- Email: [email protected]
Effect of bisphosphonates on renal function in patients with osteoporosis
European Geriatric Medicine 4 (2013) 380–383
Available online at
www.sciencedirect.com
Research paper
Effect of bisphosphonates on renal function in patients with osteoporosis L. Gifre a,*, P. Peris a,b, A. Monegal a,b, A. Martı´nez-Ferrer a, ˜ abens a,b M.V. Herna´ndez a, N. Guan a b
Metabolic Bone Diseases Unit, Service of Rheumatology, Hospital Clı´nic, IDIBAPS, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain CIBERehd, Hospital Clı´nic of Barcelona, Barcelona, Spain
A R T I C L E I N F O
A B S T R A C T
Article history: Received 2 April 2013 Accepted 10 June 2013 Available online 5 July 2013
The aim of this study was to analyze renal function and its long-term evolution in patients treated with bisphosphonates (BP) for osteoporosis. Methods: One hundred patients (89F/11 M) (mean age of 70 9 years) treated with BP for osteoporosis during at least 1 year were consecutively included. Renal function (evaluated by serum creatinine and Cockroft-Gault for estimation of creatinine clearance [CrCl] before and after treatment), and clinical data (presence of hypertension, diabetes and anti-inflammatory treatment) were recorded in all patients. Renal insufficiency was considered as CrCl < 60 ml/min and impaired renal function as a decrease of 25% CrCl during treatment. Results: The mean treatment time with BP was 49 31 months. Thirty-nine percent of patients had CrCl < 60 before starting BP and only three patients had creatinine 1.4 mg/dl. Patients with CrCl < 60 were older (78 7 vs. 66 7, P < 0.001) than patients with CrCl > 60. In the whole group, there were no significant changes in renal function during BP treatment (baseline creatinine 0.91 0.2 vs. 0.89 0.3 posttreatment; CrCl baseline 66 20 vs. 66 23 post-treatment, P = ns). However, 10% of patients had renal function impairment independently of the type of BP treatment and comorbidities. Age was correlated with serum creatinine values (r = 0.27, P = 0.007) and the changes of creatinine (r = 0.26, P = 0.009) and CrCl values (r = –0.25, P = 0.012). A CrCl < 45 ml/min was an independent predictor of renal function impairment. Conclusions: Nearly 40% of patients treated for osteoporosis have renal insufficiency, a finding related to age. Although a significant decrease in CrCl was not observed in relation to BP treatment, 10% of patients showed impairment in renal function, suggesting the need to control CrCl in these patients. ß 2013 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved.
Keywords: Bisphosphonates Renal impairment Renal insufficiency Renal function
1. Introduction Bisphosphonates (BP) are the most commonly used treatment for osteoporosis [1–3]. Although, these agents have shown a good safety profile, several cases of renal impairment after treatment have been described, especially after intravenous administration [4,5], a finding that has not been confirmed in randomised controlled-trials [1,3]. Nonetheless, it should be pointed out that most of the osteoporosis clinical trials did not enrol patients based on a pre-specified creatinine clearance (CrCl) including individuals with normal serum creatinine values. The lack of clinical data in patients with osteoporosis and severe renal impairment and the fact that BP are not metabolized and excreted via the renal system have led to warnings related to the use of these compounds in
* Corresponding author. Tel.: +34 932275400; fax: +34 93279386. E-mail address: [email protected] (L. Gifre).
