Article

An Update on Medication-Related Osteonecrosis

of the Jaw in Patients with Osteoporosis
Authors: Benjamin Bennett,1 *Hasan Tahir,2,3 Kohmal Solanki,4
Nayeem Ali4

1. Barnet Hospital, Royal Free London NHS Foundation

Trust, UK
2. Department of Rheumatology, Royal Free London NHS
Foundation Trust, UK
3. Division of Medicine, University College London, UK
4. Department of Oral and Maxillofacial Surgery,
Barts Health NHS Trust, London, UK
*Correspondence to [email protected]

Tahir has received payment or honoraria from AbbVie, Eli Lilly

and Company, Novartis, and UCB; and travel support from the
Disclosure: American College of Rheumatology (ACR), European League
Against Rheumatism (EULAR), Novartis, and UCB. Bennett,
Solanki, and Ali have declared no conflicts of interest.

Received: 01.03.23

Accepted: 11.04.23

Bisphosphonate, bisphosphonate-related osteonecrosis

Keywords: ofthe jaw, denosumab, medication-related osteonecrosis of
the jaw (MRONJ), osteonecrosis, osteoporosis, romosozumab.

EMJ Rheumatol. 2023; DOI/10.33590/emjrheumatol/10300262.

Citation:
https://doi.org/10.33590/emjrheumatol/10300262.

Abstract
Medication-related osteonecrosis of the jaw (MRONJ) is a feared complication of
anti-resorptive or anti-angiogenic therapy, presenting with non-healing areas of
bone, which may form de novo or after dental intervention. The condition primarily
affects patients under the care of oncologists and rheumatologists. Patients using
these medications under the care of rheumatologists are predominantly being
treated for osteoporosis, a highly prevalent condition causing considerable morbidity
and mortality in the European population.

In the two decades since the condition was first described, there has been
considerable progress in the understanding of the pathophysiology of the condition,
although this remains incomplete. Additionally, clinicians may now benefit from
long-term follow-up data to give a more evidence-based approach to MRONJ
risk stratification. At present, there is considerable variation between guidelines
produced by advisory groups. This paper focuses exclusively on the osteoporotic
cohort, and aims to review recent findings to explore the differences in risk profiles
between osteoporotic and oncological cohorts, as well as between different anti-
resorptive medications. Further sections discuss prevention and management of
MRONJ in osteoporosis, including the timing of tooth extraction, and consider the
direction of future research. The findings suggest that patients with osteoporosis
treated with bisphosphonates carry an extremely low risk of MRONJ, although

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denosumab presents a higher risk. Nevertheless, the reduced fracture rate from
prompt treatment with anti-resorptives likely outweighs the risk of MRONJ. Dental
hygiene should be optimised to reduce risk, and tooth extraction should take place
in a timely fashion, with no convincing evidence to support the use of drug holidays.
Treatment at present favours a surgical approach, with potential roles for antibiotics,
but at present there is insufficient evidence for other medical adjuncts.

Key Points

1. Patients with osteoporosis should be recognised as being at considerably reduced risk of

medication-related osteonecrosis of the jaw (MRONJ) relative to oncology patients, and risk stratified
accordingly to avoid unnecessary delays to treatment.

2. The route and duration of antiresorptive administration appears not to significantly affect the risk of
MRONJ, but there is a dose-dependent risk, which does not appear to be reduced by a drug holiday.

3. Tooth extraction is recommended if required, without delay. Higher risk patients should have
extraction performed under the care of a maxillofacial service, and all patients with established MRONJ
should also be referred.

