The term renal osteodystrophy encompasses all

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1 Proceedings of the ISPD 2001 The IXth Congress of the ISPD June 26 29, 2001, Montréal, Canada Peritoneal Dialysis International, Vol. 21 (2001), Supplement /01 $ Copyright 2001 International Society for Peritoneal Dialysis Printed in Canada. All rights reserved. CURRENT ISSUES IN THE MANAGEMENT OF SECONDARY HYPERPARATHYROIDISM AND BONE DISEASE Sharon M. Moe Indiana University School of Medicine, Indianapolis, Indiana, U.S.A. The term renal osteodystrophy encompasses all types of metabolic bone disease found in dialysis patients. Bone is a dynamic tissue, constantly being remodelled. Bone turnover is tightly regulated by numerous hormones and cytokines, of which parathyroid hormone (PTH) is the most important. OVERVIEW OF RENAL OSTEODYSTROPHY KEY WORDS: Renal osteodystrophy; adynamic bone disease; secondary hyperparathyroidism. Correspondence to: S.M. Moe, Wishard Memorial Hospital, Indiana University School of Medicine, 1001 W. 10th Street, OPW 526, Indianapolis, Indiana U.S.A. smoe@iupui.edu High-turnover bone disease can either be osteitis fibrosa cystica, owing to secondary hyperparathyroidism, or mixed uremic lesion, with features of high turnover plus mineralization abnormalities. Persistent and severe hyperparathyroidism owing to hyperphosphatemia, hypocalcemia, and low levels of calcitriol can lead to osteitis fibrosa cystica. Control of those factors is critical for prevention and treatment. Low-turnover bone disease can either be osteomalacia a disorder of bone mineralization related in most cases in dialysis patients to aluminum or adynamic (aplastic) bone disease. Adynamic bone disease is characterized by low serum intact PTH levels (generally less than 200 pg/ml) and low bone-specific alkaline phosphatase levels (1 3). The bone histology reveals decreased bone formation, principally owing to a paucity of osteoblasts and osteoclasts alike. Osteoid is also decreased. (In osteomalacia on the other hand, osteoid is increased.) Those findings contrast with the findings in osteoporosis, which is an overall decrease in bone mass. Osteoporosis is best diagnosed by a bone densitometry scan such as dualenergy X-ray absorptiometry (DEXA). That test reveals how much bone is present, but not how it is arranged. In contrast, renal osteodystrophy is a disorder of bone remodelling that is best diagnosed by bone biopsy. The biopsy reveals how the bone is arranged, but is not very accurate in determining how much bone is present (bone volume). The two conditions can coexist, and some experts believe that adynamic bone may simply be osteoporosis. The prevalences of the various forms of renal osteodystrophy have changed over the past decade. Whereas osteitis fibrosa cystica was previously the predominant lesion, the incidence of adynamic bone disease has recently increased (Table 1). Those changes may reflect the numerous changes that have occurred during that period in the dialysis population, the dialysis regimen, and the supportive care of patients (6). Adynamic bone disease is particularly prevalent in peritoneal dialysis patients. The causes of adynamic bone disease are unknown, but risk factors include age, oversuppression of PTH, diabetes, and possibly calcium overload (2,3,7 9). Couttenye et al (3) recently reported that the use of higher-calcium dialysate was associated with development of adynamic bone disease. The long-term sequelae of adynamic bone disease are unknown, but patients with the condition are at risk for fracture (10,11) and hypercalcemia. In end-stage renal disease (ESRD), where urinary excretion of calcium is absent, oral and dialytic cal- TABLE 1 Changing Pattern of Renal Osteodystrophy in Dialysis Patients Percentage of patients 1993 (1) 1972 (4) 1986 (5) HD CAPD Osteitis fibrosa cystica 22% 68% 38% 9% Mild osteitis fibrosa cystica 45% 0% 13% 21% Mixed uremic lesions 9% 0% 11% 4% Osteomalacia 24% 25% 2% 6% Adynamic bone disease 0% 7% 36% 61% HD = hemodialysis; CAPD = continuous ambulatory peritoneal dialysis. S241