these patients. Thus, BP are not indicated in patients with renal impairment, especially with CrCl < 30 ml/min [6]. As both osteoporosis and renal insufficiency are known to become more prevalent with age, it is important to control the renal safety of BP for osteoporosis treatment. In addition, these individuals frequently have comorbidities, such as hypertension, diabetes, or anti-inflammatory drug consumption which may also affect renal function. Therefore, the aim of this study was to analyze renal function in patients treated with BP for osteoporosis and its long-term evolution. 2. Patients and methods This one-year cross-sectional study consecutively included 100 patients (89 females/11 males) aged 54–86 (mean SD 70 9 years) with osteoporosis, at their annual follow-up, who had been receiving treatment with BP for at least 1 year. We included patients attending an outpatient Metabolic Bone Diseases Unit who fulfilled
1878-7649/$ – see front matter ß 2013 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved. http://dx.doi.org/10.1016/j.eurger.2013.06.008
L. Gifre et al. / European Geriatric Medicine 4 (2013) 380–383
the inclusion criteria: having osteoporosis treated with BP for at least 1 year and data on renal function prior to the onset of BP and at the time of evaluation. Clinical data, including the evaluation of comorbidities (presence of hypertension, diabetes and anti-inflammatory treatment), type of BP used, duration of treatment and body mass index (BMI) were recorded in all patients. We evaluated serum calcium and phosphate, liver and renal function tests by standard procedures in all patients prior to BP treatment and at the time of the visit (post-treatment). CrCl was estimated in all patients according to the Cockroft-Gault equation (based on age, sex, weight and creatinine) [7]. Renal insufficiency was defined as a CrCl < 60 ml/min (severe renal insufficiency was defined as CrCl < 30 ml/min) [6]. Renal impairment was defined as any of following abnormalities: an increase 0.5 mg/dl over the baseline serum creatinine value if the baseline value was > 1.4 mg/dl; a decrease 25% in CrCl from the baseline value [8]. The diagnosis of osteoporosis was established by densitometric criteria [9]. Ethical approval was obtained from our hospital Ethics Committee and all participants provided informed consent. Data are expressed as mean SD (standard deviation of the mean). The Student’s T and the non-parametric Kruskal–Wallis tests were used to compare differences for continuous variables. Differences between proportions were assessed by the Chi square test. Logistic regression analysis was used to identify the independent predictors for renal impairment and to estimate the odds ratio and the 95% CI. A two-tailed P value of < 0.05 was considered statistically significant. 3. Results The characteristics of the patients are shown in Table 1.
Alendronate and risedronate were the most frequently used BP, with 43% and 41% of the patients being treated with these agents, respectively while the remainder was treated with ibandronate (11%) and intravenous zoledronate (5%). The mean duration of treatment with BP was 49 31 months (range: 12–134). Thirtyeight percent of patients had associated hypertension, 17% had diabetes and 28% were also treated with anti-inflammatories. Thirtynine patients had CrCl < 60 ml/min before starting BP treatment with one having values < 30 ml/min; only three patients had serum creatinine values 1.4 mg/dl at this time. Patients with CrCl < 60 were older (78 7 vs. 66 7, P < 0.001) and had lower BMI (26 3 vs. 28 4, P = 0.02) than patients with CrCl > 60. There were no significant differences in the presence of associated disorders (hypertension or diabetes) between the two groups. Treatment with anti-inflammatories was more frequent among patients with CrCl > 60 (36% vs. 15%, P = 0.02). There were no significant changes in renal function during BP treatment (basal serum creatinine 0.91 0.2 vs. 0.89 0.3 mg/dl post-treatment, P = ns; basal CrCl 66 20 vs. 66 23 post-treatment, P = ns) or when patients were evaluated based on CrCl (CrCl < or > 60). However, when we evaluated renal function impairment (decrease in CrCl 25% and/or increase 0.5 mg/dl in serum creatinine), 10% of patients had renal function impairment (15% in CrCl < 60 group vs. 7% in CrCl > 60 group, P = ns) with five patients presenting CrCl values < 30 ml/min at this time. Patients with renal impairment were older and had higher creatinine values at baseline and more frequently (50% vs. 17%, P = 0.016) showed moderante renal insufficiency (CrCl < 45) than those without renal impairment (Table 2). Renal function impairment was independent of the type of BP treatment (five out ten patients were treated with risedronate, four with alendronate and one with ibandronate). None of the patients treated with zoledronate showed renal impairment. Although no significant differences were observed in the presence of associated comorbidities Table 2 Characteristics of the patients according to renal function evolution. Renal impairmenta n = 10
No renal impairment n = 90
P
Age (years)
77 9 (59–86)
69 9 (54–86)
0.012
Gender (female/male)
9/1
80/10
0.915
Creat. at baseline (mg/dl)
1.06 0.32 (0.6–1.64)
0.89 0.17 (0.62–1.75)
0.049
CrCl at baseline (ml/min)
65 37 (34–145)
65 17 (30–110)
0.352
Creat. after BP treatment (mg/dl)
1.40 0.48 (0.8–2.23)
0.83 0.20 (0.49–1.92)
0.001
CrCl after BP treatment (ml/min)
44 24 (21–94)
68 19 (28–105)
0.003
Comorbidities (%) Hypertension Diabetes Anti-inflammatory use
60 30 40
36 16 27
0.131 0.249 0.373
Type of BP used (%) Alendronate Risedronate Ibandronate Zoledronate
40 50 10 0
43 40 11 6
0.847
58 32 (12–104)
48 31 (12–134)
0.315
Table 1 Clinical characteristics of the patients. All participants n = 100 Age (years) Gender BMI (kg/m2)
70 9 (54–86) 89 females/11 males 27 4 (19–39)
Comorbidities (%) Hypertension Diabetes Anti-inflammatory use
38 17 28
Type of bisphosphosphonate used (%) Aledronate Risedronate Ibandronate Zoledronate
43 41 11 5
Duration of treatment (months)
49 31 (12–134)
Cause of osteoporosis (%) Postmenopausal Glucocorticoids Others
65 22 13
Creatinine at baseline (mg/dl) Patients with creatinine at baseline 1.4 mg/dl (%)
0.91 0.2 (0.6–1.75) 3
CrCl at baseline (ml/min) Patients with CrCl < 30 ml/min (%) Patients with CrCl 30 to 60 ml/min (%) Patients with CrCl > 60 ml/min (%)
66 20 (30–145) 1 38 61
Duration of treatment (months)
Values are mean SD (range), unless otherwise indicated. BMI: body mass index; CrCl: creatinine clearance.
