# Adverse effects of the PENTO(CLO) protocol in the prevention and management of iatrogenic head and neck bone necrosis in cancer patients: A systematic review and meta-analysis

## TL;DR

This study reviews the side effects of PENTO and PENTOCLO protocols used to prevent and treat bone necrosis in cancer patients.

## Contribution

The study provides the first meta-analysis of adverse effects of PENTO(CLO) protocols for osteoradionecrosis and MRONJ.

## Key findings

- The pooled adverse effect rate of PENTO(CLO) protocols was 15%, with gastrointestinal symptoms being most common.
- Adverse effects were more frequent during treatment than prevention and more prevalent with PENTOCLO.
- No studies reported adverse effects in MRONJ patients, highlighting a gap in research.

## Abstract

To assess the proportion of adverse effects (AEs) associated with the use of PENTO or PENTOCLO protocols for the prevention and management of osteoradionecrosis (ORN) and medication-related osteonecrosis of the jaw (MRONJ).

A systematic literature search was conducted across six databases (PubMed, Scopus, Embase, Web of Science, LILACS, and Cochrane Library) and gray literature, with no restrictions on date or language. Studies were eligible if they involved adults (≥ 18 years) with or at risk for ORN or MRONJ and reported AEs associated with PENTO or PENTOCLO for prevention or treatment. A proportion meta-analysis estimated the overall frequency of AEs. Subgroup analyses compared AE rates between prevention and treatment contexts and between the two regimens.

Of 1,075 records screened, 9 studies met the inclusion criteria. No studies reported AEs in MRONJ patients; all focused on ORN. The pooled AE proportion was 15% (95% CI: 3.6%–11.5%; p < 0.1; I2 = 55.8%). Gastrointestinal symptoms were the most reported AEs (46.38%), followed by neurovegetative effects (18.84%). AEs were more frequent in treatment settings and more prevalent in patients using PENTOCLO (28%).

The PENTO(CLO) protocols were associated with a 15% overall AE rate, predominantly gastrointestinal symptoms. AEs occurred more often during treatment and with the PENTOCLO regimen. These findings highlight the need for close monitoring and further studies to assess safety in MRONJ patients.

The online version contains supplementary material available at 10.1007/s00520-026-10428-0.