Review and update: oncogenic osteomalacia-rickets.

Oncogenic or tumor-induced osteomalacia-rickets is a syndrome characterized by hypophosphatemia, renal phosphate wasting, and decreased serum 1,25-dihydroxyvitamin D3 levels. The tumors secrete a phosphaturic substance that causes total body phosphate depletion, leading to osteomalacia or rickets. Although the tumors are histologically polymorphous, personal review of 16 tumors documented to cause this syndrome revealed four morphologic patterns. The first contained 10 unique-appearing, mixed connective tissue tumors having variably prominent vessels, osteoclastlike giant cells, focal microcystic changes, dystrophic calcification, osseous metaplasia, and/or poorly developed cartilagelike areas. With one exception, all tumors of this group occurred in soft tissue and were benign. The single malignant tumor originated in bone, recurred locally, and metastasized to lung. The remaining tumors occurred in bone and showed benign clinical behavior. They resembled tumors known to occur in bone, that is osteoblastomalike (3 tumors), nonossifying fibromalike (2 tumors), and ossifying fibromalike (1 tumor).     

Review and Update: Oncogenic Osteomalacia-Rickets

Oncogenic or tumor-induced osteomalacia-rickets is a syndrome characterized by hypophosphatemia, renal phosphate wasting, and decreased serum 1,25-dihydroxyvitamin D₃ levels. The tumors secrete a phosphaturic substance that causes total body phosphate depletion, leading to osteomalacia or rickets. Although the tumors are histologically polymorphous, personal review of 16 tumors documented to cause this syndrome revealed four morphologic patterns. The first contained 10 unique-appearing, mixed connective tissue tumors having variably prominent vessels, osteoclastlike giant cells, focal microcystic changes, dystrophic calcification, osseous metaplasia, and/or poorly developed cartilagelike areas. With one exception, all tumors of this group occurred in soft tissue and were benign. The single malignant tumor originated in bone, recurred locally, and metastasized to lung. The remaining tumors occurred in bone and showed benign clinical behavior. They resembled tumors known to occur in bone, that is osteoblas-tomalike (3 tumors), nonossifying fibromalike (2 tumors), and ossifying fibromalike (1 tumor).     

Fibroblast growth factor (FGF) 23 works as a phosphate-regulating hormone and is involved in the pathogenesis of several disorders of phosphate metabolism

Fibroblast growth factor (FGF) 23 was identified as the latest member of the FGF family. Subsequent studies showed that FGF23 reduces the serum phosphate level by suppressing proximal tubular phosphate reabsorption. This phosphaturic action of FGF23 derives from the suppressive effect of FGF23 on the expression of type 2a and 2c sodium-phosphate cotransporter in the brush border membrane of proximal tubules. At the same time, FGF23 reduces the serum level of 1,25-dihydroxyvitamin D [1,25(OH)2D] which results in suppressed intestinal phosphate absorption. Establishment of an enzyme-linked immunosorbent assay for FGF23 indicated that excess actions of FGF23 result in hypophosphatemic rickets/osteomalacia such as X-linked, autosomal dominant, autosomal recessive hypophosphatemic rickets/osteomalacia, and tumor-induced rickets/osteomalacia. In contrast, deficiency of FGF23 action causes hyperphosphatemic tumoral calcinosis. These results indicate that FGF23 is a hormone regulating serum phosphate and 1,25(OH)2D levels.     

Review and Update: Oncogenic Osteomalacia-Rickets

Oncogenic or tumor-induced osteomalacia-rickets is a syndrome characterized by hypophosphatemia, renal phosphate wasting, and decreased serum 1,25-dihydroxyvitamin D₃ levels. The tumors secrete a phosphaturic substance that causes total body phosphate depletion, leading to osteomalacia or rickets. Although the tumors are histologically polymorphous, personal review of 16 tumors documented to cause this syndrome revealed four morphologic patterns. The first contained 10 unique-appearing, mixed connective tissue tumors having variably prominent vessels, osteoclastlike giant cells, focal microcystic changes, dystrophic calcification, osseous metaplasia, and/or poorly developed cartilagelike areas. With one exception, all tumors of this group occurred in soft tissue and were benign. The single malignant tumor originated in bone, recurred locally, and metastasized to lung. The remaining tumors occurred in bone and showed benign clinical behavior. They resembled tumors known to occur in bone, that is osteoblas-tomalike (3 tumors), nonossifying fibromalike (2 tumors), and ossifying fibromalike (1 tumor).     

