Type Of Bisphosphonate Research Articles

Factors associated with osteonecrosis of the jaw in women with breast cancer receiving high-dose bisphosphonates to prevent breast cancer metastases as part of the SWOG 0307 trial.

552 Background: Bisphosphonates reduce the risk of bone metastases in postmenopausal women with early-stage breast cancer but carry the risk of osteonecrosis of the jaw (ONJ). We used the data collected in the S0307 trial to describe factors associated with provoked and unprovoked ONJ. Methods: In S0307, 6097 patients with Stage I-III breast cancer who had surgery were randomized to receive zoledronic acid (ZA) 4mg IV monthly for 6 months, then every 3 months, clodronate (CL) 1600mg daily, or ibandronate (IB) 50mg daily for three years, with no difference in bone metastases or disease-free survival. Patients completed dental procedures prior to and had a dental exam at enrollment. Pearson’s Chi-squared and Student’s T-test were used to test differences in categorical and continuous variables, respectively; logistic regression was used test independent association. Results: Of 5836 evaluable women, 48 developed ONJ, which was associated with bisphosphonate type (28/2124 (1.26%) for ZA, 8/2185 (0.36%) for CL and 12/1527 (0.77%) for IB (p = 0.002). Median time to onset of ONJ was 24.9 (1.4-66.6) for ZA, 41.2 months (range 33.8-67.4) for CL, 23.9 (2.1-75.3) for IB (p = 0.0447). Infection was present in 21 (43.8%) and absent in 20. ONJ was considered unprovoked in 20 (41.7%) and provoked by dental extraction in 20 (41.7%), periodontal disease in 14 (29.2%), denture trauma in 6 (12.5%), other dental surgery in 3 (6.3%). ONJ was associated with dental calculus (OR 2.03 (95% CI: 1.08-3.81), gingivitis (OR 2.11, 95% CI: 1.12-3.98), and periodontal disease (OR 2.87, 95% CI 1.45-5.53) that were moderate/severe and > 4mm periodontitis (OR 2.20, 95% CI 1.18-4.08). Patients with provoked and unprovoked ONJ had similar amounts of dental disease and lesion location. ONJ was not associated with dentures, plaque, chemotherapy, corticosteroids or renal adverse events. In multivariate analysis (limited by small sample), only bisphosphonate type was associated with ONJ. Conclusions: ONJ prevalence was low, likely due to patients completing dental procedures before enrollment. ZA carried a higher risk of ONJ (though current adjuvant dosing interval recommendations are less frequent), with time to onset similar to IB. Oral CL and IB (not currently available in the United States) are thus likely more appropriate for patients with poor dental health. Clinical trial information: NCT00127205.

In vitro Effect of Bisphosphonates on Squamous Cell Carcinoma from Tongue Tissue

The purpose of this in vitro study was to evaluate the efficacy of three different types of bisphosphonates: Actonel (risedronate sodium), Fosamax (alendronic acid) and Ossica (ibandronic acid) on a squamous carcinoma cell line (SCC-4) with tongue tissue origin. The cell viability was assessed after a stimulation period of 24h and the Alamar Blue test was performed. The assessment revealed that the viability of squamous cell carcinoma was slightly reduced after treatment with the smallest concentration of bisphosphonates, with a lowest rate (89%) recorded for Actonel. When a concentration of 2 and 2.5 mM was used, the cell viability was between 85-89% independently of the type of bisphosphonates used. The higher concentrations of 3 mM, 4 mM showed a significant reduction of 72% when using Fosamax, and 68% when using Ossica. We can state that the viability of tongue squamous cell carcinoma cells decreases as the concentration of bisphosphonates used increases.

Symptoms and Upper Gastrointestinal Mucosal Injury Associated with Bisphosphonate Therapy.

