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• W2068698599 abstract "Osteodystrophy in the millennium. Despite three decades of intensive research on the derangements of calcium phosphate metabolism of renal failure, several unresolved issues are still with us at the turn of the millennium: poor control of hyperphosphatemia, relative inefficacy of active vitamin D to prevent progressive parathyroid hyperplasia, and persistence of bone disease despite lowering of parathyroid hormone (PTH) and administration of active vitamin D. Although predictions are problematic, it is not unreasonable to hope that, barring unforeseen side effects, calcimimetics will prove to be valuable for suppressing or even preventing hyperparathyroidism, thus potentially replacing, at least in part, active vitamin D. There is also reason to hope that more effective phosphate binders with fewer side effects will become available and that controlled studies will provide a rationale for the administration of estrogens to dialyzed women. As regards understanding the pathological mechanisms, one can anticipate that the disturbances leading to autonomous growth of parathyroid cells will be elucidated and the signals involved in osteoclast/osteoblast differentiation pathways and osteoclast/osteoblast coupling will be clarified, with obvious impact on patient management. Osteodystrophy in the millennium. Despite three decades of intensive research on the derangements of calcium phosphate metabolism of renal failure, several unresolved issues are still with us at the turn of the millennium: poor control of hyperphosphatemia, relative inefficacy of active vitamin D to prevent progressive parathyroid hyperplasia, and persistence of bone disease despite lowering of parathyroid hormone (PTH) and administration of active vitamin D. Although predictions are problematic, it is not unreasonable to hope that, barring unforeseen side effects, calcimimetics will prove to be valuable for suppressing or even preventing hyperparathyroidism, thus potentially replacing, at least in part, active vitamin D. There is also reason to hope that more effective phosphate binders with fewer side effects will become available and that controlled studies will provide a rationale for the administration of estrogens to dialyzed women. As regards understanding the pathological mechanisms, one can anticipate that the disturbances leading to autonomous growth of parathyroid cells will be elucidated and the signals involved in osteoclast/osteoblast differentiation pathways and osteoclast/osteoblast coupling will be clarified, with obvious impact on patient management. The literature is replete with warnings against making predictions about the future. Unable to resist the insistence of the organizers, we had to give in and commit ourselves to make predictions, but we find consolation in the consideration that either we are right (in which case future generations will praise us for our clairvoyance) or we are wrong (in which case our predictions will be painlessly and thoroughly forgotten anyway). This is an interesting time to take one step back and to consider where we might go from here. A number of remarkable developments have recently occurred, both in regard to strategies of patient management and in regard to basic understanding of molecular mechanisms. It is useful first to take stock of what problems persist in 1999 and then speculate about potential future directions. The main problem, perhaps the major problem in the management of divalent ion metabolism, continues to be insufficient control of hyperphosphatemia. As one case in point, even in Japan, where the average weight of the patients is 52 kg and the average duration of hemodialysis 3 × 4.2 ± 0.5 hr1.Shinzato T. Nakai S. Akiba T. Yamazaki C. Sasaki R. Kitaoka T. Kubo K. Shinoda T. Kurokawa K. Marumo F. Sato T. Maeda K. Current status of renal replacement therapy in Japan: Results of the annual survey of the Japanese Society for Dialysis Therapy.Nephrol Dial Transplant. 