August 2003: 47-year-old female with a 7-year history of osteomalacia and hypophosphatemia

The August 2003 COM. A 47-year-old woman presented with a long history of muscle pain, weakness, and visual disturbances. Over the last year, she developed diplopia and left sixth nerve palsy. No other neuro-ophthalmologic abnormalities were found. Past medical and family history was unremarkable. Laboratory investigation disclosed hypophosphatemia, phosphaturia, elevated serum alkaline phosphatase activity, and normal serum calcium levels. CT scans showed a lobulated mass arising on the meningeal surface of the cavernous sinus, measuring 3x 2 x 2 cm. The lesion was partially resected and microscopic examination revealed a highly vascularized tumor composed of primitive mesenchymal cells arranged whether in a patternless-pattern or surrounding thin-walled, branching vascular spaces and thick-walled hyalinized vessels. Other eye-catching features were microcystic areas, multinucleated osteoclastic-like giant cells, scattered islands of mature adipocytes, foci of hemorrhage, thrombosed medium-sized-to-large vessels, and hemosiderin-laden macrophages. After surgery, the patient recovered from the muscle pain and weakness, with a significant improvement of serum calcium and alkaline phosphatase levels and phosphate blood levels. Taken together, the clinical and pathologic features were consistent with a diagnosis of phosphaturic mesenchymal tumor (mixed connective tissue variant) of the cavernous sinus in a setting of oncogenic osteomalacia. No further treatment was carried out. The patient has been followed for the last 4 years with no evidence of recurrent disease. Oncogenic osteomalacia is a rare clinical entity characterized by hypophosphatemia, phosphaturia, and a low concentration of 1,25-dihydroxyvitamin D(3) caused by a neoplasm. Pathologists should be aware of this entity, because surgical excision of the tumor is usually curative.     

1,25-Dihydroxyvitamin C3-stimulated active uptake of phosphate by rat jejunum

An assay system for measuring an active phosphate uptake in rat jejunal disks has been developed and used to study the rat's response to 1,25-dihydroxyvitamin D3. The active component of phosphate uptake is stimulated by added KCl, fructose, sodium, and CaCl2, but not MgCl2. Half-saturation values obtained with this assay are 0.08 mM (1,25-dihydroxyvitamin D3-treated) and 0.11 mM (D-deficient). The maximal velocities are 9.6 nmol . cm-2 . min-1 (D-deficient). Using a 5-min preincubation and a 15-min incubation, a dose-response curve for 1,25-dihydroxyvitamin D3 shows 6 pmol to be the lowest dose to give a significant response and 60 pmol to be the level at which the maximal response is reached. Measurement of phosphate uptake versus time after dosing with 1,25-dihydroxyvitamin D3 (300 pmol) revealed a biphasic response with peaks at 8 and 36 h and a trough at 20 h.     

Vitamin-D-dependent rickets type II. Resistance of target organs to 1,25-dihydroxyvitamin D.

Studies were done to determine the cause for hypocalcemia, secondary hyperparathyroidism, osteomalacia and osteitis fibrosa cystica in a 22-year-old black woman. The patient had normal serum 25-hydroxyvitamin D (14 ng per milliliter) and markedly elevated serum 1,25-dihydroxyvitamin D (137 pg per milliliter). Vitamin D3, 4000 units per day for four weeks, increased the serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D to as high as 29 and 297 pg per milliliter, respectively, and corrected the hypocalcemia and secondary hyperparathyroidism. The results suggest that the disorder results from impaired end-organ response to 1,25-dihydroxyvitamin D. We propose that the entity be called vitamin-D-dependent rickets Type II.     

