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Phosphate, the renal tubule, and the musculoskeletal system
Joint Bone Spine 2001 ; 68 : 211-5 © 2001 Éditions scientifiques et médicales Elsevier SAS. All rights reserved S1297319X01002743/REV
REVIEW
Phosphate, the renal tubule, and the musculoskeletal system Michel Laroche* Service de rhumatologie, CHU Rangueil, 1, avenue J. Poulhès, 31043 Toulouse, France (Submitted for publication October 12, 2000; accepted in revised form January 10, 2001)
Summary – 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 h 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/24 h, 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’s 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. Joint Bone Spine 2001 ; 68 : 211-5. © 2001 Éditions scientifiques et médicales Elsevier SAS hypophosphatemia / phosphate / diabetes
Phosphate is a component of adenosine-triphosphate (ATP) and, as such, is involved in intracellular oxidative processes and mitochondrial respiration. Without phosphate, the neurons cannot function normally.
* Correspondence and reprints. E-mail address: [email protected] (M. Laroche).
Because phosphate is a component of ATP, it plays a pivotal role in the energy-related processes that take place in striated muscle cells and in the smooth muscle cells of the gastrointestinal tract and cardiovascular system. Finally, like calcium, phosphate is involved in bone tissue mineralization. A favorable balance between phosphate and calcium must be maintained: an increase in the calcium-phosphate product can result in calcium
212
M. Laroche
deposition within soft tissues including cartilage, tendon attachments, and blood vessel walls. Because of these physiological effects of phosphate, chronic alterations in phosphate metabolism can result in multiorgan dysfunction, particularly in bone and joint disease. REGULATION Eighty-five percent of the phosphate in the human body (600–800 g) is incorporated within the bone tissue. The remaining 15% is located, in part, within soft tissue cells and, in part, in the extracellular compartment. Only 1% is in the plasma, as monosodium or disodium phosphate and phosphoric esters. Only 12% of plasma phosphate is bound to protein [1, 2]. The normal range for serum phosphate is 0.8–1.5 mmol/L (25–45 mg/L) in adults and 1.5–2 mmol/L in children. Phosphate is absorbed both actively and passively by the small bowel and colon. Phosphate filters through the renal glomerule before undergoing active reabsorption by the renal tubule. The amount reabsorbed is almost entirely dependent on adjustments in sodiumphosphate cotransport through the epithelial cell brush border of the proximal renal tubule. Among the four phosphate cotransporters identified to date, the most abundant in the kidney is Npt2a. Targeted inactivation of the Npt2a gene in mice resulted in phosphate diabetes and hypercalciuria [3]. Short-term changes in serum phosphate levels seem regulated by transfers between the intra- and extracellular compartments. The proportion of phosphate absorbed by the bowel increases as phosphate intake decreases. Furthermore, phosphate intake directly and rapidly regulates Npt2a levels within the epithelial cells of the proximal renal tubule. The long-term regulation of phosphate homeostasis is ensured primarily by changes in the phosphate reabsorption by the renal tubule. Thus, hyperphosphatemia occurs in patients with renal failure even when phosphate intake is reduced, and conversely hypophosphatemia develops in patients with proximal tubule disorders even when supplemental phosphate is given. However, severely restricting the dietary intake of phosphate is effective in controlling hyperphosphatemia related to renal failure [4]. Several factors are involved in the regulation of serum phosphate levels. Vitamin D and its hydroxylated derivatives increase the digestive absorption of phosphate. Parathyroid hormone increases both the diges-
