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Bone Disease in Patients With Primary Hypercalciuria and Calcium Nephrolithiasis
Review Article Bone Disease in Patients With Primary Hypercalciuria and Calcium Nephrolithiasis Andrea Tasca, Luca Dalle Carbonare, Filippo Nigro, and Sandro Giannini In patients affected by calcium nephrolithiasis, primary hypercalciuria is frequently accompanied by bone demineralisation and increased susceptibility to fragility fractures. The relationship between bone loss and primary hypercalciuria is multifactorial. Organs and tissues which control calcium and phosphate metabolism – bone, intestine, and kidney – are actively involved in the pathogenesis of bone alterations which together form a multi-factorial metabolic disorder. We conducted a comprehensive evaluation of the published data concerning hypercalciuria and nephrolithiasis included in Medline from 1985 and 2005. UROLOGY 74: 22–27, 2009. © 2009 Elsevier Inc.
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ypercalciuria is a well-recognized condition found in 50%-60% of patients with kidney stones.1-4 It can be defined as a 24-hour urine calcium excretion ⬎250 mg/d in women and 300 mg/d in men when patients are consuming their usual diet.5 To adjust the urine calcium excretion for body weight, hypercalciuria can also be defined in adults as a 24-hour urine excretion ⬎4 mg/kg of body weight/d in both sexes.6 (Because of the marked differences in calcium metabolism and dietary habits, such values should not be used for infants and adolescents.) Two consecutive 24-hour samples of urine calcium excretion are generally recommended to minimize potential errors in urine collection and conservation, which could result in an underestimation of calcium excretion. Urine collection should be done with patients consuming their usual diet. Several factors influence urinary calcium excretion in humans. The most important factors are sex, body weight, and nutrient intake, such as sodium, potassium, phosphate, proteins, carbohydrates, and alcohol. Healthy subjects eliminate about 6%-7% of dietary calcium in their urine daily. Consequently, depending on age, excessive dietary calcium (⬎1500 mg/d) can be associated with the development of hypercalciuria. Dietary sodium intake can increase calcium excretion by about 20-40 mg/d for every 2.3-g increase in sodium.7 Phosphate metabolism also largely influences urine calcium excretion. Phosphate leakage and consequent hypophosphatemia stimulate the renal production of 1,25(OH)2 vitamin D, which, in turn, increases intestinal calcium absorption and can lead to hypercalciuria. Epidemiologic studies have suggested that dietary pro-
From the Department of Surgery, Division of Urology, San Bortolo Hospital, Vicenza, Italy; and the Department of Medical and Surgical Sciences, Division of Nephrology, University of Padova, Padova, Italy. Reprint requests: Andrea Tasca, M.D., Department of Surgery, Division of Urology, San Bortolo Hospital, Via Rodolfi 7, Vicenza 3600 Italy. E-mail: andrea. [email protected] Submitted: March 10, 2008, accepted (with revisions): November 4, 2008
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© 2009 Elsevier Inc. All Rights Reserved
teins are very important regulators of urinary calcium, more so than dietary calcium intake.8-10 Moderate protein diets (1.0-1.5 g protein/kg) are associated with normal calcium metabolism and presumably do not alter skeletal homeostasis. In contrast, high protein intake, particularly from animal sources, results in sustained hypercalciuria. That proteininduced effect seems to be due to an increase in bone resorption, which is secondary to the excessive acid load, as well as to the direct effects of proteins on calcium handling at the renal and intestinal level.10 Hypercalciuria is commonly divided into primary and secondary forms (Table 1).4
PRIMARY HYPERCALCIURIA Definition Albright et al.11 defined primary or idiopathic hypercalciuria as the form of excessive calcium excretion that is not associated with conditions known to increase calcium elimination. More recently, however, it has been suggested that dietetic disturbances should also be eliminated by keeping patients on a daily diet of 1000-1200 mg of calcium and no more than 1-1.5 g protein/kg body weight.10 In an early classification system of primary hypercalciuria in patients with recurrent calcium stone formation by Pak et al.,12 3 types of metabolic defects were identified as causing hypercalciuria: (a) absorptive hypercalciuria, types I and II, when primary intestinal hyperabsorption of calcium is involved; (b) absorptive hypercalciuria type III, when a primary renal leak of phosphate is present, thus inducing hypophosphatemia and, secondarily, 1,25(OH)2 vitamin D-mediated intestinal hyperabsorption of calcium; and (c) renal hypercalciuria when a primary renal leak of calcium with secondary compensatory hyperparathyroidism is present. Pak et al.12 also distinguished a form of so-called resorptive hypercalciuria, when hypercalciuria is induced 0090-4295/09/$34.00 doi:10.1016/j.urology.2008.11.014
Table 1. Causes of secondary hypercalciuria Diet-dependent Excessive dietary intake Calcium Sodium Animal protein Carbohydrates Alcohol Reduced intake/absorption Phosphate Potassium Secondary increase in intestinal calcium absorption Vitamin D overtreatment Endogenous overproduction of 1,25(OH)2 vitamin D Primary hyperparathyroidism Granulomatous diseases Lymphomas Severe hypophosphatemic diseases Increased osteoclastic resorption of bone Bone metastases Multiple myeloma Primary hyperparathyroidism Paget’s disease of bone Hyperthyroidism Prolonged immobility Reduced renal tubular resorption of calcium Loop diuretics Bartter syndrome Medullary sponge kidney disease Primary renal tubular defects Endogenous/exogenous glucocorticoid excess Genetic alterations (chloride channels, calcium-sensing receptor)
Figure 1. After one week of low calcium (ⱕ 400 mg/day), normosodic (100-150 mmol/day) and normoproteic (1-1.2 grams/kg/BW) diet, a fasting morning urine sample (h. 7.00-9.00 a.m.) should be obtained for the determination of calcium and creatinine.
Renal Tubular Calcium Leak. A defect in renal tubular calcium reabsorption can be demonstrated in both humans and genetic hypercalciuric stone-forming rats as a cause of idiopathic hypercalciuria.18,19 However, additional extensive study of so-called renal hypercalciuria demonstrated that the 2 distinctive characteristics of this form (ie, low-normal serum calcium and increased parathyroid hormone [PTH] levels) were present in a small minority of patients with primary hypercalciuria.20 It is currently believed that no more than 2%-3% of primary hypercalciuria cases are generated by a true calcium leak.
by an excessive output of calcium from bone, for example in patients with primary hyperparathyroidism. During the past 20 years, this classification scheme has been revised. Currently, it is believed that 3 different mechanisms, which possibly overlap and operate together, are involved in the pathogenesis of hypercalciuria: increased intestinal absorption of calcium, primary excessive calcium release from bone, and altered renal calcium handling.
