Bisphosphonate Group Research Articles

Comparison of efficacy of romosozumab with denosumab and risedronate in patients newly initiating glucocorticoid therapy

Abstract Context Wnt/β-catenin signaling pathway is one of the pathogenic mechanisms of glucocorticoid-induced osteoporosis (GIOP). We previously reported the potential of inhibiting sclerostin as a treatment for GIOP. Objective To compare the efficacy of romosozumab (ROMO), a monoclonal antibody against sclerostin, with existing therapy for GIOP. Methods Patients with rheumatic diseases who had not previously received treatment for osteoporosis and were newly treated with prednisolone 15 mg/day or more were randomly assigned to receive ROMO, denosumab (DMAb), or bisphosphonates (BP). After the initiation of GC therapy, we measured the bone mineral density (BMD) of the lumbar spine, femoral neck, and total hip every 6 months and bone turnover markers every 3 months for 12 months. Results Eleven patients were assigned to the ROMO group, 14 to the DMAb group, and 14 to the BP group. The median [25th to 75th percentile] percent change in lumbar spine BMD from baseline at 12 months was the greatest in the ROMO group (ROMO; 8.6 [3.1–12.4] %, DMAb; 3.3 [1.5–6.2] %, BP; -0.4 [-3.4–1.1] %). Among bone formation markers, serum levels of bone alkaline phosphatase were slightly elevated in the ROMO group, while those of N-terminal propeptide of type I procollagen and osteocalcin decreased in all three groups; however, these changes were smaller in the ROMO group. Serum levels of bone resorption markers and a urine bone quality marker decreased in all groups. Conclusion Treatment with ROMO significantly increased lumbar spine BMD in GC-treated patients, suggesting that ROMO is effective for GIOP.

The effects of pre-operative anti-osteoporotic use on total joint arthroplasty complications: A national database study

BackgroundThe current study aims to analyze the effect of pre-operative non-bisphosphonate anti-osteoporotic drugs on complication and revision rates following total joint arthroplasty (TJA). MethodsA retrospective cohort analysis of the PearlDiver (PearlDiver Technologies, Colorado Springs, CO) database was performed. The database was queried to identify all patients who underwent total hip arthroplasty (THA) or total knee arthroplasty (TKA) with history of hip or knee osteoarthritis and either osteopenia or osteoporosis. The treatment groups consisted of patients prescribed non-bisphosphonate and bisphosphonate osteomodulatory agents for 1 year prior to and following surgery. The treatment groups were matched to control cohorts by age, gender, and comorbidities. Chi-square analyses were used to compare outcomes between paired cohorts. ResultsThere were no statistically significant differences (p ≤ 0.05) in risk of aseptic loosening, broken prosthesis, dislocation of prosthetic joint, periprosthetic fracture, periprosthetic osteolysis, postoperative infection, full or partial revision, or stress fracture between both the non-bisphosphonate and bisphosphonate groups following THA or TKA. Comparisons between both groups and control cohort also yielded no significant differences. ConclusionThe current study detected no significant differences in early post-operative complications following TJA between patients treated with different classes of anti-osteoporotic medications versus untreated osteopenic/osteoporotic patients. Further research is required to fully understand the impact of osteomodulatory medications on TJA outcomes. Analysis should continue to ensure a high-quality standard of care and aim to better understand outcomes for such patients requiring TJA.

Bisphosphonate Use After Kidney Transplantation Is Associated with Lower Fracture Risk.

