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Keywords:

  • Alendronate;
  • biphosphonates;
  • bone disease;
  • bone loss;
  • osteoporosis;
  • transplant complication

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Bone mineral density (BMD) and biochemical markers of bone-turnover were evaluated in a 2-year study in 58 long-term renal transplant recipients with good renal function. In the first year of study, data were collected and patients with osteoporosis and parameters of high bone turnover were classified as being at high risk for on-going bone loss (Group A; n = 29). Patients with lesser degrees of bone loss or without biochemical parameters of high bone turnover were followed longitudinally (Group B; n = 29). Group A patients were then placed on alendronate 10 mg/day and both groups were followed for an additional year. Changes in regional BMD and bone-turnover markers between the first and second year within each group were analyzed using paired tests. BMD in Group A, which had declined at the lumbar spine (− 1.6 ± 0.5%) and total femur (− 1.5 ± 0.4%) during the first year of the study, increased on alendronate therapy at both the lumbar spine (+ 3.4 ± 0.6%, p = 0.001) and total femur (+ 1.6 ± 0.6%, p < 0.001). These patients also experienced a significant decline in levels of serum alkaline phosphatase, osteocalcin, urinary levels of deoxypyridinoline and pyridinoline. In contrast, neither BMD nor biochemical markers changed significantly over 2 years in Group B. The current results demonstrate that renal transplant patients with osteoporosis and biochemical parameters of high bone turnover are at continued risk for bone loss. Therapy with a bisphosphonate can reverse this bone loss and even increase bone mass in these patients. Whether patients with lesser degrees of bone loss and/or patients without parameters of high bone turnover can also benefit from bisphosphonate therapy deserves further study.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Osteoporosis is a serious complication of kidney transplantation. Various factors have been postulated to contribute to post-transplant bone loss, including treatment with corticosteroids, the use of cyclosporine and cyclosporine-like agents and persistent hyperparathyroidism. In a previous cross-sectional study of long-term renal transplant recipients, we observed that osteoporosis or osteopenia was present in the majority of patients, and was associated with elevated biochemical indices of bone formation and bone resorption (1). The results of a subsequent longitudinal study confirmed that bone loss is greater in those patients with elevated biochemical markers of bone-turnover (2). These findings lend support to the hypothesis that continued bone loss in long-term renal transplant patients is associated with high bone-turnover. If accelerated bone resorption does play a role in post-transplant bone loss, this would provide a strong rationale for the use of antiresorptive therapy for the prevention and treatment of this complication. The current study was performed to evaluate this hypothesis by testing the efficacy and tolerability of alendronate as a treatment for this condition.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Study population

Sixty-two patients who were more than 1 year post-renal transplantation with preserved renal function (as defined by serum creatinine ≤ 2.5 mg/dL) were invited to enroll in this study, having participated in two prior observational studies (1,2). Levels of both 25(OH) vitamin D and 1,25(OH)2 vitamin D were previously reported to be normal in these patients (1). The mean age was 48.7 ± 1.4 years and the mean time post-transplant was 7.5 ± 0.6 years. Nine patients (15.5%) had end-stage renal disease due to diabetic nephropathy, while the remainder of patients had other causes, as previously described (1). Baseline immunosuppression consisted of prednisone 5–10 mg/day (in 98% of patients); and cyclosporine (in 74%) or tacrolimus (in 7%) with 50% on a third drug (azathioprine in 45%; mycophenolate mofetil in 5%). There were no episodes of acute rejection in any subject during the study period. All female subjects were estrogen-replete, as previously described (1,2). Fifty-eight patients gave written informed consent for this study, and the protocol was approved by the Yale Human Investigation Committee.

Study protocol

The study was conducted over a 2-year period. In the first year of the study (designated as −12–0 months) measurements of bone mineral density (BMD) and biochemical indices of bone-turnover were collected to identify patients at highest risk for bone loss. In the second year of study (designated as 0–12 months) these patients were treated with alendronate, while the remaining patients were followed for a second year without intervention. Patients qualified as being at high risk for on-going bone loss (Group A; n = 29) if, at study entry, they had either osteoporosis at the hip and/or spine with high levels of bone-turnover markers (see Laboratory studies) or if they had osteopenia of the hip and/or spine and experienced > 3% bone loss at either of these sites during the first year of the study. Subjects who did not meet these criteria were assigned to Group B (n = 29). These patients were not treated with alendronate since our intent was to restrict its use to those subjects judged to be at highest risk for continued bone loss. If patients in Group A experienced adverse effects on alendronate, such as dyspepsia or myalgia, alendronate therapy was held for 1 week, then resumed at the same dose following resolution of the inciting symptom. If the symptom recurred, alendronate therapy was again held for 1 week, then resumed at a lower dose of 10 mg every other day. If the symptom recurred at the lower dose, alendronate therapy was discontinued, but scheduled measurements of BMD and laboratory tests were performed until the completion of the study. The primary endpoint was the change in BMD over the 0–12-month period. Each patient served as her (his) own control.

