Phosphore,tubule rénal et appareil ostéoarticulaire

A component of ATP, phosphate is at the hub of the energy-related mechanisms operative in muscle cells. Together with calcium, phosphate is involved in bone tissue mineralization: thus, a chronic alteration in the metabolism of phosphate can induce bone and joint disorders. Diagnosis of chronic hypophosphatemia. Serum phosphate, calcium, and creatinine should be assayed simultaneously. Serum calcium is increased in hypophosphatemia caused by hyperparathyroidism and decreased in osteomalacia. Urinary phosphate excretion should be measured in patients with a normal serum calcium level and a serum phosphate level lower than 0.80 mmol/L. A decrease in urinary phosphate excretion to less than 10 mmol/24 hours strongly suggests a gastrointestinal disorder, such as malabsorption, antacid use, or chronic alcohol abuse. In patients with a urinary phosphate excretion greater than 20 mmol/24h, the maximal rate of tubular reabsorption of phosphate (TmPO₄) and the ratio of TmPO₄ over glomerular filtration rate (GFR) should be determined to look for phosphate diabetes. Manifestations and causes of phosphate diabetes in adults. Moderately severe phosphate diabetes in adults manifests as chronic fatigue, depression, spinal pain, and polyarthralgia, with osteoporosis ascribable to increased bone resorption. Although many cases are idiopathic, investigations should be done to look for X-linked vitamin D-resistant rickets missed during childhood, a mesenchymatous tumor, or Fanconi syndrome with renal wasting of phosphate, glucose, and amino acids. Management of phosphate diabetes. Phosphate supplementation and, in patients with normal urinary calcium excretion, calcitriol produce some improvement in the symptoms and increase the bone mineral density. Whether dipyramidole is clinically effective remains unclear.     

Renal phosphate leak in patients with idiopathic hypercalciuria and calcium nephrolithiasis

Although urine phosphate loss has been associated with hypercalciuria, it is debated how frequently renal phosphate leak is present in hypercalciuric patients. We reviewed the records of 100 consecutive adult patients who were diagnosed with idiopathic hypercalciuria and calcium urolithiasis, searching for the presence of renal phosphate leak. The renal phosphate threshold, normalized for the glomerular filtration rate (TmPO4/GFR), of the hypercalciuric patients followed a normal distribution and had a good correlation with serum phosphate (r=0.77; p<0.0001). There were no correlations between TmPO4/GFR and urinary calcium or between serum phosphorus and urinary calcium. We found only nine patients (9%) with renal phosphate leak. These patients had a mean TmPO4/GFR of 2.19 mg% (0.70 mmol/l) and serum phosphorus of 2.65 mg% (0.85 mmol/l). Nevertheless, urinary calcium was not significantly different between patients with or without low TmPO4/GFR. We conclude that renal phosphate leak is an infrequent finding in patients with idiopathic hypercalciuria and is not associated with a higher urinary calcium loss.     

Frequency of renal phosphate leak among patients with calcium nephrolithiasis.

BACKGROUND: Nephrolithiasis is a frequent disorder affecting 10 to 15% of the population in Europe and the United States. More than 80% of renal stones are made of calcium oxalate and calcium phosphate. The main identified risks for calcium renal stone formation are hypercalciuria and urinary saturation. A urine phosphate (Pi) loss is often associated with hypercalciuria; furthermore, hyperphosphaturia increases urinary saturation. METHODS: To determine whether urinary phosphate loss is associated with calcium urolithiasis, we measured renal Pi threshold (TmPi) in 207 stone formers with normal parathyroid hormone (PTH) serum concentration and in 105 control subjects. RESULTS: The TmPi followed a normal distribution in both groups. The mean TmPi was significantly lower in stone formers versus controls (0.72 +/- 0.13 vs. 0.87 +/- 0.18 mmol/L, P < 0.0001) because of a shift to the left of the TmPi distribution curve in the stone former population, with no evidence for bimodal distribution. Five percent of the controls had a TmPi <0.63 versus 19% of the stone formers. Daily urinary calcium excretion was significantly higher in stone formers than in controls. Calcium excretion was also significantly higher in stone formers with TmPi <0.63 mmol/L compared with those with TmPi > or =0.63. Serum PTH and ionized calcium concentrations were not different in stone formers and in control subjects, whatever the TmPi value. CONCLUSIONS:: A low TmPi is more frequently encountered in stone formers with a normal PTH concentration than in control subjects and is associated with a high urinary Ca excretion. The hypophosphatemia induced by a renal phosphate leak may predispose the subject to calcium stone formation by increasing the serum calcitriol level, calcium excretion, and urinary saturation.     

