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Background: Osteoporosis has been recognized as a significant health issue in Thailand. Pharmacological interventions are important way to prevent fracture. However, one of the main challenges in selecting a medication is high cost, particularly for brand-name drugs. Data on generic bisphosphonate use in Thai are still lacking. Therefore, our study aimed to assess the efficacy and safety of generic risedronate in postmenopausal Thai women with osteoporosis. Methods: This prospective study was conducted at King Chulalongkorn Memorial Hospital, Bangkok, Thailand, from December 2022 to January 2024. Serum C-terminal cross-linking telopeptide of type I collagen (CTX) and procollagen type I N-propeptide (P1NP) were measured at baseline. All participants subsequently received 35 milligrams of oral risedronate once weekly for 52 weeks. Serum CTX and P1NP were remeasured at different time points. BMD was reevaluated at 52 weeks after risedronate treatment initiation. Results: A total of 80 participants were included. The mean age was 65.2 ± 6.6 years. The mean body mass index (BMI) was 23.45 ± 3.49 kg/m2. The median (IQR) serum CTX level at 12 weeks was significantly lower than that at baseline (0.28 (0.16–0.46) ng/mL versus 0.44 (0.26–0.64) ng/mL, respectively; p value < 0.01). The suppression of serum CTX was confirmed at 52 weeks after treatment initiation. Compared with those at baseline, the serum P1NP levels were significantly lower at 24 weeks after treatment initiation (30.33 (19.19–39.58) ng/mL versus 41.90 (30.33–68.67) ng/mL, respectively; p value < 0.01). In terms of the BMD assessment at 52 weeks, significant improvements were observed in both areal BMD (g/cm2) and T scores at all measured sites compared with baseline. The lumbar spine, femoral neck, and total hip BMD increased from baseline by 4.76%, 3.84% and 4.54%, respectively. Conclusion: Postmenopausal women with osteoporosis who were treated with generic risedronate demonstrated significant suppression of the bone remodelling process at 3, 6, and 12 months after treatment initiation. Additionally, significant improvements in the lumbar spine, femoral neck, and total hip BMD were observed at 12 months of therapy. These findings suggest that generic risedronate could be considered a reasonable and interesting option for treating postmenopausal women with osteoporosis in Thailand. [ABSTRACT FROM AUTHOR]

There is significant interest in using nanoparticles as new platforms for transporting and releasing drugs with limitations when directly administered into the body. In our research, we developed a platform for encapsulating risedronate using polymersomes obtained by self-assembly of a new triblock amphiphilic copolymer. This copolymer is based on polyethylene glycol (PEG) as a hydrophilic block and a statistical copolymer of vinyl benzoate (VBz) and diisopropyl fumarate (DIPF) as a hydrophobic block. The amphiphilic copolymer, synthesized by reversible addition-fragmentation chain transfer polymerization (RAFT), presented a hydrophilic block fraction mass percentage (f) of 30, which is suitable for forming vesicles through self-assembly. We obtained vesicles of approximately 54 nm using the solvent injection method, with a Z-average hydrodynamic diameter of 163 nm. Compared to the vesicles obtained from a copolymer without DIPF, the nanoparticles were smaller with a narrower size distribution. To assess the potential of these systems as a vehicle for bisphosphonates, we prepared risedronate-loaded polymersomes. The resulting particles had a similar size to their uncharged counterparts, with a risedronate content of 12 ± 2 mg per gram of polymer, as determined by HPLC. Delivery studies demonstrated sustained release of risedronate for up to 10 days. We also evaluated cell viability and cytotoxicity using murine monocyte-macrophage RAW264.7 cells. The empty or risedronate-loaded nanoparticles did not affect cell proliferation, viability, and nitric oxide production at the tested concentrations. However, the particles partially inhibited nitric oxide production induced by lipopolysaccharide (LPS) in macrophages. [ABSTRACT FROM AUTHOR]

Abstract Background Osteoporosis has been recognized as a significant health issue in Thailand. Pharmacological interventions are important way to prevent fracture. However, one of the main challenges in selecting a medication is high cost, particularly for brand-name drugs. Data on generic bisphosphonate use in Thai are still lacking. Therefore, our study aimed to assess the efficacy and safety of generic risedronate in postmenopausal Thai women with osteoporosis. Methods This prospective study was conducted at King Chulalongkorn Memorial Hospital, Bangkok, Thailand, from December 2022 to January 2024. Serum C-terminal cross-linking telopeptide of type I collagen (CTX) and procollagen type I N-propeptide (P1NP) were measured at baseline. All participants subsequently received 35 milligrams of oral risedronate once weekly for 52 weeks. Serum CTX and P1NP were remeasured at different time points. BMD was reevaluated at 52 weeks after risedronate treatment initiation. Results A total of 80 participants were included. The mean age was 65.2 ± 6.6 years. The mean body mass index (BMI) was 23.45 ± 3.49 kg/m2. The median (IQR) serum CTX level at 12 weeks was significantly lower than that at baseline (0.28 (0.16–0.46) ng/mL versus 0.44 (0.26–0.64) ng/mL, respectively; p value

Summary: This study uses NHS waiting times and osteoporosis medication community prescription datasets to assess the impact of COVID-19 on DXA waits and osteoporosis medication patterns in England. Results show significant increases in DXA waiting list times and variation in prescription rates. Investment is needed to improve waiting list times. Purpose: This study investigates the impact of COVID-19 on DXA scan waiting lists, service recovery and osteoporosis medication prescriptions in the NHS following the March 2020 national lockdowns and staff redeployment. Methods: Data from March 2019 to June 2023, including NHS digital diagnostics waiting times (DM01) and osteoporosis medication prescriptions from the English Prescribing Dataset (EPD), were analysed. This encompassed total waiting list data across England's seven regions and prescribing patterns for various osteoporosis medications. Analyses included total activity figures and regression analysis to estimate expected activity without COVID-19, using R for all data analysis. Results: In England, DXA waiting lists have grown significantly, with the yearly mean waiting list length increasing from 31,851 in 2019 to 65,757 in 2023. The percentage of patients waiting over 6 weeks for DXA scans rose from 0.9% in 2019 to 40% in 2020, and those waiting over 13 weeks increased from 0.1% in 2019 to 16.7% in 2020. Prescription trends varied, with increases in denosumab, ibandronic acid and risedronate sodium and decreases in alendronic acid, raloxifene hydrochloride and teriparatide. A notable overall prescription decrease occurred in the second quarter of 2020. Conclusion: COVID-19 has significantly increased DXA scan waiting lists with ongoing recovery challenges. There is a noticeable disparity in DXA service access across England. Osteoporosis care, indicated by medication prescriptions, also declined during the pandemic. Addressing these issues requires focused investment and effort to improve DXA scan waiting times and overall access to osteoporosis care in England. [ABSTRACT FROM AUTHOR]

Denosumab and bisphosphonates for primary osteoporosis are generally well-tolerated, but their comparative safety remains unclear. We aimed to explore the comparative safety of denosumab and bisphosphonates in primary osteoporosis. Databases such as PubMed and Google Scholar were searched for relevant peer-reviewed randomized controlled trials published in English (as of December 2023). Trials comparing adverse events (AE) between denosumab and bisphosphonates in patients with primary osteoporosis were investigated. Data were pooled using a fixed- or random-effects model to determine the risk ratios (RR) and 95% confidence intervals (CIs) for various AEs in patients treated with denosumab in comparison to patients treated with bisphosphonates. Eleven trials (5,545 patients; follow-up period: 12–24 months) were included in this meta-analysis. All trials had a risk of bias (e.g., reporting bias linked to secondary endpoints and selection bias linked to random allocation). In comparison to bisphosphonates, denosumab was significantly associated with less withdrawal due to AEs (RR = 0.49; 95% CI 0.34–0.71), more five-point major adverse cardiovascular events (RR = 2.05; 95% CI 1.03–4.09), more cardiovascular AEs (RR = 1.61; 95% CI 1.07–2.41), more infections (RR = 1.14; 95% CI 1.02–1.27), more upper respiratory tract infections (RR = 1.56; 95% CI 1.08–2.25), less vertebral fractures (RR = 0.54; 95% CI 0.31–0.93), and less abdominal pain (RR = 0.44;95% CI 0.22–0.87). We explored the comparative safety of denosumab and bisphosphonates for primary osteoporosis, some of which could be attributed to their beneficial effects. However, all trials had a risk of bias. Further investigations are required to confirm our results. [ABSTRACT FROM AUTHOR]