Hypercalcemia and elevated serum 1,25-dihydroxyvitamin D3 in a patient with hodgkin's lymphoma

Summary A 74-year-old woman was hospitalized because of decreased appetite, fatigue, and weight loss. The laboratory examination revealed hypercalcemia, a slightly increased serum creatinine level, and a markedly elevated serum level of 1,25-dihydroxyvitamin D₃. The most important finding the physical examination revealed was enlarged inguinal lymph nodes. A biopsy disclosed lymphocyte-depleted Hodgkin's disease. After steroids, but not after calcitonin, both the elevated calcitriol concentration and serum calcium normalized. In spite of intensive chemotherapy, a further episode with hypercalcemia occurred and increased 1,25-dihydroxyvitamin D₃ serum levels were observed. According to the available evidence it seems probable that the humoral hypercalcemia in this patient resulted from production of 1,25-dihydroxyvitamin D₃ in the tumor.Abbreviations 1,25(OH)₂D₃ 1,25-dihydroxyvitamin D₃ - iPTH serum immunoreactive parathyroid hormone     

Nonrandom chromosome changes in multiple sclerosis

We report on two brothers with renal hypophosphatemia, intracerebral calcifications, minor facial anomalies, and short distal phalanges. The children presented with recurrent dental abscesses; one had premature closure of the anterior fontanelle. Biochemical findings included hypophosphatemia and elevated serum alkaline phosphatase with normocalcemia. Blood levels of parathyroid hormone, 1,25(OH)₂ and 25(OH) vitamin D levels were normal; TRP (the fractional tubular reabsorption of PO₄) and TmP/GFR (the tubular maximum rate of PO₄ reabsorption in relation to GFR) were low. Both parents had a normal serum phosphate and brain CT scan without evidence of calcifications. This apparently new syndrome of renal hypophosphatemia associated with intracerebral calcifications appears to be inherited as either an autosomal recessive or an X-linked trait.     

"Idiopathic" hypercalciuria and hereditary hypophosphatemic rickets. Two phenotypical expressions of a common genetic defect

Among 59 closely related members of one Bedouin tribe, we identified 9 who had the characteristic features of hereditary hypophosphatemic rickets with hypercalciuria (HHRH). We found "idiopathic" hypercalciuria in 21 of the 50 asymptomatic members. The biochemical abnormalities observed in these 21 subjects were qualitatively similar to those in the 9 with HHRH, but were quantitatively milder. The urinary calcium concentration was 0.43 +/- 0.14 mg per milligram of creatinine (mean +/- SD) in the patients with HHRH, 0.34 +/- 0.07 in the subjects with idiopathic hypercalciuria, and 0.14 +/- 0.05 in normal subjects from the same tribe. Tubular reabsorption of phosphorus and serum phosphorus concentrations were 3.0 and 4.3 SD units below the age-related mean, respectively, in HHRH, and 1.1 SD units below the normal mean for both variables in idiopathic hypercalciuria. Mean serum levels of 1,25-dihydroxyvitamin D (1,25-(OH)2D) were 303 pg per milliliter in HHRH and 145 pg per milliliter in idiopathic hypercalciuria (upper normal limit, 110). We conclude that the subjects with hypercalciuria and the patients with HHRH shared a hereditary renal phosphate leak that led to hypophosphatemia, elevated serum concentrations of 1,25-(OH)2D, increased intestinal calcium absorption, and hypercalciuria. The magnitude of the hypophosphatemia, which regulates 1,25-(OH)2D levels, appears to determine which subjects will have hypercalciuria alone and which will also have bone disease.     

