Bisphosphonate Group Research Articles

Feasibility and Clinical Value of CT-Guided 125I Brachytherapy for Pain Palliation in Patients With Breast Cancer and Bone Metastases After External Beam Radiotherapy Failure.

Objectives: To evaluate the feasibility and clinical value of CT-guided iodine-125 (125I) brachytherapy for pain palliation in patients with breast cancer and bone metastases after external beam radiotherapy failure.Methods: From January 2014 to July 2016, a total of 90 patients, who had received the standard therapies for bone metastases but still suffered moderate-to-severe pain, were retrospectively studied. About 42 patients were treated with both 125I brachytherapy and bisphosphonates (Group A), and 48 patients were treated with bisphosphonates alone (Group B).Results: In Group A, 45 125I brachytherapy procedures were performed in 42 patients with 69 bone metastases; the primary success rate of 125I seed implantation was 92.9%, without severe complications. Regarding pain progression of the two groups, Group A exhibited significant relief in “worst pain,” “least pain,” “average pain,” and “present pain” 3-day after treatment and could achieve a 12-week-remission for “worst pain,” “least pain,” “average pain,” and “present pain.” The morphine-equivalent 24-h analgesic dose at 3 days, 4 weeks, 8 weeks, and 12 weeks was 91 ± 27, 53 ± 13, 31 ± 17, and 34 ± 12 mg for Group A, and 129 ± 21, 61 ± 16, 53 ± 15, and 105 ± 23 mg for Group B. Group A experienced a lower incidence of analgesic-related adverse events and better quality of life than Group B.Conclusion: The CT-guided 125I brachytherapy is a feasible and an effective treatment for the palliation of pain caused by bone metastases from breast cancer after external beam radiotherapy failure.

Lineage-associated connexin 43 expression in bisphosphonate-exposed rat bones

Expression of signaling proteins in bone cells depends on their embryological mesoderm-derived (e.g. tibia) or cranial neural crest (CNC)-derived (e.g. jaw) origin. Connexin 43 (Cx43) is a gap junction protein that plays an essential role in the mode of action of bisphosphonates (BP). This study aimed to investigate Cx43 expression and the influence of BP application on mesoderm- and CNC-derived bone.Using a rat model, molar extraction and tibia osteotomy with (Group 4) or without (Group 3) previous BP application was performed. Untreated (Group 1) and animals selectively treated with BPs (Group 2) served as controls. Cx43 expression was immunohistochemically determined 12 and 16 weeks postoperatively via a labeling index.Cx43 expression in CNC-derived bone was significantly higher compared with mesodermal bone. BP application decreased Cx43 expression; however, detected expression levels were still higher in jawbone (Group 2 tibia vs jaw: 5.83 ± 5.06 vs 23.52 ± 6.42; p = 0.007). During bone healing after surgical intervention (Group 3) there were no expression differences between tibia and jawbone. BP treatment prior to surgery resulted in significantly lower Cx43 expression in CNC-derived compared with tibia bone (Group 4 tibia vs jaw: 56.84 ± 15.57 vs 16.40 ± 5.66; p < 0.01).Increased Cx43 expression in jaw compared with tibia bone is in line with their embryological origins. A significant Cx43 suppression in jawbone after BP application and surgery might contribute to the selectively altered osseous turnover and development of MRONJ in CNC-derived bone.

(2-Aminobenzothiazole)-Methyl-1,1-Bisphosphonic Acids: Targeting Matrix Metalloproteinase 13 Inhibition to the Bone.

Matrix Metalloproteinases (MMPs) are a family of secreted and membrane-bound enzymes, of which 24 isoforms are known in humans. These enzymes degrade the proteins of the extracellular matrix and play a role of utmost importance in the physiological remodeling of all tissues. However, certain MMPs, such as MMP-2, -9, and -13, can be overexpressed in pathological states, including cancer and metastasis. Consequently, the development of MMP inhibitors (MMPIs) has been explored for a long time as a strategy to prevent and hinder metastatic growth, but the important side effects linked to promiscuous inhibition of MMPs prevented the clinical use of MMPIs. Therefore, several strategies were proposed to improve the therapeutic profile of this pharmaceutical class, including improved selectivity toward specific MMP isoforms and targeting of specific organs and tissues. Combining both approaches, we conducted the synthesis and preliminary biological evaluation of a series of (2-aminobenzothiazole)-methyl-1,1-bisphosphonic acids active as selective inhibitors of MMP-13 via in vitro and in silico studies, which could prove useful for the treatment of bone metastases thanks to the bone-targeting capabilities granted by the bisphosphonic acid group.