tive absorption and the renal excretion of phosphate. It acts in part by causing irreversible internalization followed by degradation of the Npt2a protein. Growth hormone and/or IGF1 levels increase with the amounts of phosphate absorbed by the bowel and reabsorbed by the renal tubule. Glucocorticoids and calcitonin seem to have modest effects related to an increase in phosphate excretion. Respiratory alkalosis and thyroxin increase phosphate reabsorption by the renal tubule, whereas acidosis has the opposite effect. The physiological role of a protein designated ‘phosphatonin’ in some articles [5, 6] remains to be determined. Phosphatonin was first identified in patients with phosphate diabetes caused by mesenchymatous tumors; excision of the tumor was promptly followed by a return to normal of serum phosphate levels. In animal studies, grafting tumor fragments or injecting supernatant from tumor cell cultures induced phosphate diabetes. Phosphatonin may be present in healthy individuals, being degraded in large part by an endopeptidase system. X-linked hypophosphatemia is caused by mutations in the PHEX gene (PHosphate-regulating gene with homology with Endopeptidases on the X chromosome), which encodes an endopeptidase expressed in bone. These mutations may decrease the degradation of phosphatonin, thus resulting in phosphatonin accumulation and hyperphosphaturia [7, 8]. Decreased Npt2a expression in renal cells has been found in Hyp mice, a strain with phosphate diabetes caused by PHEX gene mutations [9]. DIAGNOSIS AND IDENTIFICATION OF THE CAUSE OF HYPOPHOSPHATEMIA Only chronic hypophosphatemia will be discussed here. Acute hypophosphatemia, which is caused by a transfer of phosphate from the extracellular to the intracellular compartment, occurs chiefly in critically ill patients (table I) [7]. Diagnosis of hypophosphatemia Because many physiological dietary and endocrine factors can affect the metabolism of phosphate, phosphate in blood and urine should be assayed under strictly controlled conditions. In particular, the diet should be well balanced in sodium, protein, phosphate, and calcium; and the patient should refrain from drinking large amounts of alcohol on the day before sample collection. Furthermore, the samples should be taken at a time when the patient is not on medications known to
Phosphate, the renal tubule and the musculoskeletal system Table I. Diagnosis of hypophosphatemia. Acute hypophosphatemia: critically ill patient Transfer of phosphate from the extracellular to the intracellular compartment or massive loss of phosphate from the digestive tract: respiratory alkalosis, sepsis, aspirin overdosage, infusion of hypertonic glucose solutions, vomiting, or diarrhea. Chronic hypophosphatemia Abnormal serum calcium – High serum calcium: hyperparathyroidism – Low serum calcium: osteomalacia, malabsorption Normal serum calcium – Hypophosphaturia (< 10 mmol/24 h) Vomiting, diarrhea, digestive malabsorption, antacid use, alcohol abuse Increased bone tissue avidity for phosphate (sclerotic metastases) – Hyperphosphaturia (>20 mmol/24h, phosphate clearance <15 mL/min, TRP<80 %, and TmPo4/GFR< 0.8) : phosphate diabetes Diuretic agents, glucocorticoids X-linked vitamin D-resistant rickets (hypercalciuria is common) Autosomal dominant vitamin D-resistant rickets (serum calcium is normal) Complex tubular disorder (Fanconi’s syndrome: renal wasting of phosphate, glucose, and amino acids) Inappropriate phosphatonin secretion (mesenchymal tumors)
affect phosphate metabolism, such as glucocorticoids, calcitonin, bisphosphonates, and diuretic agents. Serum calcium and creatinine levels should be determined at the same time as the phosphate level. Hypophosphatemia with high serum calcium indicates hyperparathyroidism, and hypophosphatemia with low serum calcium osteomalacia. In patients with phosphate levels lower than 0.80 mmol/L and normal serum calcium levels, urinary phosphate should be measured. Hyperphosphaturia in the absence of hypophosphatemia is of no clinical relevance. Because the urinary excretion of phosphate varies widely, we recommend that phosphate and creatinine be assayed in two 24-hour urine collections and that the phosphate/creatinine (P/Cr) ratio be determined in the first urine specimen of the day using Nordin’s method [10] . Normally, 24-hour phosphate excretion is lower than 20 mmol and the P/Cr ratio is lower than 0.8. In patients with hypophosphaturia (less than 10 mmol/24 hours or a P/Cr ratio of less than 0.3, the most common causes of hypophosphatemia are gastrointestinal disorders, such as malabsorption, antacid use, and chronic alcohol abuse. Phosphate diabetes should be suspected in patients whose urinary phosphate excretion exceeds 20 mmol/