381
Values are mean SD (range), unless otherwise indicated. Creat: creatinine; CrCl: creatinine clearance; BP: bisphosphonate. a Renal impairment: defined as an increase 0.5 mg/dl over the baseline serum creatinine if the baseline value was > 1.4 mg/dl and/or a decrease 25% in CrCl from the baseline value.
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L. Gifre et al. / European Geriatric Medicine 4 (2013) 380–383
between both groups of patients, patients with renal impairment tended to have a higher number of comorbidities (Table 2). Age was correlated with serum creatinine values (r = 0.27, P = 0.007) and with changes in creatinine (r = 0.26, P = 0.009) and CrCl values (r = –0.25, P = 0.012). No relation was observed between changes in CrCl and duration of BP treatment. The logistic regression analysis showed that the probability of renal function impairment was nearly 6-fold higher in patients with CrCl < 45 ml/min at baseline (OR, 5.92; 95% CI, 1.5–23.4, P = 0.01). A CrCl < 45 ml/min was the only independent predictor variable of renal function impairment.
4. Discussion This study shows that nearly 40% of patients with osteoporosis attended in a Metabolic Bone Diseases Unit had renal insufficiency and that BP treatment did not impair renal function. Thus, no significant changes in renal function parameters, serum creatinine and CrCl were observed after a mean period of treatment of 49 months with these agents. Nevertheless, it should be pointed out that 10% of the patients showed a significant decrease in renal function, a finding that was related to age. These data are in accordance with previous studies indicating a high prevalence of renal insufficiency in aged population. Thus, in the general population in our country, 21% to 49% of individuals over 64 have renal insufficiency (ClCr < 60 ml/min) [10,11], with associated comorbidities, such as hypertension or diabetes, also influencing renal function [10,12,13]. In addition, previous studies have shown a decline in the glomerular filtration rate with aging, independently of clinically associated conditions, thereby indicating that this decline is an inevitable consequence of aging [14]. Moreover, despite most individuals having stable renal function during years, there is a subset of up to 21.6% of individuals that present a significant decrease in renal function [15]. In our study 10% of patients presented a significant impairment in renal function; these patients were older, had higher serum creatinine values and a higher frequency of decreased CrCl less than 45 ml/min at baseline, a finding also described in previous reports [12]. Nevertheless, it should be noted that determination of serum creatinine levels was not useful for evaluating renal function in these patients. Indeed, whereas only 3% of patients had serum creatinine levels over 1.4 mg/dl, nearly 40% had a CrCl under 60, clearly indicating the need to evaluate this parameter in these patients. Thus, baseline CrCl was the principal predictor for renal function impairment, with a 6-fold higher probability for this clinical complication in patients with CrCl under 45 ml/min. In the present study, treatment with BP was not associated with impairment in renal function, thus, renal function parameters, creatinine levels and CrCl did not change with treatment, even when patients were evaluated based on baseline CrCl, that is, patients with CrCl under or over 60. These results also coincide with previous data related to the effect of BP on renal function. Thus, patients receiving either oral alendronate or risedronate during 4 and 3 years, respectively, for osteoporosis did not show impairment in renal function [1,3]. In addition, the antiosteoporotic effect of these drugs seemed to be independent of baseline renal function. Conversely, intravenous BP has been related to impairment in renal function in some studies, especially when they are administered rapidly or in patients with previous renal failure [5,6,16]. Nonetheless, none of our patients treated with intravenous zoledronic acid presented a decrease in renal function and randomised controlled-trials with these agents have not shown impairment in renal function [17–20].