INTRODUCTION management of MRONJ in relation

to osteoporosis, as the two groups have
Osteoporosis is a common disease, with a mean different risk profiles, and the approach to
prevalence of 5.6% within European (EU27+2) osteoporosis is often conflated with that for
countries, and an annual cost to these countries the oncology population.
of EUR 56.9 billion.1 This figure is illustrative
of the significant morbidity and mortality The first cases described were in association
burden associated with these fractures. As the with nitrogen-containing bisphosphonates,
population of Western Europe ages, preventing which act to inhibit the mevalonate kinase
and treating this often debilitating condition pathway to induce osteoclast apoptosis.
continues to gain ever-greater importance. Bisphosphonates remain the most commonly
reported cause of MRONJ. The disease occurs
It has become apparent, however, that treatment preferentially in the mandible rather than the
or prophylaxis of osteoporosis may be associated maxilla, at a ratio of approximately 2:1, with
with medication-related osteonecrosis of the jaw 9% of cases having involvement at both sites.3
(MRONJ), predominantly occurring in patients Since the inaugural paper, further definitive
with cancer or osteoporosis, as a rare but associations have been made with other
debilitating side-effect of anti-resorptive or anti-resorptive medications, particularly
anti-angiogenic therapy, although the latter the receptor activator of nuclear factor κ-B
group is beyond the scope of this paper. MRONJ ligand inhibitor denosumab, but also the
is a relatively recently described phenomenon, newer anti-sclerostin agent, romosozumab.4,5
first appearing in the medical literature in
2003 as part of a case series from Marx et al.2 The American Academy of Oral and Maxillofacial
Since the initial description, there have been Surgeons (AAOMS) have set widely accepted
considerable advances in the understanding diagnostic criteria for MRONJ, which needs to
of the condition, which may inform changes to fulfil all three of the following criteria to make
current practice for clinicians involved in the a diagnosis:6 current or previous use of anti-
care of patients with osteoporosis. The condition resorptive therapy alone, or in combination
is most frequently described in patients in with immune modulators or anti-angiogenic
oncology and osteoporosis. This paper aims medications; exposed bone in the maxillofacial
to highlight the changes in evidence impacting region persisting for more than 8 weeks, either
current clinical practice in the prevention and visualised directly, or discovered via probing

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oral fistulae; and the absence of significant denosumab and bisphosphonates over the first
radiation exposure or metastatic disease of the 1–3 years of treatment, depending on fracture
affected area. site and gender. Although the number needed
to treat may appear relatively high, the high
The clinical course is variable, and many prevalence and severe morbidity and mortality
patients remain asymptomatic for prolonged of osteoporotic fracture must be taken into
periods. However, pain; gingival inflammation, account. If osteoporotic treatment is delayed by
ulceration, and fistulation; bony enlargement; screening and assessment, there is considerable
tooth loosening; and secondary osteomyelitis risk of subsequent preventable fractures.
may occur.7 Treatment is extremely challenging
and may involve both medical and surgical Increasing duration of therapy has been shown
approaches. Prevalence is highest in to correlate significantly with incidence of
the oncology population, thought to be a MRONJ in oncology patients. However, the data
dose-dependent result of the high cumulative for osteoporotic patients is less clear. Initial
dosages used to limit bony destruction or control support was found from a paper undertaking
malignant hypercalcaemia, with typical dosing retrospective case identification via a postal
regimens resulting in administration of doses questionnaire, demonstrating an increase
12–15 times higher per annum than those used from 0.00% prevalence at baseline to 0.21%
in osteoporosis.8 These drugs are also widely prevalence at 4 years for patients on oral
used within rheumatology services for metabolic bisphosphonates. Subsequent prospective
bone disease, most frequently in the case of controlled cohort studies failed to demonstrate
primary osteoporosis, but also for the purpose the same findings, although it should be noted
of treatment or prophylaxis of secondary that these were neither designed nor powered
osteoporosis, typically where prolonged to assess MRONJ cases.6 Both bisphosphonates
treatment with steroid therapy is required. Anti- and denosumab now benefit from long-term
resorptives also find usage in rarer metabolic follow-up data, enabling accurate assessment
bone disease such as Paget’s disease of bone, of prevalence, which is challenging existing
fibrous dysplasia, and osteogenesis imperfecta. assumptions. The prevalence of MRONJ in
Thus, consideration of risk of MRONJ presents patients exposed to bisphosphonate ranges from
a frequent challenge for the rheumatologist, 0.02–0.05%, with zoledronate showing no higher
and requires interdisciplinary collaboration risk than oral bisphosphonates. Denosumab
with maxillofacial and dental colleagues. demonstrates a 10-year prevalence of 0.30%,
and the current emerging data on romosozumab
suggest that there is a prevalence of 0.02–
IDENTIFICATION AND 0.03%.6 Given that many guidelines continue
MANAGEMENT OF to consider intravenous bisphosphonates to be
HIGH-RISK PATIENTS higher risk, this suggests that dose, rather
than route, is the differentiating factor.

