Genomewide pharmacogenetics of bisphosphonate-induced osteonecrosis of the jaw: the role of RBMS3.

UNLABELLED: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a serious adverse drug reaction. We conducted a genomewide association study to search for genetic variants with a large effect size that increase the risk for BRONJ. METHODS: We ascertained BRONJ cases according to the diagnostic criteria of the American Association of Oral and Maxillofacial Surgeons. We genotyped cases and a set of treatment-matched controls using Illumina Human Omni Express 12v1 chip (733,202 markers). To maximize the power of the study, we expanded the initial control set by including population and treatment-tolerant controls from publicly available sources. Imputation at the whole-genome level was performed to increase the number of single nucleotide polymorphisms (SNPs) investigated. Tests of association were carried out by logistic regression, adjusting for population structure. We also examined a list of candidate genes comprising genes potentially involved in the pathogenesis of BRONJ and genes related to drug absorption, distribution, metabolism, and excretion. RESULTS: Based on principal component analysis, we initially analyzed 30 white cases and 17 treatment-tolerant controls. We subsequently expanded the control set to include 60 genetically matched controls per case. Association testing identified a significant marker in the RBMS3 gene, rs17024608 (p-value < 7 × 10(-8)); individuals positive for the SNP were 5.8× more likely to develop BRONJ (odds ratio, 5.8; 95% confidence interval, 3.1-11.1). Candidate gene analysis further identified SNPs in IGFBP7 and ABCC4 as potentially implicated in BRONJ risk. CONCLUSION: Our findings suggest that genetic susceptibility plays a role in the pathophysiology of BRONJ, with RBMS3 having a significant effect in the risk.

Antiretroviral prophylaxis and the risk of cleft lip and palate: preliminary signal detection in the food and drug administration's adverse events reporting system database.

OBJECTIVE: Antiretroviral prophylaxis has been found to be effective in preventing vertical HIV transmission to the offspring of infected mothers. Because medicine and the art of public health require benefits to outweigh any plausible risks, our study aimed to explore and quantify preliminary associations between antiretroviral medications and clefting. METHODS: We analyzed 5 years of available data from the Food and Drug Administration's Adverse Events Reporting System (Medwatch program) and calculated reporting odds ratios (RORs) and their associated 95% confidence intervals (CIs). RESULTS: The medications with the highest effects were efavirenz with an ROR of 196 (95% CI, 86 to 447), lamivudine with an ROR of 60.2 (95% CI, 14.25 to 148), the combination abacavir sulfate/lamivudine/zidovudine with an ROR of 59.3, and nelfinavir with and ROR of 50.5, followed by nevirapine, lopinavir/ritonavir, and lamivudine/zidovudine. CONCLUSION: Given the multifactorial etiology of cleft lip and palate, further studies are needed to assess the relative safety of antiretroviral prophylaxis and the specific conditions or potential synergies that might lead to the development of this defect.

Bisphosphonates and time to osteonecrosis development.

Bisphosphonate-associated osteonecrosis of the jaw (BONJ) is a complication of long-term bisphosphonate (BP) use. Given the beneficial effects of BP on bone quality in patients with cancer or osteoporosis, it is of great importance to understand the risk as it relates to time to event or cumulative dose until the onset of disease. Because there is no information on the lowest toxic dose from clinical trials, here we report on a review of 71 case series published since 2003. We calculated the weighted mean time to event, as well as the minimum reported time and dose for zoledronate, pamidronate, and oral bisphosphonates. The mean time to BONJ after zoledronate treatment was calculated at 1.8 years and the minimum was 10 months; after pamidronate, the mean time was 2.8 years and the minimum was 1.5 years; and after oral BP therapy, the mean time was 4.6 years and the minimum was 3 years. Zoledronic acid seems to be the most potent among the nitrogen-containing BPs. Factors that seem to affect BONJ and time to event were invasive dental procedures and other comorbid factors such as advanced age, rheumatoid arthritis, diabetes, use of corticosteroids, vitamin D deficiency, and more. Understanding the pathophysiology of the disease requires further research.

Bisphosphonate use and the risk of adverse jaw outcomes: a medical claims study of 714,217 people.

BACKGROUND: While osteonecrosis of the jaw (ONJ) has been associated with the prolonged use of bisphosphonates (BPs), there is limited information about the risk of ONJ among users of oral BPs or about the magnitude of the risk among users of intravenous (IV) BPs. METHODS: The authors studied medical claims data from 714,217 people with osteoporosis or cancer to identify diagnostic codes or procedure codes for three outcomes: inflammatory conditions of the jaws, including osteonecrosis; major jaw surgery necessitated by necrotic or inflammatory indications; and jaw surgeries necessitated by a malignant process. The authors calculated stratified odds ratios and 95 percent confidence intervals. RESULTS: The results indicate that oral administration of BPs decreases the risk of adverse bone outcomes. In contrast, IV administration strongly and significantly increases the risk (P < .05) of adverse jaw outcomes or surgery. Across both osteoporosis and cancer, patients receiving IV BPs had a fourfold increased risk of having inflammatory jaw conditions and a greater than sixfold increased risk of having undergone major surgical resection in the jaw. CONCLUSIONS: Mode of bisphosphonate use results in different risk profiles for adverse jaw outcomes. While the authors documented an increased risk of inflammatory conditions and surgical procedures of the jaw for users of IV BPs, they did not find these observed increases for users of oral BPs. CLINICAL IMPLICATIONS: Physicians and dentists must be aware of the higher frequency of adverse jaw effects in patients receiving IV BPs, especially osteonecrosis of the jaw. While the authors' results have internal consistency, more clinical studies are needed to replicate and clarify the observed associations over long follow-up periods.

