# Presentation: 132798

## BISPHOSPHONATE RELATEDOSTEONECROSIS OF THE JAW (BRONJ)

## BISPHOSPHONATES AND WHAT HAPPENS TO BONE

- VINCENT E. DIFABIO, DDS, MS				MEMBER OF THE COMMITTEE ON HEALTHCARE AND ADVOCACY FROM THE AMERICAN ASSOCIATION OF ORAL & MAXILLOFACIAL SURGERY (AAOMS)			ASSOCIATE PROFESSOR OF ORAL & MAXILLOFACIAL SURGERY UNIVERSITY OF MARYLAND, BALTIMORE, MARYLAND 		AND PRIVATE PRACTICE OF ORAL & MAXILLOFACIAL SURGERY, FREDERICK, MARYLAND

## BISPHOSPHONATES AND WHAT HAPPENS TO BONE

- PRESENT THE POTENTIAL FOR A DIFFERENT ETIOLOGY OF BONE DESTRUCTION IN THE MAXILLA AND MANDIBLE AND
- THE NEED FOR SPECIFIC CODES TO REPRESENT THIS DIFFERENT ETIOLOGY OF BONE DESTRUCTION SEEN IN THE MAXILLA AND MANDIBLE

## OSTEONECROSIS OF THE JAW

- NOT A NEW DISEASE OR PHENOMENON
- “PHOSSY JAW” DATES BACK TO THE 19TH CENTURY
- RELATED TO MATCHSTICK MAKING
- HIGH LEVELS OF PHOSPHORUS

## BISPHOSPHONATES

- ARE USED TO TREAT SEVERAL DISEASE ENTITIES
- OSTEOPOROSIS
- CANCER PATIENTS
- RECENT PAPERS HAVE SHOWN THAT A JAW OSTEONECROSIS OF ASEPTIC ETIOLOGY IS ASSOCIATED WITH THE USE OF BISPHOSPHONATES

## OSTEOPOROSIS

- TREATED WITH BISPHOSPHONATES (BPs)
- MANY PEOPLE WORLD WIDE ARE RECEIVING THESE TYPES OF MEDICATIONS
- IS THIS TREATMENT OF OSTEOPOROSIS WITH BPs OF CONCERN???

## Osteoporosis 

**Primary disease**:    quantities of sex hormones
- _Phase 1_: trabecular bone resorption due to estrogen deficiency. Peaks after 4-8 years (women only)
- _Phase 2_: persistent, slower loss of both trabecular and cortical bone which is mainly due to decreased bone formation (men and women)

## Osteoporosis 

**Secondary disease**: consequence of other diseases or medications
- Long term steroid use, Cushing’s disease, anorexia nervosa, athletic amenorrhea, HPT, cystic fibrosis, inflammatory bowel disease, rheumatoid arthritis
- Observed in young/old, men/women
- Osteoporosis ICD-9-CM Codes: 733.0 – 733.09

## Osteoporosis 

- Unbalanced bone remodeling where
- 		bone formation = bone resorption
- Defined as a disease with low bone mass and deterioration of bone structure resulting in bone fragility and increase risk of fracture
- Females >>>Males
- Primary *vs*. Secondary

- _[Lerner AH, J. Dent Res 85. 2006](file:///../../)_

## Osteoporosis is a BIG problem in the USA!

**Surgeon General Report (2004)**
- 40% of American women > 50 yo. Will experience an osteoporotic fracture
- 13% of men 50 yo.
- By 2020 it is estimated that 50% of all Americans over the age of 50 will be at risk of developing osteoporosis
- Direct cost expenditures for 1.3 million fx per yr = $14 billion +

## OSTEOPOROSIS

- THE BIG QUESTION IS WILL THESE PATIENTS IN THE FUTURE DEVELOP A SIMILAR OSTEONECROSIS OF THE JAW???