Risk Stratification Nevertheless, patients with osteoporosis are

Recent evidence, collated in the 2022 AAOMS not a homogenous group. While the majority of
update, suggests that, as a consequence of the those treated will have primary osteoporosis,
high estimated MRONJ prevalence of 1–17% in patients with osteoporosis related to a rheumatic
the oncology population, the risks of MRONJ inflammatory disease (either the disease itself
may have received undue prominence in patients or the treatment thereof, e.g., where prolonged
receiving the medication for other indications.6,9 treatment with steroids is required) may
This may have come at the cost of an increased be at higher risk of MRONJ, with one study
number of fragility fractures in the face of demonstrating a 1.5% prevalence of MRONJ
patient and physician reluctance to use anti- in this group (n=198).11 This has a plausible
resorptives in a timely fashion on this basis. The mechanism; rheumatic inflammatory diseases,
low prevalence of MRONJ should be contrasted particularly rheumatoid arthritis, are known to
with the results from a large-scale meta-analysis be associated with MRONJ risk factors such
performed by Crandall et al.,10 which indicated as periodontitis.9 Glucocorticoids are well
a number needed to treat of between 30–89 for known to be a cause of osteoporosis,

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but are also a risk factor for MRONJ. As part This view is supported by the observation
of the wide-ranging effect of administration of that pre-existing periodontal or periapical
glucocorticoids, osteoporosis is thought to relate disease without any oral intervention/trauma
not only to induction of osteoblast apoptosis, is sufficient to cause spontaneous MRONJ in
but also to inhibition of osteoclast function via approximately 25% of identified patients,18,19 as
a separate pathway to each anti-resorptive, well as the relatively minor trauma caused by
compounding existing issues of reduced bone ill-fitting removable dentures, especially at the
turnover.12 This also applies to another putative retromylohyoid fossa.19
mechanism of MRONJ, reduced angiogenesis.
Glucocorticoids have also been shown to reduce
vascular endothelial growth factor expression, Prevention of Medication-Related
again amplifying anti-angiogenic effects of Osteonecrosis of the Jaw
bisphosphonates and denosumab, which The field currently suffers from a lack of high-
have been demonstrated in vivo through quality studies in order to assess the benefit of
murine models, contributing to emerging preventative procedures. A Cochrane review
necrosis.13,14 Larger multicentre studies would from 2017, subsequently updated in 2022, found
be required to more definitively evaluate the insufficient evidence to support the conclusion
influences of rheumatic inflammatory disease that any studied prophylactic or therapeutic
and the medications used to treat them, intervention is of benefit in MRONJ.20 But, as
which may influence stratification of tooth extraction and periodontal disease are
non-oncological patients. the most common risk factors for developing
MRONJ, prevention is predominantly targeted
Finally, poor oral health at the time of towards optimising oral health and modulating
commencing therapy is a key risk factor modifiable dental (e.g., extraction versus root-
for MRONJ. A 2005 paper from Marx et al.15 retentive treatment) or medical risk factors (e.g.,
demonstrated, from a sample of 119 patients review of anti-resorptive/anti-angiogenic and
with MRONJ, a considerably higher prevalence corticosteroid treatment).21
of periodontitis (84.0%), caries (28.6%), and
dental abscess (13.4%) than the general Routine screening of at-risk patients is
population. Tooth extraction has classically recommended across several international
been considered the key risk factor for MRONJ, consensus statements on the prevention and
but again, the osteoporotic population are at management of MRONJ.6,22,23 The Scottish
considerably lower risk, with a meta-analysis Dental Clinical Effectiveness Programme
by Gaudin et al.16 demonstrating a 0.15% rate (SDCEP) recently updated their National Institute
of MRONJ (p=<0.0001) in this cohort after for Health and Care Excellence (NICE)-accredited
tooth extraction. While no comparison study for guidance in the oral health management of
conservative and surgical strategies has been patients at risk of MRONJ to stratify patients into
performed in osteoporotic patients, a dual-centre low and high-risk groups.24 The high affinity of
study of 189 oncology patients demonstrated bisphosphonates to hydroxyapatite results in a
a dramatic difference in MRONJ development persistent dose-dependent effect that can last
after propensity matching. Those in whom up to 10 years, whereas denosumab is cleared
tooth extraction was avoided demonstrated through the reticuloendothelial system with a
approximate rates of 90% MRONJ occurrence half-life of approximately 26 days.25,26 This is
by 8 years, but those who underwent tooth reflected in the SDCEP guidance, which stratifies
extraction displayed rates of <20%, although low-risk patients as those taking denosumab
all cases in the latter group occurred within for any length of time, whereas patients on oral
2 years.17 This would support the hypothesis or intravenous bisphosphonate become high-
that local inflammation or infection is a risk with over 5 years of use.24 Indeed, after 9
predominant driver of MRONJ, and the months without denosumab, SDCEP classify the
requirement for extraction is a symptom patient as having no risk of MRONJ.
of the conditions favouring MRONJ, rather
than the direct cause.