Kidney transplant recipients are at higher risk of fractures compared to the general population. The use of bisphosphonates has been shown to increase bone mineral density after transplantation but has not been shown to lower fracture rates. Here, we aim to determine if exposure to bisphosphonates associates with lower incidence of non-vertebral fractures after kidney transplantation. We conducted a retrospective review for all Southern California Kaiser Permanente kidney transplant recipients with osteoporosis transplanted between 2000 and 2019. Baseline variables were collected. Those prescribed an oral bisphosphonate were compared to those who were not. The primary outcome was non-vertebral fracture. Chi square was used to evaluate categorical variables and Wilcoxson rank sum test for continuous variables. Propensity scores were generated to balance covariates in the bisphosphonate and non-bisphosphonate groups. Cause-specific hazard and sub distribution (Fine-Gray) methods were performed for competing risk analysis. Death censored graft survival was evaluated as a secondary outcome using standard Cox regression. There were 489 patients included in the study, 203 of which were in the bisphosphonate group. The cause specific hazard model suggested a 64% lower risk of non-vertebral fracture in the bisphosphonate group (p=0.02). The Fine-Gray hazard model treating death as a competing risk did not show lower relative incidence of non-vertebral fracture. Bisphosphonate treatment was associated with lower death censored graft failure (p=0.002). Bisphosphonate use after kidney transplantation may associate with lower risk of non-vertebral fracture after transplant. Bisphosphonate use in this study was also associated with lower death censored graft failure. Caution is advised when interpreting these results given the retrospective nature of the study.

Romosozumab Versus Bisphosphonates for preventing subsequent vertebral fractures after Balloon Kyphoplasty: Comparison Using Data from Two Prospective Multicenter Studies

Abstract Preventing subsequent fractures after vertebral augmentation is a critical clinical concern. The purpose of this study was to compare the effect of romosozumab and bisphosphonate administration on the occurrence of subsequent vertebral fractures after balloon kyphoplasty (BKP) and to identify factors associated with the occurrence of subsequent vertebral fractures. The study compared 24 patients who underwent BKP and received romosozumab with 58 control patients who underwent BKP and received bisphosphonates, all within two months of acute osteoporotic vertebral fracture and showing unfavorable MRI prognostic factors. The primary outcome was the occurrence of subsequent fracture, and the secondary outcomes were improvement in back pain visual analog scale (VAS) score. Furthermore, logistic regression analysis was conducted to adjust for confounding factors and assess the effect of osteoporosis treatment type on subsequent vertebral fractures following BKP. Subsequent vertebral fractures occurred in 16 patients in the bisphosphonate group and in one patient in the romosozumab group (P=.02). There were no significant differences between the two groups in VAS scores and their change from preoperatively to 6 months after surgery. The multivariable logistic regression analysis identified the type of osteoporosis treatment as an independent factor associated with the occurrence of subsequent vertebral fractures (Odds ratio, 18.30, P=.02). This prospective, multicenter study demonstrates that romosozumab is more effective than bisphosphonates in preventing subsequent vertebral fractures within six months after BKP. Romosozumab’s superior efficacy in reducing subsequent vertebral fractures may lead to improved long-term outcomes and quality of life, potentially making it a preferred treatment option over bisphosphonates for patients undergoing BKP.

Bisphosphonate salts as covalent and non-covalent task-specific ionic liquid synthesis

Functionalized ionic liquids, commonly referred to as task-specific ionic liquids (TSILs), represent a distinct subset within the realm of ILs. They stand out by having a functional group covalently bonded to either the cationic or the anionic counterpart of the ionic liquid. These tailored modifications confer specific properties to TSILs, making them well-suited for various applications, including catalysis, liquid–liquid extraction, and synthesis. Notably, they also find relevance in the field of nanomaterials. In this paper, we delineate the synthetic pathway for TSILs featuring imidazolinium or pyridinium cores functionalized with a bisphosphonate unit. Furthermore, we provide detailed insights into the green synthesis of imidazolinium salts constituted by a bisphosphonate moiety as the counterion. These innovative TSILs, characterized by a bisphosphonate group, pave the way for a new avenue in the selective complexation of strategic metals and the development of new drugs. 1 This underscores their potential utility in strategic metal recovery by extraction and related endeavors.

Piperazine‐derived bisphosphonate‐based ionizable lipid nanoparticles enhance mRNA delivery to the bone microenvironment

Nucleic acid delivery with mRNA lipid nanoparticles are being developed for targeting a wide array of tissues and cell types. However, targeted delivery to the bone microenvironment remains a significant challenge in the field. We report bone‐targeting ionizable lipids featuring a robust piperazine backbone, which forms strong interactions with hydroxyapatite ([Ca5(PO4)3OH]), a key component of mineralized tissues. These lipids, conjugated with derivatives of bisphosphates, demonstrate biocompatibility and low toxicity in vitro and in vivo. Our findings demonstrate the role of a piperazine backbone of a novel ionizable lipid that presents a bisphosphonate group to facilitate bone delivery. This research illustrates the rational design of ionizable lipids for next‐generation bone‐targeting delivery systems.

