BIONJ, BRONJ, MRONJ

1. Dr. VIJAYA LAKSHMI.G
Post-grauate,
Dept. Of OMFS

2. CONTENTS-
• Introduction
• Definition
• History
• Correcting the incorrect terminology
• Mechanism of action of BP’s
• Classification of BP’s
• Structure of BP’s
• Clinical use of BP’s
• Adverse effects of BP’s
• Pathophysiology of BIONJ
• Risk factors
• Clinical presentation

3. • Radiographic changes of BIONJ
• Differential diagnosis
• Diagnostic work-up
• Staging of BIONJ
• Treatment guidelines for BIONJ
• Stage specific treatment
• Management of patients with established BIONJ after iv and oral BP therapy
• Conclusion
• References

4. INTRODUCTION-
Bisphosphonate-induced osteonecrosis- Bone death caused by a bisphosphonate drug.
Bisphosphonates A class of drugs that characteristically induces dysfunction or death of osteoclasts, which can
result in osteonecrosis or brittle bone fractures.
Bisphosphonates are a class of agents used to treat osteoporosis and the complications associated with
malignant bone metastases.
Despite these benefits, osteonecrosis of the jaws has recently emerged as a significant complication among
patients receiving these drugs.

5. DEFINITION-
Exposure of portions of the jaw bone in patients who have been exposed to bisphosphonates that has persisted for
more than 8 weeks with no history of RT to the jaw

6. HISTORY-
Bisphosphonate-induced osteonecrosis of the jaws (BIONJ) in
humans was first discussed in the textbook Oral and
Maxillofacial Pathology: A Rationale for the Diagnosis and
Treatment by Marx and Stern in 2001.
At that time, this author incorrectly referred to this condition as
an avascular necrosis because the exposed bone was indeed
necrotic and did not bleed upon cutting into it.

7. BIONJ represents the second epidemic of phossy jaw.
The Phossy Jaw Epidemic of ~1850–1906
Matches invented in 1826 had poor lighting quality
1832- ‘‘strike anywhere matches’’ -chemists added white phosphorous(lower ignition temperature) which
lit easily.
Proportional to the length of time match-factory workers worked inhaling the white phosphorus, they
developed exposed bone in the jaws that failed to heal, became secondarily infected, and produced
draining fistulae just like those seen in many modern-day BIONJ patients .

8. Match-factory worker 1899. Phossy jaw causes
fistulas and collapse of the mandible most likely
due to a pathologic fracture
Modern-day bisphosphonate-induced osteonecrosis with exposed bone and a pathologic
fracture. b Draining fistulas from modern-day bisphosphonate-induced osteonecrosis of the
jaws similar to the phossy jaw in

9. A few of these workers also developed spontaneous leg fractures (femur),
similar way caused usage of by alendronate (Fosamax) for more than 6 years.
Berne Conference in Berne Switzerland and the banning of ‘‘strike
anywhere matches’’ in 1906.
Since then, rare cases of phossy jaw have been reported in fireworks-
and munitions-plant workers whose jobs entail exposure to white phosphorus
(P4O10).
Subtrochanteric femur fracture caused by
alendronate (Fosamax) use over 7 years

10. Additionally, phossy jaw and BIONJ have been linked by the demonstration that P4O10, when combined
with water, CO2, and/or tetrahydrofolate in a one-carbon transfer, and with the amino acid hydroxylysine,
all of which are common in the tracheo-bronchial tree, can produce a nitrogen-containing
bisphosphonate easily similar to pamidronate and alendronate, each of which has caused numerous
cases of BIONJ.

11. ‘‘Avascular necrosis’’ is incorrect because BIONJ is a chemical toxicity to the osteoclast→ prevents bone
renewal. AVN is, instead, secondary. As the bone fails to remodel and renew itself, the bone cells die off
replacement followed by involution of their vascularity.
‘‘Bisphosphonate-related osteonecrosis’’ (BRONJ) is inaccurate because the relationship is not defined.
‘‘Bisphosphonate associated osteonecrosis’’ (BAONJ) is incorrect as well.
‘‘Osteochemonecrosis’’ is incorrect because not all bisphosphonates have activity against cancer cells.
‘‘Bisphosphonate-induced osteonecrosis of the jaws’’ (BIONJ) is the only correct term, as bisphosphonates are
bisphosphonates are the proven causative agent. All the other reported risk factors, such as tooth extraction,
steroids, the cancer itself, smoking, etc., rarely, if ever, cause exposed bone osteonecrosis in the absence of
concomitant bisphosphonate use.
Correcting the Incorrect terminology-

12. MECHANISM OF ACTION OF BPs-
Bisphosphonates- developed in the nineteenth century, but were first investigated in the 1960s for use in
disorders of bone metabolism.
All bisphosphonates are non-metabolized synthetic analogues of pyrophosphate.
The initial rationale for their use in clinical practice was centered on their potential in preventing the
dissolution of hydroxyapatite, the principal bone mineral, and hence arresting bone loss.

