NDT Advance Access published online on November 23, 2006
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfl567
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Risedronate, an effective treatment for glucocorticoid-induced bone loss in CKD patients with or without concomitant active vitamin D (PRIUS-CKD)
Department of Internal Medicine, Osaka University School of Medicine, Suita, Japan
Correspondence and offprint requests to: Correspondence and offprint requests to: Takahito Ito, MD, PhD, FASN Department of Internal Medicine, Osaka University School of Medicine, Box A8, 2-2 Yamada-oka, Suita, 565-0871, Japan. Email: i-taka{at}umin.ac.jp
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Abstract |
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Background. Recent post hoc analysis proved the efficacy and tolerability of risedronate in osteoporotic patients with renal impairment, but the combination of active vitamin D in chronic kidney disease (CKD) patients taking glucocorticoids remains unknown.
Methods. We conducted a prospective study enroling 114 CKD patients (creatinine clearance 
30 ml/min/1.73 m2) receiving glucocorticoid therapy for 6 months. Eighty-eight subjects who had received active vitamin D (aVD) were randomly assigned to either a group treated with aVD only (group A), or to a group also receiving risedronate 2.5 mg/day (group B). The remaining patients (group C) received risedronate only.
Results. After 1 year 100 subjects were analysed. Risedronate was effective on the lumbar spine, but not on the femoral neck. The lumbar bone mineral density (BMD) significantly increased by 2.8 and 2.5% in groups B and C, respectively, but decreased by 1.0% in group A. Serum N-terminal telopeptides of type I collagen (S-NTX) and bone alkaline phosphatase (ALP) fell significantly in groups B and C at 3 and 6 months, respectively, while in group A S-NTX remained unchanged and bone ALP significantly increased. There was no significant difference between groups B and C regarding BMD and bone markers. The reduction rate of S-NTX (bone ALP) at 6 months predicted the increase in lumbar BMD at 1 year with a sensitivity of 73% (34%) and a specificity of 46.2% (100%).
Conclusions. Risedronate is effective in increasing BMD with or without aVD in CKD patients receiving long-term glucocorticoid therapy. Bone markers are of some use in predicting the response to anti-resorptive therapy.
Keywords: bisphosphonates; bone mineral density; glucocorticoids; osteoporosis; steroids; vitamin D
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Introduction |
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Long-term glucocorticoid administration plays a central role in the treatment of chronic kidney diseases (CKDs) such as chronic glomerulonephritis, autoimmune nephritis, vasculitis and nephrotic syndrome. Supraphysiological doses of glucocorticoid, however, may cause symptomatic osteoporosis (glucocorticoid-induced osteoporosis, GIO) [1], which results mainly from reduced bone formation due to direct inhibition of osteoblasts [2], enhanced urinary loss and decreased intestinal absorption of calcium (Ca) and possibly increased bone resorption [3]. The osteoporotic effects of glucocorticoid administration may occur at the beginning of the treatment (i.e. within 6 months) with as little as 2.5 mg/day prednisone equivalent [4]. In rheumatoid arthritis patients receiving glucocorticoids (5.6 mg/day prednisone equivalent) for 2 years, bone mineral density (BMD) in the lumbar spine and the femoral neck decrease at a rate of 2.0% and 0.9% per year, respectively, if no supportive therapy is given [5]. Reportedly, 30–50% of the patients taking glucocorticoids suffer from GIO.
In order to counteract the osteoporotic effects of glucocorticoid therapy, several guidelines for GIO [6] recommend the prophylactic use of bisphosphonates. Abundant evidence has accumulated on the strong, favourable and lasting effects of nitrogen-containing bisphosphonates on BMD and on fracture risk in subjects with normal renal function [7]. Although some nitrogen-containing bisphosphonates may induce acute renal failure or worsen renal function, risedronate has recently been proved to be effective and tolerable (based on estimated creatinine clearance (CrCl), incidence of adverse events and bone histomorphometric analyses) even in patients with renal impairment by post hoc analysis of pooled data from nine clinical trials [8].
