Administration Of Bisphosphonates Research Articles

Preoperative prediction for periprosthetic bone loss and individual evaluation of bisphosphonate effect after total hip arthroplasty using artificial intelligence.

This study was designed to develop a model for predicting bone mineral density (BMD) loss of the femur after total hip arthroplasty (THA) using artificial intelligence (AI), and to identify factors that influence the prediction. Additionally, we virtually examined the efficacy of administration of bisphosphonate for cases with severe BMD loss based on the predictive model. The study included 538 joints that underwent primary THA. The patients were divided into groups using unsupervised time series clustering for five-year BMD loss of Gruen zone 7 postoperatively, and a machine-learning model to predict the BMD loss was developed. Additionally, the predictor for BMD loss was extracted using SHapley Additive exPlanations (SHAP). The patient-specific efficacy of bisphosphonate, which is the most important categorical predictor for BMD loss, was examined by calculating the change in predictive probability when hypothetically switching between the inclusion and exclusion of bisphosphonate. Time series clustering allowed us to divide the patients into two groups, and the predictive factors were identified including patient- and operation-related factors. The area under the receiver operating characteristic (ROC) curve (AUC) for the BMD loss prediction averaged 0.734. Virtual administration of bisphosphonate showed on average 14% efficacy in preventing BMD loss of zone 7. Additionally, stem types and preoperative triglyceride (TG), creatinine (Cr), estimated glomerular filtration rate (eGFR), and creatine kinase (CK) showed significant association with the estimated patient-specific efficacy of bisphosphonate. Periprosthetic BMD loss after THA is predictable based on patient- and operation-related factors, and optimal prescription of bisphosphonate based on the prediction may prevent BMD loss.

Bisphosphonates Maintain BMD after Sequential Teriparatide and Denosumab in Premenopausal Women with Idiopathic Osteoporosis.

We previously reported that sequential teriparatide followed by denosumab substantially increases BMD in premenopausal idiopathic osteoporosis (PremenIOP). To determine whether administration of bisphosphonates after denosumab cessation is associated with stable BMD in PremenIOP. Open-label extension study. 24 PremenIOP Teriparatide-Denosumab Study participants. Oral alendronate (ALN), 70mg weekly, or IV zoledronic acid (ZOL), 5mg once (patient choice), was administered 7 months (M) after final denosumab dose. BMD by DXA and serum C-telopeptide (CTX) q6M; vertebral fracture assessment (VFA) and HR-pQCT q12M. 24 women with PremenIOP (aged 43 ± 8 years), severely affected with low trauma adult fractures (range 0-12; 9 with vertebral fractures) and/or very low BMD, had large BMD increases on sequential teriparatide-denosumab (spine: 25 ± 9%; total hip: 11 ± 6%). During the Bisphosphonate Extension, mean BMD and CTX changes in the entire group were small and not statistically significant at 6 or 12M.Women choosing ZOL (n = 6) versus ALN (n = 18) did not differ by baseline age, BMI, fractures, BMD, or CTX. On ZOL, there were small LSBMD declines and CTX increases, particularly between 6M and 12M, while greater stability was observed on ALN.Changes in BMD and CTX did not differ by duration of denosumab (36M vs <36M) or between 20 women who remained premenopausal and 4 who transitioned into menopause. Higher pre-teriparatide CTX, likely reflecting baseline remodeling status, predicted more spine and hip bone loss. No new vertebral (clinical or VFA screening) or non-vertebral fractures occurred. BMD remained stable in women with PremenIOP who received bisphosphonates after sequential teriparatide-denosumab therapy.

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

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

Current vision on mechanism of action of bisphosphonates. The effect of long-term administration of bisphosphonates on bone tissue (preclinical studies)

Osteoporosis (OP) is one of the common chronic diseases in the elderly, which requires long–term therapy. Bisphosphonates (BP) belong to the first-line choice medications for the treatment of OP, however, prolonged period of bisphosphonates use has been associated with increased risk of atypical femoral fractures (AFFs), medication-related osteonecrosis of the jaw (MRONJ) and the impact on fracture healing, which attracts increased attention to the current widespread use of them.The article presents the existing classes of BP according to their chemical structure and mechanism of action, differences in their antiresorptive potencies. The data of studies on animal models on the effect of BP on the mechanical properties of bone, fracture repair, as well as the development of MRONJ are presented.