Insulin-like growth factor II receptor gene-167 genotype increases the risk of oral squamous cell carcinoma in humans.

Our purpose was to evaluate inherited short tandem repeat polymorphisms of the insulin-like growth factor II receptor gene (IGF2R) in oral cancer risk. The 197 individuals that consented to participate in a hospital-based, case-control study were interviewed with a structured questionnaire and provided blood and saliva. DNA was extracted for genotyping using a PCR-based method. Odds ratios were calculated using multivariate logistic regression. Subjects carrying the heterozygous 167-bp IGF2R genotype had a 2.7-fold higher risk of oral cancer compared with subjects with other genotypes (odds ratio = 2.7, 95% confidence interval: 1.16-6.48), controlling for major confounders. Our results suggest that genetic variation of IGF2R may influence significantly the risk of oral cancer.

Oral cancer treatment costs in Greece and the effect of advanced disease.

BACKGROUND: The main purpose of the study was to quantify the direct costs of oral cancer treatment to the healthcare system of Greece. Another aim was to identify factors that affect costs and potential cost reduction items. More specifically, we examined the relationship between stage of disease, modality of treatment and total direct costs. METHODS: The medical records and clinic files of the Oral and Maxillofacial Clinic of the Athens General Hospital "Genimatas" were abstracted to investigate clinical treatment characteristics, including length of hospitalization, modes of treatment, stage of disease etc. Records of 95 patients with oral squamous cell carcinoma (OSSC), with at least six months of follow-up, were examined. The clinical data was then used to calculate actual direct costs, based on 2001 market values. RESULTS: The mean total direct costs for OSSC treatment estimated at euro 8,450 or approximately US$ 7,450. Costs depended on the stage of the disease, with significant increases in stages III and IV, as compared with stages I and II (p < 0.05). Multi-modality treatment applied mainly to patients in stages III and IV was the factor that affected the cost. Disease stage was also associated with the total duration of hospitalization (p < 0.05). CONCLUSIONS: The clinical management of advanced oral cancer is strongly associated with higher costs. Although the ideal would be to prevent cancer, the combination of high-risk screening, early diagnosis and early treatment seems the most efficient way to reduce costs, and most importantly, prolong life.

Adverse drug and device reactions in the oral cavity: surveillance and reporting.

BACKGROUND: According to the U.S. Centers for Disease Control and Prevention, 48 percent of Americans (roughly 144 million people) used at least one prescribed medication in the preceding month; 11 percent used five or more. The authors describe the U.S. Food and Drug Administration's (FDA's) MedWatch program, the safety surveillance system for drugs and devices in the United States, and the dentist's role with regard to voluntary reporting of adverse effects (AEs). They also identify the most frequent AEs in the oral cavity as reported in the FDA Adverse Event Reporting System (FAERS). METHODS: The authors reviewed the literature regarding MedWatch, and they mined data in the FAERS public database for the 100 most commonly prescribed medications and their associated AEs. RESULTS: Pharyngitis was the most common AE. Cough, dysgeusia and dysphagia also were common. CONCLUSION: The MedWatch program and its related databases contain useful information about AEs of pharmaceuticals and devices manifested in the oral cavity. Increased participation in the reporting of suspected adverse reactions will improve the national surveillance system and ultimately will protect patients' safety. PRACTICAL IMPLICATIONS: As pharmaceutical consumption increases exponentially for a growing segment of the population, and as innovation in dental technology and devices flourishes, dentists have a distinct role in safeguarding patients' well-being. Promptly reporting AEs in the oral cavity improves quality of care and protects patients' well-being.

Interaction between a single nucleotide polymorphism in the alcohol dehydrogenase 3 gene, alcohol consumption and oral cancer risk.

We investigated effects on oral cancer (OC) risk of an interaction between a single nucleotide polymorphism (SNP) in the alcohol dehydrogenase 3 (ADH3) gene and alcohol consumption levels using a hospital-based study of 93 cases and 99 controls conducted in Athens, Greece. This SNP affects ethanol metabolism in vitro and appeared to interact with alcohol consumption in a previous OC study. We also evaluated a SNP in CYP2E1, another gene involved in ethanol metabolism, reported to be associated with OC risk in a European population. Data on genotypes and risk factors obtained from interviews were analyzed using multivariate logistic regression, accounting for potential confounders. No overall (marginal) association was found between OC risk and ADH3 genotypes. An interaction between ADH3 genotypes and alcohol consumption levels, however, was suggested. In non-drinkers, the ADH3(1-1) genotype has higher risk than ADH3(1-2) or ADH3(2-2) genotypes, but for subjects consuming alcohol, lower risk was observed for ADH3. We fit a logistic regression model to estimate the increase in OC risk associated with each alcohol drink consumed per week. We estimated that OC risk increased by 31.5% per drink/week for the ADH3(2-2) genotype, 4.1% for the ADH3(1-2) genotype and 1.6% for the ADH3(1-1) genotype. Evidence of genotype-environment interaction was suggestive (p = 0.048, Wald chi p = 0.145, likelihood ratio). This finding is opposite to that reported for a population in Puerto Rico, where the ADH3(1-1) genotype seemed more sensitive to ethanol exposure. In Greece, genetic variation at the CYP2E1 SNP is almost entirely absent, with only 1 case and 1 control heterozygous for the variant. By contrast, in a population in France where an OC association was reported, the frequency of CYP2E1 heterozygotes was 5% in controls and 9% in OC cases. These findings illustrate the importance of replicating SNP associations both within and between different racial and ethnic groups and geographic regions.