We also observed a significantly lower frequency of antiinflammatory treatment in patients with renal insufficiency (CrCl < 60), a finding which may be attributed to correct clinical practice involving a decrease in the use of these compounds in patients with renal failure. This study has several limitations such as the absence of a nontreated control group, the use of retrospective data collection from the patients’ clinical histories, and the small number of patients included. Nevertheless, the results of this study are based on patients attended in a Metabolic Bone Disease Unit and therefore can be applied to current clinical practice. In conclusion, renal insufficiency is frequently observed in patients who consult for osteoporosis, a finding that was related to age. Although only 10% of patients showed long-term impairment in renal function, our results indicate the need to control CrCl in these patients, especially in those with values under 45 ml/min. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Author contribution All authors have made substantial contributions to all of the following. The conception and design of the study was performed ˜ abens and P. Peris. The acquisition of data was carried by N. Guan out by L. Gifre and A. Martı´nez-Ferrer. Intellectual analysis and interpretation of data was performed by A. Monegal and M.V. Herna´ndez and finally, drafting the article was performed by L. Gifre and P. Peris. Final approval of the version to be submitted was given by all authors. References [1] Miller PD, Roux C, Boonen S, Barton IP, Dunlap LE, Burgio DE. Safety and efficacy of risedronate in patients with age-related reduced renal function as estimated by the Cockcroft and Gault method: a pooled analysis of nine clinical trials. J Bone Miner Res 2005;20:2105–15. [2] Hernandez MV, Peris P, Monegal A, et al. Effects of intravenous pamidronate on renal function, bone mineral metabolism and bone mass in patients with severe osteoporosis. Am J Med Sci 2010;339:225–9. [3] Jamal SA, Bauer DC, Ensrud KE, et al. Alendronate treatment in women with normal to severely impaired renal function: an analysis of the fracture intervention trial. J Bone Miner Res 2007;22:503–8. [4] Markowitz GS, Appel GB, Fine PL, et al. Collapsing focal segmental glomerulosclerosis following treatment with high-dose pamidronate. J Am Soc Nephrol 2001;12:1164–72. [5] Markowitz GS, Fine PL, Stack JI, Kunis CL, Radhakrishnan J, Palecki W. Toxic acute tubular necrosis following treatment with zoledronate (Zometa). Kidney Int 2003;64:281–9. [6] Miller PD. The kidney and bisphosphonates. Bone 2011;49:77–81. [7] Perrone RD, Madias NE, Levey AS. Serum creatinine as an index of renal function: new insights into old concepts. Clin Chem 1992;38:1933–53. [8] Perazella MA, Markowitz GS. Bisphosphonate nephrotoxicity. Kidney Int 2008;74:1385–93. [9] Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO Study Group. World Health Organ Tech Rep Ser 1994;843:1–129. [10] Otero A, de Francisco A, Gayoso P, Garcia F. Prevalence of chronic renal disease in Spain: results of the EPIRCE study. Nefrologia 2010;30:78–86. [11] Almirall J, Vaqueiro M, Anton E, et al. [Prevalence of chronic kidney disease in community-dwelling elderly and associated cardiovascular risk factors]. Nefrologia 2005;25:655–62. [12] Imai E, Horio M, Yamagata K, et al. Slower decline of glomerular filtration rate in the Japanese general population: a longitudinal 10-year follow-up study. Hypertens Res 2008;31:433–41. [13] Eriksen BO, Tomtum J, Ingebretsen OC. Predictors of declining glomerular filtration rate in a population-based chronic kidney disease cohort. Nephron Clin Pract 2010;115:c41–50. [14] Fliser D, Franek E, Ritz E. Renal function in the elderly – is the dogma of an inexorable decline of renal function correct? Nephrol Dial Transplant 1997; 12:1553–5.
L. Gifre et al. / European Geriatric Medicine 4 (2013) 380–383 [15] Lindeman RD, Tobin J, Shock NW. Longitudinal studies on the rate of decline in renal function with age. J Am Geriatr Soc 1985;33:278–85. [16] Zuradelli M, Masci G, Biancofiore G, et al. High incidence of hypocalcemia and serum creatinine increase in patients with bone metastases treated with zoledronic acid. Oncologist 2009;14:548–56. [17] Reid IR, Brown JP, Burckhardt P, et al. Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med 2002;346: 653–61.
