From the Medical University of South Carolina, Charleston, SC.
The authors declare no conflict of interest.
Correspondence: Lee Leddy, MD, Medical University of South Carolina, 96 Jonathan Lucas St, MSC 622, Charleston, SC 29425. E-mail: firstname.lastname@example.org.
Oncogenic osteomalacia is a rare paraneoplastic syndrome of systemic bone demineralization secondary to a tumor-induced dysregulation of phosphorus metabolism. Originally described in 1947 by Robert McCance,1 the causative mesenchymal tumor is found in bone (53%), soft tissue (45%), and skin.2 Its small size, variable tissue type, abnormal location, and presentation pose a diagnostic challenge. Patients often experience a prolonged period of muscular weakness and bone pain before diagnosis and are frequently misdiagnosed with a variety of musculoskeletal disorders, rheumatologic diseases, and sometimes even psychiatric or neurologic disorders.3,4
With surgical removal of the tumor and the circulating endocrinologic factors, patients dramatically return to baseline. Whereas biochemical abnormalities and symptoms tend to resolve within hours, return to previous bone mineralization requires months to years to achieve. We report the case of a 63-year-old man with a 20-month course of musculoskeletal symptoms before surgical resection of a phosphaturic mesenchymal tumor. Postoperatively, the patient had returned to his previous active lifestyle when he experienced a new-onset pain and an impending insufficiency fracture. To our knowledge, this is the first case of an impending long-bone fracture after surgical resection of oncogenic osteomalacia. We additionally review the literature with discussion on pathogenesis, diagnosis, and treatment of phosphaturic mesenchymal tumors.
A previously healthy 63-year-old white man presented to a rheumatology clinic 18 months after having received a diagnosis of osteoporosis for a self-referred evaluation and second opinion. He reported an active lifestyle (body mass index, 28 kg/m2) with no history of smoking. Three years prior, he began experiencing musculoskeletal pain first in the lateral foot. The following year, left-sided rib-cage pain began while hitting golf balls. Multiple subacute rib fractures were noted on computed tomography (CT). A subsequent dual x-ray absorptiometry scan (T score of spine, −3.6; left femoral neck, −2.5) led to the diagnosis of osteoporosis, and medical management was instituted.
Despite pharmacologic treatment, his musculoskeletal pain progressed. He was no longer capable of ambulating without assistance. Computed tomography of the pelvis displayed subacute insufficiency fractures bilaterally in the pubic symphysis, left pubic bone at the anterior column of the acetabulum, right posterior iliac bone adjacent to the sacroiliac joint, and a chronic insufficiency fracture at the left S1 level (Fig. 1).
Laboratory testing displayed normal levels of serum calcium and parathyroid hormone. 25-Hydroxyvitamin D was at the low end of normal (35 ng/mL [reference range, 30–74 ng/mL]). Alkaline phosphatase was slightly elevated (263 IU/L [reference range, 25–100 IU/L]), but this would be expected in the setting of multiple fractures. Serum phosphorus was significantly low (1.4 mg/dL [reference range, 2.4–4.7 mg/dL]), whereas a 24-hour urine phosphorus was inappropriately within normal limits (493 mg/24 h). A fibroblast growth factor 23 (FGF-23) level was obtained and found to be elevated at 785 RU/mL (reference, <180 RU/mL).
An octreotide scan (111In pentetriotide scintigraphy) displayed an abnormal focus of radiotracer accumulation in the soft tissue adjacent to the medial tibial plateau (Fig. 2). A follow-up magnetic resonance imaging localized a 5 × 5 × 8-cm soft tissue mass posterior to the proximal tibia between the medial head of the gastrocnemius and soleus extending close to the tibia (Fig. 3). No invasion of the adjacent musculature, cortex, or nodal involvement was noted. A presumed diagnosis of oncogenic osteomalacia was made, and the mass was resected en bloc with negative margins by an orthopedic oncologist. Histopathology later confirmed a benign mesenchymal tumor with a low nuclear grade. No mitoses were noted. The patient was discharged from the hospital on calcium and vitamin D supplementation. Previous osteoporosis medications were discontinued.
Two weeks after the operation, the patient’s symptoms had dissipated, and he had regained the ability to walk without assistance. Serum phosphorus level had returned to normal. Abruptly, he experienced an episode of focal left-sided hip pain during minimal activity. Subsequent magnetic resonance imaging demonstrated no abnormal marrow signal adjacent to the majority of the medial femoral “pseudofracture,” consistent with a dormant Looser zone (Fig. 4). However, high T2 signal was seen extending from the apex of this, consistent with an insufficiency fracture. Radiographs of the pelvis continued to display thinning of the cortex and indistinct margins consistent with preoperative films (Fig. 5). The patient was taken back to the operating room where the impending pathologic fracture of the femur was prophylactically stabilized with intramedullary rod placement. At 6-week follow-up, he reported a return to the active lifestyle he was living 3 years prior (Table 1).
