Cumulative incidence and risk factors for medication-related osteonecrosis of the jaw during long-term prostate cancer management

Abstract

Bone-modifying agents (BMA) are extensively used in treating patients with prostate cancer with bone metastases. However, this increases the risk of medication-related osteonecrosis of the jaw (MRONJ). The safety of long-term BMA administration in clinical practice remains unclear. We aimed to determine the cumulative incidence and risk factors of MRONJ. One hundred and seventy-nine patients with prostate cancer with bone metastases treated with BMA at our institution since 2008 were included in this study. Twenty-seven patients (15%) had MRONJ during the follow-up period (median, 19 months; interquartile range, 9-43 months). The 2-year, 5-year, and 10-year cumulative MRONJ incidence rates were 18%, 27%, and 61%, respectively. Multivariate analysis identified denosumab use as a risk factor for MRONJ, compared with zoledronic acid use (HR 4.64, 95% CI 1.93-11.1). Additionally, BMA use at longer than one-month intervals was associated with a lower risk of MRONJ (HR 0.08, 95% CI 0.01-0.64). Furthermore, six or more bone metastases (HR 3.65, 95% CI 1.13-11.7) and diabetes mellitus (HR 5.07, 95% CI 1.68-15.2) were risk factors for stage 2 or more severe MRONJ. MRONJ should be considered during long-term BMA administration in prostate cancer patients with bone metastases.

Keywords: Denosumab; Jaw; Osteonecrosis; Prostate cancer; Zoledronic acid.

Figure 1

Study schematic.

Figure 2

Cumulative incidence rate of any stage of MRONJ. (A) While the majority of cases of MRONJ occurred within three years, there were also several instances of MRONJ occurring during long-term treatment. (B) The 2-year, 5-year, and 10-year cumulative incidence rates of MRONJ were 18%, 27%, and 61%, respectively. (C) In the patients receiving zoledronic acid or denosumab, denosumab use rather than zoledronic acid use was a significant risk factor for the development of MRONJ (p = 0.004). (D) In the patients with monthly BMA use or BMA use at longer than one-month intervals, BMA administration at longer than one-month intervals was associated with a lower risk of MRONJ than monthly BMA use (p = 0.044). MRONJ medication-related osteonecrosis of the jaw.

Figure 3

Cumulative incidence rate of severe MRONJ. (A) The 2-year, 5-year, and 10-year cumulative incidence rates of severe MRONJ were 7%, 21%, and 51%, respectively. (B) Among patients with or without diabetes, the incidence rate of severe MRONJ was significantly different between patients with diabetes and those without diabetes (p = 0.006). (C) Among patients with EOD grade at BMA induction ≧2 or EOD grade at BMA induction < 2, the incidence rate of MRONJ was significantly different between the patients with EOD grade ≧2 and those with EOD grade < 2 (p = 0.026). MRONJ medication-related osteonecrosis of the jaw; EOD extent of the disease.