Clinical Oral Investigations

, Volume 22, Issue 2, pp 597–615 | Cite as

Stage-specific therapeutic strategies of medication-related osteonecrosis of the jaws: a systematic review and meta-analysis of the drug suspension protocol

  • Luca Ramaglia
  • Agostino Guida
  • Vincenzo Iorio-Siciliano
  • Alessandro Cuozzo
  • Andrea Blasi
  • Anton Sculean



The most debated topic about medication-related osteonecrosis of the jaws (MRONJ) is its therapy, as there are no definitive guidelines. The aims of this systematic review were (a) to outline the best therapeutic approach according to the stage at diagnosis and (b) to perform a meta-analysis to assess whether the drug-holiday protocol may be or not an effective method in the management of MRONJ patients.

Materials and methods

The systematic review was performed following the PRISMA principles. Results were screened according to inclusion and exclusion criteria regarding staging before/after treatment, follow-up, and information provided by the authors. For statistical analysis, linear variables are reported as means and standard deviations, medians, and inter-quartile range (IQR); normality of data, according to the distribution of complete healing (primary outcome variable), was assessed with the Kolmogorov-Smirnov test. A p value < 0.05 was considered statistically significant for all tests.


Thirteen studies were selected out of 1480. None of them was case-controlled or randomized. Conservative approach showed good results at early stages, but heterogeneous result at advanced stages (100% stage 0, stage I range 81–97%, stage II range 63.6–100%, stage III 73%). Surgical approach showed heterogeneous results at all stages (stage I range 0–100%, stage II range 52–100%, stage III range 50–100%). Statistical analysis showed a significantly higher prevalence of completely healed sites in patients who followed the drug-holiday protocol.


The results suggest that the current stage-specific approach for MRONJ therapy is based on a sound clinical rationale. Conservative treatment appears to yield better outcomes at early stages, while further investigations are needed to elucidate the best protocols for the management of advanced stages. The drug-holiday protocol statistically promotes complete healing after oral surgery procedures but the application should be dictated by the condition of each patient.

Clinical relevance

At present, early MRONJ stages should be primarily treated by means of a conservative approach while more advanced stages must be carefully evaluated. Individual decisions should be made for every single case even with respect to the drug-holiday protocol.


Osteonecrosis Bisphosphonates BRONJ ARONJ MRONJ Drug-holiday protocol 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

For this type of study (e.g., systematic review and meta-analysis), formal consent is not required.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Luca Ramaglia
    • 1
  • Agostino Guida
    • 1
  • Vincenzo Iorio-Siciliano
    • 1
  • Alessandro Cuozzo
    • 1
  • Andrea Blasi
    • 1
  • Anton Sculean
    • 2
  1. 1.Department of Neurosciences, Reproductive and Odontostomatological SciencesUniversity of Naples Federico IIVia Pansini 5, 80131 NaplesItaly
  2. 2.Department of Periodontology, School of Dental MedicineUniversity of BernBernSwitzerland

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