Bone-Modifying Agents in Patients With High-Risk Metastatic Castration-Sensitive Prostate Cancer Treated With Abiraterone Acetate

The association between the use of bone-modifying agents (BMAs) and the outcomes among patients with metastatic castration-sensitive prostate cancer (mCSPC) treated with abiraterone acetate plus prednisone (AAP) remains unclear. To investigate the association between BMA use and the outcomes of patients with mCSPC receiving AAP. In this cohort study, a post hoc analysis of individual participant data from the LATITUDE trial was performed. The LATITUDE trial, a phase 3 randomized clinical trial, aimed to assess the efficacy of AAP and androgen deprivation therapy (ADT) vs dual-placebo and ADT in patients with high-risk mCSPC (data cutoff, August 15, 2018). Eligible patients had newly diagnosed prostate cancer with metastases and at least 2 of 3 high-risk factors (Gleason score ≥8, presence of ≥3 lesions on bone scan, or presence of measurable visceral metastasis). The trial was conducted at 235 sites in 34 countries. Data for the present study were evaluated from July 18 to September 23, 2023. Use of BMAs was defined as the administration of bisphosphonates and denosumab within 90 days before and after randomization. The primary outcomes were time to skeletal-related events (SREs) and overall survival (OS). An SRE was defined as a clinical or pathological fracture, spinal cord compression, palliative radiation to bone, or surgery involving bone. Differences in these outcomes were examined using the restricted mean survival time from inverse probability of treatment weighting-adjusted Kaplan-Meier curves, estimated until the last event was observed (longest time observed, 63.9 months). Treatment × covariate interactions were analyzed using weighted Cox proportional hazards regression models for the total cohort. In the total cohort of 1199 patients (956 [79.7%] younger than 75 years), 597 (49.8%) received AAP and ADT, including 474 (79.4%) younger than 75 years and 384 (64.3%) with more than 10 bone metastases (AAP cohort); 602 (50.2%) were treated with dual placebo and ADT, including 482 (80.1%) younger than 75 years and 377 (62.6%) with more than 10 bone metastases (ADT cohort). In the AAP cohort, 132 patients (22.1%) received BMAs, while in the ADT cohort, 131 (21.8%) did. Zoledronic acid was the most frequently administered BMA in both the AAP (93 [70.5%]) and the ADT (88 [67.2%]) cohorts. During the median follow-up of 51.8 (IQR, 47.2-57.0) months in the AAP cohort, BMA use was associated with a longer time to SRE (difference, 7.8 [95% CI, 4.2-11.3] months) but not with OS (difference, 1.6 [95% CI, -2.5 to 5.8] months). In the ADT cohort, BMA use was associated with both time to SRE (difference, 9.3 [95% CI, 5.2-13.3] months) and OS (difference, 5.5 [95% CI, 3.2-9.8] months). No evidence was found that the outcomes of BMA varied by AAP or ADT (hazard ratio for time to SRE, 0.99 [95% CI, 0.48-2.08]; P = .99 for interaction; hazard ratio for OS, 1.31 [95% CI, 0.88-1.96]; P = .18 for interaction). The findings of this cohort study suggest that use of BMAs was associated with a longer time to SRE in patients with high-risk mCSPC treated with ADT, with or without AAP, suggesting that BMA use might provide benefits to this population.

Hyper- and hypocalcemia: what should you watch out for?

