A REVIEW OF THE CLINICAL IMPLICATIONS OF BISPHOSPHONATES IN DENTISTRY

GL Borromeo,* CE Tsao,* IB Darby,* PR Ebeling Australian Dental Journal 2011; 56: 29

Review

2011/10/11 Instructor: Dr.

 Introduction
Orofacial conditions with similar presentations to ONJ
1. Osteoradionecrosis 2. Conditions affecting bone turnover

Bisphosphonates in different clinical settings

1. Implants 2. Periodontics 3. Orthodontics 4. Endodontics

Management of ONJ
1. Prevention 2. Treatment

BISPHOSPHONATES(BPS)
BPs are drugs used to suppress bone turnover, primarily through effects on osteoclasts. Nitrogen-Containing Bisphosphonates (NBPs) More Potent Less Potent Zoledronic acid , Pamidronate Alendronate , Risedronate Intravenously used Prevent skeletal related events (SREs) associated with malignancy Severe forms of osteogenesis imperfecta Orally used Osteoporosis Pagets disease of bone

POST-MENOPAUSAL OSTEOPOROSIS (PMO)

Alendronate , risedronate reducing vertebral, non-vertebral and hip fractures by 16 ~ 45%. Annual IV zoledronic acid reducing vertebral fractures(70%), non-vertebral fractures(25%) and hip fractures(41%)

Very low risk of jaw osteonecrosis of 1:3862

The benefit risk ratio greatly favors tx with BPs in osteoporosis.

BISPHOSPHONATE ASSOCIATED JAW OSTEONECROSIS (ONJ)

An area of exposed bone in the maxillofacial region that did not heal within eight weeks after identification by a healthcare provider, in a patient who was receiving or had been exposed to a bisphosphonate, and had not had radiation therapy to the craniofacial region.
The American Society for Bone and Mineral Research (ASBMR) ,2007

WHY THE CONDITION LOCALIZES TO THE JAWS ?

Bone turnover is higher in jaws than in general skeleton

BP accumulates in jaw at higher level

Oversuppresing turnover

Compromising jaw healing both to Injury (e.g. tooth extraction) Normal microdamage from occlusion

PATHOPHYSIOLOGY

may be multifactorial

Oversuppression of bone turnover Oversuppression of angiogenesis Altered functioning of oral mucosal cells Microbial flora Anti-inflammatory effect Genetic predisposition.

AAOMS ONJ STAGING SYSTEM

American Association of Oral and Maxillofacial Surgeons

SIGNIFICANT RISK FACTORS

1. Duration of BP exposure 2. Number of infusions 3. Zoledronic acid 4. Dental extraction 5. Advanced age

Australian Population-Based Survey, 2007 IV BP for malignancy

ONJ risk 0.88~1.15% After a dental extraction

6.79.1%

Oral BP for osteoporosis

ONJ risk 0.010.04% After a dental extraction 0.090.34 %

 Introduction Orofacial conditions with similar presentations to ONJ 1. Osteoradionecrosis 2. Conditions affecting bone turnover Bisphosphonates in different clinical settings
1. Implants 2. Periodontics 3. Orthodontics 4. Endodontics

Management of ONJ
1. Prevention 2. Treatment

OSTEORADIONECROSIS (ORN)
ORN is caused by radiotherapy to the orofacial structures creating hypoxic, hypocellular and hypovascular tissue.

Both ONJ and ORN 1. Necrosis of jaw bones 2. Susceptible to secondary infection.

Hyperbaric oxygen therapy (HBO) For ORN: beneficial For ONJ inconclusive

CONDITIONS AFFECTING BONE TURNOVER

Osteopetrosis , pyknodysostosis
Genetic disorders in which osteoclast function is impaired. Jaw osteomyelitis develops rarely

Denosumab for bone metastasis

Anti-RANKL antibody (RANKL:receptor activator of nuclear factor-B ligand ) Comparable numbers of ONJ similar to zoledronic acid

Phossy Jaw
Individuals exposed to white (yellow) phosphorous in match stick production White phosphorous is converted to a compound similar to modern NBPs.

