Use Of Bisphosphonates Research Articles

Abstract P2-02-05: Patterns of adjuvant bone modifying agent use in patients with early-stage breast cancer in the United States

Abstract Background: The bone modifying agents (BMAs), bisphosphonates, reduce risk of cancer recurrence after diagnosis of early-stage breast cancer (EBC), particularly in postmenopausal women, while another BMA, denosumab, has not been shown to improve EBC outcomes. The 2017 American Society of Clinical Oncology (ASCO) and Cancer Care Ontario (CCO) clinical guidelines recommended consideration of adjuvant bisphosphonates for postmenopausal women with EBC who are candidates for adjuvant systemic therapy. Despite this, small survey-based studies suggest that their prescribing is variable. The goal of this study was to evaluate prescribing of adjuvant BMAs in the United States before and after publication of the 2017 ASCO/CCO guidelines (ACGD). Methods: This retrospective cohort study used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database and included 11,740 patients diagnosed with stage I-III breast cancer from 2012 to 2019. We analyzed data on use of BMAs (bisphosphonates or denosumab) in the adjuvant setting, defined as receiving first dose of BMA within 24 months of breast cancer diagnosis and before diagnosis of metastatic disease. Any episodes of BMA use after a metastatic recurrence were excluded. We used Chi-squared test to compare the proportion of patients receiving adjuvant BMAs pre- and post-ACGD. We used univariable and multivariable logistic regression analyses with list-wise missing value deletions to identify predictors of adjuvant BMA prescribing. Results: Of 11,740 patients, 7,391 were diagnosed pre-ACGD and 4,349 post-ACGD. Of the pre-ACGD patients, 545 (7.4%) patients received adjuvant BMAs, and of the post-ACGD patients, 390 (9.0%) patients received adjuvant BMAs. Patients diagnosed post-ACGD were more likely to receive adjuvant BMAs compared with patients diagnosed pre-ACGD (OR 1.23; 95% confidence interval (CI) 1.08-1.42; p=0.002). Of patients age ≥ 50 (n=9,654), 522 of 6,027 (8.7%) and 360 of 3,627 (9.9%) received adjuvant BMAs pre- and post-ACGD, respectively (OR 1.146; 95% CI 0.996-1.319; p=0.0572). In multivariable analysis, age ≥ 50 years at diagnosis, post-menopausal status, having T2 or higher stage at diagnosis, adjuvant endocrine therapy, and coexisting bone loss diagnosis were significantly associated with receipt of adjuvant BMAs (Table 1). Of the 935 patients who received adjuvant BMAs, 615 (65.8%) had denosumab only, 305 (32.6%) had a bisphosphonate only, and 13 (1.4%) received both a bisphosphonate and denosumab during the course of adjuvant treatment. Two patients received an adjuvant BMA as part of a clinical trial. Conclusions: Adjuvant BMA prescribing in our cohort was overall low; there was a modest increase in uptake in patients with EBC diagnosed after the publication of the 2017 ACGD. Older age, higher T stage, endocrine therapy, and coexisting bone loss diagnoses were significantly associated with receipt of adjuvant BMAs. Despite the recommendations for bisphosphonates in the adjuvant setting in EBC, the majority of patients received denosumab only. Considering these findings, further research is required to determine barriers to BMA prescribing and factors that influence physician and patient decisions. There continues to be a need for improved implementation and dissemination of recent guidelines, including the updated 2021 ASCO/CCO recommendations which continue to endorse bisphosphonate use in the adjuvant setting. Table 1: Univariable and multivariable logistic regression analyses to identify predictors of receiving adjuvant BMAs sabs Citation Format: Nicole Odzer, Rachel Jaber Chehayeb, Maryam Lustberg, Cary P. Gross, Julia Foldi. Patterns of adjuvant bone modifying agent use in patients with early-stage breast cancer in the United States [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-02-05.

