Mineralized Tissue and Salivary Gland Physiology Program
Center for Integrative Biology and Infectious Diseases
Epidemiology Research Program
Center for Clinical Research
OBJECTIVE:
The goal of this initiative is to stimulate research to determine the pathophysiology and epidemiology of osteonecrosis of the jaw (ONJ), a morbid condition that is associated with bisphosphonate use. This initiative is intended to encourage investigations to: 1) define quantitative diagnostic criteria for ONJ, 2) conduct prospective epidemiological studies to document the prevalence, incidence and risk factors for ONJ including, but not limited to, possible risk factors such as concomitant corticosteroid therapy and chemotherapy, dental and oral surgical procedures, poor oral health, and dose, duration and type of bisphosphonate use, 3) characterize the relationship between bisphosphonate use and ONJ in animal models, 4) investigate the genetic, molecular and cellular basis of jaw-specific impaired bone healing in the presence of bisphosphonates, and 5) study the pharmacogenetics of bisphosphonates underlying ONJ. The knowledge gained from these studies will elucidate the pathophysiological mechanisms, and identify the prevalence, incidence and risk factors for ONJ associated with bisphosphonate drug therapy. This knowledge could also serve as the basis for the prediction, prevention, diagnosis, and treatment of this condition.
BACKGROUND:
The bisphosphonates are a class of drugs that inhibit the activities and functions of osteoclasts (bone resorbing cells) and perturb the differentiation of osteoblasts (bone forming cells). Intravenous bisphosphonates are primarily used to treat bone erosion and hypercalcemia associated with bone metastasis, Paget’s disease and multiple myeloma. Oral bisphosphonates are used to prevent bone loss and are prescribed for patients with osteoporosis or osteopenia. In 2003, the first report surfaced in the literature that suggests an association of ONJ with bisphosphonate use. Since then, several other reports have come to light strengthening this association. Whether bisphosphonates are causal to the development of ONJ remains to be determined. Most incidences are related to intravenous bisphosphonate use in cancer patients, but several cases are associated with oral bisphosphonates as well. Patients with ONJ present with painful, exposed and necrotic bone, which may occur following dental procedures or spontaneously, and involving predominantly the mandible. These lesions are non-healing or slow to heal, and often complicated by secondary infection. Therefore, this is a significant clinical problem of potentially broad health impact, yet with complete lack of etiological and sufficiently powered epidemiological studies.
Bisphosphonates have been in use for almost 30 years. During this time, this class of compounds has significantly expanded, with the newest compounds three orders of magnitude more potent than the original ones in in vitro antiresorption assays. Bisphosphonates are synthetic analogs of cellular inorganic pyrophosphates with a P-C-P backbone structure. The two variable sidechains on the central carbon atom confer the compound’s binding affinity to bone and antiresorptive properties, respectively. Therefore, progressive chemical modifications to these sidechains resulted in a series of compounds with increasing binding affinity to bone and antiresorptive potency. The first generation of bisphosphonates such as etidronate, tiludronate and clodronate was non-nitrogen containing. These compounds exert their action by being incorporated into osteoclasts and forming non-hydrolysable analogs of ATP, which then cause metabolic starvation and consequential apoptosis. The next generation of bisphosphonates was nitrogen-containing; some such as alendronate and pamidronate contain the primary amine moiety and others such as risedronate, zoledronate and ibandronate contain nitrogen as tertiary amines. These bisphosphonates inhibit the activity of the enzyme farnesyl diphosphate synthase of the mevalonate pathway, which in turn prevents proper post-translational modification of small GTPases cell signaling molecules in osteoclasts. In addition, evidence suggests that bisphosphonates modulate osteoblast formation and differentiation, thereby indirectly perturbing the osteoclasts. Once incorporated into bone, bisphosphonates have long term bioavailability, some for many years. Therefore, the benefits as well as risks associated with bisphosphonate use could be prolonged.