Objective The incidence of osteoporosis is increasing with the rapid aging of the Japanese population. Bisphosphonates are first-line agents used for the treatment of osteoporosis, but they can cause upper gastrointestinal mucosal injury. This study investigated symptoms and upper gastrointestinal mucosal injury associated with oral bisphosphonates. Methods Symptoms were evaluated using the F-scale questionnaire, and esophageal mucosal injury and gastroduodenal ulceration were assessed by endoscopy. Patients were stratified by the type of bisphosphonate (alendronate, risedronate, or minodronate), treatment schedule (once weekly or every four weeks), and the concomitant use of other medications [antithrombotic agents, nonsteroidal anti-inflammatory drugs (NSAIDs), or acid suppressants]. Patients The subjects included 221 patients treated with oral bisphosphonates for at least one month. Results The median F-scale total score was 4 (0-34), reflux score was 2 (0-20), and the mean dyspepsia score was 2 (0-16). Endoscopy showed esophageal mucosal injury of Grade A or worse (Los Angeles classification) in 22/221 patients (10.0%) and gastroduodenal ulcers in 9 patients (4.1%). The dyspepsia score in patients who took minodronate every four weeks was significantly lower (p<0.05) in comparison to patients who took other bisphosphonates. The dyspepsia score was significantly higher (p<0.05) and mucosal injury was significantly more frequent in patients who also used antithrombotic agents and NSAIDs. Conclusion Symptoms and upper gastrointestinal mucosal damage were not necessarily frequent or severe in patients treated with bisphosphonates. However, the concomitant use of bisphosphonates with antithrombotic agents and NSAIDs increased both symptoms and mucosal injury. The symptoms were milder in patients using minodronate once monthly.

Investigation of one bisphosphonate introduced on the structure and the dissolution of bioglass by using NMR and ICP-OES methods

Zoledronate (Z) - one type of bisphosphonate has associated with bioglass (BG) to elaborate composite material for medical applications. The mixture of glass particles in zoledronate solution was stirred, frozen and lyophilized to obtain composite material containing 0.1 wt% of zoledronate (noted composite BG-0.1Z). The NMR analysis highlighted the effects of zoledronate introduced on the structure of bioglass. The ICP-OES method was used to evaluate the dissolution of synthetic composite in a simulated body fluid (SBF). Obtained results show that the introduction of 0.1 wt% of zoledronate affecting to the dissolution and bioactivity of bioglass.

Radiographic bone loss and the risk of medication-related osteonecrosis of the jaw (MRONJ) in multiple myeloma patients-A retrospective case control study.

Risk factors for medication-related osteonecrosis of the jaws (MRONJ) include type and duration of antiresorptive drugs, dental trauma, local anatomy, systemic underlying conditions and therapy, smoking, and the presence of periodontal disease. However, there is a lack of studies elucidating the role of periodontal disease as risk predictor. In the present study, the dental charts of 100 multiple myeloma (MM) patients and 16MM patients who developed MRONJ were studied. Information about age, gender, smoking history, diabetes, steroid drug intake, type and duration of bisphosphonate (BP) treatments, MRONJ status, missing teeth, periapical lesions, widening of the periodontal ligament, and periodontal status was collected. The periodontal status was determined as a percentage of missing bone at the mesial and distal surfaces of each tooth. Multivariable logistic regression was performed to identify risk factors associated with MRONJ. In the selected model, using the COX analysis, categorical bone loss percentage is significantly associated with MRONJ (P=0.009), with hazard ratio 0.042 (high vs low) and 95% CI 0.004 to 0.453. Gender, steroid, Aredia BP type, and periapical are also significant in selected model. In conclusion, advanced alveolar bone loss and missing teeth were strongly related to the occurrence of MRONJ in MM patients.

Dynamic Analyses of the Short-Term Effects of Different Bisphosphonates Using Intravital Two-Photon Microscopy.