Investigation of the effect of oral and internal bisphosphonate use on bone density in the jaws in patients with osteoporosis in panoramic radiography

This study aims to quantitatively evaluate the effects of bisphosphonate use duration and route of administration on mandibular cortical and trabecular bone in postmenopausal women. Ninety postmenopausal women over the age of 50 were included in this study. Trabecular bone density was specified numerically by fractal dimension (FD) in the region of interest selected on the panoramic radiograph. The width of the mandibular cortical (MCW) bone under the mental foramen of the mandible was measured. Mann-Whitney U test was used for parameters that did not show a normal distribution. Spearman rho correlation test was used to determine the relationship between continuous measurement parameters. It was observed that FD and MCW of dentate and edentate individuals using bisphosphonate were statistically significantly lower than those of healthy individuals (P < .05). There was no significant correlation was found between the duration of use of bisphosphonates and the fractal values obtained from the relevant regions of the mandible (P > .05). Fractal dimension was found to be lower in oral bisphosphonate use than in intravenous bisphosphonate use. The width of the mandibular cortical bone values was found to be lower in individuals using bisphosphonate than in healthy individuals. Fractal dimension and MCW may benefit clinicians as quantitative parameters in panoramic radiography in the diagnosis of osteoporosis.

No Increased Risk of Nonunion with Bisphosphonate Use in a Medicare Claims Cohort Following Operatively Treated Long-Bone Fractures.

The diagnosis of a fragility fracture represents an important intervention event for the initiation of medical osteoporosis treatments. However, it is unclear if osteoporosis medications increase the risk of nonunion if administered in the setting of acute fracture. The purpose of the present study was to investigate whether bisphosphonates or selective estrogen receptor modulators/hormone replacement therapy (SERM/HRT) are associated with nonunion following fracture in a Medicare population. A retrospective analysis of Medicare claims from 2016 to 2019 was performed to identify patients ≥65 years of age who had a surgically treated long-bone fracture as identified with Current Procedural Terminology (CPT) codes and International Classification of Diseases, 10th Revision (ICD-10) codes. Successive claims were linked for each beneficiary through 1 year following the fracture to determine fracture union status. Multivariable logistic regression models were specified to identify the association between medications and fracture union status while controlling for age, sex, race, Charlson Comorbidity Index (CCI), and fracture type. Of the 111,343 included fractures, 10,452 (9.4%) were associated with a diagnosis of nonunion within 1 year. The nonunion group was younger (79.8 ± 8.3 versus 80.6 ± 8.4 years; p < 0.001), more likely to be White (92.4% versus 90.9%; p < 0.001), and more likely to have a CCI of ≥2 (50.9% versus 49.4%; p < 0.001). Bisphosphonate use was more common in the nonunion group (12.2% versus 11.4%; p = 0.017). When controlling for race, age, sex, and CCI, neither bisphosphonates (OR, 1.06 [95% CI, 0.99 to 1.12]; p = 0.101) nor SERM/HRT (OR, 1.13 [0.93 to 1.36]; p = 0.218) were associated with nonunion. Bisphosphonate use within 90 days post-fracture was not significantly associated with nonunion (OR, 0.94 [95% CI, 0.86 to 1.03]; p = 0.175), and the timing of medication administration did not influence fracture union status. The rate of nonunion after operatively treated long-bone fractures was 9.4%. In this cohort, use of a bisphosphonate or SERM/HRT was not associated with fracture union status at 1 year. Orthopaedic surgeons should not withhold or delay initiating medical therapies for osteoporosis in the setting of acute fracture out of concern for nonunion. Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

Near-Infrared Ratiometric Hemicyanine-Based pH Fluorescence Probe with Bone Targetability for Monitoring Bone Resorption

Accurate detection of bone resorption is extremely important in the orthodontic treatment process as it can provide a basis for clinical treatment strategies. Recently, pH-responsive fluorescence probes have received tremendous attention in bone resorption monitoring owing to their high sensitivity, good specificity, and in situ and real-time detection capabilities, but there are still some shortcomings like the increase in the risk of osteonecrosis of the jaw by use of bisphosphonate as the bone-targeting moiety and the insufficient monitoring accuracy due to susceptibility to interference. Herein, we designed and synthesized a near-infrared ratiometric hemicyanine-based pH fluorescence probe (Hcy-Asp6) with fluorescence-imaging and pH-determining capabilities, and bone targetability for more reliably and safely monitoring the bone resorption in orthodontic treatment. In vitro optical performance tests of Hcy-Asp6 revealed that the probe had high sensitivity, excellent photostability, reversibility, and strong resistance to interference, and the probe suggested excellent bone-binding ability and biocompatibility in the bone-targeting evaluation and the cytotoxicity test. Furthermore, in vitro and in vivo bone resorption monitoring assays demonstrated that this probe can detect bone resorption by fluorescence imaging and quantitative monitoring of pH associated with the bone resorption. Thus, the results indicated that this probe possessing bone targetability and accurate bone resorption-monitoring capability has an extraordinarily great clinical potential to be employed for real-time monitoring of bone resorption in orthodontic treatment and could also serve as a reference in bone resorption monitoring for other bone resorption-related diseases.

