Persistence, compliance, discontinuation rates and switch rates in denosumab and bisphosphonate treatment of bone metastases in cancer patients: reasons of switch, osteonecrosis of the jaw (ONJ) and other critical points

One changing and challenging scenario: the treatment of cancer patients with bone metastases by bisphosphonates and denosumab, the cost–benefit evaluation of different options, and the risk of medication-related osteonecrosis of the jaw (MRONJ)

“…Real-world medical treatment of bone metastases radically changed in the last decade for the following reasons: introduction of denosumab : 120 mg monthly subcutaneous injection, with several patients already receiving zoledronic acid (or other bisphosphonates), shifted to denosumab, and many others started on denosumab from the beginning [ 1 , 4 , 7 ]; introduction of zoledronic acid every 3 months : (upfront or after a period of monthly treatment) as a possible competitor [ 9 ]; fear of the rebound effect described following denosumab discontinuation and its management [ 10 ]; difference among competing drugs and schedules in term of costs, ease of administration, staff engagement, etc . [ 8 , 9 ], with the COVID-19 pandemic likely to interfere with the routine preferences; increased awareness that skeletal-related events (SREs) — the most used study endpoint in earlier antiresorptive drug trials — are not fully reliable , and the introduction of new endpoints, so called symptomatic skeletal events (SSEs) [ 11 ]; increase of expected survival for a large proportion of bone metastatic cancer patients due to the recent advances of medical treatment (endocrine therapy, chemotherapy, targeted treatments, immunotherapy); influence of MRONJ risk evaluation , given the possible MRONJ-related worsening of patient quality of life, on antiresorptive treatment planning and management , despite several controversies still exist about MRONJ definition, diagnosis, and therapy [ 12 – 14 ].…”

“…introduction of denosumab : 120 mg monthly subcutaneous injection, with several patients already receiving zoledronic acid (or other bisphosphonates), shifted to denosumab, and many others started on denosumab from the beginning [ 1 , 4 , 7 ];…”

“…At present, three main established therapies (competitors) exist; we should choose from monthly zoledronic acid, monthly denosumab, and quarterly zoledronic acid. To further complicate the picture, combinations of these therapies are possible: shift from zoledronic acid to denosumab or vice versa [ 1 , 4 ], planned shift from monthly administrations of denosumab or zoledronic acid to quarterly zoledronic acid infusion [ 1 , 4 ], and suggested strategies of quarterly 120 mg denosumab [ 9 ].…”

“…[ 3 , 7 , 18 – 20 ]; most recent reports display Kaplan–Meier actuarial curves (data not shown from randomized trials with limited follow-up) that might be helpful to perceive the uprising risk of MRONJ with longer observation times (2–4 years), especially in patients on long-term antiresorptive treatment; MRONJ risk seems to increase with longer duration of antiresorptive treatment but also with longer observation time: could it happen independently from the duration of treatment? We need more data after long-term observation, and data about survival of MRONJ patients, to be compared with survival data of other bone metastatic patients [ 21 ]; MRONJ rate increases in bone metastatic cancer patients receiving denosumab as compared with zoledronic acid [ 3 , 7 , 18 ] with even higher rates in patients shifted from zoledronic acid to denosumab [ 1 , 4 , 18 , 19 ]. This fact matches the observations made 10 years ago, when many cases of MRONJ were reported in cancer patients shifted from pamidronate to zoledronic acid [ 1 , 4 ].…”

“…We need more data after long-term observation, and data about survival of MRONJ patients, to be compared with survival data of other bone metastatic patients [ 21 ]; MRONJ rate increases in bone metastatic cancer patients receiving denosumab as compared with zoledronic acid [ 3 , 7 , 18 ] with even higher rates in patients shifted from zoledronic acid to denosumab [ 1 , 4 , 18 , 19 ]. This fact matches the observations made 10 years ago, when many cases of MRONJ were reported in cancer patients shifted from pamidronate to zoledronic acid [ 1 , 4 ]. At present, we do not know how much of this phenomenon might be linked to denosumab itself or to the length of treatment and/or follow-up; we do not know yet how the MRONJ risk might change in patients shifted from monthly denosumab to quarterly zoledronic acid or quarterly denosumab (whereas we have limited but encouraging data after the shift from monthly to quarterly zoledronic acid) [ 15 ]; recently, the surgical treatment of established MRONJ showed some evidence of benefit for patients in terms of curative potential [ 13 ].…”