Reversal of adynamic bone disease by lowering of dialysate calcium

http://www.kidney-international.org & 26 International Society of Nephrology original article Reversal of adynamic bone disease by lowering of dialysate calcium A Haris 1, DJ Sherrard 2 and G Hercz 3 1 Department of Nephrology, St Margit Hospital, Budapest, Hungary; 2 Department of Medicine, Veterans Administration Hospital and University of Washington, Seattle, Washington, USA and 3 Division of Nephrology, Humber River Regional Hospital, Toronto, Canada Adynamic bone disease (ABD) is increasingly recognized, especially in dialysis patients treated with oral calcium carbonate, vitamin D supplements, or supraphysiological dialysate calcium. We undertook this study to assess the effect of lowering dialysate calcium on episodes of hypercalcemia, serum parathyroid hormone (PTH) levels as well as bone turnover. Fifty-one patients treated with peritoneal dialysis and biopsy-proven ABD were randomized to treatment with control calcium, 1.62 mm, or low calcium, 1. mm, dialysate calcium over a 16-month period. In the low dialysate calcium group, 14 patients completed the study. This group experienced a decrease in serum total and ionized calcium levels, and an 89% reduction in episodes of hypercalcemia, resulting in a 3% increase in serum PTH values, from 6.71.6 to 24.973.6 pm (Po.1). Bone formation rates, all initially suppressed, at 18.175.6 lm 2 / mm 2 /day rose to 159759.4 lm 2 /mm 2 /day (Po.5), into the normal range (418 lm 2 /mm 2 /day). In the control group, nine patients completed the study. Their PTH levels did not increase significantly, from 7.371.6 to 9.471.5 pm and bone formation rates did not change significantly either, from 13.377.1 to 4.9711.9 lm 2 /mm 2 /day. Lowering of peritoneal dialysate calcium reduced serum calcium levels and hypercalcemic episodes, which resulted in increased PTH levels and normalization of bone turnover in patients with ABD. Kidney International (26) 7, 931 937. doi:1.138/sj.ki.51666; published online 12 July 26 KEYWORDS: renal osteodystrophy; adynamic bone disease; peritoneal dialysis Correspondence: A Haris, Department of Nephrology, St Margit Hospital, 132 Becsi St, Budapest H-132, Hungary. E-mail: agnesharis@hotmail.com Received 21 July 25; revised 25 February 26; accepted 29 March 26; published online 12 July 26 Renal osteodystrophy, one of the major complications of end-stage renal disease (ESRD), although recognized decades ago and studied extensively since then, continues to be a challenging problem for nephrologists. In the 197s and early 198s, management of hyperphosphatemia, the hyperparathyroid state, and bone aluminum deposition was the major concern. 1 Over the past 15 years, the spectrum of renal osteodystrophy has changed, and adynamic bone disease (ABD) has been increasingly recognized. ABD is characterized by reduced synthesis of bone matrix owing to decreased osteoblastic and osteoclastic activity. 2 In association with reduced bone formation rates (BFR), there is a lack of osteoid accumulation differentiating this abnormality from osteomalacia. According to the Toronto Renal Osteodystrophy Study, in the 199s the most prevalent form of bone disease was the non-aluminum-related ABD, occurring in 34% of 256 ESRD patients who underwent bone biopsy. 2 4 In a retrospective analysis of 1429 iliac crest biopsies performed in Italy between 1985 and 1994, 15.3% showed non-aluminum-related adynamic bone histology. Its frequency was fairly constant during the observational period, whereas the prevalence of aluminum bone disease gradually decreased, from 36 to 4%. 5 In another European study, 42% of 81 ESRD patients had biopsy-proven ABD, with a greater frequency noted in peritoneal than in hemodialysis (HD)-treated patients. 6 A similar result was shown by Sánchez et al., 7 who found a 63.2% frequency of low turnover bone disease in 57 patients treated with peritoneal dialysis. Interestingly, 32% of patients with advanced renal failure, before initiation of renal replacement therapy, had ABD, in spite of avoiding any vitamin D therapy. 8 One of the unresolved issues is whether ABD is a disease or just an asymptomatic condition. Theoretically, low BFR predisposes patients to the risk of poor healing of microfractures and increased fracture incidence. 9,1 Also, as the calcium (Ca)-buffering effect of bone is diminished, patients on Ca-containing phosphate binders and high dialysate Ca may have frequent episodes of hypercalcemia. 1 In addition, these episodes of hypercalcemia may result in Ca deposition in the vasculature and myocardium, shortening life expectancy in the ESRD population. 11 Kidney International (26) 7, 931 937 931

