Bisphosphonate-associated osteonecrosis of the jaw: A key role of inflammation?☆
Introduction
Postmenopausal osteoporosis, Paget's disease, and metastatic bone diseases are characterized by high bone turnover. One of the most efficient ways to treat these affections is the use of bisphosphonates. Among them nitrogen-containing bisphosphonates (NBPs) are the most potent in inhibiting bone resorption [1]. Osteonecrosis of the jaw (ONJ) associated with NBPs therapy is a recently described detrimental effect first reported in 2003 [2]. ONJ is characterized by an area of exposed bone in the maxillofacial region that does not heal within 8 weeks, in a patient who has no metastasis or radiation therapy in the craniofacial region [3]. High repeated doses of NBPs administered intravenously to cancer patients, are most frequently associated with ONJ [4], [5], [6]. In contrast, patients receiving oral NBPs for osteoporosis are less prone to ONJ [7].
Various mechanisms of NBP-associated ONJ have been proposed. It is generally admitted that this adverse effect targets the jaws because they concentrate NBPs owing to their high bone turnover compared with other anatomical sites [8], and bisphosphonate toxicity on osteoclasts [9]. It has also been proposed that NBPs may have an antiangiogenic effect, reducing blood flow and thus inducing bone cell necrosis and apoptosis [10], [11]. One alternative explanation is an “outside-in” process in which mucosal damage provides oral bacteria with access to the underlying bone, leading to bone infection and necrosis [12]. NBP soft tissue toxicity would thus be the trigger leading to necrosis of the mucosa and bone [13], [14], [15]. Genetic variations may also constitute a risk factor; it was recently shown that ONJ is associated with gene polymorphisms in multiple myeloma patients [16], [17]. Moreover, the primary disease is probably a predisposing factor as frequency of ONJ is 2 fold higher in multiple myeloma than in breast cancers despite similar NBPs treatments [6]. It is likely that ONJ results from a conjunction of environmental, metabolic and genetic factors. The role of NBPs in the process was suggested in dogs receiving clinically relevant daily oral alendronate treatment for 3 years that developed mandible bone matrix necrosis without oral exposure [18].
As there is currently no consensus on its underlying mechanism, ONJ task forces have called for more clinical and basic research [3], [7], [19], [20]. The aim of the present study was to examine clinical and histopathological features of patients with ONJ in an attempt to better understand the pathogenesis of this disorder.
Section snippets
Patients
Thirty bisphosphonate-treated patients with persistent oral bone exposure, referred by dental practitioners or oncologists to the Department of Stomatology and Oral Surgery of the University Hospitals of Geneva (Switzerland), were enrolled in this study. The patients were anonymously included in the study that complied with the Declaration of Helsinki. Each patient's detailed medical and dental histories were analyzed. Criteria for diagnosis of bisphosphonate-related osteonecrosis of the jaw,
Characteristics of the patients (Tables 1 and 2)
The distribution of the patients according to the initial pathology and potential co-morbidity factors is shown in Table 1. The cancer patients had previously received various cancer treatments but no maxillofacial radiation therapy. The female:male sex ratio was 2:1. The mean age was 69.9 ± 2.4 years (females: 68.9 ± 2.9; males: 71.3 ± 4.8). The control patients (4 women and 1 man) were treated for osteoporosis. The mean age was 73.8 ± 2.6 years (females: 72.2 ± 2.7; male: 80); among these patients 1
Discussion
ONJ has recently emerged as a serious potential adverse effect of NBP therapy. For the first time, we present data pointing to an association with local inflammation. We also propose that bone necrosis and exposure are preceded by early asymptomatic and infectious-free bone involvement.
The first noteworthy result of this study is the presence in the perinecrotic bone of bone marrow inflammation whose severity is associated with the clinical extent of ONJ. The higher bone marrow inflammation the
Acknowledgments
The authors thank Annie Llorens (laboratory technician) and the practitioners for their kind assistance.
References (51)
Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic
J. Oral Maxillofac. Surg.
(2003)- et al.