Применение бисфосфонатов при экспериментальном туберкулезном остите: КТ-визуализация

Introduction The complex treatment of osteoarticular tuberculosis is based on combination of anti-tuberculosis therapy, complete (radical) removal of involved bone and restoration of the supporting and motor function of the affected musculoskeletal segment. Inhibited activity of osteoclasts involved in osteoresorption as one of the mechanisms of reparative osteoregeneration can be involved in regulation of bone formation after radical reconstructive surgery. The objective was to explore CT signs of osteoregeneration due to multimodal treatment of experimental tuberculous osteitis with use of bisphosphonates as targeted inhibitors of osteoclasts. Material and methods An experimental study was carried out on 21 mature male Chinchilla rabbits. The first stage included bone tuberculosis simulated in the medial condyle of the right femur using invasive local infection with M. tuberculosis strains H37Rv, a virulent reference laboratory strain. Pathological focus was resected and bone graft used at the second stage. Animals receiving antituberculosis therapy (ATT), ATT and bisphosphonates (BP) and BP only were divided into three groups at the third stage. Animals were sacrificed at 3 and 6 months of surgical treatment at the fourth stage. Autopsy implantation zone, bone of the contralateral condyle and intact femur were quantitatively and qualitatively assessed using micro-CT imaging. Results Positive dynamics in bone restoration was seen in the groups. ATT group showed complete lysis of the implant with bone cavities identified and no bone restoration in half of the cases seen at 6 months. Rabbits treated with BP demonstrated absence of complete lysis of the implant and CT signs of ingrowth of bone trabeculae. CT signs of maximum osteoregeneration were noted in the group of isolated BP therapy. Discussion The use of bisphosphonates can prevent lysis of grafts preserving the osteoconductive properties and facilitating formation of new bone. Conclusion Targeted osteoclast inhibitors can be safety and efficaciously used in the complex treatment of focal infectious skeletal lesions and be recommended as a potential component of pathogenetic therapy in the postoperative treatment of infectious (tuberculous) skeletal lesions.

THE CHANGING FACE OF FEMORAL FRAGILITY FRACTURES: INCIDENCE; FRACTURE PATTERNS; AND MANAGEMENT

The purpose of this study was to determine whether there have been changes in the complexity of femoral fragility fractures presenting to our Dunedin Orthopaedic Department, New Zealand, over a period of ten years.Patients over the age of 60 presenting with femoral fragility fractures to Dunedin Hospital in 2009 −10 (335 fractures) were compared with respect to demographic data, incidence rates, fracture classification and treatment details to the period 2018-19 (311 fractures). Pathological and high velocity fractures were excluded.The gender proportion and average age (83.1 vs 83.0 years) was unchanged. The overall incidence of femoral fractures in people over 60 years in our region fell by 27% (p&lt;0.001). Intracapsular fractures (31 B1 and B2) fell by 29% (p=0.03) and stable trochanteric fractures by 56% (p&lt;0.001). The incidence of unstable trochanteric fractures (31A2 and 31A3) increased by 84.5% from 3.5 to 6.4/10,000 over 60 years (p = 0.04). The proportion of trochanteric fractures treated with an intramedullary (IM) nail increased from 8% to 37% (p &lt;0.001). Fewer intracapsular fractures were treated by internal fixation (p&lt;0.001) and the rate of acute total hip joint replacements increased from 13 to 21% (p=0.07). The incidence of femoral shaft fractures did not change significantly with periprosthetic fractures comprising 70% in both cohorts.While there has been little difference in the numbers there has been a decrease in the incidence of femoral fragility fractures likely due to the increasing use of bisphosphonates. However, the incidence of unstable trochanteric fractures is increasing. This has led to the increased use of IM nails which are increasingly used for stable fractures as well.The increasing complexity of femoral fragility fractures is likely to have an impact on implant use, theatre time and cost.

Pharmacological Interventions Targeting Pain in Fibrous Dysplasia/McCune-Albright Syndrome.