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[18] Lyles KW, Colon-Emeric CS, Magaziner JS, et al. Zoledronic acid in reducing clinical fracture and mortality after hip fracture. N Engl J Med 2007; 357:nihpa40967. [19] Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007;356: 1809–22. [20] Lafage-Proust MH. Once-yearly intravenous zoledronate does not impair renal function in postmenopausal women. Kidney Int 2008;74:557–9.
Available online at
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Research paper
Effect of bisphosphonates on renal function in patients with osteoporosis L. Gifre a,*, P. Peris a,b, A. Monegal a,b, A. Martı´nez-Ferrer a, ˜ abens a,b M.V. Herna´ndez a, N. Guan a b
Metabolic Bone Diseases Unit, Service of Rheumatology, Hospital Clı´nic, IDIBAPS, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain CIBERehd, Hospital Clı´nic of Barcelona, Barcelona, Spain
A R T I C L E I N F O
A B S T R A C T
Article history: Received 2 April 2013 Accepted 10 June 2013 Available online 5 July 2013
The aim of this study was to analyze renal function and its long-term evolution in patients treated with bisphosphonates (BP) for osteoporosis. Methods: One hundred patients (89F/11 M) (mean age of 70 9 years) treated with BP for osteoporosis during at least 1 year were consecutively included. Renal function (evaluated by serum creatinine and Cockroft-Gault for estimation of creatinine clearance [CrCl] before and after treatment), and clinical data (presence of hypertension, diabetes and anti-inflammatory treatment) were recorded in all patients. Renal insufficiency was considered as CrCl < 60 ml/min and impaired renal function as a decrease of 25% CrCl during treatment. Results: The mean treatment time with BP was 49 31 months. Thirty-nine percent of patients had CrCl < 60 before starting BP and only three patients had creatinine 1.4 mg/dl. Patients with CrCl < 60 were older (78 7 vs. 66 7, P < 0.001) than patients with CrCl > 60. In the whole group, there were no significant changes in renal function during BP treatment (baseline creatinine 0.91 0.2 vs. 0.89 0.3 posttreatment; CrCl baseline 66 20 vs. 66 23 post-treatment, P = ns). However, 10% of patients had renal function impairment independently of the type of BP treatment and comorbidities. Age was correlated with serum creatinine values (r = 0.27, P = 0.007) and the changes of creatinine (r = 0.26, P = 0.009) and CrCl values (r = –0.25, P = 0.012). A CrCl < 45 ml/min was an independent predictor of renal function impairment. Conclusions: Nearly 40% of patients treated for osteoporosis have renal insufficiency, a finding related to age. Although a significant decrease in CrCl was not observed in relation to BP treatment, 10% of patients showed impairment in renal function, suggesting the need to control CrCl in these patients. ß 2013 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved.
Keywords: Bisphosphonates Renal impairment Renal insufficiency Renal function
1. Introduction Bisphosphonates (BP) are the most commonly used treatment for osteoporosis [1–3]. Although, these agents have shown a good safety profile, several cases of renal impairment after treatment have been described, especially after intravenous administration [4,5], a finding that has not been confirmed in randomised controlled-trials [1,3]. Nonetheless, it should be pointed out that most of the osteoporosis clinical trials did not enrol patients based on a pre-specified creatinine clearance (CrCl) including individuals with normal serum creatinine values. The lack of clinical data in patients with osteoporosis and severe renal impairment and the fact that BP are not metabolized and excreted via the renal system have led to warnings related to the use of these compounds in
* Corresponding author. Tel.: +34 932275400; fax: +34 93279386. E-mail address: [email protected] (L. Gifre).
