Osteonecrosis of the Jaw and Antiresorptive Agents in Benign and Malignant Diseases: A Critical Review Organized by the ECTS

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Abstract

Context

Antiresorptive therapy significantly reduces fracture risk in patients with benign bone disease and skeletal-related events (SREs) in patients with bone metastases (BM). Osteonecrosis of the jaw (ONJ) is a rare but severe condition manifested as necrotic bone lesion or lesions of the jaws. ONJ has been linked to the use of potent antiresorptive agents, termed medication-related ONJ (MRONJ).

Objective

We aimed to identify the differences various aspects of MRONJ among distinct patient categories and provide recommendations on how to mitigate the risk and optimally manage MRONJ in each of them.

Methods

A working group of the European Calcified Tissue Society (ECTS) and 2 experts performed an updated detailed review of existing literature on MRONJ incidence, characteristics, and treatment applied in bone diseases with variable severity of skeletal insult, ranging from osteoporosis to prevention of cancer treatment–induced bone loss and SREs in cancer patients with BM.

Results

The risk for MRONJ is much higher in patients with advanced malignancies compared to those with benign bone diseases because of the higher doses and more frequent administration of antiresorptive agents in individuals with compromised general health, along with coadministration of other medications that predispose to MRONJ. The overall risk for MRONJ is considerably lower than the benefits in all categories of patients.

Conclusion

The risk for MRONJ largely depends on the underlying bone disease and the relevant antiresorptive regimen applied. Physicians and dentists should keep in mind that the benefits of antiresorptive therapy far outweigh the risk for MRONJ development.

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Most cited references 259

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Denosumab for prevention of fractures in postmenopausal women with osteoporosis.

Steven R Cummings, Javier San Martin, Michael McClung … (2009)

Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor-kappaB ligand (RANKL) that blocks its binding to RANK, inhibiting the development and activity of osteoclasts, decreasing bone resorption, and increasing bone density. Given its unique actions, denosumab may be useful in the treatment of osteoporosis. We enrolled 7868 women between the ages of 60 and 90 years who had a bone mineral density T score of less than -2.5 but not less than -4.0 at the lumbar spine or total hip. Subjects were randomly assigned to receive either 60 mg of denosumab or placebo subcutaneously every 6 months for 36 months. The primary end point was new vertebral fracture. Secondary end points included nonvertebral and hip fractures. As compared with placebo, denosumab reduced the risk of new radiographic vertebral fracture, with a cumulative incidence of 2.3% in the denosumab group, versus 7.2% in the placebo group (risk ratio, 0.32; 95% confidence interval [CI], 0.26 to 0.41; P<0.001)--a relative decrease of 68%. Denosumab reduced the risk of hip fracture, with a cumulative incidence of 0.7% in the denosumab group, versus 1.2% in the placebo group (hazard ratio, 0.60; 95% CI, 0.37 to 0.97; P=0.04)--a relative decrease of 40%. Denosumab also reduced the risk of nonvertebral fracture, with a cumulative incidence of 6.5% in the denosumab group, versus 8.0% in the placebo group (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01)--a relative decrease of 20%. There was no increase in the risk of cancer, infection, cardiovascular disease, delayed fracture healing, or hypocalcemia, and there were no cases of osteonecrosis of the jaw and no adverse reactions to the injection of denosumab. Denosumab given subcutaneously twice yearly for 36 months was associated with a reduction in the risk of vertebral, nonvertebral, and hip fractures in women with osteoporosis. (ClinicalTrials.gov number, NCT00089791.) 2009 Massachusetts Medical Society

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American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw--2014 update.

Salvatore Ruggiero, Thomas Dodson, John E Fantasia … (2014)

Strategies for management of patients with, or at risk for, medication-related osteonecrosis of the jaw (MRONJ) were set forth in the American Association of Oral and Maxillofacial Surgeons (AAOMS) position papers in 2007 and 2009. The position papers were developed by a special committee appointed by the board and composed of clinicians with extensive experience in caring for these patients and basic science researchers. The knowledge base and experience in addressing MRONJ has expanded, necessitating modifications and refinements to the previous position paper. This special committee met in September 2013 to appraise the current literature and revise the guidelines as indicated to reflect current knowledge in this field. This update contains revisions to diagnosis, staging, and management strategies and highlights current research status. The AAOMS considers it vitally important that this information be disseminated to other relevant health care professionals and organizations.

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Romosozumab Treatment in Postmenopausal Women with Osteoporosis.

