Original Article
Antiresorptives and Osteonecrosis of the Jaw

https://doi.org/10.1016/S1532-3382(12)70046-5Get rights and content

Abstract

Osteonecrosis of the jaw (ONJ) is an uncommon condition noted to occur in patients who are receiving osteoclast-targeted antiresorptive therapy. The incidence of ONJ in patients taking oral antiresorptives for the management of osteoporosis is low (approximately 1:100,000), whereas it is higher (∼10%) in patients taking intravenous bisphosphonates for the treatment of metastatic bone diseases. The etiology and pathophysiology of ONJ is unclear. No established preventive or treatment modalities are currently available. Although ONJ is a rare condition, it is imperative for oral care providers to have updated knowledge, as a large number of patients on antiresorptives are seeking oral care. In this comprehensive review, we focus on ONJ and bisphosphonate therapy and dissect the currently available evidence to establish a clinical approach to assess risk, preventive measures, and management of ONJ.

Introduction

Antiresorptives are drugs that suppress bone resorption by targeting osteoclasts. They are used for the management of osteoporosis, osteopenia, metastatic bone cancer, hypercalcemia of malignancy, and other disease conditions in which elevated osteoclastic bone resorption plays a pathogenic role. Bisphosphonates are currently the major drug in this class. In 2010 the clinical use of denosumab, a monoclonal antibody to RANKL (receptor activator for nuclear factor-kappa B ligand), was approved by US Food and Drug Administration for the treatment of postmenopausal osteoporosis and for the prevention of skeletal-related events in patients with metastatic bone cancer. In 2011, denosumab was approved as a treatment to increase bone mass in patients with breast or prostate cancer who develop osteopenia secondary to androgen deprivation or aromatase inhibitor therapies. RANKL is an essential cytokine that induces osteoclasts and therefore the inactivation of RANKL by denosumab potently suppresses osteoclastogenesis, resulting in an inhibition of bone resorption.1, 2 Although both of these antiresorptives target osteoclasts, their mechanisms are distinct. Bisphosphonates adhere to bone mineral following administration. During osteoclastic bone resorption, matrix-bound bisphosphonates are liberated, internalized, and interfere with cytoskeletal organization and ruffled border integrity, resulting in detachment of resorbing osteoclasts from bone surfaces and eventual osteoclast death.3, 4 On the other hand, denosumab restrains osteoclastogenesis by neutralizing RANKL, which is required for osteoclast precursors to differentiate into mature osteoclasts. Thus, bisphosphonates suppress bone resorption by abolishing mature osteoclasts and denosumab does so by hindering osteoclast formation from precursors. Although bisphosphonates and denosumab are different mechanistically in their antiresorptive actions, recent evidence indicates that both drugs are associated with the development of osteonecrosis of the jaw (ONJ).5, 6 The fact that ONJ is associated with both bisphosphonates and denosumab convincingly suggests that osteoclast suppression is central to the pathophysiology of ONJ. It should be noted that other less potent antiresorptives, such as calcitonin and estrogen, have not been reported to be associated with ONJ, hence the level of resorption inhibition likely affects the development of ONJ. In this review, we focus on ONJ in patients on bisphosphonate therapy and dissect the currently available evidence to establish a clinical approach to assess risk, preventive measures, and management of ONJ.

Section snippets

Mechanisms of Action

Bisphosphonates are the most popular antiresorptive agent for the management of metabolic bone disorders in which elevated osteoclastic bone resorption plays a pathogenic role. Bisphosphonates possess a strong affinity for bone mineral.7 Approximately half of the absorbed dose is excreted in urine and the remaining half binds exclusively to bone with a half-life of greater than 10 years.8, 9 Therefore, the therapeutic effects of bisphosphonates last for years. Likewise, adverse effects of