213
24 hours. To confirm the diagnosis, renal tubule function should be investigated. Creatinine clearance (ClCr) is used to evaluate the GFR. The clearance of phosphate (ClP; normal, < 15 mL/min) and the rate of tubular reabsorption of phosphate (TRP; normal, > 85%) should be determined. Then, the renal tubular phosphate threshold (TmPO4) is determined using the nomogram developed by Walton and Bijvoet [11]. A TmPO4/GFR ratio lower than 0.8 indicates phosphate diabetes. In healthy individuals, a decrease in serum phosphate triggers a decrease in urinary phosphate excretion and, consequently, in phosphate clearance. The combination of hypophosphatemia with a high phosphate clearance and a decrease, however modest, in the TRP is diagnostic for phosphate diabetes. Conversely, high phosphate clearance is without clinical relevance in subjects with normal serum phosphate levels. Assays of serum ionized calcium and parathyroid hormone ensure detection of mild hyperparathyroidism. Tests for tubular acidosis and measurements of urinary amino acids and glucose should be done to look for evidence of Fanconi’s syndrome or another complex tubular disorder. Urinary calcium excretion is often high in patients with phosphate diabetes. In some cases, this hypercalciuria is ascribable to an increase in the tubular reabsorption of calcium. In addition, chronic hypophosphatemia stimulates vitamin D hydroxylation, thereby increasing the amount of calcium absorbed by the bowel. Once phosphate diabetes is diagnosed, the cause should be sought and the consequences evaluated. Then, the most appropriate treatment can be selected. Identifying the cause of phosphate diabetes A family history of infantile rickets, delayed walking, and/or neonatal death should be sought. Additional arguments suggestive of vitamin D-resistant rickets include a small stature and bowing of the legs. Some mesenchymatous tumors cause phosphate diabetes. Severe hypophosphatemia is suggestive, as are skin lesions such as flat or large nevi, evidence of neurofibromatosis, or other skin fibromas. An abdominal ultrasound scan is useful to look for a hemangioma or hemangiopericytoma of the liver. A few cases of phosphate diabetes have been reported in patients with metastatic or nonmetastatic malignancies of the lung, prostate, or bone.
214
M. Laroche
In patients with evidence of a complex tubular disorder (presence of amino acids and/or glucose in the urine), such as Fanconi’s syndrome, a cause should be sought, in particular Sjögren’s syndrome, amyloidosis, dysglobulinemia, sarcoidosis, or heavy-metal poisoning. In most adults with moderate phosphate diabetes, investigations for a cause are unrewarding. Whether these cases of idiopathic phosphate diabetes are related to sporadic PHEX gene mutations has not been determined. BONE AND JOINT MANIFESTATIONS OF PHOSPHATE DIABETES Severe hypophosphatemia (P < 0.50 mmol/L) related to vitamin D-resistant rickets or paraneoplastic phosphate diabetes causes the typical symptoms of osteomalacia: bone pain, bone insufficiency fractures, and in some cases myopathy [12]. In patients with evidence of vitamin D-resistant rickets since childhood, extensive enthesopathy develops in adulthood [13]. Conversely, moderate phosphate diabetes (serum phosphate in the 0.6–0.8 mmol/L range) produces a nonspecific but fairly consistent pattern of diffuse pain in the muscles, tendons, and joints, with asthenia and depression. Chronic fatigue syndrome [14, 15], fibromyalgia [16], or spondyloarthropathy [17] are often suspected. Plain radiographs show loss of bone trabeculae and, in some patients, ossifying enthesitis different in appearance from the lesions seen in ankylosing spondylitis or diffuse idiopathic skeletal hyperostosis. Among patients who undergo absorptiometry, 75% have low bone mineral density with a nearly 20% decrease in the mean Z-score as compared to normal individuals. Histology shows a moderate increase in osteoclastic resorption with no osteomalacia [18, 19]. Thus, phosphate diabetes complicating moderate idiopathic proximal tubular disorders can cause osteoporosis, particularly in men, in whom this condition is not infrequent [20]. MANAGEMENT OF PHOSPHATE DIABETES The management of vitamin D-resistant rickets in children is effective and fairly well standardized. It rests on high dosages of supplemental phosphate and hydroxylated vitamin D derivatives. Conversely, the best treatment for moderate idiopathic phosphate diabetes in adults is not agreed on. In our experience, oral phos-