Although, the native or non-active type of vitamin D is often used in combination with bisphosphonates, recent meta-analyses have suggested the superiority of active vitamin D analogues over native vitamin D and/or Ca supplementation in the prevention and treatment of GIO [9]. In CKD patients with mild renal insufficiency, active vitamin D analogues such as alfacalcidol are preferable because 1
-hydoroxylase activity diminishes in parallel with renal damage and because its substrate, 25-hydoroxyvitamin D, may be lost through proteinuria [10]. But little is known about the effect of adding active vitamin D during risedronate therapy in CKD patients.
In this prospective open-label randomized clinical trial (PRIUS-CKD; the Pre-emptive Risedronate Intervention for those Undergoing Steroid therapy with CKDs), we studied the efficacy and tolerability of risedronate with and without active vitamin D analogue compared with the conventional treatment with active vitamin D in CKD patients under maintenance glucocorticoid therapy.
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Subjects and methods |
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Subjects
Out of 158 consecutive CKD out-patients receiving glucocorticoid therapy (prednisone equivalent of
2.5 mg/day) for more than 6 months, we enroled 114 patients [54 males and 60 females including 19 post-menopausal women, aged 42.5 ± 16.6 (SD) years, with CrCl of 99.6 ± 35.8 (SD) ml/min/1.73 m2]. All subjects had normal renal function or mild renal dysfunction (CrCl 30 ml/min/1.73 m2). Patients were excluded if they were being treated at the beginning of this study with bisphosphonate, native vitamin D, estrogen, selective estrogen receptor modulator (SERM), or human parathyroid hormone [1–34], or if they had concurrent diseases that affect bone turnover such as primary hyperparathyroidism and thyroid dysfunction. Kidney transplant patients and females planning pregnancy were also excluded. We obtained written informed consent from each subject participating in this study. The entire protocol was approved by the institutional review board of Osaka University Hospital and registered in the Cochrane Renal Group's database of prospective trials.
Study protocol
We conducted a prospective randomized open-label interventional study (Figure 1). The subjects who had already received active vitamin D analogues at the beginning of the study were randomly assigned to either a group without risedronate (group A) or a group with risedronate (group B). On the assumption that approximately 30% of the patients would discontinue risedronate after 1 year of treatment [11], the randomization was performed using computer software so that theoretically 40% more patients were assigned to group B than to group A. Sodium risedronate hydrate (2.5 mg/day, equivalent to 5 mg daily oral risedronate in Caucasian subjects [12]) was orally administered to group B but not to group A. The remaining patients were all assigned to group C, and were started on treatment with oral risedronate alone (2.5 mg/day). The doses of active vitamin D analogues, diuretics (e.g. thiazide), Ca supplements and ß-blockers (e.g. propranolol) were unchanged throughout the study period if patients were taking these drugs. We measured BMD every 6 months and blood chemistry at baseline and at 1, 3 and 6 months after the start of intervention. In the risedronate treatment groups (groups B and C), withdrawal from therapy was reported by the doctor in charge with the reasons for discontinuation. This study was conducted from August 2003 to May 2005.