The Importance of Alliance between Hematologists and Dentists: A Retrospective Study on the Development of Bisphosphonates Osteonecrosis of the Jaws (Bronj) in Multiple Myeloma Patients.

(1) Background: Multiple myeloma is a rare cancer that primarily affects the bone marrow. Osteoclasts are responsible for increased bone resorption and, therefore, bone destruction. Bisphosphonates are a class of drugs that can slow down bone resorption by reducing the number and action of osteoclasts. Intravenous injections of bisphosphonates (generally Zoledronic Acid) are administered to patients affected by Multiple Myeloma, but BRONJ is described as a serious side effect. This 5-year retrospective study aims to evaluate the efficacy of appropriate dental treatment protocols prior to initiating bisphosphonate therapy to prevent the development of BRONJ. (2) Methods: A total of 99 patients with symptomatic multiple myeloma were involved in this study (41–90 years, mean age 65 years, standard deviation 5 years). The data relating to the visits were tracked using a specific server and consulting the clinical reports. The AAOMS (American Association of Oral and Maxillofacial Surgeons) position was applied for both diagnosis and treatment. A total of 79 patients were examined before the administration of bisphosphonates (group A) and 20 after (group B). (3) Results: The entire sample required dental treatment: 23.2% underwent restorative therapy, 8% endodontic treatments, 44.4% tooth extractions. Periodontal disease was present in 41.4% of the patients. No osteonecrosis was observed in the first group, whereas BRONJ was found in five patients of the second one (25%) and two patients (10%) showed osteosclerotic areas under investigation [OR 0.026 (CI 0.0027 to 0.2454)]. (4) Conclusions: In the literature, there are no precise data about the prevalence of BRONJ. Despite the limitation of the present study, we point out that dental treatment before the treatment with intravenous bisphosphonates can help in reducing the incidence of BRONJ and good dental status is necessary for BRONJ prevention.

The efficacy and safety of bisphosphonate analogs for treatment of osteoporosis after spinal cord injury: a systematic review and meta-analysis of randomized controlled trials.

Rapid bone loss in the early stages of spinal cord injury (SCI) leads to an increased risk of osteoporotic fracture. A meta-analysis was conducted to assess the efficacy and safety of bisphosphonates for the treatment of osteoporosis after SCI. A literature search of the PubMed, EMBASE, Cochrane Library, and Web of Science databases identified nine randomized controlled trials with 206 individuals. This meta-analysis was performed using a random-effects model. The primary outcome was the percent change in bone mineral density (BMD) of the total hip, distal femur, and lumbar spine from baseline to 12 months. Bone turnover markers were secondary outcomes. The incidences of adverse events were assessed in order to evaluate safety. There were significant differences in BMD of the total hip and lumbar spine or serum C-terminal telopeptide between the bisphosphonate and control groups but no difference in adverse events. The percent change in BMD of the distal femur and serum type 1 procollagen N-terminal peptide from baseline to 12 months was not superior in the treatment groups. Osteoclast-mediated bone resorption was inhibited by bisphosphonate administration. Subgroup analyses of participants treated with zoledronate at different sites revealed a beneficial effect on BMD of the total hip and lumbar spine but not the distal femur. Early bisphosphonate administration after SCI was safe and beneficial to the BMD of the total hip and lumbar spine at 12 months.

Incidence and Risk of Venous Thromboembolism in Bisphosphonates and Selective Estrogen Receptor Modulators Treatment in Korea.