Fibrous dysplasia (FD) is a rare, non-inherited bone disease occurring following a somatic gain-of-function R201 missense mutation of the guanine-nucleotide binding protein alpha subunit stimulating activity polypeptide 1 (GNAS) gene. The spectrum of the disease ranges from a single FD lesion to a combination with extraskeletal features; an amalgamation with café-au-lait skin hyperpigmentation, precocious puberty, and other endocrinopathies defines McCune-Albright Syndrome (MAS). Pain in FD/MAS represents one of the most prominent aspects of the disease and one of the most challenging to treat-an outcome driven by (i) the heterogeneous nature of FD/MAS, (ii) the variable presentation of pain phenotypes (i.e., craniofacial vs. musculoskeletal pain), (iii) a lack of studies probing pain mechanisms, and (iv) a lack of rigorously validated analgesic strategies in FD/MAS. At present, a range of pharmacotherapies are prescribed to patients with FD/MAS to mitigate skeletal disease activity, as well as pain. We analyze evidence guiding the current use of bisphosphonates, denosumab, and other therapies in FD/MAS, and also discuss the potential underlying pharmacological mechanisms by which pain relief may be achieved. Furthermore, we highlight the range of presentation of pain in individual cases of FD/MAS to further describe the difficulties associated with employing effective pain treatment in FD/MAS. Potential next steps toward identifying and validating effective pain treatments in FD/MAS are discussed, such as employing randomized control trials and probing new pain pathways in this rare bone disease.

Untreated Atypical Left Femoral Shaft Fracture: A Case Report of Its Complication

Background: Bisphosphonate therapy is used to manage osteoporosis and decrease the risk of vertebral and hip fractures. These drugs act by suppressing osteoclast activity by inducing the inhibition of bone resorption and increasing bone mineral density. It has been shown that long-term use of bisphosphonate is correlated to a higher incidence of atypical femoral fractures. Case report: This is a case report of an 81-year-old female, on bisphosphonate therapy for 12 years and with chronic left thigh pain for two and a half years who developed an incomplete atypical left femur fracture. What’s special about this case is that the fracture was ignored and then progressed after three months into a complete displaced spiral fracture that required surgical fixation. Conclusion: The benefits of bisphosphonate treatment in preventing osteoporotic fractures outweigh the risk of the occurrence of these atypical fractures. Orthopedic surgeons as well as primary care physicians must keep atypical fractures in their differential diagnosis in patients presenting with prodromal symptoms and who are on long-term bisphosphonate therapy

A different indication of pisphosphonates: Bone marrow edema

Abstract Introduction Bone marrow edema (BME) is an uncommonly diagnosed, reversible condition most often affecting the hip of middle-aged men. BME is characterized clinically by the onset of disabling bone pain, usually at a single skeletal site, generally in the lower limbs and most often the hip. Diagnosis is often delayed. The increased bone turnover and low bone mineral density may indicate a potential role for bisphosphonate therapy in BME. There is some evidence of the successful use of intravenous bisphosphonates in the treatment of BME of the hip. We aimed to present two cases of BME that were successfully treated with bisphosphonates. Clinical Case 1: A 41-year-old male patient presented with left inguinal pain. His past medical history was unremarkable. The visual analog scale (VAS) was 8–9. On physical examination, there was a limited range of motion (ROM) on the left hip. Laboratory results were within normal limits. Non-contrast MRI revealed signal intensity changes consistent with BME in the left femoral head and neck of the femur, which was hypointense in T1W sections and hyperintense in T2W sections. With assisted mobilization, 3 mg IV ibandronic acid, calcium and vitamin D replacement was started. Pain control was achieved one week after bisphosphonate infusion. Complete resolution of bone marrow edema was seen in the MRI taken 2 months later (Figure 1). Bisphosphonate treatment with alendronate was completed for one year. Clinical Case 2: A 59-year-old male patient presented with right hip pain that limits his walking. He was diagnosed with BME and avascular necrosis as a result of clinical and radiological evaluation in the center he applied and he underwent a right femoral core decompression operation. He was evaluated in our clinic due to ongoing pain and limitation of movement 5 months after the operation. On physical examination, there was limited ROM on right hip. All the results of laboratory tests were normal. MRI revealed signal changes consistent with bone marrow edema in the right femoral head and neck of the femur, which was hypointense in T1W sections and hyperintense in T2W sections. With assisted mobilization, 3 mg IV ibandronic acid, calcium and vitamin D replacement was started. Pain control was achieved 10 days after bisphosphonate infusion, and he returned to working life 1 month later. Complete resolution of the BME was observed in MRI performed 10 weeks later. Completion of the bisphosphonate treatment with alendronate for 1 year was planned. Conclusion The hip is the most frequently involved joint, with diffuse BME pattern in the femoral head and intertrochanteric region observed on MRI. BME may be a precursor to avascular necrosis when the diagnosis is delayed or the treatment is not well managed. Therefore, optimal timing of medical intervention is very important. Treatment with bisphosphonates is an effective and safe treatment. Additionally, providing early mobilization may prevent the risk of avascular necrosis and the workforce loss.