Osteomalacia is a metabolic bone disorder of inadequate mineralization of mature bone resulting from a variety of inherited and acquired causes. One of the most unusual types of osteomalacia is oncogenic osteomalacia, also referred to as tumor-induced osteomalacia, in which systemic bone demineralization is caused by a neoplasm overexpressing a phosphaturic substance. Composed of spindle-shaped cells of mesenchymal origin, tumors causing osteomalacia are classified as phosphaturic mesenchymal tumor, mixed connective tissue variants.5 Although a few malignant presentations have occurred, these tumors are overwhelmingly benign with low nuclear grade and absent to very low mitotic activity.5,6
Current evidence points to FGF-23 as the causative humoral factor responsible for this type of osteomalacia.7 Through decreasing renal phosphate transporters (NaPi-IIa and NaPi-IIc) in the proximal tubule and down-regulating activating enzymes of vitamin D, FGF-23 causes inappropriate renal excretion of phosphorus and impairs phosphorus absorption from the gastrointestinal tract. In the setting of hypophosphatemia, the 24-hour renal excretion of phosphorous should be low in an attempt to maintain serum phosphorous levels; however, the phosphaturic effect of FGF-23 results in an inappropriately high level of urinary phosphorous. The resulting hypophosphatemia limits mineralization of new bone while enhancing osteoclastic resorption resulting in the hallmark findings of bone fragility and constitutional symptoms associated with oncogenic osteomalacia.
Patients presenting with new-onset osteomalacia, particularly those with atypical presentations or few risk factors, should incur a workup for potential reversible causes. Oncogenic osteomalacia should be considered in any diagnosis of hypophosphatemic osteomalacia. In our patient, the rapid course and severity of osteomalacia in the context of relatively few risk factors prompted a clinical investigation. Our patient presented with serum phosphorus well below normal limits with an inappropriately high level of phosphorus in the urine. Once acquired causes were ruled out and a negative family history of osteomalacia was obtained, an FGF-23 serum level was ordered. Given such a clinical scenario, the high sensitivity of the serum FGF-23 (100% Kainos assay, 92% Immunotopics assay) is an ideal screening test for oncogenic osteomalacia.8
An elevated FGF-23 assay should be followed with imaging modalities to localize the tumor for possible surgical planning and to confirm the diagnosis. The small size, slow-growing nature, variable location, and tissue composition pose a challenge for localization of the tumor. In this case, we used octreotide scintigraphy (Fig. 2). This method proves to be very specific, yet its sensitivity relies on the presence of somatostatin receptors. False-negative rates have been reported upward of 30%.9 A second imaging modality shown to be sensitive at times when octreotide scintigraphy has not been successful is 18F fluorodeoxyglucose positron emission tomography (PET) scan with CT.10,11 More recently, a single case report has combined the specificity of octreotide scintigraphy and sensitivity of PET/CT into Ga DOTANOC PET/CT. This technology uses a modified octreotide molecule (DOTANOC) combined with a positron emitter in addition to PET/CT.12
Surgical resection with wide margins is the treatment of choice and equates to a complete remission of symptoms within hours to days (half-life of FGF-23 is ∼45 minutes).13 Those tumors not able to be localized or resected can be treated medically. Pharmacologic treatment is essentially the same as treating other forms of hypophosphatemia (X-linked hypophosphatemia) and consists of long-term supplementation of calcium and active vitamin D.14 Recently, medical management through antagonizing FGF-23 has been investigated both directly with monoclonal antibodies15 and indirectly by exploiting the dependent relationship between FGF-23 and parathyroid hormone.16–18
Although symptoms and biochemical abnormalities resolve quickly, improvement of bone mineral density is more prolonged. In our patient, 2 weeks after surgical resection, new musculoskeletal symptoms presented. A new impending proximal femur fracture in the area of a stable Looser zone was identified (Fig. 4). To our knowledge, this is the only report of a long-bone fracture after complete surgical resection of a tumor causing oncogenic osteomalacia.
The timeline of bone remineralization after tumor removal has been studied in a small number of case reports. Umphrey et al.19 demonstrated an increase in bone mineral density of 111% in the lumbar spine and 97% at the femoral neck at 4 months after surgical resection. At 12 months, the patient’s bone mineral density had essentially normalized. Interestingly, the disease process does not appear to be completely reversible in the bones of the forearm in comparison to the spine and femur.19,20 Although the bone mineral density of the distal radius improved after surgical resection (0.128 to 0.259 g/cm2 after 12 months), it continued to have a significantly low T score (−4.9).19
In conclusion, all physicians should be aware of this unusual tumor because it is a rare clinical disease in which complete reversal of symptoms can be obtained. Through awareness, aggressive early workup, and prompt treatment, the debilitating painful symptoms and potential long-term disability can be avoided. Although symptoms may quickly disappear and the patient may be able to return to predisease activity levels, physicians and patients should be cautioned that the risk of bone fragility may, in fact, persist for months during the process of metabolic amelioration.
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