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Some authors advocate an aggressive approach

to maintaining oral health in at-risk patients, with MANAGING PREVENTION
5,000 ppm fluoride toothpaste and overnight OF MEDICATION-RELATED
fluoride gel bathing of equivocal prognosis OSTEONECROSIS OF THE JAW
dentition.27 Following on from this, dental
treatment, including dentoalveolar surgery, At present, it is inevitable that a small proportion
should proceed as normal for all patients, of patients treated with anti-resorptives will go
with the caveat of aiming for root retentive on to develop MRONJ. Management strategies
treatment in high-risk patients if possible, for established disease are also required, which
although protocols remain unstandardised.28-30 may be operative or non-operative in nature.
A non-healing extraction site of over 8 weeks If the patient has not already been referred to
necessitates maxillofacial referral. The role of a maxillofacial team, this should, of course, be
peri-/post-exodontia antibiotics in preventing performed as a matter of urgency. Non-operative
MRONJ is controversial. In a systematic review or operative strategies may be pursued at any
by Cabras et al.,31 only one out of 17 studies point within the stages of MRONJ, depending on
found a higher risk of MRONJ without antibiotics. AAOMS staging (Table 1).

So-called ‘drug holidays’, referring to temporary Certain measures are appropriate for all stages
discontinuation of bisphosphonates, remain of MRONJ. All patients should receive education
a contentious issue regarding their benefit in aiming to explain the slow rates of improvement
either prevention or treatment of MRONJ. No and resolution over a period of months to years,
consensus exists in adjudicating the balance and the intended aims of treatment, particularly
between the risk of osteoporotic fractures symptom improvement and pain control.
with that of developing MRONJ. Patients using A cornerstone of therapy is improved oral
denosumab should not undertake drug holidays, hygiene, which may help those Stage 0
as they are at increased risk of vertebral patients who will progress to the exposed bone
fractures if the drug is stopped: a post hoc variant, with one case series demonstrating
analysis of the FREEDOM trial demonstrated a progression rate of 53.1%.37 Mobile or well-
an increased multilevel vertebral fracture rate formed bony sequestra should also be removed
that was apparent within 3 months after as a potential nidus for infection. Chlorhexidine
omission of a scheduled dose.32 solution should be used in all patients with
established MRONJ, and may well prove
A recent systematic review did not show any sufficient for cure in Stage 1 patients when
evidence for a bisphosphonate holiday in used as part of a local wound care strategy,
MRONJ.33 Given the excess mortality of hip aiming to disrupt the biofilm surrounding the
fracture at 1 year is up to 36%, the benefit of necrotic bone and prevent progression of disease
fracture prevention likely outweighs the low risk accordingly.38 In Stage 2 or 3 disease, antibiotics
of MRONJ, and should be assessed using the and analgesia may be added.6
Fracture Risk Assessment (FRAX) tool to help
guide clinical decision making.34,35 A reasonable The rationale for antibiotic therapy relates
compromise in patients taking denosumab, given to the key micro-organism group within the
the half-life and apparent increased risk relative biofilm, Actinomyces spp. These facultative
to other anti-resorptives, is to plan dentoalveolar anaerobes are now thought to play a role in the
surgery for 3–4 months after the last denosumab pathogenesis of MRONJ, rather than just being a
dose, and resume 6–8 weeks post-surgery.6 superficial contaminant. In a retrospective cohort
study, Russmueller et al.39 detected Actinomyces
It is important to acknowledge, however, spp. in 89% of histologically confirmed MRONJ
that drug holidays remain appropriate for risk cases. β-lactam antimicrobials remain the agents
reduction of other complications associated with of choice, with tetracyclines being an acceptable
bisphosphonate therapy. A large retrospective alternative in patients with penicillin allergy as
Swedish study demonstrated a 70% annual Actinomyces spp. isolates have been shown to
reduction in adjusted odds ratio of atypical be almost uniformly resistant to metronidazole,
femoral fracture in bisphosphonate users and thus should be avoided.39,40
since drug cessation.36

