Oncogenic osteomalacia

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Oncogenic osteomalacia/tumor induced osteomalacia
Other namesTumor-induced osteomalacia

Oncogenic osteomalacia, also known as tumor-induced osteomalacia or oncogenic hypophosphatemic osteomalacia, is an uncommon disorder resulting in increased renal phosphate 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.

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Signs and symptoms

Adult patients may present with worsening musculoskeletal symptoms, muscle weakness, [1] myalgia, bone pain and fatigue which are followed by recurrent bone fractures. Children present with difficulty in walking, stunted growth and deformities of the skeleton (features of rickets). [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]

Cause

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. [4] A benign mesenchymal or mixed connective tissue tumor (usually phosphaturic mesenchymal tumor [5] and hemangiopericytoma) are the most common associated tumors. [6] Association with mesenchymal malignant tumors, such as osteosarcoma and fibrosarcoma, has also been reported. [6] 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.

A phosphaturic mesenchymal tumor is an extremely rare benign neoplasm of soft tissue and bone that inappropriately produces fibroblast growth factor 23. This tumor may cause tumor-induced osteomalacia, a paraneoplastic syndrome, by the secretion of FGF23, which has phosphaturic activity (by inhibition of renal tubular reabsorption of phosphate and renal conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D). The paraneoplastic effects can be debilitating and are only reversed on discovery and surgical resection of the tumor. [6]

Pathogenesis

FGF23 (fibroblast growth factor 23), and likely other phosphatonins, inhibit phosphate transport in the renal tubule and reduce calcitriol production by the kidney. Tumor production of FGF23, [7] Secreted frizzled-related protein 4 [8] and matrix extracellular phosphoglycoprotein (MEPE) [9] have all been identified as possible causative agents for the hypophosphatemia.

Diagnosis

Biochemical studies reveal hypophosphatemia (low blood phosphate), elevated alkaline phosphatase and low serum 1,25 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.

Differential diagnosis

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 endopeptidase on the X-chromosome) can be used to conclusively diagnose XHR and testing for the FGF23 gene will identify patients with ADHR.

Treatment

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 of cinacalcet has been shown to be useful. [11]

Related Research Articles

<span class="mw-page-title-main">Rickets</span> Childhood bone disorder

Rickets, scientific nomenclature: rachitis, is a condition that results in weak or soft bones in children and may have either dietary deficiency or genetic causes. Symptoms include bowed legs, stunted growth, bone pain, large forehead, and trouble sleeping. Complications may include bone deformities, bone pseudofractures and fractures, muscle spasms, or an abnormally curved spine. The analogous condition in adults is osteomalacia.

<span class="mw-page-title-main">Parathyroid hormone</span> Mammalian protein found in humans

Parathyroid hormone (PTH), also called parathormone or parathyrin, is a peptide hormone secreted by the parathyroid glands that regulates the serum calcium concentration through its effects on bone, kidney, and intestine.

<span class="mw-page-title-main">Osteomalacia</span> Softening of bones due to impaired bone metabolism

Osteomalacia is a disease characterized by the softening of the bones caused by impaired bone metabolism primarily due to inadequate levels of available phosphate, calcium, and vitamin D, or because of resorption of calcium. The impairment of bone metabolism causes inadequate bone mineralization.

<span class="mw-page-title-main">Hyperparathyroidism</span> Increase in parathyroid hormone levels in the blood

Hyperparathyroidism is an increase in parathyroid hormone (PTH) levels in the blood. This occurs from a disorder either within the parathyroid glands or as response to external stimuli. Symptoms of hyperparathyroidism are caused by inappropriately normal or elevated blood calcium excreted from the bones and flowing into the blood stream in response to increased production of parathyroid hormone. In healthy people, when blood calcium levels are high, parathyroid hormone levels should be low. With long-standing hyperparathyroidism, the most common symptom is kidney stones. Other symptoms may include bone pain, weakness, depression, confusion, and increased urination. Both primary and secondary may result in osteoporosis.

<span class="mw-page-title-main">Hypophosphatemia</span> Lack of phosphate in the blood

Hypophosphatemia is an electrolyte disorder in which there is a low level of phosphate in the blood. Symptoms may include weakness, trouble breathing, and loss of appetite. Complications may include seizures, coma, rhabdomyolysis, or softening of the bones.

<span class="mw-page-title-main">Calcitriol</span> Active form of vitamin D

Calcitriol is a hormone and the active form of vitamin D, normally made in the kidney. It is also known as 1,25-dihydroxycholecalciferol. It binds to and activates the vitamin D receptor in the nucleus of the cell, which then increases the expression of many genes. Calcitriol increases blood calcium mainly by increasing the uptake of calcium from the intestines.

Renal osteodystrophy is currently defined as an alteration of bone morphology in patients with chronic kidney disease (CKD). It is one measure of the skeletal component of the systemic disorder of chronic kidney disease-mineral and bone disorder (CKD-MBD). The term "renal osteodystrophy" was coined in 1943, 60 years after an association was identified between bone disease and kidney failure.