Prednisolone Induces an Increase in Serum Calcium Concentration: Possible Involvement of the Kidney, the Bone, and the Intestine

To evaluate the early effect of glucocorticoids on calcium metabolism, 15 subjects aged 22–58 years (5 males, 10 females) with chronic glomerulonephritis were orally treated with 40 mg daily of prednisolone. Five of these subjects were diagnosed with nephrotic syndrome and none had a serum creatinine concentration of more than 1.4 mg/dl. Serum specimens and 24-hour urine specimens were obtained just before and 24 hours after a single oral dose of prednisolone. Serum calcium, ionized calcium, phosphate, intact parathyroid hormone (PTH), intact osteocalcin and 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃), and urinary excretion of calcium, phosphate, and deoxypyridinoline were measured. Both serum calcium and ionized calcium concentrations were significantly increased from 4.39 ± 0.10 to 4.47 ± 0.09 mEq/liter (P= 0.037) and from 2.48 ± 0.04 to 2.55 ± 0.04 mEq/liter (P= 0.002), respectively, 24 hours following a single oral dose of prednisolone. Serum intact PTH concentration slightly decreased, but the difference was not significant by statistical analysis. Serum intact osteocalcin concentration was markedly suppressed. In contrast, no significant changes were observed in urinary excretion of deoxypyridinoline. Serum 1,25(OH)₂D₃ concentration measured in five patients was significantly increased. No significant changes in urinary excretion of calcium was observed in the face of these findings. It thus follows that a single oral dose of prednisolone administration increases serum calcium and ionized calcium concentrations, possibly mediated by suppressed bone formation, increased intestinal absorption of calcium, and impaired urinary excretion of calcium. Received: 19 February 1998 / Accepted: 12 March 1999     

Effect of dipyridamole on serum and urinary phosphate in X-linked hypophosphatemia

X-linked hypophosphatemia (XLH) is characterized clinically by rickets, hypophosphatemia and hyperphosphaturia. Conventional treatment of XLH with oral phosphate and vitamin D is associated with hypercalcuria and nephrocalcinosis. Recently, intravenous and oral dipyridamole has been reported to decrease fractional excretion of phosphate in adults with idiopathic hyperphosphaturia. Our objective was to determine whether oral dipyridamole therapy reduces urinary phosphate excretion and increases serum phosphate concentration in children with XLH. A prospective study was performed in six children with XLH. The average age of the patients at the start of the study was 12.5±1.0 years. The effects of 12 weeks of oral dipyridamole therapy, at 4.4±0.4 mg/kg body weight per day, on serum phosphorous, parathyroid hormone (PTH), 1,25 (OH)₂ vitamin D, osteocalcin, tubular maximum for phosphate reabsorption (TmP/GFR), urinary calcium excretion, and cyclic adenosine 3’,5’-monophosphate (cAMP) excretion, were compared to baseline levels. Our results show that there was no change in serum phosphorous concentration or TmP/GFR after 12 weeks of dipyridamole therapy. Dipyridamole therapy also had no effect on serum PTH, serum 1,25 (OH)₂ vitamin D, alkaline phosphatase, osteocalcin levels, urinary calcium or cAMP excretion. We therefore concluded that in children with XLH, a 12-week course of dipyridamole had no effect on serum phosphorous or its urinary excretion. Dipyridamole therapy is unlikely to improve the bone disease in children with XLH. Received: 7 February 2000 / Revised: 5 May 2000 / Accepted: 16 May 2000     

Severe hypophosphatemia following elective abdominal aortic bypass grafting

Serum phosphate levels and urinary phosphate excretion were investigated in ten patients undergoing elective abdominal aortic bypass grafting. The abdominal aorta was cross-clamped peroperatively for 50-95 min. The median serum phosphate was within reference range (0.80-1.55 mmol/l) during cross-clamping and for the first 24 hours after revascularization of the lower limbs. At 48 hours there was statistically significant fall in the serum phosphate level in all patients, with median reaching a nadir of 0.49 mmol/l. At 72 hours this level had risen to 0.69 mmol/l, and reference range had been regained 7 days postoperatively. The median urinary phosphate excretion (mmol) was 38.4 during the first 24 postoperative hours, and 34.7 and 10.0 on the 2 subsequent days. The median ratio of urinary phosphate to creatinine clearance was, respectively, 0.47, 0.37, 0.09 and 0.08 on postoperative days 1, 2, 3 and 7. The study indicated that patients undergoing aortic bypass grafting with protracted regional muscular ischemia may constitute a risk group with respect to development of severe postoperative hypophosphatemia.     