Fasting Hypercalciuria. Most patients with primary hypercalciuria have persistently elevated urine calcium, even after a low calcium diet or in fasting conditions, without any secondary parathyroid hyperfunction. This metabolic pattern tends to exclude a major role for both intestinal calcium hyperabsorption and renal calcium leak. The term “fasting hypercalciuria” was given to this condition, which presumably is dependent on a primary excess of calcium output from bone.21
Mechanisms of Hypercalciuria Increased Intestinal Absorption of Calcium. Recent studies have confirmed that calcium absorption is almost invariably increased in patients with primary hypercalcuria.13 The metabolism of 1,25(OH)2 vitamin D appears to be altered in some patients with absorptive hypercalciuria.14 In rats with genetically determined hypercalciuria, increased expression of the intestinal vitamin D receptor leads to increased intestinal calcium absorption, even in the absence of elevated values of serum 1,25(OH)2 vitamin D.15 However, no evidence that a similar mechanism might be operating in humans has yet been found.16 When present, altered renal handling of phosphate, leading to excessive phosphaturia and hypophosphatemia, might be responsible for overproduction of 1,25(OH)2 vitamin D and secondary intestinal calcium hyperabsorption.17
Diagnosis Once the diagnosis of hypercalciuria has been correctly made, it is necessary to exclude any secondary causes of hypercalciuria (Table 1). In the presence of documented primary hypercalciuria, several simple laboratory tests can help to identify the main metabolic defect. In brief, after 1 week of low calcium and normal sodium and protein dietary intake, a fasting morning urine sample should be obtained to determine the calcium and creatinine levels. If urine calcium excretion normalizes (with the calcium/creatinine ratio decreasing to ⬍0.11 mg/mg), a diagnosis of absorptive hypercalciuria can be made. However, if the urine calcium excretion remains elevated, the diagnosis of fasting hypercalciuria is reasonable and can be further classified as undetermined fasting hypercalciuria or renal hypercalciuria. This is determined from the serum calcium and PTH values (Fig. 1).
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Table 2. Bone mineral density in patients with primary hypercalciuria Investigator 22
Lawoyin et al., 1979 Fuss et al.,23 1983 Pacifici et al.,24 1990 Bataille et al.,25 1991 Borghi et al.,26 1991 Pietschmann et al.,27 1992 Jaeger et al.,28 1994 Weisinger et al.,29 1996 Ghazali et al.,30 1997 Giannini et al.,31 1998 Misael da Silva et al.,32 2002 Tasca et al.,33 2002 Asplin et al.,34 2003 Vezzoli et al.,35 2003 Caudarella et al.,36 2003
Measurement Method
Measurement Site
BMD Result
SPA SPA QCT QCT DPA DEXA, SPA DEXA DEXA QCT DEXA DEXA DEXA DEXA DEXA DEXA, QUS
Radius Radius Spine Spine Spine Spine, radius Spine, femur Spine, femur Spine Spine, femur Spine, femur Spine, femur Spine, femur Spine, femur Radius, finger
2N 2 2 2 2 2 2 2 2 2 2 2 2 2 2
SPA ⫽ single photon absorptiometry; DEXA ⫽ dual energy x-ray absorptiometry; DPA ⫽ dual photon absorptiometry; QCT ⫽ quantitative computed tomography; QUS ⫽ quantitative ultrasonography; N ⫽ normal; 2 ⫽ reduced.
PRIMARY HYPERCALCIURIA AND BONE DISEASE Size of Problem Because idiopathic hypercalciuria is one of the most common phenotypes in patients with kidney stones, most studies undertaken to assess bone status in patients with hypercalciuria have been conducted in patients with calcium nephrolithiasis. These studies demonstrated that although the bone density is substantially normal or only slightly reduced in patients with calcium nephrolithiasis without hypercalciuria, significant bone loss is present in patients with kidney stones and primary hypercalciuria (Table 2). Bone loss mainly involves areas of trabecular bone, such as the vertebral bodies.22-35 However, a reduction in femoral density has also been reported.28,29,31-37 These studies also showed a relatively young age group (average 50 years) and a large proportion of males. Patients with renal calculi have an increased bone fracture risk,38,39 and, among patients with kidney stones, bone loss is a predominant characteristic of hypercalciuric states. Consequently, hypercalciuria might be one of the factors explaining the increased proportion of fragility fractures seen in patients with kidney stones. Although most investigators observed significant bone loss in patients with fasting hypercalciuria but not in those with the absorptive form,24-26,31,33 others reported a decrease in bone density, irrespective of the type of primary hypercalciuria27,29,30 (ie, even in patients classified as having absorptive hypercalciuria).27-29 To justify this last finding, it was hypothesized that patients with absorptive hypercalciuria might have been consuming an inappropriately low calcium diet.27 It was also suggested that excessive stimulation of bone resorption observed in these patients could alternatively result from high consumption of dietary protein, increased serum levels of 1,25(OH)2 vitamin D, or increased sensitivity to this hormone. It has also been suggested that the absorptive and fasting types of hypercalciuria might not in fact be 2 distinct forms of defect, but rather 1 unique disorder. 24
Support for this view has come from a recent study that found that patients with hypercalciuria with the largest proportion of bone loss also presented with the greatest levels of intestinal calcium absorption.35 Pathophysiology of Primary Hypercalciuria Whatever the pathophysiologic mechanism, that primary hypercalciuria, calcium nephrolithiasis, and bone diseases are strictly linked is well established. In particular, the rate of urine calcium excretion correlates with bone loss29,35,37 and an elevation in bone turnover markers in patients with hypercalciuric stone formation.25,31,38 Thus, to better understand the relationships between primary hypercalciuria and bone loss and the pathogenetic factors shared by these 2 conditions, the roles of bone, kidney, and intestine must be considered. Bone. Since the reclassification of the types of primary hypercalciuria in patients with calcium nephrolithiasis proposed by Levy et al.,20 the term “fasting hypercalciuria” has been used to identify patients who cannot lower or normalize their urine calcium excretion appropriately after a restriction in dietary calcium consumption. Because low bone density was more frequently reported in these patients, the presence of specific factors simultaneously causing hypercalciuria and bone demineralization has been suggested. Cytokines are included among these factors because they regulate bone resorption and might be involved in the pathogenesis of bone alterations in patients with primary hypercalciuria.24 Monocytes isolated from patients with fasting hypercalciuria, but not from those with absorptive hypercalciuria, have been shown to produce an exaggerated amount of interleukin-1 (IL-1) (Table 3). This cytokine, a well-known and very potent stimulator of bone resorption processes, has been correlated with bone demineralization in patients with fasting hypercalcuria.40 Furthermore, the production and mRNA expression of IL-1 from unstimulated peripheral blood mononuclear UROLOGY 74 (1), 2009
Table 3. Cytokine levels from peripheral blood mononuclear cells in patients with primary hypercalciuria and controls Investigator
Population Sample 24
Pacifici et al. Weisinger et al.29 Ghazali et al.30
FH, AH, controls IH, NC, controls IH, DH, controls
IL-1
IL-1␣
IL-1
IL-6
TNF-␣
GM-CSF
261 ⫾ 81* — — — — — — 680 ⫾ 139† — 19 ⫾ 4‡ 2976 ⫾ 417† — — — 40 ⫾ 21§ 347 ⫾ 145¶ 236 ⫾ 136 52 ⫾ 27¶
FH ⫽ fasting hypercalciuria; AH ⫽ absorptive hypercalciuria; IH ⫽ idiopathic hypercalciuria; NC ⫽ normocalciuria; DH ⫽ dietary hypercalciuria. * P ⬍ .01, FH vs AH and controls. † P ⬍ .01, IH vs NC and controls (lipopolysaccharide stimulated). ‡ P ⬍ .05, IH vs NC and controls (lipopolysaccharide stimulated). § P ⬍ .01, IH vs DH. ¶ P ⬍ .05, IH vs controls.