1997; 12: 889-898Crossref PubMed Scopus (29) Google Scholar, predialytic serum phosphate is 1.86 ± 0.54 mM. The average predialytic serum phosphate concentration in 227 patients treated in our center is 1.78 ± 0.52 mM, despite an average use of calcium carbonate of 1.4 ± 1.8 g/day and (with 37% of the patients taking, in addition, low doses of aluminum-containing phosphate binders). Why is it so difficult to normalize serum phosphate? The main issue is the complex kinetics of elimination of phosphate. Phosphate is trapped in deep compartments, and the transfer rate constant for phosphate efflux from the intracellular to the extracellular compartment is low relative to the rate of removal of phosphate during high efficiency dialysis sessions. Most of the phosphate is removed in the first hour of dialysis and despite unchanged dialysance for phosphate, only a relatively small amount of phosphate is subsequently eliminated because serum phosphate concentrations are low. But we also believe that in many instances hyperphosphatemia is simply a surrogate marker for under-dialysis. Against this background, it is of interest that long slow dialysis sessions provide more effective removal of phosphate to the point that one may even have to add phosphate to the dialysate fluid2.Mucsi I. Hercz G. Uldall R. Ouwendyk M. Francoeur R. Pierratos A. Control of serum phosphate without any phosphate binders in patients treated with nocturnal hemodialysis.Kidney Int. 1998; 53: 1399-1404Abstract Full Text Full Text PDF PubMed Scopus (330) Google Scholar. Apart from the well-known effects of phosphate in the genesis of hyperparathyroidism3.Silver J. Moallem E. Kilav R. Sela A. Naveh-Many T. Regulation of the parathyroid hormone gene by calcium, phosphate and 1,25-dihydroxyvitamin D.Nephrol Dial Transplant. 1998; 13: 40-44Crossref PubMed Scopus (16) Google Scholar, a high serum phosphate concentration is also a predictor of poor survival on dialysis4.Block G.A. Hulbert-Shearon T.E. Levin N.W. Port F.K. Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study.Am J Kidney Dis. 1998; 31: 607-617Abstract Full Text Full Text PDF PubMed Scopus (2013) Google Scholar (abstract; J Am Soc Nephrol 9:217A, 1998). This may in part be due to calcification of coronary plaques5.Amann K. Gross M.L. London G.M. Ritz E. Hyperphosphatemia—A silent killer of patients with renal failure?.Nephrol Dial Transplant. 1999; 14: 2085-2087Crossref PubMed Scopus (89) Google Scholar, but in recent experimental studies hyperphosphatemia was also associated with cardiac microcirculatory abnormalities6.Tornig J. Kugel B. El-Shakmak A. Gross M.L. Schwarz U. Simonaviciene A. Szabo A. Ritz E. Amann K. Effects of high- and low-phosphate diet on cardiovascular changes in subtotally nephrectomized rats.Kidney Blood Press Res. 1998; 21: 104Google Scholar. The problem of phosphate control is compounded by the fact that none of the existing phosphate binders is truly satisfactory. Aluminum-containing phosphate binders are relatively contraindicated because of aluminum toxicity. Calcium-containing phosphate binders predispose to hypercalcemia7.Ritz E. Passlick-Deetjen J. Lippert J. What is the appropriate dialysate calcium concentration for the dialysis patient?.Nephrol Dial Transplant. 1996; 11: 91-95Crossref PubMed Scopus (24) Google Scholar. This has prompted the development of novel phosphate binding compounds such as polyallylamine hydrochloride (Sevelamer®)—which is effective, but with which it is difficult to consistently achieve normophosphatemia8.Bleyer A.J. Burke S.K. Dillon M. Garrett B. Kant K.S. Lynch D. Rahman S.N. Schoenfeld P. Teitelbaum I. Zeig S. Slatopolsky E. A comparison of the calcium-free phosphate binder sevelamer hydrochloride with calcium acetate in the treatment of hyperphosphatemia in hemodialysis patients.Am J Kidney Dis. 1999; 33: 694-701Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar—lanthanum carbonate, for which no published information is available, and phosphate binders on the basis of trivalent iron9.Hergesell O. Ritz E. Stabilized polynuclear iron hydroxide is an efficient oral phosphate binder in uraemic patients.Nephrol Dial Transplant. 