The essence of drug delivery is to use an appropriate carrier that delivers the active substance to the appropriate pathogenic site at a specific time. This study aims to develop a novel drug carrier characterized by the controlled and targeted release of risedronate (RSD). The search for new routes to deliver RSD is important because oral delivery has many disadvantages. The carrier proposed in this work is composed of gelatin, polyphosphates, and zinc. The zinc contained in the carrier is responsible for coordinating the drug. The resulting material releases RSD in a controlled manner. The rate of delivery of the substance to the body depends on the pH of the environment. This study investigated the delivery of RSD in a neutral environment, where the process exhibited a prolonged and consistent release rate. This process has also been studied in an acidic environment, which accelerates the release of the drug. Mixed-environment studies were also conducted. Initially, the drug was released in a neutral environment, and then the conditions rapidly changed to acidic. In this case, the carrier demonstrated high stability and controlled release, adapting the rate of drug release to the prevailing environmental conditions. The presented results indicate the great potential of the new gelatin-based carrier in the delivery of risedronate. [ABSTRACT FROM AUTHOR]

Summary: Bone strength estimates are important for fracture prevention. This study compared bone strength changes in postmenopausal women with low bone mass who were assigned to 12 months of exercise, a bone medication, or control. Exercise and bone medications benefited structure at the hip. Structure should be considered in fracture prevention research. Purpose: Exercise and bisphosphonates reduce fracture risk, but their impact on estimates of bone strength remains uncertain. This study compared changes in tibial bone strength using peripheral quantitative computed tomography (pQCT) and hip structure analysis (HSA) outcomes from dual-energy X-ray absorptiometry (DXA) scans in postmenopausal women with low bone mass assigned to 12 months of exercise, risedronate, or control. Methods: In this RCT, 276 postmenopausal women within 6 years of menopause were randomly assigned to three groups: exercise (92), risedronate (91), or control (93). Exercise included weighted jogging and progressive resistance exercises; risedronate treatment was 150 mg monthly; all groups received calcium and vitamin D. pQCT and DXA images were obtained at baseline and 6 and 12 months and compared between groups over time. Results: Participants had a mean (± SD) age of 54.5 (± 3.2) years with an average of 36.7 (± 40.7) months postmenopause. No significant differences were found between groups for the change in pQCT outcomes (volumetric bone mineral density, area, and strength estimates). At 12 months, mean percent differences (95% CI) in HSA measures between exercise and controls were as follows: intertrochanteric, cross-sectional area 2.25% (0.28, 4.12) (p =.03), cross-sectional moment of inertia (CSMI) 5.67% (1.47, 9.87) (p <.01), and section modulus (SM) 4.38% (1.02, 7.74) (p =.01), and narrow neck, average cortical thickness 2.37% (−0.08, 4.83) (p =.031). Mean percent differences (95% CI) in HSA measures between risedronate and control were as follows: intertrochanteric, CSMI 4.28% (−0.24, 8.81) (p =.03) and SM 3.35% (−0.21, 6.91) (p =.03), and shaft, subperiosteal width 0.82% (0.05, 1.58) (p =.047), CSMI 2.53% (0.88, 4.18) (p =.004), and SM 1.57% (0.34, 2.8) (p =.008). Exercise maintained neck-shaft angle compared to both control 1.27% (0.13, 2.41) (p =.04) and risedronate 1.31% (0.23, 2.39) (p =.03). All other differences for changes in HSA outcomes over time were not significantly different between the exercise and risedronate groups. Conclusion: Exercise and bisphosphonates may influence structural and strength estimates at the hip, but not at peripheral sites (tibia). Neither exercise nor bisphosphonates were found to be superior in improving estimates of hip bone strength. [ABSTRACT FROM AUTHOR]

Preparations of black cohosh extract are sold as dietary supplements marketed to relieve the vasomotor symptoms of menopause, and some studies suggest it may protect against postmenopausal bone loss. Postmenopausal women are also frequently prescribed bisphosphonates, such as risedronate, to prevent osteoporotic bone loss. However, the pharmacodynamic interactions between these compounds when taken together is not known. To investigate possible interactions, 6-month-old, female Sprague-Dawley rats underwent bilateral ovariectomy or sham surgery and were treated for 24 weeks with either vehicle, ethinyl estradiol, risedronate, black cohosh extract or coadministration of risedronate and black cohosh extract, at low or high doses. Bone mineral density (BMD) of the femur, tibia, and lumbar vertebrae was then measured by dual-energy X-ray absorptiometry (DEXA) at weeks 0, 8, 16, and 24. A high dose of risedronate significantly increased BMD of the femur and vertebrae, while black cohosh extract had no significant effect on BMD individually and minimal effects upon coadministration with risedronate. Under these experimental conditions, black cohosh extract alone had no effect on BMD, nor did it negatively impact the BMD-enhancing properties of risedronate. [ABSTRACT FROM AUTHOR]

Hydrogels are potential materials in many biomedical applications. A particularly promising application is their use in bone tissue engineering as implants or layers on the surface of titanium alloys. Disadvantage in the use of hydrogels in drug release system is often "burst release" effect what obstructs controlled release of pharmaceutically active agent. This functionality can be obtained by using an appropriate hydrogel, which has in its structure ions to which the drug is complexed. In this work, hydrogel materials containing mers with phosphate groups were prepared and used in the controlled drug release. The prepared material was functionalized with Ca2+, Mg2+, and Sr2+ ions. These ions were chosen because they support the osseointegration process. The possibility of sorption of the drug for osteoporosis (risedronate) was tested on the prepared hydrogels. Sorption was effective only on the hydrogel with calcium ions. The drug was evenly distributed throughout the hydrogel. The new hydrogel has proven to be able to retain the drug and slowly release it in small doses. We assume that the prepared material has the potential to be used as a coating for bone implants or as an implantable hydrogel for people suffering from osteoporosis. [ABSTRACT FROM AUTHOR]

The cGAS-STING pathway and the Mevalonate Pathway are druggable targets for vaccine adjuvant discovery. Manganese (Mn) and bisphosphonates are known to exert adjuvant effects by targeting these two pathways, respectively. This study found the synergistic potential of the two pathways in enhancing immune response. Risedronate (Ris) significantly amplified the Mn adjuvant early antibody response by 166-fold and fortified its cellular immunity. However, direct combination of Mn2+ and Ris resulted in increased adjuvant toxicity (40% mouse mortality). By the combination of doping property of hydroxyapatite (HA) and its high affinity for Ris, we designed Ris-functionalized Mn-HA micro-nanoparticles as an organic-inorganic hybrid adjuvant, named MnHARis. MnHARis alleviated adjuvant toxicity (100% vs. 60% survival rate) and exhibited good long-term stability. When formulated with the varicella-zoster virus glycoprotein E (gE) antigen, MnHARis triggered a 274.3-fold increase in IgG titers and a 61.3-fold surge in neutralization titers while maintaining a better long-term humoral immunity compared to the aluminum adjuvant. Its efficacy spanned other antigens, including ovalbumin, HPV18 VLP, and SARS-CoV-2 spike protein. Notably, the cellular immunity elicited by the group of gE + MnHARis was comparable to the renowned Shingrix®. Moreover, intratumoral co-administration with an anti-trophoblast cell surface antigen 2 nanobody revealed synergistic antitumor capabilities. These findings underscore the potential of MnHARis as a potent adjuvant for augmenting vaccine immune responses and improving cancer immunotherapy outcomes. Risedronate (Ris)-functionalized manganese (Mn2+)-HA adjuvant was designed, named MnHARis. The Mn2+ and Ris co-dopion successfully transformed HA crystalline rodlike precipitation into Mn/CaRis amorphous precipitates. MnHARis enhanced antigen presenting cells (APCs) activation and induced robust humoral and cellular immunity in subunit vaccines. Moreover, MnHARis demonstrated a synergistic anti-cancer effect when co-administered intratumorally with nanobody. [Display omitted] [ABSTRACT FROM AUTHOR]

Osteoporosis targeting by transdermal distribution has drawn a lot of attention as a cutting-edge, environmentally friendly platform for sustainable pain management. We investigate a novel biocompatible transdermal gel (RCNGL) containing biodegradable chitosan nanoparticles and Risedronate (RS) to treat osteoporosis. The RCNGL was formulated using the Pluronic F 127 co-polymer system and the ionic gelation process. The formulation showed a robust architecture of nanoparticle dispersion with a nano-size range of 201.8 nm when it was thoroughly analysed for Scanning Electron Microscopy, Dynamic electron Microscopy and transmission electron microscopy. At various temperatures, the entrapment efficiency was 67.53±1.05% with steady rheology and respectable porosity, validating FT-IR spectra that showed structural compatibility of RS with other excipients. The drug release test resulted in an 88% RS gel release, supporting sustained release kinetics. The ex vivo Franz diffusion study and in vitro cell uptake and distribution experiments revealed clear cell uptake and distribution with notable skin permeation displaying >70% RS release in mouse epidermal tissue. Overall, our research shows that biodegradable RCNGL may offer a potential osteoporosis and pain control strategy in clinical platforms using passive targeting.