Calcium is essential for numerous metabolic processes and is hormonally controlled. These hormonal mechanisms are surprisingly effective in regulating calcium levels very reliably within a narrow range - but deviations in serum calcium levels quite often cause clinical problems. Hypercalcemia predominantly occurs in primary hyperparathyroidism or is associated with tumors (especially osteolytic processes). Hypocalcemia is usually due to hypoparathyroidism (75% surgical, 25% primary) or vitamin D deficiency. Causal calcium management requires identification of the etiology of the disorder. Symptomatic therapy depends on the severity of the electrolyte imbalance. Calcium is lowered in hypercalcemia via forced diuresis, the administration of calcitonin and bisphosphonates or denosumab, if necessary, via dialysis. Severe hypocalcemia is corrected acutely with parenteral calcium administration and any further treatment decisions and prognosis depend on the underlying disease.

Bisphosphonates do not affect healing of a critical-size defect in estrogen-deficient mice

Bisphosphonates (BP) are anti-resorptive drugs that are widely used to prevent bone loss in osteoporosis. Since inhibition of bone resorption will cause a decrease in bone formation through a process called coupling, it is hypothesized that extended treatment protocols may impair bone healing. In this study, β-tri‑calcium-phosphate (βTCP) ceramics were inserted into critical-size long bone defects in estrogen-deficient mice under BP therapy. The study assessed the benefits of coating the ceramics with Bone Morphogenetic Protein-2 (BMP2) and an engineered BMP2 analogue (L51P) that inactivates BMP antagonists on the healing process, implant resorption, and bone formation.Female NMRI mice (11–12 weeks of age) were ovariectomized (OVX) or sham operated. Eight weeks later, after the manifestation of ovariectomy-induced osteoporotic bone changes, BP therapy with Alendronate (ALN) was commenced. After another five weeks, a femoral critical-size defect was generated, rigidly fixed, and βTCP-cylinders loaded with 0.25 μg or 2.5 μg BMP2, 2.5 μg L51P, and 0.25 μg BMP2/2.5 μg L51P, respectively, were inserted. Unloaded βTCP-cylinders were used as controls. Femora were collected six and twelve weeks post-implantation.Histological and micro-computer tomography (MicroCT) evaluation revealed that insertion of cylinders coated with 2.5 μg BMP2 accelerated fracture repair and induced significant bone formation compared to controls (unloaded cylinders or coated with 2.5 μg L51P, 0.25 μg BMP2) already six weeks post-implantation, independent of estrogen-deficiency and BP therapy. The simultaneous administration of BMP2 and L51P (0.25 μg BMP2/2.5 μg L51P) did not promote fracture healing six and twelve weeks post-implantation. Moreover, new bone formation within the critical-size defect was directly linked to the removal of the βTCP-implant in all experimental groups. No evidence was found that long-term therapy with ALN impaired the resorption of the implanted graft. However, osteoclast transcriptome signature was elevated in sham and OVX animals upon treatment with BP, with transcript levels being higher at six weeks than at twelve weeks post-surgery. Furthermore, the transcriptome profile of the developing repair tissue confirmed an accelerated repair process in animals treated with 2.5 μg BMP2 implants. L51P did not increase the bioefficacy of BMP2 in the applied defect model.The present study provides evidence that continuous administration of BP does not inhibit implant resorption and does not alter the kinetics of the healing process of critical-size long bone defects. Furthermore, the BMP2 variant L51P did not enhance the bioefficacy of BMP2 when applied simultaneously to the femoral critical-size defect in sham and OVX mice.

Surgical restoration of the upper and lower jaw after resection due to extensive lesions caused by various pathologies

Facial skeletal bone damage, namely necrosis, depends on many factors, both local and general. In most cases, this pathology starts with a common tooth extraction, followed by a long-lasting inflammatory process ending with diffuse necrosis of the facial bones, primarily the maxillary bones. The relevance of the problem lies in the deformity of the jaw after resection due to necrosis caused by various diseases: drug addiction, cardiovascular disease, diabetes, bisphosphonate administration, radiotherapy.

