MRONJ Flashcards
What are the drug classes associated with MRONJ? What are the drugs in each class?
Anti-resorbatives
- bisphosphonates
- denosumab
Antiangiogenics
- sunitinib
- sorafenib
- bevacizumab
- sirolimus
What are the drugs associated with bisphosphonates?
IV preparations
- pamidronate (Aredia)
- zoledronate acid (Zometa)
- Reclast
Oral preparations
- alendronate (Fosamax)
- risedronate (Actonel)
- ibandronate (Boniva)
Describe the mechanism of bisphosphonates
The targets of bisphosphonates are osteoclasts – it’s goal is to stop bone resorption. BP attaches to exposed hydroxyapatite and osteoclasts take up the BP along with other products like calcium, phosphate, matrix. Nitrogen containing BP such as alendronate (Fosamax) and Risedronate (Actonel) leads to disruption of ruffled border –> inactivation –> detachment. Eventual osteoblasts activity makes the BP inert and inaccessible to osteoclasts.
What is the difference between oral and IV BP in their use?
Oral is almost always for osteoporosis
IV is mostly for cancer (metastatic deposits that occur in bone)
**However, Reclast (IV) is for osteoporosis
What is the most common BP for cancer?
Zoledronic acid (Zometa)
How are osteoclasts activated?
In response to growth factors and cytokines the osteoblasts produce RANKL which binds to osteoclast precursors which express RANK –> osteoclasts.
Osteoblasts can also dampen this pathway through the production of osteoprotegerin which binds RANKL and prevents binding to osteoclast precursor.
This is why imbalances in RANKL:OPG in conditions that are hormone deficient such as post-menopause, osteoporosis, or cancer causes bone loss.
How does denosumab work?
Denosumab has the same structure as OPG – thus, able to bind RANKL and dampen the process of osteoclast formation
What is more potent, pamidronate (Aredia) or zoledronic acid (Zometa)?
Zoledronic acid (Zometa) is far more potent than pamidronate (Aredia). Denosumab is also very potent
Explain how anti-angiogenic medications work
Angiogenesis inhibitors interfere with the formation of new blood vessels by binding to various signaling molecules which disrupt the angiogenesis-signaling cascade
Tell me about sunitinib (sutent)
It is an anti-angiogenic drug that is a tyrosine kinase inhibitor.
It is useful against GIST, RCC, pNET
Tell me about sorafenib (Nexavar)
It is an anti-angiogenic drug that acts as a tyrosine kinase inhibitor
It is useful against HCC, RCC
Tell me about Bevacizumab (Avastin)
It is an anti-angiogenic drug that is a humanized monoclonal antibody.
It is useful against mCRC, NSCLC, Glio, mRCC
Tell me about Sirolimus (Rapamune)
It is an anti-angiogenic drug that is a mammalian target of rapamycin pathway
It is useful for organ rejection in renal transplants
Which two anti-angiogenic drugs have a risk for ONJ
Bevacizumab and sunitinib
What is the criteria for MRONJ diagnosis?
- History of BP/DB/AA therapy
- No history of XRT to maxillofacial region or malignant disease of jaws
- Exposed bone or bone that can be probed – occurred spontaneously or following dentoalveolar surgery
- No evidence of healing for more than 8 weeks following appropriate care
Which types of bisphosphonates are at an increased risk for MRONJ?
IV BP have an increased risk for MRONJ vs. oral BP
If a patient is taking BPs, what are the associated risks?
- Dental extractions (9x more likely) (DA surgery)
- Duration of BP therapy
- Anti-resorptive (zoledronate/denosumab > pamidronate > AA)
What are the 5 theories for MRONJ pathogenesis?
- Disruption of normal bone-turnover cycle
- Anti-angiogenesis
- Mucosal toxicity
- Inflammation/microbial biofilms
- Genetic
Why is genetics a factor in patients who have developed MRONJ?
There is evidence that these patients have had single-nucleotide polymorphisms where there is a single nucleotide change in non-coding regions of DNA
What are the candidate genes for single-nucleotide polymorphism?
The candidates are:
- COL1A1
- RANK
- MMP2
- OPG
- OPN
SNP’s in all 5 of these genes had a increase in ONJ of 57%
What is the RBMS3 gene?
It is associated with bone density + collagen formation
Patients with SNP in this gene were 5.8x more likely to develop ONJ
If MRONJ is multi-factorial the primary factor that determines spread of disease is?
Metabolic
What is the pathway to MRONJ disease?
