Tubular phosphate transport: a comparison between different methods of urine sample collection in FGF23-dependent hypophosphatemic syndromes.

OBJECTIVES: Tubular maximum phosphate reabsorption per glomerular filtration rate (TmP/GFR) is used to evaluate renal phosphate reabsorption and it is a useful tool for the differential diagnosis of hypophosphatemic syndromes. TmP/GFR is typically calculated from fasting plasma and second morning void urine samples, obtained 2 h after the first void (TmP/GFR 2 h). The purpose of this study was to evaluate if TmP/GFR calculated from 24 h urine collection (TmP/GFR 24 h) can be used as an alternative for TmP/GFR 2 h in patients with urine phosphate wasting. METHODS: We enrolled adult patients with X-linked hypophosphatemia (XLH) or tumor-induced osteomalacia (TIO). All patients underwent blood and urine sample collections, to calculate TmP/GFR 24 h and TmP/GFR 2 h. RESULTS: Twenty patients (17 XLH and 3 TIO), aged 24-78 years, were included. All patients had low TmP/GFR 2 h (0.35 mmol/L, IQR 0.24-0.47 mmol/L) and TmP/GFR 24 h (0.31 mmol/L, IQR 0.22-0.43 mmol/L). The concordance correlation coefficient between TmP/GFR 2 h and TmP/GFR 24 h was 0.86 (95 % CI: 0.69-0.93), with a systematic bias of 0.05 mmol/L (95 % limits of agreement: -0.10 to 0.20). Furthermore, in 70 % (i.e., 14 patients out of 20) and 80 % (i.e., 16 patients out of 20) of cases the difference between TmP/GFR 2 h and TmP/GFR 24 h was within ±30 % and ±35 %, respectively. CONCLUSIONS: Despite TmP/GFR 2 and 24 h show a relatively suboptimal agreement, the difference between the two parameters appears to be small and not clinically significant in the setting of adult patients with FGF23-dependent urine phosphate wasting and secondary hypophosphatemia.

Persistent urinary phosphate wasting in a patient with metastatic breast cancer: What's your diagnosis?

Tumor-induced osteomalacia (TIO) can cause severe, persistent hypo-phosphatemia due to high fibroblast growth factor-23 (FGF-23) levels, which lead to uri-nary phosphate wasting. TIO is frequently encountered in association with mesenchy-mal tumors and responds well to resection of the primary malignancy. Rarely, TIO may be seen as a paraneoplastic phenomenon with solid organ malignancies where correction of biochemical abnormalities requires ongoing phosphorus replacement. We report a case of TIO in a patient with metastatic breast cancer complicated by increased parathyroid hormone release secondary to denosumab-induced hypocalcemia. The patient required intensive intravenous and oral phosphate supplementation in addition to vitamin D repletion. A high index of clinical suspicion can yield the correct diagnosis where TIO arises in the setting of a solid organ tumor and help the clinician appropriately manage these challenging cases.

Therapeutic effects of anti-FGF23 antibodies in hypophosphatemic rickets/osteomalacia.

X-linked hypophosphatemia (XLH), characterized by renal phosphate wasting, is the most common cause of vitamin D-resistant rickets. It has been postulated that some phosphaturic factor plays a causative role in XLH and its murine homolog, the Hyp mouse. Fibroblast growth factor 23 (FGF23) is a physiological phosphaturic factor; its circulatory level is known to be high in most patients with XLH and Hyp mice, suggesting its pathophysiological role in this disease. To test this hypothesis, we treated Hyp mice with anti-FGF23 antibodies to inhibit endogenous FGF23 action. A single injection of the antibodies corrected the hypophosphatemia and inappropriately normal serum 1,25-dihydroxyvitamin D. These effects were accompanied by increased expressions of type IIa sodium-phosphate cotransporter and 25-hydroxyvitamin-D-1alpha-hydroxylase and a suppressed expression of 24-hydroxylase in the kidney. Repeated injections during the growth period ameliorated the rachitic bone phenotypes typically observed in Hyp mice, such as impaired longitudinal elongation, defective mineralization, and abnormal cartilage development. Thus, these results indicate that excess actions of FGF23 underlie hypophosphatemic rickets in Hyp mice and suggest a novel therapeutic potential of the FGF23 antibodies for XLH.

Oncogenic osteomalacia, a rare paraneoplastic syndrome due to phosphate wasting--a case report and review of the literature.

An appropriate phosphate homeostasis is absolutely required for correct bone mineralization and remodeling, for diverse signaling pathways as well as cell membrane formation. Its disequilibrium results in serious complications like hypophosphatemia and excessively reduced fractional tubule phosphate reabsorption (TRP). A rare cause of such a disturbed phosphate balance is tumor-induced osteomalacia (TIO)--a phosphate wasting disorder sometimes associated with certain mesenchymal tumors. These primitive tumors secrete so-called phosphatonins--recently identified factors involved in the regulation of phosphate homeostasis such as the secreted frizzled related protein 4 (sFRP-4), the fibroblast growth factors 7 and 23 (FGF-7/-23), or the matrix extracellular phosphoglycoprotein (MEPE). Progressive muscular weakness and spontaneous bone fractures caused by inadequate osteoid mineralization are the characteristic clinical symptoms, which completely resolve after tumor resection. Here we report a new case of TIO caused by tumor secreted FGF-23 and review the literature to facilitate the correct diagnosis of this rare disorder.

