| Abstract|| |
Chronic kidney disease (CKD) is associated with bone and mineral disturbances in the form of renal osteodystrophy. The American College of Rheumatology Guidelines for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis 2017 recommend against treatment with denosumab in adult patients who have received an organ transplant and who are continuing treatment with glucocorticoids due to lack of adequate safety data on infections in adults treated with multiple immunosuppressive agents. Therefore, this study was conducted to compare the safety of denosumab in patients with CKD, especially in a group of patients who received immunosuppressive medications, and to assess the rate of infections in such group in comparison to patients with normal renal function. We retrieved all data of patients who are receiving denosumab in our institute through search in the medical record system (Al-Shifa System). We excluded all patients with malignancy and all patients who were prescribed denosumab but did not receive it. During the period from 2006 to 2018, 314 patients were treated with denosumab therapy. Out of 84 patients who were fulfilling the inclusion criteria, 24 (28.5%) patients had normal kidney function and 60 (71.4%) patients had CKD. Forty-three percent of all patients with CKD developed side effects after taking denosumab. In comparison, only 17% of patients with normal kidney function developed side effects. Of patients with CKD and infections, 50% of them had moderate infections and required admission. Out of these patients, 76% were in immunosuppressive medications and 61% of the patients were receiving steroids more than 2.5 mg per day. Using Chi-square test and the nonparametric independent samples Kruskal–Wallis test, there was a significant association between the dose of steroids and the rate of side effects with a significance level of <0.014 and 0.009, respectively. Hypocalcemia was detected in two patients (3.3%), and they had CKD stage V. Denosumab is associated with increased risk of infection in CKD patients on steroids or multiple immuno-suppressive medications. There was no deterioration in renal function while using denosumab. In this regard, close monitoring of this group of patients is essential, as well as medication adjustments.
|How to cite this article:|
Al Adhoubi NK, Al Salmi I. Safety of denosumab in patients with chronic kidney disease. Saudi J Kidney Dis Transpl 2021;32:1235-42
| Introduction|| |
Chronic kidney disease (CKD) is associated with bone and mineral disturbances in the form of renal osteodystrophy. The above changes make patients with CKD at high risk of fracture despite having a normal bone mineral density (BMD). It is estimated that patients with CKD especially stage 3–4 have as twice risk of having bone fracture in comparison to patients with normal kidney function. This is not a surprise if we take into consideration all hormonal and biochemical changes that occur in the bone as a result of renal osteodystrophy. Renal osteodystrophy can occur in the form of osteitis fibrosa which result from secondary hyperparathyroidism which is triggered by hypocalcemia. The later results mainly from poor conversion of 25-OH-D to its active form. Another form of renal osteodystrophy is adynamic bone disease which occurs due to low bone turnover.
The World Health Organization defines osteoporosis as BMD with T-score of ≤-2.5 standard deviations (SDs) less than peak bone mass (20-year-old healthy woman average).
To determine the BMD, dual-energy X-ray absorptiometry is used to calculate the bone mineral content and the bone area. In CKD patients, the metabolic bone disease changes make the diagnosis of osteoporosis very challenging due to its direct effect in the bone architecture and adding further risk of fracture. It requires a set of investigations to rule out metabolic bone disease before making the diagnosis of osteoporosis.
The first line of treatment of osteoporosis is usually with bisphosphonate agents such as alendronate, risedronate, and zoledronic acid. Unfortunately, these agents cannot be used in patients with estimated glomerular filtration rate (eGFR) of <30 mL/min. Since bisphos-phonates are excreted from the body through the renal system via two mechanisms including direct filtration and excretion through proximal tubular system.,,
Therefore, treatment with new biological agents such as denosumab and romosozumab became a more attractive option in these groups of patients. These drugs are not cleared by the renal system, and there is no eGFR limit with their use. All these drugs act by modulating the activity of osteoclast and osteoblasts.,
Osteoclasts are responsible for bone resorption and osteoblasts for bone formation. Both processes are strictly regulated by hormones in the body. Osteoclasts are members of the monocyte/macrophage family, and bone marrow macrophages are their principal precursors. Two cytokines are indispensable for osteoclastogenesis and osteoclast activation which are receptor activator of nuclear factor-κB ligand (RANK-L) and macrophage colony-stimulating factor.