phate in a daily dosage of 1.5 g induces a marked increase in phosphaturia without noticeably increasing phosphatemia. Some authors, such as Amor et al. [21], have suggested a combination of oral phosphate and high doses of 1,25 (OH)2 D3 (up to 1 µg of calcitriol). However, hypercalciuria is a feature in 50% of these patients and is further increased by calcitriol supplementation. In our opinion, calcitriol supplementation should be reserved for patients with normal urinary calcium and serum 1,25 (OH)2 D3 levels before treatment. We have found that treatment is effective in only about one-third of patients and that clinical improvements occur slowly. However, a mean gain in bone mineral density of 2 to 3% was recorded in the study by Amor et al. [21] and in our patients. Other potential treatments require evaluation. Dipyridamole decreases phosphaturia in mice by acting on the renal tubule and seems to have a similar effect in humans [22]. In the short term, an infusion of dipyridamole can increase the TRP by more than 30%. In our patients, oral administration of dipyridamole tid significantly increased serum phosphate levels; however, the effects on clinical symptoms and bone mineral density remain to be determined. Given the short halflife of dipyridamole, a sustained-release formulation might produce more stable serum phosphate levels and, consequently, greater clinical benefits. The firstgeneration bisphosphonate etidronate increases phosphate reabsorption by the renal tubule. In early studies, it was suggested that the etidronate dosages should be adjusted to serum phosphate levels in patients with Paget’s disease. It has now been shown that a meaningful increase in serum phosphate levels is obtained only with high dosages (800 mg/day), which are associated with a risk of osteomalacia. REFERENCES 1 Levi M, Cronin RE, Knochel JP. Disorders of phosphate and magnesium metabolism. In: Coe FL, Favus MJ, Eds. Disorders of bone and mineral metabolism. New York: Raven Press; 1992. p. 587-613. 2 Yanagawa N, Lee DBN. Renal handling of calcium and phosphorus. In: Coe FL, Favus MJ, Eds. Disorders of bone and mineral metabolism. New York: Raven Press; 1992. p. 3-41. 3 Beck L, Karaplis AC, Amizuka AC, Hewson AS, Ozawa H, Tenehouse HS. Targeted inactivation of Ntp2 in mice leads to severe renal phosphate wasting, hypercalciuria and skeletal abnormalities. Proc Natl Acad Sci USA 1998 ; 28 : 5372-7. 4 Combe C, Aparicio M. Phosphorus and protein restriction and parathyroid function in chronic renal failure. Kydney Int 1994 ; 4 : 1381-6. 5 Weidner N, Santa-Cruz D. Phosphaturic mesenchymental tumors. Cancer 1987 ; 59 : 1442-54.
Phosphate, the renal tubule and the musculoskeletal system 6 Kumar R. Phosphatonin: a new phosphaturetic hormone? Nephrol Dial Transplant 1997 ; 12 : 11-3. 7 Econs MJ. New insights into the pathogenesis of inherited phosphate wasting disorders. Bone 1999 ; 25 : 131-5. 8 Drezner MK. Phex gene and hypophosphatemia. Kydney Int 2000 ; 57 : 9-18. 9 Tennehouse HS, Beck L. Renal N (+)-phosphate co-transporter gene expression in x-linked hyp and Gy mice. Kydney Int 1996 ; 49 : 1027-32. 10 Nordin BEC, Fraser R. Assesment of urinary phosphate excretion. Lancet 1966 ; 1 : 947. 11 Walton RJ, Bijvoet OLM. Normogram for the derivation of renal threshold concentration. Lancet 1975 ; 2 : 309. 12 Subramanian R, Khardori R. Severe hypophosphatemia. Pathophysiologic implications, clinical presentations and treatment. Medicine (Baltimore) 2000 ; 79 : 1-8. 13 Polisson RP, Martinez S, Khoury M, Harrell RM, Lyles KW, Friedman N, et al. Calcifications of the entheses associated with x-linked hypophosphatemic osteomalacia. N Engl J Med 1985 ; 4 : 1-6. 14 De Lorenzo F, Hargreaves J, Kakkar VV. Phosphate diabetes in patients with chronic fatigue syndrome. Postgrad Med J 1998 ; 7 : 229-32. 15 Lundberg E, Bergengren H, Lindqvist B. Mild phosphate diabetes in adults. Acta Med Scand 1978 ; 204 : 93-6. 16 Laroche M, Arlet J, Ader JL, Durand D, Tran-Van T, Mazières B. Skeletal manifestations of moderate phosphate diabetes. Clin Rheumatol 1993 ; 12 : 192-7.