Metabolic aspects of phosphate replacement therapy for hypophosphatemia after renal transplantation: impact on muscular phosphate content, mineral metabolism, and acid/base homeostasis.

Hypophosphatemia caused by renal phosphate loss occurs frequently after kidney transplantation. In assumption of systemic phosphorus depletion, the presumed deficit commonly is replaced by oral phosphate supplements. However, such treatment is debatable, because intracellular phosphorus stores have not been assessed in this setting and may not be accurately reflected by serum phosphate concentrations. Moreover, disturbances in mineral metabolism from chronic renal failure, such as hypocalcemia and hyperparathyroidism, may be prolonged with oral phosphate supplements. Conversely, a neutral phosphate salt might improve renal acid excretion and systemic acid/base homeostasis for its properties as a urinary buffer and a poorly reabsorbable anion. Twenty-eight patients with mild early posttransplantation hypophosphatemia (0.3-0.75 mmol/L) were randomly assigned to receive either neutral sodium phosphate (Na(2)HPO(4)) or sodium chloride (NaCl) for 12 weeks and examined with regard to (1) correction of serum phosphate concentration and urinary phosphate handling; (2) muscular phosphate content; (3) serum calcium and parathyroid hormone (PTH); and, (4) renal acid handling and systemic acid/base homeostasis. Mean serum phosphate concentrations were similar and normal in both groups after 12 weeks of treatment; however, more patients in the NaCl group remained hypophosphatemic (93% versus 67%). Total muscular phosphorus content did not correlate with serum phosphate concentrations and was 25% below normophosphatemic controls but was completely restored after 12 weeks with and without phosphate supplementation. However, the percentage of the energy-rich phosphorus compound adenosine triphosphate (ATP) was significantly higher in the Na(2)HPO(4) group, as was the relative content of phosphodiesters. Also, compensated metabolic acidosis (hypobicarbonatemia with respiratory stimulation) was detected in most patients, which was significantly improved by neutral phosphate supplements through increased urinary titratable acidity. These benefits of added phosphate intake were not associated with any adverse effects on serum calcium and PTH concentrations. In conclusion, oral supplementation with a neutral phosphate salt effectively corrects posttransplantation hypophosphatemia, increases muscular ATP and phosphodiester content without affecting mineral metabolism, and improves renal acid excretion and systemic acid/base status.     

Bone mass does not correlate with the serum fibroblast growth factor 23 in hemodialysis patients

Circulating fibroblast growth factor 23 (FGF23) increases renal phosphate excretion, decreases bone mineralization and is markedly increased in hemodialysis patients. Bone cells express fibroblast growth receptor 1, suggesting that FGF23 could alter bone mineralization by means of a direct effect on the skeleton and/or secondarily due to hypophosphatemia. To distinguish between these possibilities we measured serum concentrations of FGF23, parathyroid hormone, phosphate, calcium, and markers of bone remodeling, and assessed bone mineral density in 99 hemodialysis patients. FGF23 concentrations were increased in all hemodialysis patients, even in those without hyperphosphatemia, and positively correlated with serum phosphate but not with parathyroid hormone. Hemodialysis did not decrease the serum FGF23 concentration. We found no significant correlation between serum FGF23 levels and bone mineral density. Further analysis by gender or T-score did not modify these results. Serum markers of bone remodeling significantly correlated with parathyroid hormone but not with FGF23 levels. The increase in serum FGF23 concentration in hemodialysis patients cannot be solely ascribed to hyperphosphatemia. Our study suggests that the effects of FGF23 on bone mineralization are mainly due to hypophosphatemia and not a direct effect on bone.     