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Table 1: Summary of American Academy of Oral and Maxillofacial Surgeons (AAOMS) staging criteria for
medication-related osteonecrosis of the jaw severity.6

Stage Criteria
0 (Non-exposed bone Patients with no clinical evidence of necrotic bone, but who present with
variant) non-specific symptoms or clinical and radiographic findings, the latter localised in
alveolar bone only.

1 Exposed and necrotic bone or fistula that probes to the bone in patients who
are asymptomatic and have no evidence of infection/inflammation. May have
radiographic findings localised to the alveolar bone region, as in Stage 0.

2 As in Stage 1, but must be symptomatic, with evidence of infection/inflammation.

These patients are symptomatic. May have radiographic findings localised to the
alveolar bone region, as in Stage 0.

3 As in Stage 2, but with any of the following additional features: exposed necrotic
bone extending beyond the region of alveolar bone, pathological fracture, extraoral
fistula, oroantral/oronasal communication, or osteolysis extending to the inferior
border of the mandible or sinus floor.

Although there is a debate regarding the timing in Stage 1 disease can halt disease progression
of antimicrobials prior to surgery, high dose and even downstage lesions.41,42 Vescovi et
β-lactam antimicrobials in the days prior to al.43 have shown that conservative surgical
surgery appears to be a reasonable strategy.39 interventions should be considered in patients
unresponsive to 6 months of non-invasive
Excellent results have been reported for surgical therapy. In advanced disease, the controversy
intervention, which may dramatically enhance lies in when to surgically intervene. Debate still
resolution/improvement rates in comparison to exists as to whether a period of non-operative
conservative strategies.6 The decision on when therapy is beneficial in stabilising disease,
to undertake operative treatment should not as recommended in the AAOMS treatment
be based solely on the clinical or radiological algorithm, or whether aggressive primary surgery
stage of disease, but also on the projected results in a shorter time to achieving restoration
impact on quality of life, and capacity of the of mucosal integrity.6 A recent systematic
patient to undergo challenging bony and soft review compared surgical treatment options
tissue reconstruction. Surgical options typically in Stage 3 disease.44 With primary outcome
include initial debridement, saucerisation, or measures, including full mucosal healing and
sequestrectomy in Stage 1 disease. The extent disease downstaging, marginal resection without
of mandibular or maxillary bony resection in microvascular flap reconstruction resulted in a
Stage 1 and 2 disease largely depends on the full mucosal healing rate of 85% compared with
height of disease-free alveolar bone available, 54% with sequestrectomy alone. The addition
and extent of disease in relation to the inferior of microvascular flap reconstruction resulted in
alveolar nerve canal or maxillary sinus.6 By a mucosal healing rate of 97%, likely due to the
definition, Stage 3 surgical management additional benefit of a segmental resection in
necessitates segmental resection or partial more thoroughly removing all non-vital tissue.
maxillectomy and appropriate reconstruction, The success rates seen provide a firm mandate
but full discussion of reconstruction is beyond for surgical management being the mainstay of
the scope of this article. therapy at present.

There is evidence to suggest early A number of strategies have been trialled to

sequestrectomy and primary mucosal closure improve non-operative treatment options.