ABSTRACTBisphosphonates are commonly used for the treatment of bone disorders such as osteoporosis; however, the mechanism by which they affect the dynamics of living mature osteoclasts in vivo remains unknown. Here, we describe the short‐term effects of different bisphosphonates on controlling the bone resorptive activity of mature osteoclasts in living bone tissues of mice using intravital two‐photon microscopy with a pH‐sensing chemical fluorescent probe. Three types of nitrogen‐containing bisphosphonates, risedronate, alendronate, and minodronate, inhibited osteoclastic acidification during osteoporotic conditions just 12 hours after i.v. injection. Among the three types of drugs, risedronate was the most effective at increasing osteoclast motility and changing the localization of proton pumps, which led to an inhibition of bone resorption. Together, these results demonstrate that the intravital imaging system is a useful tool for evaluating the similarities and differences in currently used antibone resorptive drugs. © 2018 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Positive Effects of Bisphosphonates on Osteogenic Differentiation in Patient-Derived Mesenchymal Stem Cells for the Treatment of Osteoporosis.

Recent evidence from in vitro and in vivo studies indicates that bisphosphonates may promote osteoblastic bone formation and potently inhibit osteoclast activity. However, little is known about the potential effect of bisphosphonates on the recruitment of osteoblastic precursors from patient-derived bone marrow stromal cells due to difficulties in accessing human bone marrow from healthy and disease subjects. In this study, we evaluated the potential of using FDA-approved and clinically utilized bisphosphonates such as alendronate, ibandronate, and zoledronate to enhance the development of bone forming osteoblasts from osteoporosis patient- and healthy-person derived hBMSCs (op-MSCs and hp-MSCs, respectively). hBMSCs were obtained from postmenopausal women without endocrine diseases or receiving hormone replacement therapy. Cells were treated with or without a bisphosphonate (alendronate, ibandronate, and zoledronate) and analyzed over 21days of culture. hBMSC from osteoporosis-patient with bisphosphonates treatment demonstrated a significant increase in Alizarin red staining after 7days compared to that from healthy-person. Calcium contents and alkaline phosphatase (ALP) enzyme activity also demonstrated an increased propensity in hMSCs from osteoporosis-patient compared to those from healthy-person, although there were inter-individual variations. Gene expression levels varied among different donors. There were no significant differences in the effect on the osteoblastic differentiation of hBMSCs among alendronate, ibandronate, and zoledronate. Statistical significance in the osteoblastic differentiation of hBMSCs between the positive control group cultured in osteogenic medium alone and groups cultured in osteogenic medium supplemented with bisphosphonate was not shown either. These results might be due to various cell types of hBMSCs from individual clinical patients and concentrations of bisphosphonate used. Our study using a clinically relevant in vitro model suggests that bisphosphonate treatment is more effective for patients with osteoporosis than its preventive effect for healthy person. In addition, patient-specific responses to bisphosphonates should be considered rather than bisphosphonate type prior to prescription. Further investigations are needed to determine how bisphosphonates influence hBMSCs function to mediate bone quality and turnover in osteoporotic patients. Such studies can generate novel approaches to treat age-related osteoporotic bone loss.

Radiological Aspects of BRONJ after Dental Extractions in Ovariectomized Female Wistar Rats

Experimental study in animal model - female Wistar rats – using two types of bisphosphonates (ibandronic acid and denosumab) for treating osteoporosis induced by ovariectomy, performing extractions in the maxillary central incisors and occurance of bisphosphonates related osteonecrosis of the jaw (BRONJ) after the dental extractions. The appearance of BRONJ in female Wistar rats which had undergone ovariectomy in advance and received two types of bisphosphonates and a comparison between 3 groups show that BRONJ it is first diagnosticated radiological, before it is first signs in oral cavity. Therefore, careful monitoring of patients undergoing bisphosphonate therapy is essential in the clear and accurate diagnosis of BRONJ. According to the experiment conducted by us, the administration of this class of bisphosphonates has antibacterial effects, decrease osteoclasts activity and thus decrease the bone resorption, but as a secondary main effect it induces BRONJ after performing routine dental surgeries.