Factors associated with osteoporosis and fractures in patients with systemic lupus erythematosus: Kyoto Lupus Cohort.

Osteoporosis and compression fractures of the lumbar spine are some of the major adverse effects of glucocorticoid therapy in patients with systemic lupus erythematosus (SLE). This study examined the association between bone mineral density, bone turnover markers, presence of vertebral fractures, and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index in SLE patients. This was a cross-sectional study of 246 outpatients with SLE at the Kyoto University Hospital. Lumbar and femoral bone mineral density was measured with dual-energy X-ray absorptiometry, and the presence of vertebral fractures was determined using X-ray, computed tomography, or magnetic resonance imaging. On multiple regression analysis, both high lumbar and femoral T-scores were associated with the concomitant use of hydroxychloroquine (P = .018 and P = .037, respectively), no use of bisphosphonate or denosumab (P = .004 and P = .038, respectively), high body mass index (P < .001), and low bone-specific alkaline phosphatase level (P = .014 and P = .002, respectively). Vertebral fractures showed a significant association with Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index score (P < .001) and femoral T-score (P < .001). Vertebral fracture was associated with SLE-associated organ damage, and serum bone-specific alkaline phosphatase level is a potentially useful marker for osteoporosis monitoring in SLE patients.

Major aspects of the use of bisphosphonates for dental implants in patients with or without osteoporosis:

Introduction: In the setting of Medication-Related Osteonecrosis of the Jaw (MRONJ) it was first reported in association with the use of bisphosphonates (BP) by maxillofacial surgeons. The potency and route of administration of BPs are identified as important risk factors. Objective: It was to evaluate the use of bisphosphonates and their side effects in patients with or without osteoporosis, with emphasis on osteonecrosis of the jaws, for dental implants. Methods: The systematic review rules of the PRISMA Platform were followed. The search was carried out from October to December 2022 in the Scopus, PubMed, Science Direct, Scielo, and Google Scholar databases, using articles from 2005 to 2022. The quality of the studies was based on the GRADE instrument and the risk of bias was analyzed accordingly. according to the Cochrane instrument. Results and Conclusion: A total of 120 articles were found, and 55 articles were evaluated in full and 34 were included and developed in this systematic review study. Considering the Cochrane tool for risk of bias, the overall assessment resulted in 15 studies with a high risk of bias and 32 studies that did not meet GRADE. For patients with established osteoporosis, there are drugs that, in general, act directly on the bone remodeling process, seeking to reduce bone resorption, including BP, which are drugs of proven efficacy that act in the prevention and treatment of several bone diseases. Osteoporosis is a factor that delays the regeneration of the maxillary bone in patients submitted to implant surgery, prolonging the normal recovery time of the maxillary bone, which can vary from three to six months. Alendronate sodium is used to decrease bone resorption, the drug should be considered an adjuvant therapeutic agent for the treatment of osteoporosis. However, studies have shown that there is a risk of osteonecrosis with the use of bisphosphonates.

Dual targeting with 224Ra/212Pb-conjugates for targeted alpha therapy of disseminated cancers: A conceptual approach.

Metastases are the primary cause of death among cancer patients and efficacious new treatments are sorely needed. Targeted alpha-emitting radiopharmaceuticals that are highly cytotoxic may fulfill this critical need. The focus of this paper is to describe and explore a novel technology that may improve the therapeutic effect of targeted alpha therapy by combining two radionuclides from the same decay chain in the same solution. We hypothesize that the dual targeting solution containing bone-seeking 224Ra and cell-directed complexes of progeny 212Pb is a promising approach to treat metastatic cancers with bone and soft tissue lesions as well as skeletal metastases of mixed lytic/osteoblastic nature. A novel liquid 224Ra/212Pb-generator for rapid preparation of a dual targeting solution is described. Cancer cell targeting monoclonal antibodies, their fragments, synthetic proteins or peptides can all be radiolabeled with 212Pb in the 224Ra-solution in transient equilibrium with daughter nuclides. Thus, 224Ra targets stromal elements in sclerotic bone metastases and 212Pb-chelated-conjugate targets tumor cells of metastatic prostate cancer or osteosarcoma. The dual targeting solution may also be explored to treat metastatic breast cancer or multiple myeloma after manipulation of bone metastases to a more osteoblastic phenotype by the use of bisphosphonates, denosumab, bortezomib or hormone therapy prior to treatment. This may improve targeting of bone-seeking 224Ra and render an augmented radiation dose deposited within metastases. Our preliminary preclinical studies provide conceptual evidence that the dual 224Ra-solution with bone or tumor-targeted delivery of 212Pb has potential to inhibit cancer metastases without significant toxicity. In some settings, the use of a booster dose of purified 212Pb-conjugate alone could be required to elevate the effect of this tumor cell directed component, if needed, e.g., in a fractionated treatment regimen, where the dual targeting solution will act as maintenance treatment.