<span class="mw-page-title-main">Fibroblast growth factor 23</span> Protein found in humans

Fibroblast growth factor 23 (FGF-23) is a protein and member of the fibroblast growth factor (FGF) family which participates in the regulation of phosphate in plasma and vitamin D metabolism. In humans it is encoded by the FGF23 gene. FGF-23 decreases reabsorption of phosphate in the kidney. Mutations in FGF23 can lead to its increased activity, resulting in autosomal dominant hypophosphatemic rickets.

<span class="mw-page-title-main">Autosomal dominant hypophosphatemic rickets</span> Medical condition

Autosomal dominant hypophosphatemic rickets (ADHR) is a rare hereditary disease in which excessive loss of phosphate in the urine leads to poorly formed bones (rickets), bone pain, and tooth abscesses. ADHR is caused by a mutation in the fibroblast growth factor 23 (FGF23). ADHR affects men and women equally; symptoms may become apparent at any point from childhood through early adulthood. Blood tests reveal low levels of phosphate (hypophosphatemia) and inappropriately normal levels of vitamin D. Occasionally, hypophosphatemia may improve over time as urine losses of phosphate partially correct.

<span class="mw-page-title-main">X-linked hypophosphatemia</span> X-linked dominant disorder that causes rickets

X-linked hypophosphatemia (XLH) is an X-linked dominant form of rickets that differs from most cases of dietary deficiency rickets in that vitamin D supplementation does not cure it. It can cause bone deformity including short stature and genu varum (bow-leggedness). It is associated with a mutation in the PHEX gene sequence (Xp.22) and subsequent inactivity of the PHEX protein. PHEX mutations lead to an elevated circulating (systemic) level of the hormone FGF23 which results in renal phosphate wasting, and local elevations of the mineralization/calcification-inhibiting protein osteopontin in the extracellular matrix of bones and teeth. An inactivating mutation in the PHEX gene results in an increase in systemic circulating FGF23, and a decrease in the enzymatic activity of the PHEX enzyme which normally removes (degrades) mineralization-inhibiting osteopontin protein; in XLH, the decreased PHEX enzyme activity leads to an accumulation of inhibitory osteopontin locally in bones and teeth to block mineralization which, along with renal phosphate wasting, both cause osteomalacia and odontomalacia.

<span class="mw-page-title-main">Dent's disease</span> Medical condition

Dent's disease is a rare X-linked recessive inherited condition that affects the proximal renal tubules of the kidney. It is one cause of Fanconi syndrome, and is characterized by tubular proteinuria, excess calcium in the urine, formation of calcium kidney stones, nephrocalcinosis, and chronic kidney failure.

<span class="mw-page-title-main">PHEX</span> Protein-coding gene in the species Homo sapiens

Phosphate-regulating endopeptidase homolog X-linked also known as phosphate-regulating gene with homologies to endopeptidases on the X chromosome or metalloendopeptidase homolog PEX is an enzyme that in humans is encoded by the PHEX gene. This gene contains 18 exons and is located on the X chromosome.

<span class="mw-page-title-main">CYP24A1</span>

Cytochrome P450 family 24 subfamily A member 1 (abbreviated CYP24A1) is a member of the cytochrome P450 superfamily of enzymes encoded by the CYP24A1 gene. It is a mitochondrial monooxygenase which catalyzes reactions including 24-hydroxylation of calcitriol (1,25-dihydroxyvitamin D3). It has also been identified as vitamin D3 24-hydroxylase.(EC 1.14.15.16)

<span class="mw-page-title-main">MEPE</span> Protein-coding gene in the species Homo sapiens

Matrix extracellular phosphoglycoprotein is a protein that in humans is encoded by the MEPE gene. A conserved RGD motif is found in this protein, and this is potentially involved in integrin recognition.

<span class="mw-page-title-main">Sodium-dependent phosphate transport protein 2C</span> Protein-coding gene in the species Homo sapiens

Sodium-dependent phosphate transport protein 2C is a protein that in humans is encoded by the SLC34A3 gene.

<span class="mw-page-title-main">FAM20C</span> Protein-coding gene in the species Homo sapiens

Family with sequence similarity 20, member C also known as FAM20C or DMP4 is a protein which in humans is encoded by the FAM20C gene. Fam20C, a Golgi localized protein kinase, is a serine kinase that phosphorylates both casein and other highly acidic proteins and members of the small integrin-binding ligand, the N-linked glycoproteins (SIBLING) family at the target motif SerXGlu.

<span class="mw-page-title-main">Elevated alkaline phosphatase</span> Medical condition

Elevated alkaline phosphatase occurs when levels of alkaline phosphatase (ALP) exceed the reference range. This group of enzymes has a low substrate specificity and catalyzes the hydrolysis of phosphate esters in a basic environment. The major function of alkaline phosphatase is transporting chemicals across cell membranes. Alkaline phosphatases are present in many human tissues, including bone, intestine, kidney, liver, placenta and white blood cells. Damage to these tissues causes the release of ALP into the bloodstream. Elevated levels can be detected through a blood test. Elevated alkaline phosphate is associated with certain medical conditions or syndromes. It serves as a significant indicator for certain medical conditions, diseases and syndromes.