- Dentoalveolar injury in a patient at risk (Anti-resorptive or anti-angiogenetic therapy)
- Impaired osteoclast function (poor and delayed osseous healing/remodeling)
- Exposed, non-viable alveolar bone (compromised soft tissue healing)
- Infection/colonization of exposed, non-vital bone (biofilm formation)
- Progressive exposure, infection, necrosis
______________is higher in the jaw than anywhere else
Bone turnover
How does bone turnover rates relate to MRONJ? And what challenges this theory?
Areas of increased bone turnover is a magnet for these drugs (BP uptake was increased in these areas)
Denosumab does not bind to bone but its disease incidence is just as high – why?
The attraction of these medications is through extractions/apical/implants because you introduce the remodeling process, inflammation, area of exposed bone
What are the different stages of MRONJ
- “At risk category” – no apparent exposed/necrotizing bone in patients taking oral/IV AR/AA
- Stage 0
What is the predominant histologic feature of MRONJ?
Bone necrosis associated with acute and chronic inflammation
No histologic pattern specific for MRONJ - doesn’t look any different from necrotic bone
True or false: panorex and PA radiographs are a reliable way to screen for MRONJ early disease?
False- they are poor screening tools
What underlying disease should you be warming of when osteonecrosis or MRONJ is present?
Cancer – secondary cancers can often be residing in necrotic bone so it is important for pathologists to look at entire specimen
Just to help you organization – where and when can treatment be implemented (clinical scenarios)?
- prior to AR/AA therapy (Oral)
- prior to AR/AA therapy (IV)
- during AR/AA therapy (IV, Oral)
- patients with establish MRONJ
What is the pre-treatment therapy for osteoporosis therapy (BPs, DB, AA)?
Nothing, they have to be on drugs for 4-5 years so there is no immediate risk, just warn them
What is the pre-treatment for cancer therapy (IV BP, DB, AA)?
This is different form pre-treatment therapy for osteoporosis therapy because there is a measurable risk in a short period of time
These patients should do all dental extractions before therapy
The strategies are similar to patients undergoing pre-irradiation therapy for cancer
What is the prevention strategies for asymptomatic patients that are currently receiving monthly IV BP,DB, AA therapy?
- avoid dental procedures
- maintain routine dental care, avoid soft tissue injury
- aggressively manage dental infections non surgically (root canals are acceptable in certain situations
- consider anti-angiogenic medications as well
What is the prevention strategy for patients receiving oral bisphosphonate therapy that are asymptomatic?
They have a much lower risk than those receiving IV bisphosphonate therapy but recall that it increases with duration of exposure.
Dentoalveolar surgery is not contraindicated for those patients exposed to BPs
What is a drug holiday and is it effective?
Drug holiday is basically when you take a break from at risk drugs (2 months) to allow bone remodeling and healing (3 months). Studies do not support or refute this, too little evidence
What is the treatment recommendation for patients (all stages) with established MRONJ?
- Superficial debridement to reduce sharp surfaces and prevent trauma to soft tissues
- Remove all mobile sequestrum
- Apply a removable appliance or protective stent
- Avoid invasive dental procedures when possible
- Elective DA surgery avoided
- Biopsy not recommended unless you suspect metastasis
- Stopping therapeutic AR/AR should be consulted but most of the time benefit of therapy>stopping therapy
What is the specific treatment recommendation for stage 1 MRONJ?
- Non-surgical approach
- Daily irrigation and oral anti microbial rinse (chlorohexidine)
- Clinical follow up every 3 months
What is the recommendation for stage 2 MRONJ?
- Culture-directed antibiotic therapy
- Pain control
- Daily irritations and oral anti-microbial rinses (chlorohexidine)
- Surgical therapy considered?
- Clinical follow up every 3 months
What is the specific treatment recommendation for stage 3 MRONJ?
- Culture-directed antibiotic therapy (PO, IV)
- Pain control
- Daily oral anti microbial rinses (chlorohexidine)
- Surgical debridement/resection to reduce the volume of necrotic bone.
True or false: Discontinuation of BPs or DBs reverse ONJ lesions
False - BP discontinuation does not reverse ONJ, HOWEVER, discontinuation of DB did reverse ONJ in mice
How are most MRONJ cases discovered?
- Most of these cases are discovered incidentally by dental practitioners
What are recurrent MRONJ lesions related to?
- Bacterial infections
2. Type of treatment (surgery, larger resections, etc)
What is a new strategy for the treatment and management of MRONJ?
PTH (teriparatide):
- stimulates bone formation
- inhibits sclerostin (inhibitor of osteoblasts)
- potent anti-inflammatory effects within marrow
- enchanted soft tissue healing/collagen formation
What are the limitations to PTH?
Should only be given for 2 years because animal studies have shown osteosarcoma incidences in over 2 years.