Increasing serum osteocalcin after glycemic control in diabetic men

The pathogenesis of diabetic osteopenia is unclear. The markers of bone metabolism may show some changes in diabetic patients. In this study, we investigated the effect of glycemic control on serum osteocalcin level and urinary hydroxyproline excretion and the relations of these markers to duration of diabetes, C-peptide status, and body mass index. Twenty-seven men with poorly controlled diabetes mellitus (DM) (HbA1>9%, fasting plasma glucose>7.8 mmol/liter) between ages 25 and 60 years (means±SD 46.6±10.4) were included in the study. Duration of diabetes was 5.8±4.7 years, body mass index (BMI) was 25.9±3.5 kg/m², and fasting C-peptide was 2.33 (1.05–3.21) g/liter. None of the patients had a disease or were treated with drugs that would interfer with calcium or phosphate metabolism and/or bone structure. They were free from chronic diabetic complications. Of these patients, 11 were lost to follow-up before metabolic control was achieved. The remaining 16 patients obtained good glycemic control (HbA1<8.3%, fasting plasma glucose <7.8 mmol/liter) and completed the study. Serum osteocalcin level and urinary hydroxyproline eceretion were determined before and after glycemic control. Urinary hydroxyproline excretion was not significantly changed by glycemic control [17.8 (7.1–23.2) versus 18.1 (10.9–28.1) mg/m² day, P>0.05]. However, serum osteocalein level was significantly elevated (5.04±1.43 versus 4.17±1.83 g/liter, P=0.04). We found no correlation among fasting plasma glucose, HbA1, and fasting serum C-peptide levels with urinary hydroxyproline excretion. There was also no correlation between serum osteocalcin and fasting plasma glucose or serum C-peptide, but HbA1 was negatively correlated with serum osteocalcin (P=0.01). No correlation was found between DM duration and BMI in the patients with serum osteocalcin level and urinary hydroxyproline excretion. To eliminate the possible effect of exogenous insulin on bone metabolism, the correlation analysis between the markers and C-peptide was further repeated in oral agents-treated patients. Serum C-peptide was not correlated to serum osteocalcin or urinary hydroxyproline in this subgroup of patients. Knowing that serum osteocalcin is a marker of bone formation, we concluded that osteoblast function may improve by glycemic control in diabetic patients; this may be due to correction of metabolic abnormalities associated with insulinopenia.     

Decreased renal phosphate threshold in patients with gout.

Serum and 24-hour urinary phosphate levels in primary gout patients and control subjects were measured. About 45% of gouty patients showed mild hypophosphatemia. However, mean 24-hour urinary excretion of phosphate was significantly elevated as compared with that of controls. Gouty patients showed a significantly decreased tubular reabsorption of phosphate and renal phosphate threshold. It seems that tubular phosphate transport in gouty patients is impaired, and this is the major cause of hypophosphatemia.     

Osteomalacia as a very late manifestation of primary hyperparathyroidism

An 86-year-old woman with a history of treated hyperthyroidism and a 20-year history of untreated primary hyperparathyroidism developed generalized bone pain and a pseudofracture of the midshaft of the left femur. Laboratory examinations revealed elevated serum calcium, alkaline phosphatase, and C-terminal parathyroid hormone levels. Serum inorganic phosphate was below normal and 25-hydroxyvitamin D levels were low-normal. An undecalcified transiliac bone biopsy specimen following tetracycline double labeling revealed osteomalacia and osteitis fibrosa. Following treatment with vitamin D and phosphate, the serum inorganic phosphate level rose to normal. There was a decrease in bone pain, and the pseudofracture healed. However, the serum calcium, alkaline phosphatase, and C-terminal parathyroid hormone levels remained elevated. Longstanding primary hyperparathyroidism causes chronic hypophosphatemia and may lead to osteomalacia. Osteomalacia and its consequences may be part of the spectrum of bone disease seen in patients with longstanding primary hyperparathyroidism.     

Hypophosphatemic rickets with hypocalciuria following long-term treatment with aluminum-containing antacid

We present what we believe is the first case of rickets following prolonged treatment with aluminum containing antacids that bind phosphate, in an 18-year-old mentally retarded boy with cerebral palsy and spastic quadriplegia. As expected, serum calcitriol was increased and urinary phosphate excretion was very low. However, in contrast to all published cases of antacid induced hypophosphatemic osteomalacia in adults, despite a substantial increase in bone resorption reflected by urinary total hydroxyproline excretion, urinary calcium excretion was low rather than high, and significant hypocalcemia occurred after antacids were ceased and a phosphate salt administered. We suggest that the skeleton was so under-mineralized because of growth during prolonged phosphate deficiency, possibly augmented by anticonvulsant administration and immobilization, that increased bone resorption did not release enough calcium to cause hypercalciuria, or to prevent hypocalcemia during resumption of normal mineralization.     