Restoration of proximal periprosthetic bone loss by denosumab in cementless total hip arthroplasty.

Although bone quality is an important issue in elderly osteoporotic patients who underwent total hip arthroplasty (THA) with a cementless stem, periprosthetic bone mineral density (BMD) in the proximal femur has been reported to be decreased by 15-40% postoperatively. Some authors have examined the use of several types of bisphosphonates to prevent decreases in BMD in the proximal femur after cementless THA; however, few reports have demonstrated success in restoring BMD in the proximal medial femoral bone, such as zone 7. We conducted prospective study comparing patients who underwent cementless THA administered with denosumab (10 patients) and without denosumab (10 patients). BMD around the femoral stem were measured using a DEXA immediately after surgery, and at 6months and at 1year after surgery. No difference was found between the two groups referred to the patient's demographic data. We found that denosumab displayed definitive effects in increasing the % change in periprosthetic BMD at zone 7 by an average of 7.3% in patients with cementless THA, compared to control group who were given only vitamin D. Denosumab is one of a number of anti-osteoporotic agents to have a definitive effect on the restoration of proximal periprosthetic bone loss, especially in zone 7, after cementless THA. Denosumab contributed to the restoration of decreased periprosthetic BMD to normal levels. As the decrease in BMD in the proximal femur after THA is considered to be apparent at 6-12months after surgery, it is believed that prevention of the deterioration of bone quality is important in the proximal femur immediately after cementless THA for elderly female patients with osteoporosis.

Bisphosphonate Induced Osteonecrosis of the Jaws: Our Clinical Experience at King Hussein Medical Center, Amman, Jordan

To describe and analyze the clinical characteristics of bisphosphonate induced osteonecrosis of the jaws (BIONJ) patients diagnosed and treated at King Hussein Medical Center (KHMC), Amman, Jordan. A series of 12 patients with BIONJ was studied and analyzed retrospectively regarding age, gender, underlying disease, type, route and duration of bisphosphonate (BP) administered, site of osteonecrosis, initiating factor and treatment outcome were recorded. Follow-up period ranged from 6 months to 3 years. Patient's age ranged from 45 to 76 year old. Female to male ratio was 2:1. Most patients received IV BP as a part of the therapeutic protocol of their malignant disease; only two patients received oral BP. Mandible was more commonly involved compared to maxilla with a ratio of 5:1. In most patients the exposed necrotic bone was subsequent to an oral surgical intervention; However, in two cases the disease was initiated spontaneously. Complete wound healing was achieved in most of cases within a period ranged from 4 to 8 weeks. Two patients needed a second surgical intervention; However one patient was refractory to treatment and no wound healing achieved. Bisphosphonate (BP) induced osteonecrosis of the jaws is a rare complication of bisphosphonates (BP) therapy. Oral surgical intervention and female gender increase the risk of the disease. Early diagnosis and cessation of BP are essential to achieve success. It seems that some cases of BIONJ are refractory to the known treatment modalities. However, evaluation of treatment protocols may be needed in the future.

Bisphosphonates in multiple myeloma: an updated network meta-analysis.

Bisphosphonates in multiple myeloma: an updated network meta-analysis.

Implications of Creatinine and ALP in the Induction of Osteoporosis by Ovariectomy in Female Wistar Rats

Histological and biochemical assessment of maxillary bone necrosis induced by therapy with two bisphosphonate types used to treat osteoporosis induced in female Wistar rats, evaluation of effects on creatinine and ALP values at different time intervals. Female Wistar rats were ovariectomized to induce osteoporosis. Blood tests for ALP and creatinine were conducted. They received two types of bisphosphonates. Dental extraction was performed in each rat separately; finally, the rats were euthanized. Microscopic evaluation of the tissue fragments collected from the groups of rats was performed for the following parameters: degree of osteonecrosis, bone resorption, inflammatory infiltrate with neutrophils and mononuclear cells, number of osteoclasts, degree of proliferation of fibrous connective tissue, and local neovascularization. The biochemical and subsequently histological investigations for osteonecrosis of the jaw associated with bisphosphonate therapy in rats with induced osteoporosis provide accurate information about the extent of osteonecrosis, bone resorption, inflammatory infiltrate with mononuclear cells and neutrophils, number of osteoclasts, degree of proliferation of fibrous connective tissue, and local neovascularization. This is necessary for positive and differential diagnosis and for the treatment plan.