2 PROCEEDINGS OF THE IXTH CONGRESS OF THE ISPD DECEMBER 2001 VOL. 21, SUPPL 3 PDI cium loads must be incorporated into bone. However, adynamic bone is unable to take up excess calcium (12). Because most dialysis patients are in positive calcium balance (7), adynamic bone disease puts them at risk of soft tissue calcification. The concern to prevent adynamic bone disease and the possible hypercalcemia that may result means that avoidance of oversuppression of PTH has become standard practice in the United States. Most U.S. centers do not treat patients with vitamin D analogs if intact PTH is less than pg/ml. Unfortunately, intact PTH levels are not very predictive of underlying bone histology (2,13) (Figure 1). Although the intact PTH assay replaced the less specific N-terminal or C-terminal assay, the assay in reality detects both the truly intact (1-84 amino-acid) PTH molecule and the 7-84 amino-acid fragments, which are antagonistic. Recently a new assay has been developed, called whole PTH, or PTH CAP (cyclase activating PTH: Scantibodies Laboratory, Santee, CA, U.S.A.). In patients with renal failure, the levels of the PTH CAP are less than those of the intact assay (14,15). Monier Faugere and colleagues demonstrated that the ratio of whole to intact assays was able to predict 100% of cases with normal-to-high bone turnover, and 87.5% of cases with low bone turnover (16). More research into the practical use of the new assay and ratio is needed. Therapy with calcitriol has been shown to effectively suppress PTH secretion and is commonly used to treat high-turnover bone disease (17). The PTH level at which intervention is recommended is a matter of debate, the problems being related to the assay as described earlier. Skeletal resistance to PTH also occurs in dialysis patients, such that intact PTH levels of approximately 3 4 times the upper limits of normal are required to maintain a normal osteoblast surface and bone formation rate (Figure 1) (2,13). Thus, clinicians usually prescribe calcitriol therapy when PTH exceeds that level. Unfortunately, the treatment of secondary hyperparathyroidism with calcitriol is limited by the hyperphosphatemia and hypercalcemia that can develop. New vitamin D analogs offer hope of less hyperphosphatemia and hypercalcemia (18,19), although comparative trials with calcitriol are lacking. Thus, hypercalcemia is a problem in both low turnover and high turnover bone disease, and peritoneal dialysis patients may be at particularly high risk. CALCIUM BALANCE AND EXTRASKELETAL CALCIFICATION Patients on peritoneal dialysis are in positive calcium balance even on low-calcium-containing dialysate (7). Unfortunately, the options for further lowering dialysate calcium are limited; 2.5 mmol/l is the lowest calcium concentration currently available. The average dietary intake of calcium in a dialysis patient is 800 mg daily, of which 20% is absorbed. In addition, almost all dialysis patients consume calcium-containing phosphate binders, from which about half the elemental calcium is absorbed (20). For example, an anuric patient on a 1.5% dextrose, low calcium (2.5 mmol) bath, with four 2-L exchanges daily has a net calcium loss from dialysis of 72 mg per day. If the patient consumes a normal quantity of dietary calcium and phosphorus (160 mg daily) and 2 calcium carbonate tablets with each of three meals (251 mg calcium absorbed per tablet = 1506 mg daily), then that patient has a net calcium intake per day of 1666 mg, well above the current recommended Figure 1 Positive predictive value (PPV) of parathyroid hormone (PTH) concentration for high-turnover bone disease (2,13). S242

3 PDI DECEMBER 2001 VOL. 21, SUPPL 3 PROCEEDINGS OF THE IXTH CONGRESS OF THE ISPD dietary allowance. Some calcium is excreted in stool, but that loss is not large enough to maintain the balance. Thus, all peritoneal dialysis patients are in positive calcium balance. Patients on all forms of dialysis are prone to metastatic calcification. Braun et al found that dialysis patients had increasing coronary artery calcification with advancing age as quantified by high-resolution computed tomography (CT) scan. The magnitude of calcification was 2 5 times greater than that observed in patients with angiographically proven coronary artery disease (21). Other investigators have found that aortic and soft tissue calcification is also common in dialysis patients (22,23), including peritoneal dialysis patients (24). It has been written that metastatic calcification does not occur if the calcium phosphorus product is less than 70 (25), but that statement is based on theoretical in vitro work (26,27). In vivo, metastatic calcification occurs even with calcium phosphorus products between 50 and 70 (22 24). In a recent study reported by Goodman et al (28), electron beam CT (EBCT) analyses were conducted on 