Piperazine-derived bisphosphonate-based ionizable lipid nanoparticles enhance mRNA delivery to the bone microenvironment.

Nucleic acid delivery with mRNA lipid nanoparticles are being developed for targeting a wide array of tissues and cell types. However, targeted delivery to the bone microenvironment remains a significant challenge in the field. We report bone-targeting ionizable lipids featuring a robust piperazine backbone, which forms strong interactions with hydroxyapatite ([Ca5(PO4)3OH]), a key component of mineralized tissues. These lipids, conjugated with derivatives of bisphosphates, demonstrate biocompatibility and low toxicity in vitro and in vivo. Our findings demonstrate the role of a piperazine backbone of a novel ionizable lipid that presents a bisphosphonate group to facilitate bone delivery. This research illustrates the rational design of ionizable lipids for next-generation bone-targeting delivery systems.

Effect of bisphosphonate and denosumab treatment on TBS in Japanese breast cancer patients with AIBL.

Bisphosphonates and denosumab increase bone mineral density (BMD) for osteoporosis treatment in patients with aromatase inhibitor-associated bone loss (AIBL). This study aimed to directly compare bisphosphonates with denosumab in treating patients with AIBL and to determine the effect of denosumab on the trabecular bone score (TBS). Thirty-nine patients with AIBL receiving osteoporosis treatment (21 in the bisphosphonates group and 18 in the denosumab group) were retrospectively evaluated for changes in lumbar spine and femoral BMD, lumbar spine bone quality (assessed by TBS), and blood bone metabolic markers. The Mann-Whitney and Wilcoxon tests were used for statistical evaluation. After 24months of treatment, the lumbar spine BMD change rate was 5.82 ± 1.10% with bisphosphonates and 10.49 ± 1.20% with denosumab, with the change rate of denosumab significantly increasing over that of bisphosphonates. The change rate in femoral BMD was 2.69 ± 1.16% with bisphosphonates and 2.95 ± 1.26% with denosumab, with no significant difference between the two groups. The rate of decrease in tartrate-resistant acid phosphatase isoform 5b was significantly higher in the denosumab group. The change rate in TBS at 24months of treatment was 0.53 ± 1.26% in the bisphosphonates group and 1.08 ± 1.33% in the denosumab group, with no significant difference between the two groups. After 24months, TBS remained stable. Both bisphosphonates and denosumab may increase BMD, improve bone metabolism, and inhibit bone quality loss in patients with AIBL.

Efficacy of Bisphosphonates in Total Hip Arthroplasty Patients: Systematic Review and Meta-Analysis.

A systematic review and meta-analysis were conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A PICOS template was developed to ensure a structured approach. A search for relevant studies was performed across four databases, including Pubmed, Scopus, Embase, and Cochrane. They were all last searched on March 1st and were assessed using the Cochrane risk of bias tool for randomised studies. The final analysis included seven studies with a total of 126 study group participants and 144 control group participants. The studies looked at Bony Mass Density in terms of bone loss on Gruen's femoral zones after THA in a bisphosphonate (treatment) and control group (placebo/no treatment). The analysis revealed a statistically significant difference (p < 0.05) in favour of the bisphosphonate group in many of the included studies at 6, 12, and 24 postoperative months. This systematic review and meta-analysis, using the most recent applicable studies, showed the efficacy of bisphosphonates in limiting periprosthetic osteolysis after THA in a period between 6 and 24 postoperative months. Future studies should focus increasing group sizes and collecting results beyond the 2-year mark.

