hyperglycaemia modulated a number of genes involved in insulin signalling, glucose metabolism and intracellular lipid accumulation and exerted an additive effect on PI3KR1. These may be early molecular events that precede the development of glucolipotoxicity and insulin resistance normally associated with more prolonged periods of hyperglycaemia and hyperinsulinaemia.

Elevated free fatty acids attenuate the insulin-induced suppression of PDK4 gene expression in human skeletal muscle: potential role of intramuscular long-chain acyl-coenzyme A.

AIM: We investigated the effect of elevated plasma free fatty acid and insulin concentrations on PDK4 mRNA transcript and protein content and long-chain acyl-coenzyme A accumulation in human skeletal muscle. METHODS: On two occasions, 10 healthy men underwent hyperinsulinemic-euglycemic clamps for 6 h with (LIPID) and without (CON) iv Intralipid (20% at 90 ml/h) plus heparin (200 U prime + 600 U/h) infusion. RESULTS: Glucose disposal was approximately 50% lower at the end of the clamp in the LIPID compared with the CON trial (37.8 +/- 4.4 and 79.6 +/- 4.0 micromol/kg lean mass.min, respectively; P < 0.01). In the LIPID trial, muscle long-chain acyl-coenzyme A concentration increased after 6 h, but not 3 h of lipid infusion (P < 0.01). Muscle PDK4 mRNA, but not protein, was down-regulated by 2-fold within 3 h in both clamps and decreased further (6-fold; P < 0.01) at 6 h in the CON but not the LIPID clamp. The lipid-induced attenuation in the suppression of PDK4 gene expression was not dependent on the activation of the Akt/FOXO3 pathway. CONCLUSION: Accumulation of im lipids plays a more important role than impaired activation of Akt-mediated pathways in the regulation of muscle PDK4 gene expression in lipid-induced acute insulin-resistant states.