Antiresorptive medication-related osteonecrosis of the jaw: Incidence and preventive measures utilization in cancer patients.

Introduction

Osteonecrosis of the jaw(ONJ) is a multifactorial complication marked by the necrosis of the jawbone. The use of potent antiresorptive agents such as bisphosphonates and denosumab has been correlated to the incidence of ONJ in cancer patients. Denosumab and ZA has been reported as risk factors for ONJ in cancer patients ( Ruggiero et al., 2022 , Khan et al., 2015 ). However, incidence rates of medication related ONJ (MRONJ) vary depending on several factors, including the duration of treatment, the presence of other risk factors, and the specific cancer type.

ONJ can lead to severe complications, including pain, swelling, and exposed bone, substantially affecting the quality of life of those affected by impairing their ability to eat, speak, and perform daily activities ( Toole, 2015 , Chang et al., 2018 ). In addition to the dosing factor and frequency of using antiresorptive drugs, particularly among cancer patients, patients with advanced malignancies are more vulnerable to ONJ due to their weakened immune systems and mounted risk of infections ( Roato et al., 2023 , Zhang et al., 2021 , Khosla et al., 2007 ). Obesity, diabetes mellitus, hypertension, smoking, tooth extraction, and corticosteroid treatment are the main risk factors for developing ONJ ( Ciobanu et al. 2023 ).

Both ZA and denosumab are employed for the management of osteoporosis in individuals with bone metastases. Denosumab has been shown to have a greater risk of MRONJ compared to ZA. Denosumab and ZA may cause ONJ by inhibiting osteoclast activity, disrupting bone remodeling, and accumulating in the jaw bones. These mechanisms, together, contribute to the development of ONJ ( Kajizono et al., 2015 , Khosla et al., 2007 , Henry et al., 2011 ).

Antiresorptive agents are known to disrupt bone remodeling by targeting osteoclasts (OCs), disrupting the balance between resorption and formation regulated by the receptor activator of nuclear factor kappa-B(RANK), its ligand(RANKL), and osteoprotegerin (OPG) pathway. Bisphosphonates affect osteocytes, increasing the expression of RANKL and Sclerostin, which in turn inhibit bone formation through the WNT (Wingless-related integration site) signaling pathway. Denosumab, by suppressing OCs, similarly disrupts bone homeostasis, collectively impairing the jaw’s repair capacity and increasing the risk of MRONJ ( Kim et al. 2019 ; Dalle Carbonare et al. 2017 ).

To reduce the risk of ONJ, preventive measures such as regular dental check-ups, good oral hygiene, avoidance of dental procedures, and patient education are recommended ( Chang et al., 2018 , Karna et al., 2018 ). The Saudi Food and Drug Administration (SFDA) has approved an educational card that provides patients with information on the risk of ONJ and preventive measures to minimize the risk ( SFDA, 2023 ). The card aims to educate patients about the risk of ONJ associated with antiresorptive medications like bisphosphonates and denosumab ( Marx, Cillo Jr, and Ulloa 2007 ) and provide guidance on preventive measures. It includes information on the definition of ONJ, risk factors, signs and symptoms, and steps patients can take to reduce their risk, such as continuing correct oral hygiene, undergoing regular dentistry check-ups, and avoiding invasive dental procedures if possible ( Ruggiero et al., 2006 , García-Martínez et al., 2017 ). The education card is intended for patients receiving antiresorptive therapies, particularly those with osteoporosis or cancer with bone metastases who are at higher risk of developing ONJ. The SFDA has made this education card available to healthcare providers to distribute to their patients as part of the risk minimization measures for antiresorptive medications ( SFDA, 2023 ). This study aimed at investigating the incidence rate and preventive measures utilization in MRONJ among cancer patients treated using ZA or denosumab.

Materials and Methods

Studyydesign and data collection

This retrospective cohort single center investigation was performed at a tertiary cancer center. Among 528 eligible patients, 210 adult patients with cancer treated with ZA or denosumab were enrolled. Patient demographics, cancer type, and ZA or denosumab prescriptions were obtained from patients’ health records. Data on the incidence of ONJ and the utilization of preventive measures were also collected. All procedures involving human participants adhered to the ethical principles outlined in the Declaration of Helsinki and its later amendments.

Endpoints

The main endpoint was to determine incidence of ONJ. The secondary endpoints were to determine the utilization rate of MRONJ preventive measures and the exposure duration of antiresorptive agents to the ONJ incidence. Individuals treated with denosumab or ZA solely for hypercalcemia of malignancy and patients with osteoporosis at baseline were excluded from the study.

Statistical analysis

The statistical analysis was conducted using SPSS Version 28 (IBM, USA). Numerical data were summarized as medians with interquartile ranges (IQR) and analyzed using the Mann-Whitney test. Categorical variables were expressed as frequencies and percentages and assessed using either the Chi-square test or Fisher’s exact test, as appropriate. Logistic regression analysis was employed to identify factors associated with ONJ incidence, with statistical significance set at a two-tailed p-value of < 0.05.

