Renal Safety of Zoledronic Acid in Patients with Osteoporosis: A Retrospective Study

doi:10.21203/rs.3.rs-3103523/v1

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Research Article

Renal Safety of Zoledronic Acid in Patients with Osteoporosis: A Retrospective Study

https://doi.org/10.21203/rs.3.rs-3103523/v1

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Journal Publication

published 16 Nov, 2023

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Introduction

This study aimed to investigate the renal safety of Zoledronic Acid (ZOL) in patients with osteoporosis (OP).

Methods

A total of 1,523 patients with primary OP who received ZOL from January 2008 to October 2020 at our hospital were retrospectively analyzed. Baseline and one-year post-infusion renal function index data were analyzed in relation to clinical characteristics and comorbidities. Furthermore, the changes in renal function between a three-year consecutive infusion and a single infusion of ZOL were compared.

Results

In our study, patients with diabetes mellitus had a significantly lower estimated glomerular filtration rate than those without after one year of ZOL infusion, and their creatinine (Cr) and cystatin C (CysC) levels were significantly higher (all P < 0.05). Patients with malignant tumors had a significantly lower estimated glomerular filtration rate and higher Cr levels than those without (all P < 0.05). CysC levels were significantly higher in patients aged 65 and older and those with hypertension than in their counterparts (all P < 0.05). No adverse renal events such as acute kidney injury were detected. There were no significant differences in renal function index between the three-year continuous infusion group and the single infusion group after one year of infusion(s) (all P > 0.05).

Conclusion

ZOL infusion shows good renal safety in OP patients. Continuous infusion of ZOL did not exert a significant impact on renal function when compared to single infusion. However, the age of 65 years or older and comorbidities such as hypertension, diabetes mellitus, or malignant tumors may represent risk factors that predict adverse renal effects of ZOL infusion.

Mini Abstract

The renal safety of Zoledronic Acid treatment in osteoporosispatients remains incompletely elucidated. We found that the infusion has good renal safety in osteoporosis patients, but careful monitoring of renal function is recommended for patients who are aged 65 years or older and those with comorbidities such as hypertension, diabetes mellitus, or malignant tumors.

osteoporosis

zoledronic acid

renal function

safety

retrospective study

Osteoporosis (OP) is a systemic skeletal disease characterized by low bone mass and deterioration of bone microarchitecture with a consequent increase in fragility and susceptibility to fracture [1]. As of now, anti-resorptive drugs such as bisphosphonates (BPs), are the most widely used first-line anti-OP treatments in the clinic [2, 3]. Zoledronic acid injection (Novartis Pharmaceutical, 100ml/ 5mg), a third-generation nitrogen-containing bisphosphonate, has been approved for the treatment of postmenopausal OP, male OP, glucocorticoid-induced OP, and other metabolic osteopathy [4, 5].

During our clinical practice, we observed that a subset of OP patients treated with Zoledronic Acid (ZOL) infusion exhibited elevated creatinine (Cr), decreased estimated glomerular filtration rate (eGFR), and other renal function alterations. At present, the renal safety of ZOL treatment in OP patients remains incompletely elucidated. In the Adverse Events Reporting System of the US Food and Drug Administration (FDA), Chang et al. [6] reported that 72 patients developed renal damage following ZOL treatment, with 27 requiring dialysis and 18 experiencing mortality, thereby raising concerns regarding the renal safety of ZOL. Several investigations have suggested that ZOL carries a potential risk of renal injury, particularly in patients with comorbid conditions such as diabetes mellitus, hypertension, malignant tumor, advanced age, previous smoking history, and less hydration dose during infusion [7–11]. Withdrawal of the medication has been reported to lead to the recovery of renal function in some patients [6]. Although the incidence of such events is low, the consequences can be severe. Nevertheless, recent research has indicated that there were no significant differences in the changes of renal function and the incidence of renal adverse events between the ZOL and placebo groups [2, 12].

At present, the research findings regarding renal function changes in OP patients treated with ZOL are inconsistent, and renal safety remains somewhat unclear. This study intends to retrospectively evaluate changes in renal function among OP patients with diverse clinical characteristics and diseases after one-year of ZOL infusion, to explore the influence factors of renal function changes caused by ZOL infusion. Furthermore, the changes in renal function of OP patients after three-year consecutive infusions of ZOL were analyzed, to investigate the associated risk factors.

Subjects

The study retrospectively gathered eligible patients who were admitted to West China Hospital of Sichuan University between January 2008 and October 2020, with the diagnosis of OP and treated with ZOL, based on predefined inclusion and exclusion criteria.