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Measurements
Blood samples were drawn from ambulatory patients after an overnight fast. After 30 min of incubation at room temperature, serum was separated by centrifugation and was stored at –30°C until analysis. Blood chemistry [blood urea nitrogen, albumin (Alb), Ca, and inorganic phosphate (iP)] was measured by standard automated techniques. Serum creatinine (S-Cr) concentration was determined by an enzyme-based colorimetric assay as described previously with a slight modification [13] (TOYOBO, Osaka, Japan). Briefly, hydrogen peroxide was generated from creatinine by sequential enzyme reactions using creatinine amidohydrolase, creatine amidinohydrolase and sarcosine oxidase. In the presence of 4-aminoantipyrine and N-ethyl-N-(3-sulfopropyl)-3-methylaniline, hydrogen peroxide was converted to quinone dye showing maximum absorbance at 550 nm. CrCl was calculated according to the Cockcroft–Gault formula [14]. Serum N-terminal telopeptides of type I collagen (S-NTX) were measured using an ELIZA kit (OSTEOMARK; Mochida pharmaceutical Co., Tokyo, Japan). Intact PTH (iPTH), bone alkaline phosphate (ALP) and intact osteocalcin (iOC) were assayed using an Allegro two-site iPTH immunoradiometric assay (IRMA) kit (Nichols Institute Diagnostics, San Juan Capistrano, CA, USA), an Osteolinks-BAP high-sensitivity diagnostic enzyme immunoassay kit (Sumitomo Pharmaceuticals Co., Osaka, Japan) and a bone Gla protein (BGP) IRMA kit (Mitsubishi; Mitsubishi Yatron, Tokyo, Japan), respectively. we measured 1
,25-dihydroxyvitamin D and 25-hydroxyvitamin D using a 1,25-hydroxyvitamin D RIA kit (TFB, Toray-Fuji Bionics Llc, Tokyo, Japan: Immunodiagnostic Systems Ltd., Boldon, UK) and a 125I radioimmunoassay (RIA) kit (DiaSorin Inc., Stillwater, MN, USA), respectively. Serum Ca level was corrected for Alb by the formula (S-Ca; serum corrected Ca = Ca + (4 – Alb), if Alb < 4.0), unless otherwise stated. We measured the BMD of the second to fourth lumbar vertebrae (L2-4) and of the femoral neck with a dual-energy X-ray absorptiometer (DXA; Lunar Inc., Madison, WI, USA) in the posterioanterior projection. Values were expressed in grams per square centimetre and compared with the Asian reference value. All BMD measurements were made using the same machine. Patients whose vertebral radiographs demonstrated physical abnormalities of the spine such as aortic calcification, severe osteoarthritis, scoliosis or two or more lumbar spine fractures were excluded from analysis to avoid inaccurate estimation of lumbar BMD.
Statistical analysis
Data were analysed on a per protocol set basis. In the event of death from underlying disease, cessation of glucocorticoid therapy or discontinuation of risedronate for any reason, the data of the subject were censored after the event. Patients withdrawing within 3 months of the study period were excluded from analysis. Differences among the three groups were examined by Pearson's chi-square test, one-way analysis of variance (ANOVA) and the Kruskal–Wallis test for demographic factors, normal and non-normal continuous variables, respectively. Tukey's honestly significant difference test and the Kruskal–Wallis test with the Bonferoni correction were used for post hoc analysis for comparison. The homogeneity of groups A and B was examined in the same manner. Between-group analyses for percentage changes in BMD and bone markers at a certain time point were assessed by using an analysis of covariance model, which included baseline values as covariates and treatment groups as factors. A one-sample t-test was performed, after logarithmic transformation if necessary, for within-group analyses. Statistical tests were two-sided and P-values <0.05 were considered to be significant. Data are expressed as the mean ± SEM for continuous variables unless otherwise noted. Statistical analyses were performed with the JMP version 5.1.2J for Windows (SAS institute Inc., Cary, NC, USA).
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Results |
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Out of the 114 enrolled subjects, 88 (77.2%) received active vitamin D analogues at the beginning of the study, and groups A–C consisted of 38, 50 and 28 patients, respectively, at the time of assignment (Figure 1). Fifteen (19.2%) of 78 patients taking risedronate withdrew during the 1-year treatment period because of mild and transient adverse events such as gastrointestinal discomfort (Table 1). A total of 100 subjects were analysed. The mean glucocorticoid dose was tapered from 9.8 mg/day at baseline to 9.1, 8.0 and 7.1 mg/day at 1, 3 and 6 months, respectively. However, the cumulative doses of glucocorticoid during the study period did not differ significantly between the groups (1.64 ± 0.93, 1.34 ± 0.59, 1.24 ± 0.90 g in groups A–C, respectively, P = 0.14 for Kruskal–Wallis test). Only one case of bone fracture, requiring hospitalization, was reported in group B during the study period.
