Patients Undergoing Bisphosphonate Treatment Research Articles

Zoledronic Acid Accelerates ER Stress-Mediated Inflammation by Increasing PDE4B Expression in Bisphosphonate-Related Osteonecrosis of the Jaw.

Long-term administration of bisphosphonates can lead to a significant side effect known as bisphosphonate-related osteonecrosis of the jaw (BRONJ). Although macrophage-mediated inflammation has been established as an important factor in BRONJ, the underlying mechanism remains elusive. In the current study, the roles of endoplasmic reticulum (ER) stress in zoledronic acid (ZOL)-induced inflammation were analyzed in macrophages, and the regulatory mechanism of ER stress activation was next investigated. An in vitro model of BRONJ was established by treating RAW264.7 cells with ZOL. The activation of ER stress was analyzed by western blotting and transmission electron microscopy, and inflammation was assessed by quantitative real-time PCR and enzyme-linked immunosorbent assay. ER stress was significantly activated in ZOL-treated macrophages, and inhibition of ER stress by TUDCA, an ER stress inhibitor, suppressed ZOL-induced inflammation in macrophages. Mechanistically, phosphodiesterase 4B (PDE4B) was significantly increased in ZOL-treated macrophages. Forced expression of PDE4B promoted ER stress and inflammation, whereas PDE4B knockdown decreased ZOL-induced ER stress and inflammation in macrophages. More importantly, PDE4B inhibitor could improve ZOL-induced BRONJ in vivo. These data suggest that ZOL accelerates ER stress-mediated inflammation in BRONJ by increasing PDE4B expression. PDE4B inhibition may represent a potential therapeutic strategy for BRONJ. Subsequent research should concentrate on formulating medications that selectively target PDE4B, thereby mitigating the risk of BRONJ in patients undergoing bisphosphonate treatment.

Interactive Associations between PPARγ and PPARGC1A and Bisphosphonate-Related Osteonecrosis of the Jaw in Patients with Osteoporosis.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a rare but severe adverse effect that can occur as a result of bisphosphonate treatment. This study aimed to examine the relationship between PPARγ and PPARGC1A polymorphisms and the BRONJ development in female osteoporosis patients undergoing bisphosphonate treatment. We prospectively conducted this nested case-control study at the Ewha Womans University Mokdong Hospital between 2014 and 2018. We assessed five single-nucleotide polymorphisms (SNPs) of PPARγ and six SNPs of PPARGC1A and performed a multivariable logistic regression analysis to determine the independent risk factors for developing BRONJ. There were a total of 123 patients included in this study and 56 patients (45.5%) developed BRONJ. In the univariate analysis, PPARGC1A rs2946385 and rs10020457 polymorphisms were significantly associated with BRONJ (p = 0.034, p = 0.020, respectively), although the results were not statistically significant in the multivariable analysis. Patients with the combined genotypes of GG in both PPARγ rs1151999 and PPARGC1A rs2946385 showed a 3.03-fold higher risk of BRONJ compared to individuals with other genotype combinations after adjusting for confounders (95% confidence interval (CI): 1.01-9.11). Old age (≥70 years) and duration of bisphosphonate use (≥60 months) increased the risk of BRONJ. The area under the receiver operating characteristic curve for the predicted probability was 0.78 (95% CI: 0.69-0.87, p < 0.001), demonstrating a satisfactory level of discriminatory power. Our study elucidated that PPARγ and PPARGC1A polymorphisms were interactively associated with BRONJ development. These results have potential implications for tailoring personalized treatments for females undergoing bisphosphonate therapy for osteoporosis.

Risk factors for medication-related osteonecrosis of the jaw and salivary IL-6 IN cancer patients