## OSTEORADIONECROSIS

- NOTED WITH THE INTRODUCTION OF RADIATION THERAPY TO TUMORS OF THE HEAD AND NECK
- RADIATION CREATES HARD AND SOFT TISSUE HYPOXIA, HYPO-CELLULARITY AND HYPO-VASCULARITY
- RESULTS IN A SIGNIFICANT DECREASE IN HEALING AND NECROSIS OF BONE
- OSTEORADIONECROSIS OF THE JAWS 		ICD - 9- CM CODE:	526.89

## OSTEOMYELITIS

- BACTERIAL INFECTION OF THE BONE
- PRIMARY OR SECONDARY TO DENTAL OR OTHER ORAL INFECTIONS
- OSTEOMYELITIS OF THE BONE:  730 – 730.9 INCLUDES ACUTE AND CHRONIC and
- OSTEOMYELITIS OF THE JAW:	  526.4 and 526.5

## PATHOPHYSIOLOGY

- ALTHOUGH THE OSTEORADIONECROSIS (RADIATION INDUCED), OSTEOMYELITIS (BACTERIAL INFECTION) AND BISPHOSPHONATE RELATED OSTEONECROSIS OF THE JAW (ASEPTIC NECROSIS & DRUG INDUCED)  ARE DIFFERENT IN ETIOLOGY, THEY ARE SIMILAR IN PATHOLOGY AND SECONDARY INFECTIONS
- AND WILL THE OSTEOPOROSIS PATIENTS TREATED WITH BPs DEVELOP A SIMILAR ONJ IN THE FUTURE??

## ICD-9-CM

- WE HAVE SPECIFIC ICD-9-CM CODES FOR OSTEOPOROSIS, OSTEOMYELITIS AND OSTEORADIONECROSIS
- SO WHY NOT USE THESE CODES FOR BP RELATED ASEPTIC OSTEONECROSIS OF THE JAW OR BRON JAW??

## NEED FOR A SPECIFIC CODE 

- REPORTING INCIDENCE OF OCCURRENCE AND TRACKING
- RESEARCH
- EVALUATION & MANAGEMENT AND SURGICAL PROCEDURES OF MAXILLA AND MANDIBLE LINKED TO A SPECIFIC VS NON-SPECIFIC ICD-9CM CODE

## BISPHOSPHONATE RELATED OSTEONECROSIS OF THE JAW (ONJ)

- FIRST RECOGNIZED IN 2003 AS A COMPLICATION OF BISPHOSPHONATE THERAPY
- HIGHER FREQUENCY IN THE MANDIBLE (63%) THAN IN THE MAXILLA (38%)
- ETIOLOGY IS UNCLEAR AND IS THE SUBJECT OF CURRENT RESEARCH AND INVESTIGATION

## BRONJ

- CAN BE RELATED TO DENTAL TREATMENT
- CAN BE RELATED TO DENTAL PATHOLOGY
- CAN BE SPONTANEOUS WITH DENTAL ETIOLOGY
- CAN BE RELATED TO DENTURE IRRITATION OR WEAR
- CAN BE UNRELATED TO ANY OF THE ABOVE
- CAN BE RELATED TO LOCAL TRAUMA
- CAN BE UNKNOWN IN ETIOLOGY

## PROPOSED INDUCTION MECHANISMS

- INHIBITION OF OSTEOCLAST ACTIVITY
- REDUCES BONE TURNOVER
- REDUCING REMODELING
- DECREASED NEW BONE FORMATION
- ETIOLOGY IS UNKNOWN
- BUT IS LIKELY MULTIFACTORIAL

## BRONJ

- TRUE INCIDENCE IS DIFFICULT TO ESTIMATE
- DEPENDING ON RECENT RETROSPECTIVE REPORTS COULD BE <1%-9% OF CANCER PATIENTS RECEIVING BISPHOSPHONATES
- SEEN IN CANCER PATIENTS WITH MULTIPLE ANTINEOPLASTIC MEDICATIONS AS WELL AS BISPHOSPHONATES
- MULTIPLE MYELOMA, BREAST CANCER AND PROSTATE CANCER ARE THE PRIMARY NEOPLASMS AFFECTED
- AND WHAT ABOUT OSTEOPOROSIS PATIENTS TREATED WITH BPs?????