Genetic ablation of vitamin D activation pathway reverses biochemical and skeletal anomalies in Fgf-23-null animals

Fibroblast growth factor-23 (FGF-23) is one of the circulating phosphaturic factors associated with renal phosphate wasting. Fgf-23-/- animals show extremely high serum levels of phosphate and 1,25-dihydroxyvitamin D3, along with abnormal bone mineralization and soft tissue calcifications. To determine the role of vitamin D in mediating altered phosphate homeostasis and skeletogenesis in the Fgf-23-/- mice, we generated mice lacking both the Fgf-23 and 1alpha-hydroxylase genes (Fgf-23-/-/1alpha(OH)ase-/-). In the current study, we have identified the cellular source of Fgf-23 in adult mice. In addition, loss of vitamin D activities from Fgf-23-/- mice reverses the severe hyperphosphatemia to hypophosphatemia, attributable to increased urinary phosphate wasting in Fgf-23-/-/1alpha(OH)ase-/- mice, possibly as a consequence of decreased expression of NaPi2a. Ablation of vitamin D from Fgf-23-/- mice resulted in further reduction of total bone mineral content and bone mineral density and reversed ectopic calcification of skeleton and soft tissues, suggesting that abnormal mineral ion homeostasis and impaired skeletogenesis in Fgf-23-/- mice are mediated through enhanced vitamin D activities. In conclusion, using genetic manipulation studies, we have provided evidence for an in vivo inverse correlation between Fgf-23 and vitamin D activities and for the severe skeletal and soft tissue abnormalities of Fgf-23-/- mice being mediated through vitamin D.     

Calcium homeostasis in immobilization: an example of resorptive hypercalciuria

Prolonged immobilization may result in hypercalcemia, hypercalciuria, and osteoporosis. Although bone resorption is central to this syndrome, the mechanism of resorption is uncertain. In particular, the role of systemic calcium-regulating hormones remains unclear. In 14 immobilized subjects we measured fasting calcium excretion, 24-hour urinary calcium excretion during restricted calcium intake, the renal phosphorus threshold, plasma 1,25-dihydroxyvitamin D, nephrogenous cyclic AMP, and immunoreactive parathyroid hormone. Mean serum calcium levels were normal, but fasting and 24-hour calcium excretion were markedly elevated (0.28 mg per deciliter of glomerular filtrate and 314 mg per 24 hours, respectively). The mean levels of serum phosphorus (4.8 mg per deciliter) and the renal phosphorus threshold (4.3 mg per deciliter) were elevated. Mean plasma 1,25-dihydroxyvitamin D was strikingly reduced (9.9 pg per milliliter), as were nephrogenous cyclic (0.64 nmol per deciliter of glomerular filtrate) and immunoreactive parathyroid hormone in both assays. These findings indicate that the parathyroid--1,25-dihydroxyvitamin D axis is suppressed in patients with immobilization-induced hypercalciuria, as would be predicted by a model of resorptive hypercalciuria.     

FGF 23 et phosphatémie

Our knowledge of the regulation of phosphate metabolism has been recently modified with the identification of news factors with phosphaturic properties, the best known being FGF 23. FGF 23 inhibits the tubular reabsorption of phosphate in vitro and in vivo, and decreases the production of 1,25(OH)₂D₃ by the 1α-hydroxylase in the kidney. FGF 23 is a major factor involved in controlling phosphate homeostasis. Its production is under the negative control of phosphate and 1,25(OH)₂D₃ blood levels. Elevated FGF 23 concentrations may be found during situations responsible for chronic hypophosphatemia (vitamin D resistant rickets, bone dysplasia, oncogenic osteomalacia) and in response to the hyperphosphatemia present during renal insufficiency. Other phosphaturic factors have been proposed, like FRP-4 and FGF 7. The production of all these factors is also related to bone metabolism, especially under the dependence of proteases like the PHEX protein responsible for the X-linked form of hypophosphatemic rickets. These factors are important clues to understand the relationships between calcium and phosphate metabolism, bone mineralization and skeletal growth. Dosing FGF 23 blood level is of interest in order to explore various abnormalities of phosphore metabolism.     

Effects of vitamin D metabolites and bisphosphonates on fibronectin release from monocyte-derived macrophages.

