Anti-Resorptive Agents Flashcards
What are patients prescribed bisphosphonates? What is their MOA?
MOA: inhibit bone resorption by suppressing osteoclast activation and inducing osteoclast apoptosis (the bisphosphonate is internalized by osteoclasts)
Usually bisphosphonates attach to hydroxyapatite on surfaces undergoing active resorption. When an osteoclast attempts to resorb bone that contains bisphosphonate, the released bisphosphonate impairs the ability of the osteoclasts to form the ruffled border, to adhere to the bony surface, and to produce the protons necessary for continued bone resorption.
§ Also, bisphosphonates decrease osteoclast progenitor development and recruitment and promote osteoclast apoptosis.
Bisphosphonates also prevent osteocyte and osteoblast apoptosis
Prescribed for metastatic bone lesions, osteoporosis, and multiple myeloma, Paget’s disease
What is the half life of a bisphosphonate
half life up to 15 years
Do patients that are getting bisphosphonates for their cancer get the same dosage as those for osteoporosis?
Oncologic doses are 12 times higher than doses for osteoporosis
What are the two types of bisphosphonates?
Nitrogen containing and non-nitrogen containing. Nitrogen containing have a much greater potentcy.
Give some examples of bisphosphonates
Alendronate (Fosamax) used for osteoporosis - oral route
Ibandronate (Boniva) used for osteoporosis - oral or IV (oral = 1 pill a month, 1 injection every 3 mo)
Zoledronate (Reclast) used for osteoporosis - IV once a year
What are some alternative drugs to bisphosphonates which also act as an anti-resorptive?
Denosumab (Prolia) - human monoclonal antibody to RANKL, prevents RANK-L from activating RANK
Raloxifene (Evista) - selective estrogen receptor modulator . Mimics estrogen activity (no evidence of MRONJ)
What are other medications that have been shown to cause MRONJ besides bisphosphonates
Denosumab
Anti-angiogenic medications which inhibit angiogenesis which ar used to treat multiple cancers (Avastin, Nexavar, Sutent
Discuss general features of Denosumab
Human monoclonal antibody to RANKL
Inhibits osteoclasts formation, function, and survival
Subcutaneous injection twice per year
Not incorporated into bone so bone resorption returns to baseline at 6 months
What are symptoms of MRONJ?
Exposed necrotic non-healing alveolar bone, , purulence, pain (68%), intra and extra oral swelling, mobile teeth, fistulas
When does MRONJ happen?
Typically following invasive dental procedures but can be spontaneous
What is pathophysiology of MRONJ?
Altered bone remodeling, hypovascular bone, combined with over suppression of bone resorption
What are the diagnostic criteria for MRONJ?
Exposed bone or bone that can be probed through fistula that has been present for longer than 8 weeks in a patient with previous or current treatment with anti-resorption or anti-angiotensin agents with no history of radiation or obvious metastatic disease to jaw
What is the incidence of MRONJ for IV bisphosphonates?
Patients on IV bisphosphonates have a 7x increased risk of MRONJ after dental surgery compared to those that were not treated with bisphosphonates
0.8-52% incidence
What is the incidence of MRONJ with oral bisphosphonates?
0-8%
Surveillance data Reported incidence with tooth extraction for alendronate = 0.34%
Why is the risk for MRONJ in cancer patients and osteoporosis patients treated with bisphospnates different?
Cancer patients = IV, high dose, short period of time
Osteoporosis = oral, low dose, long period
What systemic factors increase the risk for MRONJ?
Age - increased risk in patients older than 65 yo
What TREATMENTS increase the risk for MRONJ?
Dental extractions are the most highly associated surgical tax with MRONJ
Where are you more likely to get MRONJ?
73% of MRONJ cases are in the mandible
Discuss CTX. What is it? Is it useful? What is a normal CTX value?
C terminal telopeptide = serum marker for bone turnover (byproduct from degradation of type 1 collagen) that is correlated to level of osteoclastic activity
Use as a risk indicator is questionable since there is a wide variability throughout the course of the day and rarely do patients have baseline CTX prior to antiresporptive therapy
Normal = greater than 400 picogram/mL
What is the function of a drug holiday?
Evidence that there is an average CTX increase of 25 picograms/mL each month of a drug holiday
Typically not effective with IV bisphosphonates, but can be with oral bisphosphonates.
Do you have patients get CTX tests?
No, no published data that higher CTX levels reduce the incidence of ONJ
What are the AAOMS guidelines for patients currently being treated for bone cancer on IV bisphosphonates or anti-angiogenesis agents?
Don’t do any surgery - if patient has non-restorable tooth, you should decoronate and do endorse therapy. Dental implant placement should be avoided
What are the AAOMS guidelines for patients currently being treated with oral bisphosphonates for osteoporosis?
Taking bisphosphonates for less than 4 years total
Talk about osteoclasts
Hematopoietic stem cells in bone marrow are osteoclast precursor cells. They mature as mononuclear cells and in circulation they fuse to become multinucleated due influence of IL-1, IL-2, and RANKL.
Osteoclast precursors and mature osteoclasts express RANK receptor. Molecules that work on osteoclasts
o IL-1 stimulates osteoclast differentiation
o IL-10 suppresses osteoclasts
Talk about osteoblasts
Produce RANKL which binds RANK and stimulates osteoclastic bone resorption
Produce OPG which is a decoy receptor that binds RANKL to prevent it from binding RANK
o Inhibits osteoclast differentiation, fusion, and activation
Several things induce osteoblasts to secrete RANKL
o Glucocorticoids, vit-D, IL-1, IL-6, IL-11, TNFalpha, PGE2
What is the incidence of MRONJ?
Gaudin 2015: SR MA. Occurrence rate of MRONJ following dental extraction was 3.2% for patients treated with IV anti-resorptive drugs for oncological reasons and 0.15% for oral ARD for osteoporosis. For patients taking ARD for oncological reasons, the risk of MRONJ can be minimized by performing alveolectomy and using a membrane.