## ONJ

- MULTIPLE PAPERS RELATING BPs WITH ONJ SINCE 2003
- RELATED TO METHOD OF ADMINISTRATION OF BPs:  IV VS PO
- RELATED TO THE DURATION OF ADMINISTRATION
- VERY SERIOUS SEQUELAE WHEN ONJ DEVELOPS

## BP’s Mechanism of action

**1)**  **Tissue level**
- 		**a****.** reduction of bone turnover
*	*
** ****2)****  ****Cellular level**
**	****        ****a****. ** inhibition of osteoclastic activity on the
-                bone surface** **(Rodan et al., Strewler)
**	****	****b. **inhibition of osteoclast recruitment on the
-                bone surface   (Rodan et al., Vitte et al.)
- 		**c.** osteoclast apoptosis (Hughes et al., Rogers et al.)

**Notes:**
-The action of BP’s at the molecular level have not been elucidated as of yet
-It has been proposed that BP’s interfere with osteoclast intercellular biochemical pathways, either by:
Interacting with a cell-surface receptor or...
By uptake of the BP by the osteoclast and interference with cellular metabolism
-In fact, one study has recently demonstrated that BP’s interact with a receptor on the cell surface of osteoblasts, perhaps interfering with their ability to produce bone as well

## BP’s Mechanism of action

**3)  Molecular level**
- 	Interferes with osteoclast intercellular biochemical pathways
**Inhibition of farnesyl diphosphate synthase**
**Metabolized to toxic analogue of ATP (non-nitrogen containing BP’s)**

**Strewler GJ.  N Engl J Med 2004;350:1174**

**Notes:**
-lastly, several in vitro studies have presented evidence that BP’s mediate osteoclast apoptosis at the in vitro 

## Bisphosphonates

_**Pharmacologic action**_**:**
- 	-  Inhibition of bone resorption
_**Pharmacokinetics**_**:**
- 	-  **Distribution**:  Rapid accumulation in sites of 				  increased bone 	deposition/resorption, 			  low plasma levels, ***1⁄2 life of “years”***
- 	-  **Metabolism**:  Not metabolized (nitrogen containing)
- 	-  **Excretion**:  	  Renal

**Notes:**
-Bisphosphonates, such as Aredia, Zometa, and Fosamax, are analogues of pyrophosphates whose primary mode of action is inhibition of bone resorption
-These compounds accumulate in sites of increased bone deposition and resorption, where they remain for extended periods of time and are released slowly into the circulation
(-low plasma levels for 2 to 28 days)

## Staging

_**Stage 1**_
- Characterized by exposed bone that is asymptomatic with no evidence of significant soft tissue infection

## Staging

_**Stage 2**_
- Exposed bone associated with pain, soft tissue and/or bone infection

## Staging

_**Stage 3**_
- Pathologic fracture
- Exposed bone associated with soft tissue infection or pain that is not manageable with antibiotics due to the large volume of necrotic bone.

## Staging

_**Stage 3**_
- Pathologic fracture
- Exposed bone associated with soft tissue infection or pain that is not manageable with antibiotics due to the large volume of necrotic bone.

## A 40 yo with female with a diagnosis of breast cancer and Zometa therapy (6 months) presents with pain, exposed and infected maxillary bone following extraction 

- A 40 yo with female with a diagnosis of breast cancer and Zometa therapy (6 months) presents with pain, exposed and infected maxillary bone following extraction

## Relative Potency

- Etidronate (Didronel)		1
- Tiludronate (Skelide)		10
- Pamidronate (Aredia)		100
- Alendronate (Fosamax)	1,000
- Risedronate (Actonel)		10,000
- Ibandronate (Boniva)		10,000
- Zolendronic acid (Zometa)	>100,000

## PROPOSAL

- NEW DIAGNOSTIC ICD-9CM CODE FOR THE ASEPTIC NECROSIS OF BONE IN THE JAWS:
- NEW CODE:	 733.45  JAW (MAXILLA AND MANDIBLE) AND
- APPROPRIATE NEW E CODES TO IDENTIFY THE SPECIFIC ROUTE OF ADMINISTRATION
- E933.6 ORAL BISPHOSPHONATES				AND					      E933.7  INTRAVENOUS BISPHOSPHONATES

## Combinations 

- Use E933.1	antineoplastic & immunosuppressive drugs and
- May also need to Code for the primary neoplasm (most common ones are prostate, breast and myeloma)