Fibronectin release from cultured macrophages, derived from human blood monocytes, was measured during incubation of the cells with increasing concentrations of vitamin D3 metabolites or of aminobutane bisphosphonate (AHButBP) or dichloromethylene bisphosphonate (Cl2MBP), two powerful inhibitors of bone resorption. The bisphosphonates significantly inhibited fibronectin release at 10(-8) M concentration and this inhibition was almost complete at 10(-5) M concentration. Opposite results were observed when the cells were incubated with vitamin D3 metabolites: the stimulation of fibronectin release was specific for 1,25-dihydroxyvitamin D3 relative to other vitamin D3 metabolites (1,25-dihydroxyvitamin D3 greater than 25-hydroxyvitamin D3 greater than 24,25-dihydroxyvitamin D3).     

Culturing of cells from giant cell tumour of bone on natural and synthetic calcified substrata: the effect of leukaemia inhibitory factor and vitamin D3 on the resorbing activity of osteoclast-like cells

Osteoclastic cells from giant cell tumour of bone (GCT) of bone provide a rich source for investigation of cellular mechanisms leading to formation of multinucleated cells, the resorption process and involvement of hormones and cytokines in these events. In the present study we investigated the effect of 1,25-dihydroxyvitamin D3 (VD3) and leukaemia inhibitory factor (LIF) on the resorbing potential of osteoclast of GCT origin using quantitative image-analysis of resorption lacunae in an in vitro dentine model. While VD3 unsignificantly increased the number of resorption pits and implicated surface after 7 days of GCT cell culturing, the stimulative effect of LIF was statistically significant. In cultures supplemented with LIF (5000 U/ml) the number of lacunae and resorption surface increased by 38% and 55%, respectively, when compared with control cultures. We suggest that both osteotropic agents increased osteoclastic activity, as the number of multinucleated cells was similar in control and experimental cultures. Seeding of GCT cells on biphasic calcium phosphate substratum revealed the relative inability of osteoclastic cells to resorb this synthetic material.     

Phosphatemic action of 1,25-dihydroxyvitamin D3.

The action of a single intraperitoneal injection of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) was investigated in thyroparathyroidectomized (TPTX) vitamin D-deficient phosphate-depleted rats. After 14 h, plasma inorganic phosphorus (Pi) was significantly greater in animals receiving 1,25(OH)2D3 than in D-deficient controls, but urinary Pi excretion was very low in both groups and not significantly different in the rats given 1,25(OH)2D3. Clearance studies indicated that the D-deficient controls reabsorbed more than 99% of their filtered Pi. Avid Pi reabsorption continued even after the infusion of sufficient phosphate to raise the plasma and filtered Pi to approximately 3 times normal. Fractional calcium excretion (FECa) exceeded fractional sodium excretion (FENa) by severalfold, but FECa decreased strikingly during phosphate infusion. In animals that manifested a substantial elevation of plasma Pi after 1,25(OH)2D3, FECa was significantly less than in D-deficient controls. Therefore, the increase in plasma Pi following 1,25(OH)2D3 administration occurs independently of any effect on renal Pi reabsorption and may be responsible, at least in part, for the amelioration of hypercalciuria after 1,25(OH)2D3 treatment.     

Intestinal phosphate absorption and the effect of vitamin D: a comparison of rats with mice

Previously, it was thought that intestinal phosphate transport occurred exclusively in the proximal small intestine of rodents and humans. However, a recent study has demonstrated that the ileum of mice contributes significantly to the absorption of dietary phosphate, but it is not known whether this region is also an important site of phosphate absorption in the rat. In the present study, we have investigated the mRNA and protein levels of the sodium-phosphate cotransporter, NaPi-IIb, in three regions of rat and mouse small intestine, and related its expression levels to the rate of net phosphate absorption, as measured using the in situ intestinal loop technique. 1,25-Dihydroxyvitamin D3 is an important physiological regulator of intestinal phosphate absorption that increases phosphate transport in both the duodenum and jejunum of the rat. Based on the recently proposed regional profile of phosphate absorption along the mouse small intestine, we have re-evaluated the effects of 1,25-dihydroxyvitamin D3 using three distinct regions of the mouse and rat small intestine. Our studies have revealed important differences in the intestinal handling of phosphate between mice and rats. In mice, maximal phosphate absorption occurs in the ileum, which is paralleled by the highest expression levels of NaPi-IIb mRNA and protein. In contrast, in rats maximal absorption occurs in the duodenum with very little absorption occurring in the ileum, which is similar to the pattern reported in humans. However, in both rodent species only the jejunum shows an increase in phosphate absorption in response to treatment with 1,25-dihydroxyvitamin D3.     