Denosumab is a fully humanized monoclonal antibody against the RANKL. The RANKL system is very important in the formation of osteoclast, and it affects its function and survival rate. Denosumab has been shown to reduce the risk of vertebral and nonvertebral fracture risks. Its metabolism and excretion are not dependent on the renal system, since it is cleared from the body through the reticuloendothelial system. This feature is very important when considering treating osteoporosis in patients with CKD.,,,,,, the Food and Drug Administration (FDA) had approved denosumab for the management of osteoporosis in patients with CKD in 2013 with concern of risk of hypocalcemia in patients with creatinine clearance of less than 30 mL/min.2
The American College of Rheumatology Guidelines for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis 2017 recommend against treatment with denosumab in adult patients who have received an organ transplant and who are continuing treatment with glucocorticoids due to lack of adequate safety data on infections in adults treated with multiple immunosuppressive agents.
Therefore, this study was conducted to compare the safety of denosumab in patients with CKDs and who are receiving multiple immunosuppressive medications and to assess the rate of infections in such group in comparison to patients with normal renal function.
| Patients and Methods|| |
The Royal Hospital has an internationally well-recognized electronic medical record system called Al-Shifa that uses International Classification of Diseases codes. This is a retrospective descriptive study evaluating all patients who were receiving denosumab that have been seen at the Royal Hospital throughout the period from 2006 to 2018. All adult Omani patients above 18 years who had received denosumab were included. The main indications of giving denosumab in these patients were for the management of osteoporosis and for prophylaxis of glucocorticoid-induced osteoporosis. The diagnosis of osteoporosis was made mainly based on history, BMD results, and biochemical and hormonal assay. Majority of the patients did not have bone markers done for them. Patients were divided into two groups, patients with normal kidney function and patients with CKD. The definition of chronic kidney disease depends on the presence or absence of kidney damage and the level of kidney function. People with a GFR below 60 mL/min/1.73 m2 for at least three months are classified as having CKD. However, kidney damage does not necessarily mean that an individual has CKD.
We excluded all patients with malignancy and all patients who were prescribed denosumab but did not receive it.
A list of all patients that have been diagnosed with osteoporosis by the bone densitometry and patients taking denosumab for prophylaxis of steroid-induced osteoporosis was retrieved. This list was cross-checked with the pharmacy department and confirmed that denosumab medications were dispensed to those patients. Medical records of all patients were reviewed in detail for demographics, primary kidney disease, investigations including laboratory and radiological assessment, medications, and outcomes. Baseline clinical data include history of autoimmune disease, dialysis, and if there is any history of infections or admission. Patients’ medication history was recorded including steroids and immunosuppressive therapy. Baseline laboratory data included serum creatinine, eGFR, and bone profile. Bone mineral densitometry examination reports at the femoral neck and hip were retrieved. The study was approved by the Ethical Committee of the Royal Hospital.
| Statistical Analysis|| |
Data are expressed as mean with SD or proportion. Nonparametric independent sample data were evaluated using Kruskal–Wallis test. Whereas, Chi-square was used to evaluate the association between the dose of steroids and the rate of side of side effects. Correlation analysis using spearman was conducted to evaluate the rate of infection and patients who were receiving four or more of immunosuppressive medications. Statistical analysis was performed using the statistical software IBM SPSS Statistics version 20.0 (IBM Corp., Armonk, NY, USA). All tests were performed at a two-tailed significance level of 0.05.
| Results|| |
During the study period of 2006–2018, there were 314 patients on denosumab. After excluding all patients with malignancy which were the bulk of patients who are receiving denosumab in our institute, 84 patients were included in our study for analysis.
The patients’ characteristic and demographic findings are summarized in [Table 1]. The mean (SD) of the patients’ age was around 63 years (16). Out of all patients who were fulfilling the inclusion criteria, 24 (28.5%) patients had normal kidney function and 60 (71.5%) patients had CKD. Forty-three percent of all patients with CKD developed side effects after taking denosumab. In comparison, only 17% of the patients with normal kidney function developed side effects. [Table 2] shows the different stages of CKD and the rate of side effects in each stage. In this cohort, the eGFR before using denosumab was not statistically significant among male and female patients’ groups, but there were more female patients than male patients on renal replacement therapy (P = 0.056).
|Table 2: The frequency of side effects associated with different stages of chronic kidney disease.|
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The average age of patients with normal renal function is around 55 years and the average age of patients with CKD is around 66 years.