1999; 14: 863-867Crossref PubMed Scopus (68) Google Scholar,10.Hsu C.H. Patel S.R. Young E.W. New phosphate binding agents: ferric compounds.J Am Soc Nephrol. 1999; 10: 1274-1280PubMed Google Scholar, which appear promising and are relatively cheap. Because of the importance of phosphate in triggering hyperparathyroidism3.Silver J. Moallem E. Kilav R. Sela A. Naveh-Many T. Regulation of the parathyroid hormone gene by calcium, phosphate and 1,25-dihydroxyvitamin D.Nephrol Dial Transplant. 1998; 13: 40-44Crossref PubMed Scopus (16) Google Scholar, 11.Almaden Y. Hernandez A. Torregrosa V. Canalejo A. Sabate L. Fernandez Cruz L. Campistol J.M. Torres A. Rodriguez M. High phosphate level directly stimulates parathyroid hormone secretion and synthesis by human parathyroid tissue in vitro.J Am Soc Nephrol. 1998; 9: 1845-1852PubMed Google Scholar, 12.Miyamoto K. Tatsumi S. Morita K. Takeda E. Does the parathyroid ‘see' phosphate?.Nephrol Dial Transplant. 1998; 13: 2727-2729Crossref PubMed Scopus (19) Google Scholar and predisposing to cardiovascular events4.Block G.A. Hulbert-Shearon T.E. Levin N.W. Port F.K. Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study.Am J Kidney Dis. 1998; 31: 607-617Abstract Full Text Full Text PDF PubMed Scopus (2013) Google Scholar,6.Tornig J. Kugel B. El-Shakmak A. Gross M.L. Schwarz U. Simonaviciene A. Szabo A. Ritz E. Amann K. Effects of high- and low-phosphate diet on cardiovascular changes in subtotally nephrectomized rats.Kidney Blood Press Res. 1998; 21: 104Google Scholar, efforts to modify dialysis strategies2.Mucsi I. Hercz G. Uldall R. Ouwendyk M. Francoeur R. Pierratos A. Control of serum phosphate without any phosphate binders in patients treated with nocturnal hemodialysis.Kidney Int. 1998; 53: 1399-1404Abstract Full Text Full Text PDF PubMed Scopus (330) Google Scholar and to develop new phosphate binders are of prime importance. There is no doubt that active vitamin D preparations acutely suppress parathyroid hormone (PTH) secretion. Nevertheless, although controlled evidence is not available, it appears that they cannot completely prevent development and progression of parathyroid hyperplasia. In several studies, the duration of dialysis treatment was a potent predictor of parathyroidectomy13.Mizumoto D. Watanabe Y. Fukuzawa Y. Yuzawa Y. Yamazaki C. Identification of risk factors on secondary hyperparathyroidism undergoing long-term haemodialysis with vitamin D3.Nephrol Dial Transplant. 1994; 9: 1751-1758PubMed Google Scholar. According to the EDTA registry14.Fassbinder W. Brunner F.P. Brynger H. Ehrich J.H. Geerlings W. Raine A.E. Rizzoni G. Selwood N.H. Tufveson G. Wing A.J. Combined report on regular dialysis and transplantation in Europe, XX, 1989.Nephrol Dial Transplant. 1991; 6: 5-35Google Scholar, up to 10–15% of chronic dialysis patients ultimately require parathyroidectomy. In our center, 16 of 95 patients dialyzed for more than 10 years required parathyroidectomy. Why is control of parathyroid growth unsatisfactory? There may be several causes. One important point is of course persisting hyperphosphatemia in view of the potent stimulatory effect of phosphate on parathyroid cell proliferation3.Silver J. Moallem E. Kilav R. Sela A. Naveh-Many T. Regulation of the parathyroid hormone gene by calcium, phosphate and 1,25-dihydroxyvitamin D.Nephrol Dial Transplant. 1998; 13: 40-44Crossref PubMed Scopus (16) Google Scholar, 11.Almaden Y. Hernandez A. Torregrosa V. Canalejo A. Sabate L. Fernandez Cruz L. Campistol J.M. Torres A. Rodriguez M. High phosphate level directly stimulates parathyroid hormone secretion and synthesis by human parathyroid tissue in vitro.J Am Soc Nephrol. 