15. Bisphosphonates are then internalized by the osteoclast, causing disruption of osteoclast-mediated bone
resorption at various levels.
At the tissue level, bisphosphonates
Inhibit bone resorption
Decrease bone turnover (as assessed by biochemical markers)
The degree to which these compounds will also alter bone formation is related to their effects on bone turnover,
which is closely coupled to bone formation.

16. On a cellular level, the bisphosphonates are clearly targeting the osteoclasts-
At a molecular level, it has been postulated that bisphosphonates modulate osteoclast function by
interacting with a cell surface receptor or an intracellular enzyme.
Inhibits osteoclast
recruitment Diminishes
osteoclast life
span
Inhibits osteoclastic
activity at the bone
surface.

17. They are categorised based on potency and route of administration.
CLASSIFICATION OF BPs-

18. STRUCTURE OF BPs-
Each bisphosphonate has a different R1 or R2 side chain attached to the central carbon atom.
R1 side chains determine- Affinity for bone
R2 side chains- responsible for their antiresorptive properties.
Side chains that contain a nitrogen atom are more potent than the nonnitrogen bisphosphonates.

19. These drugs can be grouped in three different classes:
1. First-generation, non-nitrogen containing BPs (e.g., clodronate and etidronate),
2. Second-generation nitrogen containing BPs (N-BPs, e.g., pamidronate and alendronate) and
3. Third-generation N-BPs (e.g., ibandronate and zoledronate) and the phosphono carboxylate analogue 3-
PEHPC.
BPs without Nitrogen side group BPs containing Nitrogen side group
Once internalized by the osteoclast, these agents
inhibit ATP–dependent intracellular enzymes
→cellular apoptosis.
Inhibit the activity of the enzyme farnesyl diphosphate
synthase in the mevalonate pathway, which blocks the
phenylation of small signaling proteins (GTPase) that
are required for osteoclast function and survival.

20. The clinical benefit of BPs is a result of their ability to decrease bone turnover via the inhibition of osteoclastic
process and is used in the treatment of complications associated with metastatic bone disease, osteoporosis, and
Paget’s disease which are related to perturbations in osteoclast function.
MALIGNANT BONE DISEASE
Myeloma-related lytic disease is secondary to increased osteoclastic activity and impaired osteoblastic activity.
Clinical use of BP’s-

21. Myeloma cells secrete
Stimulators of osteoclast
activation
- such as receptor activator of
nuclearkB ligand (RANKL)
Inhibitors of osteoblastic
activity
-soluble molecules-dickkopf 1
(DKK)
Bisphosphonates inhibit osteoclast function
block the formation of “punched-out” lytic
bony lesions and consequent
manifestations of lytic bony disease.
In a consensus statement from the Mayo Clinic, the use of BP’s in the treatment of multiple myeloma was modified
to limit the exposure of intravenous bisphosphonates and minimize the potential for BRONJ.

22. Based on clinical practice guidelines established by the American Society of Clinical Oncology,
the use of bisphosphonates is considered the standard of care for treatment of:
(1) moderate to severe hypercalcemia associated with malignancy and
(2) metastatic osteolytic lesions associated with breast cancer and multiple myeloma in conjunction with
antineoplastic chemotherapeutic agents.
In patients with osteolytic metastases, oral bisphosphonate therapy is not as efficacious as the intravenous
form in preventing skeletal complications and therefore is not indicated for this patient group.

23. Women with breast cancer
70%
Develop bone
metastasis
• Annually, about 1 million women worldwide will
develop breast cancer.
• Of those progressing to advanced disease, close
to 70% will develop bone metastases.
• This has resulted in a rampant use of these
bisphosphonates in most medical oncology
practices within the past several years.

24. Osteoporosis, a disease that is characterized by increased
skeletal fragility and low bone mineral density, is responsible for
more than 1.5 million fractures in postmenopausal women each
year.
As a result of proven clinical efficacy, bisphosphonates are
considered first-line therapy in the treatment of osteoporosis
and are the most widely prescribed antiresorptive agent.
OSTEOPOROSIS
Bisphosphonates
(Potent suppressor of osteoclast
activity)
Slow down the remodelling process
and increase bone mineral density
Reduces the risk of fracture

25. Mechanism of action of BP’s in osteoporosis

26. BPs have several common properties, including
1. Poor intestinal absorption,
2. High affinity for bone mineral,
3. Inhibitory effects on osteoclastic bone resorption
4. Prolonged bone retention, and elimination in the urine.
5. Generally well tolerated, even if side effects have been
described.
ADVERSE EFFECTS OF BPs-