IntroductionMedication-related osteonecrosis of the jaws is a severe complication of the use of antiresorptive and antiangiogenic therapy, with limited treatment options and great impact on patient’s quality pf life. ObjectiveThe aim of this study was to assess the risk factors associated with medication-related osteonecrosis of the jaws in oncologic patients undergoing bisphosphonate treatment. In addition, salivary levels of interleukin-6, IL-6, were measured to investigate their association with severity and risk of medication-related osteonecrosis of the jaws. MethodsCase-control study with 74 patients with bone metastases from solid tumors and multiple myeloma was included. Patients were divided into three groups: 1) those undergoing bisphosphonate treatment with medication-related osteonecrosis of the jaws; 2) those undergoing bisphosphonate without medication-related osteonecrosis of the jaws; and 3) those with bisphosphonate pretreatment. The demographic and medical data of the patients were collected to assess risk. The clinical evaluation was performed to diagnose medication-related osteonecrosis of the jaws and unstimulated saliva was collected for quantification of IL-6. ResultsAs result, it was observed that patients diagnosed with medication-related osteonecrosis of the jaws were submitted to higher number of bisphosphonate doses (p = 0.001) and monthly infusion protocol (p = 0.044; OR = 7.75). Patients who did not have routine followup with specialized dentists during therapy with bisphosphonate and smoking were associated with medication-related osteonecrosis of the jaws (p = 0.019; OR = 8.25 and p = 0.031; OR = 9.37 respectively). Group 1 had a higher frequency of treatment with chemotherapy and corticosteroids concomitant with bisphosphonate, and surgical dental procedures (p = 0.129). Salivary IL-6 levels showed no statistically significant difference between the groups (p = 0.571) or association with medication-related osteonecrosis of the jaws severity (p = 0.923). ConclusionA higher number of bisphosphonate cycles, monthly infusion protocol, no dental follow-up for oral health maintenance and smoking were associated with medication-related osteonecrosis of the jaws. Specialized dental follow up during bisphosphonate treatment has been shown to be an important factor in preventing this complication.

Monitoring adverse drug reactions associated with bisphosphonates therapy among Libyan patients treated in public hospitals: the case of osteonecrosis of the jaw

This study was carried out to identify ADE, associated with the use of both PO and IV Bps among Libyan patients. The results indicated that significant number of patients have suffered different ADRs when using this group of medicines, for long period of time including BRONJ. The study has introduced BRONJ as being one of the major bisphosphonate-associated risks that causes decline in patients’ quality of life, and emphasized the importance of early detection of signs and symptoms associated with ONJ, thus reducing its incidence among Bps users. The results underlined the importance of investigating the prevalence of BRONJ among Libyan patients undergoing long-term Bps treatment, as has been emphasized by both TUH’ chief maxillofacial surgeon who introduced the two cases of BRONJ in only one month and the oncology clinical pharmacist who together sensed the aggravating risk of the misuse of this group of drugs and stressed the need to develop special protocol to ensure safe treatment.The study also pointed out the importance of multidisciplinary health team, including a dentist and a pharmacist, to ensure safe and effective use of this group of medications. This study therefore opens the door to investigate the adverse consequences that face patients undergoing bisphosphonate treatment. It also introduces all precautionary measures that should be taken into consideration when prescribing and administering bisphosphonates

Saliva diagnostics in patients suffering from bisphosphonate-associated osteonecrosis of the jaw: Results of an observational study

ObjectiveOne of the severe side effects of bisphosphonate (BP) therapy is bisphosphonate-associated osteonecrosis of the jaw (BONJ). However, there is no information available about its pathogenesis. Hence, the aim of this observational study was to contribute to discerning this pathogenesis by comparing salivary quantity and quality in patients with BONJ and undergoing BP treatment. Materials and methodsThis study included 60 patients divided into three groups. The first group consisted of 20 patients with established BONJ, the second group had 20 patients undergoing BP treatment, and the third group comprised 20 healthy individuals. These groups were analysed for the flow rate of stimulated saliva, buffer capacity, and salivary pH level. ResultsReduced salivation was observed in a significantly high number of patients with established BONJ (n = 8) and those undergoing BP treatment (n = 9) in comparison with the healthy control group (n = 4; p = 0.039). Though the distribution of the mean value of stimulated saliva flow rates in patients undergoing BP treatment was lower than in the control group, the difference was not significant. Moreover, there were no significant differences in the salivary pH level and buffer capacity in patients undergoing BP treatment as compared with the healthy control group. ConclusionsIt is possible that the quantity of human saliva is affected by BP treatment. This reduction in saliva production could have a negative effect on mucosal health and is perhaps a cofactor in the pathogenesis of BONJ.

Investigation of Sustained BMP Delivery in the Prevention of Medication-Related Osteonecrosis of the Jaw (MRONJ) in a Rat Model.

Medication-related osteonecrosis of the jaw (MRONJ) poses an ongoing challenge for clinicians and researchers. Currently, there is a lack of preventative measures available for at-risk patients undergoing tooth extractions, especially those with prior bisphosphonate treatment due to osteoporosis or bone metastasis diagnoses. Here, these issues are addressed using a preventative tissue engineering strategy against MRONJ development. This study evaluates the efficacy of a poly(ethylene glycol)-heparin hydrogel as a tool for the delivery of arginylglycylaspartic acid (RGD) and recombinant human bone morphogenic protein-2 (rhBMP-2). Three groups of skeletally mature rats each receive two doses of intravenous zoledronic acid prior to surgery and undergo extraction of the right first mandibular molar with gingival closure. Experimental groups either have the sockets left empty, filled with hydrogel minus rhBMP-2, or filled with hydrogel plus rhBMP-2. Eight weeks postoperatively specimens are analyzed using radiological, histological, and scanning electron microscopy (SEM) techniques. µCT analysis shows increased bone formation with hydrogel/rhBMP-2 delivery compared to the empty socket. Hydrogel-treated groups display increased presence of osteocytes and increased osteoclastic action compared to the empty sockets. These results represent the first step toward improved delivery of rhBMP-2 and a potential MRONJ preventative for patients undergoing bisphosphonate treatment.

