Vivek Thumbigere‐Math

OBJECTIVE: To evaluate the frequency, risk factors, and clinical presentation of bisphosphonate (BP)-related osteonecrosis of the jaw (BRONJ). STUDY DESIGN: We performed a retrospective analysis of 576 patients with cancer treated with intravenous pamidronate and/or zoledronate between January, 2003 and December, 2007 at the University of Minnesota Masonic Cancer Center and Park Nicollet Institute. RESULTS: Eighteen of 576 identified patients (3.1%) developed BRONJ including 8 of 190 patients (4.2%) with breast cancer, 6 of 83 patients (7.2%) with multiple myeloma, 2 of 84 patients (2.4%) with prostate cancer, 1 of 76 patients (1.3%) with lung cancer, 1 of 52 patients (1.9%) with renal cell carcinoma, and in none of the 73 patients with other malignancies. Ten patients (59%) developed BRONJ after tooth extraction, whereas 7 (41%) developed it spontaneously (missing data for 1 patient). The mean number of BP infusions (38.1 ± 19.06 infusions vs. 10.5 ± 12.81 infusions; P<0.001) and duration of BP treatment (44.3 ± 24.34 mo vs. 14.6 ± 18.09 mo; P<0.001) were significantly higher in patients with BRONJ compared with patients without BRONJ. Multivariate Cox proportional hazards regression analysis showed that diabetes [hazard ratio (HR)=3.40; 95% confidence interval (CI), 1.14-10.11; P=0.028], hypothyroidism (HR=3.59; 95% CI, 1.31-9.83; P=0.013), smoking (HR=3.44; 95% CI, 1.28-9.26; P=0.015), and higher number of zoledronate infusions (HR=1.07; 95% CI, 1.03-1.11; P=0.001) significantly increased the risk of developing BRONJ. CONCLUSIONS: Increased cumulative doses and long-term BP treatment are the most important risk factors for BRONJ development. Type of BP, diabetes, hypothyroidism, smoking, and prior dental extractions may play a role in BRONJ development.

BACKGROUND: Previous case reports and animal studies suggest that periodontitis is associated with bisphosphonate-related osteonecrosis of the jaw (BRONJ). This case-control study is conducted to evaluate the association between clinical and radiographic measures of periodontal disease and BRONJ. METHODS: Twenty-five patients with BRONJ were matched with 48 controls. Trained examiners measured probing depth, clinical attachment level (CAL), and bleeding on probing on all teeth except third molars and gingival and plaque indices on six index teeth. Alveolar bone height was measured from orthopantomograms. Most patients with BRONJ were using antibiotics (48%) or a chlorhexidine mouthrinse (84%) at enrollment. Adjusted comparisons of patients with BRONJ versus controls used multiple linear regression. RESULTS: The average number of bisphosphonate (BP) infusions was significantly higher in patients with BRONJ compared with controls (38.4 versus 18.8, P = 0.0001). In unadjusted analyses, patients with BRONJ had more missing teeth (7.8 versus 3.1, P = 0.002) and higher average CAL (2.18 versus 1.56 mm, P = 0.047) and percentage of sites with CAL ≥3 mm (39.0 versus 23.3, P = 0.039) than controls. Also, patients with BRONJ had lower average bone height (as a fraction of tooth length, 0.59 versus 0.62, P = 0.004) and more teeth with bone height less than half of tooth length (20% versus 6%, P = 0.001). These differences remained significant after adjusting for age, sex, smoking, and number of BP infusions. CONCLUSIONS: BRONJ patients have fewer teeth, greater CAL, and less alveolar bone support compared with controls after adjusting for number of BP infusions. Group differences in antibiotics and chlorhexidine rinse usage may have masked differences in the other clinical measures.

Mineralization of bones and teeth is tightly regulated by levels of extracellular inorganic phosphate (P i ) and pyrophosphate (PP i ). Three regulators that control pericellular concentrations of P i and PP i include tissue-nonspecific alkaline phosphatase (TNAP), progressive ankylosis protein (ANK), and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). Inactivation of these factors results in mineralization disorders affecting teeth and their supporting structures. This study for the first time analyzed the effect of decreased PP i on dental development in individuals with generalized arterial calcification of infancy (GACI) due to loss-of-function mutations in the ENPP1 gene. Four of the 5 subjects reported a history of infraocclusion, overretained primary teeth, ankylosis, and/or slow orthodontic tooth movement, suggesting altered mineral metabolism contributing to disrupted tooth movement and exfoliation. All subjects had radiographic evidence of unusually protruding cervical root morphology in primary and/or secondary dentitions. High-resolution micro–computed tomography (micro-CT) analyses of extracted primary teeth from 3 GACI subjects revealed 4-fold increased cervical cementum thickness ( P = 0.00007) and a 23% increase in cementum density ( P = 0.009) compared to age-matched healthy control teeth. There were no differences in enamel and dentin densities between GACI and control teeth. Histology revealed dramatically expanded cervical cementum in GACI teeth, including cementocyte-like cells and unusual patterns of cementum resorption and repair. Micro-CT analysis of Enpp1 mutant mouse molars revealed 4-fold increased acellular cementum thickness ( P = 0.002) and 5-fold increased cementum volume ( P = 0.002), with no changes in enamel or dentin. Immunohistochemistry identified elevated ENPP1 expression in cementoblasts of human and mouse control teeth. Collectively, these findings reveal a novel dental phenotype in GACI and identify ENPP1 genetic mutations associated with hypercementosis. The sensitivity of cementum to reduced PP i levels in both human and mouse teeth establishes this as a well-conserved and fundamental biological process directing cementogenesis across species (ClinicalTrials.gov NCT00369421).

According to the American Dental Association Survey of Dental Services Rendered (published in 2007), 15 million root canal treatment procedures are performed annually. Endodontic therapy relies mainly on biomechanical preparation, chemical irrigation and intracanal medicaments which play an important role in eliminating bacteria in the root canal. Furthermore, adequate obturation is essential to confine any residual bacteria within the root canal and deprive them of nutrients. However, numerous studies have shown that complete elimination of bacteria is not achieved due to the complex anatomy of the root canal system. There are several conventional antibiotic materials available in the market for endodontic use. However, the majority of these antibiotics and antiseptics provide short-term antibacterial effects, and they impose a risk of developing antibacterial resistance. The root canal is a dynamic environment, and antibacterial and antibiofilm materials with long-term effects and nonspecific mechanisms of action are highly desirable in such environments. In addition, the application of acidic solutions to the root canal wall can alter the dentin structure, resulting in a weaker and more brittle dentin. Root canal sealers with bioactive properties come in direct contact with the dentin wall and can play a positive role in bacterial elimination and strengthening of the root structure. The new generation of nanostructured, bioactive, antibacterial and remineralizing additives into polymeric resin-based root canal sealers are discussed in this review. The effects of these novel bioactive additives on the physical and sealing properties, as well as their biocompatibility, are all important factors that are presented in this article.