cells has correlated with spinal bone loss in patients with primary hypercalciuria and nephrolithiasis.29 In addition, mononuclear cells produce an increased amount of IL-1, IL-6, and tumor necrosis factor-␣, compared with controls, after stimulation with lipopolysaccharide. Because all these cytokines are considered local mediators of bone resorption,39 bone loss might largely depend on these alterations in patients with hypercalciuria with calcium stones. Similar results were found by others.30 Excessive protein intake, especially of animal origin, was found to sharply increase urine calcium excretion and bone resorption and lead to bone loss.11 The main mechanism for these effects is the acid load produced by proteins, especially those rich in sulfur-containing amino acids.11 Accordingly, sulfate excretion and markers of protein intake, such as urinary or serum urea, also appear to correlate with bone turnover markers and density.25,27,28,41 Moderate protein restriction also induces a proportional reduction in calcium excretion and bone turnover markers in patients with calcium nephrolithiasis and primary hypercalciuria.41 Because excessive consumption of dietary protein has been repeatedly reported in patients with hypercalciuric stone formation,11,41 normalization of protein intake is highly recommended in patients with hypercalciuria. This measure is also important, because it has been noted that such patients present with hypersensitivity to protein effects on bone.41 No consistent data currently support a substantial role for calciotropic hormones in the pathogenesis of bone loss in primary hypercalciuria. Vitamin D-1,25(OH)2 was reported to be greater in patients with primary hypercalciuria than in controls, and it was observed that this hormone can induce an increase in bone resorption.42 However, the elevation in 1,25(OH)2 vitamin D levels was more frequently described in patients with absorptive hypercalciuria, whose bone density levels are generally normal or poorly diminished. It appears that 1,25(OH)2 vitamin D levels have a protective, rather than a damaging, effect on bone mass in patients with primary hypercalciuria and kidney stones.25 Apart from the very small proportion of patients who can be classified as having renal hypercalciuria,20 the PTH levels are generally normal in patients with primary hypercalciuria and are not thought to have a significant role in the pathogenesis of bone loss in this setting. UROLOGY 74 (1), 2009
Intestine. Although the classic distinction of primary hypercalciuria from absorptive hypercalciuria and fasting hypercalciuria is still maintained, a wide overlap seems to occur between the 2 forms in patients with hypercalciuric stone formation. Studies have reported a decrease in bone density in patients with absorptive hypercalciuria27; likewise, increased intestinal calcium absorption has been frequently reported in patients with fasting hypercalcuria.19 Thus, intestinal function appears to play a role in both the pathogenesis of primary hypercalciuria and the development of bone disease. The complex relationships between intestine calcium absorption and bone in women who form stones and have primary hypercalciuria was assessed using the stable strontium method.35 In that study, the greater the loss of bone mineral density, the larger the increase in intestinal calcium absorption, with calcium absorption being the best predictor of bone mass in a multiple regression model.35 Because the PTH values were similar in patients with hypercalciuric and normocalciuric stone formation, the investigators speculated that this is not a compensatory phenomenon, but probably a marker of disturbed cell calcium transport involving both intestinal and bone tissue.35 This hypothesis would also be in keeping with the view that absorptive hypercalciuria and fasting hypercalciuria might be different phenotypes and expressions of the same disorder,21 which could be sustained by some genetic influences.43 In the presence of hypercalciuria, the calcium balance can be maintained only at the expense of skeletal tissue or through an increase in intestinal calcium absorption, which can in turn limit bone loss. Restriction in dietary calcium intake, which many patients with hypercalciuric stone formation tend to do by themselves or after medical prescription, is therefore a major risk factor for bone loss in this setting. A reduction in calcium intake is well known to be associated with a negative calcium balance and bone loss.28,44,45 Some investigators44,45 reported this negative effect after a calcium-restricted diet was maintained for 2-8 years, and others have observed a significant reduction in bone density in patients with hypercalciuria after just 1 year of a low-calcium diet.9 In addition, dietary calcium restriction does not reduce the incidence of new kidney stones; in contrast, it increases the risk of developing new symptomatic renal calculi, at least in males.46 This seems to occur because of an increase in intestinal oxalate absorp25
tion due to a lack of bonding with calcium in the intestinal lumen. Together, these observations suggest that patients with hypercalciuria need to maintain appropriate dietary calcium intake. Kidney. The revision of our understanding of the pathogenetic aspects of patients with kidney stones and primary hypercalciuria led to the observation that ⬍5% of patients with hypercalciuria have a renal form of primary hypercalciuria.20 Thus, the importance of renal calcium leak as a pathogenetic factor for bone loss in these patients was completely reconsidered. However, other aspects seem to link the kidney to complex relationships occurring between hypercalciuria and bone. Increased urinary phosphate excretion was found in patients with hypercalciuria compared with normal subjects, irrespective of the presence of a true form of absorptive hypercalciuria with renal calcium leak.45,46 The bone alterations observed in patients with hypercalciuria resemble those seen in hereditary hypophosphatemic rickets with hypercalciuria in which an alteration in the bone mineralization process was observed.47-51 Also a mutation of the NPT2 gene was found in patients with calcium nephrolithiasis and decreased bone density.52 Therefore, no clear evidence definitely supports the hypothesis that renal phosphate leak might be involved in bone disease found in patients with primary hypercalciuria. Nonetheless, this investigative path appears to be a promising way to elucidate the role of the kidney in the pathogenesis of bone loss in patients with primary hypercalciuria.
CONCLUSIONS Primary hypercalciuria is a very common finding in patients with kidney stones and otherwise primary osteoporosis. It is now clear that the association between bone loss and primary hypercalciuria is not casual, but it is characterized by a complex relationship among intestinal absorption, bone metabolism, and urinary calcium excretion. However, the mechanisms involved in the pathogenesis of bone damage in patients with hypercalciuria stone formation still remain only partially understood. The organs and tissues normally involved in the control of calcium and phosphate metabolism appear to take an active part in the pathogenesis of the skeletal alterations in patients with primary hypercalciuria. The skeletal tissue, per se, the kidney, and the intestine are responsible for the appearance, persistence, and clinical course of bone loss in patients with hypercalciuric nephrolithiasis and operate together as a multitissue metabolic disorder. Table 3. References 1. Hodgkinson A, Pyrah LN. The urinary excretion of calcium and inorganic phosphate in 344 patients with calcium stone of renal origin. Br J Surg. 1958;46:10-18.
