History
A 79-year-old woman presents to the emergency department (ED) with a chief complaint of a 3-day history of right hip pain. She only mildly twisted her right leg 3 days ago; she has since had increasing pain and difficulty walking. The pain is sharp and radiates down to her right knee. It is mild when she is at rest, but it becomes severe when she attempts to walk. She has not had any weakness or numbness. She denies having any fevers. She has not had any direct trauma to the hip or falls, and there has not been any notable swelling of the leg or skin changes/rash. The review of systems also reveals that she has unintentionally lost 8.8 lb (4.0 kg) over the last 6 months. She denies having any nausea, vomiting, night sweats, cough, or shortness of breath. She has a history of multiple rib fractures that resulted from vigorous coughing 2 years ago; at that time, she was diagnosed only with osteoporosis as the cause of these fractures. She denies having any previous fractures otherwise. Her past medical history also includes chronic obstructive pulmonary disease (COPD), although she has never been a smoker. She also has known osteoarthritis of the hips, scoliosis of the thoracic spine, and a presumptive diagnosis of Paget disease on the basis of a single elevated serum alkaline phosphatase. Her medications include budesonide/eformoterol and terbutaline inhalers, oral calcium and vitamin D supplements, and weekly alendronate. A bisphosphonate was started after dual-energy x-ray absorptiometry (DXA) showed a T score of -2, which is consistent with osteopenia. Both her mother and sister had broken their hips later in their lives. She lives independently and is still driving. She denies experiencing physical abuse, and there are several family members accompanying her in the ED who show concern for her.
On physical examination, the patient appears well and is lying comfortably in bed. Her heart rate is 84 bpm and regular, with a blood pressure of 140/80 mm Hg. Her temperature is normal at 98.9°F (37.2°C), and her respiratory rate is 14 breaths/min. Her cardiovascular, respiratory, and abdominal examinations are all normal. She has moderate pain with any movement of the right leg and has groin tenderness on palpation. The right leg is shortened and externally rotated. Her peripheral pulses are palpable, and she has normal distal strength and sensation in the right lower extremity.
Her blood tests reveal a normal complete blood cell (CBC) count; however, her electrolytes show a significantly depleted phosphate concentration of 0.9 mg/dL (0.29 mmol/L; normal range, 3-4.5 mg/dL). Additional laboratory results include a creatinine of 0.68 mg/dL (60 μmol/L; normal range, <1.5>
Hint: The serum phosphate is low, but the serum calcium is preserved.
Investigation
A chest radiograph reveals multiple healed rib fractures.
Radiographs of the pelvis and right hip are obtained as well, which reveal a right femoral neck fracture.
The pelvic radiograph clearly demonstrated osteomalacia. The patient was admitted to the hospital for open reduction and internal fixation of her fractured right femoral neck. Evaluation of her left femoral neck revealed suspicion of a pseudofracture, which was also fixed. Of note were the multiple (pseudo) fractures in the pubic rami and pelvic ring.
The lowered serum phosphate was the primary clue to the underlying cause. No previous serum phosphate measurements were available for comparison. In order to determine the etiology of the hypophosphatemia, a urinary phosphate measurement must be obtained. This is best done with patient fasting, and it may be done with a single specimen. In this patient, the urinary calcium-to-creatinine ratio was normal at 0.4, and the urinary phosphate-to-creatinine ratio was elevated at 5.4. A calculation of tubular reabsorption of phosphate showed a low value of 0.325 (normal, 0.82-0.95), confirming renal phosphate wasting. A number of causes for increased urinary phosphate excretion had to be considered. Primary and secondary hyperparathyroidism were essentially excluded by the normal serum calcium and creatinine levels. Vitamin D deficiency or resistance was excluded by an adequate serum vitamin D level. Fanconi syndrome was excluded by the negative myeloma screen, normal uric acid level, and absence of glucosuria. Hereditary hypophosphatemic rickets (X-linked, autosomal dominant, or recessive) was highly unlikely because of the patient's advanced age. The serum and urine studies were, however, consistent with a diagnosis of oncogenic (or tumor-induced) osteomalacia. This acquired renal phosphate wasting syndrome of oncogenic or tumor-induced osteomalacia is now known to be caused by raised serum fibroblast growth factor (FGF)–23. The pathognomonic signs of this condition include adult-onset osteomalacia with low serum phosphate, normal serum calcium, and renal phosphate wasting. Calcitriol levels are low as a result of the weak inhibitory effect of FGF-23 on the renal 1 alpha-hydroxylase enzyme; however, they need not be measured to secure the diagnosis. The serum parathyroid hormone was mildly elevated as a result of the mild decrease in active vitamin D. The mechanism for bone loss is incompletely understood; it is partly caused by the disturbed phosphate metabolism and, to a lesser degree, the abnormal vitamin D metabolism.