Is there a role for a random measurement of 24-hour urine calcium excretion and serum total alkaline phosphatase in the determination of fracture risk in osteoporotic postmenopausal women?

Our objective was to explore whether a casual determination of 24-hour urinary calcium excretion and serum total alkaline phosphatase (TAP), in osteoporotic postmenopausal women are independent predictors for osteoporotic fracture. Subjects were 121 women with postmenopausal osteoporosis (mean age 62.8 +/- 9.9) segregated in two study groups based on prevalence of osteoporotic fractures (51 women with prevalent fractures and 70 without fractures), similar in terms of age and BMI. We measured bone mineral density (BMD) by DXA at lumbar spine and femoral neck. Vertebral fracture assessment was done by plain X ray evaluation. Routine blood tests and extensive endocrine evaluation were performed in all patients to exclude secondary causes of osteoporosis. Serum TAP, calcium, phosphate and urinary calcium excretion was measured to evaluate bone metabolism. We did not find any significant differences between groups regarding lumbar T score (-3.1/-2.9 SD), femoral neck T score (-2.2/-1.8 SD), lumbar Z score (-1.5/-1.9 SD) or femoral neck Z score (-1.5/-1.8 SD). Serum TAP was higher in fracture group (211.5 UI) comparing to non-fracture osteoporotic women (208.3 UI) without statistical significance. We were not able to find any significant difference between groups in terms of urinary calcium excretion (9.13/5.4 mEq/24h) or serum total calcium (4.8/4.9 mmol/l). CONCLUSION: in spite of a mean TAP near the upper limit of normal range which could be related to low bone mass, there is no significant relationship to fracture risk in osteoporotic postmenopausal women. Based on our data, a casual measurement of urinary calcium excretion seems irrelevant for BMD independent fracture risk assessment in this clinical setup.     

Hypercalciuric rickets: metabolic studies and pathophysiological considerations

Extensive metabolic studies were performed in a 14-year-old boy suffering from the rare clinical entity known as childhood idiopathic hypercalciuria associated with dwarfism, renal tubular abnormalities and bone lesions. The salient features were: hyperphosphaturia with hypophosphatemia, hypercalciuria with normocalcemia, elevated serum 1,25-dihydroxycholecalciferol[1,25(OH)2D3] levels, marked intestinal hyperabsorption of calcium and phosphorus, with low serum parathyroid hormone (PTH) and urinary adenosine 3':5'-cyclic monophosphate (c-AMP). Bone biopsy confirmed the clinical and radiological diagnosis of rickets. It appears that the following pathophysiological sequence is operating: primary renal phosphate leak with hypophosphatemia, increased 1,25(OH)2D3 synthesis, enhanced intestinal calcium absorption which in turn inhibits release of PTH and c-AMP. Hypercalciuria is seen to be secondary to both avid intestinal calcium absorption and depressed PTH activity, and rickets the result of phosphate depletion. Treatment with oral phosphorus only resulted in an acceleration of growth rate, cure of rickets, and return of urinary calcium excretion to normal values.     

Hormonal alterations in experimental diabetes: Role of a primary disturbance in calcium homeostasis

