Before this study, the prevalence of either hypophosphatemia and/or renal phosphate wasting in association with FD had not been examined closely. In a large series of patients with FD, we have established that renal phosphate wasting is a common finding in FD. Twenty of the 42 patients (48%) in our series show some degree of phosphate wasting. Of note is the fact that the serum phosphorus concentration of 13/20 (65%) patients with a low TmP/GFR was in the normal range, indicating that calculation of the TmP/GFR is necessary to establish phosphate wasting. We also found that the renal phosphate wasting is part of a more general proximal renal tubulopathy as manifested by altered vitamin D metabolism, proteinuria, and aminoaciduria. This is the first report indicating that a proximal renal tubulopathy is a common feature in patients with FD.
Renal phosphate wasting—endogenous Gsα mutation or phosphaturic factor?
The etiology of the phosphate wasting observed in association with FD is debated. Because Gsα mutations have been found in kidney tissue in severe, neonatal lethal MAS cases,(5) it has been suggested that the abnormality is endogenous to renal tubular cells.(19) Others speculate that it is the effect of a phosphaturic factor produced by FD bone.(20) In an effort to distinguish between these two pathogenetic mechanisms, we performed an extensive clinical and biochemical evaluation of a series of patients with FD.
PTH activation of renal tubular Gsα generates an elevation in nephrogenous cAMP,(31) which is a common finding in hyperparathyroidism.(32) Therefore, if Gsα was constitutively activated in the kidney because of the presence of activating mutations, it would be expected that FD patients with phosphate wasting also would have elevated basal nephrogenous cAMP levels. This was not observed in our study. The basal levels of nephrogenous cAMP were in the normal range in all patients and significantly lower than those in a group of patients with PHPTH. Our findings of decreased TmP/GFR in conjunction with normal basal nephrogenous cAMP suggest that a mechanism other than endogenous renal Gsα mutations is the cause of phosphate wasting, although it cannot be ruled out that some patients also may have activating mutations in renal Gsα.
Further distinguishing these findings from those seen in PHPTH is the relationship between serum phosphorus and 1,25(OH)2D3 levels. Serum phosphorus is a key regulator of 25(OH)D3-1α-hydroxylase (1α-hydroxylase) activity in the renal proximal tubule, and thus serum levels of 1,25(OH)2D3. Under normal physiological conditions, low serum phosphorus stimulates 1α-hydroxylase activity and increases the serum level of 1,25(OH)2D3.(30) In PHPTH, 1,25(OH)2D3 levels are normal or high and maintain an inverse relationship (negative correlation) to serum phosphorus.(30) We found that in FD lower serum phosphate was correlated with lower serum 1,25(OH)2D3. This suggests that there is an alteration of 1α-hydroxylase activity in FD. A similar observation has been made in TIO and X-linked hypophosphatemia but not in the phosphaturia of hyperparathyroidism.
Supporting the hypothesis that fibrous dysplastic bone elaborates a phosphaturic factor, is the report of a patient with FD and phosphate wasting in whom the phosphate wasting corrected after extensive resection of FD tissue.(13) The fact that markers of bone metabolism, as a surrogate marker for FD tissue burden, significantly correlate with TMP/GFR (Table 4) also supports the hypothesis that the etiology of the phosphate wasting is a phosphaturic factor elaborated by FD bone.
Based on characterization of patients with TIO, current thinking suggests that the abnormal phosphate metabolism is mediated by a systemic factor “phosphatonin” and that abnormalities in its metabolism result in the generation of systemic osteomalacia.(22) This putative phosphate-regulating factor has not yet been isolated, and it is not known what cell type produces it, although bone-forming cells are likely candidates.(33) Mutated cells within FD lesions may produce abnormal levels of this factor; alternatively, they may deregulate its production by normal osteogenic cells or cells elsewhere in the body. Another possibility is that the hypermetabolic fibrous dysplastic bone produces a factor(s) toxic to the kidney.