Bisphosphonates in Dentistry

Periodontal disease is an inflammatory disease that involves local alveolar bone loss in which osteoclasts play a major role. As bisphosphonates suppress osteoclastic bone resorption, the impact of oral bisphosphonates on periodontal status has been evaluated in osteoporotic patients.35, 36, 37 Although conclusions were not solid owing to small sample sizes, in general, there was a trend that patients on bisphosphonates had less clinical attachment loss and probing depth compared with those not

Osteonecrosis of the Jaw

ONJ associated with antiresorptive therapy is a great concern for both dental practitioners and patients on bisphosphonates. ONJ is also termed “bisphosphonate-related osteonecrosis of the jaw” (BRONJ). Although most of the reported ONJ cases thus far are associated with N-BPs, ONJ occurs in patients taking denosumab,6, 78, 79 a newer antiresorptive compound that particularly inhibits osteoclasts. Hence, it is now clear that bisphosphonates are not the only antiresorptives to be associated with

Perspective

Although ONJ is rare, it is a serious complication and is often devastating. The etiology and pathophysiology of ONJ are largely unknown and, therefore, no effective treatment is available to cure ONJ. This is partly because of the extremely low incidence of ONJ in patients on oral antiresorptives (approximately 1:100,000). It seems almost impossible to design meaningful clinical trials to elucidate the etiology and pathophysiology of ONJ; however, findings from recent research indicate a

References (144)

  • PJ Kribbs

    Comparison of mandibular bone in normal and osteoporotic women

    J Prosthet Dent

    (1990)
  • PJ Kribbs et al.

    Oral findings in osteoporosis. Part II: Relationship between residual ridge and alveolar bone resorption and generalized skeletal osteopenia

    J Prosthet Dent

    (1983)
  • H Kajiwara et al.

    The bisphosphonate pamidronate on the surface of titanium stimulates bone formation around tibial implants in rats

    Biomaterials

    (2005)
  • M Yoshinari et al.

    Bone response to calcium phosphate-coated and bisphosphonate-immobilized titanium implants

    Biomaterials

    (2002)
  • A Yildiz et al.

    Effect of zoledronic acid on osseointegration of titanium implants: an experimental study in an ovariectomized rabbit model

    J Oral Maxillofac Surg

    (2010)
  • GE Chacon et al.

    Effect of alendronate on endosseous implant integration: an in vivo study in rabbits

    J Oral Maxillofac Surg

    (2006)
  • BT Grant et al.

    Outcomes of placing dental implants in patients taking oral bisphosphonates: a review of 115 cases

    J Oral Maxillofac Surg

    (2008)
  • BM Bell et al.

    Oral bisphosphonates and dental implants: a retrospective study

    J Oral Maxillofac Surg

    (2008)
  • K Fizazi et al.

    Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study

    Lancet

    (2011)
  • F Saad et al.

    Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases

    Ann Oncol

    (2012)
  • SL Ruggiero et al.

    American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws—2009 update

    J Oral Maxillofac Surg

    (2009)
  • F Jadu et al.

    A retrospective study assessing the incidence, risk factors and comorbidities of pamidronate-related necrosis of the jaws in multiple myeloma patients

    Ann Oncol

    (2007)
  • R. Gliklich et al.

    Epidemiology of bisphosphonate-related osteonecrosis of the jaws: the utility of a national registry

    J Oral Maxillofac Surg

    (2009)
  • V Thumbigere-Math et al.

    Bisphosphonate-related osteonecrosis of the jaw: clinical features, risk factors, management, and treatment outcomes of 26 patients

    J Oral Maxillofac Surg

    (2009)
  • CA Migliorati et al.

    Managing the care of patients with bisphosphonate-associated osteonecrosis: an American Academy of Oral Medicine position paper

    J Am Dent Assoc

    (2005)
  • JW Hellstein et al.

    Managing the care of patients receiving antiresorptive therapy for prevention and treatment of osteoporosis: executive summary of recommendations from the American Dental Association Council on Scientific Affairs

    J Am Dent Assoc

    (2011)
  • PJ Herbozo et al.