Introduction: We conducted an all-case postmarketing surveillance study between 2008 and 2017 to evaluate the safety and effectiveness of risedronate for Paget's disease of bone (PDB) in Japan. Material and methods: This study registered all patients who received once-daily risedronate 17.5 mg for the treatment of PDB and collected data over a 48-week follow-up period per treatment cycle for each patient. Results: The safety analysis set included 184 patients (mean age, 63.7 years), 81 (44.0%) of whom previously received a bisphosphonate. Of them, 41 (22.3%) experienced 72 adverse drug reactions (ADRs), and 8 (4.3%) experienced 14 serious ADRs. Common ADRs included gastrointestinal disorders (20 patients, 10.9%) and hypocalcemia (6 patients, 3.3%). The effectiveness analysis set included 182 patients, 124 of whom completed only one treatment cycle and 58 of whom completed multiple treatment cycles. The proportions of patients who normalized serum alkaline phosphatase (ALP) concentration were 71.1% (113/159 patients) and 67.3% (33/49 patients) for the first and second treatment cycles, respectively. The relapse rate according to ALP levels after the end of treatment for the first cycle was 5.0% (95% confidence interval [CI] = 2.1–11.5) at 24 weeks and 12.9% (95% CI = 7.5–21.7) at 40 weeks. Regarding pain relief, the achievement rates were 70.0% (49/70 patients) and 30.8% (4/13 patients) for the first and second treatment cycles, respectively. Conclusion: To conclude, risedronate 17.5 mg/day is safe and effective for treating patients with PDB in daily practice. [ABSTRACT FROM AUTHOR]

Micro/Nano-scale particles are widely used as vaccine adjuvants to enhance immune response and improve antigen stability. While aluminum salt is one of the most common adjuvants approved for human use, its immunostimulatory capacity is suboptimal. In this study, we modified risedronate, an immunostimulant and anti-osteoporotic drug, to create zinc salt particle-based risedronate (Zn-RS), also termed particulate risedronate. Compared to soluble risedronate, micronanoparticled Zn-RS adjuvant demonstrated increased recruitment of innate cells, enhanced antigen uptake locally, and a similar antigen depot effect as aluminum salt. Furthermore, Zn-RS adjuvant directly and quickly stimulated immune cells, accelerated the formulation of germinal centers in lymph nodes, and facilitated the rapid production of antibodies. Importantly, Zn-RS adjuvant exhibited superior performance in both young and aged mice, effectively protecting against respiratory diseases such as SARS-CoV-2 challenge. Consequently, particulate risedronate showed great potential as an immune-enhancing vaccine adjuvant, particularly beneficial for vaccines targeting the susceptible elderly. [Display omitted] • Risedronate in particulate form enhances antibody production compared to soluble form. • Particulate risedronate adjuvant (Zn-RS) promotes antigen uptake and retention in local. • Zn-RS adjuvant enhances antigen presentation and immune cell communication. • Zn-RS adjuvanted vaccines generate broad-spectrum humoral and strong T cell responses. • Single vaccination with Zn-RS adjuvanted vaccine confers protection against SARS-CoV-2 challenge. [ABSTRACT FROM AUTHOR]

Introduction: Osteoporosis is the most prevalent bone disease in humans, affecting people of all ages but more common in postmenopausal women. Risedronate (RIS) and strontium ranelate (SR) are two clinically accessible anti-osteoporotic medicines. Objectives: To assess and compare the anti-osteoporotic effects of RIS and SR on the histologic, histomorphometric, and ultrastructural features of compact bones in a rat model of glucocorticoid-induced osteoporosis. Materials and Methods: 42 mature healthy male albino rats were randomly allocated into 6 main groups (7 rats /group) and received daily oral treatments for 12 weeks as following: negative control, RIS +ve control (2.5 mg/kg/day), SR +ve control (625 mg/kg/day), prednisolone (pred)-treated (1.5 mg/kg/day), pred + RIS (treated concurrently with prednisolone and RIS), and pred + SR (treated concurrently with prednisolone and SR). At the end of the experiment, all animals were anesthetized, sacrificed, and the femurs and tibias were excised for x-ray, histological, histomorphometric, and electron microscopic studies. Results: Oral prednisolone provoked significant osteoporotic changes as evidenced by generalized osteopenia and bone bending detected in the X-ray. Histological examination demonstrated decreased cortical bone thickness, multiple irregular perforations, reduced lamellar bone formation, and an increase in the osteoid tissue. Ultrastructural changes were observed in the form of distorted osteoblasts and osteocytes together with lysis of collagen fibrils in the bone matrix. Oral administration of RIS and SR was associated with moderate and marked improvement of prednisolone induced perturbations of the bone architecture respectively. Conclusion: Our data suggest that SR outperforms RIS in alleviating glucocorticoid-induced osteoporotic changes in cortical bone tissues. [ABSTRACT FROM AUTHOR]

Risedronate sodium (RIS) exhibits limited bioavailability and undesirable gastrointestinal effects when administered orally, necessitating the development of an alternative formulation. In this study, mPEG-coated nanoparticles loaded with RIS-HA-TCS were created for osteoporosis treatment. Thiolated chitosan (TCS) was synthesized using chitosan and characterized using DSC and FTIR, with thiol immobilization assessed using Ellman's reagent. RIS-HA nanoparticles were fabricated and conjugated with synthesized TCS. Fifteen batches of RIS-HA-TCS nanoparticles were designed using the Box–Behnken design process. The nanoparticles were formulated through the ionic gelation procedure, employing tripolyphosphate (TPP) as a crosslinking agent. In silico activity comparison of RIS and RIS-HA-TCS for farnesyl pyrophosphate synthetase enzyme demonstrated a higher binding affinity for RIS. The RIS-HA-TCS nanoparticles exhibited 85.4 ± 2.21% drug entrapment efficiency, a particle size of 252.1 ± 2.44 nm, and a polydispersity index of 0.2 ± 0.01. Further conjugation with mPEG resulted in a particle size of 264.9 ± 1.91 nm, a PDI of 0.120 ± 0.01, and an encapsulation efficiency of 91.1 ± 1.17%. TEM confirmed the spherical particle size of RIS-HA-TCS and RIS-HA-TCS-mPEG. In vitro release studies demonstrated significantly higher release for RIS-HS-TCS-mPEG (95.13 ± 4.64%) compared to RIS-HA-TCS (91.74 ± 5.13%), RIS suspension (56.12 ± 5.19%), and a marketed formulation (74.69 ± 3.98%). Ex vivo gut permeation studies revealed an apparent permeability of 0.5858 × 10−1 cm/min for RIS-HA-TCS-mPEG, surpassing RIS-HA-TCS (0.4011 × 10−4 cm/min), RIS suspension (0.2005 × 10−4 cm/min), and a marketed preparation (0.3401 × 10−4 cm/min). [ABSTRACT FROM AUTHOR]