In Group A patients, BMD was measured at − 12 months, 0 months, and after 6 and 12 months of alendronate therapy. Thus, group A patients served as their own controls before and after alendronate therapy. Serum intact parathyroid hormone (PTH), serum osteocalcin, urine pyridinoline (PYD) and deoxypyridinoline (DPD) were also measured at these time points. In Group B patients, BMD and the same laboratory parameters were measured at − 12, 0 and 12 months. Routine blood chemistries, including blood urea nitrogen (BUN), creatinine, calcium, phosphate, alkaline phosphatase and cyclosporine or tacrolimus levels, were measured every 6 months, or at greater frequency as dictated by clinical events.

Bone mineral density determinations

BMD was measured in the lumbar spine, hip, wrist and total body by dual energy X-ray absorptiometry (DEXA) using a Hologic® 4500 densitometer (Hologic, Waltham, NC, USA). Changes in BMD at the lumbar spine and total femur from − 12–0 months and 0–12 months were calculated, and expressed as annualized percent change in BMD. For changes in BMD in the hip, we limited our analysis to measurements in the total femur, to avoid repositioning difficulties inherent in the femoral neck measurement. The same scanner was used for all subjects, with the exception of one patient whose initial scan was performed with a different Hologic® 4500 densitometer at the same institution. One patient had bilateral hip prostheses, and therefore had no BMD results at the hip. The T-score is the number of standard deviations an individual BMD deviates from the mean value in young, adult-, race-, and sex-matched individuals. As recommended by the World Health Organization, we defined osteopenia as a T-score between – 1 and − 2.4, and osteoporosis as a T-score ≤–2.5 (3).

Laboratory studies and bone mineral metabolism

Serum BUN, creatinine, calcium, and phosphate were measured in the Yale New Haven Hospital Clinical Chemistry Laboratory using a standard autoanalyzer (Hitachi 747, Indianapolis, IN, USA). Creatinine clearance was calculated by the method of Cockroft Gault. Cyclosporine levels were measured in whole blood by immunoassay using a monoclonal antibody highly specific for cyclosporine. Tacrolimus levels were measured in whole blood using a microparticle enzyme immunoassay. Serum PTH was measured with an immunoradiometric assay which detects intact PTH, using a commercial laboratory (Quest, San Juan Capistrano, CA, USA). Biochemical assessment of bone turnover was performed using serum osteocalcin as an index of bone formation, and urine pyridinoline and deoxypyridinoline as indices of bone resorption (4,5). Patients were classified as having high bone turnover if they had an elevation of any of these 3 parameters. Serum osteocalcin was measured by a polyclonal radioimmunoassay (6). Concentrations of urine PYD and DPD were determined in 2-h fasting morning urine specimens by high-performance liquid chromatography and normalized to urinary creatinine excretion, as previously reported (7). Laboratory values in the first year of the study were the calculated mean of the values at − 12 and 0 months. This served as a baseline in Group A before alendronate therapy. Laboratory values in the second year of the study were calculated using the mean of the values at 6 and 12 months for Group A, and the actual values at 12 months for Group B.

Statistical analyses

All data are presented as mean ± SEM unless otherwise indicated. The Wilcoxon rank sum test was used to compare intragroup changes in regional BMD and laboratory parameters during the first year of the study (− 12–0 months) and the second year of the study (0–12 months), with each patient serving as her (his) own control, and using an intention-to-treat analysis. Calculations were performed using SPSS 6.1 for Macintosh (SPSS Inc., Chicago, IL, USA). A p-value of < 0.05 was considered statistically significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Twenty-nine patients in Group A began therapy with alendronate during the second year of the study. One patient died after 5 months of alendronate due to metastatic colon cancer. Four subjects had to discontinue alendronate therapy because of persistent gastrointestinal distress (n = 2) and myalgia (n = 2). The remaining 24 subjects in Group A completed the 12-month period of therapy. Five subjects complained of mild dyspepsia and three had mild myalgias, but neither complaint was severe enough to require discontinuation of therapy. All 29 patients in Group B completed follow-up. The clinical features of Groups A and B are shown in Table 1. The two groups were comparable in terms of age, sex distribution, renal function, and percentage of diabetes. Numbers in each group on either cyclosporine or tacrolimus were similar, as was cumulative prednisone dosage (Table 1). The groups differed mainly in their degree of bone loss. The mean T-scores at the hip and spine in Group A were significantly lower than Group B. Furthermore, 62% of Group A patients had frank osteoporosis and 93% had parameters of high bone turnover. In contrast, the majority (62%) of patients in Group B had osteopenia, while only 31% had frank osteoporosis and only half 52% had biochemical evidence of high bone turnover.