Inclusion criteria: (1) Patients with OP in the discharge diagnosis are included. That is, the T-score of bone mineral density (BMD) for the lumbar spine, femoral neck, total hip or 33% radius is ≤ -2.5 as measured by dual-energy X-ray absorptiometry (DXA); or a fragility fracture occurs in the vertebrae or hip; or the T-score of DXA is between − 2.5 and − 1.0, and a fragility fracture occurs in the distal forearm, proximal humerus or pelvis; or the mean BMD of quantitative computed tomography (QCT) is ≤ 80 mg/cm³. (2) Data of renal function indicators at baseline and one year after ZOL infusion are complete.

Exclusion criteria: (1) Patients with the diagnosis of secondary OP induced by hyperparathyroidism, Cushing syndrome, glucocorticoid-induced OP, and multiple myeloma, etc. (2) Patients with the diagnosis of other metabolic bone diseases such as osteomalacia, osteogenesis imperfecta, and Paget's disease, etc.

Research Methods

1. Study design

In this study, the Biomedical Big Data Research Center's database was utilized to identify patients hospitalized for OP and infused with ZOL at our hospital between January 2008 and October 2020. Subsequently, eligible subjects were selected, then the systematic and complete data of the enrolled subjects were obtained by consulting the hospital's electronic medical record system. The study aimed to compare changes in renal function among patients with different clinical characteristics and complicated diseases, one year after ZOL infusion, and to explore factors influencing renal function changes following ZOL infusion. Patients who received three consecutive infusions of ZOL were selected, with the data before the first infusion as the baseline and data one year after the third infusion as the final follow-up data. To observe changes in renal function more accurately, 1:1 propensity score matching (PSM) was adopted, and the influence factors found in the above study were used as matching factors to determine the corresponding subjects in the single infusion group. Then, the changes in renal function in the two groups were compared. The study was approved by the Medical Ethics Committee of West China Hospital of Sichuan University (Ethics approval number: 1063 of 2020).

2. Data collection

(1) Basic data: age, gender, height, weight, body mass index (BMI), smoking and drinking history; (2) Combined diseases: history of kidney, liver, brain, heart, immunity, and other diseases; (3) Renal function indicators: collecting Cr, blood urea nitrogen (BUN), eGFR obtained with the CKD-EPI equation, cystatin C (CysC) at baseline and 1 year after ZOL infusion; (4) Related indicators of bone metabolism: 25 hydroxyvitamin D (25OHD), 24-hour urinary calcium. All test indicators were completed by the laboratory department of West China Hospital of Sichuan University.

Statistical Analysis

SPSS 22.0 was used for statistical analysis. The continuous measurement data with normal distribution were statistically described by mean ± standard deviation (SD), whereas the continuous measurement data with non-normal distribution were described by median and quartile range (QR), and the enumeration data were described by percentage (%). The data were obtained by the Chi-square test or Fisher exact test. PSM was used to match the subjects infused with ZOL for three consecutive years with those received for one year. The changes in renal function between the two groups were compared using two independent samples t-test if the differences of changes in renal function indicators met the assumptions of normal distribution and homogeneity of variance. If the assumptions were not met, independent samples nonparametric test was used instead.

1. Renal function changes after ZOL infusion in subjects with different clinical characteristics and diseases

This study enrolled 1,523 patients and the complete data of the subjects were collected systematically by consulting the hospital's electronic medical record system. The data were classified based on various factors including gender, age (< 65, ≥ 65), BMI (≥ 24.0 kg/m², < 24.0 kg/m²), 25OHD (< 75 nmol/L, ≥ 75 nmol/L), urinary calcium (> 7.5 mmol/24h, ≤ 7.5 mmol/24h), smoking history, drinking history, and co-morbidities such as hypertension, diabetes mellitus, hyperuricemia or gout, hyperlipidemia, urinary calculus, urinary system diseases, endocrine system diseases, rheumatic immune system diseases, malignant tumor diseases, blood system diseases, respiratory system diseases, digestive system diseases or cardiovascular system diseases. The study compared the changes in renal function indicators (eGFR, Cr, BUN, CysC) of subjects in each group one year after ZOL infusion with the baseline before infusion, and the results are presented in Table 1 and Table 2.