Bone Morphogenetic Protein 2 Promotes Bone Formation in Bone Defects in Which Bone Remodeling Is Suppressed by Long-Term and High-Dose Zoledronic Acid.

The use of long-term and high-dose bisphosphate is associated with severely suppressed bone turnover and the delayed union of fractures. However, therapeutic methods to overcome the negative effects of bisphosphonate use are lacking. Bone morphogenetic proteins (BMPs) are powerful osteoinductive proteins. The development of the delivery system using BMP has been verified to have an excellent effect on fracture healing and the enhancement of osteointegration. We hypothesized that BMPs had similar effects as autografts in patients with decreased bone healing potential due to long-term bisphosphonate treatment. Forty rats were divided into the following four groups depending upon the materials implanted into the femoral defect after ten weeks of bisphosphonate (zoledronic acid) injections: Group I: absorbable collagen sponge (control); group II: demineralized freeze-dried bone graft; group III: autogenous bone graft; and group IV: rhBMP-2 with an absorbable collagen sponge. Radiographic union, micro-computed tomography (CT) analysis, manual palpation, and histologic analysis were evaluated. The radiographic union rate, manual union rate, and micro-CT bone volume in groups III and IV were significantly higher than those in groups I and II. Groups III and IV showed similar results to each other. Although the amount of immature bone in the BMP-treated group was large, the effect was similar to that of autografts in the bone defect model in which bone turnover was severely reduced by bisphosphonate treatment. BMP might be a good substitute for autografts in patients with decreased bone healing potential due to long-term bisphosphonate treatment.

Medication-induced osteonecrosis of the maxilla, potentiated by fungical infection: Case report

Osteonecrosis of the jaws induced using bisphosphonates refers to a condition characterized by the exposure of necrotic bone, usually in the face region and commonly originating from trauma. Osteonecrosis induced by bisphosphonates has its highest prevalence in the mandible and may be initially manifested by ulcerations in the oral mucosa, which expose the underlying bone due to its poor vascularization and the use of bisphosphonates. Bisphosphonates are indicated for the treatment of several comorbidities, such as malignant tumors, bone metastases, osteoporosis. Actinomycosis is rarely a pathological concern due to the low virulence of the organism, but it can manifest itself when associated with other pathologies such as osteonecrosis. The clinical case presents a patient who made prolonged use of bisphosphonates associated with low-intensity trauma evolving to maxillary osteonecrosis potentiated by actnomyses. This article aims to demonstrate the connection between actinomycosis and chronic osteonecrosis and the importance of correct diagnosis for correct treatment.

Remineralization of lytic spinal metastases after radiotherapy

BACKGROUND CONTEXTPalliative radiotherapy (RT) can lead to remineralization of osteolytic lesions thereby potentially restoring some of the weight-bearing capacity and preventing vertebral collapse. It is not clear, however, under which circumstances remineralization of osteolytic lesions occurs. PURPOSEThe aim of this study was to investigate the change in bone mineral density in spinal metastases after RT compared to a reference region, and find associated factors. STUDY DESIGNRetrospective analysis within prospective observational cohort OUTCOME MEASURESchange in bone mineral density measured in Hounsfield Units (HU). PATIENT SAMPLEpatients treated with RT for (painful) bone metastases. METHODSPatients with spinal metastases were included if computed tomography scans both pre- and post-RT were available. Bone density was measured in HU. A region of interest (ROI) was drawn manually in the metastatic lesion. As a reference, a measurement of bone density in adjacent, unaffected, and non-irradiated vertebrae was used. Factors tested for association were origin of the primary tumor, RT dose and fractionation scheme, and concomitant use of bisphosphonates. RESULTSA total of 31 patients with 49 spinal metastases, originating from various primary tumors, were included. The median age on baseline was 58 years (IQR: 53–63) and median time between baseline and follow-up scan was 8.2 months (IQR: 3.0–18.4). Difference in HU in the lesion before and after treatment was 146.9 HU (95% CI 68.4–225.4; p<.01). Difference in HU in the reference vertebra between baseline and first follow-up was 19.1 HU (95% CI -47.9 to 86.0; p=.58). Difference between reference vertebrae and metastatic lesions on baseline was -194.1 HU (95% CI -276.2 to -112.0; p<.01). After RT, this difference was reduced to -50.3 HU (95% CI -199.6 to 99.0; p=.52). Patients using bisphosphonates showed a greater increase in HU, 194.1 HU versus 60.6 HU, p=.01. CONCLUSIONSPalliative radiation of osteolytic lytic spinal metastases is positively associated with an increased bone mineral density at follow-up. The use of bisphosphonates was linked to an increased bone mineral density when used during or after RT.