27. Pathophysiology of BIONJ is multifactorial
Pathophysiology Of BIONJ-
Appears to be related to the profound inhibition of osteoclast function and bone remodeling.
Osteoclast is more directly affected because bisphosphonates are irreversibly bound to the hydroxyapatite crystals in bone and
accumulate in bone with repeated dosing due to a half-life in bone of 11 years.
Profound inhibition of osteoclast function can also inhibit normal bone turnover to an extent that local microdamage from
normal mechanical loading or injury (tooth extraction) cannot be repaired.
HYPOTHESIS 1: BONE REMODELING INHIBITION
Pathophysiology of Osteonecrosis of the Jaws Tara Aghaloo1, Renna Hazboun2, and Sotirios Tetradis3,4

28. The increased bone resorption in the setting of dental disease, coupled with the thin overlying mucosa and a direct pathway
through the periodontal ligament with the external environment, make the jaws a suitable breeding ground for BIONJ to
develop.
Another factor that points to the central role of osteoclastic bone resorption in BIONJ pathophysiology is the effect of
parathyroid hormone (PTH).
Initial case reports in osteoporotic patients and animal studies simulating osteoporosis demonstrate the improved healing of
extraction sockets and ONJ lesions with administration of parathyroid hormone, possibly due to its ability to improve bone
homeostasis, by directly stimulating osteoblastic function and indirectly increasing osteoclastic bone resorption.

29. HYPOTHESIS 2: INFLAMMATION & INFECTION
0.8–12% of patients on systemic antiresorptives for malignant disease develop ONJ
Inflammation/infection has been thought to play a role in BIONJ, often occuring after extraction of teeth with advanced
dental disease or around teeth with periodontal or periapical infection.
Evaluation of histologic specimens detect bacteria on the exposed bone, including Actinomyces species
Recent studies have shed light on the complexity of biofilm, which include fungi and viruses in addition to the bacterial
species and present challenges to eradicate infection.

30. HYPOTHESIS 3: ANGIOGENESIS INHIBITION
• Bone becomes necrotic without adequate blood supply.
• Anti-angiogenic therapies are aimed to inhibit tumor invasion and metastases, targeting vascular signaling molecules such as
vascular endothelial growth factor (VEGF).
• Zoledronic acid is a known agent that reduces circulating VEGF levels in cancer patients in vivo and reduces angiogenesis in
vitro.
• BPs, especially nitrogen-containing BPs, induce a statistically significant decrease in microvessel density in vivo.

31. Recently, new antiangiogenic therapies such as tyrosine kinase inhibitors and anti-VEGF monoclonal antibodies are associated
with ONJ development.
For these reasons, the new AAOMS guidelines (2014) have recognized antiangiogenics as a contributing factor and modified
the disease name to medication related ONJ (MRONJ).
Drugs causing Osteonecrosis of jaws other than Bisphosphonates-
1. RANKL inhibitor- Denosumab(6.9%)
2. Antiangiogenic agents
• Bevacuzimb(4.1%)
• Sunitinib(2.4%)
• Sorafenib(0.5%)
• Pazopanib(0.1%)
• Axitinib(0.1%)
3. m-TOR inhibitors
• Everolimus(0.5%)
• Temsirolimus(0.2%)

32. HYPOTHESIS 4: SOFT TISSUE TOXICITY
BP’s (especially nitrogen containing BP’s) cause direct soft tissue toxicity inducing apoptosis or decreased proliferation of
oral epithelial cells in vitro.
Oral alendronate is associated with esophageal irritation, requiring special precautions for patients during administration
However, this hypothesis has become less likely due to the lack of soft tissue toxicity reported with denosumab.

33. HYPOTHESIS 5: – INNATE OR ACQUIRED IMMUNITY DYSFUNCTION
A continued debate exists about the effect of alterned immunity on BIONJ development.
Tumor pathogenesis is often associated with an impaired immune function, and animal studies have implicated immune
deficiency in the development of ONJ.
In patients on oral BPs, steroids are also a risk factor for ONJ. This points to the potential significant contribution of
immunomodulators in the pathophysiology of the disease
Since only a minority of bisphosphonate users develop bone necrosis depending on individual genetic variations in drug
metabolism or skeletal homeostasis whether susceptible or resistant to developing BIONJ.

34. The loss of osteoclastic bone resorption, which normally liberates bone morphogenetic protein (BMP) and insulin-
like growth factors 1 and 2 (IGF1 and IGF2) that renew bone, is shared by the disease osteopetrosis, which is a
genetic loss of osteoclasts and hence osteoclastic bone resorption and results in the same clinical signs of exposed,
nonhealing bone that becomes secondarily infected and is limited to the jaws.
There are two clinical types of BIONJ that differ in prevalence, severity, prediction of risk, and treatment:
1. Intravenous BIONJ
2. Oral BIONJ

35. • Intravenous BIONJ is caused by the drugs pamidronate (Aredia, Novartis) and zoledronate (Zometa,
Novartis), both of which are used to stabilize metastatic cancer deposits in bone and treat
hypercalcemia of malignancy.
• Additionally, zoledronate used intravenously to treat osteoporosis under the trade name Reclast (Novartis)
has also caused BIONJ.
• Compared to oral BIONJ, intravenous BIONJ is more commonly seen (an estimated incidence of 12%
of those receiving the drug for 1 year or more), severe in nature and generally unresponsive to discontinuation
of the bisphosphonate and to local debridement.
• Local debridements have been noted to result in further bone exposure.
Intravenous BIONJ