these patients. Thus, BP are not indicated in patients with renal impairment, especially with CrCl < 30 ml/min [6]. As both osteoporosis and renal insufficiency are known to become more prevalent with age, it is important to control the renal safety of BP for osteoporosis treatment. In addition, these individuals frequently have comorbidities, such as hypertension, diabetes, or anti-inflammatory drug consumption which may also affect renal function. Therefore, the aim of this study was to analyze renal function in patients treated with BP for osteoporosis and its long-term evolution. 2. Patients and methods This one-year cross-sectional study consecutively included 100 patients (89 females/11 males) aged 54–86 (mean SD 70 9 years) with osteoporosis, at their annual follow-up, who had been receiving treatment with BP for at least 1 year. We included patients attending an outpatient Metabolic Bone Diseases Unit who fulfilled
1878-7649/$ – see front matter ß 2013 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved. http://dx.doi.org/10.1016/j.eurger.2013.06.008
L. Gifre et al. / European Geriatric Medicine 4 (2013) 380–383
the inclusion criteria: having osteoporosis treated with BP for at least 1 year and data on renal function prior to the onset of BP and at the time of evaluation. Clinical data, including the evaluation of comorbidities (presence of hypertension, diabetes and anti-inflammatory treatment), type of BP used, duration of treatment and body mass index (BMI) were recorded in all patients. We evaluated serum calcium and phosphate, liver and renal function tests by standard procedures in all patients prior to BP treatment and at the time of the visit (post-treatment). CrCl was estimated in all patients according to the Cockroft-Gault equation (based on age, sex, weight and creatinine) [7]. Renal insufficiency was defined as a CrCl < 60 ml/min (severe renal insufficiency was defined as CrCl < 30 ml/min) [6]. Renal impairment was defined as any of following abnormalities: an increase 0.5 mg/dl over the baseline serum creatinine value if the baseline value was > 1.4 mg/dl; a decrease 25% in CrCl from the baseline value [8]. The diagnosis of osteoporosis was established by densitometric criteria [9]. Ethical approval was obtained from our hospital Ethics Committee and all participants provided informed consent. Data are expressed as mean SD (standard deviation of the mean). The Student’s T and the non-parametric Kruskal–Wallis tests were used to compare differences for continuous variables. Differences between proportions were assessed by the Chi square test. Logistic regression analysis was used to identify the independent predictors for renal impairment and to estimate the odds ratio and the 95% CI. A two-tailed P value of < 0.05 was considered statistically significant. 3. Results The characteristics of the patients are shown in Table 1.
Alendronate and risedronate were the most frequently used BP, with 43% and 41% of the patients being treated with these agents, respectively while the remainder was treated with ibandronate (11%) and intravenous zoledronate (5%). The mean duration of treatment with BP was 49 31 months (range: 12–134). Thirtyeight percent of patients had associated hypertension, 17% had diabetes and 28% were also treated with anti-inflammatories. Thirtynine patients had CrCl < 60 ml/min before starting BP treatment with one having values < 30 ml/min; only three patients had serum creatinine values 1.4 mg/dl at this time. Patients with CrCl < 60 were older (78 7 vs. 66 7, P < 0.001) and had lower BMI (26 3 vs. 28 4, P = 0.02) than patients with CrCl > 60. There were no significant differences in the presence of associated disorders (hypertension or diabetes) between the two groups. Treatment with anti-inflammatories was more frequent among patients with CrCl > 60 (36% vs. 15%, P = 0.02). There were no significant changes in renal function during BP treatment (basal serum creatinine 0.91 0.2 vs. 0.89 0.3 mg/dl post-treatment, P = ns; basal CrCl 66 20 vs. 66 23 post-treatment, P = ns) or when patients were evaluated based on CrCl (CrCl < or > 60). However, when we evaluated renal function impairment (decrease in CrCl 25% and/or increase 0.5 mg/dl in serum creatinine), 10% of patients had renal function impairment (15% in CrCl < 60 group vs. 7% in CrCl > 60 group, P = ns) with five patients presenting CrCl values < 30 ml/min at this time. Patients with renal impairment were older and had higher creatinine values at baseline and more frequently (50% vs. 17%, P = 0.016) showed moderante renal insufficiency (CrCl < 45) than those without renal impairment (Table 2). Renal function impairment was independent of the type of BP treatment (five out ten patients were treated with risedronate, four with alendronate and one with ibandronate). None of the patients treated with zoledronate showed renal impairment. Although no significant differences were observed in the presence of associated comorbidities Table 2 Characteristics of the patients according to renal function evolution. Renal impairmenta n = 10
No renal impairment n = 90
P
Age (years)
77 9 (59–86)
69 9 (54–86)
0.012
Gender (female/male)
9/1
80/10
0.915
Creat. at baseline (mg/dl)
1.06 0.32 (0.6–1.64)
0.89 0.17 (0.62–1.75)
0.049
CrCl at baseline (ml/min)
65 37 (34–145)
65 17 (30–110)
0.352