BackgroundSelective estrogen receptor modulators (SERMs) were associated with an increased risk of venous thromboembolism (VTE) due to the estrogen effect. In this study, we investigated the effect of SERMs on VTE compared to bisphosphonates (BPs) using the Korean National Health Insurance claims database.MethodsThis was a retrospective cohort study. Women over 50 years old who were first prescribed BPs or SERMs for osteoporosis treatment in 2012 were included. The difference in VTE incidence between the SERMs and BP groups was compared. Both groups were followed up for VTE or PE occurrence, death, or until December 2016. The study population was analyzed by 3:1 matching according to age using a multivariate Cox model.ResultsThe hazard ratio (HR) for VTE was 0.72 (95% confidence interval [CI], 0.40–1.28) in the SERMs group compared to BP group. Older age (60–69 vs. 50–59 years: HR, 3.77; 95% CI, 2.07–6.86 and 70–79 vs. 50–59 years: HR, 5.88; 95% CI, 3.14–11.02), major osteoporotic fracture (HR, 1.77; 95% CI, 1.16- 2.70), atrial fibrillation (HR, 3.31; 95% CI, 1.35–8.11), and estrogen replacement (HR, 3.40; 95% CI, 2.01–5.73) all increased VTE risk. In subgroup analysis of the SERMs group, past hospitalization (HR, 2.24; 95% CI, 1.02–4.92), estrogen replacement (HR, 5.75; 95% CI, 2.29–14.39), and glucocorticoid replacement (HR, 2.71; 95% CI, 1.05–7.0) increased VTE risk.ConclusionSERMs did not increase the risk of VTE compared to BPs in Koreans with osteoporosis. However, old age and estrogen replacement both increased VTE risk.

The impact of bisphosphonates on mortality and cardiovascular risk among osteoporosis patients after cardiovascular disease

Bisphosphonates (BPs) impact on the survival and cardiovascular safety of osteoporosis patients after acute coronary syndrome (ACS) or acute ischemic stroke (AIS) was evaluated. A nationwide epidemiological study was conducted using the Taiwan National Health Insurance Research Database from 2000 to 2010. From the 1456 osteoporosis patients with previous ACS or AIS, mortality and cardiovascular safety was compared between 464 patients who used BPs and 464 patients who did not. Primary outcomes included all-cause mortality, and major adverse cardiovascular events. The BPs group had a lower risk of all-cause mortality than the control group after the 8-year follow-up (HR, 0.64; 95% CI, 0.46-0.88; P=0.006). The risks of myocardial infarction, ischemic stroke, cardiovascular death, hospitalization for heart failure or other causes of mortality were similar across groups. However, there was a higher risk of hospitalization for atrial fibrillation in the BPs group than the control group (HR, 1.76; 95% CI, 1.26-2.46; P=0.001). Among osteoporosis patients after ACS or AIS, BPs use was associated with a reduced risk of all-cause mortality. However, patients with previous cardiovascular disease who received BP treatment should be careful about the risk of atrial fibrillation.

Oral Treatment With Bisphosphonates of Osteoporosis Does Not Increase the Risk of Severe Gastrointestinal Side Effects: A Meta-Analysis of Randomized Controlled Trials.

IntroductionBisphosphonates (BPs) are first-line therapy for osteoporosis. Adherence is usually low in chronic, asymptomatic diseases, but gastrointestinal (GI) side-effects can also contribute to low adherence in BP therapy and may necessitate a review by a gastroenterologist with or without gastroscopy.AimsOur meta-analysis aims to determine the risk of severe GI adverse events due to oral BP therapy in osteoporotic patients.MethodsA systematic search was conducted in three databases up to September 2020 for randomized controlled trials (RCTs) detailing GI adverse events in adults with osteoporosis on BP compared to placebo. Risk ratios (RRs) with 95% confidence intervals (CI) were calculated for non-severe and severe adverse events indicating endoscopic procedure with the random-effects model. Statistical heterogeneity was assessed using chi2 and I2 statistics.ResultsForty-two RCTs with 39,047 patients with 9,999 non-severe and 1,503 severe GI adverse events were included. The incidence of non-severe and severe adverse events ranged between 0.3–54.9 and 0–10.3%, respectively. There was no difference between BP and control groups in terms of the risk of non-severe or severe side effects: RR=1.05 (CI: 0.98–1.12), I2 = 48.1%, and RR=1.01 (CI: 0.92–1.12), I2 = 0.0%, respectively. Subgroup analysis of the most commonly used BP, once-weekly alendronate 70 mg, revealed an association between bisphosphonates and the risk of non-severe GI adverse events, RR=1.16 (CI: 1.00–1.36), I2 = 40.7%, while the risk of severe GI side effects was not increased in this subgroup, RR=1.20 (CI: 0.83–1.74), I2 = 0.0%.ConclusionOur results show that bisphosphonates do not increase the risk of severe GI adverse events. However, the marked variability of the screening for side effects in the included studies, and the fact that in most of the studies GI diseases were exclusion criteria limits the strenght of evidence of our results. The conclusions drawn from the meta-analysis are therefore restricted to selected populations, and the results must be interpreted with caution.