Table 1. : Clinical characteristics of patients in Group A (at high risk for on-going bone loss) and Group B (not at high risk for ongoing bone loss)
 Group A (n = 29)Group B (n = 29)
  1. Plus-minus values are means ±SEM

Age (years)48.6 ± 2.046.2 ± 2.0
Sex19 M/10 F20 M/9F
Creatinine clearance (mL/min)66 ± 474 ± 4
Time after transplantation (years) 8.1 ± 0.7 7.0 ± 0.9
Patients on calcineurin inhibitors  (%)24 (83)24 (83)
Cyclosporine2321
Tacrolimus 1 3
Cumulative prednisone dose  (mg)30 251 ± 246526 026 ± 3839
Diabetes mellitus – no. (%) 4 (14) 5 (17)
BMD L1-L4 (T-score)− 1.71 ± 0.19− 0.70 ± 0.24
BMD femoral neck (T-score)− 1.71 ± 0.13− 1.10 ± 0.15
BMD total femur (T-score)− 1.43 ± 0.13− 0.67 ± 0.16
BMD wrist (T-score)− 1.59 ± 0.33− 1.20 ± 0.25

Changes in bone mineral density

Following an intention to treat analysis, patients started on alendronate (n = 29) remained in this group even if they discontinued treatment. Group A had a decline in BMD of − 1.6 ± 0.5% in the lumbar spine and − 1.5 ± 0.4% in the total femur over the first year of the study, which was reversed during the second year of study when they received alendronate therapy (Figure 1). Thus BMD at the lumbar spine increased significantly by + 3.4 ± 0.6% (p < 0.001)) and by + 1.6 ± 0.6% in the hip (p < 0.001) (Figure 1). The increase in BMD at the hip was associated with a significant improvement in T-score at this site, with the mean value increasing from − 1.43 ± 0.13 before treatment to − 1.34 ± 0.14 after a year of alendronate (p = 0.008). There was no significant change in BMD at the wrist or total body during either the first or second year of the study. When the analysis was limited to the 24 patients in Group A who completed 12 months of alendronate therapy, the findings were unchanged.

image

Figure 1. Annual change in BMD in group A in lumbar spine and hip. Mean ± SEM. p-values by Wilcoxon test between first year (before alendronate; months − 12–0) and second year of the study are (on alendronate; months 0–12) indicated.

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By comparison, Group B showed a small increase in BMD during the first year of observation (Figure 2). This is not surprising, since those individuals exhibiting significant bone loss during this period were a priori classified into Group A (see Methods). Over the second year of observation, group B showed small and nonsignificant reductions in BMD at the spine, hip (Figure 2), wrist and total body, such that over the 2 years of follow-up there was no significant change in BMD at any skeletal site in this group.

image

Figure 2. Annual change in BMD in group B in lumbar spine and hip. Mean ± SEM. p-values by Wilcoxon test between first year (months − 12–0) and second year (months 0–12) of the study are indicated.

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Laboratory studies and bone mineral metabolism

In Group A, levels of serum osteocalcin and alkaline phosphatase, urine DPD and PYD decreased significantly while on alendronate therapy (Table 2). In contrast, there were no statistically significant changes in serum osteocalcin, alkaline phosphatase, urine PYD and DPD in Group B over the duration of the study (Table 3). In both groups, there were no significant changes in serum levels of PTH, calcium and phosphate over the study period. Alendronate therapy did not adversely affect renal function, or cyclosporine or tacrolimus blood levels.

Table 2. : Biochemical characteristics of Group A during the first year (before alendronate) and during the second year of the study (on alendronate therapy)
 − 12–0 months* Before0–12 monthsƒ Onp
  • Values are means ±SEM.

  • *

    Mean of the values at − 12 and 0 months.

  • ƒ

    Mean of the values at 6 and 12 months.

  • Abbreviations: Cr, creatinine; DPD, deoxypyridinoline; NS, not significant; PTH, parathyroid hormone; PYD, pyridinoline.