Results

Patient characteristics

In the period starting January 2020 until December 2023, 528 adult individuals with cancer received ZA or denosumab ( Fig. 1 ). Among them, 318 patients were excluded because they were administered antiresorptive agents for the management of hypercalcemia of malignancy or osteoporosis. Number of patients who received ZA was 68 (32.4 %), consisting of 50 (73.5 %) females and 18 (26.5 %) males. The median age was 63.5 years. The number of patients who received denosumab was 142 (67.6 %), comprising 124 (87.3 %) females and 18 (12.7 %) males, with a median age of 65.5 years ( Table 1 ).

Theemedian age of the whole study cohort was 65 years (IQR 54, 76) showing female predominance representing 82.9 % of cases. The median body mass index (BMI) was 27.52 kg/m2 (IQR 23.59, 32.49), with obesity in over one third of patients (39 %). The comparison between patients treated by ZA and those treated by Denosumab revealed a statistically significant difference in sex distribution (P = 0.013), however, both groups were comparable in terms of age, weight, and BMI ( Table 1 ).

Regarding comorbidities in patients included in the study cohort, 56.7 % of patients had advanced diseases while 35.7 % were hypertensive and 29 % were diabetic. The proportion of patients with advanced diseases was significantly greater in ZA group than Denosumab treated patients (P < 0.001). While 8.1 % of patients were on corticosteroids therapy, only 1 patient had a pre-existing dental diseases of tooth extraction. One patient was reportedly a smoker ( Table 1 , Supplementary Figure A ).

Cancer type distribution

The cancer types were predominantly breast cancer (76.2 %). Multiple myeloma and prostate cancer were reported in 8.6 % and 5.7 % of the patients, respectively. Other types included malignancies occurring in lung (2.9 %), gastric (1.9 %), nasopharyngeal carcinoma (1.4 %), while renal cell carcinoma, cervical cancer, leiomyosarcoma, gallbladder, hepatocellular carcinoma, uterine and giant cell tumor were reported in 1 patient each (0.5 % each). There was a statistically significant (P < 0.001) difference in the type of cancer between the studied groups ( Supplementary table B ).

Incidence of antiresorptive agent MRONJ

The incidence rate of medication related osteonecrosis of the jaw (MRONJ) was 3.8 % (8 out of 210). The incidence of MRONJ was 4.4 % in ZA group (3 out of 68 patients) and 3.5 % in Denosumab group, accounting for 5 out of 142 patients ( Table 2 ). All patients who developed ONJ were females, and the cancer type was metastatic breast cancer to bone. The utilization rate of antiresorptive agent related ONJ preventive measures was 5.2 % (11 out of 210), with regular dental check-ups accounting for 3.3 % (7 out of 210) and 1.9 % (4 out of 210) for oral hygiene education. The duration of exposure to antiresorptive agents before the incidence of ONJ was twelve months for ZA and twenty four months for denosumab ( Fig. 2 ).

Risk factors among MRONJ cases

The Risk factors associated with MRONJ were assessed in cancer patients receiving either ZA or denosumab. All ONJ cases were female, suggesting that female sex is an important risk factor for MRONJ in this population.

Obesity, as measured by a BMI higher than or equal to 30 kg /m 2 , was present in only 12.5 % of the patients. Diabetes mellitus and hypertension were found in 50 % of the MRONJ patients. Tooth extraction and corticosteroid use were present in only 12.5 % of the MRONJ patients each ( Table 3 ).

The duration of use of denosumab and ZA in relation to the incidence of ONJ

There was a statistically significant relation between the duration of denosumab exposure and the incidence of ONJ (P = 0.004), with significantly longer duration among patients who developed ONJ (24 months versus 12 months) than the patients who did not develop ONJ ( Supplementary table A ). On the other hand, there was no significant relation between the duration of ZA exposure and the incidence of MRONJ indicating that Denosumab can be safer on the long-term use ( Supplementary Figure B ).

Logistic regression analysis for factors associated with the incidence of ONJ

Based on the results of univariate and multivariable logistic regression analyses, duration of antiresorptive agent exposure was significantly associated with the incidence of ONJ, as each 1 unit increase in the duration resulted in increasing the odds of experiencing ONJ by 1.09 (95 %CI: 1.01 to 1.18, P = 0.023) in the univariate model and by 1.11 (95 %CI: 1.02 to 1.22, P = 0.022) in the multivariable model ( Table 4 ).

Discussion

The study aimed to investigate the incidence and preventive measures utilization of antiresorptive agent medication-related osteonecrosis of the jaw (MRONJ) in cancer patients administered ZA or denosumab. The findings from our study provide valuable insights into the prevalence of MRONJ and the adoption of preventive strategies among cancer patients.

The study revealed that the cancer types treated with ZA or denosumab were predominantly breast cancer (77.6 %), followed by multiple myeloma (8.57 %), prostate (5.23 %), lung (3.33 %), and gastric (1.9 %) cancers. Other less common types included renal cell carcinoma, cervical cancer, nasopharyngeal carcinoma, leiomyosarcoma, gallbladder, hepatocellular carcinoma, and uterine cancer (0.47 % each). This distribution aligns with previous studies that have reported breast cancer as the most frequent type of cancer with correlation to bone metastases and the subsequent use of antiresorptive agents ( Chang, Hakam, and McCauley 2018 ).