Background Bisphosphonates are a class of medication commonly used to treat osteoporosis. Alendronate is recommended as the first-line treatment; however, long-term adherence (both treatment compliance and persistence) is poor. Alternative bisphosphonates are available, which can be given intravenously and have been shown to improve long-term adherence. However, the most clinically effective and cost-effective alternative bisphosphonate regimen remains unclear. What is the most cost-effective bisphosphonate in clinical trials may not be the most cost-effective or acceptable to patients in everyday clinical practice. Objectives Explore patient, clinician and stakeholder views, experiences and preferences of alendronate compared to alternative bisphosphonates. Update and refine the 2016 systematic review and cost-effectiveness analysis of bisphosphonates, and estimate the value of further research into their benefits. Undertake stakeholder/consensus engagement to identify important research questions and further rank research priorities. Methods The study was conducted in two stages, stages 1A and 1B in parallel, followed by stage 2: Stage 1A – we elicited patient and healthcare experiences to understand their preferences of bisphosphonates for the treatment of osteoporosis. This was undertaken by performing a systematic review and framework synthesis of qualitative studies, followed by semistructured qualitative interviews with participants. Stage 1B – we updated and expanded the existing Health Technology Assessment systematic review and clinical and cost-effectiveness model, incorporating a more comprehensive review of treatment efficacy, safety, side effects, compliance and long-term persistence. Stage 2 – we identified and ranked further research questions that need to be answered about the effectiveness and acceptability of bisphosphonates. Results Patients and healthcare professionals identified a number of challenges in adhering to bisphosphonate medication, balancing the potential for long-term risk reduction against the work involved in adhering to oral alendronate. Intravenous zoledronate treatment was generally more acceptable, with such regimens perceived to be more straightforward to engage in, although a portion of patients taking alendronate were satisfied with their current treatment. Intravenous zoledronate was found to be the most effective, with higher adherence rates compared to the other bisphosphonates, for reducing the risk of fragility fracture. However, oral bisphosphonates are more cost-effective than intravenous zoledronate due to the high cost of zoledronate administration in hospital. The importance of including patients and healthcare professionals when setting research priorities is recognised. Important areas for research were related to patient factors influencing treatment selection and effectiveness, how to optimise long-term care and the cost-effectiveness of delivering zoledronate in an alternative, non-hospital setting. Conclusions Intravenous zoledronate treatment was generally more acceptable to patients and found to be the most effective bisphosphonate and with greater adherence; however, the cost-effectiveness relative to oral alendronate is limited by its higher zoledronate hospital administration costs. Future work Further research is needed to support people to make decisions influencing treatment selection, effectiveness and optimal long-term care, together with the clinical and cost-effectiveness of intravenous zoledronate administered in a non-hospital (community) setting. Limitations Lack of clarity and limitations in the many studies included in the systematic review may have under-interpreted some of the findings relating to effects of bisphosphonates. Trial registration This trial is registered as ISRCTN10491361. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR127550) and is published in full in Health Technology Assessment; Vol. 28, No. 21. See the NIHR Funding and Awards website for further award information. Plain language summary Background Bisphosphonates are drug treatments commonly used to treat osteoporosis. Alendronate is the most used and is taken by mouth, weekly at a specific time of the week, which can be challenging. Less than one in four people continue this treatment beyond 2 years. Alternative bisphosphonates are available, which vary in frequency and how they are administered. The most acceptable and best value-for-money regimen is unclear. Aim Our aim was to determine how effective alternative bisphosphonates are compared to alendronate at preventing fractures and whether reduction in fracture risk was achieved at a reasonable financial cost, but acceptable to patients. Design and methods The study was conducted in two stages, stages 1A and 1B in parallel, followed by stage 2: Stage 1A: a review of the published evidence on patients’ and doctors’ views, experiences and preferences regarding different bisphosphonate treatment regimens, followed by interviews with patients and healthcare professionals. Stage 1B: an update of an existing study on how effective bisphosphonates are in preventing fragility fractures caused by osteoporosis and whether they are good value for money. Stage 2: identification of questions that need to be answered about the effectiveness and acceptability of bisphosphonate treatments. Results Taking bisphosphonate medication often involves quite a lot of effort by patients, particularly when taking alendronate tablets. A yearly infusion of zoledronate treatment was more acceptable, easier to engage with and the most effective treatment compared to alendronate. However, the cost of administering zoledronate in hospital made alendronate better value for money. Conclusions Bisphosphonates are effective in reducing the risk of fracture, but ‘continuing with treatment’, particularly alendronate tablets, remains a challenge. A yearly infusion of zoledronate offers an acceptable and effective treatment, but further research is needed to support patients and healthcare professionals in making decisions about the various treatments, benefits and cost savings of administering zoledronate outside of hospital and in the community. Scientific summary Background Alendronate (ALN) is recommended as the first-line osteoporosis treatment to prevent osteoporotic fractures; however, long-term adherence (both treatment compliance and persistence) is poor. Alternative bisphosphonates (BP) are available, which vary in frequency of use and/or route of administration and have been shown to improve long-term adherence compared to ALN. However, the most clinically effective and cost-effective alternative regimen remains unclear. Furthermore, clinicians should optimise dosing regimens on the basis of the patient’s understanding, preference and characteristics. What is the most cost-effective BP in clinical trials may not be the most cost-effective or acceptable to patients in everyday clinical practice. Objectives Explore patient, clinician and stakeholder views, experiences and preferences of ALN compared to alternative BP. Update and refine the 2016 systematic review and cost-effectiveness analysis of BP and estimate the value of further research into the relative benefits. Undertake stakeholder/consensus engagement to identify important research questions and further rank research priorities. Methods The study was conducted in two stages, stages 1A and 1B in parallel, followed by stage 2: Stage 1A: we elicited patient and clinician experiences of different BP regimens to understand their preferences and those of other stakeholders compared to ALN. This was undertaken by performing a systematic review and framework synthesis of qualitative studies around clinician and patient views, followed by semistructured qualitative interviews with multidisciplinary stakeholders. Stage 1B: we updated and expanded the existing Health Technology Assessment systematic review and clinical and cost-effective health economic model (2016), incorporating a more comprehensive review of treatment efficacy, safety, side effects, compliance and long-term persistence. The model takes a NHS and Personal Social Services perspective, with future costs and quality-adjusted life-years (QALYs) discounted at 3.5% per annum. Costs are reported in pound sterling based on 2021 prices. Stage 2: using an approach based on the James Lind methodology for identification and prioritisation of research questions, we identified questions that needed to be answered about the effectiveness and acceptability of BP. Findings from stages 1A and 1B, together with multidisciplinary meetings, identified areas of uncertainty. These questions were then ranked in a multidisciplinary, nationally representative stakeholder event, conducted online over MS Teams. Results We identified, through a systematic review of previous studies on patient and clinician experiences of BP treatment, how patients and healthcare professionals make sense (coherence) of BP by balancing perceptions of need against concerns, how uncertainty prevails about BP-perceived effectiveness and a number of individual and service factors that have potential to increase self-efficacy in recommending and adhering to BP. The qualitative interview study examining experiences of alternate BP regimens found that intravenous (IV) BP zoledronate (ZOL) treatment was generally more acceptable to patients. Such IV regimens were perceived to be more straightforward to engage in, although a portion of patients taking ALN were satisfied with their current treatment. The systematic review and network meta-analysis of previous studies of effectiveness found that IV ZOL was the most effective BP compared to ALN, risedronate and oral ibandronate for reducing the risk of fragility fractures. Adherence was higher in IV ZOL users. It was found that clinical decision-making could be facilitated by considering adherence patterns in BP users who were at increased risk of fracture. However, the higher hospital administration costs for IV ZOL meant that the incremental cost-effectiveness ratios for IV ZOL compared to ALN were greater than £30,000 per QALY across all risk categories. This was despite the fact that IV ZOL was predicted to result in fewer fractures than ALN, due to its higher treatment persistence and a longer offset period. The prioritisation exercise highlighted a need for further research to tackle the issues relating to patient factors influencing treatment selection and effectiveness, including in younger adults, how to optimise long-term care and support patient and clinician decision-making and the clinical and cost-effectiveness of giving IV ZOL in alternate settings to hospital care. Conclusions We have identified the factors that influence how patients and clinicians make sense of BP, described the experience of BP taking in terms of burden and identified factors that both facilitate and hinder confidence in taking and prescribing and monitoring BP. IV ZOL treatment was generally more acceptable to patients. IV ZOL was found to be the most effective BP and with greater adherence; however, the cost-effectiveness of IV ZOL relative to ALN was limited by the high hospital administration costs. Further research is needed to support people to make decisions influencing treatment selection and effectiveness and establish how to optimise long-term care. In addition, research is needed to explore the clinical and cost-effectiveness of IV ZOL delivered in alternate settings, such as in the community, compared to ALN treatment. Patient and public involvement We have worked closely with the Royal Osteoporosis Society (ROS) and the Nottingham ROS (NotROS) Support Group, who together have influenced the design of this application, choice of study outcomes and were involved throughout the study. Trial registration This trial is registered as ISRCTN10491361. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: NIHR127550) and is published in full in Health and Social Care Delivery Research; Vol. 28, No. 21. See the NIHR Funding and Awards website for further award information.

Preparations of black cohosh extract are sold as dietary supplements marketed to relieve the vasomotor symptoms of menopause, and some studies suggest it may protect against postmenopausal bone loss. Postmenopausal women are also frequently prescribed bisphosphonates, such as risedronate, to prevent osteoporotic bone loss. However, the pharmacodynamic interactions between these compounds when taken together is not known. To investigate possible interactions, 6-month-old, female Sprague-Dawley rats underwent bilateral ovariectomy or sham surgery and were treated for 24 weeks with either vehicle, ethinyl estradiol, risedronate, black cohosh extract or coadministration of risedronate and black cohosh extract, at low or high doses. Bone mineral density (BMD) of the femur, tibia, and lumbar vertebrae was then measured by dual-energy X-ray absorptiometry (DEXA) at weeks 0, 8, 16, and 24. A high dose of risedronate significantly increased BMD of the femur and vertebrae, while black cohosh extract had no significant effect on BMD individually and minimal effects upon coadministration with risedronate. Under these experimental conditions, black cohosh extract alone had no effect on BMD, nor did it negatively impact the BMD-enhancing properties of risedronate.