Creat. after BP treatment (mg/dl)
1.40 0.48 (0.8–2.23)
0.83 0.20 (0.49–1.92)
0.001
CrCl after BP treatment (ml/min)
44 24 (21–94)
68 19 (28–105)
0.003
Comorbidities (%) Hypertension Diabetes Anti-inflammatory use
60 30 40
36 16 27
0.131 0.249 0.373
Type of BP used (%) Alendronate Risedronate Ibandronate Zoledronate
40 50 10 0
43 40 11 6
0.847
58 32 (12–104)
48 31 (12–134)
0.315
Table 1 Clinical characteristics of the patients. All participants n = 100 Age (years) Gender BMI (kg/m2)
70 9 (54–86) 89 females/11 males 27 4 (19–39)
Comorbidities (%) Hypertension Diabetes Anti-inflammatory use
38 17 28
Type of bisphosphosphonate used (%) Aledronate Risedronate Ibandronate Zoledronate
43 41 11 5
Duration of treatment (months)
49 31 (12–134)
Cause of osteoporosis (%) Postmenopausal Glucocorticoids Others
65 22 13
Creatinine at baseline (mg/dl) Patients with creatinine at baseline 1.4 mg/dl (%)
0.91 0.2 (0.6–1.75) 3
CrCl at baseline (ml/min) Patients with CrCl < 30 ml/min (%) Patients with CrCl 30 to 60 ml/min (%) Patients with CrCl > 60 ml/min (%)
66 20 (30–145) 1 38 61
Duration of treatment (months)
Values are mean SD (range), unless otherwise indicated. BMI: body mass index; CrCl: creatinine clearance.
381
Values are mean SD (range), unless otherwise indicated. Creat: creatinine; CrCl: creatinine clearance; BP: bisphosphonate. a Renal impairment: defined as an increase 0.5 mg/dl over the baseline serum creatinine if the baseline value was > 1.4 mg/dl and/or a decrease 25% in CrCl from the baseline value.
382
L. Gifre et al. / European Geriatric Medicine 4 (2013) 380–383
between both groups of patients, patients with renal impairment tended to have a higher number of comorbidities (Table 2). Age was correlated with serum creatinine values (r = 0.27, P = 0.007) and with changes in creatinine (r = 0.26, P = 0.009) and CrCl values (r = –0.25, P = 0.012). No relation was observed between changes in CrCl and duration of BP treatment. The logistic regression analysis showed that the probability of renal function impairment was nearly 6-fold higher in patients with CrCl < 45 ml/min at baseline (OR, 5.92; 95% CI, 1.5–23.4, P = 0.01). A CrCl < 45 ml/min was the only independent predictor variable of renal function impairment.
4. Discussion This study shows that nearly 40% of patients with osteoporosis attended in a Metabolic Bone Diseases Unit had renal insufficiency and that BP treatment did not impair renal function. Thus, no significant changes in renal function parameters, serum creatinine and CrCl were observed after a mean period of treatment of 49 months with these agents. Nevertheless, it should be pointed out that 10% of the patients showed a significant decrease in renal function, a finding that was related to age. These data are in accordance with previous studies indicating a high prevalence of renal insufficiency in aged population. Thus, in the general population in our country, 21% to 49% of individuals over 64 have renal insufficiency (ClCr < 60 ml/min) [10,11], with associated comorbidities, such as hypertension or diabetes, also influencing renal function [10,12,13]. In addition, previous studies have shown a decline in the glomerular filtration rate with aging, independently of clinically associated conditions, thereby indicating that this decline is an inevitable consequence of aging [14]. Moreover, despite most individuals having stable renal function during years, there is a subset of up to 21.6% of individuals that present a significant decrease in renal function [15]. In our study 10% of patients presented a significant impairment in renal function; these patients were older, had higher serum creatinine values and a higher frequency of decreased CrCl less than 45 ml/min at baseline, a finding also described in previous reports [12]. Nevertheless, it should be noted that determination of serum creatinine levels was not useful for evaluating renal function in these patients. Indeed, whereas only 3% of patients had serum creatinine levels over 1.4 mg/dl, nearly 40% had a CrCl under 60, clearly indicating the need to evaluate this parameter in these patients. Thus, baseline CrCl was the principal predictor for renal function impairment, with a 6-fold higher probability for this clinical complication in patients with CrCl under 45 ml/min. In the present study, treatment with BP was not associated with impairment in renal function, thus, renal function parameters, creatinine levels and CrCl did not change with treatment, even when patients were evaluated based on baseline CrCl, that is, patients with CrCl under or over 60. These results also coincide with previous data related to the effect of BP on renal function. Thus, patients receiving either oral alendronate or risedronate during 4 and 3 years, respectively, for osteoporosis did not show impairment in renal function [1,3]. In addition, the antiosteoporotic effect of these drugs seemed to be independent of baseline renal function. Conversely, intravenous BP has been related to impairment in renal function in some studies, especially when they are administered rapidly or in patients with previous renal failure [5,6,16]. Nonetheless, none of our patients treated with intravenous zoledronic acid presented a decrease in renal function and randomised controlled-trials with these agents have not shown impairment in renal function [17–20].