Real world clinical outcomes when discontinuing denosumab or bisphosphonates in patients with surgically managed osteoporotic vertebral compression fractures: a population-based cohort study

BACKGROUND CONTEXTOsteoporotic vertebral compression fractures (OVCFs) are common fragility fractures. Patients who undergo surgical treatment for their initial OVCFs warrant particular attention because there is an elevated risk of subsequent vertebral fractures and other types of fragility fractures. However, the optimal osteoporosis treatment for this specific patient group is less investigated. PURPOSEThis study compares the risk of subsequent osteoporotic fractures and mortality rate for patients who are initiated with denosumab and bisphosphonates and determines the effect of adherence to treatment. STUDY DESIGNRetrospective nationwide cohort study PATIENT SAMPLEA total of 2,858 patients who had surgically-managed osteoporotic vertebral compression fractures. OUTCOME MEASURESThe risk of osteoporotic fractures, vertebral fractures, nonvertebral fractures and death. METHODSThis is a retrospective nationwide cohort study that uses the National Health Insurance Research Database. Patients aged ≥50 years who were admitted for surgical interventions for OVCF between 2012 and 2016 and subsequently received denosumab or bisphosphonates for one year were included. Patients were stratified according to their antiosteoporosis medications and adherence to treatment. A multivariable, time-varying Cox proportional hazards model was used to determine the risk of osteoporotic fractures, vertebral fractures, nonvertebral fractures and death. RESULTSA total of 2,858 patients were included in this study: 1,123 patients in the denosumab group and 1,735 patients in the bisphosphonates group. Compared to persistent denosumab users, the nonpersistent denosumab users, persistent bisphosphonate users and nonpersistent bisphosphonate users had a greater risk of osteoporotic fractures, with respective hazard ratios of 1.64 (95% confidence interval [CI], 1.16–2.32), 1.74 (95% CI, 1.25–2.42) and 1.53 (95% CI, 1.14–2.06). If osteoporotic fractures were divided into nonvertebral and vertebral fractures, none of the groups exhibited an increased risk of vertebral fractures compared to persistent denosumab users, with an HR of 1.00 (95% CI: 0.54–1.88) for nonpersistent denosumab users, 1.64 (95% CI: 0.96–2.81) for persistent bisphosphonate users and 1.52 (95% CI: 0.95–2.43) for nonpersistent bisphosphonate users. However, there was a significantly greater risk of nonvertebral fracture, with respective hazard ratios of 2.04 (95% CI, 1.33–3.11), 1.80 (95% CI, 1.18–2.76) and 1.56 (95% CI, 1.06–2.27) for nonpersistent denosumab users, persistent bisphosphonate users and nonpersistent users. Noteworthy, nonpersistent denosumab users exhibited a significantly greater risk of mortality than persistent denosumab users, with a hazard ratio of 3.12 (95% CI, 2.22–4.38). CONCLUSIONSIn terms of patients with OVCFs who require hospitalization and surgical intervention, those who receive ongoing denosumab treatment exhibit less risk of developing subsequent osteoporotic fractures than those who receive bisphosphonates or nonpersistent denosumab treatment. However, discontinuation of denosumab is associated with a significantly increased risk of subsequent fractures and mortality. Therefore, adherence to the treatment is crucial for patients who are initiated with denosumab.

Significance of zoledronic acid in the adjuvant therapy in patients with breast cancer