Bisphosphonate use and the risk of breast cancer: a meta-analysis of observational studies.

To summarize current evidence of the association of bisphosphonate use with breast cancer risk, we used a systematic review and meta-analysis of observational studies to explore this issue. A comprehensive search was conducted on PubMed, EMBASE, and the Cochrane Library. Pooled relative risk (RR) estimates and 95% confidence intervals (CIs) were calculated using the random effects model. Bisphosphonate use was associated with a 16% lower breast cancer risk (pool RR0.84, 95%CI 0.77-0.90, n=8). A protective effect of bisphosphonate was found in cohort studies (RR 0.85, 95%CI 0.80-0.90, n=4) and case-control studies (RR 0.78, 95%CI 0.64-0.96, n=4).We also found that the use of bisphosphonate resulted in a statistically significant reduction in all breast cancer risk (RR 0.87, 95%CI 0.81-0.93) and greater reduction in invasive breast cancer risk (RR 0.78, 95%CI 0.68-0.91) and contralateral breast cancer risk (RR, 0.41; 95% CI, 0.20-0.84).With respect to the type of bisphosphonate, we found that alendronate and etidronate resulted significant reduction in breast cancer risk. The short-term use of bisphosphonate (<1y) led to nonsignificant change (RR 0.93, 95%CI 0.86-1.00), but a significant 26% reduction of breast cancer risk was noted with long-term use (>1y) (RR 0.74, 95%CI 0.66-0.83). Our results supported bisphosphonate as being effective in preventing breast cancer, including invasive and contralateral breast cancer. Furthermore, the long-term use (>1y) of bisphosphonate was more significant in lowering breast cancer risk.

Influence of bisphosphonates on the adherence and metabolism of epithelial cells and gingival fibroblasts to titanium surfaces.

To evaluate the effects of sodium alendronate (SA) and zoledronic acid (ZA), on the adhesion and metabolism of epithelial cells and gingival fibroblasts to titanium surfaces considering cell functions related to an effective mucosal barrier around the implant. Cells were seeded onto titanium discs and incubated for 24h. Then, serum-free DMEM containing selected bisphosphonates (0, 0.5, 1, or 5μM) was added for 24 and 48h. Factors related to the achievement of an effective mechanical and immunological barrier-cell adhesion, viability, collagen epidermal growth factor, and immunoglobulin synthesis-were evaluated. Data were analyzed by Kruskal-Wallis and Mann-Whitney tests as well as by ANOVA and Tukey's tests, (α=0.05). The presence of bisphosphonates culminated in lower cell adhesion to the titanium discs, particularly for SA at 5μM (40%) and ZA at all concentrations (from 30 to 50%, according to increased concentrations). Reduced cell viability occurred after exposing these cells to ZA (40%); however, only 5μM SA-treated cells had decreased viability (30%). Reduced synthesis of growth factors and collagen was observed when cells were reated with ZA (20 and 40%, respectively), while about 70% of IgG synthesis was enhanced. Bisphosphonates negatively affected the adhesion and metabolism of oral mucosal cells, and this effect was related to the type of bisphosphonate as well as to concentration and period of treatment. The negative effects of bisphosphonates on oral mucosal cells can hamper the formation of an effective biological seal in osseointegrated implants.

Zoledronic acid and alendronate sodium and the implications in orthodontic movement.

