Tumor-induced osteomalacia

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Tumor-induced osteomalacia, also known as oncogenic hypophosphatemic osteomalacia or oncogenic osteomalacia, is an uncommon disorder resulting in increased renal phosphate excretion, hypophosphatemia and osteomalacia.

Signs and symptoms[edit]

Adult patients have worsening myalgias, bone pains and fatigue which are followed by recurrent fractures. Children present with difficulty in walking, stunted growth and deformities of the skeleton (features of rickets).[1]


Biochemical studies reveal hypophosphatemia (low blood phosphate), elevated alkaline phosphatase and low serum 1, 25 dihydroxyvitamin D levels. Routine laboratory tests do 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, a search for the causative tumor should begin. These are small and difficult to define. Gallium-68 DOTA-Octreotate (DOTA-TATE) positron emission tomography (PET) scanning is the best way to locate these tumors.[2] If this scan is not available, other options include Indium-111 Octreotide (Octreoscan) SPECT/CT, whole body CT or MRI imaging.


FGF23 (fibroblast growth factor 23) inhibits phosphate transport in the renal tubule and reduces calcitriol production by the kidney. Tumor production of FGF23,[3] frizzled-related protein 4 [4] and matrix extracellular phosphoglycoprotein (MEPE)[5] have all been identified as possible causative agents for the hypophosphatemia.

Causative tumors[edit]

Tumor-induced osteomalacia is usually referred to as a paraneoplastic phenomenon, however, the tumors are usually benign and the symptomatology is due to osteomalacia or rickets.[6] A benign mesenchymal or mixed connective tissue tumor (usually phosphaturic mesenchymal tumor and hemangiopericytoma) are the most common associated tumors.[7] Association with mesenchymal malignant tumors, such as osteosarcoma and fibrosarcoma, has also been reported.[7] Locating the tumor can prove to be difficult and may require whole body MRI. Some of the tumors express somatostatin receptors and may be located by octreotide scanning.

Differential diagnosis[edit]

Serum chemistries are identical in tumor-induced osteomalacia, X-linked hypophosphatemic rickets (XHR) and autosomal 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 endopepetidase on the X-chromosome) can be used to conclusively diagnose XHR and testing for the FGF-23 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, treatment with calcitriol (1-3 µg/day) and phosphorus (1-4 g/day in divided doses) is instituted. Tumors which secrete somatostatin receptors may respond to treatment with octreotide. If hypophosphatemia persists despite calcitriol and phosphate supplementation, administration of cinacalcet has been shown to be useful [8]

Popular culture[edit]

In season 2 of the USA Network series Royal Pains, Reshma Shetty (as Divya Katdare) diagnoses a storm chaser (Jamie Ray Newman) with recurring fractures to have tumor-induced osteomalacia.

External links[edit]

  • Royal Pains season 2, episode Astraphabia [1]


  1. ^ Jan de Beur SM Tumor-induced osteomalacia JAMA 2005 Sep 14;294(10):1260-7 PMID 16160135
  2. ^ Clifton-Bligh, R. J.; Hofman, M. S.; Duncan, E.; Sim, I. -W.; Darnell, D.; Clarkson, A.; Wong, T.; Walsh, J. P.; Gill, A. J.; Ebeling, P. R.; Hicks, R. J. (2013). "Improving Diagnosis of Tumor-Induced Osteomalacia with Gallium-68 DOTATATE PET/CT". Journal of Clinical Endocrinology & Metabolism 98 (2): 687–694. doi:10.1210/jc.2012-3642. PMID 23295468. 
  3. ^ Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Shimada T; Mizutani S; Muto T; Yoneya T; Hino R; Takeda S; Takeuchi Y; Fujita T; Fukumoto S; Yamashita T Proc Natl Acad Sci U S A 2001 May 22;98(11):6500-5 doi:10.1073/pnas.101545198 PMID 11344269
  4. ^ Secreted frizzled-related protein 4 is a potent tumor-derived phosphaturic agent.Berndt T; Craig TA; Bowe AE; Vassiliadis J; Reczek D; Finnegan R; Jan De Beur SM; Schiavi SC; Kumar R J Clin Invest 2003 Sep;112(5):785-94 doi:10.1172/JCI200318563 PMID 12952927
  5. ^ MEPE, a new gene expressed in bone marrow and tumors causing osteomalacia. Rowe PS; de Zoysa PA; Dong R; Wang HR; White KE; Econs MJ; Oudet CL Genomics 2000 Jul 1;67(1):54-68 doi:10.1006/geno.2000.6235 PMID 10945470
  6. ^ Carpenter TO Oncogenic osteomalacia—a complex dance of factors N Engl J Med. 2003 April 24:348(17):175-8 PMID 12711747
  7. ^ a b Zadik Y, Nitzan DW (October 2011). "Tumor induced osteomalacia: A forgotten paraneoplastic syndrome?". Oral Oncol 48 (2): e9–10. doi:10.1016/j.oraloncology.2011.09.011. PMID 21985764. 
  8. ^ Geller J L et al Cinacalcet in the management of tumor-induced osteomalacia J Bone Mineral Research 2007 Jun; 22(6)931-37 PMID 17352646

Further reading[edit]

Chong WH, Molinolo AA, Chen CC, Collins MT., Tumor-induced osteomalacia Endocr Relat Cancer. 2011 Jun 8;18(3):R53-77 [2]