Adynamic bone disease: An update and overview

REVIEW JNEPHROL 2005; 18: Adynamic bone disease: An update and overview Giorgio Coen Associate Professor of Nephrology, La Sapienza University, Nephrology and Hypertension Unit, Ospedale Israelitico, Rome - Italy ABSTRACT: Key words: INTRODUCTION Over the last 50 years a large body of studies has been dedicated to renal osteodystrophy. The interest in this complication of chronic renal failure has been mainly prompted by the long survival of patients with chronic renal failure following the introduction of dialysis treatment. The relative longevity of uremic patients undergoing dialysis is accompanied by several further clinical problems, among which one of the most relevant is the disordered mineral metabolism and the skeletal problems related to increased severity of metabolic bone disease. Initially, what came to the attention of clinical researchers was chiefly secondary hyperparathyroidism and in a number of cases the osteomalacic lesions, isolated or associated to hyperparathyroid bone disease (1-3). Osteomalacia was initially believed to be mainly due to vitamin D deficiency and to metabolic acidosis (3-5). Later, with the discovery of the toxicity of aluminium (6,7) contained in the dialysis water and absorbed with the aluminium containing phosphate chelating agents, osteomalacia was principally attributed to aluminium accumulation in the skeleton and also to aluminium induced inhibition of PTH secretion by the parathyroids. Aluminium accumulation in the skeleton was considered responsible for two types, or histologic variants, of low turnover renal osteodystrophy, namely osteomalacia and aplastic or adynamic bone disease (8). While pure osteomalacia was histologically characterized by reduced bone turnover associated to increased uncalcified osteoid tissue with increased osteoid seam thickness, due to a marked slowing of the calcification process, adynamic bone disease was a condition of decreased bone turnover, scarce number of osteoblastic and osteoclastic cells, however without increase in osteoid tissue and osteoid thickness (8). This type of renal osteodystrophy was mainly the result of a severe decrease in osteoid synthesis, however not accompanied by decreased mineralization rate. Therefore the pathogenetic mechanism of the two types of low turnover osteodystrophy are completely different (9). In the following years with the special attention given to avoid aluminium exposure (10,11) through the depuration of net water, and exclusion or marked limitation in the administration of aluminium containing phosphate chelating agents, like aluminum hydroxide, a progressive fall in the incidence of pure osteomalacia has been observed in the western countries, down to a small percentage of cases (12-14), while adynamic bone disease, far from disappearing, has become more frequent, reaching in some case series, from different parts of the world, the proportion up to 30-50 percent (15-17). Adynamic bone disease was also observed in predialysis conservative chronic renal failure (5, 18, 19). The percentage of patients with adynamic bone disease was lower in some case reports of patients with no or a relatively low aluminium exposure (20-22), and also in pediatric patients (23). The diagnosis of adynamic bone disease rests on an histomorphometric and histodynamic based finding of a low bone turnover, together with lack of increased www.sin-italy.org/jnonline/vol18n2/ 1

Adynamic bone disease thickness of osteoid seams and osteoid area. However, values of normal population bone turnover are scarce and in some reports reference values were used which were either insufficient or from other centers or countries far from the study site. In addition normal bone turnover evaluated on trabecular bone can be traced down to extremely low levels so that distinguishing a normal from a really low bone turnover is very difficult. Bone Formation Rate (BFR), the basic parameter for the evaluation of bone turnover, was calculated using different methods in some reports, providing questionable results. Therefore many reported cases, based as usual on evaluation of cancellous bone with the exclusion of cortical bone, should probably be considered patients with a low-normal turnover (9), rather than the often used erroneous label of adynamic bone disease. It was evident that aluminium was only one of the risk factors, but the majority of cases were probably a consequence of different reasons (24). It was observed that most of the cases of adynamic bone disease were found in patients with relatively low PTH serum levels (24, 25), below 100 pg/ml of the intact PTH assay, but cases of this histologic pattern were also observed, even if more rarely, in the interval of PTH 100 to 300 pg/ml. Therefore it is now recognized that low PTH levels are an important and essential risk factor of adynamic bone disease. Malnutrition has been considered among the causes of decreased serum PTH levels. A Japanese study on a large cohort of patients on hemodialysis discovered that low levels of serum albumin and urea nitrogen increased the odds ratio for developing hypoparathyroidism (26). This finding led to the conclusion that the nutritional state may be one of the major factors contributing to PTH deficiency and low turnover bone disease (27). In addition, for reasons so far not explained, the histologic pattern was more frequent in males than in female patients. Diabetes mellitus was also found to be associated to less elevated PTH serum levels, less severe varieties of renal osteodystrophy and increased prevalence of adynamic bone disease (28, 29). Also advanced age was reported as an independent factor (18). Therefore, once excess bone aluminium deposits in the skeleton were excluded as a cause of ABD, one of the most essential factors causing decreased bone turnover and relatively quiescent bone appeared to be the low level of serum PTH. However, this conclusion cannot be considered entirely satisfactory, since there are cases of adynamic bone disease with PTH serum levels appreciably higher than normal reference values. Even in the range of PTH below 100 pg/ml, many patients with adynamic bone disease have PTH serum levels 1-2 times higher than the upper normal level of the hormone. Therefore the uremic milieu is per se an important cause of so called resistance of bone to PTH (30, 31). Normal bone turnover in patients with chronic renal failure requires increased levels of PTH, maybe on the order of at least 3-5 times the upper range of normality. Any time the patients are confronted with any factor which lowers the PTH serum levels to relatively low values, bone turnover will slow down to subnormal levels and a pattern of adynamic bone disease may be generated. This has been found by several authors to be the case as the result of vitamin D treatment, with special regard to calcitriol (32). When monitored by bone biopsies, treatment of secondary hyperparathyroidism of chronic renal failure with intravenously or per os pulsed calcitriol was accompanied in a large proportion of cases by the development of adynamic bone disease. In addition, administration of calcium containing phosphate chelating agents, which up to recently were administered in relatively elevated amounts without the present restraint to prevent hypercalcemia, is probably an important cause of decreased PTH serum levels and development of adynamic bone disease. Patients on peritoneal dialysis, usually with serum calcium levels higher than in hemodialysis patients, are more likely to form adynamic bone disease (17). Therefore in chronic renal failure bone tissue appears to be resistant to PTH. We do not know which uremic toxins are important and at play in the induction of bone resistance. A downregulation of PTH receptors in osteoblastic cells has been postulated. In addition it is known that several receptors in uremic patients are downregulated, mainly in the parathyroid cells, namely vitamin D receptors and calcium sensing receptors. However these derangements, which are common in later and more severe stages of parathyroid hyperplasia, do not explain what is happening in bone cells. Possible uremic toxins causing dysfunction of PTH receptors have been reported. The PTH receptor in bone has been reported to be downregulated (33). And also low molecular weight uremic inhibitors of osteoblast function have been found in uremic patients (34). In addition humoral factors are present in the uremic serum ultrafiltrate able to decrease PTH-stimulated camp generation by a mechanism that involves a decrease in PTH1R, a fact which can at least in part explain skeletal resistance in chronic renal failure (35). In the last few years much attention has been dedicated to several PTH molecular species which are found to be increased in the circulation of patients with chronic renal failure, and have been found to be endowed with biologic activity opposing that of PTH 1-84. The intact PTH assay does not measure only the intact 1-84 PTH molecule, but also several PTH molecular species, like 7-84 PTH, which have been shown to be inactive on the PTHR1 receptor, the most important receptor of the intact molecule PTH. Lack of the 2

