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NEJM 
Editorial

Volume 348:1705-1708 April 24, 2003 Number 17

Oncogenic Osteomalacia � A Complex Dance of Factors
Thomas O. Carpenter, M.D.

Oncogenic osteomalacia has fascinated physiology-minded physicians for decades. The traditional name for this peculiar disorder connotes its classification as a paraneoplastic phenomenon. Such a characterization is a bit off the mark, however, in that the involved "neoplasm" is often (but not always) of limited clinical significance apart from its causal role in the musculoskeletal disease. Tumors responsible for oncogenic osteomalacia are usually benign rather than invasive, whereas generalized, debilitating osteomalacia and rickets are the important clinical problems for the patient. The assay for the measurement of circulating levels of fibroblast growth factor 23 (FGF-23), the development of which is described by Jonsson et al.1 in this issue of the Journal, may prove to be useful in the investigation and management of oncogenic osteomalacia.

Clinical Presentation

The clinical presentation of oncogenic osteomalacia is reminiscent of that of the more common disorder X-linked hypophosphatemia,2 which has been studied intensively and serves as the prototypic hypophosphatemic disorder. Oncogenic osteomalacia, like X-linked hypophosphatemia, is manifested by decreased mineralization of newly formed bone and the clinical findings of osteomalacia. In growing children, rachitic deformities of the growth plates occur. A useful clinical distinction between the two disorders is the patient's age at the onset of the disease: oncogenic osteomalacia is an acquired phenotype, whereas X-linked hypophosphatemia tends to become evident during the second year of life. There are exceptions to this generalization: a later onset of X-linked and autosomal dominant hypophosphatemic rickets does occur. Patients with oncogenic osteomalacia frequently present with fractures and more severe bone pain than that which occurs in X-linked hypophosphatemia and often report muscle weakness � an unusual symptom in patients with X-linked hypophosphatemia.

The characteristic hypophosphatemia results from an excessive renal loss of phosphate. The serum calcium level is usually normal, but mild hypocalcemia has been described. Elevations of serum alkaline phosphatase activity are typical, and the severity of this abnormality can exceed that seen in X-linked hypophosphatemia. Serum levels of parathyroid hormone have been variably reported as low and as elevated but are most frequently normal. Low or normal circulating levels of 1,25-dihydroxyvitamin D are observed, despite ambient hypophosphatemia, a major physiological stimulus for 1,25-dihydroxyvitamin D production; 1,25-dihydroxyvitamin D levels in oncogenic osteomalacia are often lower than those in patients with X-linked hypophosphatemia. Thus, the typical clinical and biochemical phenotype is similar to that of X-linked hypophosphatemia, but the severity of the abnormality is often greater in oncogenic osteomalacia.

Evaluation

When these clinical features occur in an older child or an adult, particularly in the absence of any relevant family history of disease, oncogenic osteomalacia should be suspected. A careful search for a tumor is an important step in the evaluation of such patients. A substantial number of deaths can be avoided by removal of the causative tumor, and in some cases, an occult cancer may be identified. Tumors are often quite small and not detectable on physical examination or routine radiography. There appears to be a propensity for these tumors to arise in the head and neck, and detailed computed tomography or magnetic resonance imaging of the sinuses and jaw areas is suggested. The occurrence of tumors at skeletal sites is not uncommon in patients with oncogenic osteomalacia. Successful localization of causative tumors with the use of indium-111 pentetreotide or octreotide scintigraphy has been demonstrated.3,4 Technetium-99 methylene diphosphonate scintigraphy has also been used but is likely to reveal uptake of isotope in areas of active osteomalacia, rather than to localize a tumor. With increasing awareness of this syndrome, and increasingly refined imaging techniques, we may discover that such tumors are not as rare as they were once thought to be.

The report by Jonsson et al. of a serum assay for the tumor-derived factor FGF-23 will most likely add to the armamentarium for the diagnosis of this condition and may help to establish whether tumors have been completely removed by surgery. Circulating levels of FGF-23, however, are increased in patients with X-linked hypophosphatemia; thus, this measure does not appear to distinguish between the two conditions. Furthermore, it is not clear whether the assay preferentially recognizes the intact FGF-23 molecule or C-terminal fragments of it. Specific identification of various molecular species may provide critical information regarding the role of FGF-23 processing in the pathogenesis of hypophosphatemia.

Treatment and Course

The clinical course of oncogenic osteomalacia is dramatically affected by removal of the tumor, which, if it is possible, is the treatment of choice. The serum phosphate level, indexes of renal phosphate wasting, and circulating levels of 1,25-dihydroxyvitamin D return to normal within hours to days after the removal of the tumor.5 Serum biochemical markers of bone turnover, such as the osteocalcin level and alkaline phosphatase activity, tend to take longer to normalize; long-term skeletal changes may require months to be corrected.6 The rapid biochemical response is remarkable, however, and the complete resolution of long-standing symptoms is a major relief to patients. Rarely in the treatment of metabolic diseases does a physician encounter such a complete reversal of debilitating symptoms � a truly gratifying experience.