Osteoporosis, a condition that primarily affects postmenopausal women and senior adults, presents a substantial public health dilemma despite its subtle manifestations. It is frequently dubbed the "silent disease of the twenty-first century." Osteoporosis is characterised by an imbalance in bone resorption and formation. The study was conducted over the course of one year in a 300-bed hospital, involving 150 patients. Individuals between the ages of 51 and 60 have an increased risk of developing osteoporosis and osteopenia, according to this study. In comparison with males, osteoporosis predominantly impacts women. Low bone mineral density among low-income populations as a result of inadequate nutrition, a high incidence of osteopenia and osteoporosis among postmenopausal women, and vitamin D deficiency among people living in cities are all contributory factors to the prevalence of osteoporosis in India. According to estimates, a considerable proportion of individuals in India suffer from osteoporosis and hip fractures at an earlier stage than in Western nations. We used the WHO's FRAX online instrument to ascertain the risk of fracture in this study. The management of this condition encompasses a wide range of aspects. For both men and women, pharmacological treatments such as denosumab, risedronate, alendronate, zoledronic acid, and bisphosphonates are among the treatment options for osteoporosis. In addition, nonpharmacological approaches to management are advised, including weight-bearing exercise, nicotine cessation, adequate calcium and vitamin D consumption, and fall prevention techniques. Individualised treatment options should be made based on risk-benefit analysis, patient preferences, fracture risk profile, and cost. The primary objective of this study is to provide a comprehensive examination of the existing diagnostic techniques, therapeutic approaches, and potential lifestyle modifications for osteoporosis.

Abstract Background To examine the effects of local risedronate application with xenografts on healing of rabbit skull defects using histological, histomorphometric, immunohistochemical, and three-dimensional radiological methods. Methods Two critical-sized defects with a diameter of 10 mm were created in 16 rabbits and filled with xenogenic bone graft and xenogenic bone graft + 5 mg risedronate in the control I and risedronate (RIS) groups, respectively. Residual graft, new bone, soft tissue areas, and bone volume were evaluated in the 4- and 8-week study groups. Results In both the 4- and 8-week samples, the RIS group samples had significantly higher mean new bone area values than the C group (p 0.05). The results of radiological evaluation showed that the bone density value was significantly higher in the C group than in the RIS group at either time point (p

Background: Atypical femur fractures (AFFs) are stress or insufficiency fractures often associated to long term use of bisphosphonates (BPs). AFFs are usually not comminuted, sometimes bilateral involving the subtrochanteric region or the diaphysis. Prodromal symptoms may have been present for weeks or months before AFFs. The aim of this case report is to highlight that the correlation between the duration of BPs therapy and the risk of AFFs may be not so strong as reported in the literature, and to evaluate the tools available to the physician for preventing this complication. Case report: A 54 years old woman was transported by ambulance to our emergency department following an accidental fall in the street. She experienced bilateral thigh collapse accelerating her step while crossing the street and was unable to get up complaining severe pain in both lower limbs. X-rays showed bilateral complete transverse fracture of the femoral diaphysis. Early treatment in emergency department has been application of trans-tibial traction; on the same day the patient was admitted to orthopaedic department. Investigating patient's medical history, it emerged that the only medication she had been taking was Risedronate, for only 18 months, for a diagnosis of osteoporosis 6 years earlier. As prodromal symptom, about 6 months before hospitalization, she started experiencing bilateral thigh pain, without investigating it. Subsequently she underwent fixation with anterograde long intramedullary nails. Both femurs were treated in the same operating session. From the day after surgery, she began passive mobilization and strengthening of postural muscles; on the fourth day after surgery she began the protocol of re-education to standing and walking with progressive load over time. Conclusion: This case report highlights the possible limitations of the current management of BPs therapy. The occurrence of AFFs may not be solely dependent on the duration of BPs therapy and the age of patients, as widely acknowledged in the current literature. The management of BPs therapy may require a redefinition, with the need, according to the authors, to evaluate the introduction of therapeutic windows, especially in patients with clinical signs of high risk of AFFs.

Risedronate-loaded mPEG-coated hydroxyapatite, thiolated chitosan-based (coated) and non-coated nanoparticles were tested for their potential effects in the treatment of osteoporosis. The prepared nanoparticles were evaluated for their bone-targeting potential by inducing osteoporosis in female Wistar rats via oral administration of Dexona (dexamethasone sodium phosphate). In vivo pharmacokinetic and pharmacodynamic studies were performed on osteoporotic rat models treated with different formulations. The osteoporotic model treated with the prepared nanoparticles indicated a significant effect on bone. The relative bioavailability was enhanced for RIS-HA-TCS-mPEG nanoparticles given orally compared to RIS-HA-TCS, marketed, and API suspension. Biochemical investigations also showed a significant change in biomarker levels, ultimately leading to bone formation/resorption. Micro-CT analysis of bone samples also demonstrated that the RIS-HA-TCS-mPEG-treated group showed the best results compared to other treatment groups. Moreover, the histology of bone treated with RIS-HA-TCS-mPEG showed a marked restoration of the architecture of trabecular bone along with a well-connected bone matrix and narrow inter-trabecular spaces compared to the toxic group. A stability analysis was also carried out according to ICH guidelines (Q1AR2), and it was found that RIS-HA-TCS-mPEG was more stable than RIS-HA-TCS at 25 °C. Thus, the results of present study indicated that mPEG-RIS-HA-TCS has excellent potential for sustained delivery of RIS for the treatment and prevention of osteoporosis, and for minimizing the adverse effects of RIS typically induced via oral administration. [ABSTRACT FROM AUTHOR]

Cancer metastasis or the spread of cancer cells from main tumor to other parts of the body is the most common cause of morbidity and mortality in cancer patients. Due to applications of risedronate (RES) and zoledronate (ZLA) in the medical field, the solvation effects, reactivity studies, and molecular dynamics (MD) are reported. The solvation-free energy in water (hydration-free energy) indicates good solubility in an aqueous medium, a factor that corroborates the biological activity. The O...H distances (P=O to OH) gives interactions in vacuum and solvents. Change in free energy for the RES and ZLA with both solvents indicated the process happen in spontaneously. Van der walls interactions demonstrated that the intramolecular hydrogen bonds at O4–C15 (RES) and at O8–H21, O3–H22, N10–H19, and O6–H17 (ZLA). MD and simulation of the ligand bound main WNT5A were studied in details to understand the nature of possible binding motifs and structurally stable conformations. [ABSTRACT FROM AUTHOR]

The essence of drug delivery is to use an appropriate carrier that delivers the active substance to the appropriate pathogenic site at a specific time. This study aims to develop a novel drug carrier characterized by the controlled and targeted release of risedronate (RSD). The search for new routes to deliver RSD is important because oral delivery has many disadvantages. The carrier proposed in this work is composed of gelatin, polyphosphates, and zinc. The zinc contained in the carrier is responsible for coordinating the drug. The resulting material releases RSD in a controlled manner. The rate of delivery of the substance to the body depends on the pH of the environment. This study investigated the delivery of RSD in a neutral environment, where the process exhibited a prolonged and consistent release rate. This process has also been studied in an acidic environment, which accelerates the release of the drug. Mixed-environment studies were also conducted. Initially, the drug was released in a neutral environment, and then the conditions rapidly changed to acidic. In this case, the carrier demonstrated high stability and controlled release, adapting the rate of drug release to the prevailing environmental conditions. The presented results indicate the great potential of the new gelatin-based carrier in the delivery of risedronate.

Background: To examine the effects of local risedronate application with xenografts on healing of rabbit skull defects using histological, histomorphometric, immunohistochemical, and three-dimensional radiological methods. Methods: Two critical-sized defects with a diameter of 10 mm were created in 16 rabbits and filled with xenogenic bone graft and xenogenic bone graft + 5 mg risedronate in the control I and risedronate (RIS) groups, respectively. Residual graft, new bone, soft tissue areas, and bone volume were evaluated in the 4- and 8-week study groups. Results: In both the 4- and 8-week samples, the RIS group samples had significantly higher mean new bone area values than the C group (p < 0.05). In both groups, the values for the new bone area were significantly higher in the 8-week-old samples than in the 4-week-old samples (p < 0.05). The h scores obtained for sialoprotein and osteopontin did not differ significantly between the groups at either time point (p > 0.05). The results of radiological evaluation showed that the bone density value was significantly higher in the C group than in the RIS group at either time point (p < 0.05). Conclusions: Although this study aimed to demonstrate the effect of risedronate on the osteoconductive properties of xenografts when applied locally, targeted results could not be achieved. [ABSTRACT FROM AUTHOR]