The exact epidemiology of this condition is unknown. It is certainly rare, by 1999, only approximately 100 cases had been reported in the literature.[1] On the basis of the description of these cases, the clinical presentation appears to be wide and ranges from musculoskeletal pain, proximal muscle weakness, and bony tenderness to frank osteomalacia and pathologic fractures. It is vital to check the serum phosphate level in any patient with unexplained musculoskeletal symptoms and/or pathologic fractures. Confirmation of the diagnosis can be made with a serum FGF-23 measurement.
FGF-23 is a phosphatonin secreted autonomously from tumor cells in oncogenic osteomalacia. FGF-23 inhibits the sodium-phosphate cotransporter in the renal tubules, such that less phosphate is reabsorbed, resulting in urinary phosphate wasting. Of the phosphate that the kidneys filter each day, 85% to 90% of it is reabsorbed by the sodium-phosphate cotransporters in the renal tubules. Autosomal dominant hypophosphatemic rickets is caused by mutations in the FGF-23 gene, located on chromosome 12p13. Part of the metabolism of FGF-23 is degradation by PHEX, a membrane-bound endopeptidase; however, uncontrolled secretion of FGF-23 by certain tumor cells saturates the PHEX degradation capability, which allows FGF-23 action to be unlimited. Serum levels of FGF-23 are almost universally elevated in this condition, and they can be monitored after treatment for identification of disease recurrence.[2] Other putative phosphatonins are the topic of active research.
The vast majority of the causative tumors are small, benign, and themselves asymptomatic,[3][3] If STIR MRI is unhelpful, an octreotide scan can be performed for localization of the tumor.
T2-weighted short-tau inversion-recovery (STIR) magnetic resonance imaging (MRI) is recommended as the first step in locating the tissues. Any abnormal areas should be scanned in more detail to find the causative tumor. Once identified, the tumor must be removed. The serum FGF-23 level and serum phosphate concentration should normalize postoperatively. If not normalized, further exploration for the causative tumor is indicated. The histology usually reveals a phosphaturic mesenchymal tumor (mixed connective tissue variant) or a hemangiopericytoma. In the majority of cases, the nuclear grade is said to be low. Mitotic activity is usually low or absent, and the cellularity is also low. Although most cases appear relatively well-circumscribed on low-power magnification, even the benign tumors may infiltrate the surrounding connective tissues. The finding of osteoid-type tissue within the tumor is common in both soft-tissue and bone samples. The matrix may be noted to be highly calcified, which correlates with the finding of numerous osteoclast-like giant cells. More than 50% of the soft-tissue samples show a partial shell of woven bone. In one series only 3 samples (less than 10%) fit the criteria for being labeled "malignant," indicating that this is a relatively rare event. As such, this condition is rarely fatal, and morbidity can be avoided by timely diagnosis and tumor removal.
This patient was treated with an oral high-dose phosphate supplement to normalize her serum phosphate before her operation. She then had an open reduction and internal rotation performed, with an uncomplicated postoperative course. She successfully completed a course of inpatient rehabilitation and was discharged to home without incident. Her preoperative serum FGF-23 was measured and found to be elevated at 355 U/mL (normal range, 3-45 U/mL). A STIR MRI image indicated an area of abnormality in her left ethmoid sinus. A computed tomography (CT) scan of her sinuses revealed a mass lesion in the left posterior ethmoid sinus obstructing the left sphenoidal sinus, with no sign of bony destruction. Review of the literature revealed that sinus tumors cause 5-10% of cases of oncogenic osteomalacia.[3] This patient proceeded to undergo an uneventful resection of this tumor, which was a mesenchymal hemangiopericytoma of the phosphaturic type. She made a full clinical recovery with normalization of her serum phosphate levels postoperatively; serum FGF-23 did not need to be measured provided that the phosphate levels remain normal. In the event that they remain low, then the FGF-23 should be rechecked, and if this is persistently elevated a further search for the causative tumor should be made. DXA was not repeated because the diagnosis of osteomalacia made this redundant.
Questions
You diagnose the patient you are examining with osteomalacia and suspect that the disease may be oncogenic in nature. Which of the following methods is considered the best for finding the tumor responsible for oncogenic osteomalacia?
Answer first before you scroll down.
Answer:
Not all patients will have radiologic evidence of osteomalacia at onset; therefore, a full skeletal survey is not helpful and exposes the patient to too high a level of radiation. The tumors are usually benign and often small. STIR MRI T2-weighted imaging is the most helpful study; further dedicated imaging for any areas of abnormality detected on this scan should be performed. Octreotide scanning is generally considered the second best imaging study.
References
- Drezner MK. Chapter 65, Table 1. In: Favus MJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins;1999:331-7.
- Jonsson KB, Zahradnik R, Larsson T, et al. Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. N Engl J Med. 2003;348:1656-63.
- Folpe AL, Fanburg-Smith JC, Billings SD, et al. Most osteomalacia-associated mesenchymal tumors are a single histopathologic entity. An analysis of 32 cases and a comprehensive review of the literature. Am J Surg Pathol. 2004;28:1-30.
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