Correspondence *Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, 221 Longwood Avenue, Boston, MA 02115, USA

Email fhalperin@partners.org

The case

A previously healthy 32-year-old man presented to his primary care physician with a 5-month history of pain in his right posterior chest, which had improved over the last month. During the previous several weeks he had developed pain in his right ankle and left hip that prevented him from participating in his previous exercise routine of running and lifting weights.

His past medical history included a diagnosis of rheumatic fever at the age of 12 years, which presented with inflammatory arthritis of his ankles and feet. At the time of presentation he was not taking any medications; he had no other medical problems and there was no significant history of any diseases in his family. Physical examination revealed a tender fullness over the right posterior ribcage and tenderness to palpation in the right mid-foot. Diagnostic studies included a normal X-ray of the right foot and a chest X-ray, which showed a mass-like opacity over the ninth right rib (Figure 1). The patient was referred to an orthopedic surgeon for assessment of his rib mass.

Figure 1 Chest X-ray of the patient at initial presentation.

Mass-like opacity projecting over the ninth right rib can be observed.

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When he presented to the orthopedic surgeon several weeks later, the patient's symptoms had progressed. He had pain in both feet, both hips, upper and lower back and right posterior chest. Laboratory examinations revealed a low serum phosphorus concentration (0.49 mmol/l) and an elevated serum level of alkaline phosphatase (144 U/l; Table 1). A bone scan revealed markedly increased radiotracer uptake in the ninth right rib, and lesser uptake in two other ribs and in both feet (Figure 2A). On MRI of the right foot and left hip there was bone marrow edema, which was interpreted as being consistent with stress-related injuries. A biopsy taken from the rib lesion showed spindle-cell proliferation with osteoclast-like giant cells, which was thought to be a benign or reactive process. The plan of management was to follow the mass with serial imaging. At this time, the patient's low phosphorus level was not addressed.

Figure 2 Bone scans of the patient when first tested and 3 months later.

(A) On the initial bone scan, increased radiotracer uptake can be observed in the ninth right rib, and lesser uptake in two other ribs and both feet, that are attributable to metastasis or trauma. (B) On the bone scan taken 3 months later, additional rib lesions can be observed, which were shown on plain film to be rib fractures, and new intense uptake in both sacroiliac joints that represents sacral insufficiency fractures as confirmed by pelvic MRI.

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Table 1 Results of the patient's laboratory examinations.

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Four months after his initial presentation, the patient was referred to a rheumatologist for evaluation of his persistent musculoskeletal pain, which had progressed to the point of difficulty with deep inspiration, walking, and other activities of daily living. Physical examination revealed tenderness over multiple bones and reduced motion of the spine and ribcage without definite joint deformities. The initial differential diagnosis included a variant of spondylitis as well as microfractures related to metabolic bone disease. A complete laboratory evaluation was performed (Table 1). Notably, calcium levels remained normal, serum phosphorus levels decreased (0.42 mmol/l), 1,25-dihydroxyvitamin D levels were inappropriately low (49.4 pmol/l), and alkaline phosphatase levels further increased (202 U/l), as compared with initial levels. Urinary phosphorus levels were markedly elevated (17.5 mmol/l) with a very low renal threshold phosphate concentration (maximal rate of tubular phosphate reabsorption divided by glomerular filtration rate [TmP/GFR], 0.36 mmol/l). On repeat bone scan there were additional rib lesions, shown on plain film to be rib fractures, and new, intense uptake in both sacroiliac joints (Figure 2B), representing sacral insufficiency fractures as confirmed by pelvic MRI.

A presumptive diagnosis of tumor-induced osteomalacia (TIO) was made. Fibroblast growth factor 23 (FGF-23) levels were elevated (439 10³ relative units/l; Table 1). Potassium-phosphorus 500 mg, three times daily and calcitriol (1,25-dihydroxicholecalciferol) 0.5 g, three times daily were prescribed. Resection of the rib lesion was recommended.