Table 1

Changes in renal function one year after zoledronic acid infusion in subjects with different clinical characteristics
Group	Indicators
Group	Changes in eGFR (mL/min/1.73m²)	Changes in Cr (umol/L)	Changes in BUN (mmol/L)	Changes in CysC (ug/L)
Gender
Female (n = 1,345)	-2.34 (-8.26,2.86)	2.00 (-5.00,8.00)	0.08 (-0.80,0.95)	0.00 (-70.00,60.00)
Male (n = 178)	-1.91 (-7.12,3.73)	0.90 (-6.33,7.00)	0.10 (-0.90,1.00)	0.00 (-70.00,80.00)
P Value	0.278 ^a	0.100 ^a	0.856 ^a	0.558 ^a
Age
< 65 years old (n = 494)	-2.12 (-6.56,2.63)	2.00 (-4.00,7.35)	0.08 (-0.70,1.00)	-10.00 (-70.00,50.00)
≥ 65 years old (n = 1,029)	-2.35 (-9.05,3.54)	1.90 (-6.00,8.65)	0.10 (-0.89,0.92)	0.00 (-70.00,80.00)
P Value	0.329 ^a	0.536 ^a	0.534 ^a	0.046 ^a
BMI (kg/m²) ^b
≥24.0 (n = 558)	-2.14 (-8.94,2.89)	1.80 (-5.10,8.28)	0.10 (-0.80,1.00)	-5.00 (-72.50,70.00)
< 24.0 (n = 921)	-2.25 (-7.77,3.06)	2.00 (-5.00,8.00)	0.00 (-0.81,0.91)	0.00 (-70.00,60.00)
P Value	0.715 ^a	0.680 ^a	0.233 ^a	0.927 ^a
25OHD (nmol/L) ^b
<75 (n = 982)	-1.91 (-7.62,3.21)	1.00 (-5.03,8.00)	0.00 (-0.89,0.90)	0.00 (-80.00,60.00)
≥ 75 (n = 385)	-2.69 (-8.21,2.43)	3.00 (-4.00,8.50)	0.14 (-0.61,1.07)	0.00 (-60.00,70.00)
P Value	0.133 ^a	0.087 ^a	0.052 ^a	0.141 ^a
Urine calcium (mmol/24h) ^b
> 7.5 (n = 191)	-1.95 (-7.29,3.65)	2.00 (-5.00,8.00)	0.10 (-0.99,0.90)	-10.00 (-80.00,30.00)
≤7.5 (n = 843)	-2.36 (-7.58,2.40)	2.00 (-4.10,8.00)	0.10 (-0.70,1.00)	0.00 (-70.00,70.00)
P Value	0.732 ^a	0.745 ^a	0.680 ^a	0.053 ^a
Smoking (n = 108)	-3.10 (-9.54,2.15)	3.00 (-5.85,10.00)	-0.20 (-1.08,1.05)	10.00 (-67.50,80.00)
Non-smoking (n = 1,415)	-2.24 (-7.90,3.08)	1.90 (-5.00,8.00)	0.10 (-0.80,0.90)	0.00 (-70.00,62.50)
P Value	0.155 ^a	0.375 ^a	0.419 ^a	0.320 ^a
Drinking (n = 76)	-1.21 (-7.32,2.56)	0.90 (-5.00,6.00)	-0.20 (-1.00,1.10)	-30.00 (-110.0,60.00)
Non-drinking (n = 1,447)	-2.34 (-8.14,3.06)	2.00 (-5.00,8.00)	0.10 (-0.80,0.91)	0.00 (-70.00,70.00)
P Value	0.900 ^a	0.621 ^a	0.642 ^a	0.065 ^a
Note: ^a Non-parametric test of two independent samples. ^b Data are missing: BMI is 1,479 cases (missing about 2.89%), 25OHD is 1367 cases (missing about 10.24%), and urinary calcium is 1,034 cases (missing about 32.11%).