Summary Chronic diabetes mellitus in the rat is attended by a reduced bone turnover and growth arrest, decreased circulating immunoreactive parathyroid hormone (iPTH), and hypercorticosteronism. Since chronic insulin deficiency in the rat is associated with intestinal hyperabsorption of calcium and a positive calcium balance that may account for the decreased iPTH, as well as other hormonal alterations observed in these animals, we studied the effect of long-term (5 week) dietary calcium restriction (0.1% Ca, 0.8% P) in control and streptozotocin-induced diabetic rats. Chronic diabetic rats reared on a normal calcium (1.2% Ca) diet had increased serum calcium and phosphate (Pi) concentrations and were markedly hypercalciuric and phosphaturic compared with controls. Serum corticosterone was increased and iPTH markedly decreased in the diabetic animals. Dietary Ca restriction (0.1% Ca) decreased urinary calcium excretion and resulted in a comparable phosphaturic response in both control and diabetic rats. Moreover, although Ca restriction in diabetic animals had no appreciable effect on serum insulin, serum glucose, or urinary glucose excretion, it was associated with a marked increase in circulating iPTH; this resulted in serum concentrations comparable with that observed in control animals reared on the low Ca diet. These results support the hypothesis that the decreased circulating iPTH observed in chronic diabetic rats results predominantly from their intestinal hyperabsorption of Ca. In contrast to control animals, diabetic rats reared on a low Ca diet failed to maintain their serum Ca despite the marked increase in serum iPTH and striking decrease in calciuria, thus underscoring the reliance of these animals on intestinal hyperabsorption of Ca to maintain Ca balance under conditions of adequate Ca intake. Serum corticosterone was insignificantly altered by dietary Ca restriction in control rats; hypercorticosteronism, characteristically observed in diabetic rats, was normalized by Ca restriction. We conclude that a primary disturbance in Ca homeostasis may contribute, in part, to hormonal alterations observed in chronic experimental diabetes.     

Chronic respiratory alkalosis induces renal PTH-resistance, hyperphosphatemia and hypocalcemia in humans.

The effects of chronic respiratory alkalosis on divalent ion homeostasis have not been reported in any species. We studied four normal male subjects during a four-day control period (residence at 500 m), during six days of chronic respiratory alkalosis induced by hypobaric hypoxia (residence at 3450 m), followed by a six-day eucapnic recovery period (500 m) under metabolic balance conditions. Chronic respiratory alkalosis (delta PaCO2, -8.4 mm Hg, delta[H+] -3.2 nmol/liter) resulted in a sustained decrement in plasma ionized calcium concentration (delta[IoCa++]p, -0.10 mmol/liter, P less than 0.05) and a sustained increment in plasma phosphate concentration (delta[PO4]p, +0.14 mmol/liter, P less than 0.005) associated with increased fractional excretion of Ca++ (+0.5%, P less than 0.005), decreased phosphate clearance (-6.1 ml/min, P less than 0.025) and decreased excretion of nephrogenous cAMP (-1.5 nmol/100 ml GFR, P less than 0.0025). Urinary phosphate excretion decreased by 15.4 mmol/24 hr on day 1 of chronic respiratory alkalosis (P less than 0.0025), but returned to control values by day 6 despite hyperphosphatemia. Serum intact [PTH] did not change. Sustained hypomagnesuria (-0.8 mmol/24 hr, P less than 0.05) occurred during chronic respiratory alkalosis and was accounted for, at least in part, by decreased fractional excretion of Mg++ (-0.7%, P less than 0.05) in the absence of change in plasma magnesium concentration. Serum 1,25(OH)2D levels were unchanged by chronic respiratory alkalosis. In conclusion, the decrease in nephrogenous cAMP generation despite unchanged serum intact PTH concentration suggests that chronic respiratory alkalosis results in impaired renal responsiveness to PTH as manifested by alterations in PTH-dependent renal calcium and phosphate transport.(ABSTRACT TRUNCATED AT 250 WORDS)     

Elevated levels of serum bone gamma-carboxyglutamic acid-containing protein in postmenopausal women

A total of 26 subjects, 13 premenopausal and 13 postmenopausal women, aged between 46 and 52 were examined for their cortical thickness of the clavicle, serum bone gamma-carboxyglutamic acid-containing protein (BGP, osteocalcin), serum alkaline phosphatase, serum calcium, serum inorganic phosphate, urinary calcium/creatinine and urinary inorganic phosphate/creatinine. Serum BGP was significantly higher in postmenopausal than in premenopausal women. Serum alkaline phosphatase also tended to elevate in postmenopausal women, while there were no significant differences in cortical thickness of the clavicle, serum calcium, serum inorganic phosphate, urinary calcium/creatinine and urinary inorganic phosphate/creatinine between the two. Considering that both serum BGP and serum alkaline phosphatase are markers of bone formation, these findings indicate that menopause firstly accelerates bone turnover preceding age-related bone loss.     

