Bisphosphonates, Osteoporosis, and Osteonecrosis of the Jaw: A Critical Review of a Large Nested Case-Control Study.

ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: A large national cohort study of the association between bisphosphonates and osteonecrosis of the jaw in patients with osteoporosis: A nested case-control study. Kwon JW, Park EJ, Jung SY, Sohn HS, Ryu H, Suh HS. JDR Clin Res Suppl 2015;94(9) Suppl 2:213S-9S. SOURCE OF FUNDING: 2014 Pusan National University Research Grant TYPE OF STUDY/DESIGN: Nested matched case-control study.

Economic crisis, austerity and unmet healthcare needs: the case of Greece.

BACKGROUND: The programme for fiscal consolidation in Greece has led to income decrease and several changes in health policy. In this context, this study aims to assess how economic crisis affected unmet healthcare needs in Greece. METHODS: Time series analysis was performed for the years 2004 through 2011 using the EU-SILC database. The dependent variable was the percentage of people who had medical needs but did not use healthcare services. Median income, unemployment and time period were used as independent variables. We also compared self-reported unmet healthcare needs drawn from a national survey conducted in pre-crisis 2006 with a similar survey from 2011 (after the onset of the crisis). A common questionnaire was used in both years to assess unmet healthcare needs, including year of survey, gender, age, health status, chronic disease, educational level, income, employment, health insurance status, and prefecture. The outcome of interest was unmet healthcare needs due to financial reasons. Ordinary least squares, as well as logistic regression analysis were conducted to analyze the results. RESULTS: Unmet healthcare needs increased after the enactment of austerity measures, while the year of participation in the survey was significantly associated with unmet healthcare needs. Income, educational level, employment status, and having insurance, private or public, were also significant determinants of unmet healthcare needs due to financial reasons. CONCLUSIONS: The adverse economic environment has significantly affected unmet health needs. Therefore health policy actions and social policy measures are essential in order to mitigate the negative impact on access to healthcare services and health status.

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.

Oral and pharyngeal cancer in women.

Although in the United States the incidence of oral and pharyngeal cancer (OPC) has been significantly higher in men than in women, the identification of human papilloma virus as a risk factor for OPC has focused new scrutiny on who may develop OPC. One surprising element is that non-Hispanic white women have a higher incidence of OPC than of cervical cancer. OPC is thus a woman's disease, and diligence is needed to ensure that the occurrence of OPC in women does not go undetected by their oral health care providers.

Association between polymorphisms of DNA repair gene ERCC5 and oral squamous cell carcinoma.

OBJECTIVE: Short nucleotide polymorphism in ERCC5 (rs751402), a key molecule in DNA damage repair, was analyzed in 575 individuals who were either control subjects with no clinical evidence of malignant transformation of the oral mucosa or subjects with oral squamous cell carcinoma (OSCC). STUDY DESIGN: All participants provided a blood sample, demographic data, and information on habitual use of tobacco, alcohol, and areca nut. RESULTS: rs751402 homozygocity for C allele was found to confer a statistically significant protection against OSCC (adjusted odds ratio 0.56, 95% confidence interval 0.35-0.89; P = .01), whereas rs751402 T alleles were associated with increased risk. CONCLUSIONS: Our findings suggest that there is an association between rs751402 polymorphism and incidence of oral cancer. ERCC rs751402 CC genotype is significantly associated with decreased risk of OSCC, whereas the T allotype is correlated with higher risk of OSCC.

Challenges in global improvement of oral cancer outcomes: findings from rural Northern India.

BACKGROUND: In India, 72% of the population resides in rural areas and 30-40% of cancers are found in the oral cavity. The majority of Haryana residents live in villages where inadequate medical facilities, no proper primary care infrastructure or cancer screening tools and high levels of illiteracy all contribute to poor oral cancer (OC) outcomes. In this challenging environment, the objective of this study was to assess the association between various risk factors for OC among referrals for suscipious lesions and to design and pilot test a collaborative community-based effort to identify suspicious lesions for OC. SETTING: Community-based cross sectional OC screening. PARTICIPANTS: With help from the Department of Health (DOH), Haryana and the local communities, we visited three villages and recruited 761 participants of ages 45-95 years. PARTICIPANTS received a visual oral cancer examination and were interviewed about their dental/medical history and personal habits. Pregnant women, children and males/females below 45 years old with history of OC were excluded. MAIN OUTCOME: Presence of a suspicious oral lesion. RESULTS: Out of 761 participants, 42 (5.5%) were referred to a local dentist for follow-up of suspicious lesions. Males were referred more than females. The referral group had more bidi and hookah smokers than non smokers as compared to non referral group. The logistic regression analysis revealed that smoking bidi and hookah (OR = 3.06 and 4.42) were statistically significant predictors for suspicious lesions. CONCLUSIONS: Tobacco use of various forms in rural, northern India was found to be quite high and a main risk factor for suspicious lesions. The influence of both the DOH and community participation was crucial in motivating people to seek care for OC.