To evaluate orthodontic tooth movement (OTM) in rats treated with two types of bisphosphonates (BPs), alendronate sodium (A) and zoledronic acid (Z). In all, 15 male Wistar rats were randomly divided into three groups. Group OTM+A: orthodontic tooth movement and subcutaneous administration of alendronate sodium (2.5mg/kg); Group OTM+Z: orthodontic tooth movement and subcutaneous administration of zoledronic acid (0.02mg/kg), and Group OTM: orthodontic tooth movement and subcutaneous injection of saline. The BPs were administered once a day during 25days before OTM started and during 10days of OTM. The left upper first molar was moved with a stainless-steel closed coil spring which delivered an initial force of 0.4N. OTM was measured with a digital caliper comparing the moved and the contralateral side. The histomorphometric analysis counted the number of osteoclasts, inflammatory cells, blood vessels and fibroblasts (n/104 m2 ) in periodontal ligament (PDL) of the distobuccal root. A reduction of 58.3% of OTM was found in Group OTM+A and 99.6% in Group OTM+Z, when compared with Group OTM. There was a significant decrease of osteoclasts and inflammatory cells in BP-treated groups. Blood vessels and fibroblastic cells decreased mainly in Group OTM+Z. Alendronate sodium and zoledronic acid have similar effects on the periodontal tissue during orthodontic treatment in rats. Especially, zoledronic acid can affect orthodontic tooth movement.

Osteonecrosis of the Mandible Associated with Bisphosphonate Treatment

This study analyzes 35 patients with bisphosphonate-related osteonecrosis of the mandible (BRONJ) diagnosed and treated in the Oral and Maxillofacial Surgery Clinic of St. Spiridon Hospital Iasi. The inclusion criteria were in line with the recommendations of the American Association of Oral and Maxillofacial Surgery (AAOMS). The analysis included the underlying disease, the type of bisphosphonate and the route of administration, the duration of treatment as well as the osteonecrosis triggering factor. Surgery was consistent with the condition of the disease, ranging from debridement and sequestrectomy to alveolar marginal and even segmental bone resections. The results of the study were similar with the data from the literature suggesting that the condition is more common in the lower jaw compared to the upper jaw, and the main risk factors are dental extraction and intravenous bisphosphonate administration.

Bisphosphonates use and risk of gastric cancer: an updated meta-analysis of cohort and case-control studies.

Studies evaluating the association between bisphosphonates exposure and gastric cancer (GC) risk have reached inconsistent conclusions. The purpose of this updated meta-analysis was to assess whether bisphosphonates exposure were associated with an increased risk of GC. We searched PubMed and Embase database and reviewed reference lists of retrieved articles to identify potential studies. Study selection and data abstraction were performed by two independent observers. We calculated pooled odds ratios and 95% CIs using the random effects models. The pooled relative risk showed no significant relationship between bisphosphonates exposure and GC risk (adjusted OR, 0.996, 95% CI, 0.860-1.152). The results were stable across stratified analysis on study design, sex, and duration of follow-up and geographic locations. We also investigated whether different types of bisphosphonates affected the pooled RR. Neither use of bisphosphonates, alendronate, nor etidronate was associated with GC risk. Our meta-analysis found no overall association between GC risk and bisphosphonates use. Further studies with large sample size and more covariate adjustments are needed.

Developing efficient protocols for synthesis, antiosteoarthritic, antiinflammatory assessments and docking studies of nitrogen-containing bisphosphonate derivatives

