Impact of Bisphosphonate-related Osteonecrosis of the Jaw on Osteoporotic Patients after Dental Extraction: A Population-Based Cohort Study

Background and Aims

Little is currently known about the risk of developing bisphosphonate-related osteonecrosis of the jaw (BRONJ). This study sought to determine the incidence of BRONJ in osteoporotic patients. We also sought to identify the nature and types of risk factors of osteonecrosis of jaw (ONJ) related to the use of oral bisphosphonates (BPs).

Materials and Methods

Data from the National Health Insurance system of Taiwan. This cohort study included 19,399 adult osteoporosis patients received dental extraction in 2000-2010 (osteoporosis cohort) and 38,669 age and gender matched comparisons selected from dental extraction people without osteoporosis and osteonecrosis history (comparison cohort). All study subjects were followed from the date of their dental extraction (index date) to the development of ONJ and were included in the study up to 2011 or were lost to the study, whichever occurred first. Cox proportional hazard regression was used to estimate the hazard ratio and 95% confidence intervals for the two cohorts.

Results

Patients with osteoporosis had a significantly higher risk to develop ONJ than healthy persons (adjusted HR, 2.05; 95% confidence interval, 1.58–2.65). The risk of ONJ increased with the severity of osteoporosis, no matter whether patient with cancer or not. A cumulative effect of dental extraction frequency may increase the risk of ONJ.

Conclusions

We concluded that ONJ is caused by a number of factors. Osteoporosis and past dental history play the very important roles, while BPs play the synergistic effect.     

A Retrospective Review of Patients with Atypical Femoral Fractures While on Long-Term Bisphosphonates: Including Pertinent Biochemical and Imaging Studies

ObjectiveTo elucidate the effects of prolonged bisphosphonate (BP) exposure on the development of atypical fragility fractures, and to define the associated risk factors.MethodsApproval was obtained from the institutional review board, and a retrospective chart analysis was performed on 51 patients who had been on BPs for at least 3 years and had complete subtrochanteric or diaphyseal femoral fracture(s) between January 2005 and April 2011. All relevant data were available for 25 patients (mean age, 67.52 years). All fractures included in the study were low- or no-energy. Relevant clinical and demographic data were collected regarding age, gender, ethnicity, height, weight, and comorbid medical conditions. Imaging and laboratory data collected on all patients included: calcium, alkaline phosphatase, 25-hydroxyvitamin D (25-OHD), intact parathyroid hormone, serum c-telopeptide, and urine n-telopeptide levels, bone mineral density, radiography, and magnetic resonance imaging.ResultsMost of the patients in this study were Caucasian, were on alendronate, had bilateral findings, and almost half had prodromal symptoms. The 25-OHD level was suboptimal (<30 ng/mL) in 45.8% of the patients. Mean BP duration was 9.84 years, and mean bone density was in the osteopenic, not osteoporotic, range.ConclusionCharacteristics of patients with atypical BP-related fracture include relatively young age, long duration of BP use, suboptimal 25-OHD level, and bone density in the nonosteoporotic range. All of these may be significant risk factors for insufficiency fracture development. (Endocr Pract. 2013;19:456-461)     

Bisphosphonates and Risk of Cardiovascular Events: A Meta-Analysis

Background and Objectives

Some evidence suggests that bisphosphonates may reduce atherosclerosis, while concerns have been raised about atrial fibrillation. We conducted a meta-analysis to determine the effects of bisphosphonates on total adverse cardiovascular (CV) events, atrial fibrillation, myocardial infarction (MI), stroke, and CV death in adults with or at risk for low bone mass.

Methods

A systematic search of MEDLINE and EMBASE through July 2014 identified 58 randomized controlled trials with longer than 6 months in duration that reported CV events. Absolute risks and the Mantel-Haenszel fixed-effects odds ratios (ORs) and 95% confidence intervals (CIs) of total CV events, atrial fibrillation, MI, stroke, and CV death were estimated. Subgroup analyses by follow-up duration, population characteristics, bisphosphonate types, and route were performed.