Metastatic pancreatic cancer mimicking medication related osteonecrosis of the jaw—A rare clinical presentation

AbstractPancreatic cancer is a highly aggressive malignancy with a poor prognosis owing to its rapid progression, high mortality rate, and alarming 5‐year survival rate of 5%. Skeletal metastases represent an understated site of metastasis in patients with pancreatic cancer, occurring in about 5%–20% of these patients. The clinical presentation of metastasis to the jaws and osteonecrosis of jaw can exhibit similarities, which may lead to an erroneous diagnosis or create a diagnostic dilemma. We present a case of a 62‐year‐old male patient diagnosed with pancreatic adenocarcinoma and a prior history of bisphosphonate administration who displayed symptoms such as jaw pain, numbness, reduced mouth opening, and an extra‐oral swelling involving a recent tooth extraction site, likely due to medication‐related osteonecrosis of the jaw (ONJ). Despite initial conservative treatment, the patient's symptoms persisted, prompting further investigation. Depending on the specific context and clinical scenario, it is crucial to employ a comprehensive approach such as clinical examination, radiographic imaging, histopathological examination and monitoring the progression of symptoms over time for accurate diagnosis and timely management. This article presents a rare case of metastatic pancreatic cancer mimicking medication related ONJ, highlighting the clinical dilemma and challenges encountered when presenting symptoms and signs are ambiguous. While the prognosis for such cases is generally poor, dentists and healthcare providers should remain vigilant regarding potential sites of metastasis in cases of pancreatic adenocarcinoma.

Warfarin and bisphosphontes interaction in patients undergoing total knee arthroplasty

BackgroundPatients undergoing knee arthroplasty (TKA) surgery need anticoagulant therapy, mainly warfarin for prevention of venous thromboembolism (VTE). Warfarin is mainly eliminated by renal glomerular filtration where 92 % of warfarin is excreted in urine. Warfarin overdose may lead to significant bleeding and warfarin underdosing may cause VTE and other complications. Thus, international normalized ratio (INR) monitoring is crucial in TKA patients taking warfarin. Great interest has been expressed in bisphosphonate to reduce periprosthetic osteoporosis in patients undergoing total joint arthroplasty. Many human case reports and cohort studies proved bisphosphonates induced impaired renal function. ObjectivesThe main goal of the current study is to examine the pharmacodynamin effect of bisphosphonates on warfarin excretion and clinical effects in patients undergoing TKA surgery. MethodsFifty patients undergoing TKA were recruited in the current study. Twenty five patients were given warfarin and twenty five patients were given warfarin and bisphosphonates starting three days after surgery. INR, major bleeding events and minor bleeding events were followed up in all recruited patients for one month after surgery. Resultswarfarin plus zoledronic acid group had significantly higher percent of post INR greater than 4 (p = 0.022) and significantly higher percent of minor bleeding events (p = 0.041) than warfarin only group. ConclusionConcomitant administration of bisphosphonates may increase warfarin bleeding adverse effects in elderly patient undergoing TKA.

Prediction of the development of hypocalcemia in primary hyperparathyroidism patients 1–3 days after radical parathyroidectomy