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2. Smith LH, VanDenBerg CJ, Wilson DM. Nutrition and urolithiasis. N Engl J Med. 1980;98:87-89. 3. Pak CY. Medical management of nephrolithiasis. J Urol. 1982;128: 1157-1164. 4. Pak CY, Ohata M, Lawrence EC, et al. The hypercalciurias: causes, parathyroid functions, and diagnostic criteria. J Clin Invest. 1974; 54:387-400. 5. Heaney RP, Recker RR, Ryan RA. Urinary calcium in perimenopausal women: normative values. Osteoporos Int. 1999;9:13-18. 6. Kerstetter JE, O’Brian KO, Insogna KL. Low protein intake: the impact on calcium and bone homeostasis in humans. J Nutr. 2003;133:855S-861S. 7. Nordin BE, Need AG, Morris HA, et al. The nature and significance of the relationship between urinary sodium and urinary calcium in women. J Nutr. 1993;123:1615-1622. 8. Hegsted M, Schuette SA, Zemel MB, et al. Urinary calcium and calcium balance in young men as affected by level of protein and phosphorus intake. J Nutr. 1981;111:553-562. 9. Zemel MB. Calcium utilization: effect of varying level and source of dietary protein. Am J Clin Nutr. 1988;48:880-883. 10. Kerstetter JE, O’Brien KO, Insogna KL. Dietary protein, calcium metabolism, and skeletal homeostasis revisited. Am J Clin Nutr. 2003;78:584S-592S. 11. Albright F, Henneman P, Benedict PH, et al. Idiopathic hypercalciuria: a preliminary report. Proc R Soc Med. 1953;46:1077-1081. 12. Pak CY, Britton F, Peterson R, et al. Ambulatory evaluation of nephrolithiasis: classification, clinical presentation and diagnostic criteria. Am J Med. 1980;69:19-30. 13. Vezzoli G, Tanini A, Ferrucci L, et al. Influence of calcium-sensing receptor gene on urinary calcium excretion in stone-forming patients. J Am Soc Nephrol. 2002;13:2517-2523. 14. Broadus AE, Insogna KL, Lang R, et al. Evidence for disordered control of 1,25-dihydroxyvitamin D production in absorptive hypercalciuria. N Engl J Med. 1984;311:73-80. 15. Li XQ, Tembe V, Horwitz GM, et al. Increased intestinal vitamin D receptor in genetic hypercalciuric rats: a cause of intestinal calcium hyperabsorption. J Clin Invest. 1993;91:661-667. 16. Zerwekh JE, Reed BY, Heller HJ, et al. Normal vitamin D receptor concentration and responsiveness to 1,25-dihydroxyvitamin D3 in skin fibroblasts from patients with absorptive hypercalciuria. Miner Electrolyte Metab. 1998;24:307-313. 17. Prié D, Ravery V, Boccon-Gibod L, et al. Frequency of renal phosphate leak among patients with calcium nephrolithiasis. Kidney Int. 2001;60:272-276. 18. Bushinsky DA. Genetic hypercalciuric stone-forming rats. Curr Opin Nephrol Hypertens. 1999;8:479-488. 19. Bataille P, Fardellone P, Ghazali A, et al. Pathophysiology and treatment of idiopathic hypercalciuria. Curr Opin Rheumatol. 1998; 10:373-388. 20. Levy FL, Adams-Huet B, Pak CYC. Ambulatory evaluation of nephrolithiasis: an update of a 1980 protocol. Am J Med. 1998;98: 50-59. 21. Weisinger JR. New insights in the pathogenesis of idiopathic hypercalciuria: the role of bone. Kidney Int. 1996;49:1507-1518. 22. Lawoyin S, Sismilich S, Browne R, et al. Bone mineral content in patients with calcium urolithiasis. Metabolism. 1979;28:1250-1254. 23. Fuss M, Gillet C, Simon J, et al. Mineral content in idiopathic renal stone disease and in primary hyperparathyroidism. Eur Urol. 1983;9:32-34. 24. Pacifici R, Rothstein M, Rifas L, et al. Increased monocyte interleukin-1 activity and decreased vertebral bone density in patients with fasting idiopathic hypercalciuria. J Clin Endocrinol Metab. 1990;71:138-145. 25. Bataille P, Achard JM, Fournier A, et al. Diet, vitamin D and vertebral mineral density in hypercalciuric calcium stone formers. Kidney Int. 1991;39:1193-1205. 26. Borghi L, Meschi T, Guerra A, et al. Vertebral mineral content in diet-dependent and diet-independent hypercalciuria. J Urol. 1991; 146:1334-1338.
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27. Pietschmann F, Breslau NA, Pak CY. Reduced vertebral bone density in hypercalciuric nephrolithiasis. J Bone Miner Res. 1992; 12:1383-1388. 28. Jaeger P, Lippuner K, Casez JP, et al. Low bone mass in idiopathic renal stone formers: magnitude and significance. J Bone Miner Res. 1994;10:1525-1532. 29. Weisinger JR, Alonzo E, Bellorin-Font E, et al. Possible role of cytokines on the bone mineral loss in idiopathic hypercalciuria. Kidney Int. 1996;49:244-250. 30. Ghazali A, Fuentes V, Desaint C, et al. Low bone mineral density and peripheral blood monocyte activation profile in calcium stone formers with idiopathic hypercalciuria. J Clin Endocrinol Metab. 1997;82:32-38. 31. Giannini S, Nobile M, Sartori L, et al. Density and skeletal metabolism are altered in idiopathic hypercalciuria. Clin Nephrol. 1998;50:94-100. 32. Misael da Silva AM, dos Reis LM, Pereira RC, et al. Involvement in idiopathic hypercalciuria. Clin Nephrol. 2002;57:183-191. 33. Tasca A, Cacciola A, Ferrarese P, et al. Alterations in patients with idiopathic hypercalciuria and calcium nephrolithiasis. Urology. 2002;59:865-869. 34. Asplin JR, Bauer KA, Kinder J, et al. Bone mineral density and urine calcium excretion among subjects with and without nephrolithiasis. Kidney Int. 2003;63:662-669. 35. Vezzoli G, Rubinacci A, Bianchin C, et al. Intestinal calcium absorption is associated with bone mass in stone-forming women with idiopathic hypercalciuria. Am J Kidney Dis. 2003;42:11771183. 36. Caudarella R, Vescini F, Buffa AB. Mass loss in calcium stone disease: focus on hypercalciuria and metabolic factors. J Nephrol. 2003;16:260-266. 37. Barkin J, Wilson DR, Manuel MA, et al. Mineral content in idiopathic calcium nephrolithiasis. Miner Electrolyte Metab. 1985; 11:19-24. 38. Satton RAL, Walker VR. Bone resorption and hypercalciuria in calcium stone formers. Metabolism. 1986;35:485-488. 39. Manolagas SC. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev. 2000;21:115-137.