Table 2

Changes in renal function one year after zoledronic acid infusion in subjects with different combined diseases
Group	Indicators
Group	Changes in eGFR (mL/min/1.73m²)	Changes in Cr (umol/L)	Changes in BUN (mmol/L)	Changes in CysC (ug/L)
Hypertension (n = 610)	-2.26 (-8.83,3.42)	1.95 (-5.03,9.00)	0.10 (-0.80,1.00)	0.00 (-60.00,90.00)
Non-hypertension (n = 913)	-2.33 (-7.71,2.79)	2.00 (-5.00,8.00)	0.00 (-0.80,0.90)	-10.00 (-80.00,60.00)
P value	0.881 ^a	0.603 ^a	0.506 ^a	0.012 ^a
Diabetes (n = 338)	-3.55 (-10.36,1.11)	3.50 (-3.23,10.13)	0.20 (-0.80,1.20)	10.00 (-52.50,70.00)
Non-diabetic (n = 1,185)	-2.00 (-7.57,3.56)	1.00 (-5.70,7.70)	0.00 (-0.80,0.90)	-10.00 (-80.00,60.00)
P value	0.001 ^a	0.001 ^a	0.133 ^a	0.035 ^a
Hyperuricemia/ gout (n = 85)	-0.77 (-7.75,4.52)	0.00 (-6.00,9.75)	-0.35 (-1.22,1.13)	20.00 (-47.50,100.0)
Non-hyperuricemia/ gout (n = 1438)	-2.34 (-8.13,2.85)	2.00 (-5.00,8.00)	0.10 (-0.80,0.95)	0.00 (-70.00,60.00)
P value	0.298 ^a	0.573 ^a	0.218 ^a	0.085 ^a
Hyperlipoidemia (n = 280)	-2.04 (-7.71,3.19)	1.00 (-5.63,8.00)	-0.02 (-0.70,0.90)	10.00 (-57.50,70.00)
Non-hyperlipidemia (n = 1,243)	-2.34 (-78.16,2.92)	2.00 (-5.00,8.00)	0.10 (-0.83,1.00)	0.00 (-70.00,60.00)
P value	0.817 ^a	0.694 ^a	0.830 ^a	0.170 ^a
Urinary calculus (n = 66)	-1.63 (-7.51,2.77)	3.00 (-5.00,8.50)	0.00 (-1.00,0.96)	0.00 (-62.50,62.50)
Non-urinary calculus (n = 1,457)	-2.32 (-8.16,3.04)	2.00 (-5.00,8.00)	0.10 (-0.80,0.95)	0.00 (-70.00,70.00)
P value	0.935 ^a	0.596 ^a	0.689 ^a	0.841 ^a
Tumor (n = 176)	-2.95 (-9.79,1.19)	3.00 (-3.00,10.80)	0.10 (-0.70,0.89)	0.00 (-50.00,60.00)
Non-tumor (n = 1,347)	-2.18 (-7.91,3.29)	1.90 (-5.00,8.00)	0.10 (-0.80,1.00)	0.00 (-70.00,70.00)
P value	0.041 ^a	0.018 ^a	0.839 ^a	0.575 ^a
Urinary system (n = 597)	-2.27 (-8.16,2.70)	2.00 (-5.00,8.00)	0.03 (-0.70,0.91)	0.00 (-70.00,70.00)
Non-urinary system (n = 926)	-2.32 (-8.08,3.20)	2.00 (-5.00,8.00)	0.10 (-0.83,0.97)	-10.00 (-80.00,60.00)
P value	0.528 ^a	0.642 ^a	0.662 ^a	0.189 ^a
Endocrine system (n = 1,079)	-2.38 (-8.44,2.70)	2.00 (-5.00,8.00)	0.03 (-0.84,0.98)	0.00 (-70.00,70.00)
Non-endocrine system (n = 444)	-1.75 (-7.28,3.67)	2.00 (-6.00,7.00)	0.10 (-0.70,0.90)	-10.00 (-90.00,60.00)
P value	0.057 ^a	0.161 ^a	0.579 ^a	0.056 ^a
Rheumatism immunity system (n = 344)	-2.34 (-7.94,2.35)	2.00 (-4.75,8.80)	0.00 (-0.80,1.00)	0.00 (-60.00,80.00)
Non-rheumatic immunity system (n = 1,179)	-2.30 (-8.17,3.49)	1.60 (-5.00,8.00)	0.10 (-0.80,0.90)	0.00 (-72.5,60.00)
P value	0.570 ^a	0.167 ^a	0.837 ^a	0.104 ^a
Blood system (n = 161)	-2.35 (-8.92,2.77)	2.00 (-5.00,8.00)	0.00 (-1.10,1.05)	0.00 (-70.00,50.00)
Non-blood system (n = 1,362)	-2.30 (-7.88,3.08)	2.00 (-5.00,8.00)	0.10 (-0.80,0.91)	0.00 (-70.00,70.00)
P value	0.857 ^a	0.804 ^a	0.746 ^a	5.429 ^a
Respiratory system (n = 416)	-2.54 (-8.26,3.15)	2.00 (-6.00,9.00)	0.04 (-0.90,0.97)	0.00 (-80.00,80.00)
Non-respiratory system (n = 1,107)	-2.20 (-8.08,2.94)	2.00 (-5.00,8.00)	0.10 (-0.80,0.95)	0.00 (-70.00,60.00)
P value	0.654 ^a	0.929 ^a	0.580 ^a	0.470 ^a
Digestive system (n = 752)	-2.37 (-7.87,2.59)	2.00 (-5.00,8.00)	0.10 (-0.71,1.00)	0.00 (-70.00,60.00)
Non-digestive system (n = 771)	-2.14 (-8.29,3.77)	2.00 (-6.00,8.00)	0.00 (-0.89,0.90)	0.00 (-80.00,70.00)
P value	0.422 ^a	0.623 ^a	0.360 ^a	0.651 ^a
Cardiovascular system (n = 900)	-2.33 (-8.47,2.87)	1.90 (-5.00,9.00)	0.10 (-0.80,1.00)	0.00 (-70.00,77.50)
Non-cardiovascular system (n = 623)	-2.27 (-7.53,3.46)	2.00 (-5.00,7.00)	0.07 (-0.80,0.90)	-10.00 (-80.00,60.00)
P value	0.344 ^a	0.398 ^a	0.735 ^a	0.055 ^a
Note: ^a Non-parametric test for two independent samples.