BACKGROUND: It was impossible to predict the development of hypocalcemia following parathyroidectomy (PTE) in patients with primary hyperparathyroidism (PHPT) until now. Hypocalcemia may be accompanied by myalgia, generalized seizures up to tetany, and arrhythmias. Hypocalcemia following PTE can be prevented by preoperative cholecalciferol supplementation. However, patients with severe hypercalcemia above 3 mmol/L do not receive vitamin D due to the risk of hypercalcemia progression. Despite the existing data showing the safety of cholecalciferol therapy in case of mild elevation of serum calcium, not all patients are prescribed vitamin D supplementation, probably due to the lack of a suitable tool to assess the postoperative hypocalcemia risks.AIM: To design a mathematical model and a software tool for predicting hypocalcemia 1–3 days post-PTE in PHPT patients using the patient’s demographic and clinical data, laboratory test results and preoperative therapy status.MATERIALS AND METHODS: This retrospective study included 478 PHPT patients diagnosed with adenomas and carcinomas of the parathyroid gland (PTG) who underwent radical PTE between 1993–2010 or 2018–2020 at the Endocrinology Research Centre. The following parameters were analyzed: sex; age; laboratory markers prior to calcimimetic and antiresorptive therapy: PTH, total calcium, phosphorus; osteocalcin (OC), alkaline phosphatase (ALP), C-terminal telopeptide of type 1 collagen. Also we analyzed 25-hydroxyvitamin D (25(OH)D); bone mineral density (BMD) measured by X-ray densitometry; medical history of low-energy fractures; preoperative therapy with denosumab, bisphosphonates, cinacalcet, cholecalciferol. Categorical gradient boosting (CatBoost) was built to predict the risk of postoperative hypocalcemia.RESULTS: The prevalence of severe osteoporosis is higher in the postoperative hypocalcemia group compared to the nonhypocalcemia group (27% vs. 15%), wherein the frequency of preoperative administration of cholecalciferol in this group is lower (8% vs. 25%). A CatBoost model was built to predict postoperative hypocalcemia using 13 predictors (sex, age, PTH, serum total calcium, phosphorus, OC, BMD reduction, 25(OH)D, administration of cholecalciferol, bisphosphonates, denosumab, and cinacalcet. The proposed model http://194.87.111.169/hypocalcemia for post-PTE hypocalcemia in PHPT patients achieved the following metrics: positive predictive value 73.3%-86.7%; negative predictive value 74.9%-89.3%.CONCLUSION: The model can be used to choose the appropriate preand postoperative approaches for patients who undergo rPTE.

Evaluating Route of Administration for Bisphosphonates in Patients with Metastatic Breast Cancer to the Bone: A Literature Review

Introduction: Metastatic bone disease, the condition where tumor cells spread from their origin tissue to bone, is common for breast and prostate cancer. Two main hypotheses, referred to as Paget’s “seed and soil” theory and Ewing’s anatomical theory, describe the homing of cancer cells to the bone. When breast cancer becomes metastatic and the tumor spreads to the bone, skeletal-related events can occur. Many patients use bone-modifying agents such as bisphosphonates (BPs) to manage skeletal deterioration. Given the longstanding history of BPs, this review aims to evaluate the efficacy and side effects of oral versus intravenous BPs as adjuvant treatment options for patients with metastatic breast cancer. Methods: Relevant literature was sourced through a search of the PubMed and Google Scholar databases, using established inclusion criteria for screening papers published between 1889 and the present. Results: Currently, there are three generations of BPs. Literature on the different generations reports that studies mainly use first-generation BPs for Paget’s disease and there is no significant effect of first-generation BPs on breast cancer survival rate. Second-generation BPs showed effectiveness in prolonging the progression of bone metastasis and decreasing distant recurrences to the bone in breast cancer patients. In attempts to improve the health outcomes of BPs, researchers examined third-generation BPs and found that they decreased skeletal-related events and pain levels. Discussion: Comparing oral to intravenous administration of BPs, both had overall similar effects in reducing skeletal complications; however, the side effects resulting from BP use vary depending on the route of administration. Patients administered intravenous BPs exhibit an acute phase response and renal complications, while oral BPs cause disruptions in the gastrointestinal tract. Cost-effectiveness varied by study depending on assumptions made in the analytic models. Conclusion: This novel review investigates the development of each generation of BPs to compare the implications of oral and intravenous administration. By accounting for differences across the three generations, healthcare providers can make informed decisions about BPs and create treatment plans tailored to the individual patient. Future research may explore how preexisting risk factors contribute to the occurrence of adverse effects of BP use.

Administration of alendronate exacerbates ammonium chloride-induced acidosis in mice.