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17 Amor B, Clemente PJ, Rajzbaum G, Poiraudeau S, Friedlander G. Adult-idiopathic phosphate diabetes. I. Chronic pseudoinflammatory back pain and osteopenia. Rev Rhum [Engl Ed] 1995 ; 62 : 175-81. 18 Laroche M, Moulinier L, Bon E, Cantagrel A, Mazières B. Renal tubular disorders and arteriopathy of the lower limbs: risk factors for osteoporosis in men. Osteoporos Int 1994 ; 4 : 309-13. 19 Laroche M, Arlet J, Ader JL, Durand D, Cantagrel A, TranVan T, et al. Ostéoporose masculine, une étiologie méconnue : la tubulopathie proximale idiopathique modérée. Rev Rhum Mal Osteoartic 1992 ; 59 : 3-9. 20 Legroux-Gérot I, Blanckaert F, Solau-Gervais E, Neghaban M, Duquesnoy B, Delcambre B, et al. Causes of osteoporosis in males. A review of 160 cases. Rev Rhum [Engl Ed] 1999 ; 66 : 404-9. 21 Amor B, Clemente PJ, Roux C. Adult-onset idiopathic phosphate diabetes. II. Time-course of clinical, laboratory test and bone mineral density abnormalities under combined phosphate and calcitriol therapy. Rev Rhum [Engl Ed] 1995 ; 62 : 183-8. 22 Friedlander G, Prié D, Amiel C. Diabètes phosphatés de l’adulte : nouvelle approche diagnostique et thérapeutique. In: Sèze Sde, Ryckewaert A, Kahn MF, Kuntz D, Dryll A, Meyer O, et al., Eds. L’Actualité rhumatologique 1997. Paris: Expansion Scientifique Française; 1997. p. 229-36.
REVIEW
Phosphate, the renal tubule, and the musculoskeletal system Michel Laroche* Service de rhumatologie, CHU Rangueil, 1, avenue J. Poulhès, 31043 Toulouse, France (Submitted for publication October 12, 2000; accepted in revised form January 10, 2001)
Summary – 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 h 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/24 h, 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’s 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. Joint Bone Spine 2001 ; 68 : 211-5. © 2001 Éditions scientifiques et médicales Elsevier SAS hypophosphatemia / phosphate / diabetes
Phosphate is a component of adenosine-triphosphate (ATP) and, as such, is involved in intracellular oxidative processes and mitochondrial respiration. Without phosphate, the neurons cannot function normally.
* Correspondence and reprints. E-mail address: [email protected] (M. Laroche).
Because phosphate is a component of ATP, it plays a pivotal role in the energy-related processes that take place in striated muscle cells and in the smooth muscle cells of the gastrointestinal tract and cardiovascular system. Finally, like calcium, phosphate is involved in bone tissue mineralization. A favorable balance between phosphate and calcium must be maintained: an increase in the calcium-phosphate product can result in calcium
212
M. Laroche
deposition within soft tissues including cartilage, tendon attachments, and blood vessel walls. Because of these physiological effects of phosphate, chronic alterations in phosphate metabolism can result in multiorgan dysfunction, particularly in bone and joint disease. REGULATION Eighty-five percent of the phosphate in the human body (600–800 g) is incorporated within the bone tissue. The remaining 15% is located, in part, within soft tissue cells and, in part, in the extracellular compartment. Only 1% is in the plasma, as monosodium or disodium phosphate and phosphoric esters. Only 12% of plasma phosphate is bound to protein [1, 2]. The normal range for serum phosphate is 0.8–1.5 mmol/L (25–45 mg/L) in adults and 1.5–2 mmol/L in children. Phosphate is absorbed both actively and passively by the small bowel and colon. Phosphate filters through the renal glomerule before undergoing active reabsorption by the renal tubule. The amount reabsorbed is almost entirely dependent on adjustments in sodiumphosphate cotransport through the epithelial cell brush border of the proximal renal tubule. Among the four phosphate cotransporters identified to date, the most abundant in the kidney is Npt2a. Targeted inactivation of the Npt2a gene in mice resulted in phosphate diabetes and hypercalciuria [3]. Short-term changes in serum phosphate levels seem regulated by transfers between the intra- and extracellular compartments. The proportion of phosphate absorbed by the bowel increases as phosphate intake decreases. Furthermore, phosphate intake directly and rapidly regulates Npt2a levels within the epithelial cells of the proximal renal tubule. The long-term regulation of phosphate homeostasis is ensured primarily by changes in the phosphate reabsorption by the renal tubule. Thus, hyperphosphatemia occurs in patients with renal failure even when phosphate intake is reduced, and conversely hypophosphatemia develops in patients with proximal tubule disorders even when supplemental phosphate is given. However, severely restricting the dietary intake of phosphate is effective in controlling hyperphosphatemia related to renal failure [4]. Several factors are involved in the regulation of serum phosphate levels. Vitamin D and its hydroxylated derivatives increase the digestive absorption of phosphate. Parathyroid hormone increases both the diges-