Effectiveness and Safety of Treatments to Prevent Fractures in People With Low Bone Mass or Primary Osteoporosis: A Living Systematic Review and Network Meta-analysis for the American College of Physicians.

The prevalence of osteoporosis is increasing in the United States. To evaluate low bone mass and osteoporosis treatments to prevent fractures. Ovid MEDLINE ALL, Ovid Evidence Based Medicine Reviews: Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and ClinicalTrials.gov from 2014 through February 2022. Adults receiving eligible interventions for low bone mass or osteoporosis. Randomized controlled trials (RCTs) for fracture outcomes, and RCTs and large observational studies (n ≥1000) for harms. Abstracted by 1 reviewer and verified by a second. Independent, dual assessments of risk of bias and certainty of evidence (CoE). We included 34 RCTs (in 100 publications) and 36 observational studies. Bisphosphonates and denosumab reduced hip, clinical and radiographic vertebral, and other clinical fractures in postmenopausal females with osteoporosis (moderate to high CoE). Bisphosphonates for 36 months or more may increase the risk for atypical femoral fractures (AFFs) and osteonecrosis of the jaw (ONJ), but the absolute risks were low. Abaloparatide and teriparatide reduced clinical and radiographic vertebral fractures but increased the risk for withdrawals due to adverse events (WAEs; moderate to high CoE). Raloxifene and bazedoxifene for 36 months or more reduced radiographic vertebral but not clinical fractures (low to moderate CoE). Abaloparatide, teriparatide, and sequential romosozumab, then alendronate, may be more effective than bisphosphonates in reducing clinical fractures for 17 to 24 months in older postmenopausal females at very high fracture risk (low to moderate CoE). Bisphosphonates may reduce clinical fractures in older females with low bone mass (low CoE) and radiographic vertebral fractures in males with osteoporosis (low to moderate CoE). Few studies examined participants with low bone mass, males, or Black-identifying persons, sequential therapy, or treatment beyond 3 years. Bisphosphonates, denosumab, abaloparatide, teriparatide, and romosozumab, followed by alendronate, reduce clinical fractures in postmenopausal females with osteoporosis. Abaloparatide and teriparatide increased WAEs; longer duration bisphosphonate use may increase AFF and ONJ risk though these events were rare. American College of Physicians. (PROSPERO: CRD42021236220).

Mandibular Rezeksiyon Sonrası Geniş Kemik Defektinin ve Mandibular Sinirin Rejenerasyonu

Few cases of spontaneous bone regeneration after extensive resection of the jaw bone have been reported, but there are not too many reports that show spontaneous nerve regeneration. In this case, we report spontaneous bone and nerve healing in a 67-year-old female patient. She was diagnosed with medication-related osteonecrosis of the jaw due to previous bisphosphonate use. After segmental resection, stabilization was achieved using a reconstruction plate. Three years later, panoramic radiography was taken, and bone formation was seen horizontally and vertically, not around the plate but on the upside. More than that, the patient didn't feel her low lip since the operation as expected. But after 6 months, in routine check-ups, she discerns the feeling of the lower lip again from the patient. There is approximately 60% sensation compared to the right side.

Central Giant Cell Reparative Granuloma (CGCRG) of the Jaw in Children Treated with Neoadjuvant Bisposphonates: Review and a Case Report.