39 young dialysis patients (below 30 years of age). Of 16 dialysis patients between 20 years and 30 years of age, 14 (88%) had positive EBCT scans (that is, coronary artery calcification). Only 3 controls (5%) had positive scans. Dialysis patients with coronary artery calcification had significantly higher Ca P products (mean: 65.0) than did dialysis patients without calcification (mean: 56.4) (28). Interestingly, patients with calcification had received, on average, nearly twice the daily dose of calcium in the form of phosphate binders than had the patients without calcification (28). We found similar, elevated levels of phosphorus and Ca P product associated with calciphylaxis (29). Marchais et al (30) found that elevated serum phosphorus in dialysis patients was associated with increased carotid artery thickening, tensile stress, and left ventricular hypertrophy. Interestingly, a study in non dialysis patients also found that the presence of atherosclerotic disease by coronary angiogram correlated with increasing serum phosphorus levels (31). In vitro work has demonstrated that media concentrations greater than 6.2 mg/dl are associated with increased calcification of vascular smooth muscle cells in vitro (32). Those studies clearly indicate that the previously accepted serum phosphorus level of <7 mg/dl, and the Ca P product of <70 are not acceptable. Support can be found in a study by Block et al (33), who found that patients with elevated phosphorus (>6.5 mg/dl) and Ca P product (>73) had an increased relative mortality risk. Follow-up data indicated that the cause of death was primarily coronary artery disease and sudden death (34), which supports a predisposition to vascular calcification in dialysis patients. Clearly, maintaining a near-normal serum phosphorus and Ca P product is of the utmost importance, but maintaining a near-normal calcium balance would also seem to be prudent. Unfortunately, as the earlier example demonstrated, controlling serum phosphorus with calcium-containing phosphate binders and simultaneously maintaining a neutral or negative calcium balance is nearly impossible. The advent of sevelamer (Renagel: Genzyme Therapeutics, Cambridge, MA, U.S.A.) offers an important alternative in the treatment of hyperphosphatemia in renal failure. However, further complicating the therapeutic challenge is the use of vitamin D for the treatment of hyperparathyroidism. Calcitriol increases absorption of both calcium and phosphorus across the intestine. The new vitamin D analogs, paricalcitol (Zemplar: Abbott Laboratories, Abbott Park, IL, U.S.A.) and doxercalciferol (Hectorol: Bone Care International, Middleton, WI, U.S.A.) are probably less hypercalcemic and hyperphosphatemic than calcitriol (Calcijex: Abbott Laboratories). However, published controlled comparison trials are lacking for both compounds (19,35). A new class of pharmacologic agents, the calcimimetics, directly bind to the calcium sensing receptor on the parathyroid gland, and fool the gland into sensing hypercalcemia, thereby inhibiting release of PTH. These agents offer a more physiologic approach to the treatment of hyperparathyroidism, without an elevation in the Ca P product. In fact, preliminary studies presented at the American Society of Nephrology 2000 meeting demonstrated that calcium and phosphorus levels both decreased with the use of calcimimetics. If long-term studies continue to demonstrate such results, the breakthrough will represent a major advance in the treatment of secondary hyperparathyroidism. PATHOPHYSIOLOGY OF VASCULAR CALCIFICATION Although vascular calcification was initially felt to be an innocent bystander, recent evidence suggests that it is a tightly regulated process resembling mineralization in bone (36 43). Lessons learned from bone have been applied to vascular tissue. Work in the last decade has demonstrated that vascular smooth muscle cells or vascular pericytes, or both, are capable of producing bone-like proteins in cell culture, including matrix Gla protein, bone morphogenic protein-2 (BMP-2), alkaline phosphatase, bone sialoprotein, osteonectin, and osteopontin [reviewed in (44) and (45)]. The cells are capable of forming bone nodules S243