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40. Gowen M, Mundy GR. Actions of recombinant interleukin 1, interleukin 2 and interferon gamma on bone resorption in vitro. J Immunol. 1986;136:2478-2482. 41. Giannini S, Nobile M, Sartori L, et al. Acute effects of moderate dietary protein restriction in patients with idiopathic hypercalciuria and calcium nephrolithiasis. Am J Clin Nutr. 1999;9: 267-271. 42. Maierhofer WJ, Gray RW, Cheung HS, et al. Bone resorption stimulated by elevated serum 1 and 25 (OH)2-vitamin D concentrations in healthy men. Kidney Int. 1983;24:555-560. 43. Frick KK, Bushinsky DA. Molecular mechanisms of primary hypercalciuria. J Am Soc Nephrol. 2003;14:1082-1095. 44. Fuss M, Pepersack T, Bergman P, et al. Low calcium diet in idiopathic urolithiasis: a risk factor for osteopenia as great as in primary hyperparathyroidism. Br J Urol. 1990;65:560-563. 45. Hess B. Low calcium diet in hypercalciuric calcium nephrolithiasis: first do not harm. Scan Microsc. 1996;10:547-554. 46. Curhan GC, Willett WC, Rimm EB, et al. A prospective study of dietary calcium and other nutrients and the risk of symptomatic kidney stones. N Engl J Med. 1993;328:833-838. 47. Heilberg IP, Martini LA, Szejnfeld VL. Bone disease in calcium stone forming patients. Clin Nephrol. 1994;42:175-182. 48. Bordier P, Rychewart A, Gueris J, et al. On the pathogenesis of so-called idiopathic hypercalciuria. Am J Med. 1977;63:398-409. 49. Steiniche T, Mosekilde L, Christensen MS, et al. A histomorphometric determination of iliac bone remodeling in patients with recurrent renal stone formation and idiopathic hypercalciuria. Acta Pathol Microbiol Immunol Scand. 1989;97:309-316. 50. Malluche HH, Tschoepe W, Ritz E, et al. Abnormal bone histology in idiopathic hypercalciuria. J Clin Endocrinol Metab. 1980;50:654658. 51. Zerwekh JE, Sakhaee K, Breslau NA, et al. Impaired bone formation in male idiopathic osteoporosis: further reduction in the presence of concomitant hypercalciuria. Osteoporos Int. 1992;2:128134. 52. Prié D, Huart V, Bakouh N, et al. Nephrolithiasis and osteoporosis associated with hypophosphatemia caused by mutations in the type 2a sodium phosphate cotransporter. N Engl J Med. 2002;347:983-991.
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H
ypercalciuria is a well-recognized condition found in 50%-60% of patients with kidney stones.1-4 It can be defined as a 24-hour urine calcium excretion ⬎250 mg/d in women and 300 mg/d in men when patients are consuming their usual diet.5 To adjust the urine calcium excretion for body weight, hypercalciuria can also be defined in adults as a 24-hour urine excretion ⬎4 mg/kg of body weight/d in both sexes.6 (Because of the marked differences in calcium metabolism and dietary habits, such values should not be used for infants and adolescents.) Two consecutive 24-hour samples of urine calcium excretion are generally recommended to minimize potential errors in urine collection and conservation, which could result in an underestimation of calcium excretion. Urine collection should be done with patients consuming their usual diet. Several factors influence urinary calcium excretion in humans. The most important factors are sex, body weight, and nutrient intake, such as sodium, potassium, phosphate, proteins, carbohydrates, and alcohol. Healthy subjects eliminate about 6%-7% of dietary calcium in their urine daily. Consequently, depending on age, excessive dietary calcium (⬎1500 mg/d) can be associated with the development of hypercalciuria. Dietary sodium intake can increase calcium excretion by about 20-40 mg/d for every 2.3-g increase in sodium.7 Phosphate metabolism also largely influences urine calcium excretion. Phosphate leakage and consequent hypophosphatemia stimulate the renal production of 1,25(OH)2 vitamin D, which, in turn, increases intestinal calcium absorption and can lead to hypercalciuria. Epidemiologic studies have suggested that dietary pro-
From the Department of Surgery, Division of Urology, San Bortolo Hospital, Vicenza, Italy; and the Department of Medical and Surgical Sciences, Division of Nephrology, University of Padova, Padova, Italy. Reprint requests: Andrea Tasca, M.D., Department of Surgery, Division of Urology, San Bortolo Hospital, Via Rodolfi 7, Vicenza 3600 Italy. E-mail: andrea. [email protected] Submitted: March 10, 2008, accepted (with revisions): November 4, 2008
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© 2009 Elsevier Inc. All Rights Reserved
teins are very important regulators of urinary calcium, more so than dietary calcium intake.8-10 Moderate protein diets (1.0-1.5 g protein/kg) are associated with normal calcium metabolism and presumably do not alter skeletal homeostasis. In contrast, high protein intake, particularly from animal sources, results in sustained hypercalciuria. That proteininduced effect seems to be due to an increase in bone resorption, which is secondary to the excessive acid load, as well as to the direct effects of proteins on calcium handling at the renal and intestinal level.10 Hypercalciuria is commonly divided into primary and secondary forms (Table 1).4
PRIMARY HYPERCALCIURIA Definition Albright et al.11 defined primary or idiopathic hypercalciuria as the form of excessive calcium excretion that is not associated with conditions known to increase calcium elimination. More recently, however, it has been suggested that dietetic disturbances should also be eliminated by keeping patients on a daily diet of 1000-1200 mg of calcium and no more than 1-1.5 g protein/kg body weight.10 In an early classification system of primary hypercalciuria in patients with recurrent calcium stone formation by Pak et al.,12 3 types of metabolic defects were identified as causing hypercalciuria: (a) absorptive hypercalciuria, types I and II, when primary intestinal hyperabsorption of calcium is involved; (b) absorptive hypercalciuria type III, when a primary renal leak of phosphate is present, thus inducing hypophosphatemia and, secondarily, 1,25(OH)2 vitamin D-mediated intestinal hyperabsorption of calcium; and (c) renal hypercalciuria when a primary renal leak of calcium with secondary compensatory hyperparathyroidism is present. Pak et al.12 also distinguished a form of so-called resorptive hypercalciuria, when hypercalciuria is induced 0090-4295/09/$34.00 doi:10.1016/j.urology.2008.11.014
Table 1. Causes of secondary hypercalciuria Diet-dependent Excessive dietary intake Calcium Sodium Animal protein Carbohydrates Alcohol Reduced intake/absorption Phosphate Potassium Secondary increase in intestinal calcium absorption Vitamin D overtreatment Endogenous overproduction of 1,25(OH)2 vitamin D Primary hyperparathyroidism Granulomatous diseases Lymphomas Severe hypophosphatemic diseases Increased osteoclastic resorption of bone Bone metastases Multiple myeloma Primary hyperparathyroidism Paget’s disease of bone Hyperthyroidism Prolonged immobility Reduced renal tubular resorption of calcium Loop diuretics Bartter syndrome Medullary sponge kidney disease Primary renal tubular defects Endogenous/exogenous glucocorticoid excess Genetic alterations (chloride channels, calcium-sensing receptor)
Figure 1. After one week of low calcium (ⱕ 400 mg/day), normosodic (100-150 mmol/day) and normoproteic (1-1.2 grams/kg/BW) diet, a fasting morning urine sample (h. 7.00-9.00 a.m.) should be obtained for the determination of calcium and creatinine.
Renal Tubular Calcium Leak. A defect in renal tubular calcium reabsorption can be demonstrated in both humans and genetic hypercalciuric stone-forming rats as a cause of idiopathic hypercalciuria.18,19 However, additional extensive study of so-called renal hypercalciuria demonstrated that the 2 distinctive characteristics of this form (ie, low-normal serum calcium and increased parathyroid hormone [PTH] levels) were present in a small minority of patients with primary hypercalciuria.20 It is currently believed that no more than 2%-3% of primary hypercalciuria cases are generated by a true calcium leak.
by an excessive output of calcium from bone, for example in patients with primary hyperparathyroidism. During the past 20 years, this classification scheme has been revised. Currently, it is believed that 3 different mechanisms, which possibly overlap and operate together, are involved in the pathogenesis of hypercalciuria: increased intestinal absorption of calcium, primary excessive calcium release from bone, and altered renal calcium handling.