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As with prophylaxis, no clear benefit to a There has been some interest in the use of bone
drug holiday of any anti-resorptive has been turnover markers to predict recovery, which have
observed, and the majority of studies favour proved disappointing in predicting risk of MRONJ,
lack of benefit. While the prolonged half-life where the majority of research attention has
of bisphosphonates supports these results, been focused.51 One retrospective study found
the shorter half-life of denosumab, at just 26 a statistically significant difference between the
days, would suggest a benefit to withdrawal.45 levels of bone turnover biomarkers of serum
However, in order to avoid rebound bone loss osteocalcin, C telopeptide, and bone alkaline
at discontinuation, a separate agent would phosphatase in patients who recovered and
need to be implemented. In the absence of those who did not. However, the results should
MRONJ, denosumab cessation is now typically be interpreted with caution, given the trial
accompanied by zoledronate to maintain bone design and absence of documentation of
density gains from the period of denosumab potentially confounding issues such as bony
therapy.46 In a patient with established MRONJ, it metastases, a particularly pertinent issue
is currently assumed that adding anti-resorptive given the high numbers of oncology patients
therapy would be counterproductive. Withdrawal included.52 Nevertheless, a sensitive and specific
of anti-resorptives after confirmation of MRONJ, biomarker would be of great utility in guiding
therefore, cannot be recommended at this stage the ongoing management of these patients.
in time, although further evidence may emerge,
particularly surrounding romosozumab.
CONCLUSION AND KEY POINTS
One therapy that has shown particular promise
in improving MRONJ resolution rates is Over the last 20 years, significant progress
teriparatide, with Kim et al.47 noting a statistically has been made in the understanding of
significant difference in the percentage of the underlying pathophysiology of MRONJ.
patients achieving resolution or improvement Nevertheless, our mechanistic understanding
and also in rate of change over a 6-month remains incomplete, and many clinical guidelines
period, albeit within a retrospective design. A have not been recently updated to reflect
further study suggested equivalence of weekly the increased body of evidence available. As
and daily injections, although with just one such, the authors would make the following
patient in each arm.48 A placebo-controlled, suggestions for patients with osteoporosis:
prospective, randomised controlled trial of
teriparatide failed to demonstrate statistical • Unnecessary delays for routine dental review
significance, which may have related either to before starting bisphosphonates are likely
the short duration of therapy of just 8 weeks, to worsen outcomes, but regular dental
or to the small study size (n=34).49 It would review is important to optimise oral health
be tempting to consider the possibility of and prevent MRONJ.
initiating teriparatide to continue treating both
the MRONJ and osteoporosis and allow for • The route and duration of anti-resorptive
denosumab cessation, but the DATA-Switch trial administration appears not to significantly
has provided evidence that teriparatide alone is affect the risk of MRONJ, but there is a
insufficient to prevent bone loss after cessation dose-dependent risk.
of denosumab.50 A high-quality prospective,
randomised controlled trial, ideally with both • Tooth extraction is recommended if required,
weekly and daily administration arms, is required without delay. Higher risk patients should
before teriparatide can be recommended as an have extraction performed under the care
integral part of medical management of MRONJ. of a maxillofacial service.
After initial medical and surgical strategies have
been implemented, patients must remain under • There is limited evidence to support drug
close follow-up in order to assess response. At holidays for the purpose of decreasing
present, clinical history and oral examination, MRONJ risk, but they do reduce the risk
coupled with radiographic surveillance, are the of atypical femoral fracture.
mainstay of this process.

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• Further research to stratify the risk of • Surgical management remains the

MRONJ within the osteoporotic cohort cornerstone of therapy. Antibiotics are
through study of rheumatic inflammatory the only medical adjunct with convincing
diseases and drugs used to treat them evidence of benefit in MRONJ at present.
would be highly beneficial.