Central giant cell reparative granuloma (CGCRG) of the jaw is a neoformation localized in the mandible or in the maxillary bone and characterized by fibrous tissue, osteoclast-like giant cells and reactive bone formation. The CGCRG is a less frequent benign tumor but sometimes it is characterized by an aggressive behavior with a very rapid growth. It affects the young adults mainly and the children occasionally. Nowadays no medication therapy is approved for CGCRG in pediatric cases. We present a case of an aggressive form of a mandibular CGCRG in a 5-year child with Arnold-Chiari syndrome. This case is unique for the use of bisphosphonates (BPs) as neoadjuvant therapy in pediatrics. The therapy were administrated with the purpose of arresting the rapid growth of the tumor in order to avoid a demolitive surgery to the young patient. The child was without symptoms and presented an unusual swelling in the left mandible developed in a few weeks. The lesion was diagnosed by a CT scan and it was confirmed by a biopsy performed for histopathological assessment a few days later. The drug therapy consisted of seven cycles iv of Zoledronate associated to Calcium Gluconate. The child was closely observed through clinical and serological evaluations during the following months. About five months after the last cycle of BPs the child underwent CT scan and a conservative surgical treatment, consisted in a deep curettage, was programmed. Seven months after surgery the aesthetic profile of the patient improved and CT scan reported a significant calcic neoapposition in the area of the previous bone lesion. After more than one year from surgery, no relapse was observed. This case report demonstrates that BPs can be used safely in pediatric patients with CGCRG. Especially BPs could have a role as neoadjuvant therapy: If administrated before surgical treatment BPs avoid the necessity of resective surgery and reduce the risk of recurrence in pediatric CGCRG after conservative curettage.

Infections in cancer patients with medication-related osteonecrosis of the jaws

Introduction: The association between bisphosphonates and osteonecrosis of the jaws has been widely reported in the literature. Despite the higher incidence and the poor prognosis in cancer patients, there is still little understanding of risk factors for infectious complications in these patients. Objective: Evaluate the factors associated with infectious events related to osteonecrosis induced by zoledronic acid (ZA) in oncological patients. Methods: It was a retrospective, longitudinal and observational study that included 21 patients and collected the following variables: age; oncological disease; classification of necrosis; affected bone; triggering factor; frequency of ZA use; the number of ZA doses at the time of necrosis; smoking; cancer activity at the time of necrosis; use of corticosteroids; previous or current treatment with chemotherapy, immunosuppressive and antiangiogenics drugs. The outcome of interest was the number of new infection episodes. Results: 33% of patients showed only one infectious event after MRONJ diagnosis, 28.6% of the cases had two, 19% - four, 9.5% - three, one patient had six and another seven infection episodes. Among all the studied variables only the classification of osteonecrosis, Class.2 + 3: 2.06 (±2.08) vs. Class. 1: 0.00 (±0.54)-p: 0.05 and the frequency of ZA use, Monthly: 2.09 (±1.64) vs. Quarterly: 0.25 (±0.46)-p: 0.002 showed highest incidence of infectious events. In the binary logistic regression, monthly use of bisphosphonate (OR:15; 1.34-16.64) and necrosis in the mandible (OR:10.8; 1.0-11.7) were associated with infection. Conclusion: MRONJ in cancer patients can be associated with recurrent infections and mandibular involvement, and monthly ZA use is potential risk factor for poor prognosis.

Treatment of Apical Periodontitis Induced BRONJ with Endodontic Treatment

Bisphosphonate-related osteonecrosis of the jaw (BRONJ), which is one of the serious side effects of bisphosphonates, has an increasing clinical importance due to the widespread use of bisphosphonates in the treatment of many diseases such as osteoporosis, osteopenia, Paget's disease, osteogenesis imperfecta, and multiple myeloma. BRONJ can spontaneously develop in the jawbones. In addition, many factors such as tooth extraction, periodontal diseases, and local trauma can trigger BRONJ. In our case, it was detected that the lesion appearing like BRONJ in the left lower jaw of the 67-year-old female patient with a history of oral bisphosphonate use developed due to apical periodontitis resulting from the tooth numbered 34. Root canal treatment was administered to the relevant tooth of the patient, the fistula tract was closed after this treatment, and as a result of the CBCT examination, it was observed that the enlargement in the necrotic bone area stopped. In addition, the patient's complaints about the relevant tooth disappeared. As a result, endodontic treatment is an effective treatment approach in the treatment of BRONJ developing due to apical periodontitis. In order to avoid the risk of BRONJ, a detailed oral examination should be performed before starting the bisphosphonate treatment, and necessary endodontic, restorative and periodontal treatments should be followed.