o r i g i n a l a r t i c l e A Haris et al.: Reversal of adynamic bone disease The serum Ca level is one of the major determinants of parathyroid hormone (PTH) secretion. In continuous ambulatory peritoneal dialysis (CAPD) patients, the continuous positive Ca balance resulting from the elevated dialysate Ca may result in suppressed PTH levels. Consequently, the present study was undertaken to investigate the role of suppressed PTH levels in the development of low turnover bone disease. The aim was to assess whether lowering of dialysate Ca is able to enhance PTH secretion, increase BFR, and improve bone histology in patients treated with peritoneal dialysis and biopsy-proven ABD. RESULTS The patients biochemical results are summarized in Table 1. By lowering the peritoneal dialysis fluid Ca content, in the low Ca group, serum total Ca (tca) decreased from 2.437.6 to 2.137.3 mm (Po.1), and serum-ionized Ca (ica) dropped from 1.257.2 to 1.97.2 mm (Po.1). There was no significant change in tca (from 2.197.8 to 2.187.3 mm) and ica levels (from 1.187.1 to 1.157.2 mm) in the control Ca group. The serum PTH level rose significantly, from 6.71.6 to 24.973.6 pm, when administering low Ca peritoneal dialysis fluid (Po.1), but it did not show significant change, 7.371.6 pm at baseline and 9.471.5 pm after 16.372.1 months, in the patients treated with the control dialysate Ca (Figure 1). None of the groups demonstrated significant differences in the serum phosphate, alkaline phosphatase, or magnesium levels at either baseline or at the end of the study. After an average of 16.372.1 months the bone biopsies were repeated. In the low Ca group, the BFR increased significantly, from 18.175.6 to 159759.4 mm 2 /mm 2 /day, reaching the normal BFR (418 mm 2 /mm 2 /day). In comparison, no significant improvement was found in the controls, BFR changing from 13.377.1 to 4.9711.9 mm 2 /mm 2 /day (Figure 2). In the low Ca group, five of the 14 patients bone histology altered, two to osteitis fibrosa, three to mild lesion with nine remaining adynamic. Among the nine control patients, bone histology changed to mild lesion in one patient, whereas the other eight remained adynamic. Figure 3 shows the association between the individual BFR changes (expressed as values at the end of the study minus values at baseline) plotted against the individual PTH (expressed as values at the end of the follow-up period minus values at baseline). We also determined the osteoid area, marrow fibrosis, trabecular bone, fibrotic area, osteoid surface, eroded surface, and percentage of stainable aluminum on the bone surface in all biopsy specimens. None of the mean values of these parameters showed significant differences, comparing the low Ca or control Ca groups at any time point. Surface aluminum in the low Ca group: 14.874.5% at baseline and 18.974.5% at follow-up, and in the control Ca group: 14.975.4 and 2.2175.7%, did not differ significantly. Bone mineral density was measured at the time of the first and second biopsies. It consisted of bone mineral index and bone mineral density at the hip, assessing the whole body, femoral neck and trochanter areas, and lumbar spine (L1 L4). None of these values changed significantly in either comparison of the two groups, or within the groups at baseline and at follow-up (Table 2). Analysis of data did not show any impact of PTH changes on bone density. The patients tolerated the administration of low Ca dialysate well. Hypercalcemia, defined as serum-ionized Ca 41.35 mm, decreased in the low Ca group, from 1.67.6 down to.177.9 episodes/patient-year, which was highly significant (Po.5). It occurred in the control Ca group as many as.697.5 episodes/patient-year initially, and showed a nonsignificant change to.537.22 PTH (pm) 3 25 2 15 1 7.3 5 6. 