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- Materials and Methods
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.
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- Materials and Methods
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)|
|Age (years)||48.6 ± 2.0||46.2 ± 2.0|
|Sex||19 M/10 F||20 M/9F|
|Creatinine clearance (mL/min)||66 ± 4||74 ± 4|
|Time after transplantation (years)|| 8.1 ± 0.7|| 7.0 ± 0.9|
|Patients on calcineurin inhibitors (%)||24 (83)||24 (83)|
|Tacrolimus|| 1|| 3|
|Cumulative prednisone dose (mg)||30 251 ± 2465||26 026 ± 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.
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.
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* Before||0–12 monthsƒ On||p|
|Creatinine (mg/dL)|| 1.5 ± 0.1|| 1.6 ± 0.1||NS|
|Calcium (mg/dL)|| 9.6 ± 0.1|| 9.5 ± 0.1||NS|
|Phosphate (mg/dL)|| 3.1 ± 0.1|| 3.1 ± 0.8||NS|
|PTH (pg/mL)||165.1 ± 46.3||122.1 ± 14.9||NS|
|Alkaline phosphatase (U/L)|| 75.0 ± 1.5|| 64.3 ± 4.8||0.0001|
|Osteocalcin (ng/mL)|| 11.4 ± 1.1|| 7.4 ± 1.5||0.005|
|Urine DPD (nmol/nmol Cr)|| 35.9 ± 4.3|| 28.4 ± 5.4||0.037|
|Urine PYD (nmol/nmol Cr)||125.9 ± 12.8|| 82.1 ± 12.1||0.007|
Table 3. : Biochemical characteristics of Group B during the first and second year of the study
| ||− 12–0 months*||0–12 monthsƒ||p|
|Creatinine (mg/dL)|| 1.5 ± 0.1|| 1.6 ± 0.1||NS|
|Calcium (mg/dL)|| 9.6 ± 0.1|| 9.4 ± 0.1||NS|
|Phosphate (mg/dL)|| 3.2 ± 0.1|| 3.1 ± 0.1||NS|
|PTH (pg/mL)||84.3 ± 7.4||89.3 ± 8.5||NS|
|Alkaline phosphatase (U/L)||78.2 ± 4.9||75.3 ± 4.9||NS|
|Osteocalcin (ng/mL)||12.3 ± 2.0||14.0 ± 5.2||NS|
|Urine DPD (nmo/nmol Cr)||31.0 ± 8.8||25.1 ± 6.6||NS|
|Urine PYD (nmol/nmol Cr)||93.6 ± 19.9||76.6 ± 12.9||NS|
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- Materials and Methods
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.