  • Normal values: parathyroid hormone, 10–65 pg/mL; alkaline phosphatase, 30–114 µ/l; osteocalcin, < 13 ng/mL; pyridinoline, 25–83 nmol/nmol creatinine (females), 23–65 nmol/nmol creatinine (males); deoxypyridinoline, 6–23 nmol/nmol creatinine (females), 6–26 nmol/nmol creatinine (males).

Creatinine (mg/dL)  1.5 ± 0.1  1.6 ± 0.1NS
Calcium (mg/dL)  9.6 ± 0.1  9.5 ± 0.1NS
Phosphate (mg/dL)  3.1 ± 0.1  3.1 ± 0.8NS
PTH (pg/mL)165.1 ± 46.3122.1 ± 14.9NS
Alkaline phosphatase (U/L) 75.0 ± 1.5 64.3 ± 4.80.0001
Osteocalcin (ng/mL) 11.4 ± 1.1  7.4 ± 1.50.005
Urine DPD (nmol/nmol Cr) 35.9 ± 4.3 28.4 ± 5.40.037
Urine PYD (nmol/nmol Cr)125.9 ± 12.8 82.1 ± 12.10.007
Table 3. : Biochemical characteristics of Group B during the first and second year of the study
 − 12–0 months*0–12 monthsƒp
  • Values are means ±SEM.

  • *

    Mean of the values at − 12 and 0 months.

  • ƒ

    Value at 12 months.

  • Abbreviations: Cr, creatinine; DPD, deoxypyridinoline; NS, not significant; PTH, parathyroid hormone; PYD, pyridinoline.

  • Normal values: parathyroid hormone, 10–65 pg/mL; alkaline phosphatase 30–114 µ/l; osteocalcin, < 13 ng/mL; pyridinoline, 25–83 nmol/nmol creatinine (females), 23–65 nmol/nmol creatinine (males); deoxypyridinoline, 6–23 nmol/nmol creatinine (females), 6–26 nmol/nmol creatinine (males).

Creatinine (mg/dL) 1.5 ± 0.1 1.6 ± 0.1NS
Calcium (mg/dL) 9.6 ± 0.1 9.4 ± 0.1NS
Phosphate (mg/dL) 3.2 ± 0.1 3.1 ± 0.1NS
PTH (pg/mL)84.3 ± 7.489.3 ± 8.5NS
Alkaline phosphatase (U/L)78.2 ± 4.975.3 ± 4.9NS
Osteocalcin (ng/mL)12.3 ± 2.014.0 ± 5.2NS
Urine DPD (nmo/nmol Cr)31.0 ± 8.825.1 ± 6.6NS
Urine PYD (nmol/nmol Cr)93.6 ± 19.976.6 ± 12.9NS

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

The current study demonstrates that in long-term (> 1 year) renal transplant patients with high bone-turnover osteoporosis or osteopenia, bisphosphonate therapy can effectively decrease the rate of bone loss and can, in fact, increase bone mass over a year of treatment. The drug was well tolerated by the majority of our patients although drug toxicity did lead to discontinuation of treatment in 13.8% of patients.

Osteoporosis and osteopenia are important complications after transplantation, and may results in significant morbidity. In the renal transplant population, bone disease is multifactorial in etiology. The effects of glucocorticoids, calcineurin inhibitors and pre-existing bone disease (either osteitis fibrosis cystica or adynamic bone disease) all conspire to reduce bone mass in this population (1,2,8–12). In our original cross-sectional study, we found that urinary levels of PYD and DPD were independent predictors of bone mass at the hip, with urine PYD being the strongest predictor of bone mass, raising the possibility that elevated rates of bone resorption contribute to accelerated bone loss in long-term renal transplant recipients (1). This idea is supported by findings in a subsequent longitudinal study, which demonstrated that patients with elevated biochemical indices of bone turnover have a higher rate of bone loss over 1 year than those without high bone turnover (2). In the aggregate, these data, when combined with the results of the current study, suggest that assessing bone-turnover rates in renal transplant patients may be helpful in identifying those patients who are at greatest risk for continued bone loss. Such patients may benefit from antiresorptive therapy.

Bisphosphonates have long been used in the treatment of high bone-turnover diseases. They bind preferentially to skeletal sites where turnover rates are high, such as in trabecular bone, and directly suppress the number and activity of osteoclasts (13). Fewer osteoclasts are recruited to bone remodeling sites and the differentiation of osteoclast precursors is impaired. By decreasing resorption, trabecular thinning is lessened and the number of trabecular perforations is reduced, both of which can cause impaired bone strength.