Fanconi syndrome or Fanconi's syndrome is a syndrome of inadequate reabsorption in the proximal renal tubules of the kidney. The syndrome can be caused by various underlying congenital or acquired diseases, by toxicity, or by adverse drug reactions. It results in various small molecules of metabolism being passed into the urine instead of being reabsorbed from the tubular fluid. Fanconi syndrome affects the proximal tubules, namely, the proximal convoluted tubule (PCT), which is the first part of the tubule to process fluid after it is filtered through the glomerulus, and the proximal straight tubule, which leads to the descending limb of loop of Henle.

Burosumab, sold under the brand name Crysvita, is a human monoclonal antibody medication approved 2018 for the treatment of X-linked hypophosphatemia and tumor-induced osteomalacia.

<span class="mw-page-title-main">Phosphate diabetes</span> Medical condition

Phosphate diabetes is a rare, congenital, hereditary disorder associated with inadequate tubular reabsorption that affects the way the body processes and absorbs phosphate. Also named as X-linked dominant hypophosphatemic rickets (XLH), this disease is caused by a mutation in the X-linked PHEX gene, which encodes for a protein that regulates phosphate levels in the human body. phosphate is an essential mineral which plays a significant role in the formation and maintenance of bones and teeth, energy production and other important cellular processes. phosphate diabetes is a condition that falls under the category of tubulopathies, which refers to the pathologies of the renal tubules. The mutated PHEX gene causes pathological elevations in fibroblast growth factor 23 (FGF23), a hormone that regulates phosphate homeostasis by decreasing the reabsorption of phosphate in the kidneys.

References

  1. 1 2 Kaur T, Rush ET, Bhattacharya RK (March 2019). "Phosphaturic Mesenchymal Heel Tumor Presenting with Tumor-Induced Osteomalacia". AACE Clinical Case Reports. 5 (2): e138 –e141. doi:10.4158/ACCR-2018-0300. PMC   6873860 . PMID   31967019.
  2. ↑ Jan de Beur SM (September 2005). "Tumor-induced osteomalacia". JAMA. 294 (10): 1260–1267. doi:10.1001/jama.294.10.1260. PMID   16160135.
  3. ↑ Chong WH, Molinolo AA, Chen CC, Collins MT (June 2011). "Tumor-induced osteomalacia". Endocrine-Related Cancer. 18 (3): R53 –R77. doi:10.1530/ERC-11-0006. PMC   3433741 . PMID   21490240.
  4. ↑ Carpenter TO (April 2003). "Oncogenic osteomalacia--a complex dance of factors". The New England Journal of Medicine. 348 (17): 1705–1708. doi:10.1056/NEJMe030037. PMID   12711747.
  5. ↑ Wasserman JK, Purgina B, Lai CK, Gravel D, Mahaffey A, Bell D, Chiosea SI (September 2016). "Phosphaturic Mesenchymal Tumor Involving the Head and Neck: A Report of Five Cases with FGFR1 Fluorescence In Situ Hybridization Analysis". Head and Neck Pathology. 10 (3): 279–285. doi:10.1007/s12105-015-0678-1. PMC   4972751 . PMID   26759148.
  6. 1 2 3 Zadik Y, Nitzan DW (February 2012). "Tumor induced osteomalacia: a forgotten paraneoplastic syndrome?". Oral Oncology. 48 (2): e9-10. doi:10.1016/j.oraloncology.2011.09.011. PMID   21985764.
  7. ↑ Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S, et al. (May 2001). "Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia". Proceedings of the National Academy of Sciences of the United States of America. 98 (11): 6500–6505. Bibcode:2001PNAS...98.6500S. doi: 10.1073/pnas.101545198 . PMC   33497 . PMID   11344269.
  8. ↑ Berndt T, Craig TA, Bowe AE, Vassiliadis J, Reczek D, Finnegan R, et al. (September 2003). "Secreted frizzled-related protein 4 is a potent tumor-derived phosphaturic agent". The Journal of Clinical Investigation. 112 (5): 785–794. doi:10.1172/JCI18563. PMC   182208 . PMID   12952927.
  9. ↑ Rowe PS, de Zoysa PA, Dong R, Wang HR, White KE, Econs MJ, Oudet CL (July 2000). "MEPE, a new gene expressed in bone marrow and tumors causing osteomalacia". Genomics. 67 (1): 54–68. doi:10.1006/geno.2000.6235. PMID   10945470.
  10. ↑ Clifton-Bligh RJ, Hofman MS, Duncan E, Sim I, Darnell D, Clarkson A, et al. (February 2013). "Improving diagnosis of tumor-induced osteomalacia with Gallium-68 DOTATATE PET/CT". The Journal of Clinical Endocrinology and Metabolism. 98 (2): 687–694. doi: 10.1210/jc.2012-3642 . PMID   23295468.
  11. ↑ Geller JL, Khosravi A, Kelly MH, Riminucci M, Adams JS, Collins MT (June 2007). "Cinacalcet in the management of tumor-induced osteomalacia". Journal of Bone and Mineral Research. 22 (6): 931–937. doi: 10.1359/jbmr.070304 . PMID   17352646.

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