We also observed a significantly lower frequency of antiinflammatory treatment in patients with renal insufficiency (CrCl < 60), a finding which may be attributed to correct clinical practice involving a decrease in the use of these compounds in patients with renal failure. This study has several limitations such as the absence of a nontreated control group, the use of retrospective data collection from the patients’ clinical histories, and the small number of patients included. Nevertheless, the results of this study are based on patients attended in a Metabolic Bone Disease Unit and therefore can be applied to current clinical practice. In conclusion, renal insufficiency is frequently observed in patients who consult for osteoporosis, a finding that was related to age. Although only 10% of patients showed long-term impairment in renal function, our results indicate the need to control CrCl in these patients, especially in those with values under 45 ml/min. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Author contribution All authors have made substantial contributions to all of the following. The conception and design of the study was performed ˜ abens and P. Peris. The acquisition of data was carried by N. Guan out by L. Gifre and A. Martı´nez-Ferrer. Intellectual analysis and interpretation of data was performed by A. Monegal and M.V. Herna´ndez and finally, drafting the article was performed by L. Gifre and P. Peris. Final approval of the version to be submitted was given by all authors. References [1] Miller PD, Roux C, Boonen S, Barton IP, Dunlap LE, Burgio DE. Safety and efficacy of risedronate in patients with age-related reduced renal function as estimated by the Cockcroft and Gault method: a pooled analysis of nine clinical trials. J Bone Miner Res 2005;20:2105–15. [2] Hernandez MV, Peris P, Monegal A, et al. Effects of intravenous pamidronate on renal function, bone mineral metabolism and bone mass in patients with severe osteoporosis. Am J Med Sci 2010;339:225–9. [3] Jamal SA, Bauer DC, Ensrud KE, et al. Alendronate treatment in women with normal to severely impaired renal function: an analysis of the fracture intervention trial. J Bone Miner Res 2007;22:503–8. [4] Markowitz GS, Appel GB, Fine PL, et al. Collapsing focal segmental glomerulosclerosis following treatment with high-dose pamidronate. J Am Soc Nephrol 2001;12:1164–72. [5] Markowitz GS, Fine PL, Stack JI, Kunis CL, Radhakrishnan J, Palecki W. Toxic acute tubular necrosis following treatment with zoledronate (Zometa). Kidney Int 2003;64:281–9. [6] Miller PD. The kidney and bisphosphonates. Bone 2011;49:77–81. [7] Perrone RD, Madias NE, Levey AS. Serum creatinine as an index of renal function: new insights into old concepts. Clin Chem 1992;38:1933–53. [8] Perazella MA, Markowitz GS. Bisphosphonate nephrotoxicity. Kidney Int 2008;74:1385–93. [9] Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO Study Group. World Health Organ Tech Rep Ser 1994;843:1–129. [10] Otero A, de Francisco A, Gayoso P, Garcia F. Prevalence of chronic renal disease in Spain: results of the EPIRCE study. Nefrologia 2010;30:78–86. [11] Almirall J, Vaqueiro M, Anton E, et al. [Prevalence of chronic kidney disease in community-dwelling elderly and associated cardiovascular risk factors]. Nefrologia 2005;25:655–62. [12] Imai E, Horio M, Yamagata K, et al. Slower decline of glomerular filtration rate in the Japanese general population: a longitudinal 10-year follow-up study. Hypertens Res 2008;31:433–41. [13] Eriksen BO, Tomtum J, Ingebretsen OC. Predictors of declining glomerular filtration rate in a population-based chronic kidney disease cohort. Nephron Clin Pract 2010;115:c41–50. [14] Fliser D, Franek E, Ritz E. Renal function in the elderly – is the dogma of an inexorable decline of renal function correct? Nephrol Dial Transplant 1997; 12:1553–5.
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