Synthesis and biological evaluation of indolylglyoxylamide bisphosphonates, antimitotic microtubule-targeting derivatives of indibulin with improved aqueous solubility

Indibulin (D-24851) derivatives with bisphosphonate fragment connected to the N1 atom of imidazole ring were synthesized by alkylation of (indolyl-3)methylglyoxylates with ethylenebisphosphonate. Biological evaluation of targeted compounds 4a–d using the phenotypic sea urchin embryo assay provided evidence that replacing of p-chlorobenzene ring in indibulin by bisphosphonate group did not eliminate antimitotic microtubule destabilizing activity. The most active molecule, tetraacid 5a, at physiological pH formed tetrasodium salt 6a with aqueous solubility value of at least 10 mg/mL. Molecule 5a was more potent in the sea urchin embryo assay than the parent indibulin. This compound also exhibited pronounced cytotoxicity against A549 lung carcinoma and A375 melanoma cell lines.

The Type of Antiresorptive Treatment Influences the Time to Onset and the Surgical Outcome of Medication-Related Osteonecrosis of the Jaw

Few data exist focusing on differences in the time to disease onset and the success rates in patients suffering from medication-related osteonecrosis of the jaw (MRONJ) dependent on their different antiresorptive treatment. The purpose of this study was to analyze and compare these variables for patients treated with bisphosphonate (BP) or denosumab (DNO) and for patients who switched the antiresorptive drug (BP/DNO). A retrospective single-center cohort study with patients suffering from MRONJ was conducted. The predictor variable was the antiresorptive treatment, the outcome variables were 1)time to onset of MRONJ (time of antiresorptive treatment to MRONJ diagnosis) and 2) treatment success (mucosal integrity 12months postoperatively). The other variables include data on demographic, underlying disease, MRONJ stage, and trigger events. Cox and logistic regression, Phi-coefficient, Cramer's V, and Kruskal-Wallis tests were applied. One hundred thirty-two patients were included and divided into 3 groups: group I (BP) n=45 patients, n=59 lesions; group II (BP/DNO) n=42 patients, n=71 lesions; and group III (DNO) n=45 patients, n=62 MRONJ lesions. Treatment success and time to onset differed significantly between the groups: success rates in group I BP (84.7%) were significantly lower (P=.04) than in group II BP/DNO (91.5%, P=.12) and group III DNO (90.3%, P=.35). The onset was significantly earlier in group III DNO (median 2.0years, Q0.25: 1.49, Q0.75: 2.98; confidence interval 95%: 1.93 to 2.83) than in group II BP/DNO (median 4.07years, Q0.25: 1.64, Q0.75: 6.70; confidence interval 95%: 3.55 to 5.68) and group I BP (median 3.86years, Q0.25: 1.69, Q0.75: 6.46; confidence interval 95%: 3.43 to 5.87). The different antiresorptive drugs show distinctive characteristics of time to onset and treatment success with the lowest success rates in the BP group and the earliest onset in the DNO group. The switch of the antiresorptive therapy (BP to DNO) did not influence the outcome variables negatively.

Mesenchymal Stem Cells Coated with Synthetic Bone-Targeting Polymers Enhance Osteoporotic Bone Fracture Regeneration.

Osteoporosis is a progressive skeletal disease characterized by reduced bone density leading to bone fragility and an elevated risk of bone fractures. In osteoporotic conditions, decrease in bone density happens due to the augmented osteoclastic activity and the reduced number of osteoblast progenitor cells (mesenchymal stem cells, MSCs). We investigated a new method of cell therapy with membrane-engineered MSCs to restore the osteoblast progenitor pool and to inhibit osteoclastic activity in the fractured osteoporotic bones. The primary active sites of the polymer are the N-hydroxysuccinimide and bisphosphonate groups that allow the polymer to covalently bind to the MSCs’ plasma membrane, target hydroxyapatite molecules on the bone surface and inhibit osteolysis. The therapeutic utility of the membrane-engineered MSCs was investigated in female rats with induced estrogen-dependent osteoporosis and ulnar fractures. The analysis of the bone density dynamics showed a 27.4% and 21.5% increase in bone density at 4 and 24 weeks after the osteotomy of the ulna in animals that received four transplantations of polymer-modified MSCs. The results of the intravital observations were confirmed by the post-mortem analysis of histological slices of the fracture zones. Therefore, this combined approach that involves polymer and cell transplantation shows promise and warrants further bio-safety and clinical exploration.