Coen first 6 aminoacids of the N-term extremity of the molecule is accompanied by a biologic activity paradoxically different from the entire molecule. Studies by Slatopolsky et al (36) have shown that this PTH moiety antagonizes the hypercalcemic effect of PTH 1-84 in parathyroidectomized rats. In addition it is not able to induce the production of cyclic AMP in ROS cells in vitro. Administration of PTH 1-84 to rats induces increased phosphaturia which is blunted by the simultaneous administration of PTH 7-84. Therefore it was believed at the beginning that the proportion of PTH entire molecule and of PTH 7-84 within the intact assay could modulate the resultant total biologic activity of PTH. A relative inhibition of PTH activity in the case of a relative increase of the proportion of the 7-84 molecule could be expected. An increase in 7-84 PTH serum levels should have resulted in a resistance to the entire hormone through a competitive inhibition at the PTHR1 receptor level. This finding has immediately prompted some clinical researchers (37) to utilize the serum ratio PTH 1-84/7-84 as a useful index in the identification of low turnover bone disease, with special regard to adynamic bone disease. The results of these studies have been contradictory. However, most of reports on the subject have refuted the importance of this ratio as of diagnostic value (38-40). The discovery of the circulating PTH species truncated at the N-terminal of the molecule has opened the path to an important number of studies, theoretically of profound physiological and pathological impact. It has been observed that the PTH 7-84 is mainly produced directly by the parathyroid glands when confronted with increased calcium concentration in the milieu. This molecular species with hypocalcemic effect was found to be unable to bind to the PTHR1 receptor (41), while it does bind to a C-terminal PTH receptor mostly found in large amounts on osteocytes (42). Therefore, it was easy to speculate that in case of increasing calcium levels in the organism the parathyroids are able to decrease PTH 1-84 output and conversely increase the secretion of PTH 7-84, which would act through the osteoblasts and on osteoclastic differentiation in modulating serum calcium through its hypocalcemic activity. However this interesting hypothesis is not in line with the observation that the concentrations of PTH 7-84 which are able to counteract PTH 1-84, at least in the resorption process in experimental in vitro setting (43), were in the order of 100 times higher. In any case, these studies in general have shown clearly that PTH acts through different receptors located on bone cells, and is able to bind the N-terminal or the C-terminal part of the molecule with different effects. However there is no indication that PTH 1-84 and 7-84 compete for the same receptor. Deficiency of insulin-like growth factors and of some cytokines essential for osteoblastic function have been reported in uremia (44-47). In addition CKD probably is a factor of direct impairment of bone remodeling, even in the absence of low PTH serum levels. Experimentally, the administration of BMP-7 to rats with adynamic bone disease stimulates osteoblastic cells with reversal of the low turnover condition (48). BMP-7, which is expressed in the renal tubule, with special regard to the collecting duct, has been shown to be an osteoblastic stimulating substance able to induce the development of osteoblastic cells from undifferentiated precursors. We do not know whether a deficiency of this factor could be considered a cause of adynamic bone disease in humans. In the situation of uremia, the circulating levels of this factor are reduced. Thus, decreases in skeletal BMP influence could be a factor in deficient skeletal remodeling associated with CKD, as the experimental results seemed to suggest. Other possible mediators of bone turnover have also been examined for their possible factor of adynamic bone. In particular osteoprotegerin known to decrease bone turnover by reducing the differentiation of monocytemacrophage into osteoclasts through inactivation of RANKL, has been considered as a possible factor inducing low turnover in ABD. Some studies have