Significantly lower eGFR and significantly higher Cr and CysC were observed in patients with diabetes mellitus or malignant tumor, and significantly higher CysC was observed in patients with hypertension, one year after ZOL infusion compared to those without these conditions (all P < 0.05). No significant differences were found in patients with hyperuricemia or gout, hyperlipidemia, urinary calculus, urinary system diseases, endocrine system diseases, rheumatic immune system diseases, blood system diseases, respiratory system diseases, digestive system diseases, or cardiovascular system diseases (no significant difference was found among the groups). A significant increase in CysC was observed in patients aged 65 and above compared to those under 65 (P < 0.05). However, the renal function of OP patients one year after ZOL infusion was not significantly affected by gender, BMI, 25OHD, urinary calcium, drinking history, or smoking history (all P > 0.05).There were no renal adverse events such as acute renal injury found in the study.

2. Retrospective Analysis of Renal Safety for Single and Three-year Consecutive Intravenous Infusion of ZOL

2.1 Basic characteristics of two groups of subjects

Out of the 1,523 initially screened participants, 854 were selected for further analysis. Among them, 138 received a three-year consecutive ZOL infusions, while 716 received a single infusion. Baseline indicators were compared between the two groups and found to be not significantly different in terms of age, BMI, drinking and smoking history, presence of diabetes mellitus, hypertension, malignant tumor, urinary calculus, urinary system diseases, endocrine system diseases, rheumatic immune system diseases, digestive system diseases, cardiovascular system diseases, and renal function indicators (eGFR, Cr, BUN, CysC) before the first ZOL infusion (all P > 0.05) (Table 3).

Table 3

Comparison of basic clinical characteristics between single and three-year consecutive infusion groups
Indicators	Group		P Value
Indicators	Three-year infusion (n = 138)	One-year infusion (n = 716)	P Value
Age (years)	68.60 ± 9.07	69.88 ± 9.52	0.161^a
Age group [n (%)]			0.920^b
< 65	41 (29.71)	216 (30.17)
≥ 65	97 (70.29)	500 (69.83)
BMI (kg/m²)	23.37 ± 3.77	23.33 ± 13.86	0.971^a
Gender [n (%)]			0.038^b
Male	16 (11.59)	64 (8.94)
Female	122 (88.41)	652 (91.06)
eGFR (mL/min/1.73m²)	87.94 (76.06,97.07)	87.25 (74.16,96.00)	0.338^c
Cr (µmol/L)	62.00 (56.03,72.03)	62.00 (54.00,72.95)	0.338^c
BUN (mmol/L)	5.72 (4.89,6.85)	5.60 (4.60,6.71)	0.169^c
CysC (mg/L)	0.98 (0.88,1.13)	0.99 (0.89,1.14)	0.691^c
Smoking history [n (%)]	13 (9.42)	40 (5.59)	0.120^b
Drinking history [n (%)]	10 (7.25)	30 (4.19)	0.058^b
Diabetes mellitus [n (%)]	35 (25.36)	181 (25.28)	0.984^b
Hypertension [n (%)]	56 (40.58)	292 (40.78)	0.965^b
Malignant tumor [n (%)]	13 (9.42)	82 (11.45)	0.487^b
Urinary calculi [n (%)]	6 (4.35)	26 (3.63)	0.685^b
Urinary System Diseases [n (%)]	50 (36.23)	274 (38.27)	0.702^b
Endocrine System diseases [n (%)]	105 (76.09)	509 (71.09)	0.256^b
Rheumatic immune system diseases [n (%)]	33 (23.91)	145 (20.25)	0.360^b
Hematology system diseases [n (%))	14 (10.14)	77 (36.23)	0.882^b
Respiratory system diseases [n (%)]	41 (29.71)	199 (27.79)	0.679^b
Digestive system diseases [n (%)]	37 (26.81)	215 (30.03)	0.477^b
Cardiovascular system diseases [n (%)]	80 (57.97)	426 (69.50)	0.777^b
Note: ^a ANOVA analysis of variance; ^b Chi-square test, in which the Fisher’s exact test was used for drinking history; ^c Non-parametric test of two independent samples.