tive absorption and the renal excretion of phosphate. It acts in part by causing irreversible internalization followed by degradation of the Npt2a protein. Growth hormone and/or IGF1 levels increase with the amounts of phosphate absorbed by the bowel and reabsorbed by the renal tubule. Glucocorticoids and calcitonin seem to have modest effects related to an increase in phosphate excretion. Respiratory alkalosis and thyroxin increase phosphate reabsorption by the renal tubule, whereas acidosis has the opposite effect. The physiological role of a protein designated ‘phosphatonin’ in some articles [5, 6] remains to be determined. Phosphatonin was first identified in patients with phosphate diabetes caused by mesenchymatous tumors; excision of the tumor was promptly followed by a return to normal of serum phosphate levels. In animal studies, grafting tumor fragments or injecting supernatant from tumor cell cultures induced phosphate diabetes. Phosphatonin may be present in healthy individuals, being degraded in large part by an endopeptidase system. X-linked hypophosphatemia is caused by mutations in the PHEX gene (PHosphate-regulating gene with homology with Endopeptidases on the X chromosome), which encodes an endopeptidase expressed in bone. These mutations may decrease the degradation of phosphatonin, thus resulting in phosphatonin accumulation and hyperphosphaturia [7, 8]. Decreased Npt2a expression in renal cells has been found in Hyp mice, a strain with phosphate diabetes caused by PHEX gene mutations [9]. DIAGNOSIS AND IDENTIFICATION OF THE CAUSE OF HYPOPHOSPHATEMIA Only chronic hypophosphatemia will be discussed here. Acute hypophosphatemia, which is caused by a transfer of phosphate from the extracellular to the intracellular compartment, occurs chiefly in critically ill patients (table I) [7]. Diagnosis of hypophosphatemia Because many physiological dietary and endocrine factors can affect the metabolism of phosphate, phosphate in blood and urine should be assayed under strictly controlled conditions. In particular, the diet should be well balanced in sodium, protein, phosphate, and calcium; and the patient should refrain from drinking large amounts of alcohol on the day before sample collection. Furthermore, the samples should be taken at a time when the patient is not on medications known to
Phosphate, the renal tubule and the musculoskeletal system Table I. Diagnosis of hypophosphatemia. Acute hypophosphatemia: critically ill patient Transfer of phosphate from the extracellular to the intracellular compartment or massive loss of phosphate from the digestive tract: respiratory alkalosis, sepsis, aspirin overdosage, infusion of hypertonic glucose solutions, vomiting, or diarrhea. Chronic hypophosphatemia Abnormal serum calcium – High serum calcium: hyperparathyroidism – Low serum calcium: osteomalacia, malabsorption Normal serum calcium – Hypophosphaturia (< 10 mmol/24 h) Vomiting, diarrhea, digestive malabsorption, antacid use, alcohol abuse Increased bone tissue avidity for phosphate (sclerotic metastases) – Hyperphosphaturia (>20 mmol/24h, phosphate clearance <15 mL/min, TRP<80 %, and TmPo4/GFR< 0.8) : phosphate diabetes Diuretic agents, glucocorticoids X-linked vitamin D-resistant rickets (hypercalciuria is common) Autosomal dominant vitamin D-resistant rickets (serum calcium is normal) Complex tubular disorder (Fanconi’s syndrome: renal wasting of phosphate, glucose, and amino acids) Inappropriate phosphatonin secretion (mesenchymal tumors)