The effects of mechanically loaded osteocytes and inflammation on bone remodeling in a bisphosphonate-induced environment.

Bisphosphonate-related osteonecrosis of the jaw is a disease appearing after tooth removal in patients undergoing bisphosphonate treatment for metastasizing cancers and osteoporosis. The complexity of the condition requires a multicellular model to address the net effects of two key risk factors: mechanical trauma (pathologic overload) and inflammation. In this work, a system comprised of a polydimethylsiloxane chip and mechanical loading device is used to expose bisphosphonate-treated osteocytes to mechanical trauma. Specifically, osteocytes are treated with the potent nitrogen-containing bisphosphonate, zoledronic acid, and exposed to short-term pathologic overload via substrate stretch. During bone remodeling, osteocyte apoptosis plays a role in attracting pre-osteoclasts to sites of damage; as such, lactate dehydrogenase activity, cell death and protein expression are evaluated as functions of load. Additionally, the effects of osteocyte soluble factors on osteoclast and osteoblast functional activity are quantified. Osteoclast activity and bone resorption are quantified in the presence and absence of inflammatory components, lipopolysaccharide and interferon gamma. Results suggest that inflammation associated with bacterial infection may hinder bone resorption by osteoclasts. In addition, osteocytes may respond to overload by altering expression of soluble signals that act on osteoblasts to attenuate bone formation. These findings give insight into the multicellular interactions implicated in bisphosphonate-related osteonecrosis of the jaw.

Frequency and associated factor of atypical periprosthetic femoral fracture after hip arthroplasty

BackgroundAtypical femoral fracture (AFF) is a serious complication after the use of bisphosphonates, and periprosthetic femoral fracture (PFF) appeared as a common complication after hip arthroplasty, especially in senile patients. Although American Society for Bone and Mineral Research has excluded PFFs from the definition of AFFs, several case reports found PFF patients undergoing bisphosphonate treatment, have fractures resembling AFF and the authors suggested that AFF can also occur in operated femurs after hip arthroplasty. To date, the frequency and risk factors of atypical PFF are unknown. The purpose of our study was (1) to evaluate the proportion of atypical PFF among Vancouver type B PFFs, and (2) to determine the association between occurrence of atypical PFF and use of bisphosphonate. MethodsWe reviewed medical records and radiographs of 67 Vancouver type B PFFs (67 patients) due to low-energy trauma and classified them into atypical PFF group and ordinary PFF group. We calculated the proportion of atypical PFFs among PFFs and identified risk factors for atypical PFF. ResultsAmong the 67 PFFs, 7 fractures (10.4%) were classified as atypical PFF. Longer duration of bisphosphonate use was an independent risk factor of atypical PFF. (Odds ratio 2.600, 95% CI 1.184–5.709, p = 0.017). ConclusionIn accordance with wide use of bisphosphonate, atypical PFFs after hip arthroplasty are not rare anymore. Physicians should suspect the atypical PFF, when they meet low-energy fracture in bisphosphonate users, and radiographs show features of AFF.

Knowledge and Attitude of Dentists Regarding Patients Undergoing Bisphosphonate Treatment: a Comparative Questionnaire

Abstract Background: Osteonecrosis of the jaw is an uncommon but serious complication related to oral and intravenous bisphosphonate (BP) therapy. Its pathogenesis is not well understood, and there are no universal protocols accepted to treat it. The aim of our study was to use the same questionnaire as four years ago to evaluate the awareness of dentists in Tîrgu Mureș regarding the dental treatments that can be applied in patients on BP therapy, and to assess how their knowledge on the subject has evolved over these years. Material and method: We used the same questionnaire-based study as four years ago among dentists in Tîrgu Mureș, raising important issues such as: is the patient asked about current or previous treatments with BPs, do they perform surgical treatment in these patients, do they know under what conditions they can perform this treatment, or do they deem it necessary to contact the prescriber before surgical treatment. Results: One-hundred twenty questionnaires were returned. The majority of respondents (n = 113, 94.2%) included the question regarding the use of BPs in their medical records. Of all respondents, 48 (40%) perform dental or surgical treatments on patients undergoing BP therapy, 68 (56.7%) do not perform dental or surgical treatments on these patients, and four of the respondents (3.3%) did not know the answer. One hundred (83.3%) respondents always contact the prescriber prior to surgery in these patients, regardless of how BPs are administered. Conclusions: According to the findings of the present study, many of the respondent doctors have heard about BPs and their complications, but they are not aware of the fundamental concepts of bisphosphonate-related osteonecrosis of the jaw prevention and treatment protocols. In the absence of appropriate protocols, the quality of life of these patients is compromised.