References treatments to prevent fractures: of the jaw. Cochrane Database

1. Kanis JA et al. SCOPE 2021: a an updated systematic review. Ann Syst Rev. 2017;10(10):CD012432.
new scorecard for osteoporosis Intern Med. 2014;161(10):711-23.
21. McGowan K et al. Risk factors for
in Europe. Arch Osteoporos. 11. Schwaneck EC et al. Osteoporosis medication-related osteonecrosis
2021;16(1):82 therapy in patients with of the jaws: a systematic review.
2. Marx RE. Pamidronate (Aredia) inflammatory rheumatic diseases Oral Dis. 2018;24(4):527-36.
and zoledronate (Zometa) induced and osteonecrosis of the jaw. Z
Rheumatol. 2020;79(2):203-9. 22. Yoneda T et al.; Japanese Allied
avascular necrosis of the jaws: Committee on Osteonecrosis of
a growing epidemic. J Oral 12. Kim H-J et al. Glucocorticoids the Jaw. Antiresorptive agent-
Maxillofac Surg. 2003;61(9):1115-7. suppress bone formation via related osteonecrosis of the
3. Woo S-B et al. Narrative the osteoclast. J Clin Invest. jaw: position paper 2017 of the
[corrected] review: 2006;116(8):2152-60. Japanese Allied Committee on
bisphosphonates and Osteonecrosis of the Jaw. J Bone
13. Nauck M et al. Corticosteroids Miner Metab. 2017;35(1):6-19.
osteonecrosis of the jaws. Ann inhibit the expression of the
Intern Med. 2006;144(10):753-61. vascular endothelial growth factor 23. Campisi G et al. Medication-related
4. Jung S et al. A 5-year gene in human vascular smooth osteonecrosis of jaws (MRONJ)
retrospective cohort study of muscle cells. Eur J Pharmacol. prevention and diagnosis:
denosumab induced medication 1998;341(2-3):309-315. italian consensus update
related osteonecrosis of the jaw 2020. Int J Environ Health Res.
14. Gkouveris I et al. Vasculature 2020;17(16):5998.
in osteoporosis patients. Sci Rep. submucosal changes at early
2022;12(1):8641. stages of osteonecrosis of the jaw 24. Oral health management of
5. Cosman F et al. 2016. (ONJ). Bone. 2019;123:234-45. patients at risk of medication-
Romosozumab treatment in related osteonecrosis of the jaw.
15. Marx RE et al. Bisphosphonate- Br Dent J. 2017;222(12):930.
postmenopausal women with induced exposed bone
osteoporosis. N Eng J Med. (osteonecrosis/osteopetrosis) of 25. Cremers SCLM et al.
2016;375(16):1532-43. the jaws: risk factors, recognition, Pharmacokinetics/
6. Ruggiero SL et al. American prevention, and treatment. J Oral pharmacodynamics of
Association of Oral and Maxillofac Surg. 2005;63(11): bisphosphonates: use for
Maxillofacial Surgeons’ position 1567-75. optimisation of intermittent
paper on medication-related therapy for osteoporosis. Clin
16. Gaudin E et al. Occurrence and risk Pharmacokinet. 2005;44(6):
osteonecrosis of the jaw–2022 indicators of medication‐related
update. J Oral Maxillofac Surg. 551-70.
osteonecrosis of the jaw after
2022;80(5):920-43. dental extraction: a systematic 26. Hanley DA et al. Denosumab:
7. Estilo CL et al. Osteonecrosis review and meta‐analysis. J Clin mechanism of action and clinical
of the maxilla and mandible in Periodontol. 2015;42(10):922-32. outcomes. Int J Clin Pract.
patients with advanced cancer 2012;66(12):1139-46.
17. Soutome S et al. Relationship
treated with bisphosphonate between tooth extraction and 27. Patel V et al. New cancer therapies
therapy. Oncologist. development of medication-related and jaw necrosis. Br Dent J.
2008;13(8):911-20. osteonecrosis of the jaw in cancer 2015;219(5):203-7.
8. Khan AA et al.; International patients. Sci Rep. 2021;11(1):17226.
28. Pick E et al. Evaluation of
Task Force on Osteonecrosis of 18. Thumbigere‐Math V et al. preventive treatment protocols
the Jaw. Case-based review of Periodontal disease as a risk for patients under antiresorptive
osteonecrosis of the jaw (ONJ) factor for bisphosphonate‐related therapy undergoing tooth
and application of the international osteonecrosis of the jaw. J extraction at a Swiss university
recommendations for management Periodontol. 2014;85(2):226-33. clinic. Int J Environ Health Res.
from the international task 2021;18(18):9924.
force on ONJ. J Clin Densitom. 19. Niibe K et al. Osteonecrosis of
2017;20(1):8-24. the jaw in patients with dental 29. Şahin O et al. Prevention of
prostheses being treated with medication related osteonecrosis
9. De Pablo P et al. Periodontitis in bisphosphonates or denosumab. of the jaw after dentoalveolar
systemic rheumatic diseases. Nat J Prosthodont Res. 2015;59(1):3-5. surgery: an institution’s experience.
Rev Rheumatol. 2009;5:218-24. J Clin Exp Dent. 2020;12(8):e771-6.
20. Beth-Tasdogan NH et al.
10. Crandall CJ et al. Comparative Interventions for managing 30. Smith SJ et al. Tooth extraction
effectiveness of pharmacologic medication-related osteonecrosis protocols for patients on