There was no significant association between gender and the rate of infection (P = 0.138).
Among CKD patients, 26 patients (43%) developed infection during the treatment with denosumab. Of which, 50% of them had moderate infections and required admission. Out of these patients, 76% were in immunosuppressive medications and 61% of the patients were receiving steroids more than 2.5 mg per day. Hypocalcemia was detected in two patients (3.3%), and they had CKD stage V.
Among patients with normal renal function, four patients had side effects: one had musculoskeletal side effects, two patients had mild upper respiratory tract infection (URTI) and both patients were receiving steroids and immunosuppressive therapy, and one patient had moderate infection [Table 3].
Using Chi-square test and the nonparametric independent samples Kruskal–Wallis test, there was a significant association between the dose of steroids and the rate of side effects with significance level of <0.014 and 0.009, respectively. Thirty-seven percent of the patients with CKD were receiving oral steroids in comparison to 29% of the patients with normal renal function. The average steroid dose intake among both groups was the same around 4.5 mg.
There was a trend toward statistical significance between the average dose of steroids among male and female patients, with female patients being having higher doses of steroids than male patients (P = 0.06).
All patients who were on denosumab and had mild URTI infections were receiving immuno-suppressive therapy apart from one patient who was a case of epidermolysis bullousa dystrophica. In addition, a few patients (4%) developed musculoskeletal side effects.
By using the Kruskal–Wallis test, there was no correlation between the total dose of denosumab and the rate of different side effects. Furthermore, the total duration denosumab intake, the distribution of patients’ age, and distribution of eGFR and creatinine were the same across all categories of side effects from denosumab.
Subgroup analysis of all patients who were on biologics and receiving denosumab revealed a total of 14 patients on different biological therapies over different courses of patient illness. Out of these patients, five (36%) had musculoskeletal side effects.
Tocilizumab was administered to six patients, two of whom had a moderate infection.
Among the three patients receiving anti-TNF therapy, one had a moderate infection. Three patients received rituximab; two of them had moderate infections. Furthermore, tofacitinib was prescribed to two patients, one of whom was suffering from a moderate infection.
Analysis using Chi-square showed a significant association with P score of ≤0.0001 between the rate of infection and patients who were receiving four or more of immuno-suppressive medications. Correlation analysis using Spearman correlation coefficient showed a significant correlation of 0.351 with a significance level of 0.001.
BMD reports were recruited in 60% of the patients who were receiving denosumab. Of these BMD reports, around 70% of the patients showed improvement or stable BMD changes in the lumbar and hip region and 30% of the patients showed worsening in their BMD.
There was no gender difference in patients who had improvement or worsening in the hip or lumbar spine BMD (P = 0.677 and 0.975, respectively).
| Discussion|| |
Safety of medications in patients with CKD is fundamental principal that every clinician needs to be aware of. Since these groups of patients having several comorbidities and are receiving multiple medications, which all keep them at high-risk group of acquiring infection.
This study compares the rate of infections in patients receiving denosumab with CKD in comparison to patients with normal renal function. Our study revealed a high rate of infections in patients with CKD, especially advanced stage 4 and 5. Forty-three percent of all patients with CKD developed side effects after taking denosumab. In comparison, only 17% of the patients with normal kidney function developed side effects.
From which, 50%–56% of the patients with CKD stage 4 and 5 developed side effects while receiving denosumab [Table 2]. There is a paucity of reports that had studied the rate of infections in patients receiving denosumab. Stopeck et al reported in their paper about the safety of long-term denosumab therapy in patients with metastatic breast and prostate cancer, and they showed an infection rate of about 40%. The reported infections include nasopharyngitis, urinary tract infections, influenza, and pneumonia.,
In this study, we found that CKD patients on steroids had a higher risk of getting infections in comparison to patients who are not receiving steroids. This is not a surprise since glucocorticoid intake on its own is associated with high risk of infection.
