1/30/19 1 Osteonecrosis of the Jaws: Updates for the Practicing Dentist Tara Aghaloo DDS, MD, PhD Professor Oral and Maxillofacial Surgery Assistant Dean for Clinical Research UCLA School of Dentistry HISTOLOGY AND PHYSIOLOGY • Osteocytes • Bone cells • Osteoclasts • Resorb (remove) bone • Osteoblasts • Form new bone • Central canal • Blood supply • Periosteum • Surrounding tissue • Blood supply BONE REACTIONS • Osteomyelitis • Bone infection limited to area of insult • Osteoradionecrosis (ORN) • Limited bone death associated with radiation therapy • Osteonecrosis of the Jaws (ONJ) • Generalized changes in bone metabolism secondary to drug reactions Bacterial Infection Radiation Therapy Medication Induced INITIAL CONFUSION • Osteomyelitis- bacterial infection • Osteoradionecrosis (ORN)- radiation damage • Medication Related Osteonecrosis of the Jaws (MRONJ; ONJ)- medication induced DEFINITION • Current or previous treatment with bisphosphonate or denosumab • Exposed bone or bone that can be probed through an extra or intramural fistula in the maxillofacial region for more than 8 weeks • No history of radiation therapy to the jaws AAOMS position paper on ONJ. JOMS 2007, 2009, 2014.
Transcript
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Osteonecrosis of the Jaws: Updates for the Practicing Dentist
Tara Aghaloo DDS, MD, PhDProfessor
Oral and Maxillofacial SurgeryAssistant Dean for Clinical Research
UCLA School of Dentistry
HISTOLOGY AND PHYSIOLOGY
• Osteocytes• Bone cells
• Osteoclasts• Resorb (remove) bone
• Osteoblasts• Form new bone
• Central canal• Blood supply
• Periosteum• Surrounding tissue• Blood supply
BONE REACTIONS
• Osteomyelitis• Bone infection limited to area of
insult• Osteoradionecrosis (ORN)
• Limited bone death associated with radiation therapy
• Osteonecrosis of the Jaws (ONJ)• Generalized changes in bone
metabolism secondary to drug reactions
Bacterial Infection
Radiation Therapy
Medication Induced
INITIAL CONFUSION• Osteomyelitis- bacterial infection• Osteoradionecrosis (ORN)- radiation damage• Medication Related Osteonecrosis of the Jaws (MRONJ; ONJ)-
medication induced
DEFINITION• Current or previous treatment with
bisphosphonate or denosumab
• Exposed bone or bone that can be probed through an extra or intramural fistula in the maxillofacial region for more than 8 weeks
• No history of radiation therapy to the jaws
AAOMS position paper on ONJ. JOMS 2007, 2009, 2014.
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MEDICATIONS• Antiresorptives
• Inhibit osteoclastic bone resorption• Decreased bone metabolism• Unable to resorb old dead bone and replace it with new bone• Therefore.. at risk for development of OSTEONECROSIS
ANTI-RESORPTIVE INDICATIONS• Primary bone cancers
• Multiple myeloma
• Reduce spread of disease• Reduce bone pain• Minimize spontaneous fracture
• Metastatic cancers• Breast
• Prostate• Hypercalcemia of malignancy• Osteoporosis
• Paget’s disease
ANTI-RESORPTIVE INDICATIONS
• Aredia (Pamidronate)
• Novartis-1991
• Zometa (Zoledronate)
• Novartis-2001
• Xgeva (Denosumab)
• Amgen- 2010
• Fosamax (Alendronate)
• Merck-1997
• Actonel (Risedronate)
• Proctor and Gamble-1998
• Boniva (Ibandronate)
• Roche-2005
• Reclast (Zoledronate)
• Novartis-2007
• Prolia (Denosumab)
• Amgen (2010)
Malignancy Osteoporosis
DENOSUMAB• Human monoclonal antibody to inhibit Receptor Activator of Nuclear factor
kappa-Beta ligand (RANKL)• Inhibits osteoclast differentiation and function, thus inhibiting bone resorption
• Prolia (Amgen)• Osteoporosis- every 6 months
• Xgeva (Amgen)• Bone metastasis from solid tumors (breast, prostate, etc.)• Injection each month
RELATIVE POTENCYDrug Relative Potency
Etidronate (Didronel) 1
Tiludronate (Skelid) 10
Pamidronate (Aredia) 100
Alendronate (Fosamax) 1,000
Risedronate (Actonel) 10,000
Ibandronate (Boniva) 10,000
Zoledronate (Zometa) 100,000
Denosumab ?