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.

Association between Gly1619ARG polymorphism of IGF2R domain 11 (rs629849) and advanced stage of oral cancer.

Insulin-like growth factor II receptor (IGF2R) degrades mitogen and hence is associated with tumor suppressor function. The aim of this study was to assess whether genetic variation in the mitogen-binding domain of IGF2R, Gly1619Arg, disrupts normal function of IGF2R and contributes to further progression and distant metastasis of localized oral squamous cell carcinoma (OSCC). Gly1619Arg polymorphism of IGF2R domain 11 (rs629849) was assessed in blood samples of 113 individuals with histology-confirmed OSCC, and IGF2R genotypes were correlated with the stage of tumor (localized; TMN stages I-II versus advanced; TMN stages III-IV). After controlling for demographic covariates and known risk factors for oral cancer, such as tobacco, alcohol, and areca nut use, threefold increased risk of advanced stage of OSCC was noted in those subjects who had one or two copies of the IGF2R-A-allele when compared with the GG genotype. In contrast, when compared with the carriers of the A-allele, the GG genotype demonstrated to be protective against advanced disease (adjusted odds ratios of 0.32). IGF2R genetic polymorphism may be associated with decreased function of IGF2 receptor there by contributing to the advancement and distant metastasis of localized oral cancer.

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.

Alcohol intake and folate antagonism via CYP2E1 and ALDH1: effects on oral carcinogenesis.

The interaction of folate and alcohol consumption has been shown to have an antagonistic effect on the risk of oral cancer. Studies have demonstrated that increased intake of folate decreases the risk of oral cancer, while greater alcohol consumption has an opposite effect. However, what is poorly understood is the biological interaction of these two dietary factors in relation to carcinogenesis. We hypothesize that cytochrome P450 2E1 (CYP2E1) and the family of aldehyde dehydrogenase 1 (ALDH1) enzymes may play a causal role in the occurrence of oral cancer. Chronic and high alcohol use has been implicated in the induction of CYP2E1, which oxidizes ethanol to acetaldehyde. Acetaldehyde is a known carcinogen. As the first metabolite of ethanol, it has been shown to interfere with DNA methylation, synthesis and repair, as well as bind to protein and DNA to form stable adducts, which lead to the eventual formation of damaged DNA and cell proliferation. Studies using liver cells have demonstrated that S-adenosyl methionine (SAM), which is a product of folate metabolism, regulates the expression and catalytic activity of CYP2E1. Our first hypothesis is that as increased levels of folate lead to higher concentrations of SAM, SAM antagonizes the expression of CYP2E1, which results in decreased conversion of ethanol into acetaldehyde. Thus, the lower levels of acetaldehyde may lower risk of oral cancer. There are also two enzymes within the ALDH1 family that play an important role both in ethanol metabolism and the folate one-carbon pathway. The first, ALDH1A1, converts acetaldehyde into its non-carcinogenic byproduct, acetate, as part of the second step in the ethanol metabolism pathway. The second, ALDH1L1, also known as FDH, is required for DNA nucleotide biosynthesis, and is upregulated at high concentrations of folate. ALDH1L1 appears to be a chief regulator of cellular metabolism as it is strongly downregulated at certain physiological and pathological conditions, while its upregulation can produce drastic antiproliferative effects. ALDH1 has three known response elements that regulate gene expression (NF-Y, C/EBPß, and RARα). Our second hypothesis is that folate interacts with one of these response elements to upregulate ALDH1A1 and ALDH1L1 expression in order to decrease acetaldehyde concentrations and promote DNA stability, thereby decreasing cancer susceptibility. Conducting future metabolic and biochemical human studies in order to understand this biological mechanism will serve to support evidence from epidemiologic studies, and ultimately promote the intake of folate to at-risk populations.

The impact of bisphosphonates on oral health: lessons from the past and opportunities for the future.