suggested that the accumulation of osteoprotegerin in uremia could be a factor of bone resistance to PTH (49). The results of a cross-sectional study with bone biopsies on hemodialysis patients, however, are against this hypothesis (50). Also leptin, known to induce a direct in vitro suppressive effect on osteoclastic and osteoblastic activity, was not found to be involved as a factor in adynamic bone disease (51), since patients on hemodialysis with adynamic bone disease had on average serum leptin levels, even corrected for body mass index, not different from the other histologic categories. The question whether adynamic bone disease should be considered an independent disease or only a variant of renal osteodystrophy is difficult to resolve. Trying to find an answer to this question could be considered a somewhat futile exercise, and only a semantic problem. However, as reported above, ABD is generally found as a histologic diagnosis in cases with low serum PTH levels, and no special clinical evidence suggests its diagnosis. In addition, the basic mechanisms leading to this low turnover bone disease are probably linked to the uremic state and become evident in case of reduction of PTH serum levels. Therefore this expression of bone disease is part of the general pathophysiology of bone in uremia. With regard to the consequences of adynamic bone disease, they might to a certain extent differ from those observed in the high turnover varieties of renal osteodystrophy. It has been reported that adynamc bone disease is a cause of more frequent bone fractures. In addition, due to the low bone turnover which 3

Adynamic bone disease is a characteristic of the disease, blood calcium is more inclined to increase occasionally due to the decreased buffering of calcium coming from the gut, enhanced in the case of treatment with vitamin D. Therefore adynamic bone disease is considered a risk factor for arterial calcification. The increased danger of fractures in patients with adynamic bone disease is likely due to the decreased bone remodeling, an important aid in the prevention and repair of fatigue microdamage, with possible accumulation of microdamage and fracture. The hypothesis that fracture risk may be increased in adynamic bone disease has been reported by Piraino and by Atsumi (52, 53). According to Piraino et al (52) increased incidence of fractures was observed in low turnover osteodystrophy mainly in the ribs. Their histodynamic values for bone turnover was high enough to include most normal subjects. The patients had increased bone aluminum deposits and were probably affected by osteomalacia, a condition more frequently associated with rib fractures. In the report of Atsumi et al (53) no histology was reported, and no evaluation was made of skeletal aluminium deposits. The fractures observed in the spine may have been due to osteomalacia. In addition, Coco et al (54) have reported that low PTH serum levels are associated with increased hip fractures. However the patient cohort was composed of blacks and caucasians with different bone structure and inherent different risk of fractures. In addition hip fractures are extremely frequent in the dialysis population, probably due to factors other than low bone turnover. In the general experience (9) the occurrence of bone fracture in low turnover osteodystrophy and in hypoparathyroidism with low bone turnover is very rare. Therefore there is no evidence that adynamic bone disease carries a real risk of fractures. In addition a recent report by Ubara et al (55), based on the fact that there is no decrease in bone mineral density in hypoparathyroid patients (56), has provided some evidence that physical activity in patients with low turnover bone disease activates a modeling of bone trabeculae, called minimodeling, due to direct activation of osteoblasts and formation of bone unrelated to the process of bone resorption, like in the remodeling process. This mechanism could be able to add bone tissue, strengthening the bone trabecular structure. Therefore it is unlikely that low turnover bone disease of the adynamic bone disease variety is a factor of increased bone fractures. Increased extraskeletal calcification in adynamic bone disease has been reported to be a real danger (16, 57). The adynamic bone is unable to buffer calcium coming from dialysis fluid or from intestinal absorption (58). Hypercalcemia is a common result in ABD leading to extraskeletal and cardiovascular