Introduction •  Bisphosphonates used over past 40 years to treat variety of

diseases •  Osteoporosis •  Pagets’ disease •  Hypercalcaemia of malignancy •  Osteolytic lesions of multiple myeloma •  Bone metastases associated with breast, prostate, lung and

other soft tissue tumours Prevalence

•  Top 100 most prescribed medicines in US (Epstein et al., 2012)

•  30 million presciptions in US •  190 million worldwide (Madrid and Sanz, 2009) •  IV-bisphosphonates, Zolendronate and Pamidronate,

prescribed to over 2.5 million patients worldwide •  Prevalence of osteoporosis – 75 million in US, Europe and

Japan (Gutta and Louis, 2007)

Incidence of Bisphosphonate Related Osteonecrosis of the jaw (BRONJ)

Osteoporosis 4.3% Malignancies 0.9-5.5% Breast cancer 1.2-11% Multiple Myeloma 3.0-21% Prostate cancer 3.0-19% Walter et al., (2012) Borromeo et al., (2011) 0.01-0.04% in patients with osteoporosis on oral BP ↑9 fold following xla 0.88-1.15% in patients with cancer on iv-BP ↑ 6.7-9.1% following xla

Classification of bisphosphonates Bisphosphonates are classified as: 1.  Non-nitrogen containing bisphosphonates (BP) 2.  Nitrogen containing bisphosphonates (N-BP)

Cellular mechanism- Non-nitrogen containing bisphosphonates

•  Formation of non-hydrolysable (AppCp) cytotoxic metabolites (Roelofs et al., 2006, 2010).

•  Intracellular accumulation of these metabolites within osteoclasts inhibits their function.

•  Induction of osteoclast apoptosis (Coxon et al., 2006).

Biochemical mechanism-Nitrogen containing bisphosphonates •  Interfere with specific metabolic pathways

•  Mevalonate biosynthetic pathway that leads to cholesterol and sterol synthesis (Amin et al., 1992).

•  Internalised selectively into osteoclasts during the resorption of drug coated bone (van Beek et al., 1999, 2003)

•  Reduce osteoclastic activity ,bone remodelling and turnover (Fleisch, 2002, Marx et al., 2005, Coxon et al., 2006 and Russell, 2007)

•  Other hypotheses proposed:oral epithelium, fibroblasts, keratinocytes and macrophages, all of which can lead to impaired wound healing. (Scheper et al., 2009, Cozin et al., 2011, Ravosa et al., 2011, Scheller et al., 2011, Kharazmi et al., 2012)

“A REVIEW OF BISPHOSPHONATES—POSSIBLE MODES OF ACTION, ALTERNATIVE DRUGS AND IMPLICATIONS FOR DENTAL IMPLANT TREATMENT”

Dr Elliott Ballantyne B.A. Mod (Physiology), B.A., BDentSc (TCD), MFD RCSI, MSc (Dental Implantology) University of Bristol and The Dental Implant Clinic, Bath, UK.

Risk Factors associated with osteonecrosis Systemic Factors Age Systemic disease (renal failure, anemia, obesity, diabetes) Smoking Concurrent medication Immunosuppressants Chemotherapeutic agents Bisphosphonate related risk factors Potency Duration of treatment Local risk factors Dentoalveolar surgery Oral infection (periodontal and dental abscesses) Poor oral hygiene Intraoral trauma

Aims and Objectives 1.  Highlight the pharmacophysiological modes of

action of both Oral and IV Bisphosphonates. 2.  Discuss the implications of bisphosphonate

therapy on dental implant treatment. 3.  Discuss the alternative drugs to

bisphosphonates. 4.  Discuss the current recommendations and

guidelines for dental implant therapy in patients receiving bisphosphonate therapy based on the available evidence.

5.  Devise an appropriate clinical protocol for the management of bisphosphonate treated patients.

Materials and Methods •  An electronic Medline search was conducted to find relevant articles from both medical and dental literature between 1950

and 31st December 2014, that fulfilled specifically defined inclusion and exclusion criteria. The Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials and Embase were searched for English language studies published between 2000 and 31stDecember 2014.

•  The literature search was completed by cross checking the references cited in all relevant identified publications to ensure that no articles were missed.

Types of study •  The main difficulty with studies on this topic is obtaining a large enough prospective sample to determine the rate of failure.

The statistical requirements for a study to be relevant were well explained in a recent study by Goss et al., (2010). Statistically, if an adverse event occurs at a rate of 1 in 100 and a statistical level of significance of P = .05 is required, then a very large study population is needed, over 10,000 patients, to achieve statistical significance.