Normal FGF23 Levels in Adult Idiopathic Phosphate Diabetes

Fibroblast growth factor 23 (FGF23), a recently discovered phosphaturic substance playing a key role in genetic and oncogenic phosphate diabetes, is involved in the physiological regulation of phosphate metabolism. Moderate idiopathic phosphate diabetes (IPD) leading to male osteoporosis and diffuse pain resembling fibromyalgia has been described. The aim of our study was to define the role of FGF23 in the mechanism of IPD. The study concerned 29 patients with IPD, mean age 53 ± 11 years, of whom 72% were men. Fifteen subjects without bone disease and with normal serum phosphate and calcium levels were used as controls. Phosphate diabetes was confirmed by phosphate reabsorption level <85% and phosphate reabsorption threshold (TmPO4/GFR) <0.83. Known causes of phosphate diabetes were excluded. Fasting level of FGF23, serum phosphate, 1-25(OH)₂D₃, and parathyroid hormone were measured in patients and compared with FGF23 and serum phosphate in healthy controls. Spinal and hip bone mineral density (BMD) were measured by osteodensitometry. Sixteen of 29 patients had diffuse pain, 10 had osteoporosis according to the World Health Organization criteria, and 11 had osteopenia. Serum phosphate was significantly lower in patients than in controls, but FGF23 levels did not differ. Compared to patients with normal bone status, patients with osteopenia and osteoporosis had significantly decreased FGF23 levels, whereas serum phosphate was identical in the two groups. In all patients, serum phosphate and FGF23 were positively correlated and FGF23 and 1-25(OH)₂D₃ were negatively correlated. FGF23 seems not be a cause of IPD, and the FGF23/phosphate/1-25(OH)₂D₃ axis appeared to be functional.     

Renal handling of calcium in the early newborn period

Urinary calcium excretion was studied in two matched groups of 28 clinically-well preterm and fullterm infants between 24 and 48 hours of life. In the developmental period from 28 to 40 weeks gestation, urinary calcium excretion was positively correlated to the gestational age (r = 0.583, P less than 0.01), serum calcium levels (r = 0.512, P less than 0.01), the rate of glomerular filtration (r = 0.715, P less than 0.001), and urinary cyclic AMP excretion (r = 0.717, P less than 0.001). Urinary calcium excretion was independent of sodium and calcium intake, and urinary sodium and phosphate excretion. The mean fractional total calcium excretion and fractional ionized calcium excretion in babies less than or equal to 32 weeks was less than 1.0%, compared to greater than 2.5% for sodium. Serum calcium levels were positively correlated with gestational age (r = 0.803, P less than 0.001), and serum phosphate levels (r = 0.85, P less than 0.001). Whole blood ionized calcium levels were positively correlated to gestational age (r = 0.625, P less than 0.001), and serum total calcium levels (r = 0.440, P less than 0.05). The newborn kidney in babies less than or equal to 32 weeks gestation, did not have impaired conservation of calcium as for sodium; and neither sodium nor calcium intake appeared to affect urinary calcium excretion in the well newborn infant. Probably neither excess excretion of calcium nor serum phosphate levels contribute to early neonatal hypocalcemia.     

Uninterrupted oral bisphosphonate (pamidronate) therapy of patients with osteoporosis is not associated with chronic stimulation of parathyroid hormone secretion

We have previously reported that long-term uninterrupted treatment of patients with osteoporosis with oral pamidronate is associated with increases in bone mineral content (BMC) of the lumbar spine which could not be explained by the antiresorptive action of the drug alone, raising the possibility of an additional effect of the treatment on skeletal tissue. Administration of suppressive doses of the bisphosphonate to patients with excessive osteoclastic resorption is followed by transient decreases in serum calcium and increases in parathyroid hormone (PTH) concentrations. It is possible, therefore, that chronic pamidronate therapy may stimulate PTH secretion, which in turn has been previously shown to have anabolic effects on the skeleton. To test this hypothesis we examined the changes in serum calcium, PTH and phosphate concentrations every 6 months in 33 patients with vertebral osteoporosis and no biochemical evidence of increased bone turnover, treated with oral pamidronate 150 mg daily. Serum alkaline phosphatase and urinary hydroxyproline excretion decreased significantly by 20% and 28%, respectively, after 6 months of treatment and remained at this level for the following 18 months. These changes were associated with significant increases in spinal BMC, as expected. Serum calcium, PTH and phosphate did not change from baseline values either in the whole group or when the patients were divided according to the use or not of calcium supplements. Our results exclude chronic stimulation of PTH secretion as a factor contributing to long-term increases in bone mass in patients with osteoporosis and adequate calcium intake during continuous oral pamidronate therapy.