Root canal treatment of compromised teeth as alternative treatment for patients receiving bisphosphonates: 60-month results of a prospective clinical study.

This 60-month prospective study aimed to evaluate tooth survival and healing rates after root canal treatment in patients taking bisphosphonates (BPs). Secondary outcomes were complications and clinical variables observed during and after treatment. Root canal treatment was performed using manual K-file canal instrumentation and a carrier-based filling technique with an epoxy resin-based sealer. Teeth without adequate root/crown integrity were restored by trained operators at the tissue level (TL group) to prevent occlusal/mechanical stress and to enable periapical lesion healing without the risk of root fracture. Other teeth were restored with normal occlusal contacts (OC group). Healthy patients who had undergone one or more root canal treatments of the same type constituted the control group. The relationships of the following variables to survival and health status were examined (chi-squared test and multivariate analysis, P=0.05): age, gender, smoking habit, tooth location, treatment type, BPs treatment, BPs exposure, initial periapical index (PAI) and occlusal restoration. Survival curves were constructed using Kaplan-Meier analysis, with extraction serving as the end-point. In total, 65 patients with 109 root canal-treated teeth who were taking BPs were included. At 60months, data from 57 patients (52F, 5M; median age 65.7±8.6years) who had undergone 96 root canal treatments were analysed (drop-out rate=16.9%). The survival rate was 85%, and the success rate was 76%. The control group consisted of 46 patients (21F, 25M; median age 60.3±7.2years) who had undergone 102 root canal treatments. The survival rate was 88%, with 12 teeth lost during follow-up. The success rate was 73%. In the BP group, 55 teeth were restored normally (OC group) and 41 teeth were restored at the tissue level (TL group). No difference in the success or survival rate was observed between the BP and control groups (P>0.05). Univariate Kaplan-Meier analysis revealed that only tooth type significantly affected survival status in the BP group. The analysis revealed the clinical relevance of smoking, tooth location and initial PAI on patients' health status (P<0.05). Root canal treatments and post-endodontic restoration with tissue-level filling procedures represent a safe approach for severely damaged teeth in patients receiving BPs having comparable results to root filled teeth restored with occlusal contacts and to the control group.

Incidence of and risk for osteonecrosis of the jaw in Korean osteoporosis patients treated with bisphosphonates: A nationwide cohort-study.

To estimate the incidence of osteonecrosis of the jaw (ONJ) in patients treated with bisphosphonates (BPs) and to identify clinical risk factors that increase the risk for ONJ in Korean osteoporosis patients. We used data acquired from the Korean National Health Insurance Service. Among 2,140,149 participants with osteoporosis in 2012, we selected 164,926 new BP users and 164,926 age- and sex-matched control subjects. The control group included only patients with no prescriptions for BPs between January 1, 2011, and December 31, 2016. Participants were followed for 4years. Over the 4-year follow-up period, the cumulative incidence rates of ONJ were 20.9 and 6.9 per 100,000 person-years in the BP and control groups, respectively. The BP group had an increased risk for ONJ compared to the control group after adjusting for multiple variables (hazard ratio [HR] 3.72, 95% CI 2.70-5.11). Advanced age (≥70years), comorbid diseases such as diabetes, hypertension, and rheumatoid arthritis (RA) were independent risk factors for the development of ONJ. In addition, tooth extraction (HR 9.85), gingivitis, and periodontal disease (HR 4.78) were strongly associated with ONJ. ONJ incidence was 21 per 100,000 person-years in osteoporosis patients receiving bisphosphonates. Clinical factors including advanced age, diabetes, RA, dental disease, as well as BP use were significantly associated with ONJ.

Bisphosphonate Versus Bisphosphonate and Calcitonin for the Treatment of Moderate to Severe Hypercalcemia of Malignancy.

