A 40-year-old man presents to the emergency department with a 1-week history of progressive weakness of his arms and legs, intermittent cramps in his fingers and feet, and pain in “all of his bones.” These symptoms have limited his activity level. He reports having sharp and dull pain in the bilateral ribs and feet for the past 2 years. Over the course of the last year, he has had progressive pain involving his shoulders, arms, and legs, as well as joint pain in his wrists, knees, and ankles. He has no trauma or fracture history or fever. He has no known medical problems, no history of renal stones, and no loss of height.
On physical examination, his vitals signs are stable. He is afebrile and normotensive with a pulse rate of 96 beats/min. His height is 71 in (177.8 cm). He appears weak and in distress from pain. On musculoskeletal examination, he has full range of motion against gravity but not to slight resistance in the bilateral upper and lower extremities. There is no muscle atrophy in the hands or feet. Pain is elicited on palpation of muscles in the upper arms, lower arms, thighs, and calves. There is no joint swelling or effusions.
Laboratory test results:
Basic chemistry panel, normal
Complete blood cell count, normal
Calcium = 8.9 mg/dL (8.2-10.2 mg/dL) (SI: 2.2 mmol/L [2.1-2.6 mmol/L])
Phosphate = 1.1 mg/dL (2.3-4.7 mg/dL) (SI: 0.4 mmol/L [0.7-1.5 mmol/L])
Albumin = 4.2 g/dL (3.5-5.0 g/dL) (SI: 42 g/L [35-50 g/L])
Alkaline phosphatase = 150 U/L (50-120 U/L) (SI: 2.5 μkat/L [0.84-2.00 μkat/L])
Intact PTH = 104 pg/mL (10-65 pg/mL) (SI: 104 g/L [10-65 ng/L])
25-Hydroxyvitamin D = 20 ng/mL (25-80 ng/mL [optimal]) (SI: 49.9 nmol/L [62.4-199.7 nmol/L])
1,25-Dihydroxyvitamin D = <8 pg/mL (16-65 pg/mL) (SI: 20.8 pmol/L [41.6-169.0 pmol/L])
Chest x-ray shows bilateral rib fractures in various stages of healing but no abnormal masses in the bones or lungs. The patient is admitted to the hospital for medical treatment and further testing.
Which of the following is the best next test to evaluate for the underlying etiology of this patient’s condition?
A. Serum protein electrophoresis
B. Fibroblast growth factor 23 measurement
C. Bone-specific alkaline phosphatase measurement
D. Bone mineral density assessment
E. Serum C-telopeptide measurement
Answer: B
This patient presents with progressive weakness and bone pain associated with severe hypophosphatemia, elevated alkaline phosphatase, and inappropriately low calcitriol. This is suspicious for tumor-induced osteomalacia (TIO) or oncogenic osteomalacia, a paraneoplastic syndrome associated with tumors of mesenchymal origin (eg, sclerosing angioma, benign angiofibroma, hemangiopericytoma, chondrosarcoma). The radiologic imaging shows bilateral rib fractures with no trauma history. Typically, tumors associated with TIO are slow growing, small, and very difficult to localize, which can delay diagnosis of the underlying etiology of osteomalacia.
Tumors associated with TIO overproduce fibroblast growth factor 23 (Answer B), which causes renal tubular loss of phosphate and inhibits 1α-hydroxylase, thus lowering the 1,25-dihydroxyvitamin D level and perpetuating hypophosphatemia. In normal physiology, a low serum phosphate level should activate the 1α-hydroxylase enzyme and cause 1,25-dihydroxyvitamin D to rise to stimulate more intestinal absorption of both phosphate and calcium; this is inhibited by fibroblast growth factor 23 in TIO. In the workup of this disorder, a ratio of tubular maximum reabsorption of phosphate to glomerular filtration rate will be lower than expected for the degree of hypophosphatemia. TIO may be difficult to distinguish from inherited forms of hypophosphatemic rickets (X-linked and autosomal dominant, which are caused by mutations in the PHEX and FGF23 genes, respectively). However, a careful evaluation of the family history can exclude a genetic cause of osteomalacia.
Bone turnover markers can be quite elevated in these patients, but documenting their levels (Answers C and E) will not establish a diagnosis. Multiple myeloma could lead to bone pain and fractures, but with normal renal function and normal complete blood cell count, it is less likely in this case. Thus, performing serum electrophoresis (Answer A) is incorrect. With TIO, the bone density reflects low mineralization and bone mass; however, assessing bone mineral density (Answer D) will not be informative as to the etiology.
Definitive treatment of TIO involves localizing the underlying tumor and treating it, most often by surgery or radiation. As the localization of these small tumors can be challenging, immediate medical therapy should include both calcitriol (to increase intestinal absorption of phosphate and calcium) and potassium phosphate, with the goal of alleviating bone pain.
Educational Objective
Diagnose tumor-induced osteomalacia, a paraneoplastic syndrome, due to overproduction of fibroblast growth factor 23 by the tumor.
Reference(s)
Jan de Beur SM. Tumor-induced osteomalacia. In: Favus MJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 6th ed. American Society for Bone and Mineral Research. 2006:345-351.
Jonsson KB, Zahradnik R, Larsson T, et al. Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. N Engl J Med. 2003:348(17):1656-1663. PMID: 12711740
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