Bone disease is highly prevalent in patients with chronic kidney disease (CKD), leading to an increased risk of bone fractures. This is due in part to metabolic acid-induced bone dissolution. Bisphosphonates (BPPs) are a potential treatment for inhibiting bone dissolution; however, there are limited studies observing the use of BPPs on acidotic patients. We aimed to determine efficacy of BPPs on maintaining bone health and pH regulation in acid-exposed mice. Using a diet-induced murine model of metabolic acidosis, we examined bone structure, composition, and mechanics as well as blood gases for three groups: control, acidosis, and acidosis + bisphosphonates (acidosis+BPP). Acidosis was induced for 14 days and alendronate was administered every 3 days for the acidosis+BPP group. The administration of BPP had little to no effect on bone structure, mechanics, and composition of the acidosis bones. However, administration of BPP did cause the mice to develop more severe acidosis than the acidosis only group. Overall, we discovered that BPPs may exacerbate acidosis symptoms by inhibiting the release of buffering ions from bone. Therefore, we propose that BPP administration should be carefully considered for those with CKD and that alkali supplementation could help minimize acidifying effects.

Retrospective evaluation of acute kidney injury in horses treated with nonnitrogenous bisphosphonates (2013-2020): 8 cases.

To describe a population of horses with acute kidney injury (AKI) following administration of bisphosphonates including clinical signs, clinicopathologic data, treatment, and outcome. Retrospective study from August 2013 to July 2020. Veterinary university teaching hospital. Eight adult horses with AKI following administration of nonnitrogenous bisphosphonates. None. Five horses received intramuscular clodronate (5/8; 62.5%) and 3 horses received intravenous tiludronate (3/8; 37.5%). Six horses (6/8; 75%) received concurrent nonsteroidal anti-inflammatory drugs. The most common initial presenting complaint was poor appetite (6/8; 75%), followed by abnormal urination (2/8; 25%). At the time of initial evaluation, the mean serum or plasma creatinine was 451.72±190.06μmol/L (5.11±2.15mg/dL) and BUN was 18.84±8.85mmol/L (52.75±24.77mg/dL). Five horses (5/6; 83.3%) had either an increased number of red blood cells (n=4) or hemoprotein (n=1) in the urine. All horses were treated with IV isotonic, balanced crystalloids either as a bolus, continuous rate infusion, or a combination of the 2. Seven horses (7/8; 87.5%) survived the initial episode of AKI and 1 horse (1/8; 12.5%) was euthanized. Of the 7 surviving horses, 2 horses (2/7; 28.5%) went on to develop chronic renal dysfunction. Warmblood breeds were overrepresented in the AKI group (P=0.008; odds ratio: 11.5, 95% confidence interval: 1.8-72.1), when compared to horses that received bisphosphonates during the study period and did not develop AKI. Bisphosphonate administration, with or without concurrent nonsteroidal anti-inflammatory drugs, can be associated with AKI in horses. Serum creatinine should be monitored prior to and following bisphosphonate treatment to minimize this risk. Further evaluation of renal function is warranted in horses that develop clinical signs of poor appetite, lethargy, or altered urination in the days following bisphosphonate treatment.

862 Successful Surgical Management of Chylothorax Secondary to Gorham-Stout Disease

Abstract Introduction Gorham-Scout Disease (GSD) is a rare skeletal disorder of unknown aetiology characterised by progressive osteolysis and excessive lymphovascular proliferation. Chylothorax is a severe and life-threatening complication of GSD that confers a poor prognosis. Literature review reveals only one previous case of successful surgical management for chylothorax secondary to GSD. Case presentation A teenage asylum seeker presented with a large left pleural effusion on a background of chronic left flank collection secondary to lymphovascular malformation. Cytological analysis of the fluid drained from chest drain insertion confirmed a chylothorax. A posterior rib excision biopsy helped to confirm the diagnosis of GSD. She had VATS ligation of the thoracic duct and talc pleurodesis, however, due to recollection and ongoing symptomatic discomfort, she subsequently underwent left thoracotomy, decortication of lung and pleurectomy. These surgical interventions helped to stabilise the chylothorax with ongoing management for GSD related to radiotherapy and pain control via the administration of bisphosphonates. Conclusions GSD is a rare disease that can develop a number of severe complications including a chylothorax. Management via surgical and radiotherapeutic techniques can provide long term remission, however, other modalities may be needed in order to optimise analgesic requirements.