Historically, intravenous (IV) bisphosphonates with calcitonin are the treatment of choice for hypercalcemia of malignancy. However, evidence is lacking. The objective of this study was to compare the use of bisphosphonate versus bisphosphonate with calcitonin for moderate to severe hypercalcemia of malignancy. This was a retrospective study evaluating patients who received bisphosphonate and/or calcitonin for treatment of moderate to severe hypercalcemia of malignancy. Patients received usual care plus either (1) bisphosphonate or (2) bisphosphonate with calcitonin. The primary outcome was change in corrected serum calcium concentrations 48 hours after treatment. Secondary outcomes included corrected calcium levels, incidence of normocalcemia and hypocalcemia, time to normocalcemia, hospital length of stay, and cost avoidance. The 48-hour decrease in corrected calcium was less in the bisphosphonate group than in the combination group (2.4 [1.6-3.4] vs 3.9 [3.5-5.3]; P < 0.001). However, initial calcium levels in the combination group were higher than in the bisphosphonate group, and calcium levels at 24, 48, and 72 hours were similar. Secondary outcomes did not differ. Average cost avoidance with bisphosphonate monotherapy was $11 248 per patient and $291 448 per year. In the treatment of moderate to severe hypercalcemia of malignancy, IV bisphosphonate in combination with calcitonin resulted in a higher difference in corrected calcium levels at 48 hours compared with bisphosphonate therapy alone. However, corrected calcium levels in the first 72 hours, time to normocalcemia, and clinical outcomes were similar. The addition of calcitonin increases cost without substantial clinical benefit, and providers may consider avoiding calcitonin.

Effect of bisphosphonates or teriparatide on mechanical complications after posterior instrumented fusion for osteoporotic vertebral fracture: a multi-center retrospective study

BackgroundThe optimal treatment of osteoporosis after reconstruction surgery for osteoporotic vertebral fractures (OVF) remains unclear. In this multicentre retrospective study, we investigated the effects of typically used agents for osteoporosis, namely, bisphosphonates (BP) and teriparatide (TP), on surgical results in patients with osteoporotic vertebral fractures.MethodsRetrospectively registered data were collected from 27 universities and affiliated hospitals in Japan. We compared the effects of BP vs TP on postoperative mechanical complication rates, implant-related reoperation rates, and clinical outcomes in patients who underwent posterior instrumented fusion for OVF. Data were analysed according to whether the osteoporosis was primary or glucocorticoid-induced.ResultsA total of 159 patients who underwent posterior instrumented fusion for OVF were included. The overall mechanical complication rate was significantly lower in the TP group than in the BP group (BP vs TP: 73.1% vs 58.2%, p = 0.045). The screw backout rate was significantly lower and the rates of new vertebral fractures and pseudoarthrosis tended to be lower in the TP group than in the BP group. However, there were no significant differences in lumbar functional scores and visual analogue scale pain scores or in implant-related reoperation rates between the two groups. The incidence of pseudoarthrosis was significantly higher in patients with glucocorticoid-induced osteoporosis (GIOP) than in those with primary osteoporosis; however, the pseudoarthrosis rate was reduced by using TP. The use of TP also tended to reduce the overall mechanical complication rate in both primary osteoporosis and GIOP.ConclusionsThe overall mechanical complication rate was lower in patients who received TP than in those who received a BP postoperatively, regardless of type of osteoporosis. The incidence of pseudoarthrosis was significantly higher in patients with GIOP, but the use of TP reduced the rate of pseudoarthrosis in GIOP patients. The use of TP was effective to reduce postoperative complications for OVF patients treated with posterior fusion.

Clinical and Radiographic Evaluation of Combined Treatment with Bisphosphonate Plus Platelet-Rich Fibrin versus Platelet-Rich Fibrin Alone for Severe Periodontitis with Furcation Defects

Background: This research assessed the clinical and radiographic evaluation of treatment with PRF plus bisphosphonate, compared to alone PRF in treatment of severe periodontitis with furcation defects. Methodology : This randomized, controlled radiological and clinical study enrolled 50 patients. All patients were given oral health instructions, oral prophylaxis, root planning, and relief of trauma from occlusion. The sites for therapy with PRF and PRF plus bisphosphonate were chosen randomly by the coin toss method. After they had received 6 weeks of presurgical therapy, patients underwent further clinical assessments by using different indices and assessment of level of attachment Radiographic outcomes were bone defect height, defect width, and defect depth; these were used to determine the bone defect volume. Results: This study revealed with positive results in all clinical assessments in the PRF plus bisphosphonate, as compared to PRF alone group with significant p value of less than 0.05. All radiographic parameters showed greater degrees of reduction in the parameters of platelet-rich fibrin plus bisphosphonate group, compared to the platelet-rich fibrin alone group; however, only the defect width of bone and defect volume were statistically significantly reduced in the platelet-rich fibrin plus bisphosphonate group, in comparison to the platelet-rich fibrin. Conclusion: Platelet-rich fibrin plus bisphosphonate therapy was beneficial in regeneration of periodontal ligament and improvement of periodontal status.