Fasting Hypercalciuria. Most patients with primary hypercalciuria have persistently elevated urine calcium, even after a low calcium diet or in fasting conditions, without any secondary parathyroid hyperfunction. This metabolic pattern tends to exclude a major role for both intestinal calcium hyperabsorption and renal calcium leak. The term “fasting hypercalciuria” was given to this condition, which presumably is dependent on a primary excess of calcium output from bone.21
Mechanisms of Hypercalciuria Increased Intestinal Absorption of Calcium. Recent studies have confirmed that calcium absorption is almost invariably increased in patients with primary hypercalcuria.13 The metabolism of 1,25(OH)2 vitamin D appears to be altered in some patients with absorptive hypercalciuria.14 In rats with genetically determined hypercalciuria, increased expression of the intestinal vitamin D receptor leads to increased intestinal calcium absorption, even in the absence of elevated values of serum 1,25(OH)2 vitamin D.15 However, no evidence that a similar mechanism might be operating in humans has yet been found.16 When present, altered renal handling of phosphate, leading to excessive phosphaturia and hypophosphatemia, might be responsible for overproduction of 1,25(OH)2 vitamin D and secondary intestinal calcium hyperabsorption.17
Diagnosis Once the diagnosis of hypercalciuria has been correctly made, it is necessary to exclude any secondary causes of hypercalciuria (Table 1). In the presence of documented primary hypercalciuria, several simple laboratory tests can help to identify the main metabolic defect. In brief, after 1 week of low calcium and normal sodium and protein dietary intake, a fasting morning urine sample should be obtained to determine the calcium and creatinine levels. If urine calcium excretion normalizes (with the calcium/creatinine ratio decreasing to ⬍0.11 mg/mg), a diagnosis of absorptive hypercalciuria can be made. However, if the urine calcium excretion remains elevated, the diagnosis of fasting hypercalciuria is reasonable and can be further classified as undetermined fasting hypercalciuria or renal hypercalciuria. This is determined from the serum calcium and PTH values (Fig. 1).
UROLOGY 74 (1), 2009
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Table 2. Bone mineral density in patients with primary hypercalciuria Investigator 22
Lawoyin et al., 1979 Fuss et al.,23 1983 Pacifici et al.,24 1990 Bataille et al.,25 1991 Borghi et al.,26 1991 Pietschmann et al.,27 1992 Jaeger et al.,28 1994 Weisinger et al.,29 1996 Ghazali et al.,30 1997 Giannini et al.,31 1998 Misael da Silva et al.,32 2002 Tasca et al.,33 2002 Asplin et al.,34 2003 Vezzoli et al.,35 2003 Caudarella et al.,36 2003
Measurement Method
Measurement Site
BMD Result
SPA SPA QCT QCT DPA DEXA, SPA DEXA DEXA QCT DEXA DEXA DEXA DEXA DEXA DEXA, QUS
Radius Radius Spine Spine Spine Spine, radius Spine, femur Spine, femur Spine Spine, femur Spine, femur Spine, femur Spine, femur Spine, femur Radius, finger
2N 2 2 2 2 2 2 2 2 2 2 2 2 2 2
SPA ⫽ single photon absorptiometry; DEXA ⫽ dual energy x-ray absorptiometry; DPA ⫽ dual photon absorptiometry; QCT ⫽ quantitative computed tomography; QUS ⫽ quantitative ultrasonography; N ⫽ normal; 2 ⫽ reduced.
PRIMARY HYPERCALCIURIA AND BONE DISEASE Size of Problem Because idiopathic hypercalciuria is one of the most common phenotypes in patients with kidney stones, most studies undertaken to assess bone status in patients with hypercalciuria have been conducted in patients with calcium nephrolithiasis. These studies demonstrated that although the bone density is substantially normal or only slightly reduced in patients with calcium nephrolithiasis without hypercalciuria, significant bone loss is present in patients with kidney stones and primary hypercalciuria (Table 2). Bone loss mainly involves areas of trabecular bone, such as the vertebral bodies.22-35 However, a reduction in femoral density has also been reported.28,29,31-37 These studies also showed a relatively young age group (average 50 years) and a large proportion of males. Patients with renal calculi have an increased bone fracture risk,38,39 and, among patients with kidney stones, bone loss is a predominant characteristic of hypercalciuric states. Consequently, hypercalciuria might be one of the factors explaining the increased proportion of fragility fractures seen in patients with kidney stones. Although most investigators observed significant bone loss in patients with fasting hypercalciuria but not in those with the absorptive form,24-26,31,33 others reported a decrease in bone density, irrespective of the type of primary hypercalciuria27,29,30 (ie, even in patients classified as having absorptive hypercalciuria).27-29 To justify this last finding, it was hypothesized that patients with absorptive hypercalciuria might have been consuming an inappropriately low calcium diet.27 It was also suggested that excessive stimulation of bone resorption observed in these patients could alternatively result from high consumption of dietary protein, increased serum levels of 1,25(OH)2 vitamin D, or increased sensitivity to this hormone. It has also been suggested that the absorptive and fasting types of hypercalciuria might not in fact be 2 distinct forms of defect, but rather 1 unique disorder. 24
Support for this view has come from a recent study that found that patients with hypercalciuria with the largest proportion of bone loss also presented with the greatest levels of intestinal calcium absorption.35 Pathophysiology of Primary Hypercalciuria Whatever the pathophysiologic mechanism, that primary hypercalciuria, calcium nephrolithiasis, and bone diseases are strictly linked is well established. In particular, the rate of urine calcium excretion correlates with bone loss29,35,37 and an elevation in bone turnover markers in patients with hypercalciuric stone formation.25,31,38 Thus, to better understand the relationships between primary hypercalciuria and bone loss and the pathogenetic factors shared by these 2 conditions, the roles of bone, kidney, and intestine must be considered. Bone. Since the reclassification of the types of primary hypercalciuria in patients with calcium nephrolithiasis proposed by Levy et al.,20 the term “fasting hypercalciuria” has been used to identify patients who cannot lower or normalize their urine calcium excretion appropriately after a restriction in dietary calcium consumption. Because low bone density was more frequently reported in these patients, the presence of specific factors simultaneously causing hypercalciuria and bone demineralization has been suggested. Cytokines are included among these factors because they regulate bone resorption and might be involved in the pathogenesis of bone alterations in patients with primary hypercalciuria.24 Monocytes isolated from patients with fasting hypercalciuria, but not from those with absorptive hypercalciuria, have been shown to produce an exaggerated amount of interleukin-1 (IL-1) (Table 3). This cytokine, a well-known and very potent stimulator of bone resorption processes, has been correlated with bone demineralization in patients with fasting hypercalcuria.40 Furthermore, the production and mRNA expression of IL-1 from unstimulated peripheral blood mononuclear UROLOGY 74 (1), 2009
Table 3. Cytokine levels from peripheral blood mononuclear cells in patients with primary hypercalciuria and controls Investigator
Population Sample 24
Pacifici et al. Weisinger et al.29 Ghazali et al.30
FH, AH, controls IH, NC, controls IH, DH, controls
IL-1
IL-1␣
IL-1
IL-6
TNF-␣
GM-CSF
261 ⫾ 81* — — — — — — 680 ⫾ 139† — 19 ⫾ 4‡ 2976 ⫾ 417† — — — 40 ⫾ 21§ 347 ⫾ 145¶ 236 ⫾ 136 52 ⫾ 27¶
FH ⫽ fasting hypercalciuria; AH ⫽ absorptive hypercalciuria; IH ⫽ idiopathic hypercalciuria; NC ⫽ normocalciuria; DH ⫽ dietary hypercalciuria. * P ⬍ .01, FH vs AH and controls. † P ⬍ .01, IH vs NC and controls (lipopolysaccharide stimulated). ‡ P ⬍ .05, IH vs NC and controls (lipopolysaccharide stimulated). § P ⬍ .01, IH vs DH. ¶ P ⬍ .05, IH vs controls.
