The Impact of Bisphosphonate in Dental Practice

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Bertram McDonald
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1 The Impact of Bisphosphonate in Dental Practice Talib A. Najjar,DMD,MDS,PhD Professor OMF Surgery UMDNJ-Uneversity Hospital Newark,NJ,USA BIONJ is a big Problem Now it is tip of the iceberg Exposed, non-healing bone in the oral cavity Phossy-Jaw- Historical Entity Lorinser, 1845: first reported cases Industrial laborers working w/ white phosphorus powder Matchmaking, fireworks factories Missile factories Clinical presentation Nonhealing mucosal wound following extraction Pain Fetid odor Suppuration Necrosis w/ bony sequestra Extra-oral fistulae Miles, Hunter: 20% mortality due to infections Pre-antibiotic era Conservative treatment Selective debridement Minimal mucosal manipulation Topical agents: copper sulfate BRONJ: Historical Context Rare reports prior to : Marx reported 36 patients 2004: Ruggiero et al reported 63 pts (from ) 2005: Migliorati reported 5 cases 2005: Estilo et al reported 13 cases Sept. 2004: Novartis (manufacturer of Aredia & Zometa) altered labeling to include language concerning osteonecrosis of the jaws 2005: FDA issued warning for entire drug class (including oral bisphosphonates) Oral Bisphosphonate On October 1, 2007, FDA announced that it was reviewing safety data that raised concerns about a potential increased risk for atrial fibrillation in patients treated with bisphosphonate drug. An article and an accompanying letter to the editor in the May 3, 2007, issue of The New England Journal of Medicine described increased rates of serious atrial fibrillation in two different studies of women ages 65 to 89 years old with osteoporosis treated with Bisphosph11/12/2008 This information reflects FDA s current analysis of available bisphosphonates, Reclast and Fosamax. FDA Drug Safety Communication: Ongoing safety review of oral bisphosphonates and atypical subtrochanteric femur fractures SafetyCommunication issued by FDA in Bisphosphonate inhibits osteoclastic activity Induces apoptosis in osteoclasts Inhibits differentiation of osteoclast precursor cells May have antiangiogenic properties All of which leads to increased bone density. Prevention and treatment of osteoporosis in postmenopausal women Increase bone mass in men with osteoporosis 1

2 Tx of glucocorticoid-induced osteoporosis Tx of Paget s disease of bone and osteogenesis imperfecta Hypercalcemia of malignancy Bone metastases of solid tumors breast and prostate carcinoma; other solid tumors Osteolytic lesions of multiple myeloma Basic Chemical Composition of Bisphosphonate Pyrophosphate compound (essential for normal cellular functioning) Substitution of Carbon for Oxygen Resistance to hydrolysis Bone matrix accumulation Extremely long half-life Nitrogen-containing side chain Increases potency, toxicity Direct link to BRONJ cases Biologic Action of Bisphosphonates Osteoclastic toxicity Apoptosis Inhibited release of bone induction proteins BMP, ILG1, ILG2 Reduced bone turnover, resorption Reduced serum calcium* Hypermineralization* sclerotic changes in lamina dura of alveolar bone * = goal of medicinal use Current Bisphosphonate 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 Bisphosphonate Pharmacokinetics Etidronate (Didronel) Available in both oral and IV preparations Oral: FDA approved for Paget s disease in 1970 s. Treats the hypertrophic calcifications that occur from bone injury and limit excess bone production. Dose: 5 mg/kg per day IV: approved for use in hypercalcemia of malignancy Dose: 7.5 mg/kg per day for 3 days Risk of osteomalacia w/prolonged therapy do not treat >2 yrs No documented cases of BRONJ Does not contain nitrogen Paget s Diseases Characterizes by: Abnormal bone remodeling Enlarged head and jaw bones Patient frequently change hat, eyeglasses and dentures Cotton-wool appearance in the radiograph Loss of sight and hearing High Alkaline Phosphatase 2