Furthermore, there are other factors that act as confounders such as multiple comorbidities, immunosuppressive therapies, and the age of the patients. The average age of the subjects in this cohort is approximately (63 ±16) years old, which can be considered a confounding variable.
Denosumab is approved by FDA to be used for prophylaxis of steroid-induced osteoporosis. Sawamura et al reported the safety and efficacy of denosumab in the treatment of glucocorticoid-induced osteoporosis. They reported only mild URTI in 6.9% of the patients in their cohort. The denosumab registration trial had reported some mild skin infections with no evidence of any serious life-threatening infection.
There was no deterioration in renal function while using denosumab. This similar finding was reported before by several reports including the FREEDOM trial.,, Denosumab demonstrates efficacy in patients with CKD despite the CKD stage. BMD reports that were recruited in our cohort showed that around 70% of the patients showed either improvement or stable BMD changes in both hips and lumbar region.
We reported a rate of 3.3% of hypocalcemia that occur in patients with stage 5 CKD. Hypocalcemia happens as a result of the inadequate renal conversion of 25-OH-D to one, 25-OH2-D (calcitriol) that happens in kidney failure. Another factor that contributes to hypocalcemia in advanced CKD is phosphate retention, inflicting calcium-phosphate precipitates.
Ungprasert et al reported a life-threatening hypocalcemia with prolongation of QTc interval associated with the use of denosumab in a patient with moderate renal insufficiency. In this case, the patient was treated with IV calcium gluconate and the patient’s symptoms improved.
The rate of hypocalcemia in our cohort was lower than the rate reported by some studies which range between 5.5% and 20.8%.,,,,
The lower rate of hypocalcemia in our cohort can be attributed primarily to the fact that a majority of our patients with advanced CKD receive calcium supplements and vitamin D supplements.
One additional adverse effect we did not report in our cohort related to osteonecrosis of the jaw (ONJ), which can occur with long-term administration of denosumab, especially at high doses, as in malignant metastatic bone disease. The prevalence of ONJ was reported by some studies to be approximately 1.9%. The most common risk factor associated with ONJ is exposure to dental procedures such tooth extraction, wearing of dental appliance, and poor oral hygiene.
The major limitation of this study is it is a retrospective study with small sample size. Patients in this study had multiple comorbidities including hypertension, ischemic heart disease, diabetes mellitus, and connective tissue diseases. These diseases on its own are risk factors for poor immunity and increasing the risk of infections. In addition, patients received steroids which may contribute to an increased risk of infection if combined with other immunosuppressive therapy. Further, the fact that all patients were recruited from the same hospital, and this is a tertiary care hospital, may result in a referral bias.
However, this study reflects real-world data with day-to-day practice, and it gives us an idea how to manage these patients with different comorbidities and complications. A large-scale, multicenter prospective study involving a large sample size should be conducted in order to examine the effects of osteoporosis biological treatment in patients with chronic kidney disease with the aim of determining the rate of infections in some specific cohorts, such as those receiving multiple immunosuppressive therapies.
It is recommended that caution be exercised when prescribing denosumab to patients taking three or more immunosuppressive medications. Consequently, reducing the number of immunosuppressive medications, if possible, may prove beneficial to individuals taking denosumab.
| Conclusion|| |
Denosumab has been associated with an increased risk of infection in patients with chronic kidney disease taking steroid medications or immunosuppressive medications. There were no deteriorations in kidney function during treatment with denosumab.
Hypocalcemia is a potential side effect that may develop in patients with advanced stages of chronic kidney disease. Supplementation with calcium and vitamins, along with close monitoring, should be considered for this group.
Conflict of interest: None declared.
| References|| |
Schipper LG, Fleuren HW, van den Bergh JP, Meinardi JR, Veldman BA, Kramers C. Treatment of osteoporosis in renal insufficiency. Clin Rheumatol 2015;34:1341-5.
Ott SM. Therapy for patients with CKD and low bone mineral density. Nat Rev Nephrol 2013;9:681-92.
Miller PD. Chronic kidney disease and osteoporosis: Evaluation and management. Bonekey Rep 2014;3:542.
de Beus E, Boer WH. Denosumab for treatment of immobilization-related hypercalcaemia in a patient with advanced renal failure. Clin Kidney J 2012;5:566-71.