36. • Oral BIONJ mostly results from alendronate (Fosamax, Merck) use (97% of oral BIONJ cases), but
risedronate and ibandronate also rarely cause BIONJ.
• All three of these drugs are used to prevent or treat osteoporosis.
• Although the incidence of oral BIONJ is 0.1% (21,000 to 24,000 women) and even some men develop
BIONJ, depending on which drug is taken, its dose, its potency, and time.
• Oral BIONJ is seen less frequently than intravenous BIONJ, is less extensive and less severe when it
forms, and is responsive to discontinuation of the bisphosphonate, know as a drug holiday, and minor
debridement surgery during a drug holiday.
Oral BIONJ

37. The difference in severity of clinical BIONJ is not due to potency but rather to the route of administration.
Seventy percent of the iv BPs dose is rapidly absorbed into bone and has a half-life of over 11 years.
The lack of response to discontinuation of the iv BPs is due to the large accumulation of the drug in bone and
depletion of the osteoclast precursors in bone marrow.
Oral bisphosphonate more gradually accumulates in the bone and requires a longer term drug use to reach toxic
levels. Long term use of an oral BPs produces a clinically more severe exposed bone similar in severity to
intravenous bisphosphonate use and also brings about a risk for spontaneous fractures of the femur.
Oral bisphosphonates are very poorly absorbed in the small intestine, with 0.63% bioavailability.

38. RISK FACTORS FOR BIONJ-
The most common oral manifestation is exposed necrotic jaw bone. Tooth extractions and oral surgical
intervention appear to place patients on BP therapy at risk of ONJ, especially after intravenous BP
treatments.
Patients with a history of inflammatory
dental disease (e.g., periodontal and dental
abscesses) are at a sevenfold increased risk
of developing BIONJ.

39. A patient may be considered to have BIONJ if all of the following clinical conditions are present:
(1) current or previous treatment with a bisphosphonate;
(2) exposed, necrotic bone in the maxillofacial region that has persisted for more than 8 weeks; and
(3) no history of radiation therapy to the jaws.
Clinical Presentation-
• Asymptomatic exposed bone discovered during a routine dental examination 31%
• Develop spontaneously or after Dentoalveolar procedures.
• Area of exposed Bone Present with pain.=68%
• Mobile teeth, with either a Cutaneous fistula, Mucosal fistula, or bone exposed through the skin Purulent
Discharge.-Culture
• Swelling. 17%
• Paresthesia.

40. BIONJ in posterior mandible BIONJ in maxilla BIONJ in a maxillary torus
It has been observed that lesions are found more commonly in the mandible than the maxilla (2 : 1 ratio). The
predilection for the jaws is due to the fact that the alveolar bone of the jaws remodels at a rate 10 times faster
than that of long bones because of occlusion and denture wearing and is therefore much more dependent on
osteoclast-mediated bone remodeling.
More commonly in areas with thin mucosa overlying bony prominences, such as tori, bony exostoses, mylohyoid
ridge and in areas of greater occlusal load. The size of the affected area can range from a nonhealing extraction
site to necrosis of the entire jaw.

41. The posterior lingual cortex receives the greatest
occlusal load and therefore requires more bone
remodeling, making it a primary site for drugs or
diseases that reduce osteoclast function.
Bisphosphonate-induced osteonecrosis of the
posterior lingual cortex of the mandible in an area of
high occlusal load.

42. a Osteonecrosis of the mandible,
b in a completely edentulous patient

43. Radiographs may appear normal due to maintenance of the bone mineral from the death of osteoclasts.
Little or no ossification at a previous extraction site may represent an early radiographic sign.
Variable areas of osteolysis combined with osteosclerosis, thickening of lamina dura and widening of the periodontal
ligament as well as general hypermineralization or sclerosis in the alveolar bone is noted.
In advanced cases, small and large sequestra with involucrums may be noted, and pathologic fractures occur in later
stages.
Radiographic changes of BIONJ-

44. Generalized sclerosis of the lamina dura seen in a patient taking a bisphosphonate.

45. A sequestrum and a pathologic fracture from
bisphosphonate-induced osteonecrosis caused by Zometa.
Significant sclerosis of the lamina dura and
widening of the periodontal ligament space
seen in a patient taking a bisphosphonate.