Osteonecrosis associated with dental implants in patients undergoing bisphosphonate treatment

Bisphosphonate-related jaw necrosis (BRONJ) associated with dental implants is a rare but continuously reported complication. To verify clinical and pathological characteristics of BRONJ around dental implants, the present study analyzed clinical, radiographic and histopathological findings of these lesions. Nineteen patients were diagnosed with osteonecrosis of the jaw associated with dental implants and treated at our institute from 2008 to 2011. The patients' medical history, demographic features, radiographic, and histopathological findings along with information on bisphosphonates (BP) administration were analyzed. The majority of BRONJ patients associated with dental implants used oral BP for osteoporosis. The patients were divided into two groups: BP initiation before (n = 16) and after (n = 3) implant surgery. Only three patients (15.8%) could be regarded as "implant surgery-triggered" BRONJ. Many patients (n = 9) showed successful osteointegration after fixture installation to an average of 35 months (11-82 months) until the development of osteonecrosis. The histological features of the lesion showed that the necrotic bone with empty lacunae was infiltrated by inflammatory cells and bacterial colonies. Viable osteocytes were also observed in some areas of the bony specimens. Three types of bone destruction pattern were observed: (i) complete necrosis of the bone around the implant (frozen type), (ii) extensive osteolysis around the implant with or without sequestra (osteolytic type), and (iii) sequestration of bone with an implant maintaining direct implant-bone contact (en block sequestration type). These findings could be existed at the same lesions depending on the degree of local bone destruction and the severity of the infection. These results and those of others suggested that already osseointegrated dental implants can also cause the osteonecrosis around the implant after BP administration. En block sequestration of bone with implant might be one of the characteristics of implant-related BRONJ, which is different from peri-implantitis-induced bone destruction. The possible role of microcracks in this type of bone destruction needs to be examined further.

Urinary pentosidine and plasma homocysteine levels at baseline predict future fractures in osteoporosis patients under bisphosphonate treatment

To clarify what kind of risk factors predict incident fractures in patients treated with bisphosphonates, the authors investigated the relationship between baseline characteristics and incident vertebral fracture in Japanese osteoporosis patients undergoing bisphosphonate treatment. This was a multi-center follow-up study conducted at three centers, in which a total of 251 Japanese patients with osteoporosis (mean age 70.5years) from the three centers were followed for 3.2±2.0years. Baseline data, including pre-existing fractures, bone mineral density in the lumbar spine (LBMD), bone metabolic markers, urinary pentosidine, and plasma homocysteine, were evaluated. Changes in LBMD, bone turnover markers, and incident fractures after the treatment were followed. Sixty-one patients developed incident vertebral fractures; this group of patients was older and had lower LBMD, a higher prevalent vertebral fracture number, and higher homocysteine and pentosidine levels than patients who did not develop incident vertebral fractures. Changes in LBMD, urinary N-terminal telopeptides of type I collagen (NTX), and bone-derived alkaline phosphatase showed no significant association with the occurrence of vertebral fractures. Cox's proportional hazard model demonstrated that age, prevalent fracture, pentosidine, and homocysteine were independent predictors of the incident vertebral fracture rate under bisphosphonate treatment. Higher baseline levels of pentosidine and homocysteine in osteoporosis patients are potential risk factors for incident vertebral fractures when these patients are treated with bisphosphonates. Further clarification is needed to explain why such patients have higher fracture susceptibility.