Effects of low dose bisphosphonates treatment on the mandibular bone in rats with and without mini-implants application: an experimental model

Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ) is a pathological condition observed in patients underwent oral surgical procedures during bisphosphonates treatment. Although several studies have focused on the BRONJ, the exact pathophysiological pathways remain still unclear. In this study we aimed to observe the effects of the low-dose bisphosphonates administration on mandibular bone of rats with and without mini-implants application. For this study we used 28 male Wistar rats, divided in in two groups: 1) control group, treated with saline solution (n = 14 rats); 2) ZA group, treated with low dose zoledronic acid (n=14 rats). After 6 weeks of treatment, the half of each group underwent mini-implant application. All rats were sacrificed and their mandibles were analyzed by light microscopy and scanning electron microscopy (SEM). Our data have shown a healthy bone tissue of control group both with and without mini-implant application. In the treated group empty osteocyte lacunae have been observed and they slightly increase in rats with mini-implant application. Although that, no bone exposition has been observed. By that, during low dose zoledronic acid treatment we can observe the presence of empty osteocytes lacunae, also called “primary lesion”, that not seem to be sufficient alone to determine osteonecrosis of the jaw spontaneously or even after mini-implant application.

Gene-repaired iPS cells as novel approach for patient with osteogenesis imperfecta.

Introduction: The benefits of patient's specific cell/gene therapy have been reported in relation to numerous genetic related disorders including osteogenesis imperfecta (OI). In osteogenesis imperfecta particularly also a drug therapy based on the administration of bisphosphonates partially helped to ease the symptoms. Methods: In this controlled trial, fibroblasts derived from patient diagnosed with OI type II have been successfully reprogrammed into induced Pluripotent Stem cells (iPSCs) using Yamanaka factors. Those cells were subjected to repair mutations found in the COL1A1 gene using homologous recombination (HR) approach facilitated with star polymer (STAR) as a carrier of the genetic material. Results: Delivery of the correct linear DNA fragment to the osteogenesis imperfecta patient's cells resulted in the repair of the DNA mutation with an 84% success rate. IPSCs showed 87% viability after STAR treatment and 82% with its polyplex. Discussion: The use of novel polymer Poly[N,N-Dimethylaminoethyl Methacrylate-co-Hydroxyl-Bearing Oligo(Ethylene Glycol) Methacrylate] Arms (P(DMAEMA-co-OEGMA-OH) with star-like structure has been shown as an efficient tool for nucleic acids delivery into cells (Funded by National Science Centre, Contract No. UMO-2020/37/N/NZ2/01125).

The feasibility of discriminating BRONJ lesion bone with Raman spectroscopy.

With the frequent use of Bisphosphonates (BPs), the morbidity of BP-related osteonecrosis of the jaw (BRONJ) is also increasing. However, the prevention and treatment of BRONJ is faced with enormous challenges. This study aimed to illuminate the influence of BP administration in the rat mandible and explore the feasibility of discriminating BRONJ lesion bone with Raman spectroscopy. First, we explored the time- and mode-dependent effects of BP administration on the rat mandible with Raman spectroscopy. Second, the BRONJ rat model was constructed, and the lesion and healthy bone components were analyzed using Raman spectroscopy. When only BPs were administered, no rats showed BRONJ symptoms, and no difference could be found in the Raman spectra. However, when combined with local surgery, six (6/8) rats showed BRONJ symptoms. The Raman spectra also showed a significant difference between the lesion and healthy bone. In the progression of BRONJ, BPs and local stimulation play an essential role. Both BPs administration and local stimulation need to be controlled to prevent BRONJ. Moreover, BRONJ lesion bone in rats could be discriminated with Raman spectroscopy. This novel method would become a complement in the treatment of BRONJ in the future.