Introduction. Zoledronic acid is a medicine belonging to the bisphosphonate group. Its action is to inhibit the function of osteoclasts, which leads to a reduction in bone resorption. This preparation has a proven effect in the treatment of osteoporosis and Paget’s disease. Bisphosphonates have also found use in the treatment of breast cancer. Studies conducted for many years indicate that zoledronic acid works most favorably in combination with adjuvant therapy. Breast cancer patients who are postmenopausal and being treated with chemotherapy are at risk of bone mass loss and hypercalcemia. Bisphosphonates effectively manage this. In addition, zoledronic acid indirectly exerts anticancer effects by modulating the immune system. All this allows us to conclude that taking this drug reduces the risk of bone metastasis in breast cancer patients. Dosage is also key in all this. There are several regimens offered to osteoporosis and breast cancer patients. So far, the following have been studied: conventional dosing (4 mg IV every 3-4 weeks), maintenance dosing (4 mg IV every 3-6 months) and metronomic dosing (1 mg IV weekly). It cannot be ruled out that each of these regimens may have a different antitumor effect. By reviewing scientific works, we aim to present the treatment options with zoledronic acid for breast cancer patients. We will describe the impact on their results depending on the dosage and we will present the other side of the coin, which are the side effects of taking this preparation. Aim. This review provides an overview of the effects and impact of zoledronic acid in adjuvant therapy in patients with breast cancer. Material and methods. The article presents the current state of knowledge on zoledronic acid as an adjuvant treatment option in breast cancer patients. It is a detailed literature review using Google Scholar, PubMed and Journal of Education Health and Sport platforms. Publications using the following key words were analyzed: bisphosphonates, zoledronic acid, osteoporosis, breast cancer, bone metastases. Conclusion. Women diagnosed with breast cancer should be treated in a multidisciplinary manner. We treat early detected cancers to achieve complete remission. Long-term survival is our primary goal, and in pursuing it we should consider the potential impact of this treatment on the patient’s skeletal system. Clinical studies allow us to conclude that there is a correlation between the initiation of antiresorptive therapy at an early stage of cancer and overall survival. Additionally, zoledronic acid significantly reduced the number of fractures. The collected data allow us to conclude that the addition of zoledronic acid to the established treatment regimens has a potentially positive effect on the group of postmenopausal patients undergoing tamoxifen treatment or with existing bone metastases. Keywords: bisphosphonates, zoledronic acid, breast cancer, osteoporosis, bone metastases.

Non-nitrogen-containing bisphosphonates and nitrogen-containing bisphosphonates for the treatment of atherosclerosis and vascular calcification: A meta-analysis.

The role of non-nitrogen-containing bisphosphonates (non-N-BPs) and nitrogen-containing bisphosphonates (N-BPs) in the treatment of atherosclerosis (AS) and vascular calcification (VC) is uncertain. This meta-analysis was conducted to evaluate the efficacy of non-N-BPs and N-BPs in the treatment of AS and VC. The PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, and Wanfang databases were searched from their inception to July 5th, 2023. Eligible studies comparing bisphosphonates (BPs) versus no BPs in the treatment of AS and VC were included. The data were analyzed using Review Manager Version 5.3. Seventeen studies were included in this meta-analysis. Twelve were randomized control trials (RCTs), and 5 were nonrandomized studies. Overall, 813 patients were included in the BPs group, and 821 patients were included in the no BPs group. Compared with no BP treatment, non-N-BP or N-BP treatment did not affect serum calcium (P > .05), phosphorus (P > .05) or parathyroid hormone (PTH) levels (P > .05). Regarding the effect on serum lipids, non-N-BPs decreased the serum total cholesterol (TC) level (P < .05) and increased the serum triglyceride (TG) level (P < .01) but did not affect the serum low-density lipoprotein cholesterol (LDL-C) level (P > .05). N-BPs did not affect serum TC (P > .05), TG (P > .05) or LDL-C levels (P > .05). Regarding the effect on AS, non-N-BPs did not have a beneficial effect (P > .05). N-BPs had a beneficial effect on AS, including reducing the intima-media thickness (IMT) (P < .05) and plaque area (P < .01). For the effect on VC, non-N-BPs had a beneficial effect (P < .01), but N-BPs did not have a beneficial effect (P > .05). Non-N-BPs and N-BPs did not affect serum calcium, phosphorus or PTH levels. Non-N-BPs decreased serum TC levels and increased serum TG levels. N-BPs did not affect serum lipid levels. Non-N-BPs had a beneficial effect on VC, and N-BPs had a beneficial effect on AS.

Dental Implant Failure in Post-Menopausal Women on Oral Bisphosphonates: A Systematic Review and Meta-Analysis.