46. Small sequestrum from bisphosphonate induced
osteonecrosis caused by more than 6 years of Fosamax
use seen in CT
BRONJ-CT
Focal sclerosis, Thickened lamina dura.
Early sequestrum formation,
presence of reactive Bone

47. BRONJ-Imaging
• Bone Scintigraphy-Technetium 99m Bone Scanning-Sensitive in Developed necrosis
Bone scintigraphy is limited due to its low spatial resolution, difficulty in differentiating between inflammatory and
malignant processes, and the fact that metric analyses are not possible with this technique
• MRI scan
• PET scan

48. BIONJ is usually evident by the patient's history, clinical observations of exposed bone, and certain radiographic
clues.
Other entities that can cause exposed bone, such as osteopetrosis, osteoradionecrosis, mucormycosis, florid
cemento-osseous dysplasia, and, rarely, a chronic suppurative osteomyelitis, can be ruled out by history,
radiographs, and knowledge of the disease mechanism.
DIFFERENTIAL DIAGNOSIS-

49. For both intravenous and oral BIONJ, a panoramic and CT scan of the jaws is recommended.
While the morning fasting serum C-terminal telopeptide (CTX) blood test is useful as an index of bone-turnover suppression
in the noncancer patient, useful in assessing risk and response to drug discontinuation or a drug holiday in the appropriate
patient.
CTX shows false in-
1. cancer patient due to the cancer splitting of collagen fragments, which cross react with the CTX test and provide falsely
high volumes.
2. Patients currently taking methotrexate or steroids or who have used oral bisphosphonates for 7 or more years, the CTX
results are falsely low due to suppression of the bone marrow precursors of osteoclasts as well as other cell lineages.
Therefore, the CTX is valuable only in the noncancer, usually osteoporotic patient who has taken an oral bisphosphonate
for less than 7 years.
Diagnostic work-up

50. A clinical staging system has been developed to more accurately categorize patients with BRONJ.
STAGING OF BIONJ-
Fonseca volume 2- DIAGNOSIS AND MANAGEMENT OF BISPHOSPHONATE-RELATED OSTEONECROSIS OF THE JAWS (BRONJ)
Salvatore L. Ruggiero Chapter 27

51. The clinical appearance and history are sufficient to distinguish ONJ from other delayed bone and wound-healing pathologies.

52. Stage 1a: exposed bone area <1 cm Stage 1b: exposed bone area>1 cm

53. Stage 2a: exposed bone area<2 cm
Stage 2b: bone exposure area>2 cm

54. Stage 3a: multiple areas of bone exposure without significant
osteolysis, oral cutaneous fistulas, or pathological fractures
Stage 3b: bone exposure[3 cm, associated with significant
osteolysis

55. Stage 3b: bone exposure and oral
cutaneous fistulas
a Pathological fractures associated,
b with stage 3b bone exposure

56. The position paper of the American Association of Oral and Maxillofacial Surgeons (AAOMS) on BIONJ,
published in 2009, identified five different categories for BIONJ staging-
‘‘At risk’’: No evidence of necrotic bone in patients treated with oral or intravenous bisphosphonates
Stage 0: No clinical evidence of necrotic bone, but non-specific clinical findings and symptoms
Stage 1: Exposed and necrotic bone in patients who are asymptomatic and have no evidence of infection
Stage 2: Exposed and necrotic bone in patients with pain and clinical evidence of infection
Stage 3: Exposed and necrotic bone in patients with pain, infection, and one or more of the following: necrotic-
bone exposure extending beyond the region of alveolar bone (i.e., inferior border and ramus in the mandible,
maxillary sinus and zygoma in the maxilla) resulting in pathological fracture, extra-oral fistula, oral antral/oral
nasal communication, and/or osteolysis extending to the inferior border of the mandible or sinus floor.

57. Unfortunately, the stagings put forth by several organizations include pain as a major component of their staging—when pain is
actually not related to the mechanism of BIONJ or to its severity—and are thus overly complicated and inaccurate.
A more logical staging of BIONJ that directly relates to extent and severity of the disease and therefore guidance of
treatment is the following:
Stage I: Exposed bone in one quadrant
Stage II: Exposed bone in two quadrants
Stage III: Exposed bone in three or more quadrants or exposed bone extending into the maxillary sinus or exposed bone with
osteolysis to the inferior border or exposed bone with a pathologic fracture
Marx-Oral and Maxillofacial Pathology 2012

58. Stage I BIONJ by virtue of one quadrant of exposed
bone.
Stage II BIONJ by virtue of two quadrants of exposed bone

59. Stage III BIONJ by virtue of exposed bone extending into the maxillary sinus.

60. Stage III BIONJ by virtue of exposed bone with osteolysis
to the inferior border of the mandible
Stage III BIONJ by virtue of a pathologic fracture

61. Treatment Guidelines of BIONJ-
The goal of treatment for patients at risk of developing BIONJ or who have active disease is to preserve the quality of life by
controlling pain, managing infection, and preventing the development of new areas of necrosis.
Treatment strategies range from conservative local wound care to aggressive resective surgery of all necrotic bone
Guidelines for prophylactic management or treatment have been structured to address three distinct
clinical scenarios:
(1) patients who are about to initiate intravenous bisphosphonate therapy,
(2) patients receiving either oral or intravenous bisphosphonate therapy and,
(3) patients with established BRONJ.