The median incidence rate of MRONJ in our study was 3.8 % (8 out of 210 patients), with ZA and denosumab having incidence rates of 1.42 % (3 out of 210) and 2.38 % (5 out of 210), respectively. These findings are comparable to published data ( Karna et al. 2018 ).

All patients who developed MRONJ in this study were females, and the cancer type was metastatic breast cancer to bone. Female predominance can be because of hormonal influences, such as estrogen's role in bone remodeling. This observation is consistent with previous reports that have identified female gender and breast cancer as significant risk factors for developing ONJ ( Kyrgidis et al. 2008 ). The obesity may not be a major contributing factor to the development of MRONJ in this particular group. However, it is important to note that the sample size is relatively small, and a larger study may be needed to draw more definitive conclusions about the risk of obesity in MRONJ. The high prevalence of DM and HTN noted in this study and other studies ( Kim et al., 2021 , Hess et al., 2008 ) among the study participants highlights the need for careful monitoring and management of these conditions in this patient population to minimize the risk of MRONJ. Diabetes is well known to results in chronic inflammation and delayed wound healing. Therefore, DM may aggravate jawbone necrosis when combined with ZA or denosumab. Hypertension, often associated with vascular dysfunction, could compromise blood supply to the jaw, further contributing to ONJ risk. Tooth extraction and corticosteroid use may contribute to the development of MRONJ, they appear to be less prevalent in this particular study population compared to female sex, DM, and HTN ( Khan et al., 2015 , McGowan et al., 2018 ). The utilization rate of antiresorptive agent related ONJ preventive measures was 5.2 % (11 out of 210 patients), with regular dental check-ups accounting for 3.3 % (7 out of 210) and oral hygiene education for 1.9 % (4 out of 210). The low utilization rates observed in our study may indicate a need for improved education and awareness among healthcare providers and patients regarding the importance of preventive measures ( Ruggiero et al., 2006 , García-Martínez et al., 2017 ). Preventive measures involve oral hygiene protocols and regular follow-ups. The low utilization rate of ONJ preventive measures observed in this study (5.2 %) highlights significant gaps in patient education and healthcare provider awareness. Contributing factors may include a lack of adherence to educational programs. It is, therefore, recommended to introduce changes to the dental care system by following oral care protocols suggested by experts, as detailed before ( Mauceri et al. 2022 ).

The duration of exposure to antiresorptive medications before the incidence of ONJ was 12 months for ZA and 24 months for denosumab. These results comes in agreement with published reports that have suggested a cumulative effect of antiresorptive agents on the progress of ONJ. A study by Marx et al. (2005) reported that the risk of ONJ increased with the duration of exposure to bisphosphonates, particularly after 12 months of treatment ( Kajizono et al., 2015 , Marx et al., 2007 ).

Regarding risk factors, obesity was not statistically associated with ONJ, indicating that it may not be a major contributing factor to the development of MRONJ in this group ( Marx, Cillo Jr, and Ulloa 2007 ). However, it is important to note that the sample size is relatively small, and a larger study may be needed to draw more definitive conclusions about the risk of obesity in MRONJ. Diabetes mellitus and hypertension were both present in almost half of the MRONJ patients, suggesting that these comorbidities may be important risk factors for MRONJ in cancer patients receiving antiresorptive agents ( Ciobanu et al., 2023 , Karna et al., 2018 , McGowan et al., 2018 ).

The results of this work emphasize the need for careful monitoring and management of risk factors such as DM and HTN. Although the educational information was available, this study showed the insufficiency of using the available educational resources, and the lack of education of cancer patients receiving antiresorptive agents. A potential limitation of this study is the retrospective design and the relatively small sample size, which may introduce selection bias; a population-based cohort study would provide more robust and generalizable findings.

Conclusion

The study highlights the incidence and preventive measures utilization of MRONJ among cancer patients treated with ZA or denosumab. The findings reveal a median incidence rate of ONJ at 3.8 %, with a higher incidence noted among patients treated with denosumab. The study emphasizes the significance of female sex, DM, and HTN as key risk factors. It is noteworthy that all patients who developed ONJ had advanced disease. The utilization of preventive measures, particularly regular dental check-ups, was found to be relatively low, indicating a need for enhanced education and awareness among both healthcare providers and patients. These results highlight the critical need for implementing effective preventive strategies to reduce the risk of ONJ in cancer patients undergoing antiresorptive therapies.

Ethical Statement

The study was approved by the Internal Review Board of Madinah health cluster. This study was conducted in accordance with ethical standards and approved by the Regional Ethical Committee at the Ministry of Health, Madinah, Saudi Arabia. The Institutional Review Board (IRB) approval was granted (No. 24-073).

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Footnotes

Supplementary data to this article can be found online at https://doi.org/10.1016/j.sdentj.2024.12.005 .

Supplementary material

The following are the Supplementary data to this article:

Supplementary Data 1

Supplementary Data 2

Supplementary Data 3

Supplementary Data 4

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Associated Data

Supplementary Materials

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