affect phosphate metabolism, such as glucocorticoids, calcitonin, bisphosphonates, and diuretic agents. Serum calcium and creatinine levels should be determined at the same time as the phosphate level. Hypophosphatemia with high serum calcium indicates hyperparathyroidism, and hypophosphatemia with low serum calcium osteomalacia. In patients with phosphate levels lower than 0.80 mmol/L and normal serum calcium levels, urinary phosphate should be measured. Hyperphosphaturia in the absence of hypophosphatemia is of no clinical relevance. Because the urinary excretion of phosphate varies widely, we recommend that phosphate and creatinine be assayed in two 24-hour urine collections and that the phosphate/creatinine (P/Cr) ratio be determined in the first urine specimen of the day using Nordin’s method [10] . Normally, 24-hour phosphate excretion is lower than 20 mmol and the P/Cr ratio is lower than 0.8. In patients with hypophosphaturia (less than 10 mmol/24 hours or a P/Cr ratio of less than 0.3, the most common causes of hypophosphatemia are gastrointestinal disorders, such as malabsorption, antacid use, and chronic alcohol abuse. Phosphate diabetes should be suspected in patients whose urinary phosphate excretion exceeds 20 mmol/
213
24 hours. To confirm the diagnosis, renal tubule function should be investigated. Creatinine clearance (ClCr) is used to evaluate the GFR. The clearance of phosphate (ClP; normal, < 15 mL/min) and the rate of tubular reabsorption of phosphate (TRP; normal, > 85%) should be determined. Then, the renal tubular phosphate threshold (TmPO4) is determined using the nomogram developed by Walton and Bijvoet [11]. A TmPO4/GFR ratio lower than 0.8 indicates phosphate diabetes. In healthy individuals, a decrease in serum phosphate triggers a decrease in urinary phosphate excretion and, consequently, in phosphate clearance. The combination of hypophosphatemia with a high phosphate clearance and a decrease, however modest, in the TRP is diagnostic for phosphate diabetes. Conversely, high phosphate clearance is without clinical relevance in subjects with normal serum phosphate levels. Assays of serum ionized calcium and parathyroid hormone ensure detection of mild hyperparathyroidism. Tests for tubular acidosis and measurements of urinary amino acids and glucose should be done to look for evidence of Fanconi’s syndrome or another complex tubular disorder. Urinary calcium excretion is often high in patients with phosphate diabetes. In some cases, this hypercalciuria is ascribable to an increase in the tubular reabsorption of calcium. In addition, chronic hypophosphatemia stimulates vitamin D hydroxylation, thereby increasing the amount of calcium absorbed by the bowel. Once phosphate diabetes is diagnosed, the cause should be sought and the consequences evaluated. Then, the most appropriate treatment can be selected. Identifying the cause of phosphate diabetes A family history of infantile rickets, delayed walking, and/or neonatal death should be sought. Additional arguments suggestive of vitamin D-resistant rickets include a small stature and bowing of the legs. Some mesenchymatous tumors cause phosphate diabetes. Severe hypophosphatemia is suggestive, as are skin lesions such as flat or large nevi, evidence of neurofibromatosis, or other skin fibromas. An abdominal ultrasound scan is useful to look for a hemangioma or hemangiopericytoma of the liver. A few cases of phosphate diabetes have been reported in patients with metastatic or nonmetastatic malignancies of the lung, prostate, or bone.
214
M. Laroche
In patients with evidence of a complex tubular disorder (presence of amino acids and/or glucose in the urine), such as Fanconi’s syndrome, a cause should be sought, in particular Sjögren’s syndrome, amyloidosis, dysglobulinemia, sarcoidosis, or heavy-metal poisoning. In most adults with moderate phosphate diabetes, investigations for a cause are unrewarding. Whether these cases of idiopathic phosphate diabetes are related to sporadic PHEX gene mutations has not been determined. BONE AND JOINT MANIFESTATIONS OF PHOSPHATE DIABETES Severe hypophosphatemia (P < 0.50 mmol/L) related to vitamin D-resistant rickets or paraneoplastic phosphate diabetes causes the typical symptoms of osteomalacia: bone pain, bone insufficiency fractures, and in some cases myopathy [12]. In patients with evidence of vitamin D-resistant rickets since childhood, extensive enthesopathy develops in adulthood [13]. Conversely, moderate phosphate diabetes (serum phosphate in the 0.6–0.8 mmol/L range) produces a nonspecific but fairly consistent pattern of diffuse pain in the muscles, tendons, and joints, with asthenia and depression. Chronic fatigue syndrome [14, 15], fibromyalgia [16], or spondyloarthropathy [17] are often suspected. Plain radiographs show loss of bone trabeculae and, in some patients, ossifying enthesitis different in appearance from the lesions seen in ankylosing spondylitis or diffuse idiopathic skeletal hyperostosis. Among patients who undergo absorptiometry, 75% have low bone mineral density with a nearly 20% decrease in the mean Z-score as compared to normal individuals. Histology shows a moderate increase in osteoclastic resorption with no osteomalacia [18, 19]. Thus, phosphate diabetes complicating moderate idiopathic proximal tubular disorders can cause osteoporosis, particularly in men, in whom this condition is not infrequent [20]. MANAGEMENT OF PHOSPHATE DIABETES The management of vitamin D-resistant rickets in children is effective and fairly well standardized. It rests on high dosages of supplemental phosphate and hydroxylated vitamin D derivatives. Conversely, the best treatment for moderate idiopathic phosphate diabetes in adults is not agreed on. In our experience, oral phos-