If a tumor is not found, or if an identified tumor is not resectable, it is recommended that vitamin D metabolites (preferably calcitriol) and oral phosphate salts be used in a manner similar to that used in the treatment of X-linked hypophosphatemia.2 This treatment usually provides some benefit, although it does not result in a complete clinical response. Long-term treatment with intravenous phosphate, together with oral calcium and vitamin D, has been successfully used when oral phosphate salts were not tolerated.7 This therapy can result in bloodstream infection related to a central venous catheter and thus should be used only when the promise of a benefit is greater than the risk of catheter-related complications. As a short-term treatment, octreotide therapy rapidly corrected the serum phosphate level and alkaline phosphatase activity in a patient with a tumor that had been detected by octreotide scintigraphy.4

Most tumors associated with oncogenic osteomalacia are benign, consisting of mesenchymal cells or mixed connective tissue. Soft-tissue tumors are often vascular, with abundant spindle or giant cells, and are frequently reported as hemangiopericytomas. Tumors that arise in bone are usually classified as chondroblastic�osteoblastic, ossifying, or nonossifying fibromas, as categorized by Weidner and Santa Cruz.8 Occasional malignant tumors have been reported.9 According to one report, osteosarcoma was discovered in a patient who had had oncogenic osteomalacia for many years before its source was identified.10 Other patients have had recurrent disease that has progressed and become fatal. Thus, it is highly recommended that the surgeon establish a margin of resection that is free of tumor, particularly in the case of tumors with substantial atypia or mitotic elements.

Pathophysiology and Candidate Mediators

Despite improvements in our understanding of oncogenic osteomalacia and X-linked hypophospha-temia, the puzzle has not been completely solved. Loss of function of the PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome) protease determines the X-linked hypophosphatemia phenotype, but how this occurs remains a mystery.2 Specific mutations of FGF-23 result in autosomal dominant hypophosphatemic rickets11; this may be due to a mutation-induced inhibition of processing.12 The injection of FGF-23�transfected cells into mice results in the characteristic features of oncogenic osteomalacia.13 On the other hand, other factors identified from tumors responsible for oncogenic osteomalacia have been implicated in phosphate homeostasis; these factors include frizzled-related protein 4, matrix extracellular phosphoglycoprotein, and unidentified substances with small molecular weights.14 Figure 1 shows the central role of FGF-23 in the proposed mechanisms underlying hypophosphatemic disorders.


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 		 Figure 1. Proposed Roles of Fibroblast Growth Factor 23 (FGF-23) in the Generation of Phosphate Wasting.

It is speculated that three mechanisms may occur. First, FGF-23 is a secretory product of tumors associated with oncogenic osteomalacia, accounting for increased circulating levels of FGF-23 in patients with oncogenic osteomalacia. The secreted form of the molecule is not known, but it is depicted here as an intact protein. Second, specific mutations of arginine residues at position 176 or 179 of FGF-23 disrupt the sequence motif recognized by furin proteases, presumably resulting in altered processing or decreased degradation of the protein � the putative mechanism of disease in autosomal dominant hypophosphatemic rickets. Third, the loss of function of PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome), which occurs in X-linked hypophosphatemia, results in increased circulating levels of FGF-23. Whether the PHEX protein functions as a protease to cleave FGF-23 at the depicted site or elsewhere is unknown. It is not clear whether FGF-23 acts directly on the renal tubule or whether another FGF-23�mediated signal is necessary. The putative cleavage site of FGF-23 between the arginine residue at position 179 and the serine residue at position 180 is noted.

 
 
A number of important questions remain. Does PHEX degrade FGF-23, thereby accounting for increased levels in patients with X-linked hypophosphatemia? Is FGF-23 the direct mediator responsible for impaired transport of phosphate by the renal tubules and the impaired regulation of vitamin D metabolism, or does another factor in a complex cascade of signals perform this function? Is the bone disease simply a result of prolonged hypophosphatemia, or does FGF-23 or another tumor-derived substance have a direct effect on the skeleton? What are the roles of frizzled-related protein 4 and matrix extracellular phosphoglycoprotein? The finding that increased circulating FGF-23 levels occur in X-linked hypophosphatemia as well as in oncogenic osteomalacia argues that these two disorders do share a common pathophysiological pathway. Further clinical investigation made possible by this new assay may shed further light on the complex pathophysiology involved.

 

Dr. Carpenter reports having received consulting fees from Merck and Genzyme and a grant from CuraGen.


Source Information

From the Section of Pediatric Endocrinology, Yale University School of Medicine, New Haven, Conn.

References

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