12.5 18.3 Control calcium 12.1 17.5 2.6 Low calcium 14.2 8.1 7.4 1.4 7.4 8. 8. 8.1 18.8 6.9 16.7 11.1 6 12 18 24 3 36 42 48 54 6 Weeks Figure 1 Serum PTH levels as measured every 6 weeks during the study period in the two treatment groups. PTH rose significantly in the low Ca group (Po.1), but did not change significantly in the control group. 4.8 24.9 9.4 Table 1 Biochemical results Control Ca Low Ca Before After P-value Before After P-value tca (mm) 2.197.8 2.187.3 NS 2.437.6 2.137.3 Po.1 ica (mm) 1.187.1 1.157.2 NS 1.257.2 1.97.2 Po.1 PO 4 (mm) 1.77.12 1.727.13 NS 1.897.13 1.927.14 NS Mg (mm) 1.247.6 1.227.3 NS 1.217.5 1.27.5 NS ALP (U/l) 87.3711.4 76.578.9 NS 79.76.9 84.975.9 NS PTH (pm) 7.371.6 9.471.5 NS 6.71.6 24.973.6 Po.1 Ca, calcium; tca, total serum calcium; ica, serum ionized calcium; PO 4, serum phosphate; ALP, serum alkaline phosphatase (normal 3 11 U/l); Mg, serum magnesium; PTH, serum parathyroid hormone (normal 1 6 pm); NS, nonsignificant. 932 Kidney International (26) 7, 931 937

A Haris et al.: Reversal of adynamic bone disease o r i g i n a l a r t i c l e episodes/patient-year during the study. The number of hypocalcemic episodes was small: three patients experienced one episode each of serum-ionized Ca levels o1. mm. The episodes of hypocalcemia were detected biochemically, with the patients remaining asymptomatic during these episodes. Hypocalcemia did not occur in the control group. According to the study design, vitamin D was not given to any of the patients during the study period. DISCUSSION It has been noted that bone pain and proximal myopathy develop frequently in patients with aluminum-associated bone disease. However, these complications do not characterize non-aluminum-related ABD. Whether ABD is a benign, asymptomatic condition of ESRD has been a matter of debate since its first description. Nevertheless, a few articles have commented on increased morbidity and mortality associated with this condition. The two major concerns are the frequent episodes of hypercalcemia with possible soft tissue calcification, and increased risk for fractures due to the impaired remodelling process. 1,11 In order to avoid these complications, the most recent Dialysis Outcome Quality Initiative (DOQI) guidelines suggest that in cases of ABD, PTH should be allowed to rise, aiming for increased bone turnover rates. 12 The most likely mechanism for the occurrence of ABD is the relative hypoparathyroidism seen in these patients. As the serum-ionized Ca level is one of the most powerful factors BFR(μm 2 /mm 2 /day) 22 2 18 16 14 12 1 8 6 4 2 22 2 18 159±59.4 16 14 12 P<.5 1 P=NS 8 4.9±11.9 6 18.1±5.6 4 13.3±7.1 2 1st biopsy 2nd biopsy 1st biopsy 2nd biopsy Control calcium Low calcium Figure 2 BFR increased significantly in the low Ca group, reaching the normal BFR, but no significant improvement was found in the control Ca group. affecting PTH secretion, a continuously positive Ca balance associated with oral Ca carbonate (CaCO 3 ) treatment, vitamin D administration, and supraphysiological dialysate Ca may lead to oversuppression of parathyroid gland activity. 13,14 In addition, in diabetic patients, who nowadays represent almost 5% of the ESRD patient population, both hyperglycemia and insulin deficiency inhibit PTH secretion, and the advanced glycosylated end-products modified bone matrix proteins may alter the responsiveness of osteoblasts to the regulatory hormones and cytokines. 15 Other factors have also been associated with ABD, including parathyroidectomy, advanced age, short dialysis history, males in the CAPD population, malnutrition, and hypermagnesemia. 