cells has correlated with spinal bone loss in patients with primary hypercalciuria and nephrolithiasis.29 In addition, mononuclear cells produce an increased amount of IL-1, IL-6, and tumor necrosis factor-␣, compared with controls, after stimulation with lipopolysaccharide. Because all these cytokines are considered local mediators of bone resorption,39 bone loss might largely depend on these alterations in patients with hypercalciuria with calcium stones. Similar results were found by others.30 Excessive protein intake, especially of animal origin, was found to sharply increase urine calcium excretion and bone resorption and lead to bone loss.11 The main mechanism for these effects is the acid load produced by proteins, especially those rich in sulfur-containing amino acids.11 Accordingly, sulfate excretion and markers of protein intake, such as urinary or serum urea, also appear to correlate with bone turnover markers and density.25,27,28,41 Moderate protein restriction also induces a proportional reduction in calcium excretion and bone turnover markers in patients with calcium nephrolithiasis and primary hypercalciuria.41 Because excessive consumption of dietary protein has been repeatedly reported in patients with hypercalciuric stone formation,11,41 normalization of protein intake is highly recommended in patients with hypercalciuria. This measure is also important, because it has been noted that such patients present with hypersensitivity to protein effects on bone.41 No consistent data currently support a substantial role for calciotropic hormones in the pathogenesis of bone loss in primary hypercalciuria. Vitamin D-1,25(OH)2 was reported to be greater in patients with primary hypercalciuria than in controls, and it was observed that this hormone can induce an increase in bone resorption.42 However, the elevation in 1,25(OH)2 vitamin D levels was more frequently described in patients with absorptive hypercalciuria, whose bone density levels are generally normal or poorly diminished. It appears that 1,25(OH)2 vitamin D levels have a protective, rather than a damaging, effect on bone mass in patients with primary hypercalciuria and kidney stones.25 Apart from the very small proportion of patients who can be classified as having renal hypercalciuria,20 the PTH levels are generally normal in patients with primary hypercalciuria and are not thought to have a significant role in the pathogenesis of bone loss in this setting. UROLOGY 74 (1), 2009
Intestine. Although the classic distinction of primary hypercalciuria from absorptive hypercalciuria and fasting hypercalciuria is still maintained, a wide overlap seems to occur between the 2 forms in patients with hypercalciuric stone formation. Studies have reported a decrease in bone density in patients with absorptive hypercalciuria27; likewise, increased intestinal calcium absorption has been frequently reported in patients with fasting hypercalcuria.19 Thus, intestinal function appears to play a role in both the pathogenesis of primary hypercalciuria and the development of bone disease. The complex relationships between intestine calcium absorption and bone in women who form stones and have primary hypercalciuria was assessed using the stable strontium method.35 In that study, the greater the loss of bone mineral density, the larger the increase in intestinal calcium absorption, with calcium absorption being the best predictor of bone mass in a multiple regression model.35 Because the PTH values were similar in patients with hypercalciuric and normocalciuric stone formation, the investigators speculated that this is not a compensatory phenomenon, but probably a marker of disturbed cell calcium transport involving both intestinal and bone tissue.35 This hypothesis would also be in keeping with the view that absorptive hypercalciuria and fasting hypercalciuria might be different phenotypes and expressions of the same disorder,21 which could be sustained by some genetic influences.43 In the presence of hypercalciuria, the calcium balance can be maintained only at the expense of skeletal tissue or through an increase in intestinal calcium absorption, which can in turn limit bone loss. Restriction in dietary calcium intake, which many patients with hypercalciuric stone formation tend to do by themselves or after medical prescription, is therefore a major risk factor for bone loss in this setting. A reduction in calcium intake is well known to be associated with a negative calcium balance and bone loss.28,44,45 Some investigators44,45 reported this negative effect after a calcium-restricted diet was maintained for 2-8 years, and others have observed a significant reduction in bone density in patients with hypercalciuria after just 1 year of a low-calcium diet.9 In addition, dietary calcium restriction does not reduce the incidence of new kidney stones; in contrast, it increases the risk of developing new symptomatic renal calculi, at least in males.46 This seems to occur because of an increase in intestinal oxalate absorp25
tion due to a lack of bonding with calcium in the intestinal lumen. Together, these observations suggest that patients with hypercalciuria need to maintain appropriate dietary calcium intake. Kidney. The revision of our understanding of the pathogenetic aspects of patients with kidney stones and primary hypercalciuria led to the observation that ⬍5% of patients with hypercalciuria have a renal form of primary hypercalciuria.20 Thus, the importance of renal calcium leak as a pathogenetic factor for bone loss in these patients was completely reconsidered. However, other aspects seem to link the kidney to complex relationships occurring between hypercalciuria and bone. Increased urinary phosphate excretion was found in patients with hypercalciuria compared with normal subjects, irrespective of the presence of a true form of absorptive hypercalciuria with renal calcium leak.45,46 The bone alterations observed in patients with hypercalciuria resemble those seen in hereditary hypophosphatemic rickets with hypercalciuria in which an alteration in the bone mineralization process was observed.47-51 Also a mutation of the NPT2 gene was found in patients with calcium nephrolithiasis and decreased bone density.52 Therefore, no clear evidence definitely supports the hypothesis that renal phosphate leak might be involved in bone disease found in patients with primary hypercalciuria. Nonetheless, this investigative path appears to be a promising way to elucidate the role of the kidney in the pathogenesis of bone loss in patients with primary hypercalciuria.
CONCLUSIONS Primary hypercalciuria is a very common finding in patients with kidney stones and otherwise primary osteoporosis. It is now clear that the association between bone loss and primary hypercalciuria is not casual, but it is characterized by a complex relationship among intestinal absorption, bone metabolism, and urinary calcium excretion. However, the mechanisms involved in the pathogenesis of bone damage in patients with hypercalciuria stone formation still remain only partially understood. The organs and tissues normally involved in the control of calcium and phosphate metabolism appear to take an active part in the pathogenesis of the skeletal alterations in patients with primary hypercalciuria. The skeletal tissue, per se, the kidney, and the intestine are responsible for the appearance, persistence, and clinical course of bone loss in patients with hypercalciuric nephrolithiasis and operate together as a multitissue metabolic disorder. Table 3. References 1. Hodgkinson A, Pyrah LN. The urinary excretion of calcium and inorganic phosphate in 344 patients with calcium stone of renal origin. Br J Surg. 1958;46:10-18.