Evidence for disordered control of 1,25-dihydroxyvitamin D production in absorptive hypercalciuria

In previous studies, we observed increases in the circulating concentration and production rate of 1,25-dihydroxyvitamin D (1,25-(OH)2D) in a large majority of patients with the syndrome of absorptive hypercalciuria. In the present study, the hypothesis that 1,25-(OD)2D production might be relatively autonomous in this syndrome was tested by fashioning a suppression test in which patients were challenged with a short-term increase in dietary calcium intake. We found that contrary to our hypothesis, the circulating concentration of 1,25-(OH)2D was remarkably sensitive to calcium intake in 15 patients with absorptive hypercalciuria (mean decrease, from 74 to 49 pg per milliliter, P less than 0.001). When this challenge was prolonged for two weeks, however, patients with absorptive hypercalciuria had evidence of an apparent "escape" phenomenon, in which the circulating concentration of 1,25-(OH)2D rebounded toward its initial level and the renal tubular phosphate threshold fell markedly. These findings provide evidence for disordered control of renal phosphate handling and 1,25-(OH)2D production in absorptive hypercalciuria and suggest a linked rather than a cause-and-effect relation between these two abnormalities.     

Biological activity of 24,24-difluoro-1,25-dihydroxyvitamin D3

The biological activity of 24,24-difluoro-1,25-dihydroxyvitamin D3 was compared with 1,25-dihydroxyvitamin D3 in the rat. The 24,24-difluoro-1,25-dihydroxyvitamin D3 has a potency of approximately 5-10 times that of 1,25-dihydroxyvitamin D3 in the known in vivo vitamin D responsive systems. These systems include intestinal calcium transport, bone calcium mobilization, calcification of epiphyseal plate cartilage, and elevation of plasma calcium and phosphorus concentrations. Thus, 24,24-difluoro-1,25-dihydroxyvitamin D3 is the first known analogue with higher potency than 1,25-dihydroxyvitamin D3 in vivo.     

Parathyroid hormone, 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D concentration in elderly patients

Summary In 50 patients of a geriatric hospital (33 women, aged 65–96 years, mean age 80 years, and 17 men, aged 68–91, mean age 78.3 years) calcium, albumin, phosphate, urea, creatinine, parathyroid hormone, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D were determined. Forty patients with serum creatinine levels up to 1.4 mg/dl (124 mol/l) and 10 patients with creatinine concentrations 1.5 mg/dl (132mol/l) were evaluated. In patients with normal creatinine, a positive correlation was found between parathyroid hormone and age (r=0.41;P<0.01). In patients with elevated creatinine, negative correlations were found in 1,25-dihydroxyvitamin D and calcium (r=–0.724;P<0.05), 1,25dihydroxyvitamin D and creatinine (r=–0.79;P<0.01) and 1,25-dihydroxyvitamin D and phosphate (r=–0.87;P< 0.002). The best correlation was observed in patients with elevated serum creatinine for 1,25-dihydroxyvitamin D and phosphate (r=–0.91;P< 0.001). The results suggest that low levels of calcium and phosphate stimulate the 1-hydroxylation of 25-hydroxyvitamin D even in advanced age and that the calcium metabolism of these patients is frequently disturbed. Nineteen patients had low levels of 25-hydroxyvitamin D, indicating an insufficient supply of vitamin D or rare exposure to sunlight. In 49 of 50 patients, one ore more of the parameters of calcium metabolism were outside the normal range.Abbreviations 25-OH-D 25-hydroxyvitamin D - 1,25(OH)₂D 1,25-dihydroxyvitamin D - PTH parathyroid hormone Supported by the Deutsche Forschungsgemeinschaft (Schm 405–407)