Osteonecrosis of the jaw and bisphosphonate treatment for osteoporosis
Bone
(2008) - et al.
Is bisphosphonate-associated osteonecrosis of the jaw caused by soft tissue toxicity?
Bone
(2007) - et al.
Inhibition of oral mucosal cell wound healing by bisphosphonates
J. Oral Maxillofac. Surg.
(2008) - et al.
Bisphosphonate-related osteonecrosis of the jaw is associated with polymorphisms of the cytochrome P450 CYP2C8 in multiple myeloma: a genome-wide single nucleotide polymorphism analysis
Blood
(2008) - et al.
Mandible matrix necrosis in beagle dogs after 3 years of daily oral bisphosphonate treatment
J. Oral Maxillofac. Surg.
(2008) - et al.
Dissociation of the pro-apoptotic effects of bisphosphonates on osteoclasts from their anti-apoptotic effects on osteoblasts/osteocytes with novel analogs
Bone
(2006) - et al.
Risedronate and alendronate suppress osteocyte apoptosis following cyclic fatigue loading
Bone
(2007) - et al.
Calcitonin receptor antibodies in the identification of osteoclasts
Bone
(1999) - et al.
Visualizing mineral binding and uptake of bisphosphonate by osteoclasts and non-resorbing cells
Bone
(2008)
Effects of suppressed bone turnover by bisphosphonates on microdamage accumulation and biochemical properties in clinically relevant skeletal sites in beagles
Bone
Alterations in canine vertebral bone turnover, microdamage accumulation, and biochemical properties following 1-year treatment with clinical treatment doses of risedronate or alendronate
Bone
Histidine decarboxylase-stimulating and inflammatory effects of alendronate in mice: Involvement of mevalonate pathway, TNFα, macrophages and T-cells
Int. Immunopharmacol.
Nonexposed bisphosphonate-related osteonecrosis of the jaws: another clinical variant?
J. Oral Maxillofac. Surg.
Sinus tracts: an early sign of bisphosphonate-associated osteonecrosis of the jaws?
J. Oral Maxillofac. Surg.
Pathophysiology, risk factor and management of bisphosphonate-associated osteonecrosis of the jaw: is there a diverse relationship of amino- and non-aminobisphosphonates?
Crit. Rev. Oncol. Hematol.
Bisphosphonate-associated osteonecrosis: a long-term complication of bisphosphonate treatment
Lancet Oncol.
Incidence of osteonecrosis of the jaw in women with postmenopausal osteoporosis in the health outcomes and reduced incidence with zoledronic acid once yearly pivotal fracture trial
JADA
Cellular and molecular mechanisms of action of bisphosphonates
Cancer
Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the american society for bone and mineral research
J. Bone Miner. Res.
Osteonecrosis of the jaw and bisphophonates
N. Engl. J. Med.
Osteonecrosis of the jaw in cancer after treatment with bisphophonates: incidence and risk factors
J. Clin. Oncol.
Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates
J. Bone Miner. Res.
Alveolar bone remodelling in the rat: normal status and effects of PTX and PTH on remodelling sequence and the osteoclastic pool
Calcif. Tissue Res.
The pharmacology of bisphosphonates and new insights into their mechanisms of action
J. Bone Miner. Res.
Cited by (184)
A multifunctional composite hydrogel promotes treatment of bisphosphonate-related osteonecrosis of the jaws
2023, Applied Materials TodayThe effect of drug holiday on preventing medication-related osteonecrosis of the jaw in osteoporotic rat model
2023, Journal of Orthopaedic TranslationHigh through-put sequencing analysis of changes in oral flora in rats before and after zoledronate administration
2022, British Journal of Oral and Maxillofacial SurgeryRisk factors for medication-related osteonecrosis of the jaw and salivary IL-6 IN cancer patients
2022, Brazilian Journal of Otorhinolaryngology
- ☆
Source of support: This work was supported in part by the Société Francophone de Médecine Buccale et Chirurgie Buccale.