1998; 9: 1845-1852PubMed Google Scholar, 12.Miyamoto K. Tatsumi S. Morita K. Takeda E. Does the parathyroid ‘see' phosphate?.Nephrol Dial Transplant. 1998; 13: 2727-2729Crossref PubMed Scopus (19) Google Scholar. Another important point is the fact that parathyroid hyperplasia, at least advanced (nodular) hyperplasia, is largely irreversible. It is true that in animal experiments, hyperplastic glands of uremic rats can regress15.Lewin E. Wang W. Olgaard K. Reversibility of experimental secondary hyperparathyroidism.Kidney Int. 1997; 52: 1232-1241Abstract Full Text PDF PubMed Scopus (45) Google Scholar, but this may not be an adequate model for what is seen in chronically uremic patients, i.e., nodular parathyroid hyperplasia with monoclonal growth16.Arnold A. Brown M.F. Urena P. Gaz R.D. Sarfati E. Drueke T.B. Monoclonality of parathyroid tumors in chronic renal failure and in primary parathyroid hyperplasia.J Clin Invest. 1995; 95: 2047-2053Crossref PubMed Scopus (361) Google Scholar, loss of heterozygosity with loss of putative tumor suppressor genes17.Chudek J. Ritz E. Kovacs G. Genetic abnormalities in parathyroid nodules of uremic patients.Clin Cancer Res. 1998; 4: 211-214PubMed Google Scholar and reduced expression of the vitamin D receptor18.Fukuda N. Tanaka H. Tominaga Y. Fukagawa M. Kurokawa K. Seino Y. Decreased 1,25-dihydroxyvitamin D3 receptor density is associated with a more severe form of parathyroid hyperplasia in chronic uremic patients.J Clin Invest. 1993; 92: 1436-1443Crossref PubMed Scopus (535) Google Scholar and calcium receptor19.Gogusev J. Duchambon P. Hory B. Giovannini M. Goureau Y. Sarfati E. Drueke T.B. Depressed expression of calcium receptor in parathyroid gland tissue of patients with hyperparathyroidism.Kidney Int. 1997; 51: 328-336Abstract Full Text PDF PubMed Scopus (418) Google Scholar, respectively. It appears plausible20.Szabo A. Merke J. Beier E. Mall G. Ritz E. 1,25 (OH) 2 vitamin D3 inhibits parathyroid cell proliferation in experimental uremia.Kidney Int. 1989; 35: 1049-1056Abstract Full Text PDF PubMed Scopus (234) Google Scholar, but is currently unproven, that prophylaxis, i.e., normalization of phosphatemia21.Fournier A. Oprisiu R. Hottelart C. Yverneau P.H. Ghazali A. Atik A. Hedri H. Said S. Sechet A. Rasolombololona M. Abighanem O. Sarraj A. El Esper N. Moriniere P. Boudailliez B. Westeel P.F. Achard J.M. Pruna A. Renal osteodystrophy in dialysis patients: diagnosis and treatment.Artif Organs. 1998; 22: 530-557Crossref PubMed Scopus (36) Google Scholar and administration of low doses of active vitamin D22.Ritz E. Kuster S. Schmidt-Gayk H. Stein G. Scholz C. Kraatz G. Heidland A. Low-dose calcitriol prevents the rise in 1,84-iPTH without affecting serum calcium and phosphate in patients with moderate renal failure (prospective placebo-controlled multicentre trial).Nephrol Dial Transplant. 1995; 10: 2228-2234PubMed Google Scholar, may interfere with the development of parathyroid hyperplasia. One must also consider the alternative possibility: that signals other than hyperphosphatemia and diminished active vitamin D are involved in the genesis of parathyroid hyperplasia. In this context, recent observations on the prevention of parathyroid hyperplasia by calcimimetic agents23.Wada M. Furuya Y. Sakiyama J. Kobayashi N. Miyata S. Ishii H. Nagano N. The calcimimetic compound NPS R-568 suppresses parathyroid cell proliferation in rats with renal insufficiency. Control of parathyroid cell growth via a calcium receptor.J Clin Invest. 1997; 100: 2977-2983Crossref PubMed Scopus (234) Google Scholar are of considerable interest. At present, the potential role of these agents in the prevention and control of parathyroid hyperplasia cannot be properly assessed. In the distant past it had been hoped that once PTH concentrations were kept within the normal range and once active vitamin D was administered, the structure and the dynamics of bone would be normalized. A number of investigators24.Quarles L.D. Lobaugh B. Murphy G. Prospective trial of pulse oral versus intravenous calcitriol treatment of hyperparathyroidism in ESRD.Kidney Int. 1994; 45: 1710-1721Abstract Full Text PDF PubMed Scopus (250) Google Scholar,25.Solal M.E. Sebert J.L. Boudailliez B. Marie A. Moriniere P. Gueris J. Bouillon R. Fournier A. Comparison of intact, midregion, and carboxy terminal assays of parathyroid hormone for the diagnosis of bone disease in hemodialyzed patients.J Clin Endocrinol Metab. 