62. • Nonrestorable teeth and those with a poor prognosis should be extracted.
• Elective dentoalveolar surgery should also be completed at this time.
• bisphosphonate therapy should be delayed at least 2 to 3 weeks to ensure that adequate osseous healing and allow the site to
mucosalize.
• Dental prophylaxis and caries control are critical to maintaining functionally sound teeth and must be continued throughout
therapy.
• Patients with full or partial dentures should be examined for areas of mucosal trauma, especially along the lingual flange
region.
Treatment objective for patients who are about to initiate intravenous bisphosphonate
treatment

63. Asymptomatic
Patients on iv BP
therapy

64. Patients receiving oral bisphosphonates are at much reduced risk of developing BRONJ given the significantly lower potency of
these medications.
Most cases of BIONJ occurring after 3 years of exposure (except in patients who were also receiving chronic steroid therapy).
• Patients considered “at risk” should be educated the importance of dental hygiene, regular dental evaluations, and
specifically instructed to report any pain, swelling, or exposed bone that would either predict or characterize BIONJ.
• Patients on oral bisphosphonate for less than 3 years have no other risk factors for BIONJ, no alteration or delay in the
planned surgery is typically necessary.
Guidelines for Patients on Oral BPs Therapy-

65. • Patients who have taken an oral bisphosphonate for more than 3 years (or less if exposed to chronic steroid
medication)-
Discontinuation of the oral bisphosphonate for 3 months before oral surgery may reduce the risk.
The bisphosphonate can be restarted once osseous healing has occurred.
The rationale for this approach is based on a study by Bone in which markers for bone remodeling began to increase
within months following withdrawal of oral bisphosphonate medications in osteoporotic women. This suggests that
osteoclastic function was also returning. Measuring surrogate markers of bone resorption may prove useful in monitoring the
level of osteoclast function and bone remodeling capacity, which can then be used to establish a more accurate assessment of
risk in patients receiving bisphosphonates.

66. Patients with established BRONJ
The main goal of therapy for patients with established BRONJ is to maintain or preserve the quality of life while supporting
the oncologic or osteoporotic treatment. This can be achieved by controlling pain and the secondary infection that is common
for most of these patients.
• prevent the extension of existing areas of necrosis and the development of new lesions.
• avoid elective dentoalveolar surgical procedures since these surgical sites are the most likely to result in areas of exposed
necrotic bone.
• Loose segments of bony sequestrum should be removed without exposing uninvolved bone.
• The extraction of grossly mobile or symptomatic teeth within exposed, necrotic bone should be considered since it is
unlikely that the extraction will exacerbate the established necrotic process.

67. The treatment algorithms for this new disease entity are based on a compilation of clinical data and treatment experiences
from several case series and a consensus of expert opinions. Prospective studies evaluating management strategies and
short- and long-term outcomes of therapy are needed.
The initial strategies for treating these patients with exposed bone were similar to those for osteomyelitis or
osteoradionecrosis and were not successful.
Surgical débridement was not uniformly effective in eradicating the necrotic bone or limiting the progression of this process
due to difficulty in obtaining a surgical margin with viable bleeding bone because the entire jawbone has been exposed to
the pharmacologic influence of the bisphosphonate.

69. Fonseca volume 2- DIAGNOSIS AND MANAGEMENT OF BISPHOSPHONATE-RELATED OSTEONECROSIS OF THE JAWS (BRONJ)
Salvatore L. Ruggiero Chapter 27
Stage-specific BRONJ treatment recommendations

70. Flow chart showing a summary of the
treatment for patients in this study.

71. Stage III BIONJ with secondary infection and a cutaneous
fistula in a cancer patient who received Zometa.
Soft tissue loss seen as secondary infection has caused soft
tissue lysis, erythema, and exposed necrotic bone through the
skin.
Intravenous BIONJ treatment and prognosis-

72. Excision of affected skin and flap surgery to replace the soft
tissue was necessary in this advanced case.
Extensive necrotic bone with a line of demarcation
with unaffected bone.

73. Resection specimen identifies the necrotic bone, a pathologic fracture, and margins of unaffected bone.

74. Titanium plate reconstruction of the defect.
A large trapezius myocutaneous flap was necessary to replace the
affected soft tissue component.

75. Healed flap and resolution of Stage III BIONJ.

76. Bisphosphonate-induced osteonecrosis of the
maxilla around dental implants.
When the necrotic bone extends into the sinus floor, the
bony sinus wall or floor must be removed and the
secondarily infected sinus membrane must be completely
removed.

77. Secondarily infected sinus membrane and mucous cysts removed in the
debridement.
Pedicled buccal fat pad advanced into the defect
Resolved BIONJ and healed mucosa.