Results

Absolute risks over 25–36 months in bisphosphonate-treated versus control patients were 6.5% versus 6.2% for total CV events; 1.4% versus 1.5% for atrial fibrillation; 1.0% versus 1.2% for MI; 1.6% versus 1.9% for stroke; and 1.5% versus 1.4% for CV death. Bisphosphonate treatment up to 36 months did not have any significant effects on total CV events (14 trials; ORs [95% CI]: 0.98 [0.84–1.14]; I² = 0.0%), atrial fibrillation (41 trials; 1.08 [0.92–1.25]; I² = 0.0%), MI (10 trials; 0.96 [0.69–1.34]; I² = 0.0%), stroke (10 trials; 0.99 [0.82–1.19]; I² = 5.8%), and CV death (14 trials; 0.88 [0.72–1.07]; I² = 0.0%) with little between-study heterogeneity. The risk of atrial fibrillation appears to be modestly elevated for zoledronic acid (6 trials; 1.24 [0.96–1.61]; I² = 0.0%), not for oral bisphosphonates (26 trials; 1.02 [0.83–1.24]; I² = 0.0%). The CV effects did not vary by subgroups or study quality.

Conclusions

Bisphosphonates do not have beneficial or harmful effects on atherosclerotic CV events, but zoledronic acid may modestly increase the risk of atrial fibrillation. Given the large reduction in fractures with bisphosphonates, changes in osteoporosis treatment decision due to CV risk are not justified.     

Oral Contraceptives and Breast Neoplasia: A Retrospective Study

Between 1 December 1968 and 31 December 1971 345 women aged 16-39 years with a lump in the breast (90 malignant and 255 benign) were interviewed at five London teaching hospitals together with 347 matched controls suffering from acute medical or surgical conditions or admitted to hospital for routine elective surgery. Questions were asked about each patient''s medical, obstetric, menstrual, contraceptive, and social histories.The data do not suggest that the use of oral contraceptives is related in any way to the risk of breast cancer but provide some evidence that the preparations may actually protect against benign breast disease. This protective effect is largely confined to women who continue to use oral contraceptives and have used them altogether for more than two years. Such women appear to have only about 25% as great a risk of being admitted to hospital for a breast biopsy as women who have never used oral contraceptives at all.     

Bisphosphonates and Connexin 43: A Critical Review of Evidence

Abstract

Bisphosphonates (BPs) are drugs commonly used in the treatment of various disease arising or affecting bone tissue. There is a standard use in bone neoplasia and metastasis, hormonal and developmental disorders as well as for compensation of adverse effects in several medical therapies. Many in-vivo and in-vitro studies have assessed the efficacy of this drug and its function in cellular scale. In this concern, BPs are described to inhibit the resorptive function of osteoclasts and to prevent apoptosis of osteoblasts and osteocytes. They can preserve the osteocytic network, reduce fracture rate, and increase the bone mineral content, which is therapeutically used. Connexin 43 (Cx43) is a crucial molecule for basal regulation of bone homeostasis, development, and differentiation. It is described for signal transduction in many physiological and pathological stimuli and recently to be involved in BP action.     

Effects of Bisphosphonates on Osteoporosis Induced by Duchenne Muscular Dystrophy: A Prospective Study

Objective: Duchenne muscular dystrophy (DMD) is a severe X-linked progressive neuromuscular disease that brings a significantly increased risk of osteoporosis and bone fractures. We prospectively evaluated the effects of oral and intravenous bisphosphonates on the bones of children with DMD.Methods: This study included a total of 52 children with DMD. They were divided into zoledronic acid (ZOL), alendronate (ALN), and control groups according to bone mineral density (BMD) and history of fragility fractures. For 2 years, all patients took calcium, vitamin D, and calcitriol. Meanwhile, 17 patients received infusions of ZOL, and 18 patients received ALN. BMD, serum levels of alkaline phosphatase (ALP) and the cross-linked C-telopeptide of type I collagen (β-CTX) were evaluated.Results: After 24 months of treatment, the percentage changes in lumbar spine BMD were 23.2 ± 9.7% and 23.6 ± 8.8% in the ZOL and ALN groups (all P<.01 vs. baseline). The increases did not differ between the ZOL and ALN groups, but were significantly larger than those of the control group (P<.01). Serum β-CTX and ALP levels, respectively, were decreased by 44.4 ± 18.0% and 31.9 ± 26.7% in the ZOL group and by 36.0 ± 20.3% and 25.8 ± 14.4% in the ALN group (all P<.01 vs. baseline).Conclusion: Zoledronic acid and alendronate had similar protective effects to increase bone mineral density and reduce bone resorption in children with DMD, which were superior to treatment of calcium, vitamin D, and calcitriol.Abbreviations: 25OHD = 25 hydroxyvitamin D; ALN = alendro-nate; ALP = alkaline phosphatase; ALT = alanine aminotransferase; BMD = bone mineral density; BP = bisphosphonate; Ca = calcium; β-CTX = cross-linked C-telopeptide of type I collagen; DMD = Duchenne muscular dystrophy; FN = femoral neck; GC = glucocorticoid; LS = lumbar spine; ZOL = zoledronic acid     