phate in a daily dosage of 1.5 g induces a marked increase in phosphaturia without noticeably increasing phosphatemia. Some authors, such as Amor et al. [21], have suggested a combination of oral phosphate and high doses of 1,25 (OH)2 D3 (up to 1 µg of calcitriol). However, hypercalciuria is a feature in 50% of these patients and is further increased by calcitriol supplementation. In our opinion, calcitriol supplementation should be reserved for patients with normal urinary calcium and serum 1,25 (OH)2 D3 levels before treatment. We have found that treatment is effective in only about one-third of patients and that clinical improvements occur slowly. However, a mean gain in bone mineral density of 2 to 3% was recorded in the study by Amor et al. [21] and in our patients. Other potential treatments require evaluation. Dipyridamole decreases phosphaturia in mice by acting on the renal tubule and seems to have a similar effect in humans [22]. In the short term, an infusion of dipyridamole can increase the TRP by more than 30%. In our patients, oral administration of dipyridamole tid significantly increased serum phosphate levels; however, the effects on clinical symptoms and bone mineral density remain to be determined. Given the short halflife of dipyridamole, a sustained-release formulation might produce more stable serum phosphate levels and, consequently, greater clinical benefits. The firstgeneration bisphosphonate etidronate increases phosphate reabsorption by the renal tubule. In early studies, it was suggested that the etidronate dosages should be adjusted to serum phosphate levels in patients with Paget’s disease. It has now been shown that a meaningful increase in serum phosphate levels is obtained only with high dosages (800 mg/day), which are associated with a risk of osteomalacia. REFERENCES 1 Levi M, Cronin RE, Knochel JP. Disorders of phosphate and magnesium metabolism. In: Coe FL, Favus MJ, Eds. Disorders of bone and mineral metabolism. New York: Raven Press; 1992. p. 587-613. 2 Yanagawa N, Lee DBN. Renal handling of calcium and phosphorus. In: Coe FL, Favus MJ, Eds. Disorders of bone and mineral metabolism. New York: Raven Press; 1992. p. 3-41. 3 Beck L, Karaplis AC, Amizuka AC, Hewson AS, Ozawa H, Tenehouse HS. Targeted inactivation of Ntp2 in mice leads to severe renal phosphate wasting, hypercalciuria and skeletal abnormalities. Proc Natl Acad Sci USA 1998 ; 28 : 5372-7. 4 Combe C, Aparicio M. Phosphorus and protein restriction and parathyroid function in chronic renal failure. Kydney Int 1994 ; 4 : 1381-6. 5 Weidner N, Santa-Cruz D. Phosphaturic mesenchymental tumors. Cancer 1987 ; 59 : 1442-54.
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17 Amor B, Clemente PJ, Rajzbaum G, Poiraudeau S, Friedlander G. Adult-idiopathic phosphate diabetes. I. Chronic pseudoinflammatory back pain and osteopenia. Rev Rhum [Engl Ed] 1995 ; 62 : 175-81. 18 Laroche M, Moulinier L, Bon E, Cantagrel A, Mazières B. Renal tubular disorders and arteriopathy of the lower limbs: risk factors for osteoporosis in men. Osteoporos Int 1994 ; 4 : 309-13. 19 Laroche M, Arlet J, Ader JL, Durand D, Cantagrel A, TranVan T, et al. Ostéoporose masculine, une étiologie méconnue : la tubulopathie proximale idiopathique modérée. Rev Rhum Mal Osteoartic 1992 ; 59 : 3-9. 20 Legroux-Gérot I, Blanckaert F, Solau-Gervais E, Neghaban M, Duquesnoy B, Delcambre B, et al. Causes of osteoporosis in males. A review of 160 cases. Rev Rhum [Engl Ed] 1999 ; 66 : 404-9. 21 Amor B, Clemente PJ, Roux C. Adult-onset idiopathic phosphate diabetes. II. Time-course of clinical, laboratory test and bone mineral density abnormalities under combined phosphate and calcitriol therapy. Rev Rhum [Engl Ed] 1995 ; 62 : 183-8. 22 Friedlander G, Prié D, Amiel C. Diabètes phosphatés de l’adulte : nouvelle approche diagnostique et thérapeutique. In: Sèze Sde, Ryckewaert A, Kahn MF, Kuntz D, Dryll A, Meyer O, et al., Eds. L’Actualité rhumatologique 1997. Paris: Expansion Scientifique Française; 1997. p. 229-36.