78. Oral BIONJ is resolvable in almost all cases and responds well to discontinuation of the drug.
The initial CTX value of oral BIONJ is usually lower than the threshold of risk at 150 pg/mL (normal is greater than 350
pg/mL) and is most often below 100 pg/mL.
During the drug holiday of 9 months, the osteoclast precursors in the bone marrow repopulate the osteoclast populations at a
rate dependent on the length of bisphosphonate use and accumulated dose. This results in gradual increase in the CTX value.
When the CTX value increases over 150 pg/mL, about 40% of cases have been observed to spontaneously resolve with either
exfoliation of the exposed bone or resorption of it together with mucosal healing.
Oral BIONJ treatment and prognosis-

79. Exposed bone in a patient who received 4 years of Fosamax
therapy (CTX = 72 pg/mL).
Healed mucosa following spontaneous sequestrectomy 9 months after
beginning a drug holiday (CTX = 212 pg/mL).

80. Bisphosphonate-induced osteonecrosis due to Fosamax
therapy for 5 years (CTX = 55 pg/mL)
Radiographic view of this patient shows a sequestrum and involucrum
developing during a 6-month drug holiday (CTX = 243 pg/mL)
50% have responded to simple office-based debridements with primary mucosal closure.

81. Sequestrum removed in a straightforward office procedure
after the 6-month drug holiday (CTX = 243 pg/mL). Healed BIONJ area.

82. With a continued drug holiday and a CTX = 243
pg/mL, the lone canine tooth was removed and dental
implants were placed.
Restored and functional dental implants in the maxilla and the site of the
previous BIONJ in the mandible due to the drug holiday.
Once the tissue heals, dental implants can be safely placed provided bisphosphonate therapy is not reinitiated.

83. Exposed necrotic bone in the edentulous mandible caused
by 10 years of Fosamax use.
Planned resection and incision design for this Stage III oral
BIONJ.
Only in 10% of oral BIONJ cases required resection, usually due to the long-term use (over 7 years) of an oral
bisphosphonate

84. Exposed mandible prior to resection.
Rigid titanium reconstruction plate placed on the intact
mandible prior to the resection.

85. Resection of the mandible to bleeding bone that
also has residual healthy marrow spaces.
Replacement of the rigid titanium plate
Resolved BIONJ with facial form and jaw function
maintained by the rigid titanium plate.

86. When a CTX test is not considered or is unavailable, a drug holiday of 9 months or greater can be relied on to return
adequate bone healing to the jaws in all oral bisphosphonate cases.

87. Utility of Hyperbaric Oxygen in Treatment of Bisphosphonate-Related Osteonecrosis of the Jaws
John J. Freiberger, MD, MPH*, J Oral Maxillofac Surg 67:96-106, 2009, Suppl 1
Historically, the healing effects of HBO have been attributed to the establishment of beneficial oxygen gradients or the
correction of hypoxia-impaired leukocyte pathogen killing ,recent research has revealed that HBO also generates reactive
oxygen species (ROS) and reactive nitrogen species (RNS) that affect signaling processes critical to wound healing.
• Induces Fibroblast growth.
• Increases Collagen formation.
• Stimulates Angiogenesis.
• Inhibits Aerobic & Anaerobic bacteria
• Inhibit Bacterial toxin formation.
• Increases 10 fold oxygen in Tissue.

88. ‘‘Wilfred-Hall Protocol’’
Marx & Ames 1st Outlined a standard ORN with adjunctive HBO.
Stage I: 30 Dives. If the wound shows no definitive clinical improvement + 10 Dives= 40 .
Failure to heal after 3 months = Stage II.
Stage II: The exposed bone is removed by Alveolar Sequestrectomy + 20 Dives= 60
Failure to heal occurs = Stage III.
Stage III: Pathological #, OCF, CT of resorption to the inferior border Mandible.Maxilla.Zygoma.
30 Dives+ Surgical resection to Bleeding Bone & Bony Reconstruction & Soft tissue +10Dives
If healing fails, additional surgery +10 Dives.

89. Pentoxifyllin &Tocopherol vitamin E –BIONJ
Pentoxifylline is a Methylxanthine derivative that exerts
• An anti-TNF_ effect, increases Erythrocyte Flexibility,
• Dilates blood vessels, Inhibits inflammatory reactions ,
• Inhibits proliferation of Human Dermal Fibroblasts & the Production of extracellular matrix and increases
collagenase activity .
With Tocopherol (vitamin E), which scavenges Reactive oxygen species that were generated during oxidative stress
by protecting cell membranes against peroxidation of lipids, partial inhibition of TGF-_1, and expression of
procollagen genes, so reducing fibrosis.
• These two drugs act synergistically as potent antifibrotic agents.
• Pentoxifyllin dosage-400 mg sustained release twice daily
• Vitamin E 1000 IU for 36 months.