1991; 73: 516-524Crossref PubMed Scopus (147) Google Scholar noted that on average bone turnover in dialyzed uremic patients was normal only when the measured immune reaction 1,84 iPTH concentrations were 2- to 3-fold above the normal range. The explanation for this observation is not unambiguous. The assay apparently measures bio-inactive fragments26.Lepage R. Roy L. Brossard J.H. Rousseau L. Dorais C. Lazure C. D'amour P. A non-(1-84) circulating parathyroid hormone (PTH) fragment interferes significantly with intact PTH commercial assay measurements in uremic samples.Clin Chem. 1998; 44: 805-809Crossref PubMed Scopus (305) Google Scholar, so that in these studies measured 1,84 iPTH concentrations may have been spuriously elevated. On the other hand, in many organs including bone tissue, expression of PTH/PTH-related polypeptide receptor is diminished in renal failure27.Urena P. Ferreira A. Morieux C. Drueke T. de Vernejoul M.C. PTH/PTHrP receptor mRNA is down-regulated in epiphyseal cartilage growth plate of uraemic rats.Nephrol Dial Transplant. 1996; 11: 2008-2016Crossref PubMed Scopus (83) Google Scholar,28.Urena P. Kubrusly M. Mannstadt M. Hruby M. Trinh M.M. Silve C. Lacour B. Abou-Samra A.B. Segre G.V. Drueke T. The renal PTH/PTHrP receptor is down-regulated in rats with chronic renal failure.Kidney Int. 1994; 45: 605-611Abstract Full Text PDF PubMed Scopus (148) Google Scholar, so that it is conceivable that there is an element of hyporesponsiveness to PTH at the receptor level and abnormalities on the postreceptor level are also certainly not excluded. Finally, in many hormonal systems it is not only the concentration of the hormone, but also the temporal pattern of hormone concentrations, that determines end-organ response. Pulsatile secretion of luteinizing hormone (LH)–releasing hormone (RH) provokes LH secretion by the hypophysis, while continuous administration of LH-RH blocks LH release and is used for medical ablation of the hormone. In this context it is of interest that the pattern of pulsatile PTH secretion is strikingly abnormal in uremic patients29.Schmitt C.P. Huber D. Mehls O. Maiwald J. Stein G. Veldhuis J.D. Ritz E. Schaefer F. Altered instantaneous and calcium-modulated oscillatory PTH secretion patterns in patients with secondary hyperparathyroidism.J Am Soc Nephrol. 1998; 9: 1832-1844PubMed Google Scholar. Preliminary studies in conjunction with the Department of Pediatrics, Heidelberg, show that the bone cell response to PTH depends on the temporal pattern of exposure to PTH (unpublished data). It is uncertain whether abnormalities in the calcium regulatory hormones fully explain adynamic bone disease in patients with low PTH. One has certainly also to consider alternative possibilities. Recently we compared subtotally nephrectomized, parathyroidectomized rats that received either solvent or nonhypercalcemic doses of aminoterminal rat PTH and 1,25(OH)2D330.Szabo A. Freesmeyer M.G. Abendroth K. Stein G. Rosivall L. El-Shakmak A. Ritz E. Physiological doses of calcium regulatory hormones do not normalize bone cells in uraemic rats.Eur J Clin Invest. 1999; 29: 529-535Crossref PubMed Scopus (8) Google Scholar. Bone histology was not restored to normal by administration of the calcium-regulatory hormones. Such unresponsiveness might be explained by the artefactual non-pulsatile mode of administration or by an element of resistance to PTH or 1,25(OH)2D3, as discussed above, but recent insights into the regulation of osteoclast and osteoblast developmental pathways suggest interesting alternative possibilities31.Hruska K.A. Teitelbaum S.L. Renal osteodystrophy.N Engl J Med. 1995; 333: 166-174Crossref PubMed Scopus (164) Google Scholar,32.Hruska K. New concepts in renal osteodystrophy.Nephrol Dial Transplant. 