5,7,9,16 2 In patients treated with CAPD, Ca mass transfer depends on the dialysate Ca concentration, the amount of ultrafiltrate and the patient s actual serum-ionized Ca level. In the Ca mass balance studies of Bender et al., 21 use of 1.75 mm dialysate Ca resulted in a positive Ca balance in the patients, but use of 1.25 mm Ca dialysate produced net Ca removal, and this was proportional to the amount of ultrafiltration. Armstrong et al. 22 showed that administration of 1.25 mm dialysate Ca resulted in decreased serum-ionized Ca levels and increased PTH values in a 3-month period when aluminum, but not Ca-containing, phosphate binders were given. Nevertheless, during the second phase of that study, Changes in BFR (μm 2 /mm 2 /day) 8 7 6 5 4 3 2 1 1 1 R 2 =.4261 Control calcium R 2 =.3569 Low calcium 1 2 3 4 5 6 Changes in PTH (pm) Figure 3 Association between the individual BFR changes (expressed as values at the end of the study minus values at baseline) plotted against the individual serum PTH changes (expressed as values at the end of the follow-up period minus values at baseline). Table 2 Bone mineral density and Z-scores Control Ca Low Ca Before After P-value Before After P-value Whole-body BMD (g/cm 2 ) 1.57.7 1.77.5 NS 1.117.3 1.97.4 NS L1 L4 BMD (g/cm 2 ) 1.67.7 1.77.7 NS.997.3.997.3 NS Z-score (%) 11.976.2 18.976.1 NS 99.572.8 98.973.5 NS Femoral neck BMD (g/cm 2 ).777.5.757.5 NS.757.4.727.4 NS Z-score (%) 98.175.9 94.974.2 NS 93.674.4 9.474.6 NS Trochanter BMD (g/cm 2 ).627.5.617.6 NS.657.4.647.4 NS Z-score (%) 91.476.4 89.476.6 NS 92.74.6 9.174.6 NS BMD, bone mineral density; Z-score, number of s.d. from the age-matched average value; NS, nonsignificant. Kidney International (26) 7, 931 937 933

o r i g i n a l a r t i c l e A Haris et al.: Reversal of adynamic bone disease when Ca salts were used as phosphate binders, the ionized Ca and PTH values returned to baseline, demonstrating that tca balance could be restored when the patients consumed oral Ca medications. 22 Similarly, Chagnac et al. 23 found that in spite of peritoneal Ca removal with 1. and 1.25 mm dialysate Ca, the daily Ca balance was still positive owing to intestinal absorption of the mineral in patients on CaCO 3 and alfacalcidiol treatment. During healthy bone remodelling, an actual Ca load is immediately buffered by bone, and hypercalcemia does not develop. Ca kinetic studies have shown that patients with ABD have a decreased capacity for buffering of Ca by bone and therefore may be unable to handle an extra Ca load. 24 Our previous studies have shown that hypercalcemia (tca42.7 mm) occurred most frequently in patients with low turnover bone disease. 13 Repeated hypercalcemic episodes and elevated Ca phosphate products enhance metastatic calcifications in soft tissues, most importantly in the vascular system, myocardium, and cardiac valves. 25 27 In the study of Goodman et al., 28 severe coronary calcifications could be detected even in young HD patients. London et al. 11 found frequent, rapidly progressive aortic valve calcification, associated with very poor prognosis, in ESRD patients. Although long-term survival studies of CAPD patients with ABD are not available yet, it theoretically seems reasonable to assume that iatrogenic hypercalcemia may play an important role in the cardiovascular morbidity of this population. 29,3 With an impaired remodelling process, patients with ABD are prone to poor repair of microfractures, 18 and suffer more frequent episodes of fractures. Coco and Rush 31 reviewed the hip fracture incidence and found 56 episodes in 1272 ESRD patients over a 1-year period. This frequency was 17.4 times higher than that seen in the general population, occurring at a significantly younger age, resulting in a 64% mortality rate in the affected patients. More interestingly, patients with PTH levels less than 7.2 pm had the highest risk for hip fractures, and even PTH levels less than 21.4 pm predicted this complication, whereas higher values were unrelated. The investigators also found that survival of the entire dialysis population was significantly decreased in the subgroup of patients with the lower PTH values. Vertebral fractures also occur more frequently in dialysis patients than in a healthy, age-matched population. In the study of Atsumi et al., 32 2.9% of 187 male HD patients had one or more vertebral compression fractures. Surprisingly, the subgroup with the lowest tertile of serum PTH values had the highest risk, and the subgroup with the highest tertile had intermediate risk for this complication, suggesting that ABD, as compared to hyperparathyroid bone disease, has a greater predisposition for vertebral fractures. 