A systematic review was designed to investigate the effect of treatment with oral bisphosphonate (BP) on osseointegration of dental implants and the incidence of BP-related osteonecrosis of the jaw (BRONJ) in postmenopausal women. Multiple electronic databases, including MEDLINE (PubMed), EMBASE, and SCOPUS, were searched to find all eligible articles published since 1990. All titles and abstracts retrieved by searching information sources were evaluated independently by 2 authors against the eligibility criteria. The number of cases ranged from 11 to 235, and the number of controls ranged from 14 to 343. Alendronate was used in all other studies. Risedronate was used in 6 studies, while ibandronate was used in 4 studies. The number of implants in cases ranged from 25 to 1267, while in controls, the number of implants ranged from 28 to 1450. The time between the placement of implant and the follow-up visit ranged from 4-6 months to 8 years. The results show that out of 2582 placed implants, 50 (1.94%) failed in BP-treated patients. This is while out of 4050 placed implants, 188 (4.6%) failed in the non-BP group. The results from the meta-analysis demonstrated that BP therapy is significantly associated with increased implant failure rates (RR = 1.73 [95% CI, 1.03-2.83], P = .04). Overall, the qualitative assessment of this review suggests that oral treatment with BPs in postmenopausal women does not increase the rate of dental implant failure. Thus, further studies with larger sample sizes should compare BP and non-BP groups in regard to dental implants.

Comparative effectiveness and safety outcomes between denosumab and bisphosphonate in South Korea.

Both bisphosphonates and denosumab are the mainstays of treatment for osteoporosis to prevent fractures. However, there are still few trials directly comparing the prevention of fractures and the safety of 2 drugs in the treatment of osteoporosis. We aimed to compare the efficacy and safety between denosumab and bisphosphonates using a nationwide claims database. The database was covered with 10 million, 20% of the whole Korean population sampled by age and sex stratification of the Health Insurance Review and Assessment Service in South Korea. Among 228 367 subjects who were over 50yr of age and taking denosumab or bisphosphonate from January 2018 to April 2022, the analysis was performed on 91 460 subjects after 1:1 propensity score matching. The primary outcome was treatment effectiveness; total fracture, major osteoporotic fracture, femur fracture, pelvic fracture, vertebral fracture, adverse drug reactions; acute kidney injury, chronic kidney disease, and atypical femoral fracture. Total fracture and osteoporotic major fracture, as the main outcomes of efficacy, were comparable in the denosumab and bisphosphonate group (HR 1.06, 95% CI, 0.98-1.15, P= .14; HR 1.13, 95% CI, 0.97-1.32, P= .12, respectively). Safety for acute kidney injury, chronic kidney disease, and atypical femoral fracture also did not show any differences between the 2 groups. In subgroup analysis according to ages, the denosumab group under 70yr of age had a significantly lower risk for occurrences of acute kidney injury compared to the bisphosphonate group under 70yr of age (HR 0.53, 95% CI, 0.29-0.93, P= .03). In real-world data reflecting clinical practice, denosumab and bisphosphonate showed comparable effectiveness for total fractures and major osteoporosis fractures, as well as safety regarding acute kidney injury, chronic kidney disease, and atypical femoral fracture.

Deprescribing bisphosphonates in the osteoporosis treatment in older people

The term deprescribing (de-prescribe) means the abolition of appointments. In the modern researches, deprescribing is presented as a planned and controlled process of dose reduction or drug cessation, which can potentially harm the patient and/or does not benefit the patient. The target population for deprescribing is the older people, as old age and limited life expectancy are themselves reasons to try to reduce and optimize the drug load. Frailty syndrome or dementia, decreased kidney function and comorbidity are expected to coexist with polypragmasy and inconsistent appointments of different specialists. In foreign and domestic scientific studies there are manuals and recommendations on deprescribing of various groups of drugs for the elderly and seniors: proton pump inhibitors, sugary drugs, psychotropic drugs and others. However, with regard to osteoporosis drug therapy, the concept of deprescribing is debated rather sparingly, despite the possible serious side effects of osteoporosis treatment in the older age group.The review presents data from small clinical studies and systematic reviews describing deprescribing antiosteoporotic drugs from the bisphosphonate group, the reasons for their withdrawal and its consequences for the elderly and seniors with osteoporosis, as well as the analysis of tools for optimizing pharmacotherapy in elderly and seniors with respect to deprescribing of bisphosphonates.