2.2 Renal safety analysis of subjects after 1:1 PSM

Among the selected subjects, 138 individuals received ZOL infusion for three consecutive years. The study indicates that age, diabetes mellitus, hypertension, and malignant tumors may impact renal function following ZOL infusion. To accurately observe renal function changes in the three-year infusion group and single infusion group, 135 matched cases were selected using the 1:1 PSM method based on age, diabetes mellitus, hypertension, and malignant tumors (Table 4). Results showed no significant differences in eGFR, Cr, BUN, and CysC changes between the two groups (all P > 0.05).

Table 4

Comparison of renal safety between single infusion and three-year consecutive infusions of zoledronic acid after 1:1 PSM
Indicators	Median (quartile range)		U Value P Value
Indicators	Three-year infusion (n = 135)	One-year infusion (n = 135)	U Value P Value
Change in eGFR (mL/min/1.73m²)	-3.13(-11.73,3.70)	-1.99(-7.73,4.08)	8294.500	0.202^a
Change in Cr (µmol/L)	-0.50(-6.60,6.00)	2.00(-6.00,8.00)	8371.000	0.248^a
Change in BUN (mmol/L)	-0.10(-0.90,1.03)	-0.50(-1.20,1.05)	8794.500	0.620^a
Change in CysC (µg/L)	-20.00(-90.00,50.00)	-10.00(-100.0,60.00)	9000.500	0.861^a
Note: ^a Non-parametric test of two independent samples

About 60% of ZOL can act on bones rapidly after infusion, while the remaining portion is eliminated through the kidneys within 24 hours [13]. A retrospective investigation involving 122 patients with hormone-resistant prostate cancer and bone metastases who underwent ZOL treatment (average of eight infusions) demonstrated that 29 out of 122 patients (23.8%) developed renal impairment events (an increase of ≥ 0.5 mg/dL over the baseline serum creatinine value according to the result of the last creatinine serum test before ZOL treatment, if the baseline value was < 1.4 mg/dL; or an increase of ≥ 1.0 mg/dL over the baseline serum creatinine value, if the baseline value was ≥ 1.4 mg/dL) [8]. Previous research has posited that ZOL poses a potential hazard to renal health, particularly for individuals who have comorbidities such as diabetes mellitus or hypertension, advanced age, malignant tumors, or a history of smoking [8–10]. The renal damage of ZOL may be related to insoluble compound formation in the proximal renal tubules or ZOL's inhibitory effects on renal tubular cell metabolism [14–15]. Additionally, basic studies have suggested that ZOL may have genotoxic and cytotoxic effects on renal cells, leading to mitochondrial-mediated apoptosis, inhibited cytoplasmic division, and damage to renal epithelial cell regeneration [13].

However, some randomized, controlled clinical studies have demonstrated the renal safety of annual infusion of ZOL in postmenopausal OP patients. A three-year study of over 5,000 postmenopausal OP patients showed no significant differences in renal function changes or adverse events between ZOL and placebo groups (renal failure 0.10% in the ZOL group and 0.18% in the placebo group, P > 0.05) [12]. ZOL infusion may cause short-term blood creatinine elevation in postmenopausal OP women with a creatinine clearance rate higher than 30 ml/min, but the three-year long-term renal function is safe. Furthermore, the HORIZON-PFT study demonstrated a gradual decline in renal function among OP patients receiving ZOL treatment, which was consistent with age-related renal function changes, compared to those receiving a placebo [2]. In line with the findings of previous studies, our investigation did not reveal any untoward renal event, specifically acute renal injury, in any participant. Furthermore, no notable differences were observed in renal function between the cohort of 135 patients who received a three-year consecutive infusion of ZOL and a matched group of 135 subjects who were given a single infusion. The infusion of ZOL in patients with primary OP demonstrated a favorable renal safety profile, and the repeated administration of ZOL did not significantly affect renal function compared to a single infusion. However, a report by Chang et al. [6] documented significant renal function impairment in multiple patients following intravenous infusion of ZOL, which may have been attributed to their cancer diagnosis and the considerably higher cumulative dose of intravenous ZOL administered every 3–4 weeks as opposed to the annual ZOL infusion in OP patients. Additionally, other aggravating factors such as preexisting renal disease and concurrent use of nephrotoxic agents may have contributed to renal dysfunction in cancer patients and could have been important determinants of the study outcomes.