Skeletal Metastases in Pancreatic Cancer: A Retrospective Study and Review of the Literature

Background: Skeletal metastases represent an underappreciated site of metastasis in patients with pancreatic cancer. Previous reports have estimated the prevalence to range from 5 percent to 20 percent. With the use of gemcitabine and novel targeted agents such as erlotinib, there has been a modest increase in survival in patients with advanced pancreatic cancer. As such, it is anticipated that previously uncommon occurrences such as skeletal metastases will become more frequent.     

Effects of Bisphosphonates on Bone of Osteoporotic Men With Different Androgen Levels: A Case-Control Study

ObjectiveOsteoporosis in men has been neglected despite its association with disability and mortality. We evaluated the effect of bisphosphonates (BPs) on bone mineral density (BMD) and bone turnover biomarkers of osteoporotic men with different androgen levels.MethodsThis case-control study included 136 osteoporotic men who were divided into normal group (n = 75) and hypogonadism group (n = 61) (patients treated with testosterone were excluded) according to their serum testosterone levels (cutoff value, 350 ng/dL). BMD, serum testosterone, total alkaline phosphatase, and cross-linked C-telopeptide of type I collagen were detected. The relationship between testosterone levels and BMD at baseline was evaluated. All patients were treated with BPs for 2 years. We compared the effects of BPs on BMD and bone turnover biomarkers between the 2 groups.ResultsAt baseline, there were no significant differences in BMD and bone turnover biomarkers between the 2 groups. Testosterone levels were positively correlated with BMD in the hypogonadism group. After treatment, the lumbar BMD increased by 7.65% ± 1.54% and 7.47% ± 1.88% in normal and hypogonadism groups, respectively (both P < .01 vs baseline) and hip BMD increased without significant differences between the 2 groups. Serum cross-linked C-telopeptide of type I collagen and alkaline phosphatase levels decreased without significant differences between the 2 groups (all P < .01 vs baseline).ConclusionTestosterone level is positively correlated with BMD in men with hypogonadism. In osteoporotic men, BPs significantly increase spine and hip BMD and decrease bone resorption. The efficacy of BPs is similar in men with or without hypogonadism.     

Umbilical Hernia — A Retrospective Study

One hundred thirty-four cases of umbilical hernia in adults were analyzed as to etiologic and other significant factors. Congenital umbilical hernia is of much higher incidence in black people than white. This is not true of acquired umbilical hernia. On retrospection it was noted that congenital hernias that persisted into adult years had been 1.5 cm or more in diameter in infancy. This indicates that hernia size is a criterion for repair early in life.     

Exenatide Use in the Management of Metabolic Syndrome: A Retrospective Database Study

ObjectiveTo evaluate the effect of exenatide therapy on cardiometabolic risk factors and anthropometric parameters in patients with metabolic syndrome.MethodsFrom June 2005 to June 2007, we performed a retrospective analysis of data extracted from the records of adult patients with metabolic syndrome being treated with exenatide. Diagnosis of any type of diabetes mellitus was exclusionary. Patients were initiated on exenatide therapy, 5 mcg, 1 hour before their morning and evening meals for the first month and were instructed to titrate up to 10 mcg. Cardiometabolic risk factors (total cholesterol, high-denssity lipoprotein cholesterol, triglycerides, calculated low- density lipoprotein cholesterol, and blood pressure) and anthropometric parameters (absolute body weight, body mass index, and abdominal girth) were measured at baseline and at 16 ± 4 weeks after initiating exenatide therapy. Data collected also included age, sex, metabolic syndrome diagnosis, and other concomitant medication used in the management of endocrine disorders.ResultsThe study population consisted of 299 patients (259 women, 40 men) with an age range of 18 to 74 years. Exenatide treatment was associated with significant reductions in mean body weight (P < .001) and body mass index (P < .001). Weight loss in 76.6% of patients was concomitant with a significant reduction in mean abdominal girth (P < .001). Further analysis revealed significant decreases in mean triglycerides (P < .001), total cholesterol (P < .01), and both systolic (P < .01) and diastolic blood pressure (P < .03). Approximately 60.2% of patients used metformin concomitantly, and half either decreased or discontinued metformin therapy.ConclusionsThis is the first report examining the effect of exenatide on patients with metabolic syndrome. We observed a significant improvement in cardiometabolic risk factors and anthropometric parameters as a result of exenatide over the treatment interval. (Endocr Pract. 2008;14:993-999)     

