| Oncogenic osteomalacia/tumor induced osteomalacia | |
|---|---|
| Other names | Tumor-induced osteomalacia |
Oncogenic osteomalacia, also known as tumor-induced osteomalacia or oncogenic hypophosphatemicosteomalacia, is an uncommon disorder resulting in increased renalphosphate excretion,hypophosphatemia and osteomalacia. It may be caused by a phosphaturic mesenchymal tumor. Symptoms typically include autonomic dysfunction, crushing fatigue, severe muscle weakness and brain fog due to the low circulating levels of serum phosphate.
Adult patients may present with worsening musculoskeletal symptoms,muscle weakness,[1]myalgia,bone pain andfatigue which are followed by recurrentbone fractures. Children present withdifficulty in walking,stunted growth and deformities of the skeleton (features ofrickets).[2] There can also be a significant delay between the beginning of symptoms to diagnosis, which research reflects as being between 2.5 and 28 years.[3][1]
Tumor-induced osteomalacia is usually referred to as aparaneoplastic phenomenon, however, the tumors are usuallybenign and the symptomatology is due to osteomalacia or rickets.[4] A benignmesenchymal or mixedconnective tissue tumor (usuallyphosphaturic mesenchymal tumor[5] andhemangiopericytoma) are the most common associated tumors.[6] Association with mesenchymal malignant tumors, such asosteosarcoma andfibrosarcoma, has also been reported.[6]Locating the tumor can prove to be difficult and may require whole bodyMRI. Some of the tumors expresssomatostatin receptors and may be located byoctreotide scanning.
A phosphaturic mesenchymal tumor is an extremely rarebenignneoplasm ofsoft tissue andbone that inappropriately producesfibroblast growth factor 23. Thistumor may cause tumor-induced osteomalacia, aparaneoplastic syndrome, by the secretion of FGF23, which has phosphaturic activity (byinhibition ofrenaltubular reabsorption ofphosphate and renal conversion of25-hydroxyvitamin D to1,25-dihydroxyvitamin D). The paraneoplastic effects can be debilitating and are only reversed on discovery andsurgical resection of the tumor.[6]
FGF23 (fibroblast growth factor 23), and likely other phosphatonins, inhibit phosphate transport in the renal tubule and reduce calcitriol production by thekidney. Tumor production of FGF23,[7]Secreted frizzled-related protein 4[8] andmatrix extracellular phosphoglycoprotein (MEPE)[9] have all been identified as possible causative agents for the hypophosphatemia.
Biochemical studies reveal hypophosphatemia (low blood phosphate), elevatedalkaline phosphatase and low serum1,25 dihydroxyvitamin D levels. Routine laboratory tests may not include serum phosphate levels and this can result in considerable delay in diagnosis. Even when low phosphate is measured, its significance is often overlooked. The next most appropriate test is measurement of urine phosphate levels. If there is inappropriately high urine phosphate (phosphaturia) in the setting of low serum phosphate (hypophosphatemia), there should be a high suspicion for tumor-induced osteomalacia. FGF23 (see below) can be measured to confirm the diagnosis but this test is not widely available.
Once hypophosphatemia and phosphaturia have been identified, begin a search for the causative tumor, which may be small and difficult to detect. Gallium-68 DOTA-Octreotate (DOTA-TATE) positron emission tomography (PET) scanning is the best way to locate these tumors.[10] If this scan is not available, other options include Indium-111 Octreotide (Octreoscan) SPECT/CT, whole body CT or MRI imaging.
Serum chemistries are identical in tumor-induced osteomalacia,X-linked hypophosphatemic rickets (XHR) andautosomal dominant hypophosphatemic rickets (ADHR). A negative family history can be useful in distinguishing tumor induced osteomalacia from XHR and ADHR. If necessary,genetic testing for PHEX (phosphate regulating gene with homologies to endopeptidase on the X-chromosome) can be used to conclusively diagnose XHR and testing for the FGF23 gene will identify patients with ADHR.
Resection of the tumor is the ideal treatment and results in correction of hypophosphatemia (and low calcitriol levels) within hours of resection. Resolution of skeletal abnormalities may take many months.
If the tumor cannot be located, begin treatment with calcitriol (1–3 μg/day) and phosphate supplementation (1–4 g/day in divided doses). Tumors that express somatostatin receptors may respond to treatment with octreotide. If hypophosphatemia persists despite calcitriol and phosphate supplementation, administration ofcinacalcet has been shown to be useful.[11]