High cystatin C levels are associated with old age, male, great weight, great height, current cigarette smoking, and high serum C-reactive protein (CRP) levels [16]. Therefore, high CysC levels in patients with hypertension or older than 65 may be related to age-related or other confounding factors. It is not necessarily a result of ZOL infusion, but only a factor to be considered for the assessment of renal function with ZOL. Our study suggests that patients with diabetes mellitus and malignant tumors are at an increased risk of ZOL-related renal damage, as their renal function decreased significantly compared to those without these conditions. Therefore, it is essential to monitor the renal function of such patients closely and observe any changes after ZOL infusion. Our findings are consistent with previous studies that have shown that ZOL poses a potential risk of kidney damage, particularly in patients with diabetes mellitus, hypertension, malignancy, or advanced age [8–10]. However, these studies only focused on patients with cancer, and no research has been conducted on the risk factors of ZOL-related renal damage in OP patients, which may explain why our study did not find a correlation between smoking history and ZOL-related renal damage [17]. It is noteworthy that in our study, the decline in renal function in diabetic patients may be associated with the progression of diabetic nephropathy, while in cancer patients, it may be linked to the nephrotoxicity of anti-cancer drugs and the effect of the disease itself on the kidney. To further investigate and confirm the risk factors of ZOL-related renal damage in OP patients, future prospective studies with a larger sample size are warranted.

There are some limitations in this study. Firstly, it included the patients with OP in the discharge diagnosis as the study subjects and collected their discharge diagnoses to determine the disease-related risk factors. Some clinical data such as the test index were missing. All this may affect the data integrity and the accuracy of the study results. Secondly, patients who did not follow the doctor's advice in time and were not included due to the lack of follow-up data, potentially introducing selection bias. In addition, due to the limitation of the retrospective study, it was not possible to determine if subjects had new disease histories or concurrent drug use that may have affected renal function during the follow-up period. Acute kidney injury in the days following infusion was also not examined. Furthermore, the lack of a control group of patients not treated with ZOL and potential confounding factors may affect the study results.

In conclusion, based on the findings of this study, it can be inferred that ZOL infusion is associated with good renal safety among OP patients, and repetitive infusions are not significantly linked with adverse effects on the renal function when compared to a single infusion. However, it is crucial to enhance renal function monitoring in elderly patients (65 years and above) and those with hypertension, diabetes mellitus, or malignant tumor. Furthermore, clinicians should remain vigilant for unfavorable renal events following ZOL infusion and monitor changes in renal function. Moving forward, larger prospective studies are warranted to assess the clinical benefits of this risk prediction in OP patients.

Statements and Declarations

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Conflict of Interest

The authors have no relevant financial or non-financial interests to disclose.

Author Contributions

QW and DCC designed the study. YHM collected data and wrote the manuscript. QW, DCC and CYL made critical revisions to the manuscript. SX, ZYX and YZ helped with the data collection and analysis. All authors contributed to the article and approved the submitted version.

Ethics Statement

The studies involving human participants were reviewed and approved by the Medical Ethics Committee of West China Hospital of Sichuan University. For this type of study formal consent is not required.