Osseointegration of Dental Implants in Patients Undergoing Bisphosphonate Treatment: A Literature Review

Bisphosphonates (BPs) are an important group of drugs used for the treatment of metabolic and oncologic pathologies involving the skeletal system. Osteonecrosis of the jaw (ONJ) is a complication observed in patients using oral or intravenous (IV) BPs. It was suggested that all patients undergoing BP therapy who are expected to receive dental implants should be informed of the possible risks of development of ONJ. The aim of this literature review is to assess the osseointegration of dental implants in patients undergoing BP therapy. The MEDLINE-PubMed databases of The National Library of Medicine, National Institutes of Health, Bethesda, Maryland, were searched for articles addressing the focused question: Can dental implants osseointegrate and remain functionally stable in patients undergoing oral and IV BP therapy? Databases were searched from 1995 up to and including February 2010 using the following terms in different combinations: bisphosphonate, dental implant, immediate-loading, implant survival rate, intravenous, oral, osseointegration, and osteonecrosis. The initial search yielded 89 articles. Scrutiny of the titles and abstracts reduced the number of articles to 12 (seven case reports and five retrospective studies). In 10 studies, the patients were using oral BPs, and in two studies, patients were using IV BPs. Six case reports showed that the placement of implants in patients using BPs could yield a successful osseointegration and function. Four retrospective studies demonstrated that BPs did not have a negative influence on implant success. Two studies showed a negative impact of BPs on implant success. Dental implants can osseointegrate and remain functionally stable in patients using BPs.

Bisphosphonate-Related Osteonecrosis of the Jaw Associated With Dental Implants

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a well-documented devastating side effect of long-term bisphosphonate (BP) use. There is scarce information in the literature on BRONJ associated with dental implants (DIs). The purpose of this study was to present a large series of cases of this association. The files of all patients with BRONJ associated with DIs who were treated in the department of oral and maxillofacial surgery from 2003 to 2009 were reviewed. Data on demographics, medical background, type, and duration of BP treatment before the development of BRONJ, mode of therapy, and therapeutic outcome were retrieved. Of the 27 patients enrolled into the study, 11 (41%) developed BRONJ while taking oral BPs and 16 (59%) developed BRONJ associated with intravenous BPs. BRONJ developed after mean periods of 68 months (median, 60), 16.4 months (median, 13), and 50.2 months (median, 35) in patients on alendronate, zoledronic acid, and pamidronate, respectively. Only 6 patients developed BRONJ during the first 6 months after DI placement. When BP treatment had been started before DI placement, there was a mean duration of 16.2 months (median, 11) until the appearance of BRONJ development. Long-term antibiotics and only essential surgical procedures comprised the treatment of choice, and the response rate was considerably better for patients taking the oral type of BPs. There was no significant association between BRONJ and diabetes, steroid intake, or smoking habits. Patients undergoing BP treatment and who receive DIs require a prolonged follow-up period to detect any development of BRONJ associated with DIs.

Does Adjuvant Bisphosphonate in Early Breast Cancer Modify the Natural Course of the Disease? A Meta-Analysis of Randomized Controlled Trials

To address whether the use of bisphosphonates in the adjuvant setting of breast cancer might have any effect on the natural course of the disease, a meta-analysis was conducted of published and unpublished randomized controlled trials found in PubMed, the Cochrane Central Register of Controlled Trials, the ISI Web of Knowledge, and abstracts of major international conferences up to January 2009. All trials that randomized patients with primary breast cancer to undergo adjuvant treatment with any bisphosphonate versus non-use were considered eligible. Analysis included data from 13 eligible trials involving 6886 patients randomized to treatment with bisphosphonates (n = 3414) or either placebo or no treatment (n = 3472). Compared with no use, adjuvant breast cancer treatment with bisphosphonates did not reduce the overall number of deaths (odds ratio [OR], 0.708; 95% CI, 0.482-1.041; P = .079), bone metastases (OR, 0.925; 95% CI, 0.768-1.114; P = .413), overall disease recurrences (OR, 0.843; 95% CI, 0.602-1.181; P = .321), distant relapse (OR, 0.896; 95% CI, 0.674-1.192; P = .453), visceral recurrences (OR, 1.051; 95% CI, 0.686-1.609; P = .820), or local relapses (OR, 1.056; 95% CI, 0.750-1.487; P = .756). No significant heterogeneity was observed among the trials except for estimates of deaths and disease recurrences (P = .034 and P = .016, respectively). In subgroup analyses, use of zoledronic acid was associated with a statistically significant lower risk for disease recurrence (OR, 0.675; 95% CI, 0.479-0.952; P = .025). However, these results should be interpreted with caution because the statistical significance for this association was weak and might be attributed to chance from multi-test analyses. Use of zoledronic acid was not associated with any significant difference in death (OR, 0.642; 95% CI, 0.388-1.063) and bone metastasis rates (OR, 0.661; 95% CI, 0.379-1.151). Currently available evidence does not support the hypothesis that use of bisphosphonates in adjuvant treatment of early breast cancer will alter the natural course of the disease. Nonetheless, a nonsignificant trend seems to exist for better outcomes in patients undergoing bisphosphonate treatment. Until further evidence from new clinical trials becomes available, adjuvant bisphosphonates should not be recommended routinely.