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INCIDENCE
• IV bisphosphonates: 0.8-12%
• >1% at 12 mo - 11% at 4 yr• Time to onset: 18 mo for ZA
39-72 mo for pamindronate • SQ denosumab
• 0.7-1.7%
AAOMS Position Paper JOMS 2014, 2009, 2007; ASBMR Task Force Report. J Bone Miner Res 2007; Marx RE. Quintessence, 2011, 2007; ADA Council of Scientific Affairs, JADA, 2006; Lo et al. JOMS 2010; Kwon et al. J Dent Res Suppl, 2015; Mavrokokki et al. JOMS 2007; Lee et al. Osteoporosis Int 2014; Dodson. OMS Clinics NA, 2015
• Oral bisphosphonates: • 0.01-0.1%
• Minimum duration or 2 yr.• Increased to 0.09-0.5% after extraction
• Meta-analysis confirms 2.3-fold risk• 3.8 risk ONJ in oral BP vs. control
• May be underdiagnosed or unexposed• Increased in alendronate, osteoporosis, dental
AAOMS Position Paper JOMS 2014, 2009, 2007; ASBMR Task Force Report. J Bone Miner Res 2007; Marx RE. Quintessence, 2011,2007; ADACouncil of Scientific Affairs, JADA, 2006; Kos. Arch Med Sci, 2014; Dimopoulos et al. , 2009; Oteri et al. J Osteoporosis, 2013
• Extractions
• Why are teeth extracted?• Poorer oral hygiene, more advanced
dental caries, more advanced periodontal disease are associated with ONJ vs. control
• Statistically significant decrease in ONJ with preventive measures
• Exposed bone that is asymptomatic with no evidence of significant soft tissue infection
STAGE 2 ONJ
• Exposed bone associated with pain, soft tissue and/or bone infection
STAGE 3 ONJ
• Exposed bone associated with soft tissue infection or pain that is not manageable with antibiotics due to the large volume of bone
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STAGE 3 ONJ
• Exposed bone associated with soft tissue infection or pain that is not manageable with antibiotics due to the large volume of bone
• Beyond the alveolar bone and to adjacent structures such as inferior border, sinus, nasal cavity
• Pathologic fracture
INITIATING FACTOR
• 152 cases with IV BPs• Half occurred after procedure (36% ext, 9% perio surgery, 3% implant, 1% apico)• 26% due to uncontrolled periodontal disease• 75% PREVENTABLE
WHY THE JAWS?
• Most unprotected bones in the body• Very thin overlying mucosa• Only bones with external projections (teeth)• Frequently exposed surgically• Higher bone remodeling rate• Only location where bone and mucosa are in close proximity• Toxicity to mucosal tissue?
WHAT EVIDENCE CAN WE USE FROM TRANSLATIONAL STUDIES?
What do we recommend for our patients?
WHAT EVIDENCE CAN WE USE FROM TRANSLATIONAL STUDIES?
1. Minimize ONJ risk2. Treatment of ONJ
WHAT EVIDENCE CAN WE USE FROM TRANSLATIONAL STUDIES?
1. Minimize ONJ risk2. Treatment of ONJ
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PERIODONTAL DISEASE AND ONE
• Periodontal disease and a potent anti-resorptive is necessary and sufficient to induce ONJ in rats
• Radiographic and histologicfeatures of ONJ in rats similar to humans
Aghaloo et al. J Bone Miner Res, 2011
PERIAPICAL DISEASE AND ONJ
• Increased prevalence of ONJ when extracting diseased teeth
• Radiographic severity of sclerosis, periosteal bone formation, and non-healing extraction sockets
intervention• Biopsy if suspected metastasis• Chlorhexidine rinses as
needed• Oral antibiotics as needed
• Surgical removal for extreme cases
• Root canal treatment of suspicious teeth
• No dentures over areas of necrosis
PREVENTION PROTOCOL
• Prior to antiresorptive therapy• Routine clinical dental exam that may include a panoramic
radiograph to detect potential dental and periodontal infections
• Remove abscessed and non-restorable teeth and teeth with severe periodontal disease
• Remove teeth with poor long-term prognosis• Functionally rehabilitate salvageable dentition• Educate patients on oral hygiene and signs of diseases
PREVENTION PROTOCOL
• During IV systemic antiresorptive therapy• Avoid invasive dental procedures where possible• Maintain routine dental cleanings, avoid soft-tissue injury
(especially at lingual plate or tori)• Ensure good fit of dentures• Aggressively manage dental infections on surgically (root
canal tx if possible)• Regular dental assessments after initiating bisphosphonate
therapy (frequency dependent upon risk)
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PREVENTION PROTOCOL
• Oral bisphosphonate therapy• Much lower risk, but NOT zero• Dentoalveolar surgery NOT contraindicated• No change in normal treatment protocol?• Should we stop treatment?• Lab tests?