Chinese Society of Osteoporosis and Bone Mineral Research, Guidelines for the diagnosis and management of primary osteoporosis. Chin. J. Osteoporosis & Bone Miner Res. 10, 413–444 (2017)
D.M. Black, P.D. Delmas, R. Eastell, I.R. Reid, S. Boonen, J.A. Cauley et al., Once-Yearly Zoledronic Acid for Treatment of Postmenopausal Osteoporosis. N Engl. J. Med. 356, 1809–1822 (2007). https://doi.org/10.1056/NEJMoa067312
K.E. Ensrud, Bisphosphonates for Postmenopausal Osteoporosis. Jama. 325, 96 (2021). https://doi.org/10.1001/jama.2020.2923
P.M. Camacho, S.M. Petak, N. Binkley, D.L. Diab, L.S. Eldeiry, A. Farooki et al., American Association of Clinical Endocrinologists/American College of Endocrinology Clinical Practice Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis-2020 Update. Endocr. Pract. 26, 1–46 (2020). https://doi.org/10.4158/gl-2020-0524suppl
Chinese Society of Osteoporosis and Bone Mineral Research, Guidelines for the diagnosis and management of male osteoporosis. Chin. J. Osteoporosis & Bone Miner Res. 13, 381–395 (2020)
J.T. Chang, L. Green, J. Beitz, Renal Failure with the Use of Zoledronic Acid. N Engl. J. Med. 349, 1676–1679 (2003). https://doi.org/10.1056/NEJM200310233491721
R. Bergner, B. Siegrist, N. Gretz, G. Pohlmeyer-Esch, B. Kranzlin, Nephrotoxicity of Ibandronate and Zoledronate in Wistar Rats with Normal Renal Function and after Unilateral Nephrectomy. Pharmacol. Res. 99, 16–22 (2015). https://doi.org/10.1016/j.phrs.2015.04.016
W.K. Oh, K. Proctor, M. Nakabayashi, C. Evan, L.K. Tormey, T. Daskivich et al., The Risk of Renal Impairment in Hormone-Refractory Prostate Cancer Patients with Bone Metastases Treated with Zoledronic Acid. Cancer. 109, 1090–1096 (2007). https://doi.org/10.1002/cncr.22504
Y.J. Cha, Y.J. Lee, Risk Factors for Renal Impairment in Patients with Solid Tumors or Multiple Myeloma Treated with Zoledronic Acid. Int. J. Clin. Pharmacol. Ther. 51, 274–282 (2013). https://doi.org/10.5414/CP201823
A. Munier, V. Gras, M. Andrejak, N. Bernard, M.J. Jean-Pastor, S. Gautier et al., Ann. Pharmacother. 39, 1194–1197 (2005). https://doi.org/10.1345/aph.1E589. Zoledronic Acid and Renal Toxicity: Data from French Adverse Effect Reporting Database
X. Dai, Y. Deng, Y. Luo, J. Xie, H. Ma, Effect of Different Hydration Doses on Renal Function in Patients with Primary Osteoporosis Treated with Zoledronic Acid: A Hospital-Based Retrospective Cohort Study. Med. (Baltim). 99, e20831 (2020). https://doi.org/10.1097/MD.000 0000000020831
S. Boonen, D.E. Sellmeyer, K. Lippuner, A. Orlov-Morozov, K. Abrams, P. Mesenbrink et al., Renal Safety of Annual Zoledronic Acid Infusions in Osteoporotic Postmenopausal Women. Kidney Int. 74, 641–648 (2008). https://doi.org/10.1038/ki.2008.193
S. Singireesu, S.K. Mondal, S. Yerramsetty, S. Misra, Zoledronic Acid Induces Micronuclei Formation, Mitochondrial-Mediated Apoptosis and Cytostasis in Kidney Cells. Life Sci. 203, 305–314 (2018). https://doi.org/10.1016/j.lfs.2018.04.059
J.A. Kanis, C.J. Preston, A.J. Yates, R.C. Percival, K.I. Mundy, R.G. Russell, Effects of Intravenous Diphosphonates on Renal Function. Lancet. 1, 1328 (1983). https://doi.org/10.1016/s0140-6736(83)92434-0
I. Sehitoglu, L. Tumkaya, R. Bedir, Y. Kalkan, M.C. Cure, A.F. Yucel et al., Zoledronic Acid Aggravates Kidney Damage During Ischemia Reperfusion Injury in Rat. J. Environ. Pathol. Toxicol. Oncol. 34, 53–61 (2015). https://doi.org/10.1615/jenvironpatholtoxicoloncol.2015012424
E.L. Knight, J.C. Verhave, D. Spiegelman, H.L. Hillege, D. Zeeuw, G.C. Curhan et al., Factors influencing serum cystatin C levels other than renal function and the impact on renal function measurement. Kidney Int. 65, 1416–1421 (2004). https://doi.org/10.1111/j.1523-1755.2004.00517.x
D. Rosella, P. Papi, R. Giardino, E. Cicalini, L. Piccoli, G. Pompa, Medication-Related Osteonecrosis of the Jaw: Clinical and Practical Guidelines. J. Int. Soc. Prev. Community Dent. 6, 97–104 (2016). https://doi.org/10.4103/2231-0762.178742

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Renal Safety of Zoledronic Acid in Patients with Osteoporosis: A Retrospective Study

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