Abstract Background Risedronate is a bisphosphonate with poor oral absorption. An extremely hydrophilic molecule that has a high affinity for bone, risedronate also inhibits the farnesyl diphosphate synthase enzyme, inhibiting osteoclastic activity and reducing bone turnover and resorption. Autogenous bone grafts contain osteogenic cells and osteoinductive factors that are essential for bone regeneration and are therefore considered the gold standard. Thus, this study aimed to investigate the impact of local risedronate administered with autogenous bone grafts on the healing of defects in rabbit skulls using histological, histomorphometric, immunohistochemical, and three-dimensional radiological methods. Methods Two 10-mm-diameter critical-size defects were created in 16 rabbits and filled with autogenous bone graft and autogenous bone graft + 5 mg risedronate in the control (C) and risedronate (RIS) groups, respectively. Residual graft, new bone, soft tissue areas, and bone volume were evaluated in the 4- and 8-week study groups. Results There were no statistically significant differences in bone graft, new bone, or soft tissue area between the groups at 4 weeks (p > 0.05). At 8 weeks, the new bone area was significantly higher in the RIS group than in the C group (p 0.05). The radiologically measured total bone volume was significantly higher in the RIS group than in the C group at both time points (p

Summary: The study results indicate that women with osteoporosis initiated on gastro-resistant risedronate have a lower risk of fracture than those initiated on immediate release risedronate or alendronate. A large proportion of women discontinued all oral bisphosphonate therapies within 1 year of treatment start. Purpose: Using a US claims database (2009–2019), we compared risk of fractures between women with osteoporosis initiated on gastro-resistant (GR) risedronate and those initiated on (a) immediate release (IR) risedronate or (b) immediate release alendronate. Methods: Women aged ≥ 60 years with osteoporosis who had ≥ 2 oral bisphosphonate prescription fills were followed for ≥ 1 year after the first observed bisphosphonates dispensing (index date). Fracture risk was compared between the GR risedronate and IR risedronate/alendronate cohorts using adjusted incidence rate ratios (aIRRs), both overall and in subgroups with high fracture risk due to older age or comorbidity/medications. Site-specific fractures were identified based on diagnosis codes recorded on medical claims using a claims-based algorithm. Persistence on bisphosphonate therapy was evaluated for all groups. Results: aIRRs generally indicated lower fracture risk for GR risedronate than IR risedronate and alendronate. When comparing GR risedronate to IR risedronate, statistically significant aIRRs (p < 0.05) were observed for pelvic fractures in the full cohorts (aIRRs = 0.37), for any fracture and pelvic fractures among women aged ≥ 65 years (aIRRs = 0.63 and 0.41), for any fracture and pelvic fractures among women aged ≥ 70 years (aIRRs = 0.69 and 0.24), and for pelvic fracture among high-risk women due to comorbidity/medications (aIRR = 0.34). When comparing GR risedronate to alendronate, statistically significant aIRRs were observed for pelvic fractures in the full cohorts (aIRR = 0.54), for any fracture and wrist/arm fractures among women aged ≥ 65 years (aIRRs = 0.73 and 0.63), and for any fracture, pelvic, and wrist/arm fractures among women aged ≥ 70 years (aIRRs = 0.72, 0.36, and 0.58). In all cohorts, ~ 40% completely discontinued oral bisphosphonates within 1 year. Conclusions: Discontinuation rates of oral bisphosphonate therapy were high. However, women initiated on GR risedronate had a significantly lower risk of fracture for several skeletal sites than women initiated on IR risedronate/alendronate, particularly those aged ≥ 70 years. [ABSTRACT FROM AUTHOR]

Paget's disease of bone (PDB) is a focal bone disorder caused by a marked dysregulation of osteoblasts and osteoclasts in basic multicellular units, leading to abnormal and disorganized deposition of collagen fibers (the so-called 'woven bone'). Therefore, pagetic bones are increased in size, and at increased risk for bone pain, deformities, fractures, osteoarthritis, and, more rarely, neoplastic degeneration. In this review, we revise the available information concerning the pharmacological treatment of PDB. PDB progresses slowly within the affected skeletal sites and, if untreated, often leads to bone overgrowth, with bone pain, deformity, and a likely increased risk of complications. Thus, the primary goal of treatment is the restoration of a normal bone turnover, in order to relieve bone pain or other symptoms and possibly prevent the complications. PDB long remained a poorly treatable disorder until the discovery of antiresorptive agents such as calcitonin first and bisphosphonates (BPs) later. With the recent development of potent intravenous BPs like zoledronate, allowing a better control of disease activity over the long term with a single infusion, has contributed to a marked improvement of the clinical management of this invalidating disorder. [ABSTRACT FROM AUTHOR]

Summary: A retrospective study of 121 patients who stopped denosumab (Dmab) then received no treatment (NT), risedronate (RIS), alendronate (ALN), or zoledronic acid (ZOL). Bone density (spine and hip) during and after Dmab discontinuation was measured. Treatment with ALN or ZOL, not NT and RIS, mitigated BMD loss after Dmab discontinuation. Introduction: Denosumab (Dmab) discontinuation is associated with bone loss and multiple vertebral fractures. The purpose was to compare bone mineral density (BMD) change in patients following Dmab discontinuation with no subsequent treatment (NT) and three bisphosphonate (BP) treatments: risedronate (RIS), alendronate (ALN), and zoledronic acid (ZOL). Methods: In a review of 121 patients aged 71.2 ± 8.1 years, discontinuing Dmab (mean 5.4 doses), 33 received NT and 88 received BP (22 RIS; 34 ALN; 32 ZOL). BMD change after 1 year was compared between groups at the lumbar spine (LS), femoral neck (FN), and total hip (TH). Risk factors for bone loss after Dmab discontinuation were compared between groups and incidence of vertebral fractures was determined. Results: Following Dmab discontinuation, LS mean change (g/cm2; 95% CI) was for NT: − 0.041 (− 0.062 to − 0.021); RIS: − 0.035 (− 0.052 to − 0.017); ALN: − 0.005 (− 0.020 to 0.009); and ZOL: − 0.009 (− 0.025 to 0.008). Differences in LS were found between NT and ALN (p = 0.015), and NT and ZOL (p=0.037), but not between NT and RIS. The only significant difference in TH was found between NT and ZOL (p 0.034) with no group differences in FN. BMD gains during Dmab treatment were associated with BMD loss after Dmab discontinuation. In a subset, discontinuation after Dmab treatment (> 5 doses) followed by ALN (n = 22) and ZOL (n = 11) showed no difference in BMD. Five of 7 vertebral fractures occurred after Dmab discontinuation in NT. Conclusion: Subsequent treatment with ALN or ZOL but not NT and RIS mitigates BMD loss after Dmab discontinuation. [ABSTRACT FROM AUTHOR]

Osteoporosis (OP) occupies one of the leading places in the structure of morbidity in people over 50 years of age, and its social significance is associated with the main complications – low-energy fractures of the vertebral bodies and bones of the peripheral skeleton, which lead to an increase in disability and mortality among the elderly, being a serious problem for public health. One of the doctor’s goals is the timely administration of anti-osteoporotic treatment. Bisphosphonates (BP) are first-line drugs for the treatment of OP. Since 1995, nitrogen-containing BPs have been widely used, they demonstrate their effect primarily by inhibiting the activity of osteoclasts and stimulating their apoptosis. The efficacy and safety of this class of drugs have been confirmed by numerous studies and many years of clinical practice. Since 2005, the production of generics of alendronic acid began, and later, after the patent protection of other BFs was closed, generics of risedronic, ibandronic and zoledronic acids appeared. In 2019, two domestic generics were registered – ibandronic acid 3 mg for intravenous (IV) injection once every 3 months (Rezoviva) and zoledronic acid 5 mg in 100 ml solution for IV injection once a year (Osteostatics). Since 2020 they have been introduced into clinical practice as part of import substitution, which increased the availability of these drugs and reduced the health care costs.