calcifications. The inability to buffer serum calcium has been evidenced with calcium kinetic studies, which demonstrate the reduction of exchangeable calcium pool in low turnover bone and hypoparathyroidism (58). A recent study of London et al (59) has shown in 58 patients on hemodialysis the relationship between bone histology and the extent of arterial calcifications. Patients with high scores of arterial calcifications were characterized by lower serum parathyroid hormone, low osteoclastic number and osteoblastic surface, low bone turnover and frequent elevated percentage of uminum stained surfaces. The high arterial calcification score is associated with bone histomorphometry suggestive of low bone activity and adynamic bone disease. The therapeutic approach to adynamic bone disease is mainly based on prevention (60). Elimination of aluminum toxic exposure is done by excluding aluminium containing phosphate chelating agents and by depuration of net water for dialysis. Depuration of aluminum from water is a very important procedure which has markedly abated serum levels of dialysis patients (61). In addition prevention is also carried out by reducing the intake of calcium carbonate or acetate for phosphate chelation to a value of elemental calcium of 1.5-2 g a day, and by the use of non-calcium, non-aluminum containing phosphate chelating agents, like sevelamer hydrochloride and lanthanum carbonate. The calcium concentration of dialysate must be lower than 1.5 mmoles. Treatment with calcitriol and analogues should aim at a PTH target between 150 and 300, as requested by the K/DOQI (62), knowing, however, that a small number of cases of adynamic bone diseases occurs even in this range of PTH values. In the case of low PTH levels below 100 pg/ml, therapeutic measures should be promoted to increase PTH secretion, generally by provoking mild hypocalcemia during the dialysis session through the use of dialysis fluid with a calcium concentration of 1.25 mm, or by decreasing the intake of elemental calcium contained in the food and in the chelating agents. Address for correspondence: Prof. Giorgio Coen, M.D. Via Dandolo, 75 00153 Rome, Italy giorgio.coen@fastwebnet.it 4

Coen REFERENCES 1. Stanbury WS, Lumb GA, Mawer EB. Osteodystrophy developing spontaneously in the course of chronic renal failure. Arch Intern Med 1969; 124; 274-81. 2. Sherrard DJ, Baylink DJ, Wergedal JE, Mahoney NA. Quantitative histologic studies on the pathogenesis of uremic bone disease. J Clin Endocrinol Metab 1974; 39: 119-35. 3. Mora Palma FJ, Ellis H, Cook DB, Dewar JH, Ward MK, Wilkinson R, et al. Osteomalacia in patients with chronic renal failure before dialysis or transplantation. Q J Med 1983; 52: 332-48. 4. Eastwood JB, Stamp TC, De Wardener HE, Bordier PJ, Arnaud CD. The effect of 25-hydroxy vitamin D3 in the osteomalacia of chronic renal failure. Clin Sci Mol Med 1977; 52: 499-508. 5. Coen G, Mazzaferro S, Ballanti P, et al. Renal bone disease in 76 patients with varying degrees of predialysis chronic renal failure. Nephrol Dial Transplant 1996; 11: 813-9. 6. Ward MK, Feest TG, Ellis HA, Parkinson IS, Kerr DN. Osteomalacic dialysis osteodystrophy: Evidence for a water-borne aetiological agent, probably aluminium. Lancet 1978; 1: 841-5. 7. Hodsman AB, Sherrard DJ, Alfrey AC, et al. Bone aluminum and histomorphometric features of renal osteodystrophy. J Clin Endocrinol Metab 1982; 54: 539-46. 8. Sherrard D, Oh S, Maloney N, Andress O, Coburn J. Renal osteodystrophy: Classification, cause and treatment. In: Frame BPJ, Jr, ed. Clinical disorders of bone and mineral metabolism Amsterdam: Excerpta Medica 1983; 254-9. 9. Parfitt AM. Renal bone disease: A new conceptual framework for the interpretation of bone histomorphometry. Curr Opin Nephrol Hypertens 2003; 12: 387-403. 10. Kerr DNS, Ward MK, Aize RES, et al. Aluminum-induced dialysis osteodystrophy: The demise of Newcastle bone disease? Kidney Int 1986; 29 (suppl 18): S58-64. 11. Baker LRI. Prevention of renal osteodystrophy. Miner Electrolyte Metab 1991; 17: 240-9. 12. Ballanti P, Wedard BM, Bonucci E. Frequency of adynamic bone disease and aluminum storage in Italian uraemic patients a retrospective analysis of 1429 iliac crest biopsies. Nephrol Dial Transplant 1996; 11: 663-7. 13. Monier-Faugere MC, Malluche HH. Trends in renal osteodystrophy: A survey from 1983-to 1995 in a titql of 2248 patients. Nephrol Dial Transplant 1996; 11 (suppl 3): S111-20. 