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The characteristics of the study population at baseline are shown in Table 2. Those patients who were not previously on active vitamin D therapy (group C) had significantly higher levels of iPTH, bone ALP, iOC and lower BMD at the lumbar spine and at the femoral neck than the patients with preceding active vitamin D therapy (groups A and B). S-NTX showed the same trend as bone ALP. There was no significant difference between groups A and B except for iPTH. All the groups had comparable levels of 25-hydroxyvitamin D and CrCl. Underlying renal diseases of our subjects are shown in Table 3.
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After 1 year of treatment, risedronate significantly increased BMD at the lumbar spine by 2.8 ± 1.3% and 2.1 ± 1.0% from baseline in groups B and C, respectively. In group A, which did not take risedronate, BMD decreased from baseline (–1.2 ± 0.6%) but did not change significantly (Figure 2A). Changes in BMD at the femoral neck were not obvious in any group (Figure 2B). There was only one case in group B whose lumbar BMD at 1 year had increased by nearly 40% from baseline because of the artifact by bone deformity without fracture, which was excluded at the time of analysis.
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Risedronate significantly decreased S-NTX after 3 months in groups B (P < 0.01) and C (P < 0.05), but not in group A (Figure 3A). The mean percentage changes in S-NTX from baseline at 6 months were +4.7, –19.6 and –14.6% in groups A–C, respectively (P < 0.05 for group A vs B). Bone ALP decreased at 6 months in groups B and C by 11.6 and 10%, respectively, but gradually increased in group A by up to 26.9% at 6 months (P < 0.05 for group A vs B or C) (Figure 3B). The changes in CrCl throughout the study period were comparable in all the groups (Table 4).
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The relationships between the change in the lumbar BMD from baseline at 1 year and the changes in each bone turnover marker after 3 and 6 months treatment with risedronate are shown in Figure 4. After stratification into tertiles by the reduction rate of bone markers at each time point, there was a mild (but not statistically significant) tendency of a stepwise increase in the lumbar BMD with the greater reduction in S-NTX at 6 months (Figure 4A). The mean percentage change in BMD in the highest tertile did not show a significant increase. A similar relation was weakly seen at 3 months in both markers (data not shown). As for bone ALP, the lowest tertile demonstrated a significant increase at 6 months, but the highest and intermediate tertiles did not (Figure 4B). The greater reduction than minimum significant change (MSC; 14.2 and 23.1% in S-NTX and bone ALP, respectively [15]) as positive in S-NTX and bone ALP at 6 months, the increase in lumbar BMD at 1 year was predicted with a sensitivity of 73.0 and 34.1%, a specificity of 46.2 and 100%, an accuracy of 66.0 and 49.1% and a positive predictive value of 81.8 and 100%, respectively. The same analysis was attempted in group A, but there was no such relation between the changes in lumbar BMD and in bone turnover markers (data not shown). The baseline values of bone turnover markers were not associated with percentage changes in lumbar BMD after 1 year of risedronate treatment (Figure 5).
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Discussion |
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The present study demonstrated that risedronate effectively counteracts bone resorption in CKD patients who take glucocorticoids, and that bone turnover markers are of some use in predicting the long-term efficacy of risedronate treatment.
CKD leads to bone loss as renal function declines, due primarily to reduced vitamin D activity and the consequent stimulation of parathyroid function in addition to the osteoporotic effect of glucocorticoid therapys which is often used in the treatment of underlying kidney diseases. Active vitamin D theoretically counteracts with both mechanisms. In fact the baseline iPTH levels in groups A and B were repressed compared with group C. But the BMD of group A, with normal to slightly impaired renal function, persistently decreased during the study period even though the dose of glucocorticoid was small (Figure 2). This clearly shows that monotherapy of active vitamin D failed to maintain the bone mass of CKD patients receiving glucocorticoids. The reasons for this different result from the previous study, in which 1.0 µg of alfacalcidol and 500 mg of Ca supplementation increased the lumbar BMD of the patients receiving long-term glucocorticoid therapy by 2.0% [16], might reside in CKD as underlying disease or in the dose of active vitamin D and Ca.