4 PROCEEDINGS OF THE IXTH CONGRESS OF THE ISPD DECEMBER 2001 VOL. 21, SUPPL 3 PDI in vitro in the presence of a phosphorus donor, betaglycerophosphate, identical to the requirements for bone nodule formation from osteoblasts in vitro (39,42, 43,46,47). In a manner similar to that used by osteoblasts, the phosphorus is cleaved by membrane alkaline phosphatase to form free phosphorus that enters the vascular smooth muscle cell via a sodium/phosphate co-transporter (47). We have found immunohistochemical evidence for expression of these bone proteins during calciphylaxis (29) and in inferior epigastric arteries obtained at the time of renal transplantation (48). More convincing evidence of the importance of those proteins in vascular cell differentiation and calcification has been gained from knockout mice models. Animals deficient in matrix Gla protein (MGP) have impaired mineralization of the cartilage growth plate (leading to osteopenia) and severe vascular calcification (leading to ruptured aneurysms as a cause of death) (49). In those mice, the medial layer of the vessel was replaced with chondrocyte-like cells that became calcified (49). Another knockout mouse model aimed at understanding osteoporosis osteoprotegerin-deficient mice also had vascular calcification, which was a surprise (50). Osteoprotegerin (OPG) is normally produced by osteoblasts and can bind to RANKL (receptor activator of nuclear factor κb ligand) on osteoblasts to prevent binding of the RANKL to RANK on osteoclasts. The latter binding leads to osteoclast differentiation. Thus, when OPG is decreased, more RANKL is available to bind to RANK and more osteoclastic bone resorption occurs. If OPG is increased, less RANKL is available to bind to RANK and less osteoclastic bone resorption occurs. Thus, OPG holds therapeutic promise as an anti-osteoporosis agent. That possibility is particularly exciting given the realization that the OPG RANKL system is regulated by tumor necrosis factor alpha (TNFα), BMP-2, 1,25(OH) 2 D 3, estrogen, glucocorticoids, and parathyroid hormone [reviewed in (51)], and thus may be a common final pathway for numerous bone factors. The relationship of vascular calcification and osteoporosis has also been observed clinically. Epidemiologic studies in postmenopausal women and the aging general population have demonstrated that patients with osteoporosis have increased atherosclerosis and increased coronary artery calcification (52 55). The ability of bone to mineralize appears to peak at age years. Thereafter, bone mass decreases gradually, with a 5-year acceleration at the time of menopause in women (56). Interestingly, coronary artery calcification progresses from the age of years until death (57). Drake et al (58) recently found genetic evidence linking atherosclerosis with osteoporosis in mice with S244 diet-induced atherosclerotic disease. This same inverse relationship has been found in dialysis patients: Braun et al found a significant inverse correlation between coronary artery calcification by EBCT and bone-mineral density by CT (21). In dialysis patients, coronary artery calcification and cardiovascular mortality are increased as compared with the general population (59). Similarly, the prevalences of low bone mass and hip fractures are increased in dialysis patients as compared with the general population (10,60,61). Dialysis patients in their 40s have a relative risk of hip fracture 80-fold that of age-and-sexmatched controls (60). In a multivariate analysis, the risk factors for hip fracture included age, sex, duration of dialysis, and presence of peripheral vascular disease (62). The latter association is particularly interesting. Peripheral vascular disease, like cardiovascular disease, is linked to bone loss (63). In studies evaluating coronary artery calcification in dialysis patients, similar risk factors emerge: age and duration of dialysis. Thus, it is plausible that in the aging general population and in dialysis patients alike, some factor or factors lead to preferential osteogenesis with subsequent calcification in vascular tissue over bone. Much work needs to be done to fully understand the pathogenesis of this problem. SUMMARY Recent research has demonstrated active bone-like remodelling of vascular tissue in dialysis and non dialysis patients. Cross-sectional studies indicate that the presence of vascular calcification is inversely related to bone mass. Theoretically, the relationship implies that maintaining normal bone turnover and mass may help to decrease vascular calcification. In addition, it is now apparent that phosphorus and the Ca P product need to be kept as close to normal as possible. 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