Background: Risedronate is a bisphosphonate with poor oral absorption. An extremely hydrophilic molecule that has a high affinity for bone, risedronate also inhibits the farnesyl diphosphate synthase enzyme, inhibiting osteoclastic activity and reducing bone turnover and resorption. Autogenous bone grafts contain osteogenic cells and osteoinductive factors that are essential for bone regeneration and are therefore considered the gold standard. Thus, this study aimed to investigate the impact of local risedronate administered with autogenous bone grafts on the healing of defects in rabbit skulls using histological, histomorphometric, immunohistochemical, and three-dimensional radiological methods. Methods: Two 10-mm-diameter critical-size defects were created in 16 rabbits and filled with autogenous bone graft and autogenous bone graft + 5 mg risedronate in the control (C) and risedronate (RIS) groups, respectively. Residual graft, new bone, soft tissue areas, and bone volume were evaluated in the 4- and 8-week study groups. Results: There were no statistically significant differences in bone graft, new bone, or soft tissue area between the groups at 4 weeks (p > 0.05). At 8 weeks, the new bone area was significantly higher in the RIS group than in the C group (p < 0.05). The h scores obtained from sialoprotein and osteopontin did not differ significantly between the groups (p > 0.05). The radiologically measured total bone volume was significantly higher in the RIS group than in the C group at both time points (p < 0.05). Conclusions: In this study, risedronate enhanced the osteoconductive properties of autogenous bone grafts and rapidly created better-quality bone. This could improve future patient outcomes. [ABSTRACT FROM AUTHOR]

In estrogen-receptor-positive tumors, adjuvant endocrine therapy has been shown to be highly beneficial for both overall and disease-free survival. Estradiol is key in regulating bone and mineral physiology, and several studies found a strong correlation between these therapies and the risk of fractures. Since these therapies are often given for 5 through 10 years, the timing for bisphosphonates or denosumab initiation seems essential to managing bone metabolism. However, gray zones and discrepancies between guidelines remain as to the best threshold when to start antiresorptive treatment, or whether antiresorptive treatment should be administered to every woman undergoing adjuvant endocrine therapy, independent of their risk factors for fractures. Treatment options and strategies should be discussed at the start of hormone adjuvant therapy to come to a shared decision with the patient, with the final aim of reducing the risk of future fractures as much as possible. This review will cover present guidelines and literature on antiresorptive treatment in this setting, to provide clinicians with useful clues for managing these patients. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To assess the efficacy of third-generation bisphosphonates in relieving or stopping the progression of superficial hearing loss of otosclerosis in early stage. MATERIALS AND METHODS: A retrospective, descriptive study conducted at the Mexican Institute of Otology and Neurotology including patients with diagnosis of early otosclerosis and hearing loss in low tones who started treatment with risedronate 35 mg once a week for 6 months and audiometry at the end of treatment. Statistical analysis: paired Student t test. RESULTS: There were included 20 patients: 12 women and 8 men. Average age was of 44 years; 29 ears were evaluated: 16 right side and 13 left side. Air conduction: low tones average pretreatment was 31.1 dB and post-treatment 24.1 dB (p < 0.05). Bone conduction: low tones average was 12.5 dB pretreatment and 9.1 dB post-treatment (p = ns). No significant changes were found in the average of all frequencies or in the pure tone average in air or bone conduction because our patients, being selected at the early stage of the disease, had no hearing compromise in medium and high tones. CONCLUSIONS: Third-generation bisphosphonates contribute to reduce hearing loss in early stages of otosclerosis. Further long-term studies with periodic monitoring are needed to corroborate improvement or stabilization of hearing and standardize the optimal treatment time. [ABSTRACT FROM AUTHOR]

The article discusses the evidence surrounding the efficacy and safety of various bone health agents in mitigating the rebound phenomenon in cancer populations. Topics include the approval of antiresorptive agents for the management of metastatic bone disease in patients with solid tumors, common adverse effects for zoledronate, and clinical scenarios where discontinuation of denosumab should be considered.

Risedronate sodium (RIS) exhibits limited bioavailability and undesirable gastrointestinal effects when administered orally, necessitating the development of an alternative formulation. In this study, mPEG-coated nanoparticles loaded with RIS-HA-TCS were created for osteoporosis treatment. Thiolated chitosan (TCS) was synthesized using chitosan and characterized using DSC and FTIR, with thiol immobilization assessed using Ellman’s reagent. RIS-HA nanoparticles were fabricated and conjugated with synthesized TCS. Fifteen batches of RIS-HA-TCS nanoparticles were designed using the Box–Behnken design process. The nanoparticles were formulated through the ionic gelation procedure, employing tripolyphosphate (TPP) as a crosslinking agent. In silico activity comparison of RIS and RIS-HA-TCS for farnesyl pyrophosphate synthetase enzyme demonstrated a higher binding affinity for RIS. The RIS-HA-TCS nanoparticles exhibited 85.4 ± 2.21% drug entrapment efficiency, a particle size of 252.1 ± 2.44 nm, and a polydispersity index of 0.2 ± 0.01. Further conjugation with mPEG resulted in a particle size of 264.9 ± 1.91 nm, a PDI of 0.120 ± 0.01, and an encapsulation efficiency of 91.1 ± 1.17%. TEM confirmed the spherical particle size of RIS-HA-TCS and RIS-HA-TCS-mPEG. In vitro release studies demonstrated significantly higher release for RIS-HS-TCS-mPEG (95.13 ± 4.64%) compared to RIS-HA-TCS (91.74 ± 5.13%), RIS suspension (56.12 ± 5.19%), and a marketed formulation (74.69 ± 3.98%). Ex vivo gut permeation studies revealed an apparent permeability of 0.5858 × 10−1 cm/min for RIS-HA-TCS-mPEG, surpassing RIS-HA-TCS (0.4011 × 10−4 cm/min), RIS suspension (0.2005 × 10−4 cm/min), and a marketed preparation (0.3401 × 10−4 cm/min).

Risedronate-loaded mPEG-coated hydroxyapatite, thiolated chitosan-based (coated) and non-coated nanoparticles were tested for their potential effects in the treatment of osteoporosis. The prepared nanoparticles were evaluated for their bone-targeting potential by inducing osteoporosis in female Wistar rats via oral administration of Dexona (dexamethasone sodium phosphate). In vivo pharmacokinetic and pharmacodynamic studies were performed on osteoporotic rat models treated with different formulations. The osteoporotic model treated with the prepared nanoparticles indicated a significant effect on bone. The relative bioavailability was enhanced for RIS-HA-TCS-mPEG nanoparticles given orally compared to RIS-HA-TCS, marketed, and API suspension. Biochemical investigations also showed a significant change in biomarker levels, ultimately leading to bone formation/resorption. Micro-CT analysis of bone samples also demonstrated that the RIS-HA-TCS-mPEG-treated group showed the best results compared to other treatment groups. Moreover, the histology of bone treated with RIS-HA-TCS-mPEG showed a marked restoration of the architecture of trabecular bone along with a well-connected bone matrix and narrow inter-trabecular spaces compared to the toxic group. A stability analysis was also carried out according to ICH guidelines (Q1AR2), and it was found that RIS-HA-TCS-mPEG was more stable than RIS-HA-TCS at 25 °C. Thus, the results of present study indicated that mPEG-RIS-HA-TCS has excellent potential for sustained delivery of RIS for the treatment and prevention of osteoporosis, and for minimizing the adverse effects of RIS typically induced via oral administration.

Oral bisphosphonates are a key intervention in the treatment of osteoporosis and in reducing the risk of fragility fractures. Their use is supported by over 3 decades of evidence; however, patient adherence to oral bisphosphonates remains poor in part due to complex dosing instructions and adverse events, including upper gastrointestinal symptoms. This problem has led to the development of novel oral bisphosphonate formulations. Buffered, effervescent alendronate is dissolved in water and so seeks to reduce upper gastro-intestinal adverse events, and gastro-resistant risedronate aims to reduce the complexity of dosing procedure (e.g. fasting prior to consumption) whilst still maintaining the efficacy of fracture risk reduction. Clinical trials and real-world data have been employed to demonstrate some benefits in terms of reduced upper gastro-intestinal adverse events, adherence, persistence and health economic outcomes. This report describes the result of an ESCEO (European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis) expert working group, which explores where oral bisphosphonates sit in current clinical practice guidelines, review their risk–benefit profile and the consequences of poor adherence before exploring novel oral bisphosphonate formulations and their potential clinical and health economic impact. Further research is required but there are signs that these novel, oral bisphosphonate formulations may lead to improved tolerance of oral bisphosphonates and thus, improved adherence and fracture outcomes. [ABSTRACT FROM AUTHOR]

Background and Objectives: The majority of research on the effects of osteoporosis drugs has measured the bone mineral density (BMD) of the spine and femur through dual-energy X-ray absorptiometry (DEXA) and compared and analyzed the effects of the drugs through changes in the BMD values. This study aims to compare osteoclast and sclerostin expression in osteocytes after risedronate therapy by obtaining femoral heads from patients with hip fractures. Materials and Methods: We obtained the femoral heads of 10 female patients (age: ≥65 years) who received risedronate therapy for at least 1 year through hip arthroplasty during 2019–2021 (risedronate group). Meanwhile, 10 patients who had never received osteoporosis treatment were selected as controls using propensity scores with age, body mass index, and bone density as covariates (control group). While the osteoclast count was evaluated using tartrate-resistant acid phosphatase (TRAP) staining, the sclerostin expression in osteocytes was assessed using immunohistochemistry. Moreover, Western blotting and polymerase chain reaction (PCR) were performed for receptor activation of nuclear factor kappa-Β ligand (RANKL), RANK, osteoprotegerin (OPG), sclerostin, and bone morphogenetic protein-2 (BMP2). Results: TRAP staining revealed significantly more TRAP-positive cells in the control group (131.75 ± 27.16/mm2) than in the risedronate group (28.00 ± 8.12/mm2). Moreover, sclerostin-positive osteocytes were expressed more in the control group (364.12 ± 28.12/mm2) than in the risedronate group (106.93 ± 12.85/mm2). Western blotting revealed that the expressions of RANKL, RANK, sclerostin, and BMP2 were higher in the control group than in the risedronate group (p < 0.05). Furthermore, RANK, sclerostin, and OPG protein levels were higher in the control group than in the risedronate group. Conclusions: In this study, the risedronate group demonstrated lower osteoclast activity and sclerostin expression in osteocytes in the femoral head than the control group. [ABSTRACT FROM AUTHOR]