14. Malluche HH. Aluminium and bone disease in chronic renal failure. Nephrol Dial Transplant 2002; 17 (suppl 2): S21-4. 15. Couttenye MM, D Haese P, Verschoren WM, et al. Low bone turnover in patients with renal failure. Kidney Int 1999; 56 (suppl): S70-6. 16. Mucsi I, Hercz G. Relative hypoparathyroidism and adynamic bone disease. Am J Kidney Dis 1999; 317: 405-9. 17. Sherrard DJ, Hercz G, Pei Y, et al. The spectrum of bone disease in end-stage renal failure: An evolving disorder. Kidney Int 1998; 43: 436-42. 18. Torres A, Lorenzo V, Hernandez D, et al. Bone disease in predialysis, hemodialysis and CAPD patients: Evidence for a better response to PTH. Kidney Int 1995; 47: 1434-42. 19. Hernandez D, Conception M, Torres A, et al. Adynamic bone disease with negative aluminum staining in predialysis patients: Prevalence and evolution after maintenance dialysis. Nephrol Dial Transplant 1994; 9: 517-23. 20. Coen G, Ballanti P, Bonucci E, Calabria S, Costantini S, Ferrannini M, Giustini M, Giordano R, Nicolai G, Manni M, Sardella D, Tagi F. Renal osteodystrophy in predialysis and hemodialysis patients: Comparison of histologic patterns and diagnostic predictivity of intact PTH. Nephron 2002; 91: 103-11. 21. Hamdy NA, Kanis J, Beneton M, et al. Effect of alfacalcidol on natural course of bone disease in mild to moderate renal failure. Br Med J 1995; 310: 358-63. 22. Hutchison A, Freemont A, Lumb G, Gokal R. Renal osteodystrophy in CAPD. Adv Perit Dial 1991; 7: 237-9. 23. Mathias RS, Salusky IB, Harmon WH, Paredes A, Emans J, Segre GV, Goodman WG. Renal bone disease in pediatric patients and young adults treated by hemodialysis in a children s hospital. J Am Soc Nephrol 1993; 12: 1938-46. 24. Morinière P, Cohen Solal M, Belbrick S, et al. Disappearance of aluminic bone disease in a long term asymptomatic dialysis population restricting Al(OH)3 intake: Emergence of an idiopathic adynamic bone disease not related to aluminium. Nephron 1989; 53: 93-101. 25. Salusky I, Coburn J, Brill J, Slatopolsky E, Fine R, Goodman W. Bone disease in pediatric patients undergoing dialysis with CAPD or CCPD. Kidney Int 1988; 33: 975-82. 26. Akizawa T, Kinugasa E, Kurihara S, et al. Parathyroid hormone deficiency is an indicator of poor nutritional state and prognosis in dialysis patients. J Am Soc Nephrol 199; 10: 616A. 27. Fukagawa M, Akizawa T, Kurokawa K. Is aplastic osteodystrophy a disease of malnutrition? Curr Opin Nephrol Hypertens 2000; 9: 363-7. 28. Pei Y, Hercz G, Greenwood C, et al. Risk factors for renal osteodystrophy: A multivariant analysis. J Bone Miner Res 1995; 10: 149-56. 29. Krakauer JC, McKenna MJ, Buderer NF, et al. Bone loss and bone turnover in diabetes mellitus. Diabetes 1995; 44: 775-82. 30. Massry SG, Coburn JW, Lee DB, et al. Skeletal resistance to parathyroid hormone in renal failure. Studies in 105 human subjects. Ann Intern Med 1973; 78: 357-64. 31. Fugakawa M, Iwasaki Y, Kazama JJ. Skeletal resistance to parathyroid hormone as a background abnormality in uremia. Nephrology 2003; 8: S50-2. 32. Goodman WG, Ramirez JA, Belin TR, Chon Y, Gales B, Segre GV, Salusky IB. Development of adynamic bone in patients with secondary hyperparathyroidism after intermittent calcitriol therapy. Kidney Int 1994; 46: 1160-6. 33. Urena P, Ferreira A, Morieux C, et al. PTH/PTHrP receptor mrna is downregulated in epiphyseal cartilage growth plate of uremic rats. Nephrol Dial Transplant 1996; 11: 2008-16. 34. Andress DL, Howard GP, Birnbaum RS. Identification of a low molecular weight inhibitor of osteoblast mitogenesis in uremic plasma. Kidney Int 1991; 39: 942-5. 35. Disthabanchong S, Hassan H, McConckey CL, Martin KJ, Gonzales EA. Regulation of PTH1 receptor expression by uremic ultrafiltrate in UMR 106-01 osteoblastic cells. Kidney Int 2004; 65: 897-903. 36. Slatopolsky E, Finch J, Clay P, Martin D, Sicard G, Singer G, Gao P, Cantor TL, Dusso A. A novel mechansim for skeletal resistance in uremia. Kidney Int 2000; 58: 753-61. 37. Monier-Faugere MC, Geng Z, Mawad H, Friedlez RM, Gao P, Cantor TL, Malluche HH. Improved assessment of bone turnover by the PTH-(1-84)/large C-PTH fragments ratio in ESRD patients. Kidney Int 2001; 60: 1460-8. 38. Coen G, Bonucci E, Ballanti P, Balducci A, Calabria S, Nicolai G, Fischer MS, Lifrieri F, Manni M, Morosetti M, Moscaritolo E, Sardella D. PTH 1-84 and PTH 7-84 in the noninvasive 5