Felicia Cosman, Daria Crittenden, Jonathan D. Adachi … (2016)

Background Romosozumab, a monoclonal antibody that binds sclerostin, increases bone formation and decreases bone resorption. Methods We enrolled 7180 postmenopausal women who had a T score of -2.5 to -3.5 at the total hip or femoral neck. Patients were randomly assigned to receive subcutaneous injections of romosozumab (at a dose of 210 mg) or placebo monthly for 12 months; thereafter, patients in each group received denosumab for 12 months, at a dose of 60 mg, administered subcutaneously every 6 months. The coprimary end points were the cumulative incidences of new vertebral fractures at 12 months and 24 months. Secondary end points included clinical (a composite of nonvertebral and symptomatic vertebral) and nonvertebral fractures. Results At 12 months, new vertebral fractures had occurred in 16 of 3321 patients (0.5%) in the romosozumab group, as compared with 59 of 3322 (1.8%) in the placebo group (representing a 73% lower risk with romosozumab; P<0.001). Clinical fractures had occurred in 58 of 3589 patients (1.6%) in the romosozumab group, as compared with 90 of 3591 (2.5%) in the placebo group (a 36% lower risk with romosozumab; P=0.008). Nonvertebral fractures had occurred in 56 of 3589 patients (1.6%) in the romosozumab group and in 75 of 3591 (2.1%) in the placebo group (P=0.10). At 24 months, the rates of vertebral fractures were significantly lower in the romosozumab group than in the placebo group after each group made the transition to denosumab (0.6% [21 of 3325 patients] in the romosozumab group vs. 2.5% [84 of 3327] in the placebo group, a 75% lower risk with romosozumab; P<0.001). Adverse events, including instances of hyperostosis, cardiovascular events, osteoarthritis, and cancer, appeared to be balanced between the groups. One atypical femoral fracture and two cases of osteonecrosis of the jaw were observed in the romosozumab group. Conclusions In postmenopausal women with osteoporosis, romosozumab was associated with a lower risk of vertebral fracture than placebo at 12 months and, after the transition to denosumab, at 24 months. The lower risk of clinical fracture that was seen with romosozumab was evident at 1 year. (Funded by Amgen and UCB Pharma; FRAME ClinicalTrials.gov number, NCT01575834 .).

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Author and article information

Journal

Journal ID (nlm-ta): J Clin Endocrinol Metab

Journal ID (iso-abbrev): J Clin Endocrinol Metab

Journal ID (publisher-id): jcem

Title: The Journal of Clinical Endocrinology and Metabolism

Publisher: Oxford University Press (US )

ISSN (Print): 0021-972X

ISSN (Electronic): 1945-7197

Publication date Collection: May 2022

Publication date (Electronic): 18 December 2021

Publication date PMC-release: 18 December 2021

Volume: 107

Issue: 5

Pages: 1441-1460

Affiliations

[1 ] Department of Endocrinology, 424 General Military Hospital , 564 29 N Efkarpia Thessaloniki, Greece

[2 ] Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, “Sapienza” University of Rome , 00185 Rome, Italy

[3 ] Unit of Endocrinology and Diabetes, Departmental Faculty of Medicine and Surgery, Campus Bio-Medico University of Rome , 00128 Rome, Italy

[4 ] Department of Oral and Maxillofacial Surgery, 424 General Military Hospital , 56429 Thessaloniki, Greece

[5 ] Division of Endocrinology and Metabolism and Geriatrics, McMaster University , L8N3Z5 Hamilton, Ontario, Canada

[6 ] Bone Center, Department of Internal Medicine, Erasmus MC , 2040 Rotterdam, the Netherlands

[7 ] Department of Medicine, CHU Brugmann, Université Libre de Bruxelles , 1050 Brussels, Belgium

Author notes

Correspondence: Athanasios D. Anastasilakis, PhD, Department of Endocrinology, 424 General Military Hospital, Ring Rd, 564 29 N Efkarpia, Thessaloniki, Greece. Email: a.anastasilakis@ 123456gmail.com .

These authors share first co-authorship of this work.

Author information

Athanasios D Anastasilakis https://orcid.org/0000-0002-9624-6296

Andrea Palermo https://orcid.org/0000-0002-1143-4926

Article

Publisher ID: dgab888

DOI: 10.1210/clinem/dgab888

PMC ID: 9016445

PubMed ID: 34922381

SO-VID: 1a982dcd-185e-452e-a01f-50bfb103bc65

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence ( https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

History

Date received : 05 November 2021

Date: 08 December 2021

Date: 06 January 2022

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Osteonecrosis of the Jaw and Antiresorptive Agents in Benign and Malignant Diseases: A Critical Review Organized by the ECTS

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Abstract

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Objective

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Related collections

Journal of the ASEAN Federation of Endocrine Societies

Most cited references 259

Denosumab for prevention of fractures in postmenopausal women with osteoporosis.

American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw--2014 update.

Romosozumab Treatment in Postmenopausal Women with Osteoporosis.

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