Phosphaturic mesenchymal tumor with symptoms related to osteomalacia that appeared one year after tumorectomy.

A 45-year-old man was admitted to our hospital because of bone pain and hypophosphatemia. He had undergone surgery 2 years previously for a "benign unclassified mesenchymal tumor" in the skull, but there were no clinical symptoms related to osteomalacia. His laboratory examination revealed low serum phosphate, high alkaline phosphatase, and normal calcium levels. The diagnosis of tumor-induced osteomalacia due to phosphaturic mesenchymal tumor mixed connective tissue variant (PMTMCT) was made by re-examining the pathologic specimens. Oral supplementation with phosphate and 1-25-dihydroxyvitamin D relieved his clinical symptoms and laboratory values returned to normal. However, subcutaneous administration of octreotide had no clinical effect. Clinicians and pathologists should be aware of the existence of PMTMCT especially nonphosphaturic or asymptomatic variants of this disorder.

Phosphaturic mesenchymal tumor: a case report.

Osteomalacia induced by tumor is a rare phenomenon in which the resection of tumor is followed by dramatic amelioration of clinical signs and symptoms. We hereby report a case of a 66 years old male who presented with features of osteomalacia in which the characteristic clinical presentation was associated with the phosphaturic mesenchymal tumor, mixed connective tissue variant. The case is reported for its rarity.

Biomarkers and imaging in non-malignant and malignant osteomalacia.

Deoxypyridinium (DPD) cross-links are a specific parameter for collagen type I degradation. We report the longitudinal tracking of DPD in relation to other bone markers and imaging techniques in a patient with osteomalacia and secondary hyperparathyroidism from reduced light exposure due to attire. This patient was first admitted for diffuse skeletal pain. X-rays showed general demineralization and Looser's transformation zones in the neck of the left femur. MRI examinations of the pelvis and the proximal femora demonstrated bilateral signs of acute sacroiliitis, as well as edema-like lesions in the femoral heads and necks bilaterally. The baseline parathyroid hormone level was 8 times higher than the normal upper limit, whereas 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels were significantly reduced. A 7-fold increase in free urinary DPD and a 17-fold increase in bone-specific alkaline phosphatase (bone-AP) were also measured. Percutaneous transiliac bone biopsy revealed markedly increased osteoidosis. Osteomalacia was diagnosed due to chronically reduced sun exposure caused by restrictive attire, and cholecalciferol substitution therapy was begun. After a follow-up of 28 weeks, non-specific parameters of bone turnover (parathyroid hormone, total alkaline phosphatase, serum calcium and serum phosphate) had normalized, while DPD, as a specific bone degradation marker, and bone-AP, as a bone formation parameter, both remained elevated. This example underlines the validity of DPD and bone-AP as indicators of increased bone metabolism: not only were they the parameters with the highest baseline deviation, but they were also the last to normalize.

Characteristics of biochemical markers in patients with metabolic bone disorders.

Biochemical markers of bone turnover are expected to have some different characteristics among bone metabolic disorders. We compared bone formation markers: serum total alkaline phosphatase (s-Alp), serum osteocalcin (s-OC) and serum carboxy-terminal propeptide of type I collagen (s-PICP); and bone resorption markers: serum carboxy-terminal telopeptide of type I collagen (s-ICTP), urinary pyridinoline (u-Pyr) and urinary deoxypyridinoline (u-Dpyr) to examine which marker is the most suitable and reliable to evaluate bone turnover in patients with osteoporosis (n = 29), osteomalacia (n = 10), primary hyperparathyroidism (n = 6) and renal osteodystrophy (n = 21). The value of s-Alp in the osteomalacia group was significantly higher than those in the normal control group and the osteoporosis group (p < 0.001), and T-score of s-Alp was significantly higher than those of s-OC and s-PICP in the osteomalacia group. The values of u-Pyr and u-Dpyr in the primary hyperparathyroidism group were significantly higher than those in the other groups (p < 0.001). S-PICP, which are not dependent upon renal function, was much higher in the renal osteodystrophy group than in all other groups. In the osteoporosis group, T-score of s-ICTP was significantly higher than those of s-OC. Thus, s-Alp was a good marker in osteomalacia, u-Pyr and u-Dpyr in primary hyperparathyroidism, s-PICP in renal osteodystrophy, and s-ICTP in osteoporosis.

Oncogenic osteomalacia: is there a new phosphate regulating hormone?