Evaluating the comparability of osteoporosis treatments using propensity score and negative control outcome methods in UK and Denmark electronic health record databases.

Evidence on the comparative effectiveness of osteoporosis treatments is heterogeneous. This may be attributed to different populations and clinical practice, but also to differing methodologies ensuring comparability of treatment groups before treatment effect estimation and the amount of residual confounding by indication. This study assessed the comparability of denosumab vs oral bisphosphonate (OBP) groups using propensity score (PS) methods and negative control outcome (NCO) analysis. A total of 280 288 women aged ≥50yr initiating denosumab or OBP in 2011-2018 were included from the UK Clinical Practice Research Datalink (CPRD) and the Danish National Registries (DNR). Balance of observed covariates was assessed using absolute standardized mean difference (ASMD) before and after PS weighting, matching, and stratification, with ASMD >0.1 indicating imbalance. Residual confounding was assessed using NCOs with ≥100 events. Hazard ratio (HR) and 95%CI between treatment and NCO were estimated using Cox models. Presence of residual confounding was evaluated with 2 approaches (1) >5% of NCOs with 95% CI excluding 1, (2) >5% of NCOs with an upper CI <0.75 or lower CI >1.3. The number of imbalanced covariates before adjustment (CPRD 22/87; DNR 18/83) decreased, with 2%-11% imbalance remaining after weighting, matching, or stratification. Using approach 1, residual confounding was present for all PS methods in both databases (≥8% of NCOs), except for stratification in DNR (3.8%). Using approach 2, residual confounding was present in CPRD with PS matching (5.3%) and stratification (6.4%), but not with weighting (4.3%). Within DNR, no NCOs had HR estimates with upper or lower CI limits beyond the specified bounds indicating residual confounding for any PS method. Achievement of covariate balance and determination of residual bias were dependent upon several factors including the population under study, PS method, prevalence of NCO, and the threshold indicating residual confounding.

Assessing bone formation on hydrophilic and hydrophobic implant surfaces in a murine model treated with bisphosphonates.

To evaluate the osseointegration of implants with hydrophobic (HFB) and hydrophilic (HFL) surfaces in a murine model of high-dose bisphosphonates (BPs). Sixty-four rats were randomly allocated into four groups: control group with HFB implants (CG-HFB), control group with HFL implants (CG-HFL), BP group with HFB implants (BP-HFB), and BP group with HFL implants (BP-HFL). Animals were euthanized after 15 and 45 days (n=8). The dependent variables assessed were the removal torque (biomechanical analysis), the bone volume around the implants (%BV/TV) (microtomographic analysis), the bone-implant contact (%BIC), the bone between the threads (%BBT) (histomorphometric analysis), and the expression of bone metabolism markers (immunohistochemistry analysis). The CG-HFL and BP-HFL groups presented higher removal torque than the CG-HFB and BP-HFB implants. The %BIC of the CG-HFL surfaces was slightly higher than that of the CG-HFB implants. The BP-HFB and BP-HFL groups presented a higher %BIC than that of the CG-HFB and CG-HFL groups (p<0.001). BP therapy also increased the %BBT at both implant surfaces. Higher levels of ALP were observed in the matrix region of bone tissue on the HFL surfaces than on the HFB surfaces. Both surfaces enable osseointegration in rats under BP therapy. The study demonstrates that hydrophobic (HFB) and hydrophilic (HFL) implant surfaces can promote osseointegration in rats undergoing bisphosphonate therapy. The HFL surfaces exhibited improved biomechanical performance, higher bone-implant contact, and increased bone volume, suggesting their potential clinical relevance for implant success in individuals on bisphosphonate treatment.