Tartaglione L, Pasquali M, Rotondi S, Muci ML, Covic A, Mazzaferro S. Positioning novel biologicals in CKD-mineral and bone disorders. J Nephrol 2017;30:689-99.
Dave V, Chiang CY, Booth J, Mount PF. Hypocalcemia post denosumab in patients with chronic kidney disease stage 4-5. Am J Nephrol 2015;41:129-37.
DusilováSulková S, Horáček J, Šafránek R, Gorun P, Viklický O, Palička V. Denosumab associated with bone density increase and clinical improvement in a long-term haemo-dialysis patient. Case report and review of the literature. Acta Med (Hradec Kralove, Czech Republic) 2014;57:30-3.
Anastasilakis A, Toulis K, Polyzos S, Anastasilakis C, Makras P. Long-term treatment of osteoporosis: Safety and efficacy appraisal of denosumab. Ther Clin Risk Manag 2012;8:295-306.
Cheng BC, Chen YC. Young patients and those with a low eGFR benefitted more from denosumab therapy in femoral neck bone mineral density. Clin Rheumatol 2017;36:929-32.
Yamasaki M, Yuasa T, Uehara S, et al. Improvement of renal function by changing the bone-modifying agent from zoledronic acid to denosumab. Int J Clin Oncol 2016;21:1191-5.
Hiramatsu R, Ubara Y, Sawa N, et al. Denosumab for low bone mass in hemodialysis patients: A noncontrolled trial. Am J Kidney Dis 2015;66:175-7.
Buckley L, Guyatt G, Fink H, et al. 2017 American College of Rheumatology Guideline for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Rheumatol 2017;69:1521-37.
Levey A, Eckardt K, Tsukamoto Y, Levin A, Coresh J, Rossert J et al. Definition and classification of chronic kidney disease: A position statement from kidney disease: Improving Global Outcomes (KDIGO). Kidney International. 2005;67(6):2089-2100.
Stopeck AT, Fizazi K, Body JJ, et al. Safety of long-term Denosumab therapy: Results from the open label extension phase of two phase 3 studies in patients with metastatic breast and prostate cancer. Support Care Cancer 2016; 24:447-55.
Chen CL, Chen NC, Liang HL, et al. Effects of denosumab and calcitriol on severe secondary hyperparathyroidism in dialysis patients with low bone mass. J Clin Endocrinol Metab 2015;100:2784-92.
Sawamura M, Komatsuda A, Togashi M, Wakui H, Takahashi N. Effects of denosumab on bone metabolic markers and bone mineral density in patients treated with glucocorticoids. Intern Med 2017;56:631-6.
Bover J, Bailone L, López-Báez V, et al. Osteoporosis, bone mineral density and CKD-MBD: Treatment considerations. J Nephrol 2017;30:677-87.
Jamal SA, Ljunggren O, Stehman-Breen C, et al. Effects of denosumab on fracture and bone mineral density by level of kidney function. J Bone Miner Res 2011;26:1829-35.
Block GA, Bone HG, Fang L, Lee E, Padhi D. A single-dose study of denosumab in patients with various degrees of renal impairment. J Bone Miner Res 2012;27:1471-9.
Ungprasert P, Cheungpasitporn W, Srivali N, Kittanamongkolchai W, Bischof EF. Life-threatening hypocalcemia associated with denosumab in a patient with moderate renal insufficiency. Am J Emerg Med 2013;31:2.e1-2.
Killen JP, Yong K, Luxton G, Endre Z. Life-threatening hypocalcaemia associated with denosumab in advanced chronic kidney disease. Intern Med J 2016;46:746-7.
Lambe G, Malvathu R, Thomas HM, Graves A. Hypocalcaemic tetany occurring post a single denosumab dose in a patient with stage 4 chronic kidney disease, followed by calcium- and calcitriol-induced hypercalcaemia. Nephrology (Carlton) 2015;20:583-4.
Talreja DB. Severe hypocalcemia following a single injection of denosumab in a patient with renal impairment. J Drug Assess 2012;1:30-3.
Issa Al Salmi
Department of Renal Medicine, Royal Hospital, Muscat
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3]