The patient underwent surgical excision of the mass 6 months after initial presentation. Pathology showed features consistent with a phosphaturic mesenchymal tumor. Resection margins were clean, and osteomalacia was present in the surrounding bone tissue. The patient's phosphorus level normalized during the first few postoperative days. By postoperative day 15 all laboratory values had normalized (Table 1). The patient's bone pain continued to improve and 6 months postoperatively it had completely resolved.

Discussion of diagnosis

TIO is a paraneoplastic syndrome of both renal phosphate wasting and abnormal vitamin D metabolism. It is characterized biochemically by high urinary and low serum phosphorus levels, and low or inappropriately normal serum calcitriol levels (hypophosphatemia is a stimulus for production of calcitriol, so levels in the normal range are in fact abnormal in the context of a low serum phosphorus level).^{1, 2, 3} Symptoms of TIO include bone pain (often confused with joint pain), fatigue and muscle weakness. Impaired bone mineralization can eventually result in stress and insufficiency fractures (i.e. fractures that occur in the absence of trauma, related to the application of a physiologic force to abnormal bone). These might not be discernible on initial radiographs. A definitive diagnosis can only be made if tumor resection proves to be curative.²

TIO is caused by circulating tumor-secreted factors, which induce hypophosphatemia and hyperphosphaturia. These phosphaturic peptides are now known as phosphatonins, and FGF-23 is the most extensively described. Under normal circumstances, FGF-23 has an important role in maintaining phosphorus homeostasis.^{3, 4} In patients with TIO, however, circulating levels of FGF-23 on average are higher, which results in phosphate wasting.^{5, 6, 7}

Animal studies have demonstrated that FGF-23 inhibits sodium-dependent phosphate reabsorption in the proximal renal tubules and 1-hydroxylation of 25-hydroxyvitamin D, which, over time, lead to the biochemical and skeletal abnormalities characteristic of TIO. FGF-23 levels decrease significantly and biochemical and skeletal abnormalities improve when the culprit tumors are resected.^{3, 4, 5} FGF-23 also has a central role in the pathogenesis of autosomal dominant hypophosphatemic rickets (ADHR), which is caused by a mutation in the FGF23 gene that makes the peptide resistant to degradation by regulatory proteases (Box 1).⁷

Some patients with TIO have normal FGF-23 levels.^{6, 8} This, together with the examination of TIO-associated tumor genes, led to the discovery of other phosphatonins, including secreted frizzled-related protein 4 (sFRP-4), matrix extracellular phosphoglycoprotein (MEPE) and fibroblast growth factor 7 (FGF-7), whose roles in TIO and normal phosphorus homeostasis are under investigation.³

TIO is a rare condition. Our case illustrates the importance of considering the diagnosis of TIO and assessing serum phosphorus levels in all patients with unusual, persistent musculoskeletal symptoms. Measurement of the phosphorus concentration needs to be specifically requested, as it is no longer part of the standard comprehensive chemistry panel. Otherwise, the diagnosis might be missed or significantly delayed, as is often the case in this disorder.

When the phosphorus concentration is low and TIO is suspected, serum levels of calcium, alkaline phosphatase, parathyroid hormone, 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D should be measured, and a routine chemistry panel should be performed, to help distinguish TIO from other causes of hypophosphatemia and osteomalacia. A spot or 2-hour urine sample should be measured for calcium, creatinine, and phosphorus levels, for calculation of TmP/GFR. A nomogram is used to derive TmP/GFR from serum phosphorus and tubular reabsorption of phosphate (TRP = 1 – [urine phosphorus level] [serum creatinine level]/[urine creatinine level] [serum phosphorus level], all in consistent units). In our patient, TmP/GFR was low despite hypophosphatemia, which indicates renal phosphorus wasting.^{2, 9}