90. • Stimulates osteoclast activity to promote bone resorption and remodeling.
• LLLT-mediated increase in blood flow by angiogenesis and capillary growth as well as an increase in growth factor
release (TGF, PDGF, bFGF, IL6, IL8, IL1a)
• Neocollagen formation
• Anti-bacterial activity particular versus Actinomyces and anaerobes species.
Laser can be used in the conservative surgical treatment of BIONJ patients. The procedure involves the vaporization of
necrotic bone until healthy bone is reached. The minimal penetration of the erbium laser (0.1 mm) guarantees safety and
allows for precise, minimally invasive surgery, inducing a much lower increase in bone temperature than conventional
rotary tools (cold ablation).

91. A total of 78 patients from 17 centres were identified with ONJ. A majority of patients identified with ONJ had used Pamidronate
or Zoledronate (93.6%) intravenously. 94.9% of patients had received BP in the course of treatment for malignancies and a
majority had also received prior chemotherapy or exogenous steroids. 82.1% of patients had received BP for more than 1 year. The
mean time from the introduction of BP to the development of ONJ in 24 patients from our department was 31.8 months.
Conclusions: The most common intraoral manifestation was exposed necrotic jawbone.
Tooth extractions and oral surgical intervention appear to place patients on BP therapy at risk of ONJ, especially after intravenous
BP treatments.
“Bis-phossy jaws”- High and low risk factors for bisphosphonate-induced osteonecrosis of the jaw
Mario H. ABU, Journal of Cranio-Maxillofacial surgery,2008

92. A prospective study was designed to review the surgical management of cases of ONJ that did not respond to conservative
management.
Forty patients, referred with ONJ that did not respond to conservative management, were treated surgically and followed up for
6 months to 4 years. Four patients were taking i.v. BPT as part of their bone cancer management and 16 were taking oral BPT
for osteoporosis.
Surgical procedure: involved antibiotic therapy, surgical debridement of all necrotic bone and tension-free primary closure.
Results: All 40 cases healed uneventfully with no wound breakdown during follow-up.
Surgical management of Bisphosphonate induced osteonecrosis of the jaws,
RA Williamson, IJOMS,2009

93. In most protocols, the affected bone is removed completely and bony edges are rounded off. The defect should be closed by
a multiple layer technique, for example using periosteal split flap, the mylohyoid muscle or the buccal fat pad. The flap
should be well perfused tissue and build a thick scar to seal off the bone from the oral flora .
Pathological fractures still remain challenging. Healing after primary closure of the soft tissue wound and casting via cast-
cap splint has been described to be successful in an osteoporotic patient three years after interruption of oral alendronate
treatment. However, in patients with intravenous BP-treatment, it is unlikely, that the fractured bone has potential to heal.
Rigid internal fixation in connection with multilayer wound closure and cancellous bone augmentation where
applicable seems to be state of the art.
53rd SFSCMFCO Congress 3
Update MRONJ and perspectives of its treatment
4 P.J. Voss Q1, P. Poxleitner, R. Schmelzeisen, A. Stricker, W. Semper-Hogg *, J Stomatol Oral Maxillofac Surg xxx (2017) xxx–xxx

94. • New and innovative treatment strategies comprise treatment with a chair-side harvested platelet rich plasma, platelet
rich fibrin or mesenchymal stem cell concentrate that can be added to the wound before wound closure .
• Chloramines such as Perisolv could help to reduce bacterial load before surgery.

95. Preoperative radiographs: OPG and CBCT (coronal view): osseous lesions with non-healing extraction sockets in the
right Maxilla showing involvement of the maxillary sinus.
Intraoperative intraoral situation. Fistula in the
region of the first molar in the right Maxilla
following tooth extraction. The raising of the
mucoperiostal flap reveals typical signs of
advanced osteonecrosis of the jaw.

96. Standard protocol of surgical wound closure
using multiple layer technique, step 1. Deep
incision, mobilization and quilting of the
vestibular periosteum under the palatal
mucosa with resorbable sutures.
Standard protocol of surgical wound closure
using multiple layer technique, step 2 and 3.
Back stitches using vestibular matrace sutures
to adapt the mucosa. Finally, a running suture
allows a well-vascularized wound closure.

97. CONCLUSION-
BIONJ is a multifactorial disease in patients with primary or metastatic bone malignancy or osteoporosis undergoing
systemic antiresorptive therapy.
Imunomodulators such as steroids or chemotherapy, as well as immunocompromised states from disease such as diabetes,
and antiangiogenics are significant modifiers that may increase disease prevalence or severity when combined with
inflammation/infection or trauma in the presence of antiresorptives.
Understanding pathophysiologic mechanisms of ONJ will help explore targeted treatment interventions to reduce
development and improve management of patients with established disease.

98. REFERENCES-
1. Fonseca volume 2- DIAGNOSIS AND MANAGEMENT OF BISPHOSPHONATE-RELATED OSTEONECROSIS
OF THE JAWS (BRONJ) Salvatore L. Ruggiero Chapter 27
2. Marx-Oral and Maxillofacial Pathology 2012
3. Francesco Saverio De Ponte- Bisphosphonates and osteonecrosis of the jaw

99. Thank you…