32 The benefits of low dialysate Ca include prevention of hypercalcemia, allowing for increased use of both Ca salts and vitamin D products. Nevertheless, long-term treatment of unselected CAPD patients with low dialysate Ca may result in uncontrolled PTH secretion and development of hyperparathyroidism. Weinreich et al. 33 compared the effect of 1. and 1.75 mm dialysate Ca on PTH secretion in a 2-year period in normocalcemic patients, with PTH levels of 14 and 6.4 pm, respectively. He found that in the low Ca group, 23% of the patients developed severe secondary hyperparathyroidism despite maintaining normal serum Ca levels; in comparison, hyperparathyroidism occurred in only 1% of the patients on 1.75 mm dialysate Ca. 33 Buijsen et al. 34 and Duncan et al. 35 established that in normo- and hypercalcemic patients with pre-existing secondary hyperparathyroidism, long-term low dialysate Ca led to a further increase in PTH secretion, and that the higher the PTH level at baseline, the higher the risk for the development of hyperparathyroidism. 34,35 The morbidity resulting from elevated serum PTH levels is as serious as those resulting from suppressed PTH levels. Ca homeostasis, and therefore our therapeutic approach, will likely be changed substantially with the increasing administration of Ca- and metal-free phosphate binders. It can be expected that, beside phosphate-binding properties, the effects of these agents, for example, sevelamer hydrochloride, lanthanum, or polynuclear iron preparations, will result in a more neutral Ca balance, reduced incidence of hypercalcemic episodes and hypercalcemia-induced PTH suppression. Indeed, Braun et al., 36 who compared the effects of Ca-free phosphate binders and CaCO 3 in a 1-year study in hemodialysed patients, found lower serum Ca, less episodes of hypercalcemia, and higher PTH levels in the sevelamertreated group despite more frequent vitamin D supplementation. Whereas PTH level decreased by 38% in the CaCO 3 group, it increased by 22% in the sevelamer-treated patients. The bone turnover also increased in the sevelamer group. The administration of Ca-free phosphate binders also proved to be beneficial in avoiding aortic and coronary calcifications. Based on these findings, the preference is for non-ca binders. Nevertheless, many patients continue on Ca-based binders owing to cost and tolerance issues. In the present study, we investigated whether lowering of peritoneal dialysate Ca concentration for an extended period of time was able to enhance PTH secretion, and consequently BFR, in patients with biopsy-proven ABD. The study was designed as long as 16 months to allow sufficient time for changes in BFR to occur, and also to assess how well the new formulation was tolerated, that is, whether it can be administered as maintenance therapy for CAPD patients on a long-term basis. Administration of 1. mm dialysate Ca for 16.372.1 months resulted in significantly decreased serum tca and ica levels, a simultaneous 3% increase in the PTH values and normalization of the BFR. Although we did not measure Ca absorption from the gut, we might assume, based on the above mentioned studies, that our patients developed a very mildly positive or zero Ca balance when assessing the combined effects of low Ca dialysate, Ca removal by ultrafiltration, and intestinal Ca absorption from orally administered CaCO 3. As the bone density measurements 934 Kidney International (26) 7, 931 937

A Haris et al.: Reversal of adynamic bone disease o r i g i n a l a r t i c l e did not show decreasing bone mineral content over the 16-month period, we believe that the use of low Ca dialysate was able to stimulate PTH release without causing substantial Ca loss from bone. Most significantly, the elevated parathyroid activity was able to normalize bone turnover in the study patients, whereas no significant change could be observed in the control group. The patients tolerated the low dialysate Ca well, with hypocalcemia occurring infrequently. The number of hypercalcemic episodes decreased significantly, which allowed us to administer sufficient amounts of CaCO 3, for phosphate control, and lowered the risk of metastatic calcification in the patients. Patients on low Ca dialysate improved BFR significantly, the average BFR reaching the normal range by the time of the second biopsy. Nevertheless, there were differences in the increase of the individual