    Severe spontaneous cases of bisphosphonate-related osteonecrosis of the jaws

    J Oral Maxillofac Surg

    (2007)
  • JV Bagan et al.

    Jaw osteonecrosis associated with bisphosphonates: multiple exposed areas and its relationship to teeth extractions. Study of 20 cases

    Oral Oncol

    (2006)
  • SA Almazrooa et al.

    Bisphosphonate and nonbisphosphonate-associated osteonecrosis of the jaw: a review

    J Am Dent Assoc

    (2009)
  • JJ Body et al.

    A study of the biological receptor activator of nuclear factor-kappaB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer

    Clin Cancer Res

    (2006)
  • DH Henry et al.

    Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma

    J Clin Oncol

    (2011)
  • MJ Rogers

    New insights into the molecular mechanisms of action of bisphosphonates

    Curr Pharm Des

    (2003)
  • BJ Gertz et al.

    Clinical pharmacology of alendronate sodium

    Osteoporos Int

    (1993)
  • SA Khan et al.

    Elimination and biochemical responses to intravenous alendronate in postmenopausal osteoporosis

    J Bone Miner Res

    (1997)
  • AJ Roelofs et al.

    Fluorescent risedronate analogues reveal bisphosphonate uptake by bone marrow monocytes and localization around osteocytes in vivo

    J Bone Miner Res

    (2010)
  • JC Frith et al.

    Clodronate and liposome-encapsulated clodronate are metabolized to a toxic ATP analog, adenosine 5′-(beta, gamma-dichloromethylene) triphosphate, by mammalian cells in vitro

    J Bone Miner Res

    (1997)
  • FP Coxon et al.

    Protein geranylgeranylation is required for osteoclast formation, function, and survival: inhibition by bisphosphonates and GGTI-298

    J Bone Miner Res

    (2000)
  • LJ Melton et al.

    Bone density and fracture risk in men

    J Bone Miner Res

    (1998)
  • LJ Melton et al.

    Perspective. How many women have osteoporosis?

    J Bone Miner Res

    (1992)
  • DB Kimmel

    Mechanism of action, pharmacokinetic and pharmacodynamic profile, and clinical applications of nitrogen-containing bisphosphonates

    J Dent Res

    (2007)
  • SC Abraham et al.

    Alendronate-associated esophageal injury: pathologic and endoscopic features

    Mod Pathol

    (1999)
  • JM Ryan et al.

    Alendronate-induced esophagitis: case report of a recently recognized form of severe esophagitis with esophageal stricture—radiographic features

    Radiology

    (1998)
  • PD Miller et al.

    Safety and efficacy of risedronate in patients with age-related reduced renal function as estimated by the Cockcroft and Gault method: a pooled analysis of nine clinical trials

    J Bone Miner Res

    (2005)
  • JA Jamal et al.

    Alendronate treatment in women with normal to severely impaired renal function: an analysis of the fracture intervention trial

    J Bone Miner Res

    (2007)
  • PD Miller

    Treatment of osteoporosis in chronic kidney disease and end-stage renal disease

    Curr Osteoporos Rep

    (2005)
  • S Adami et al.

    The acute-phase response after bisphosphonate administration

    Calcif Tissue Int

    (1987)
  • N Zojer et al.

    Comparative tolerability of drug therapies for hypercalcaemia of malignancy

    Drug Saf

    (1999)
  • DK Wysowski et al.

    Alendronate and risedronate: reports of severe bone, joint, and muscle pain

    Arch Intern Med

    (2005)
  • D Thiebaud et al.

    An in vitro and in vivo study of cytokines in the acute-phase response associated with bisphosphonates

    Calcif Tissue Int

    (1997)
  • K Thompson et al.

    Activation of gammadelta T cells by bisphosphonates

    Adv Exp Med Biol

    (2010)
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