Even more prevalent than phosphate wasting and derangement of vitamin D metabolism is the finding of proteinuria and aminoaciduria in most of the patients in this series. Proteinuria and aminoaciduria also are seen in TIO.(21) The magnitude of the proteinuria was mild (the highest value was 291 mg/24 h) and characterized by the presence of low molecular weight proteins in the urine. Relative to the glomerulonephropathies, in which grams of protein per day can be detected in the urine, the proteinuria in FD is not likely to be of major clinical significance. The aminoaciduria was variable with respect to the number of amino acids in which the concentration was elevated in the urine. The pattern was that of a generalized aminoaciduria, indicating that it was not an isolated transport system that was affected. Interestingly, the aminoaciduria was further characterized by the consistent presence of unknown metabolites in the urine of patients with FD (Fig. 4).
The etiology of the aminoaciduria is not clear. Some have suggested that high PTH and/or low serum vitamin D can directly impact the renal tubule and cause aminoaciduria.(34) Although hyperparathyroidism can be associated with aminoaciduria, this is an uncommon finding and in those cases in which it is present, it usually is an isolated glycinuria.(34) It is not likely that changes in vitamin D metabolism or hyperparathyroidism account for the common place occurrence of aminoaciduria seen in our patients. Although 7 patients (17%) had serum vitamin D levels low enough to induce secondary hyperparathyroidism at the initial evaluation (data not shown), the secondary hyperparathyroidism resolved with vitamin D replacement. The data shown in this study represent evaluations done at least 3 months after vitamin D replacement and normalization of serum PTH. Furthermore, only 2 (5%) of the patients had persistent abnormalities in vitamin D levels [decreased serum 1,25(OH)2D3] at the time of testing; yet 40 (94%) of the patients had some degree of aminoaciduria.
The renal findings in FD patients are similar to those observed in patients with TIO, X-linked hypophosphatemia, autosomal dominant hypophosphatemia, and the Fanconi syndrome. In these conditions the renal findings are phosphate wasting, mild proteinuria, aminoaciduria, and normal nephrogenous cAMP.(21, 24 35 36) The absence of carbonaturia, glucosuria, and acidosis in FD distinguishes it from the Fanconi syndrome. Thus, it appears that the phosphate wasting observed in association with FD is more similar to that seen in the phosphotonin-mediated phosphate wasting syndromes, TIO, and X-linked and autosomal dominant hypophosphatemia and distinct from that seen in either PHPTH or the tubular damage (Fanconi) syndromes.
Given the recent report that FD lesions can be osteomalacic,(25) the finding of renal phosphate wasting is of clinical significance. Renal phosphate wasting with chronically low serum phosphorus (or perhaps even low to normal levels in growing children) may influence the development of lesional osteomalacia. Undermineralization of FD bone may contribute to the development of the shepherd's crook deformity of the proximal femur, the quality of fracture healing, and to the rare but serious complication of platybasis of the skull. Therefore, it is critical to assess the phosphate status of patients with FD. We currently prescribe phosphorus supplementation for patients both with low serum phosphorus and with low-normal serum phosphorus but a low TmP/GFR. As in other patients with phosphate wasting syndromes, phosphate supplementation usually results in secondary hyperparathyroidism, the prevention of which is brought about by adding vitamin D (calcitriol) to the regimen. Long-term studies in FD patients are required to determine if raising serum phosphorus levels will improve the quality and mechanical properties of osteomalacic bone in FD. Furthermore, it is clinically relevant to determine the presence or absence of phosphate wasting before treatment with bisphosphonates, which have been reported to be beneficial in the treatment of FD, but in certain circumstances, may themselves be associated with mineralization defects.(37)
Our data show that a renal tubulopathy manifested by phosphate wasting, altered vitamin D metabolism, low molecular weight proteinuria, and aminoaciduria is common in FD/MAS. In fact, the renal tubulopathy represents the most common metabolic feature in this group of patients. Our findings suggest that the cause may be a circulating factor produced by fibrous dysplastic bone, although the presence of mutations in renal Gsα cannot be excluded and may contribute. Further study is needed to determine the precise pathogenetic mechanisms and appropriate clinical care.