•  The heterogeneity of the studies researched, in terms of study design and outcome measure, mean that this review presents a descriptive analysis of relevant papers. A meta-analysis to compare and contrast results from different studies was not possible.

Guidelines for treating your patients on bisphosphonates Patients on iv-bisphosphonates Consult with prescribing physician. Teeth that cannot be restored: endodontic treatment of the remaining roots should be considered. Elective dentoalveolar surgical procedures: present an unnecessary risk and are contraindicated in patients undergoing treatment with iv-bisphosphonates. Oral Bisphosphonates If there is an urgent need for oral surgery while taking oral bisphosphonates, as in the presence of odontogenic abscesses requiring extraction or abscess drainage to decrease pain and to manage infection, the patient should be subjected to the appropriate procedure rather than maintaining the condition of pain and infection. It is necessary to inform the patient of possible risks. Patients receiving oral bisphosphonates less than 3 years It is not necessary to change or delay the oral surgical/implant/periodontal treatment plan. Patients receiving oral bisphosphonates less than 3 years with at least one systemic risk factor (Co-morbidity) It is necessary to contact the physician to discontinue the bisphosphonate (drug holiday) for at least 3 months before the surgical procedure and the resumption should be delayed until 3 months after. Patients receiving oral bisphosphonates greater than 3 years Dependent on the dose and duration of the oral bisphosphonate prescribed. Contact the physician to agree an interruption of the drug for 3 months before to 3 months after the surgical session. (There is no evidence to support or dismiss the effectiveness of a drug holiday. For a standard 70mg dose of Alendronate administered for 7 years, it can take 9 months for bone marrow osteoclasts to become sufficiently active again.) Patients receiving oral bisphosphonates with co-morbidity risk factor Increased risk of osteonecrosis. Consult with prescribing physician.

Operative protocol for patients receiving oral bisphosphonates Perioperative oral antibiotics for 7 days, starting 48 hours before surgical intervention. Oral antibiotics Doxycycline or amoxicillin and clavulanic acid (875 mg/125 mg) every 12 hours or, in cases of penicillin allergy, clindamycin 600 mg every 8 hours. The surgical procedures can be performed under local anaesthesia, sedation or GA. After surgery, all bony edges around the region of surgery should be strictly smoothened by use of a surgical bur. For cases of tooth extraction: Full thickness vestibular mucoperiostal flap Release the periosteum for primary closure Follow up patients at 1, 2, 4, and 12 weeks and 6 and 12 months postsurgery. Antiseptic mouth rinsing, using 0.2% CHX 3 times a day. Removal of the sutures 14 days after surgery. Dental prostheses removed, strictly, for at least 3 weeks postsurgery.

Results •  The initial search of Medline and Embase databases,

regarding bisphosphonates and dental implants, yielded a total of 37 articles which were considered for the study. On further investigation 27 studies met the study inclusion criteria. 10 articles failed to meet the inclusion criteria and so were excluded from the results.

•  A total of 8 retrospective studies and 2 case series studies evaluated the success rate of dental implants in patients with a history of bisphosphonate use. The remaining 17 articles consisted of case series and case reports.

•  2 articles were obtained from the Cochrane Library that were considered to be relevant in terms of interventions for treating osteonecrosis of the jaw bones associated with bisphosphonates.

•  A second search of the Medline and Embase databases, regarding Bisphosphonates (MeSH) in conjunction with the terms; “oral soft tissues”, “oral hard tissues”, “avascular necrosis”, “jaw bone” and “modes/mechanisms of action” yielded a total of 51 articles when limited to English language studies that were human related.

Alternative anti-resorptive medication •  Calcitonin is a peptide hormone secreted by the

C-cells of the thyroid gland, which inhibits bone resorption and lowers blood calcium by directly but transiently inhibiting osteoclast activity. Calcitonin is still sometimes used for pain relief after vertebral fracture.

•  SERMs (Selective Estrogen Receptor Modulators) are substitutes for classical estrogens, but among these only raloxifene and bazedoxifene continue to be used. Other drugs such as strontium salts have been introduced in some but not all countries.

•  Anti-RANK- ligand antibody, denosumab, like bisphosphonates, can reduce the occurrence of fractures at all major skeletal sites, vertebral and non-vertebral sites, including hips.

•  Cathepsin K inhibitor, odanacatib, have been announced and regulatory approval is expected soon.