Proceedings of the Closed Round Table and Italian Consensus on the Medication-Related Osteonecrosis of Jaws (MRONJ) at the Symposium of Italian Society of Oral Pathology and Medicine (SIPMO) Ancona, 20 October 2018 - Part III
E. Practices at risk of inappropriateness in Drug Holiday (temporary suspension vs therapeutic suspension for patients at risk of MRONJ). Yes vs No The Drug Holiday is a controversial issue (due to inconsistent literature data), involving both drug prescribers (e.g. oncologists, hematologists, bone health specialists, general practitioners) and oral and dental specialists. Consequently, some assumptions are to be underlined. “Drug holiday” can have different meanings in medical literature when referred to MRONJ. We have to distinguish: a) temporary and preventative suspension of drug therapy (e.g. bisphosphonates, denosumab, and sometimes antiangiogenic drugs) in a patient at risk of MRONJ, in case of dentistry procedures (e.g. tooth extraction or jawbone surgery) potentially inducing or highlighting jawbone necrosis (with/without bone exposure); frequently the feared MRONJ risk is due to both prolonged treatment and bone trauma; b) suspension of drug therapy (e.g. bisphosphonates, denosumab) after established diagnosis of MRONJ, hypothetically finalized to stop or to slow osteonecrosis process; c) suspension of drug therapy (bisphosphonates, denosumab) potentially inducing MRONJ after a supposed unfavorable cost-benefit balance, due to lowered efficacy or increased real (or feared) side effects; for example, due to fear of MRONJ or atypical femur fracture after several years of bisphosphonate or denosumab treatment. As the second and the third meaning have scarce literature data at this moment, this document will only afford the first meaning of “drug holiday”. Two different populations are usually recognized as at risk of MRONJ due to antiresorptive treatment (e.g. bisphosphonates, denosumab), even with very different MRONJ incidence: i) cancer and myeloma patients with bone disease receiving antiresorptive drugs at higher doses and more frequently (e.g. monthly 4mg i.v. zoledronic acid, or monthly 120mg s.c. denosumab administration); ii) osteometabolic patients and people affected by other nonmalignant diseases (osteoporosis, Paget disease, etc.) receiving antiresorptive drugs at lower doses and less frequently (e.g. oral bisphosphonates; yearly 5mg i.v. zoledronic acid; bi-yearly 60mg s.c. denosumab). Consequently, the distinctive MRONJ risk of these two patient populations reflects on different evaluation of possible “Drug Holiday”. However, it is to be noted that some special patient subsets escape this dichotomy: - patients suffering from RA (Rheumatoid Arthritis), showing higher MRONJ risk than osteoporosis patients; - cancer patients (i.e. breast and prostate cancer patients) receiving preventative low-dose antiresorptive drugs due to risk of CTIBL (Cancer Treatment Induced Bone Loss), with MRONJ risk next to that of osteoporotic patients; - cancer patients receiving both antiangiogenic and high dose antiresorptive drugs, at even higher MRONJ risk than those receiving only antiresorptive therapy. Furthermore, the evaluation for a possible drug holiday has to consider that the ONJ risk sensibly depends on drug exposure time (years of administration) and the observation time (time since the initial administration) in both two main patient populations: active cancer and myeloma patients, and osteoporotic patients. Finally, a careful imaging study of the patient (i.e. by Computed Tomography exams) is recommended before balancing pros and cons of drug holiday in case of tooth extraction (or other bone trauma) in a symptomatic patient at risk of ONJ. Practices at risk of inappropriateness #1 performing dental extraction or oral surgery in patients with active cancer and myeloma bone disease and in therapy with i.v. high-dose bisphosphonates without concerting any temporary suspension (drug holiday) with the prescriber (oncologist / haematologist) #2 suspending indiscriminately therapy with antiresorptive drugs (i.e. bisphosphonates, denosumab) prescribed for osteoporosis (or its prevention), at least in the first three years of assumption, in case of necessity of extraction or programmed oral surgery #3 performing dental extraction or oral surgery in patient with active cancer and myeloma bone disease and in therapy with denosumab without concerting any temporary suspension (drug holiday) with the prescriber (oncologist / haematologist) Good practices #1 plan, in cancer patients, combined assessment by prescriber (i.e. high risk versus low risk of fracture and other SREs, Skeletal-Related Events) and by dentist (i.e. high risk versus low risk of post-extraction complications) to determine whether or not the need for precautionary suspension of i.v. high-dose bisphosphonate, before and after the dental management. This combined assessment is mandatory in the absence of univocal data on the efficacy and need to suspend zoledronic acid or other bisphosphonates to reduce the risk of "post-extraction" ONJ, and in consideration of conflicting data on the anti-angiogenic effect of zoledronic acid [20–23]. #2 plan, in osteometabolic patients, combined assessment by prescriber (i.e. high risk versus low risk of fracture)* and by dentist (i.e. high risk versus low risk of post-extraction complications) to determine whether or not the need for precautionary suspension of the drug, before and after the dental procedure. In particular, to evaluate mutually the risk-benefit ratio (probability of fracture** versus probability of ONJ) if the therapy continues for over three years. * The fracture risk can be determined objectively and correctly by applying the DeFRA79 algorithm validated by AIFA (www.defra-osteoporosi.it), Italian version of the FRAX algorithm. ** The suspension of denosumab determines within the 3-6 following months a rebound of the fracture risk especially in patients at high risk of fracture (those provided for denosumab by the AIFA therapeutic plan) [24–26]. #3 plan, in cancer patients, combined assessment by prescriber (i.e.,...