AB0081 THE ROLE OF LOCAL BISPHOSPHONATES IN THE PRESERVATION OF THE BMD IN THE ZONE OF SURGICAL BONE DEFECT (ANIMAL STUDIES)

Background:One of the reasons for failures in Arthroplasty is the preservation in the postoperative period in the bone adjacent to the implant of the prevalence of resorption over bone formation. The possibility of inhibition of resorption by bisphosphonates, including their local use in the composition of the biocomposite material, aggravates the situation due to the simultaneous oppression of bone formation. A low level of remodeling in these cases leads to a further loss of bone mass in the intervention zone.Objectives:To evaluate in the experiment the effect of bisphosphonates in the biocomposite material on the bone mass both in the surgical intervention zone and in the segment as a whole.Methods:The study was conducted as a comparison with the control. 60 females of white non-linear rats, body weight 130-150 g. were divided into 6 groups. In 3 groups, the defect of the tibia was filled with a biocomposite material in the form of a gel (patent No. 2325170) connected to various bisphosphonates Ibandronic acid (Bonviva), zoledronic acid (Aklasta), alendronate sodium (Fosamax) was used in conjunction with a non-demineralized lyophilized bone implant. Groups, the defect was filled with a non-demineralized lyophilized bone implant with biocomposite material without bisphosphonate, in the second control group, non-demineralized lyophils th e bone implants without biocomposite matreiala in tretey- defect is not filled.Assessment of bone mineral density (BMD) in the intervention area and in the segment as a whole was performed using X-ray densitometry (Hologic, Small Animals Program Performing and Analyzing Small Animal Studies). Results Comparison (simple dispersion analysis) of the MIC of all groups using bisphosphonates on the one hand, with the MIC of all control groups on the other hand, revealed significant differences (p &lt;0.002).Results:The analysis, using the paired t-test, the average MIC values in the combined group using bisphosphonates and the pooled control group, confirmed that the BMD in the zone of intervention in the bisphosphonate group was significantly higher than in the control: 0.320 ± 0.008 g / cm2, respectively, versus 0.285 ± 0.019 g / cm2 (p = 0.002). If the group was excluded from the analysis, where the defect was not filled, the tendency to differences remained: 0.320 ± 0.008 g / cm2 vs. 0.308 ± 0.002 g / cm2 (p = 0.11).Mean BMDs of the whole segment with the use of bisphosphonates also proved to be significantly higher than in the control, both with the inclusion in the analysis of the group without replacement of the defect, and with its exception. Thus, when all control groups were included in the analysis, the mean MIC values in the group with bisphosphonates were 0.30 ± 0.01 g / cm2 vs. 0.272 ± 0.12 g / cm2 (p &lt;0.001). When excluding from the analysis of the group without replacement of the defect, the MIC values were respectively: 0.307 ± 0.01 g / cm2 versus 0.285 ± 0.01 g / cm2 (p = 0.01).Conclusion:Relative to the control, an increase in BMD in the group using bisphosphonates excludes the possibility of their negative impact on the process of bone formation. The marked positive bone balance confirms the ability of bisphosphonates to maintain the remodeling mechanism at the physiological level.

Bisphosphonates Can Maintain Periprosthetic Bone Mass Density after Total Hip Replacement, with Controversy in Region of Interest 5.