 Introduction Orofacial conditions with similar presentations to ONJ

1. Osteoradionecrosis 2. Conditions affecting bone turnover Bisphosphonates in different clinical settings 1. Implants 2. Periodontics 3. Orthodontics 4. Endodontics 1. Prevention 2. Treatment

Management of ONJ

IMPLANTS
Implants in 50, 115, 101, 61 and 11 subjects with an oral BP exposure hx found no cases of ONJ

A recent South Australian study ,2009 Receiving oral BPs implant failure risk

0.88%

Topical BP Application
In animal models May enhance osseointegration of dental implants For humans Toxic effects on the oral mucosa ONJ risk

PERIODONTICS
Periodontal Disease

A precipitant of ONJ

May necessitate invasive periodontal procedures or dental extraction, and hence increase the risk of ONJ

Administration of Systemic Bisphosphonates

Reducing alveolar bone loss
The majority of animal models : yes Controlled clinical trials in humans Four trials : yes (alendronate ) One tirals: the effect was only noted in a subgroup with low mandibular bone density. One trials: no efficacy

Improving clinical parameters

Three trials : yes Two trials : no efficacy

ORTHODONTICS BPs Inhibition of orthodontic tooth movement, rather than ONJ

Topical BPs in ortho. tx for rats 1. inhibiting undesirable movement of anchor teeth 2. inhibiting post-tx relapse For humans ? caution in light of ONJ risk

Caution is advised with 1. Miniscrew skeletal anchorage devices 2. Mucosal trauma from retainers 3. Orthognathic surgery 4. Tooth extraction Discontinue BPs prior to ortho. tx ? require further investigation

ENDODONTICS
Endodontic tx. is the preferred treatment over extraction to minimize ONJ risk. If ext. direct closure of the socket by suturing antibiotic prophylaxis considered

 Introduction Orofacial conditions with similar presentations to ONJ

1. Osteoradionecrosis 2. Conditions affecting bone turnover

Bisphosphonates in different clinical settings

1. Implants 2. Periodontics 3. Orthodontics 4. Endodontics

Management of ONJ 1. Prevention 2. Treatment

PREVENTION
ONJ is often refractory to tx BPs: terminal half-life of approximately 10 years.

Before BP therapy
A comprehensive oral evaluation Invasive dental procedures and subsequent healing are best completed

Under BP therapy
Biannual f/u to ensure oral health

Under or after BP therapy

Pt using BP for osteoporosis managed in general dental practices but invasive tx like periodontal bone contouring should be modest

Pt using NBPs for malignancy management should be under the care of a dental specialist and the oncology team.

Guidelines for Cessation of Routine Oral and IV BPs prior to Invasive Dental Procedures

Before Invasive Dental Procedures

The guidelines are not consistent. Oral BPs Advising cessation 3M only when 1. BP exposure > 3Y 2. < 3Y but with glucocorticoid hx.
AAOMS,2009

IV BPs Best ceased at least 1M , and not recommenced until healing is achieved

Beta-CTX-1

A marker for bone resorption

(carboxyl-terminal cross-linked telopeptide of type I collagen )

used to predict ONJ risk prior to invasive dental tx

TREATMENT
Conservative approach If there is evidence of infection chlorhexidine 0.12% rinse and systemic antibiotics
The ASBMR guidelines

Surgical tx for debridement should be conservative or delayed

 No empirical evidence to cease BP therapy on ONJ development. Ceasing BP therapy for 3M on ONJ development
MFA,2009

Recommencement of BPs is best delayed until ONJ resolution, with either oral non-NBPs or a reduced frequency of IV NBPs, clinical condition permitting.

CONCLUSIONS
1. 2. BPs have revolutionized osteoporosis tx and confer considerable anti-fracture benefits that outweigh the small risk of ONJ. In the context of substantial uncertainty, the implications of bisphosphonate use in the dental clinical setting are still being determined. Invasive dental procedures are certainly to be avoided wherever possible in patients with a hx of BP use, especially IV BPs for cancer. Cessation of oral and IV BPs is advised, both prior to invasive dental procedures and on development of ONJ. Limited surgical debridement together with systemic and local antibiotics is the favoured management of ONJ, however, healing is not assured. More controlled clinical studies are recommended to justify the use of serum beta-CTX-1 in assessing ONJ risk.

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THANKS FOR YOUR ATTENTION!