2 Effects of extra-label bisphosphonate use on growth parameters and endocrine biomarkers of bone health in juvenile horses

Extra-label bisphosphonate use in juvenile horses is widespread despite limited scientific understanding of biological and welfare impacts on skeletally immature, exercising horses. The objective of this study was to determine the effects of bisphosphonate (clodronate disodium; CD) on endocrine regulation of bone growth, hypothesizing there would be no effect. To test this, 32 Quarter Horses were stratified by age (500 ± 13 d of age), BW (336 ± 26 kg), sex (n = 16 males, n = 16 females), and initial bone optical density by aluminum equivalence into 4 treatment groups for a 168-d trial. The experimental period was divided into 2 phases mimicking sales preparation (Phase I: d 0–83) and early performance training (Phase II: d 84–168). Horses were housed in individual stalls (3.6 m × 7.3 m) and fed diets formulated to meet nutrient requirements. Investigators were blinded, and all horses received iso-volumetric intramuscular injections of either 1.8 mg/kg BW CD (OSPHOS®) or saline (placebo) on d 0, 42, 84, and 126. Treatments consisted of control (CON; n = 8), single-dose CD (1X; n = 8; d 84), 2-dose CD (2X; n = 8; d 0, 84), and 4-dose CD groups (4X;n = 8; d 0, 42, 84, 126). Physical measurements including BW, wither height (WH), hip height (HH), body length (BL), and heart girth (HG) circumference were recorded every 42 d from d 0. Likewise, serum samples were collected every 42 d before treatment administration to quantify growth hormone (GH), calcitonin (CT), parathyroid hormone (PTH), and ionized calcium. Data were analyzed using PROC MIXED of SAS. All physical growth measurements increased over time (P ≤ 0.01) but were not affected by treatment (P ≥ 0.62). Similarly, there was no effect of treatment (P = 0.44) for GH, but concentrations tended to decrease over time as growth rate slowed (P = 0.09). A treatment ´ time interaction was observed for PTH (P = 0.05) where concentrations increased following 2 clodronate doses. Specifically, concentrations increased on d 84 in 4X and on d 126 in 2X following the second administration of clodronate while 1X and CON remained unchanged. There was no effect of treatment (P = 0.98), time (P = 0.33), nor treatment × time interaction (P = 0.61) for CT despite the increase in PTH. Ionized calcium concentrations decreased over time (P < 0.01) with no effect of treatment (P = 0.26) or treatment × time interaction (P = 0.32). These results suggest that while administration of bisphosphonate has no effect on growth morphometrics, its repetitive use alters PTH concentrations after 2 doses.

Examination of Risk Factors and Expression Patterns of Atypical Femoral Fractures Using the Japanese Adverse Drug Event Report Database: A Retrospective Pharmacovigilance Study.

Atypical femoral fracture (AFF) is a rare complication related to the use of bisphosphonates (BPs). Herein, we analyzed the risk factors and onset patterns of AFF using the Japanese Adverse Drug Event Report database and reported the findings. First, the independent risk factors for AFF were gender (female), high body mass index, and medical history of osteoporosis, arthritis, and systemic lupus erythematosus (SLE). Drug-related risk factors for AFF included BPs (i.e., alendronic acid, ibandronic acid, etidronic acid, zoledronic acid, minodronic acid, risedronic acid), denosumab, prednisolone, lansoprazole, rabeprazole, exemestane, letrozole, eldecalcitol, and menatetrenone. Therefore, it appears that AFF is influenced by a combination of patient backgrounds and drugs, and that the risk of developing AFF is particularly high in patients with fragile bones (e.g., osteoporosis, arthritis, and SLE). Second, in the analysis of AFF onset patterns, the onset of AFF from BPs and denosumab took a long time (>1 year) to develop. Analysis using a Weibull distribution showed wear-out failure-type AFF onset for BPs and denosumab, and both osteoporosis and cancer patients with long-term administration of these drugs showed a tendency to have an increased risk of onset. AFF developed earlier in osteoporosis patients with long-term administration of BPs and denosumab than in cancer patients.