Osteonecrosis of the jaw (ONJ), a challenging medical condition seen primarily among intravenous bisphosphonate (BP) users, is characterized by exposed necrotic bone that persists for more than eight weeks. While rare among people with osteoporosis treated with oral BPs, ONJ has captured the public's attention and caused significant distress. For many, the risk-benefit scale has conceptually changed, tipping steeply toward risk, while for others the benefit of increased bone mass still outweighs the possibility of ONJ. While more than seven years have passed since the first cases were published, the scientific and medical communities are not yet ready to address with certainty the issue of causal inference, nor do they have any concrete recommendations for risk assessment or management of ONJ. Equally important, the dental literature has been skewed by the perceived risk associated with prolonged use of BPs and has neglected to explore how the antiosteoclastic activity of BPs may be utilized to improve dental outcomes. This article reviews critically the current state of knowledge about the impact of bisphosphonates on oral health. Using the principles of epidemiology, the article identifies scientific gains, research challenges, and future research opportunities on the topic.

Alcohol-folate interactions in the risk of oral cancer in women: a prospective cohort study.

BACKGROUND: The aim of this cohort study was to quantify the effect of alcohol on the risk of oral cancer in different strata of folate intake, controlling for known confounders. METHODS: A cohort of 87,621 women in the Nurses' Health Study was followed up from 1980 to 2006, and 147 incident oral cancer cases were reported and confirmed. Data on alcohol intake and diet were obtained through self-reported food frequency questionnaires every 4 years. Cox proportional regression analysis was conducted to estimate the adjusted risk ratios (RR) and 95% confidence intervals (95% CI). RESULTS: When compared with nondrinkers, the adjusted RRs (95% CIs) for alcohol intake were 0.59 (0.39-0.87) for 0.1-14.9 g/d, 1.15 (0.67-1.97) for 15-29.9 g/d, and 1.92 (1.08-3.40) for ≥30 g/d. We observed a significant interaction between alcohol and folate intakes (P = 0.02). The cancer risk for subjects with high alcohol (≥30 g/d) and low folate (<350 µg/d) intakes was significantly elevated (RR, 3.36; 95% CI, 1.57-7.20) as compared with nondrinkers with low folate intake. The risk associated with high alcohol intake (≥30 g/d) was reduced to 0.98 (0.35-2.70) in the high-folate (≥350 µg/d) group as compared with nondrinkers with high folate intake. CONCLUSIONS: High alcohol intake is associated with significantly increased oral cancer risk, especially in women with low folate intake. IMPACT: A significant interaction between alcohol and folate intakes seems to affect oral cancer risk in women, a finding with potential public health utility.

Effect of CC chemokine ligand 5 and CC chemokine receptor 5 genes polymorphisms on the risk and clinicopathological development of oral cancer.

Inflammation can be induced by cytokines, chemokines, and their receptors, and it is believed to be a risk factor on tumor initiation and progression. The contribution of CC chemokine ligand 5 (CCL5) and CC chemokine receptor 5 (CCR5) on the risk and prognosis of oral cancer is still poorly investigated. The aims of this study were to investigate the impacts of single nucleotide polymorphisms (SNPs) in CCL5 and CCR5 genes and the synergistic effects of these SNPs on the risk and clinicopathological characteristics of oral cancer. In this case-control study, a total of 253 oral cancer patients and 347 controls were recruited. The genetic polymorphisms of CCL5-28, -403 and CCR5-59029 were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) genotyping analysis. The results of statistical analysis showed that the subjects with CCL5-28 CG, CCL5-28 CG or GG, and CCL5-403 TT polymorphic genotype as well as the subjects with the combinations of CCL5-28 CG/-403 CT and CCL5-28 CG/-403 TT genotypes having a significant higher risk to oral cancer than those with wild-type genotypes. Moreover, the oral cancer patients with the combination of CCL5-28 CG/-403 TT genotype presented a lower risk for developing a moderately or poorly differentiated status as compared to those with the combination of CCL5-28 CC/-403 CC genotype. These results suggest that the SNPs in CCL5-28 and -403 genes could increase the risk to have oral cancer, and the combinative effect of CCL5-28 CG and -403 TT genes might also increase the oral cancer risk but reduce the clinicopathological development of oral cancer patients.

Antimetastatic effects of Terminalia catappa L. on oral cancer via a down-regulation of metastasis-associated proteases.