patients serum PTH and BFR. On the other hand, neither PTH nor BFR increased significantly in the control Ca group. As the serum phosphorous levels did not show a significant difference between the biopsies or between the groups, we assume that changes in BRF occurred owing to low Ca dialysate inducing gradual, continuous increases in PTH levels. According to the data, we believe that the predictor of BFR is the rise in serum PTH levels, rather than the baseline PTH or phosphate levels. Although BFR improved significantly in the low Ca group, some of the patients BFR did not achieve a high enough level to be classed as a different bone histology. It is possible that the relatively high doses of CaCO 3 were still able to maintain a positive Ca balance in these individuals. With the new, Cafree phosphate binders, lower Ca intake could likely stimulate BFR further. In our opinion, the value of our study is to provide histological evidence that bone metabolism is sensitive to exogenous Ca exposure, and can substantially be altered by modifying Ca balance. Although Ca-free phosphate binders will have a substantially different effect on Ca and bone metabolism, most of the patients on renal replacement therapy are still prescribed CaCO 3 as the phosphate binder, owing to the high cost of the newer medications. Although the gold standard in assessing the patients bone disease is bone biopsy, measurements of PTH levels are more widely used to guide therapeutic decisions given the lack of widespread use of biopsies. Wang et al. 37 found a close correlation (r ¼.71) between intact PTH levels and BFR in 175 dialysis patients without aluminum toxicity. Based on their results, PTH levels can be used as an alternative to a bone biopsy in guiding clinical practice. According to the recently published paper by Block et al., 38 disorders of mineral metabolism play an important role in the morbidity and mortality of patients with ESRD. The authors pointed out that hyperphosphatemia especially, but also moderate to severe hyperparathyroidism and hypercalcemia, are associated with not only bone disease, but cardiovascular disease as well. The present study was not designed to examine cardiovascular morbidity, but provided evidence that therapy of mineral abnormalities in dialysis patient can be ameliorated in different ways. Our medical decision in the future, in an individual patient, should be based not only on the serum levels of Ca, phosphorus, or PTH but also on considerations regarding the long-term cardiovascular effects of our interventions. In summary, our results suggest that in CAPD patients with ABD, sufficient decrease of the dialysate Ca leads to increased PTH secretion, and the enhanced hormonal activity is able to activate bone remodelling. We propose that in CAPD patients, as in HD patients, dialysate Ca concentration needs to be individualized. In patients with suppressed PTH levels and biopsy-proven ADB, temporarily lowering dialysate Ca may correct relative hypoparathyroidism, normalizing bone turnover. Nevertheless, serum Ca and PTH levels need to be followed carefully, and the length of treatment with low dialysate Ca needs to be evaluated so as to avoid hypocalcemia, worsening bone mineral content, and development of secondary hyperparathyroidism. MATERIALS AND METHODS This prospective, partially randomized study was undertaken in 51 stable ESRD patients on maintenance CAPD, each of whom had biopsy-proven ABD. The patients underwent four 2-l exchanges per day. Before the study, all of them were using commercially available dialysate containing 1.62 mm Ca (Dianeal, Baxter Healthcare Corporation, One Baxter Parkway, Deerfield, IL, USA). They were assigned into two groups: 24 patients were switched to 1 mm Ca ( low Ca group ) and 27 continued CAPD with peritoneal dialysis fluid containing 1.62 mm of Ca ( control Ca group ). The composition of the control dialysis solution was Na 132 mm, Cl 12 mm, Ca 1.62 mm, magnesium.25 mm, lactate 35 mm, and glucose 1.5, 2.5, or 4.25% according to the need of the patients. The low, 1. mm Ca dialysis solution was manufactured for the purposes of this study, with the same Na, Cl, magnesium, and lactate composition as the standard, commercially available