Endoscopic Biopsy in Gastrointestinal Neuroendocrine Neoplasms: A Retrospective Study

Background

Gastrointestinal neuroendocrine neoplasms (GI-NENs) are often located in the deep mucosa or submucosa, and the efficacy of endoscopic biopsy for diagnosis and treatment of GI-NENs is not fully understood.

Objective

The current study analyzed GI-NENs, especially those diagnosed pathologically and resected endoscopically, and focused on the biopsy and cold biopsy forceps polypectomy (CBP) to analyze their roles in diagnosing and treating GI-NENs.

Methods

Clinical data of all GI-NENs were reviewed from January 2006 to March 2012. Histopathology was used to diagnose GI-NENs, which were confirmed by immunohistochemistry.

Results

67.96% GI-NENs were diagnosed pathologically by endoscopy. Only 26.21% were diagnosed pathologically by biopsies before treatment. The diagnostic rate was significantly higher in polypoid (76.47%) and submucosal lesions (68.75%), than in ulcerative lesions (12.00%). However, biopsies were only taken in 56.31% patients, including 51.52% of polypoid lesions, 35.56% of submucosal lesions and 100.00% of ulcerative lesions. Endoscopic resection removed 61.76% of GI-NENs, including six by CBP, 14 by snare polypectomy with electrocauterization, 28 by endoscopic mucosal resection (EMR) and 15 by endoscopic submucosal dissection (ESD). 51.52% polypoid GI-NENs had infiltrated the submucosa under microscopic examination. CBP had a significantly higher rate of remnant (33.33%) than snare polypectomy with electrocauterization, EMR and ESD (all 0.00%).

Conclusions

Biopsies for all polypoid and submucosal lesions will improve pre-operative diagnosis. The high rate of submucosal infiltration of polypoid GI-NENs determined that CBP was inadequate in the treatment of GI-NENs. Diminutive polypoid GI-NENs that disappeared after CBP had a high risk of remnant and should be closely followed up over the long term.     

快速成型技术在颌骨缺损修复中应用的临床研究

目的：研究以CAD／CAM快速成型模型预成钛支架行颌骨缺损功能和外形重建的临床疗效。方法：选择四川大学华西口腔医院收治的5例颌骨良性肿瘤患者,术前螺旋CT及快速成型技术预成实体模型,并通过反求工程技术将健侧颌骨外形复制,制备钛修复体行患侧缺损修复,观察术后效果。结果：术后3个月、6个月复查患者对自身颌骨功能及外形较满意,均未出现因修复体导致的严重不良反应,张口度都接近恢复至正常,张口运动未出现明显异常,咬合关系良好。结论：运用快速成型技术设计并利用反求工程技术制造的个性化修复体进行颌骨缺损修复的方法能较好地恢复患者颌面部的功能和外形,副反应小,可以达到比较满意的修复效果。     

Inadequate Dissemination of Phase I Trials: A Retrospective Cohort Study

Background

Drug development is ideally a logical sequence in which information from small early studies (Phase I) is subsequently used to inform and plan larger, more definitive studies (Phases II–IV). Phase I trials are unique because they generally provide the first evaluation of new drugs in humans. The conduct and dissemination of Phase I trials have not previously been empirically evaluated. Our objective was to describe the initiation, completion, and publication of Phase I trials in comparison with Phase II–IV trials.