Adynamic bone disease diagnosis of renal bone disease. Am J Kidney Dis 2002; 40: 348-54. 39. Salusky IB, Goodman W, Kuizon BD, Lavigne JR, Zahranik RJ, Gales B, Wang HJ, Elashoff RM, Juppner H. Similar predictive value of bone turnover using first- and second-generation immunometric PTH assays in pediatric patients treated with peritoneal dialysis. Kidney Int 2003; 63: 1801-8. 40. Marangella M, Migliardi M, Dutto F, Mengozzi G, Berrutti S, Gallone G, Aimo G, Ramello A, Fonzo D. Intact wwhole bioactive parathormone: Problems arising from comparing different methods. G Ital Nefrol 2002; 19: 467-75. 41. Nguyen-Yamamoto L, Rousseau L, Brossard JH, Lepage R, D Amour P. Synthetic carboxyl-terminal fragments of parathyroid hormone (PTH) decrease ionized calcium concentration in rats by acting on a receptor different from the PTH/PTH related peptide receptor. Endocrinology 2001; 142: 1386-92. 42. Divieti P, Inomata N, Chapin K, Singh R, Juppner H, Bringhurst FR. Receptors for the carboxyl-terminal region of PTH 1-84 are highly expressed in osteocytic cells. Endocrinology 2001; 142: 916-25. 43. Divieti P, John MR, Juppner H, Bringhurst FR. Human PTH- (7-84) inhibits bone resoprtion in vitro via actions independent of the type 1 PTH/PTHrP receptor. Endocrinology 2002; 143: 171-6. 44. Hoyland J, Picton M. Cellular mechanisms of renal osteodystrophy. Kidney Int 1999; 56 (suppl 73): S8-13. 45. Coen G, Mazzaferro S, Ballanti P, Bonucci E, Sardella D. Plasma insulin like growth factor and bone formation parameters in predialysis chronic renal failure. Miner Electrolyte Metab 1991; 17: 153-9. 46. Weinreich T, Zapf J, Schmidt-Gayk H, Ritzel H, Delling G, Reichel H. Insulin growth factors 1 and 2 serum concentrations in dialysis patients with secondary hyperparathyroidism and adynamic bone disease. Clin Nephrol 1999; 51: 27-33. 47. Jehle P, Ostertag A, Schulten K, et al. Insulin like growth factor system component in hyperparathyroidism and renal osteodystrophy. Kidney Int 2000; 57: 423-36. 48. Li T, Surendran K, Zawaide MA, Mathew S, Hruska KA. Bone morphogenetic protein 7, a novel treatment for chronic renal and bone disease. Curr Opin Nephrol Hypertens 2004; 13: 417-22. 49. Kazama JJ, Shigematsu T, Tsuda E, et al. Increased circulating levels of osteoclastogenesis inhibitory factor osteoprotegerin in patients with chronic renal failure: Possible roles in skeletal resistance to PTH in uremia. Am J Kidney Dis 2002; 39: 525-32. 50. Coen G, Ballanti P, Balducci A, Calabria S, Fischer MS, Jankovic L, Manni M, Morosetti M, Moscaritolo E, Sardella D, Bonucci E. Serum osteoprotegerin and renal osteodystrophy. Nephrol Dial Transplant 2002; 17: 233-8. 51. Coen G, Ballanti P, Fischer MS, et al. Serum leptin in dialysis renal osteodystrophy. Am J Kidney Dis 2003; 42: 1036-42. 52. Piraino B, Chen T, Cooperstein L, et al. Fractures and vertebral bone mineral density in patients with renal osteodystrophy. Clin Nephrol 1988; 30: 57-62. 53. Atsumi K, Kushida K, Yamazaki K, et al. Risk factors for vertebral fractures in renal osteodystrophy. Am J Kidney Dis 199; 33: 287-93. 54. Coco M, Rish H. Increased incidence of hip fracture in dialysis patients with low serum parathyroid hormone. Am J Kidney Dis 1999; 33: 1115-21. 55. Ubara Y, Fushimi T, Tagami T, Sawa N, Hoshino J, Yokota M, Katori H, Takemoto F, Hara S. Histomorphometric features of bone in patients with primary and secondary hypoparathyroidism. Kidney Int 2003; 63: 1809-16. 56. Nikura K, Akizawa T, Satoh Y, et al. Relative hypoparathyroidism in hemodialysis patients. Miner Electrolyte Metab 1995; 21: 101-3. 57. Cannata Andia JB. Hypokinetic azotemic osteodystrophy. Kidney Int 1998; 54: 1000-16. 58. Kurz P, Monier-Faugere MC, Bognar B, et al. Evidence for abnormal calcium homeostasis in patients with adynamic bone disease. Kidney Int 1994; 46: 855-61. 59. London GM, Marty C, Marchais SJ, Guerin AP, Metivier F, De- Vernejoul MC. Arterial calcifications and bone histomorphometry in end-stage renal disease. J Am Soc Nephrol 2004-12-17; 15: 1943-51. 60. Salusky IB, Goodman WG. Adynamic renal osteodystrophy: Is there a problem? J Am Soc Nephrol 2001; 12: 198-5. 61. Mazzaferro S, Perruzza I, Costantini S, Pasquali M, Onorato L, Sardella D, Giordano R, Ciaralli L, Ballanti P, Bonucci E, Cinotti GA, Coen G. Relative roles of intestinal absorption and dialysis-fluid-related exposure in the accumulation of aluminium in haemodialysis patients. Nephrol Dial Transplant 1997; 12: 2679-82. 62. Ecknoyan G, Levin A, Levin NW. K/DOQI Clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis 2003; 42 (suppl 3): S1-80. Received: Revised: Accepted: Società Italiana di Nefrologia 6