We report herein, two synthetic approaches to three types of nitrogen-containing bisphosphonates (N-BPs) in moderate to high yields (58–88%). Ester cleavage of selected bisphosphonates was undertaken to obtain their N-BP-acid analogs. Based on the reported bisphosphonate properties and the prospective biological prediction using computer-assisted molecular modeling (CAMM), new compounds were evaluated in a mouse model of antigen-induced arthritis (AIA) and the delayed-type hypersensitivity granuloma reaction (DTH-GRA) for chronic inflammation. Pharmacological results showed that N-BP-acids are more favorable for antiarthritis activity than N-BP-esters. On the other hand, the majority of N-BPs revealed good antiinflammatory potency compared to their acid analogs. The results also showed that the presence of a free thiol group in a molecule enhances the anti-inflammatory activity. Furthermore, bioscreening results were in good agreement with the prediction investigation. A hypothesis of molecular modeling study, including fitting of the synthesized compounds into 3D-pharmacophore using Discovery Studio 2.5 software and their docking into the human farnesyl pyrophosphate synthase (hFPPS, PDB code: 2F8C protein) showed good results consistent with the observed pharmacological properties.

Sinusitis and oroantral fistula in patients with bisphosphonate-associated necrosis of the maxilla.

BackgroundThe management of bisphosphonate related necrosis of the jaw has become clinical routine. While approximately two thirds of the lesions are in the mandible, one third is located in the maxilla. In 40–50 % of maxillary necrosis the maxillary sinus is involved, leading to maxillary sinusitis and oro-antral communications.MethodsThis retrospective single center study includes all patients with diagnosis of BP-ONJ of the maxilla and concomitant maxillary sinusitis. The information collected includes age, gender, primary disease, bisphosphonate intake, involving type of bisphosphonate, route of administration and duration of BP treatment previous to surgical treatment and treatment outcome.ResultsA total of 12 patients fulfill the criteria of the diagnosis of maxillary sinusitis associated to maxillary necrosis, of which 6 Patients showed purulent sinusitis. All patients underwent surgical treatment with complete resection of the affected bone and a multilayer wound closure. A recurrence appeared in one patient with open bone and no sign of sinusitis and was treated conservatively.ConclusionsPurulent maxillary Sinusitis is a common complication of bisphosphonate-related necrosis of the maxilla. The surgical technique described can be suggested for the treatment of these patients.

“Bisphosphonates: Possible Modes of Action and Implications for Dental Implant Treatment. A Review of the Literature”

Bisphosphonates (BP) have been commonly used over the past 40 years to treat osteoporosis, Pagets’ disease, hypercalcemia of malignancy, osteolytic lesions of multiple myeloma and bone metastases associated with breast, prostate, lung and other soft tissue tumours. The main aims of this review are to: 1. Highlight the fundamental pharmacophysiological modes of action of both nitrogen and non-nitrogen bisphosphonates on bone 2. Explore their potential effects on oral hard and soft tissues 3. Discuss the implications of bisphosphonate therapy on dental implants, in particular their contribution to implant failure 4. Discuss the current recommendations and guidelines for dental implant therapy in patients receiving bisphosphonate therapy based on the available evidence. Two distinct types of bisphosphonates have been classified and differentiated according to their mode of action, chemical structure, potency, delivery, bioavailability, dosage and half-life. Bisphosphonates are classified as: 1) Nonnitrogen containing bisphosphonates (BP) and 2) Nitrogen containing bisphosphonates (N-BP). 27 studies met the study inclusion and exclusion criteria, with 8 retrospective studies and 2 case series studies evaluating the success rate of dental implants in patients with a history of bisphosphonate use, while the remaining 17 articles consisted of case series and case reports. While there are shortcomings associated with many of the reported studies, there does appear to be a certain risk associated with the both implant placement and the maintanence of osseointegrated implants in patients receiving oral bisphosphonates. A Southern Austrailian study estimated the risk of implant failure in patients receiving oral bisphosphonates to be 0.88%. Late implant failures appear to occur in patients treated with oral bisphosphonate exposure for a period >3 years especially in patients who have existing integrated implants,while early failures appear to occur in patients treated with bisphosphonates before or at the time of implant placement. Although the results from these retrospective studies and case series are conflicting to some extent, they have heightened awareness of the possible complication of BRONJ and bisphosphonate related implant failure from long term bisphosphonate use, be it oral or iv-bisphosphonates.