Methods and Findings

We reviewed a cohort of all protocols approved by a sample of ethics committees in France from January 1, 1994 to December 31, 1994. The comparison of 140 Phase I trials with 304 Phase II–IV trials, showed that Phase I studies were more likely to be initiated (133/140 [95%] versus 269/304 [88%]), more likely to be completed (127/133 [95%] versus 218/269 [81%]), and more likely to produce confirmatory results (71/83 [86%] versus 125/175 [71%]) than Phase II–IV trials. Publication was less frequent for Phase I studies (21/127 [17%] versus 93/218 [43%]), even if only accounting for studies providing confirmatory results (18/71 [25%] versus 79/125 [63%]).

Conclusions

The initiation, completion, and publications of Phase I trials are different from those of other studies. Moreover, the results of these trials should be published in order to ensure the integrity of the overall body of scientific knowledge, and ultimately the safety of future trial participants and patients.     

Pigmented Villonodular Synovitis: A Retrospective Multicenter Study of 237 Cases

Purpose

To review clinical characteristics of pigmented villonodular synovitis (PVNS) in China.

Methods

Electronic medical records (EMR) of four Chinese institutes were queried for patients with histologically proven PVNS between January 2005 and February 2014. Their data were collected including gender, age at diagnosis, clinical presentation, affected site, symptom duration, comorbidities, treatment strategy, recurrence and routine laboratories.

Results

A total of 237 patients with biopsy-proven PVNS were investigated. The gender ratio was 1.35 for a female predominance (101 males and 136 females). The average age was 36 years (range, 2 to 83 years). The median delay from initial clinical symptom to diagnosis was 18 months. Main affected areas were the knee (73.84%) and the hip (18.14%). Forty patients had a clear history of joint trauma. Six patients were concurrently diagnosed with PVNS and avascular necrosis (AVN). Five patients suffered from PVNS following implantation of orthopaedic devices including artificial prosthesis, plate and wire. One hundred and twenty-nine patients underwent arthroscopic synovectomy and 108 open synovectomy. Altogether 48 patients (26 males and 22 females) had recurrence of disease. The relapse rate was 24% (knee) and 6.98% (hip), 20.93% (open surgery) and 19.44% (arthroscopy), respectively. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) rate were elevated in 45.83% and 38.41% of the patients respectively.

Conclusions

To our knowledge, this study is the largest sample size of PVNS patients reported as well as the largest sample of PVNS with concurrent AVN reported to date. Our outcomes suggest that PVNS shows a female predominance, occurs mostly between 20–40 years and favors the knee and hip. Recurrence is frequent, particularly in the knee. Serum ESR and CRP may be elevated in some patients. Additionally, the present study supports the theory of an association between PVNS and orthopedic surgery, which is not limited to joint replacement.     

Use of Oral Bisphosphonates in Primary Prevention of Fractures in Postmenopausal Women: A Population-Based Cohort Study

Oral bisphosphonates are first-line drugs in the treatment of osteoporosis under most guidelines, and have been shown to decrease risk of first fracture only in asymptomatic vertebral fractures and in clinical trial populations that are generally very different from the general population.

Objective

To compare incidence of first osteoporotic fracture in two cohorts of postmenopausal women, one treated with bisphosphonates and the other only with calcium and vitamin D.

Design

Retrospective population cohort study with paired matching based on data from electronic health records.

Setting

Women aged 60 years and older in 2005, from 21 primary care centers in a healthcare region of Spain.

Participants

Two groups of women aged 60 years and older (n = 1208), prescribed either calcium and vitamin D (CalVitD) or bisphosphonates (BIPHOS) with or without calcium and vitamin D, were compared for the end point of first recorded osteoporotic-related fracture, with 5-years follow-up.

Main Outcome Measure

Incidence of first fracture: Vertebral fracture, osteoporosis with pathological fracture, fracture of the upper humeral epiphysis, fracture of the lower radial epiphysis, or femur fracture.

Results

Estimated 10-year risk of fracture was 11.4% (95% confidence interval: 9.6 to 13.2), 11.8% (9.2 to 14.3) in the BIPHOS group and 11.1% (8.6 to 13.6) in the CalVitD group. No significant differences were found between groups in total fractures (Hazard ratio = 0.934 (0.67 to 1.31)) or location (vertebral, femoral, radial or humeral).

Conclusions

In postmenopausal women, bisphosphonates have not been shown to better decrease risk of first fracture compared with calcium and vitamin D therapy alone.