Total hip replacement (THR) is the standard surgical treatment of hip diseases. Periprosthetic bone mass density (BMD) loss may be a cause for revision surgery. Bisphosphonates (BPs) are now the principal class medications for osteoporosis. To demonstrate the effect of BPs on treating periprosthetic osteoporosis after THR via a meta-analysis of randomized controlled trials (RCTs). A comprehensive search of PubMed, EMBASE, the Web of Science and the Cochrane Central Register of Controlled Trials was performed for RCTs on the effect of BPs on treating periprosthetic osteoporosis after THR and clinical outcomes relative to controls. The primary outcome measures were the change in BMD in each region of interest (ROI), the change in serum bone turnover marker levels, the change in functional parameters and the risk of adverse effects (AEs). The final search was performed in March, 2020. Nine RCTs were included. A total of 359 patients met the inclusion criteria. BPs can clearly maintain periprosthetic BMD in ROIs at 1, 2, 3, 4, 6 and 7 at 6, 12 and 24 months. In addition, BPs can clearly decrease serum procollagen type 1 N-terminal propeptide (P1NP) levels at 12 months. There was no significant difference in the risk of AEs between the BP and control groups; however, BPs can cause more patients to decline participation. BPs can effectively maintain overall periprosthetic BMD, but BMD in ROI 5 remains controversial. In addition, the safety of BPs is relatively high, but the compliance may be relatively low.

Evolving spectrum of drug-induced uveitis at the era of immune checkpoint inhibitors results from the WHO's pharmacovigilance database

PurposeDrug-induced uveitis is a rare but sight-threatening condition. We seek to determine the spectrum of drug-induced uveitis at the era of immune checkpoint inhibitors (ICI). MethodsRetrospective pharmacovigilance study based on adverse drug reactions reported within VigiBase, the WHO international pharmacovigilance database. We included deduplicated individual case safety reports (ICSRs) reported as ‘uveitis’ at Preferred Term level according to the Medical Dictionary for Drug Regulatory Activities between 1967 and 04/28/2019. We performed a case/non-case analysis to study if suspected drug-induced uveitis were differentially reported for each suspected treatment compared to the full database. We excluded drugs with potential indication bias. Results1404 ICSRs corresponding to 37 drugs had a significant over-reporting signal with a median age of 57 [42–68] years and 45.7% of males. We identified five major groups of treatments: bisphosphonates (26.9%), non-antiviral anti-infectious drugs (25.4%), protein kinase inhibitors (15.5%), ICI (15.0%), and antiviral drugs (11.1%). Severe visual loss was reported in 12.1% of cases. ICI and protein kinase inhibitors were the most recently emerging signals. The time to onset between first infusion and uveitis was significantly different between groups ranging from 5 days [2–19] in the bisphosphonate group to 138.5 [47.25–263.75] in protein kinase inhibitors group (p < 0.0001). Anti-Programmed Cell death 1 represented more than 70% of ICI-induced uveitis. We identified Vogt-Koyanagi-Harada (VKH)-like syndrome as being associated with ICI use. ConclusionsThe spectrum of drug-induced uveitis has changed with the evolution of pharmacopeia and the recent emergence of ICIs. VKH-like syndrome has been reported with ICI and protein kinase inhibitors therapy.

A New [68Ga]Ga-HBED-CC-Bisphosphonate as a Bone Imaging Agent.

Positron emission tomography (PET) imaging using 68Ga-labeled bisphosphonates to target bone metastasis could be a valuable tool in cancer diagnosis and monitoring therapeutic treatment. A 68Ga labeled ligand, N,N'-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid (HBED-CC) containing one bisphosphonate group (HBED-CC-BP, 1) was prepared and evaluated. The new ligand, 1, reacted rapidly to form [68Ga]Ga-1, via complexing with [68Ga]GaCl3 eluted from a commercially available 68Ge/68Ga generator (in a sodium acetate buffer at pH 4, reaching >95% labeling yield at room temperature in 5 min). The resulting [68Ga]Ga-1 showed excellent stability in vitro and in vivo. [68Ga]Ga-1 displayed high binding affinity to hydroxyapatite and good uptake in the tibia and femur bone of normal mice. Biodistribution and MicroPET imaging studies of [68Ga]Ga-1 in normal mice and rats showed excellent bone uptake and retention comparable to that of Na[18F]F. The results suggested that [68Ga]Ga-1 might be suitable as a bone imaging agent in humans and it could be useful as a convenient alternative to the current bone imaging PET agent, Na[18F]F, without the need of a near-by cyclotron. Also, an automated synthesis module was developed to produce clinical doses of [68Ga]Ga-1 in a consistent and reproducible manner. Currently, the investigation new drug application (IND) for [68Ga]Ga-HBED-CC-BP, [68Ga]Ga-1, has received FDA approval, and it is currently under clinical trial (IND #129870).