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Article

bisphosphonate therapy: an osteonecrosis of the jaws using 46. Anastasilakis AD et al. Zoledronate
update. J Int Acad Periodontol. local wound care. J Oral Maxillofac for the prevention of bone loss in
2017;20(1):38-47. Surg. 2018;76(11):2332-9. women discontinuing denosumab
treatment. A prospective 2‐year
31. Cabras M et al. Lack of evidence 39. Russmueller G et al. The clinical trial. J Bone Miner Res.
in reducing risk of MRONJ association of medication-related 2019;34(12):2220-8.
after teeth extractions with osteonecrosis of the jaw with
systemic antibiotics. J Oral Sci. Actinomyces spp. infection. Sci 47. Kim KM et al. Distinctive role of
2021;63(3):217-26. Rep. 2016;6:31604. 6-month teriparatide treatment
on intractable bisphosphonate-
32. Cummings SR et al. Vertebral 40. Steininger C, Willinger B. related osteonecrosis of the jaw.
fractures after discontinuation of Resistance patterns in Osteoporos Int. 2014;25(5):
denosumab: a post hoc analysis of clinical isolates of pathogenic 1625-32.
the randomized placebo-controlled Actinomyces species. J Antimicrob
FREEDOM trial and its extension. J Chemother. 2016;71(2):422-7. 48. Yoshiga D et al. Weekly
Bone Miner Res. 2018;33(2):190-8. teriparatide injections successfully
41. Giudice A et al. Can surgical treated advanced bisphosphonate-
33. Schilcher J et al. Risk of atypical management improve resolution of related osteonecrosis of the jaws.
femoral fracture during and after medication-related osteonecrosis Osteoporos Int. 2013;24(8):
bisphosphonate use. Acta Orthop. of the jaw at early stages? A 2365-9.
2015;86(1):100-7. prospective cohort study. J Oral
Maxillofac Surg. 2020;78(11): 49. Sim IW et al. Teriparatide promotes
34. Kanis JA. Assessment of 1986-99. bone healing in medication-
osteoporosis at the primary related osteonecrosis of the jaw:
health care level: report of a WHO 42. Klingelhöffer C et al. Evaluation of a placebo-controlled, randomized
Scientific Group. 2007. Available at: surgical outcome and influencing trial. J Clin Onc. 2020;38(26):
https://frax.shef.ac.uk/FRAX/pdfs/ risk factors in patients with 2971-80.
WHO_Technical_Report.pdf. Last medication-related osteonecrosis
accessed: 18 April 2023. of the jaws. J Craniomaxillofac 50. Leder BZ et al. Denosumab
Surg. 2016;44(10):1694-9. and teriparatide transitions in
35. Abrahamsen B et al. Excess postmenopausal osteoporosis (the
mortality following hip fracture: a 43. Vescovi P et al. Conservative DATA-Switch study): extension
systematic epidemiological review. surgical management of stage of a randomised controlled trial.
Osteoporos Int. 2009;20(10): I bisphosphonate-related Lancet. 2015;386(9999):1147-55.
1633-50. osteonecrosis of the jaw.
Int J Dent. 2014;2014:107690. 51. Awad ME et al. Serum C-terminal
36. Ottesen C et al. Efficacy of a high- cross-linking telopeptide level
dose antiresorptive drug holiday 44. Vanpoecke J et al. Medication- as a predictive biomarker of
to reduce the risk of medication- related osteonecrosis of the jaw osteonecrosis after dentoalveolar
related osteonecrosis of the jaw (MRONJ) stage III: conservative surgery in patients receiving
(MRONJ): a systematic review. and conservative surgical bisphosphonate therapy:
Heliyon. 2020;6(4):e03795. approaches versus an aggressive Systematic review and meta-
surgical intervention: a systematic analysis. J Am Dent Assoc.
37. Fedele S et al. Nonexposed review. J Craniomaxillofac Surg.
variant of bisphosphonate- 2019;150(8):664-75.
2020;48(4):435-43.
associated osteonecrosis of the 52. Schubert L et al. Bone turnover
jaw: a case series. Am J Med. 45. Kawahara M et al. Clinical markers can predict healing time in
2010;123(11):1060-4. considerations for medication- medication-related osteonecrosis
related osteonecrosis of the jaw: of the jaw. Support Care Cancer.
38. Hadaya D et al. Nonsurgical a comprehensive literature review.
management of medication-related 2021;29:7895–7902.
Int J Implant Dent. 2021;7(1):47.

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