The incidence and mortality of oral cancer in Taiwan have been increased during the last decade, which could be mainly resulted from the difficulty in treatment related to metastasis. As a potential and popular folk medicine, Terminalia catappa leaves have been proven to possess various biological benefits including anti-cancer activities. However, the detailed effects and molecular mechanisms of T. catappa leaves on the metastasis of oral cancer cells were still unclear. Thus, SCC-4 oral cancer cells were subjected to a treatment with ethanol extracts of T. catappa leaves (TCE) and then analyzed for the effect of TCE on the migration and invasion. Modified Boyden chamber assays revealed that TCE treatment significantly inhibited the cell migration/invasion capacities of SCC-4 cells. Furthermore, results of zymography and western blotting showed that activities and protein levels of MMP-2, MMP-9 and u-PA were all inhibited by TCE. Further studies indicated that TCE may inhibit phosphorylation of ERK1/2, JNK1/2 and Akt while the expression of nuclear protein NF-kappaB, c-Jun and c-Fos were inhibited as well. EMSA assay revealed that the DNA-binding activity with AP-1 and NF-kappaB was also decreased by TCE. In conclusion, TCE may serve as a powerful chemopreventive agent against oral cancer metastasis.

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.

Zoledronate, smoking, and obesity are strong risk factors for osteonecrosis of the jaw: a case-control study.

PURPOSE: Bisphosphonates (BPs) effectively treat metastatic bone disease, hypercalcemia, and osteoporosis. BP exposure, however, may be associated with osteonecrosis of the jaw (ONJ). The aim of the present study was to estimate the magnitude of the association between intravenous (IV) BP exposure and ONJ, and to identify potential confounders. MATERIALS AND METHODS: Using a case-control study design, the investigators identified and adjudicated a sample of cases with ONJ and matched them randomly with 5 controls per case. The controls were matched to cases on age, gender, cancer type, and date of cancer diagnosis. The medical records were abstracted and data on BP exposure, cancer therapy, and comorbidities were recorded. Statistical analyses were carried out using conditional logistic regression in Stata 9.0 (Stata Corp, College Station, TX). RESULTS: Thirty cases of ONJ were identified at Massachusetts General Hospital from February 2003 through February 2007. Zoledronate was found to confer significant risk toward development of ONJ (adjusted odds ratio = 31.8, P < .05). Although a trend toward increased risk was noted for pamidronate, this association was not significant after controlling for zoledronate. Obesity and smoking were associated significantly with ONJ development, whereas oral BPs had no effect. CONCLUSION: In this study, cancer patients who had received zoledronate exhibited a significant 30-fold increase in their risk to develop ONJ. More studies are needed to elucidate the exact role of obesity and smoking in the development of ONJ, and the complex interactions of IV BPs with other chemotherapies during cancer treatment.

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.

The 3' UTR IGF2R-A2/B2 variant is associated with increased tumor growth and advanced stages in non-small cell lung cancer.

Normal function of insulin-like growth factor II receptor (IGF2R) gene has been associated with negative control of tumor growth in vivo and in vitro. Rare alleles at a 3' UTR short tandem repeat polymorphism of IGF2R are known to decrease transcript stability. One such allele (A2/B2) increases significantly the risk of oral squamous cell carcinoma and non-small cell lung carcinoma (NSCLC) in Caucasians. To determine potential association(s) between A2/B2 presence and development and/or progression of disease, we examined in 103 NSCLC patients, free of IGF2R allelic imbalance aberrations, the 3' UTR allelic status in relation to tumor kinetic parameters (proliferation index-PI and apoptotic index-AI) and clinicopathological data. PCR and automated sequence analyses were employed to genotype the IGF2R 3' UTR polymorphism. Given that, oncogenic mitogens, which escape degradation by IGF2R, can also activate p53 through a DNA damage response, the patterns between p53 status and IGF2R genetic constitution were also evaluated in relation to the above parameters. The A2/B2 variant was significantly more common (p=0.005, chi2-test) in lung cancer patients (25% vs 15%). Its presence was accompanied by high cellular proliferation (p=0.028, t-test) along with increased tumor cell growth (GI=PI/AI) (p=0.022, t-test) and it was significantly found in advanced stages. Also, patients carrying the A2/B2 in their genetic constitution that exhibit aberrant p53 expression have faster growing tumors and progress more rapidly to advanced stages. In conclusion, the IGF2R-A2/B2 variant probably provides a selective advantage for NSCLC progression through increased tumor growth.