3 Amidronate (Aredia) Available only as IV preparation b/c of poor GI absorption and high freq of GI symptoms Approved for tx of hypercalcemia of malignancy one-time dose of mg Also used for Paget s disease Also used for osteoporosis pt s who are unable to tolerate other bisphosphonates Zolendronate (Zometa) Only available in IV preparation Approved for tx of hypercalcemia of malignancy 4mg IV over no less than 15 mins Alendronate (Fosamax) Available as oral preparation Osteoporosis Treatment dose: 10 mg/day or 70 mg weekly Prevention dose : 5 mg/day or 25 mg weekly Less inhibition of bone mineralization More suitable for long-term administration 17 million Rxs written in 2003 Risedronate (Actonel) Also available as oral preparation Approved for tx of osteoporosis 6 million Rxs written in mg daily and 35 mg weekly Dose for prevention of osteoporosis is same as for treatment Oral Bisphosphonate Effects on Bone Fosamax and Actonel have a half life in bone of 11 years Reclast (zoledronic acid) First FDA approved April 2007 Ibandronate (Boniva) Most recently approved for tx and prevention of osteoporosis 2.5mg daily or 150 mg monthly Bisphosphonate Side Effects Upset stomach Inflammation/erosions of esophagus Fever/flu-like symptoms Slight increased risk for electrolyte disturbance Uveitis Musculoskeletal joint pain And of course BIONJ Manifests as exposed, devitalized bone in the maxillofacial region for 8 weeks There is a prior history or current use of BP No history of radiation therapy to the jaws BIONJ- Clinical Presentation Exposed alveolar bone Open mucosal wound Necrotic bone Spontaneous or Traumatic Extractions, periodontal surgery, apicoectomy, implant placement Infection Purulence, bone pain Orocutaneous fistula Staging of BIONJ Proposed by AAOMS Stage 0: No clinical evidence of necrotic bone, but present with non-specific symptoms or clinical and radiographic findings not attributable to dental or periodontal disease, as Symptoms odontalgiadull, aching bone painsinus pain, which may be associated with inflammation and thickening of the maxillary sinus wallaltered neurosensory function Loosening of teeth periapical-periodontal fistula Radiographic Findings Alveolar bone loss or resorption changes to trabecular pattern-dense woven bone and persistence of unremodeled bone in extraction sockets thickening-obscuring of periodontal ligament inferior alveolar canal narrowing 3

4 Stage 1: Exposed/necrotic bone, asymptomatic, no infection Stage 2: Exposed/necrotic bone, pain, clinical evidence of infection Stage 3: Exposed/necrotic bone, pain, infection, one or more of the following: Pathologic fracture extra-oral fistula osteolysis extending to inferior border Similar Clinical Entities to BIONJ Osteoradionecrosis (ORN): avascular bone necrosis 2 radiation Osteomyelitis (including dry socket:thrombosis of small blood vessels leading to infection within bone marrow Steroid-induced osteonecrosis:more common in long bones exposed bone very rare Retrospective studies with limited sample sizes Marx: Zometa: exposed bone within 6-12 months Aredia: months Estimates of cumulative incidence of BRONJ range from 0.8% to 12% Marx: 5-15% Including Subclinical osteonecrosis Incidence will rise: Increased recognition Increased duration of exposure Increased follow-up Estimated Incidence of BRONJ 2 nd Oral BPs 190 million oral BP prescriptions dispensed worldwide Increased BRONJ development after 3 years of Alendronate usage (Marx) Estimated incidence of BRONJ w/ weekly administration of alendronate: 0.01% to 0.04% After extractions, increased to 0.09% to 0.34% Merck study PROBE study, Kaiser Permanente (Lo, O Ryan) Survey of 13,000 pts using oral BP Prevalence of BRONJ: 0.06% (1:1,700) Estimated Incidence of BRONJ 2 nd Oral BPs Although the incidence of BRONJ among oral bisphosphonate users is lower than users of the intravenous form, it is believed that, in time, the cumulative effects of oral bisphosphonates will become manifest in the population. Why BIONJ effects only in the Jaws Bones? Alveolar crest has high remodeling rate (Dixon et al 1997) 10 times the remodeling of the tibia Greater uptake of Tc 99m in bone scans Occlusal forces compression at root apex and furcations Tension on lamina dura and periodontal ligament Remodeling of lamina dura in response to tension Risk Factors for Development of BRONJ Drug-related factors Potency of BP Zoledronate > pamidronate > oral BPs Duration of therapy Local factors Dentoalveolar surgery Extractions, implants, periapical surgery, periodontal surgery w/ osseous injury 7-fold risk for BRONJ with IV BPs, 5 to 21-fold risk in some studies Local anatomy: lingual tori, mylohyoid ridge, palatal tori Mandible > maxilla (2:1) Concomitant oral disease 7-fold risk for BRONJ with IV BPs Demographic/systemic factors Age: 9% increased risk for every passing decade Multiple myeloma patients treated w/ IV BPs 4