TREATMENT PROTOCOL
• Established osteonecrosis• Consultation between oral and maxillofacial surgeons, general
dentists, and the treating oncologist is strongly recommended• Superficial bony debridement to reduce sharp surfaces and
prevent further trauma to adjacent tissues• A removable appliance or protective stent may be used to
protect exposed bone or adjacent tissues• Avoid invasive dental procedures
II Symptomatic treatment with antibiotics, antibacterial mouth rinse, pain control, debridement
III Antibacterial mouth rinse, antibiotic therapy, surgical debridement and resection
Ruggiero et al. JOMS , 2014
NON-OPERATIVE THERAPY
• Is this effective?
• However…
• Studies very limited
• What is success?
• Variable definition: mucosal healing, absence of pain, no infection, etc.
Author Year #cases IV Oral Success rate
Hoefert 2017 17 17 0 Full Healing (20%)
Lazarovici 2009 101 85 16Full healing (18%)
Partial Healing (52%)
Nicolatou-
Galitis2011 47 47 9
Full healing (14.9%)
Pain Decrease (80.9%)
Janquera 2009 9 9 0 Full healing (33.3%)
Melea 2014 38 38 0 Full healing (60%)
SURGICAL THERAPY
• Surgical therapy is EFFECTIVE!
• However…
• Is it aggressive?
• What is success?
• Can patients tolerate surgery?
• Are there other options based on translational or clinical findings?
Author Year #cases IV Oral Success rate
Kim 2017 325 325
Sequestrectomy (71%)
Saucerization (78%)Mandibulectomy
(73%)(100%)
Ruggiero 2015 337 234 103Surgery (79.6%)
Nonsurgery (20.4%)
Lopes 2015 33 31 2 Full Healing (87%)
Graziani 2012 347Debride (49%)
Resect (68%)
Stanton 2009 33 30 3 Full Healing (85%)
Wilde 2011 33 33 0 Full Healing (88%)
Williamson 2010 40 24 16 Full Healing (100%)
Abu-Id 2008 22 Full Healing (87%)
Wutzl 2008 41 Full Healing (58.5%)
Patient with Stage 3 ONJ
• 63 y/o male with h/o metastatic prostate CA
• History of monthly Aredia use• Referred from dentist due to
necrotic bone LLQ present for several months
• Failed several months of conservative treatment
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Patient with Stage 3 ONJ Patient with Stage 3 ONJ
Patient with Stage 3 ONJ Patient with Stage 3 ONJ
WHAT DO WE KNOW?
Inflammation/ infection
Anti-resorptive treatment ONJ+
LOCAL AGGRESSIVE WOUND CARE
• Well established association of infection/ inflammation and ONJ
• Does elimination of the local, noxious environment around ONJ lesions lead to disease resolution?
Hadaya et. al., JOMS, 2018
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LOCAL AGGRESSIVE WOUND CARE
LOCAL AGGRESSIVE WOUND CARE
Hadaya et. al., JOMS, 2018
LOCAL AGGRESSIVE WOUND CARE
Hadaya et. al., JOMS, 2018
Hadaya et. al., JOMS, 2018
• 73 year old male • metastatic prostate cancer on IV zolendronate• implant previously placed in site #15
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• 53 year old female • metastatic breast cancer on denosumab• implants previously placed in sites #13, 30• implants after denosumab #19• extensive extraoral swelling
Can we identify “Stage 0” ONJ, and predict its clinical course?
STUDY METHODS
• Radiographic parameters of trabecular sclerosis, cortical erosion, periosteal reaction, sequestration, and crater like defects were used as predictors of bone exposure in patients with possible ONJ.
• Classified as absent, localized, or extensive.
• The sum of findings was defined as the Composite Radiographic Index (CRI).
• Patients with no ONJ (dental disease) had a minimal CRI.• Patients that progressed to Bone Exposure (BE) had a high CRI, with sequestration seen in a major of these patients.
• Patients that did not progress to Bone Exposure (NBE) had a lower CRI with no sequestration.
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Hadaya et. al., JBMR, epub, 2018
NEW OSTEOPOROSIS DRUGS: ROMOSOZUMAB
• Sclerostin secreted by osteocytes and blocks Wnt signaling
• Sclerostin antibody inhibits LRP 5/6 and inhibits the inhibitor, allowing Wnt signaling to continue and increase bone formation
Hadaya et. al., JBMR, epub, 2018
Hadaya et. al., JBMR, epub, 2018
TAKE HOME POINTS
• Pre-antiresorptive preventive dentistry• Encourage hygiene/increased dental maintenance• Consider drug holiday • Extractions, implants, grafting, perio surgery• Focused informed consent with risks• Patient education• Diagnose and treat MRONJ early•Consider vigorous wound care instead of surgery•Consider patient factors
TAKE HOME POINTS• Many animal models that support
potential clinical protocols
• Anti-resorptive discontinuation?
• Denosumab? BPs?
• Before or after extraction?
• Anabolic agents for treatment?
• PTH, BMP-2?
• Surgical or non-surgical treatment? NEED FOR MORE RIGOROUS RESEARCH
• 50 million Americans with osteoporosis and osteopenia