Risedronate significantly increased BMD at the lumbar spine but not at the femoral neck, which might simply mirror the fact that glucocorticoids induce osteoporosis especially in the lumbar spine [5]. Alternatively, this might be because cortical bone is less sensitive to bisphosphonate than trabecular bone [17]. The percentage increase in lumbar BMD after 1 year of risedronate treatment of our CKD patients was comparable with those of the patients with other diseases [18,19]. In our study, risedronate alone and in combination with active vitamin D did not differ in terms of the percentage increase in lumbar BMD, while the combination of bisphosphonate and active vitamin D for primary osteoporosis is superior to bisphosphonate alone [20]. This may be again because the dose of active vitamin D in our study was less than in the former study (0.41 vs 1.0 µg/day). It is noteworthy that hypercalciuria and resultant renal damage may occur when more than 0.5 µg alfacalcidol equivalent of active vitamin D is used. We think that these harmful events should be avoided, especially in CKD patients.
The usage and meaning of bone turnover markers in GIO have not yet been established well. Generally, suppression of enhanced bone turnover is thought to improve bone mineralization to increase BMD. Although not significant, a mild positive relation between the reduction rate of S-NTX and bone ALP, and the increase in BMD denotes the utility of bone turnover markers in the treatment of glucocorticoid-induced bone loss in CKD patients with anti-resorptive agents (Figure 4). Our data imply that the reduction rate of S-NTX and bone ALP is a better predictor of the favourable effects of risedronate than the baseline values. Both S-NTX and bone ALP are, however, not perfect markers for such patients, as S-NTX is affected with renal excretion or function and bone ALP with transcriptional regulation by glucocorticoids [21]. Indeed, the temporal increase in bone ALP level without any intervention in group A (Figure 3B) was supposedly caused in part by the reduced dose of glucocorticoid, and a similar change was reported by Wallach et al. [19]. As for S-NTX, Hamano et al. [22] recently invented the ‘Resorption Index’ in order to reduce renal interference in S-NTX. Until a new bone resorption marker that is not affected by kidney function and glucocorticoid doses comes into clinical practice, these bone markers will at least be of some help as clinical indices in the treatment of glucocorticoid-induced bone loss in CKD patients.
Some bisphosphonates are reported to induce severe adverse events such as osteonecrosis of the jaw [23], nephrotic syndrome [24] and oversuppression of bone turnover leading to brittle bones [25]. In our study, we observed glucocorticoid-related suppression of iOC at baseline (Table 2) and a decrease in bone ALP during risedronate treatment (Figure 3B). It remains to be elucidated whether long-term administration of risedronate to CKD patients receiving glucocorticoid therapy for years is safe and good for bone metabolism, and whether risedronate monotherapy and combination with active vitamin D have endocrinologically identical effect to the subsequent parathyroid function in CKD patients. We also need to follow-up the radiographic fractures of our subjects in order to confirm the clinical impact of increased BMD by risedronate.
In conclusion, risedronate, with or without active vitamin D, is an effective treatment for glucocorticoid-induced bone loss in CKD patients in terms of BMD. We can predict in part the response to the treatment with bone markers.
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Acknowledgements |
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This work is supported in part by Sanofi-Aventis (Tokyo, Japan) as declared as the conflict of interest.
Conflict of interest statement. The cost for the measurement of 25-hydroxy vitamin D was supported by Sanofi-Aventis selling sodium risedronate hydrate in Japan.
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References |
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[Abstract/Free Full Text]
Accepted in revised form: 28. 8.06
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