1998; 13: 2755-2760Crossref PubMed Scopus (60) Google Scholar. In osteoclast and osteoblast differentiation, the calcium regulatory hormones influence only late steps, while colony-stimulating factors (mCSF, gmCSF) or interleukins (IL-6, IL-11) affect early steps. In addition, a circulating molecule of the tumor necrosis factor (TNF) receptor family, osteoprotegerin, is produced in the kidney. It inhibits late stages of osteoclast development, so that one would expect increased osteoclastogenesis if this factor is not present. This was not observed in our study30.Szabo A. Freesmeyer M.G. Abendroth K. Stein G. Rosivall L. El-Shakmak A. Ritz E. Physiological doses of calcium regulatory hormones do not normalize bone cells in uraemic rats.Eur J Clin Invest. 1999; 29: 529-535Crossref PubMed Scopus (8) Google Scholar. But circulating substances may also interfere with osteoblast function. As a case in point, Andress33.Andress D.L. Howard G.A. Birnbaum R.S. Identification of a low molecular weight inhibitor of osteoblast mitogenesis in uremic plasma.Kidney Int. 1991; 39: 942-945Abstract Full Text PDF PubMed Scopus (33) Google Scholar documented the presence of a low molecular weight inhibitor of osteoblast mitogenesis in the plasma of uremic patients. There are further possibilities to consider. In principle, in the genesis of the low bone turnover (adynamic bone disease), either agonists of bone formation could be suppressed or promotors of bone formation be deficient. Known suppressors include IL-1134.Hughes F.J. Howells G.L. Interleukin-11 inhibits bone formation in vitro.Calcif Tissue Int. 1993; 53: 362-364Crossref PubMed Scopus (57) Google Scholar and IL-435.Watanabe K. Tanaka Y. Morimoto I. Yahata K. Zeki K. Fujihira T. Yamashita U. Eto S. Interleukin-4 as a potent inhibitor of bone resorption.Biochem Biophys Res Commun. 1990; 172: 1035-1041Crossref PubMed Scopus (92) Google Scholar, particularly osteogenic protein-1 or bone morphogenetic protein 7, which is produced by normal renal tubular cells (abstract; J Am Soc Nephrol 4:700, 1993) and is presumably reduced or absent in renal failure. Because of the considerable therapeutic potential for the treatment of osteoporosis, many pharmaceutical companies have launched considerable efforts to define these factors. Osteoprotegerin and osteoprotegerin ligand (formerly called TRACE) have been isolated and sequenced. Furthermore, factors essential for osteoblast differentiation, e.g., core-binding factor alpha 1 (CBFA-1) (heterozygous loss of which causes cleidocranial dysplasia in humans) have also been identified36.Bonn D. Crumbling bones yield to molecular biology.Lancet. 1999; 353: 1586Abstract Full Text Full Text PDF Scopus (155) Google Scholar. The physiology of these factors in renal failure requires further study, but this whole field potentially opens exciting new perspectives for understanding adynamic bone disease. Even though we have managed to lower PTH and administer active vitamin D, new disturbances are now observed that cannot be fully explained by abnormalities of calcium regulatory hormones. Estrogens affect the parathyroid gland as well as bone37.Silver J. Epstein E. Naveh-Many T. Oestrogen deficiency—does it have a role in the genesis of skeletal problems in dialysed women?.Nephrol Dial Transplant. 