An FGF-23 level can be confirmatory of the diagnosis of TIO. In one series, among 22 patients with clinical evidence of TIO, between 5 and 19 patients had elevated FGF-23 levels, depending on which of the three available assays was used. The sensitivity for the assay used in this case (C-terminal ELISA; Immunotopics, San Clemente, CA) was 92% for patients with confirmed tumors.⁸

Tumors associated with TIO usually originate from bone or soft tissue and are typically benign. The most common histological subtype is 'phosphaturic mesenchymal tumor, mixed connective tissue type'.¹⁰ Localization of the causative tumor is essential, as its resection is the definitive treatment of TIO. Although in our case the tumor was readily apparent on the chest radiograph, these tumors can occur in elusive anatomic locations; therefore, it can be challenging to find them. Careful physical examination, with special attention to the oral cavity and extremities, where these tumors commonly occur, is an important part of the diagnostic evaluation.²

Imaging modalities that have been used for tumor localization include X-ray, CT and MRI. Since a significant proportion of these lesions arise in the nasopharynx and sinuses, CT of the sinus should be considered when other imaging modalities are unrevealing. Because some tumors express surface somatostatin receptors, octreotide scans have been investigated as a diagnostic tool for refractory cases.¹¹ (Octreotide scanning or radiolabeled octreotide scintigraphy is a nuclear imaging method by which radiolabeled octreotide is injected into the patient and then whole body follow-up images are taken. Tumors that have surface somatostatin receptors bind the octreotide and light up on images.) There are also case reports on the successful use of PET scanning.¹²

Differential diagnosis

Osteomalacia, a failure of mineralization of newly formed osteoid tissue, has an extensive differential diagnosis (Table 2). There are three osteomalacia syndromes associated with renal phosphate wasting and abnormal vitamin D metabolism: TIO, ADHR and X-linked hypophosphatemia (XLH). Whereas TIO is acquired, XLH and ADHR are caused by genetic mutations, which, as indicated by their names, differ in their mode of inheritance.¹³ Previous documentation of a normal phosphorus level and a careful assessment of family history are therefore essential to differentiate between these disorders. Although XLH and ADHR typically present in childhood, ADHR can exhibit variable and delayed onset.¹⁴ Distinct pathophysiologic processes result in excess circulating phosphatonins in all three syndromes (Box 1),^{1, 2, 3} leading to inhibition of renal tubular phosphate reabsorption and down-regulation of renal 1-hydroxylase.

Table 2 Differential diagnosis of osteomalacia.

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Discussion of treatment options

The definitive treatment of TIO is complete resection of the tumor, which results in the amelioration of muscle and bone pain and healing of the osteomalacia within several months. Until the tumor is found and resected, or in cases that are managed medically because of inability to localize the tumor, patients require phosphorus (1–4 g per day, in divided doses) as well as calcitriol supplementation (1–3 g per day, once daily or in divided doses). These enhance renal and gastrointestinal phosphorus reabsorption and prevent the development of secondary and tertiary hyperparathyroidism. Therapy should be tailored to the improvement of symptoms and normalization of phosphorus, alkaline phosphatase and parathyroid hormone levels. Complete normalization of phosphorus levels is often difficult because of renal wasting and the gastrointestinal adverse effects (e.g. diarrhea and dyspepsia) of oral phosphorus supplementation.² Patients should be monitored for complications of the medications, which include hypercalcemia, nephrocalcinosis and nephrolithiasis. The use of octreotide in refractory cases has been reported, with variable success.¹⁵

Conclusion

Tumor-induced osteomalacia is a rare condition characterized by tumor-related renal phosphate wasting and abnormal vitamin D metabolism, which results in progressively worsening weakness, bone pain, and insufficiency fractures. This case highlights the importance of considering this disorder and measuring serum phosphorus levels in all patients with unusual, persistent musculoskeletal symptoms. If the tumor can be localized, surgical resection is curative.

References

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Subject areas under which this article appears: Bone and mineral metabolism