Anticancer effect of zoledronic acid in endocrine-resistant breast cancer cells via HER-2 signaling

HER-2 overexpression is a major mechanism involved in endocrine-resistant breast cancer, which has very limited treatment options. Zoledronic acid (ZA) is a drug in the bisphosphonate group used to treat osteoporosis. ZA was reported to exhibit activity in various cancers, with higher efficacy associated with estrogen-deprivation states. ZA inhibits cell proliferation in lung cancer through the epidermal growth factor receptor signaling pathway. Because endocrine-resistant breast cancer cells overexpress HER-2 and grow independently without estrogen, ZA may exert anticancer effects in these cell types. The inhibitory effects and mechanisms of ZA in endocrine-resistant cells through HER-2 signaling were investigated. The efficacy of ZA was higher in the endocrine-resistant breast cancer cells when compared with the wild-type cells. ZA also exhibited a synergistic effect with fulvestrant and may circumvent fulvestrant resistance. ZA decreased phosphorylated ERK (pERK) levels in resistant cell lines and attenuated HER-2 signaling in tamoxifen- and fulvestrant-resistant cells. ZA significantly decreased HER-2 levels and its downstream signaling molecules, including pAKT and pNF-κB in fulvestrant-resistant breast cancer cells. This inhibitory effect may explain the lower IC50 values of ZA in fulvestrant-resistant cells compared with tamoxifen-resistant cells. Moreover, ZA inhibited the migration and invasion in the resistant cell lines, suggesting an ability to inhibit tumor metastasis. The results indicate that ZA has potential for repurposing as an adjuvant treatment for patients with endocrine-resistant breast cancer.

The Effects of Switch Therapy in Osteoporosis Treatment after Romosozumab after Comparing with Prior Treatment.

Rationale. Although romosozumab is one of the most effective treatments for osteoporosis by increasing bone mineral density in the lumbar spine and femur and recommended for denosumab as switch therapy, these effects regarding its prior treatment have not yet been evaluated clearly. This study focused on the effects of switch therapy from romosozumab to denosumab in regard to prior treatment of osteoporosis including bone mineral density and bone turnover marker and other related factors. Patient Concerns. 15 osteoporotic patients were assigned to the naïve group, 15 were assigned to the teriparatide group, and 10 were assigned to the bisphosphonate group. Interventions. Patients who were treated as outpatients for osteoporosis with romosozumab for 1 year and switched to denosumab between 2020 and 2022 at our hospital were examined. Our hospital registry included 40 osteoporotic patients who were over 65 years of age with bone mineral density (bone mineral density): T score <-2.5 standard deviations (SDs) and fracture assessment tool (FRAX) score >20%. Outcomes. The naïve group had the highest increase in LS BMD among these three groups during switch therapy from romosozumab to denosumab, while there were no significant differences about adverse drug events and serum Ca concentration among them. There was no incidence of fracture. Conclusion. These findings indicate that the effects of osteoporotic treatment of switch therapy from romosozumab to denosumab were likely to affect prior treatment of osteoporosis.

Incidence and severity of medication-related osteonecrosis of the jaw in patients with osteoporosis using data from a Korean nationwide sample cohort in 2002 to 2019: a retrospective study.

Medication-related osteonecrosis of the jaw (MRONJ) is a significant concern, particularly among patients taking bisphosphonates (BPs), denosumab, and selective estrogen receptor modulators (SERMs) for osteoporosis. Despite the known risks, large-scale cohort studies examining the incidence and severity of MRONJ are lacking. We aimed to ascertain the incidence and risk of MRONJ among these patients, whom we stratified by age groups, medication types, and duration of use. We utilized data from the National Health Insurance Service's sample cohort database, focusing on patients aged 40 years and above diagnosed with osteoporosis. The patients were divided into three groups: those prescribed BPs only, those prescribed SERMs only, and those prescribed both. The overall incidence rate of MRONJ was 0.17%. A significantly higher incidence rate was observed among those taking osteoporosis medications, particularly among females with a relative risk of 4.99 (95% confidence interval, 3.21-7.74). The SERM group also had an incidence rate comparable to that of the BP group. Severity was assessed based on the invasiveness of the treatment methods, with 71.3% undergoing invasive treatment in the medication group. This study provides valuable insights into the incidence and severity of MRONJ among a large cohort of patients with osteoporosis. It underscores the need for comprehensive guidance on MRONJ risks across different medication groups and sets the stage for future research focusing on specific populations and treatment outcomes.