solution for the control group. The Ca concentration used in this study was lower than what is currently commercially available, that is, dialysate Ca of 1.25 mm. The partial randomization means that the two groups were not exactly comparable, the serum tca and ica levels tended to be higher in the low Ca group at baseline. Owing to ethical reasons, patients with more frequent episodes of hypercalcemia were selected for the low Ca group. For the frequently hypercalcemic patients, the low Ca dialysate treatment was obviously less harmful, than the standard Ca dialysate would have been. 39,4 Twenty-three of the 51 participants finished the 16.372.1 month study period, 14 in the low Ca and nine in the control Ca group, and their data are herein presented. Their mean ages were 5773.6 and 5674.5 years, and their weights were 64.474.5 and 65.475.5 kg, respectively. There were nine male and five female patients in the low Ca, and four male and five female patients in the control Ca group. Six of 14 patients on low Ca and four of nine patients on control Ca dialysate had diabetes mellitus. Serum tca and ica, phosphate, alkaline phosphatase, and magnesium were measured by standard laboratory techniques monthly. Hypercalcemia, serum tca42.7 mm, was tracked for 6 months before initiation of study. Intact PTH levels were determined by an immunoradiomertic assay every 6 weeks. Bone mineral density measurements were performed at baseline and at the Kidney International (26) 7, 931 937 935

o r i g i n a l a r t i c l e A Haris et al.: Reversal of adynamic bone disease end of the study period. The patients, entered after undergoing documentation of ABD, had a second bone biopsy performed after 16.372.1 months of treatment. Bone biopsy specimens were obtained under local anesthesia from the anterior iliac crest using a Bordier needle. The patients were given two courses of tetracycline separated by a 17-day drugfree period. The biopsy was performed 4 1 days after the last dose of tetracycline. Bone biopsies were assessed for static and dynamic histomorphometric parameters. Separate sections were stained for aluminum on mineralizing bone surfaces. The diagnostic criteria for ABD were determined as BFRo18 mm 2 /mm 2 /day, osteoid area o15%, and marrow fibrosis o.5%. Mild bone lesion was diagnosed when BFRX18 mm 2 /mm 2 /day, the osteoid area o15%, and marrow fibrosis o.5%, and osteitis fibrosa was established if BFRX18 mm 2 /mm 2 /day, the osteoid area o15%, and marrow fibrosis 4.5%. During the study period, oral CaCO 3 dose was adjusted to maintain the serum phosphate level below 2 mm. For the patients in the low Ca group the CaCO 3 dose was increased from 1.817.25 to 3.17.57 g/day (Po.5), and in the control group from 1.857.37 to 2.757.47 g/day (Po.5). None of the patients was ingesting vitamin D. Hypercalcemic episodes were documented, and we also evaluated the reasons for dropouts in each case. Of the 28 patients who dropped out, 1 were in the low Ca group and 18 were in the control Ca group. Four patients underwent renal transplantation, eight were switched to HD, three were transferred to another peritoneal dialysis center, seven became too ill for the bone studies and the repeat biopsy, and six patients died. The study was approved by the local institutional review board and the patients signed a consent before being initiated in the study. Statistical analysis Results are expressed as the mean7s.e.m. All tests were two-sided. Comparisons between the groups were made using unpaired and paired t-tests. Po.5 was considered significant. ACKNOWLEDGMENTS This study was supported by the Extramural Grant Program, Baxter Healthcare Corporation, Research Services of the Veterans Administration, and the Nichols Institute. We thank Dr Gino Segre for PTH determinations and Ms Winnie Chan for research coordination. REFERENCES 1. Monier-Faugere MC, Malluche HH. Trends in renal osteodystrophy: a survey from 1983 to 1995 in a total of 2248 patients. Nephrol Dial Transplant 1996; 11(Suppl 3): 111 12. 2. Sherrard DJ, Hercz G, Pei Y et al. The spectrum of bone disease in end-stage renal failure an evolving disorder. Kidney Int 1993; 43: 436 442. 3. Pei Y, Hercz G. 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