In this study, renal transplant recipients with reduced bone mass, high bone turnover and ongoing bone loss (Group A) had a significant increase in BMD in response to alendronate therapy (Figure 1). In contrast, patients with osteopenia or those with osteoporosis but without parameters of high bone turnover (Group B) continued to have stable bone mass during the second year of observation (Figure 2). The improvement in BMD in Group A was associated with a 35%, 21% and 35% decrease in mean urinary levels of PYD, DPD and circulating levels of osteocalcin, respectively, all of which were statistically significant (Table 2). These markers have been shown to be valid indices of bone turnover and are unaffected by the mild degree of renal insufficiency seen in our patients (14,15) In contrast, levels of bone-turnover markers in Group B did not change significantly over the period of observation. The small number of diabetic patients in this study did not allow a separate analysis of these patients.

Prior experience with bisphosphonate therapy in the transplant population has been largely limited to their use in preventing bone loss in the immediate post-transplant period (16–20). Intravenous pamidronate has been used successfully in heart and kidney transplant recipients (16,18,19). There has been only one report of antiresorptive agents in the treatment of osteopenia and osteoporosis following kidney transplantation (20). In that study, Grotz et al. reported that daily clodronate therapy also resulted in an increase in lumbar BMD of 4.6% after 1 year. In the Grotz study, there were no a priori selection criteria for bisphosphonate therapy. However, in the age of medical cost containment, it may be helpful to identify a subset of patients who would most benefit from such therapy. Since up to one third of transplant patients with osteopenia or osteoporosis can have adynamic bone histology (21,22), a lesion which could be worsened by the use of biphosphonates, we restricted our use of alendronate to patients with osteoporosis and biochemical evidence for high bone turnover or to patients with osteopenia and a high rate of bone loss (≥ 3%/year) (Group A). Whether patients with lesser degrees of bone loss or without high bone turnover markers (Group B) would also benefit needs to be examined. The long-term use of these agents, especially in patients with greater degrees of allograft dysfunction than seen in our patients, must also be studied since delayed excretion of these agents could potentially interfere with bone remodeling.

Alendronate therapy did not adversely affect allograft function in our study. These data are consistent with those of Grotz et al. who also noted no adverse effect of clodronate on renal function. Despite the fact that our patients were on a variety of drugs that may cause gastrointestinal distress, more than 85% of our patients were able to complete 1 year of alendronate therapy. It is to be hoped that newer bisphosphonate preparations or new dosing regimens will reduce the incidence of side-effects from these drugs. A recent report indicates that once-weekly therapy with 70 mg alendronate was well tolerated and equally efficacious as 10 mg once daily (23).

Since the endpoint in our study was a change in BMD, it remains to be determined if this effect of alendronate translates into a reduced risk of fracture in transplant patients. It is encouraging that the use of alendronate in nontransplant patients with either postmenopausal osteoporosis or glucocorticoid-induced osteoporosis results in improvement of BMD and a decrease in fracture incidence (24–26). However, there may be differences between transplant-associated osteoporosis and postmenopausal bone disease, and some authors feel that BMD may not have the same predictive value in renal transplant patients as in postmenopausal osteoporosis (17,27,28). Therefore it will be important to directly examine the effect of alendronate on fracture-rates in long-term renal transplant recipients. This will require a much larger sample size and longer periods of observation.

In the current study, PTH levels, elevated in both groups, did not significantly change on alendronate therapy. The preferred therapy for long-term renal transplant patients with high bone turnover and mild elevation of PTH has yet to be determined. In contrast to patients with greater degrees of renal insufficiency, we and others have found levels of 1, 25 (OH)2 vitamin D3 to be normal in renal transplant patients with well-functioning grafts (1,29). Furthermore, treatment of renal transplant patients with 1, 25 (OH)2 vitamin D3 for 1 year did not improve bone density despite a significant decrease in levels of parathyroid hormone (29). Whether levels of PTH should be completely normalized in these patients remains to be determined.

In summary, the current results demonstrate that bisphosphonate therapy, which was relatively well tolerated, is effective at improving bone mass in renal transplant patients with osteoporosis and biochemical markers of high bone turnover. Whether the bisphosphonates will be useful in transplant patients with osteopenia, or in those without evidence for high bone-turnover is a subject for further study.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

This work was performed on the Yale University Adult GCRC (NCRR grant RR0-0125). This work was supported in part by an educational grant from the National Kidney Foundation of Connecticut. Dr Insogna is supported by grants from the NIH (AG15345 and The Yale Core Center for Musculoskeletal Disorders AR46032). The authors wish to thank Luz Vega and Alice Ellison for assistance in specimen collection and BMD scheduling, Tony Ma of the Yale Informatics Core for assistance with graphics, and the staffs of the General Clinical Research Center at Yale University and the Yale Bone Center.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References