Anti-Resorptive Agents

Question 1

What are patients prescribed bisphosphonates? What is their MOA?

Answer 1

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

Question 2

What is the half life of a bisphosphonate

Answer 2

half life up to 15 years

Question 3

Do patients that are getting bisphosphonates for their cancer get the same dosage as those for osteoporosis?

Answer 3

Oncologic doses are 12 times higher than doses for osteoporosis

Question 4

What are the two types of bisphosphonates?

Answer 4

Nitrogen containing and non-nitrogen containing. Nitrogen containing have a much greater potentcy.

Question 5

Give some examples of bisphosphonates

Answer 5

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

Question 6

What are some alternative drugs to bisphosphonates which also act as an anti-resorptive?

Answer 6

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)

Question 7

What are other medications that have been shown to cause MRONJ besides bisphosphonates

Answer 7

Denosumab
Anti-angiogenic medications which inhibit angiogenesis which ar used to treat multiple cancers (Avastin, Nexavar, Sutent

Question 8

Discuss general features of Denosumab

Answer 8

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

Question 9

What are symptoms of MRONJ?

Answer 9

Exposed necrotic non-healing alveolar bone, , purulence, pain (68%), intra and extra oral swelling, mobile teeth, fistulas

Question 10

When does MRONJ happen?

Answer 10

Typically following invasive dental procedures but can be spontaneous

Question 11

What is pathophysiology of MRONJ?

Answer 11

Altered bone remodeling, hypovascular bone, combined with over suppression of bone resorption

Question 12

What are the diagnostic criteria for MRONJ?

Answer 12

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

Question 13

What is the incidence of MRONJ for IV bisphosphonates?

Answer 13

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

Question 14

What is the incidence of MRONJ with oral bisphosphonates?

Answer 14

0-8%

Surveillance data Reported incidence with tooth extraction for alendronate = 0.34%

Question 15

Why is the risk for MRONJ in cancer patients and osteoporosis patients treated with bisphospnates different?

Answer 15

Cancer patients = IV, high dose, short period of time

Osteoporosis = oral, low dose, long period

Question 16

What systemic factors increase the risk for MRONJ?

Answer 16

Age - increased risk in patients older than 65 yo

Question 17

What TREATMENTS increase the risk for MRONJ?

Answer 17

Dental extractions are the most highly associated surgical tax with MRONJ

Question 18

Where are you more likely to get MRONJ?

Answer 18

73% of MRONJ cases are in the mandible

Question 19

Discuss CTX. What is it? Is it useful? What is a normal CTX value?

Answer 19

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

Question 20

What is the function of a drug holiday?

Answer 20

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.

Question 21

Do you have patients get CTX tests?

Answer 21

No, no published data that higher CTX levels reduce the incidence of ONJ

Question 22

What are the AAOMS guidelines for patients currently being treated for bone cancer on IV bisphosphonates or anti-angiogenesis agents?

Answer 22

Don’t do any surgery - if patient has non-restorable tooth, you should decoronate and do endorse therapy. Dental implant placement should be avoided

Question 23

What are the AAOMS guidelines for patients currently being treated with oral bisphosphonates for osteoporosis?

Answer 23

Taking bisphosphonates for less than 4 years total

Question 24

Talk about osteoclasts

Answer 24

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

Question 25

Talk about osteoblasts

Answer 25

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

Question 26

What is the incidence of MRONJ?

Answer 26

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.