The pathophysiological mechanisms underlying ONJ are unknown although several cellular processes when altered have been implicated in contributing to the condition. For example, the resorptive power of osteoclasts is essential in bone remodeling. Although bisphosphonates inhibit bone loss, they can also inhibit normal physiological bone remodeling and turnover to the extent that local microdamage of bone architecture due to mechanical loading during chewing, or local bone defects due to tooth extraction, cannot be effectively repaired. Another possibility is that bisphosphonates, some of which demonstrate antiangiogenic properties, may cause avascular necrosis of the bone. Finally, the data trends indicate that not all bisphosphonate users will eventually develop ONJ, suggesting that individual genetic variations in drug metabolism or skeletal homeostasis may confer susceptibility or resistance to developing ONJ. Several risk factors for the development of ONJ have been implicated. These include concomitant corticosteroid therapy and chemotherapy, dental procedures such as tooth extraction, poor oral health, and dose, duration and type of bisphosphonate use.
The exact incidence of bisphosphonate-associated ONJ is unknown but ranges from 0.03% to 10.5% in published reports. This is in part due to the lack of recognition of the condition and under-reporting, and lack of well characterized sufficiently powered cohorts for epidemiological studies. However, collectively, there is an extremely low incidence of ONJ for patients receiving bisphosphonate treatment for less than 12 months, suggesting that the cumulative effects of dose and time contribute to the manifestation of this adverse event.
Currently, there are no effective treatments for ONJ. Patients may be treated non-invasively with antibiotics and chlorhexidine mouth rinses to limit the extent of the damage. Surgical intervention such as local debridement or radical resection of necrotic bone often exacerbates the condition. Discontinuation of bisphosphonate use is not an effective remedy as these compounds have long resident time in the bone.
Although a causal relationship between bisphosphonates and ONJ has not been established, and other risk and comorbid factors for ONJ exist, this is clearly a new and emerging medical and dental concern. There is an urgent need to fill a significant knowledge gap in characterizing the condition, identifying the root cause, and determining individual susceptibility for the prevention and intervention of bisphosphonate-associated ONJ. This initiative will accelerate discoveries so that we can better predict who may benefit from bisphosphonate treatment without accompanying risk of ONJ, who may be prone to adverse events, and how to overcome bisphosphonate-associated ONJ. Knowledge gained from these studies may pave the way for personalized recommendations for bisphosphonate therapy, and strategies for the prevention and intervention of bisphosphonate-associated ONJ, while also managing bone cancer pain or osteoporotic bone loss.
RESEARCH TOPICS:
Human subject research, as well as the use of appropriate animal models, is acceptable. Examples of research topics that would fill the knowledge gap include but are not limited to:
Clarification of the direct and indirect effects of bisphosphonates on oral bone homeostasis and healing
Determination of the bioavailability of bisphosphonates in oral bones
Determination of genetic variations that contribute to the development of ONJ
Characterization of the molecular mechanisms of action of bisphosphonates leading to the development of ONJ
Characterization of the cellular basis of ONJ
Characterization of the combinatorial actions of bisphosphonates and other pharmacological or local bone active factors
Characterization of factors that protect against the development of ONJ
Definition and standardization of diagnostic criteria for ONJ
Clarification of the onset and time course of developing ONJ in patients
Clarification of the prevalence, incidence and severity of ONJ associated with various bisphosphonates in patient subgroups
Documentation of risk factors and their significance for the development of ONJ
Development of new approaches for the prevention and management of ONJ in bisphosphonate users
CURRENT PORTFOLIO OVERVIEW:
The NIDCR is currently not supporting any projects related to bisphosphonate-associated osteonecrosis of the jaw, however, the NIDCR plans to support a case-control and a cohort study of osteonecrosis in the three NIDCR practice-based research networks of general dental practitioners.
COLLABORATIVE ACTIVITIES:
The objectives and content of this Concept Clearance are consistent with the interests of the NIAMS, NIDDK and NIA regarding skeletal tissue research. NCI has shared interest regarding complications from the treatment of bone metastasis with bisphosphonates in certain cancer patients. These Institutes may collaborate in this initiative.
FUNDING MECHANISMS:
This initiative will utilize the R01, R21 and R03 mechanisms.