1996; 11: 565-656Crossref PubMed Scopus (10) Google Scholar. Because of the obvious importance in the genesis of postmenopausal osteoporosis, this field has been intensely investigated, but so far this has had disappointingly little impact on the management of female patients on dialysis. Estrogens have remained a Cinderella in the therapeutic repertoire of nephrologists. Only approximately 5% of amenorrheic patients had received estrogens in the modification of diet in renal disease trial. Apart from few preliminary studies38.Matuszkiewicz-Rowinska J. Skorzewska K. Radowicki S. Sokalski A. Przedlacki J. Niemczyk S. Wlodarczyk D. Puka J. Switalski M. The benefits of hormone replacement therapy in pre-menopausal women with oestrogen deficiency on haemodialysis.Nephrol Dial Transplant. 1999; 14: 1238-1243Crossref PubMed Scopus (60) Google Scholar that point to preservation or increase of bone mineral content after administration of low dose estrogens to dialyzed amenorrheic women, no information is available. Recently, estrogen analogs—e.g., raloxifen39.Delmas P.D. Bjarnason N.H. Mitlak B.H. Ravoux A.C. Shah A.S. Huster W.J. Draper M. Christiansen C. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women.N Engl J Med. 1997; 337: 1641-1647Crossref PubMed Scopus (1553) Google Scholar—have become available that selectively affect bone without causing endometrial hyperplasia and endometrial cancer. There is an urgent need to clarify the role of estrogens in the genesis, and their potential in the treatment, of bony abnormalities in uremia. Genes, or more precisely genetic polymorphisms, appear to determine both bone mass and susceptibility of the parathyroid to stimulation. Some of the genes that have been implied are the vitamin D receptor, calcium sensing receptor, isocollagens, etc. Currently this field is still murky and the results reported are conflicting40.Bover J. Bosch R.J. Vitamin D receptor polymorphisms as a determinant of bone mass and PTH secretion: from facts to controversies.Nephrol Dial Transplant. 1999; 14: 1066-1068Crossref Scopus (10) Google Scholar. Nevertheless, this field holds great promise and might open new perspectives to better define patients at high risk of secondary hyperparathyroidism or bone loss. As far as patient management is concerned, we expect that calcimimetics will become a major tool in the management of the uremic patient, both for the prevention and for the treatment of secondary hyperparathyoidism. The available evidence41.Sherrard D.J. Calcimimetics in action.Kidney Int. 1998; 53: 510-511Abstract Full Text PDF PubMed Scopus (10) Google Scholar, 42.Nemeth E.F. Steffey M.E. Hammerland L.G. Hung B.C. Van Wagenen B.C. DelMar E.G. Blandrin M.F. Calcimimetics with potent and selective activity on the parathyroid calcium receptor.Proc Natl Acad Sci USA. 1998; 95: 4040-4045Crossref PubMed Scopus (534) Google Scholar, 43.Ott S.M. Calcimimetics—new drugs with the potential to control hyperparathyroidism.J Clin Endocrinol Metab. 1998; 83: 1080-1082Crossref PubMed Scopus (15) Google Scholar, 44.Antonsen J.E. Sherrard D.J. Andress D.L. A calcimimetic agent acutely suppresses parathyroid hormone levels in patients with chronic renal failure.Kidney Int. 1998; 53: 223-227Abstract Full Text PDF PubMed Scopus (131) Google Scholar is very encouraging and it is hoped that long-term safety studies do not reveal major extraparathyroidal side effects, a concern because of the nearly ubiquitous expression of the calcium sensor. In this respect, the absence of such effects in a patient treated for 2 years is quite encouraging45.Collins M.T. Skarulis M.C. Bilezikian J.P. Silverberg S.J. Spiegel A.M. Marx S.J. Treatment of hypercalcemia secondary to parathyroid carcinoma with a novel calcimimetic agent.J Clin Endocrinol Metab. 