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2. Smith LH, VanDenBerg CJ, Wilson DM. Nutrition and urolithiasis. N Engl J Med. 1980;98:87-89. 3. Pak CY. Medical management of nephrolithiasis. J Urol. 1982;128: 1157-1164. 4. Pak CY, Ohata M, Lawrence EC, et al. The hypercalciurias: causes, parathyroid functions, and diagnostic criteria. J Clin Invest. 1974; 54:387-400. 5. Heaney RP, Recker RR, Ryan RA. Urinary calcium in perimenopausal women: normative values. Osteoporos Int. 1999;9:13-18. 6. Kerstetter JE, O’Brian KO, Insogna KL. Low protein intake: the impact on calcium and bone homeostasis in humans. J Nutr. 2003;133:855S-861S. 7. Nordin BE, Need AG, Morris HA, et al. The nature and significance of the relationship between urinary sodium and urinary calcium in women. J Nutr. 1993;123:1615-1622. 8. Hegsted M, Schuette SA, Zemel MB, et al. Urinary calcium and calcium balance in young men as affected by level of protein and phosphorus intake. J Nutr. 1981;111:553-562. 9. Zemel MB. Calcium utilization: effect of varying level and source of dietary protein. Am J Clin Nutr. 1988;48:880-883. 10. Kerstetter JE, O’Brien KO, Insogna KL. Dietary protein, calcium metabolism, and skeletal homeostasis revisited. Am J Clin Nutr. 2003;78:584S-592S. 11. Albright F, Henneman P, Benedict PH, et al. Idiopathic hypercalciuria: a preliminary report. Proc R Soc Med. 1953;46:1077-1081. 12. Pak CY, Britton F, Peterson R, et al. Ambulatory evaluation of nephrolithiasis: classification, clinical presentation and diagnostic criteria. Am J Med. 1980;69:19-30. 13. Vezzoli G, Tanini A, Ferrucci L, et al. Influence of calcium-sensing receptor gene on urinary calcium excretion in stone-forming patients. J Am Soc Nephrol. 2002;13:2517-2523. 14. Broadus AE, Insogna KL, Lang R, et al. Evidence for disordered control of 1,25-dihydroxyvitamin D production in absorptive hypercalciuria. N Engl J Med. 1984;311:73-80. 15. Li XQ, Tembe V, Horwitz GM, et al. Increased intestinal vitamin D receptor in genetic hypercalciuric rats: a cause of intestinal calcium hyperabsorption. J Clin Invest. 1993;91:661-667. 16. Zerwekh JE, Reed BY, Heller HJ, et al. Normal vitamin D receptor concentration and responsiveness to 1,25-dihydroxyvitamin D3 in skin fibroblasts from patients with absorptive hypercalciuria. Miner Electrolyte Metab. 1998;24:307-313. 17. Prié D, Ravery V, Boccon-Gibod L, et al. Frequency of renal phosphate leak among patients with calcium nephrolithiasis. Kidney Int. 2001;60:272-276. 18. Bushinsky DA. Genetic hypercalciuric stone-forming rats. Curr Opin Nephrol Hypertens. 1999;8:479-488. 19. Bataille P, Fardellone P, Ghazali A, et al. Pathophysiology and treatment of idiopathic hypercalciuria. Curr Opin Rheumatol. 1998; 10:373-388. 20. Levy FL, Adams-Huet B, Pak CYC. Ambulatory evaluation of nephrolithiasis: an update of a 1980 protocol. Am J Med. 1998;98: 50-59. 21. Weisinger JR. New insights in the pathogenesis of idiopathic hypercalciuria: the role of bone. Kidney Int. 1996;49:1507-1518. 22. Lawoyin S, Sismilich S, Browne R, et al. Bone mineral content in patients with calcium urolithiasis. Metabolism. 1979;28:1250-1254. 23. Fuss M, Gillet C, Simon J, et al. Mineral content in idiopathic renal stone disease and in primary hyperparathyroidism. Eur Urol. 1983;9:32-34. 24. Pacifici R, Rothstein M, Rifas L, et al. Increased monocyte interleukin-1 activity and decreased vertebral bone density in patients with fasting idiopathic hypercalciuria. J Clin Endocrinol Metab. 1990;71:138-145. 25. Bataille P, Achard JM, Fournier A, et al. Diet, vitamin D and vertebral mineral density in hypercalciuric calcium stone formers. Kidney Int. 1991;39:1193-1205. 26. Borghi L, Meschi T, Guerra A, et al. Vertebral mineral content in diet-dependent and diet-independent hypercalciuria. J Urol. 1991; 146:1334-1338.
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40. Gowen M, Mundy GR. Actions of recombinant interleukin 1, interleukin 2 and interferon gamma on bone resorption in vitro. J Immunol. 1986;136:2478-2482. 41. Giannini S, Nobile M, Sartori L, et al. Acute effects of moderate dietary protein restriction in patients with idiopathic hypercalciuria and calcium nephrolithiasis. Am J Clin Nutr. 1999;9: 267-271. 42. Maierhofer WJ, Gray RW, Cheung HS, et al. Bone resorption stimulated by elevated serum 1 and 25 (OH)2-vitamin D concentrations in healthy men. Kidney Int. 1983;24:555-560. 43. Frick KK, Bushinsky DA. Molecular mechanisms of primary hypercalciuria. J Am Soc Nephrol. 2003;14:1082-1095. 44. Fuss M, Pepersack T, Bergman P, et al. Low calcium diet in idiopathic urolithiasis: a risk factor for osteopenia as great as in primary hyperparathyroidism. Br J Urol. 1990;65:560-563. 45. Hess B. Low calcium diet in hypercalciuric calcium nephrolithiasis: first do not harm. Scan Microsc. 1996;10:547-554. 46. Curhan GC, Willett WC, Rimm EB, et al. A prospective study of dietary calcium and other nutrients and the risk of symptomatic kidney stones. N Engl J Med. 1993;328:833-838. 47. Heilberg IP, Martini LA, Szejnfeld VL. Bone disease in calcium stone forming patients. Clin Nephrol. 1994;42:175-182. 48. Bordier P, Rychewart A, Gueris J, et al. On the pathogenesis of so-called idiopathic hypercalciuria. Am J Med. 1977;63:398-409. 49. Steiniche T, Mosekilde L, Christensen MS, et al. A histomorphometric determination of iliac bone remodeling in patients with recurrent renal stone formation and idiopathic hypercalciuria. Acta Pathol Microbiol Immunol Scand. 1989;97:309-316. 50. Malluche HH, Tschoepe W, Ritz E, et al. Abnormal bone histology in idiopathic hypercalciuria. J Clin Endocrinol Metab. 1980;50:654658. 51. Zerwekh JE, Sakhaee K, Breslau NA, et al. Impaired bone formation in male idiopathic osteoporosis: further reduction in the presence of concomitant hypercalciuria. Osteoporos Int. 1992;2:128134. 52. Prié D, Huart V, Bakouh N, et al. Nephrolithiasis and osteoporosis associated with hypophosphatemia caused by mutations in the type 2a sodium phosphate cotransporter. N Engl J Med. 2002;347:983-991.
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