5 Race: Caucasian Cancer diagnosis multiple myeloma > breast cancer > other cancers Osteopenia/osteoporosis diagnosis concurrent w/ cancer diagnosis Additional risk factors: Corticosteroid therapy Diabetes Smoking EtOH Poor oral hygiene Chemotherapeutic drugs Early signs of Bisphosphonate toxicity Radiographs Panoramic, PA films Sclerosis of alveolus, lamina dura Widening of PDL space Tooth mobility Unrelated to alveolar bone loss Deep bone pain with no apparent etiology Risk Assessment of Bisphosphonate Toxicity by Bone Turnover Markers Serum CTX marker Measures bone resorption Assesses Oral BP risk Type I collagen telopeptide assay ELISA/RIA Quest Diagnostics Cleaved at carboxyl end by osteoclast in bone resorption NTX marker cleaved at amine end Requires 1 ml whole blood fasting Treatment Goals Preserve Quality of Life Pain Control Treat 2 infection The goal of treatment is to prevent or alleviate pain, reduce infections, and stabilize the progression of exposed bone Treatment Strategies Patients abut to initiate IV bisphosphonate tx Objective: minimize risk of developing BRONJ Dental prophylaxis, caries control, conservative restorative dentistry Adjustment of denture flanges to minimize mucosal trauma Extraction of nonrestorable teeth Completion of elective dentoalveolar surgery If systemic conditions permit: Delay Bisphosphonate therapy until dental health optimized days after extractions Maintenance of good oral hygiene, dental care Avoid invasive procedures Nonrestorable teeth: Remove crowns Endodontic treatment of remaining roots Avoid placement of implants Asymptomatic patients receiving oral BPs Less than 3 years with no clinical risk factors: Asymptomatic patients receiving IV BPs No alteration or delay in elective surgery Implants permitted Discuss risks Regular recall schedule 5

6 Discuss with prescribing physician re: alternate dosing, drug holidays, BP alternatives Asymptomatic patients receiving oral BPs (continued) Less than 3 years, concomitant steroid use Contact prescribing physician regarding drug holiday for at least 3 months prior to surgery Restarted after osseous healing complete (3 months) More than 3 years, with/without concomitant steroid use Contact prescribing physician rearding drug holiday for 3 months prior to oral surgery Restarted after osseous healing complete The importance of CTX TEST - Morning fasting serum C-Terminal - Telopeptide (CTX) bone turnover - marker - Dx = Osteonecrosis Please report results in pg/ml - Quest Diagnostics - San Juan Capistrano, CA Is a specific marker of bone turnover and therefore healing 2. Is an octapeptide fragment cleaved by the osteoclast during bone resorption 3. It has been used in most all research studies of bisphosphonates presented to the FDA. Level of CTX TEST in different patients Fosamax For 4 Years CTX = 72 pg/ml CTX TEST Fosamax Drug Holiday For 9 Months CTX = 212 pg/ml Note: The recovery from oral bisphosphonates bone turn over suppression as measured by CTX testing is delayed by: 1. Greater that 8 year use 2. Methotrexate 3. Steroids Dental Implants and Oral Bisphosphonates 1. Place implants using reference CTX as clinical guide and/or drug holiday to a CTX of 150 pg/ml or greater 2. Use a drug holiday of 9 months 3. Maintain implants as you would natural teeth or other implants Treatment Strategies Patients with Established Diagnosis of BRONJ Objectives: eliminate pain, control infection, minimize progression/occurrence of necrosis debridement may worsen condition Removal of bone serving as soft tissue irritant, loose bony sequestra Without exposure of uninvolved bone Extraction of teeth within exposed, necrotic bone Avoid elective dentoalveolar surgery Stage III disease Pathologic fractures, refractory cases Preservation of function Airway, speech compromise with large mandible resections 6

Segmental resections, titanium plate reconstruction, external fixation.

BRONJ Increased risk associated w/: Increased potency (nitrogen moiety) Dosing frequency Duration (No recommended duration to be on drug)

long-term with discontinuance of bisphosphonates For patients who will be placed on intravenous bisphosphonates, follow head/neck radiation

7 Segmental resections, titanium plate reconstruction, external fixation. All infections must be cleared first Delay reconstruction up to 3 months Avoid bone grafting CONCLUSION Bisphosphonates are associated with BRONJ Increased risk associated w/: Increased potency (nitrogen moiety) Dosing frequency Duration (No recommended duration to be on drug) Incidence of BRONJ is much lower with oral bisphosphonates than intravenous forms Detrimental effects on bone healing improves over the long-term with discontinuance of bisphosphonates For patients who will be placed on intravenous bisphosphonates, follow head/neck radiation therapy / transplant/immuno-supression protocols. REQUIRE DENTAL EVALUATION and CLEARANCE For patients who will be placed on oral bisphosphonates, strongly advise them of risks and to make sure their oral health is optomized. 7

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Talib A. Najjar, DMD, MDS, PhD Professor Oral & Maxillofacial Surgery Rutgers University

Talib A. Najjar, DMD, MDS, PhD Professor Oral & Maxillofacial Surgery Rutgers University 1 Biochemistry Interaction with Oral & Systemic Diseases Periodontal disease Jaw Bone Necrosis due to Bisphosphonate