Oncogenic osteomalacia is a syndrome associated with rare, usually mesenchymal tumours, which is characterized by hypophosphataemia, phosphaturia and low concentrations of 1,25-dihydroxyvitamin D. The reversal of clinical and biochemical abnormalities following removal of the tumour, indicates it is the source of a humoral factor that is responsible for these abnormalities. It has been demonstrated that the humoral factor inhibits renal phosphate uptake and reduces 1,25-dihydroxyvitamin D production. Although there is evidence that it may act via parathyroid hormone/parathyroid hormone-related peptide receptors and may be a peptide, the factor has not yet been identified, nor has its relationship to factors involved in X-linked hypophosphataemic rickets been established. We propose unifying hypotheses for the pathogenesis of oncogenic osteomalacia and X-linked hypophosphataemic rickets which involve defects in the PEX gene. These hypotheses do not fully explain all the available data and it remains possible that hormone(s) with little or no role in X-linked hypophosphataemic rickets may be responsible for oncogenic osteomalacia.

Evaluation of urinary hydroxypyridinium crosslink measurements as resorption markers in metabolic bone diseases.

Analyses of the urinary concentration relative to creatinine of the collagen crosslinks, pyridinoline (Pyd) and deoxy-pyridinoline (Dpd) were made in 47 patients with metabolic bone diseases to assess the validity of these assays as indicators of bone resorption. The mean values for patients with Paget's disease of bone, primary hyperparathyroidism and osteomalacia were significantly higher (P less than 0.001) than those for age-matched healthy individuals. During treatment of Paget's disease with bisphosphonates, there was a steady decline in the urinary concentration of the crosslinks to the normal range; this change occurred earlier than for serum alkaline phosphatase. There were significant correlations (P less than 0.01) between the concentrations of both crosslinks and the corresponding values for hydroxyproline. At lower crosslink concentrations, however, these relationships were less marked due to large variations in hydroxyproline values. The results show that measurements of urinary Pyd and Dpd provide clinically applicable indices of bone resorption that are more specific than other markers.

Phosphaturic mesenchymal tumors. A polymorphous group causing osteomalacia or rickets.

Reported are the pathologic features of 17 mesenchymal tumors documented as causing osteomalacia or rickets. Although these tumors were histologically polymorphous, they were classifiable into four morphological groups. In the first group there were ten unique tumors showing mixed connective tissue features and containing variably prominent vascular and/or osteoclast-like giant-cell components. Tumors of this group also displayed focal microcystic changes, osseous metaplasia, and/or poorly developed cartilaginous areas. The cartilaginous areas sometimes showed considerable dystrophic calcification. With one exception, all tumors of this group occurred in soft tissue and demonstrated benign clinical behavior. The single malignant tumor originated in bone, recurred locally, and metastasized to lung. The tumors comprising the remaining three groups (six tumors) occurred in bone, demonstrated benign clinical behavior, and were grouped according to their close resemblance to tumors known to occur in bone, that is osteoblastoma-like (four tumors), nonossifying fibroma-like (two tumors), and ossifying fibroma-like (one tumor).

Plasma creatinine and creatinine clearance in nutritional osteomalacia.

To confirm recent observations that some vitamin D deficient osteomalacic patients had low plasma creatinine concentrations, low urinary creatinine excretion, and a paradoxically low creatinine clearance, and whether these changes were due to vitamin D deficiency per se, these measurements were made in patients before and after vitamin D supplementation. The pretreatment levels were also compared with those in healthy controls and in non-osteomalacic patients without renal disease. The above changes were confirmed. After treatment with vitamin D, plasma creatinine concentrations rose, but urinary creatinine excretion and creatinine clearance did not alter. These data indicate the limitation of creatinine clearance as an index of renal function in vegetarian osteomalacic patients. Furthermore, they demonstrate the effect of vitamin D deficiency and its reversal on plasma creatinine concentrations.

The 24-h urinary cyclic adenosine 3', 5' monophosphate/creatinine ratio: an useful approach to the diagnosis of parathyroid disorders and function.

24-h urinary cyclic adenosine 3', 5'-monophosphate/creatinine (cAMP/Cr) ratio was assessed in 10 patients with hypoparathyroidism, 6 with primary hyperparathyroidism, 7 with normocalcemic hypercalciuria and recurrent nephrolithiasis, 14 with osteomalacia, 25 with Paget's disease and 53 with symptomatic postmenopausal osteoporosis. In hypoparathyroid subjects the mean values of 24 h cAMP/Cr ratio were significantly lower than the control values, whereas in patients with parathyroid adenoma the mean values were higher and fell after parathyroid surgery. Patients with nephrolithiasis due to absorptive hypercalciuria showed low or normal cAMP/Cr ratio, whereas in those with osteomalacia and mean values of cAMP/Cr ratio were significantly higher than the control values and decreased after vitamin D treatment. The mean value of the 24 h urine cAMP/Cr ratio was normal in patients with Paget's disease or postmenopausal osteoporosis and increased significantly after long term treatment with calcitonin or diphosphonate. This increase paralleled a significant decrease of calcium plasma level. A significant improvement of fractional calcium absorption was observed in women with postmenopausal osteoporosis at the end of treatment with calcitonin or diphosphonate.