1998; 83: 1083-1088Crossref PubMed Scopus (153) Google Scholar. It is difficult to predict the relative roles that calcimimetics and active vitamin D will have in the future; these roles will have to be worked out in controlled trials. It is conceivable that active vitamin D may be necessary for maintaining active calcium transport in the intestine or for exerting specific effects on the numerous target tissues which express vitamin D receptors, for instance muscle, vasculature, immune cells, etc. Secondly, we expect that we shall see more effective phosphate binders with fewer side effects. Finally, we presume that clinical nephrologists will recognize that estrogens are potent agonists on bone and will use these compounds more liberally. Clinical common sense helps to predict what is plausible and what is not with respect to management of renal bone disease. When one comes to basic research, however, one is on more uncertain ground. Presumably, the fundamental challenge will be to clarify why control of parathyroid growth is disturbed, i.e., to explain the occurrence of monoclonal growth, loss of heterozygosity with hypothetical loss of tumor suppressor genes, and de-differentiation of parathyroid cells, so that vitamin D receptor and calcium sensor molecules are no longer expressed normally. Recent studies showed alterations of genomic DNA in blood cells of dialyzed patients. One could therefore speculate that it is in the parathyroid gland as well as in the remnant kidney (in other words tissues actively proliferating in uremia, but normally exhibiting low cell turnover) that such genomic lesions lead more readily to abnormal growth, i.e., monoclonal parathyroid nodules and renal cell carcinoma, respectively. It is still puzzling why one mostly sees autonomous, but not malignant growth, in the parathyroids of uremic patients. There are also glaring deficits in our understanding of the signals of the osteoclast/osteoblast differentiation pathways and similar defects in understanding how the balance between bone resorption and formation is maintained, i.e., the coupling between the two processes. Knowledge of these mechanisms is crucial for the understanding of adynamic bone disease and bone loss, respectively. Because of the enormous potential market that treatment of osteoporosis offers, these issues are currently hotly investigated by the pharmaceutical industry, as evidenced by the recent cloning of osteoprotegerin and the osteoprotegerin ligand in pharmaceutical laboratories. The above listing may to some extent reflect personal preferences and there is undoubtedly room for many other considerations. We are skeptical whether one area, namely vitamin D analogs, holds great potential. Although these compounds are conceptually quite attractive, one sorely misses clinical head-on comparisons of efficacy and safety with calcitriol or 1-alpha. While it is dangerous to make predictions, the above insights hopefully are closer to the truth than the famous statement of Kaiser Wilhelm, who predicted in 1914: “Herrlichen Zeiten gehen wir entgegen” (“I shall lead you to the days of glory”)." @default.
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• W2068698599 date "1999-12-01" @default.
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• W2068698599 title "Osteodystrophy in the millennium" @default.
• W2068698599 cites W1813539568 @default.
• W2068698599 cites W1922554536 @default.
• W2068698599 cites W1971931756 @default.
• W2068698599 cites W1989640819 @default.
• W2068698599 cites W1997008150 @default.
• W2068698599 cites W1997883187 @default.
• W2068698599 cites W2010631350 @default.
• W2068698599 cites W2018625144 @default.
• W2068698599 cites W2022428083 @default.
• W2068698599 cites W2025443327 @default.
• W2068698599 cites W2028077111 @default.
• W2068698599 cites W2030174339 @default.
• W2068698599 cites W2031455439 @default.
• W2068698599 cites W2033484737 @default.
• W2068698599 cites W2033957914 @default.
• W2068698599 cites W2037687164 @default.
• W2068698599 cites W2044523494 @default.
• W2068698599 cites W2046397527 @default.
• W2068698599 cites W2057944836 @default.
• W2068698599 cites W2073896196 @default.
• W2068698599 cites W2076523693 @default.
• W2068698599 cites W2077131998 @default.
• W2068698599 cites W2081227689 @default.
• W2068698599 cites W2086766564 @default.
• W2068698599 cites W2093412399 @default.
• W2068698599 cites W2094803889 @default.
• W2068698599 cites W2095233918 @default.
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