In women, breast cancer (BC) is the most common cancer, and despite advancements in diagnosis and treatment, 20-30% of early stage BC patients develop metastatic disease. Metastatic BC is deemed an incurable disease, which accounts for 90% of BC related deaths, with only 26% of metastatic patients reaching a 5 year survival rate. Therefore, there is an unmet need for the prevention or treatment of metastasis in early stage breast cancer patients. Bisphosphonates (BPs) are potent inhibitors of bone resorption and are extensively used for the prevention of osteoporosis and other skeletal disorders, as well as for the treatment of secondary bone cancer in BC patients. Furthermore, the direct anticancer activity of BPs has been established in primary tumor models. However, these studies were limited by the need for dosages far above the clinical range to overcome BPs' high affinity for bones and poor accumulation in the tumor itself, which leads to toxicity, including osteonecrosis of the jaw. To decrease BP dosage, increase bioavailability, and direct anticancer activity, we used the RALA (R-) peptide delivery system to form highly stable NPs with the nitrogen containing BP, risedronate (R-RIS). In vitro studies showed that, in comparison to RIS, R-RIS nanoparticles increased cytotoxicity and reduced metastatic features such as proliferation, migration, invasion, and adhesion of metastatic BC cells to bones. Furthermore, in an in vivo model, R-RIS had increased tumor accumulation while still maintaining similar bone accumulation to RIS alone. This increase in tumor accumulation corresponded with decreased tumor volume and lungs metastasis. R-RIS has great potential to be used in combination with standard of care chemotherapy for the treatment of primary BC and its metastasis while still having its bone resorption inhibiting properties.

Both osteoporosis with related fragility fractures and cardiovascular diseases are rapidly outspreading worldwide. Since they are often coexistent in elderly patients and may be related to possible common pathogenetic mechanisms, the possible reciprocal effects of drugs employed to treat these diseases have to be considered in clinical practice. Bisphosphonates, the agents most largely employed to decrease bone fragility, have been shown to be overall safe with respect to cardiovascular diseases and even capable of reducing cardiovascular morbidity in some settings, as mainly shown by real life studies. No randomized controlled trials with cardiovascular outcomes as primary endpoints are available. While contradictory results have emerged about a possible BSP-mediated reduction of overall mortality, it is undeniable that these drugs can be employed safely in patients with high fracture risk, since no increased mortality has ever been demonstrated. Although partial reassurance has emerged from meta-analysis assessing the risk of cardiac arrhythmias during bisphosphonates treatment, caution is warranted in administering this class of drugs to patients at risk for atrial fibrillation, possibly preferring other antiresorptives or anabolics, according to osteoporosis guidelines. This paper focuses on the complex relationship between bisphosphonates use and cardiovascular disease and possible co-management issues. [ABSTRACT FROM AUTHOR]

Patients with osteoporosis often take oral bisphosphonates with food, rendering these medications ineffective. This study compared the relative absorption of four formulations of gastro-resistant (GR; formulations 1–4) risedronate 35 mg versus immediate-release (IR) risedronate 35 mg taken fasted. Secondarily, it compared the relative absorption of GR formulations administered fed and fasted, and determined the site of disintegration. Healthy participants (N = 160) were randomized to one of nine treatment groups: IR risedronate taken fasted (group A) or formulations 1–4 taken fasted or fed (groups B–I). Fasted groups fasted for 8 h pre-dose and 4 h postdose. Fed groups fasted for 7.5 h, then took risedronate with breakfast. Urine was collected until 72 h post-dose and analyzed using liquid chromatography. From each group, up to seven participants underwent scintigraphic monitoring to assess tablet disintegration. The percentage of total dose recovered in urine (A’e) was ~0.5% for group A. The A’e of formulations 1–4 taken fasted was 0.220% (90% confidence interval 0.124–0.389), 0.298% (0.122–0.730), 0.154% (0.090–0.264), and 0.108% (0.051– 0.231), respectively. With food, the A’e of formulation 1 decreased least versus fasted (−27%) compared with the A’e of formulations 2, 3, and 4 (−73%, −80%, and −65%, respectively). Formulations 1–3 disintegrated in the small intestine, formulation 4 closer to the large intestine. All GR formulations were well tolerated and in line with the known safety profile for IR risedronate. Formulation 2 had the highest absorption when taken fasted, whereas the absorption of formulation 1 was least affected by food. [ABSTRACT FROM AUTHOR]

In a randomized clinical trial in patients initiating glucocorticoid therapy (GC‐I) or on long‐term therapy (GC‐C), denosumab every 6 months increased spine and hip bone mineral density at 12 and 24 months significantly more than daily risedronate. The aim of this study was to evaluate the effects of denosumab compared with risedronate on bone strength and microarchitecture measured by high‐resolution peripheral quantitative computed tomography (HR‐pQCT) in GC‐I and GC‐C. A subset of 110 patients had high‐resolution peripheral quantitative computed tomography (HR‐pQCT) scans of the distal radius and tibia at baseline and at 12 and 24 months. Cortical and trabecular microarchitecture were assessed with standard analyses and failure load (FL) with micro‐finite element analysis. At the radius at 24 months, FL remained unchanged with denosumab and significantly decreased with risedronate in GC‐I (−4.1%, 95% confidence interval [CI] −6.4, −1.8) and, in GC‐C, it significantly increased with denosumab (4.3%, 95% CI 2.1, 6.4) and remained unchanged with risedronate. Consequently, FL was significantly higher with denosumab than with risedronate in GC‐I (5.6%, 95% CI 2.4, 8.7, p < 0.001) and in GC‐C (4.1%, 95% CI 1.1, 7.2, p = 0.011). We also found significant differences between denosumab and risedronate in percentage changes in cortical and trabecular microarchitectural parameters in GC‐I and GC‐C. Similar results were found at the tibia. To conclude, this HR‐pQCT study shows that denosumab is superior to risedronate in terms of preventing FL loss at the distal radius and tibia in GC‐I and in increasing FL at the radius in GC‐C, based on significant differences in changes in the cortical and trabecular bone compartments between treatment groups in GC‐I and GC‐C. These results suggest that denosumab could be a useful therapeutic option in patients initiating GC therapy or on long‐term GC therapy and may contribute to treatment decisions in this patient population. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

Introduction: Orthodontic relapse occurs after orthodontic treatment and shifting of teeth to unfavorable positions. Bisphosphonates’ effects on bone resorption and relapse prevention have been extensively investigated. However, topical administration, which results in local effect, is still a problem. Objective: This study aimed to investigate the effect of risedronate with gelatin hydrogel as a carrier to prevent relapse movement by inhibiting osteoclast activity. Methods: Lower incisors of 75 guinea pigs were moved distally using an orthodontic appliance until ±3 mm length. Gelatin hydrogel was fabricated to obtain a semisolid controlled release of 250 (Bis-CR250) and 500 mmol/L risedronate (Bis-CR500) and then applied intrasulcularly into the mesial subperiosteal area of 50 guinea pigs (25 in each group) every 3 days; the rest were the control (Bis-CR000). After 14 days of stabilization, the apparatus was removed. The distance decrease between incisors and the osteoclast number with TRAP staining at 0, 3, 7, 14, and 21 days were measured. ANOVA was used to determine the differences among the different time and experimental groups. Results: Both treatments showed significantly less relapse movement compared to the control (p

Abstract Patients with osteoporosis often take oral bisphosphonates with food, rendering these medications ineffective. This study compared the relative absorption of four formulations of gastro‐resistant (GR; formulations 1–4) risedronate 35 mg versus immediate‐release (IR) risedronate 35 mg taken fasted. Secondarily, it compared the relative absorption of GR formulations administered fed and fasted, and determined the site of disintegration. Healthy participants (N = 160) were randomized to one of nine treatment groups: IR risedronate taken fasted (group A) or formulations 1–4 taken fasted or fed (groups B–I). Fasted groups fasted for 8 h pre‐dose and 4 h post‐dose. Fed groups fasted for 7.5 h, then took risedronate with breakfast. Urine was collected until 72 h post‐dose and analyzed using liquid chromatography. From each group, up to seven participants underwent scintigraphic monitoring to assess tablet disintegration. The percentage of total dose recovered in urine (A’e) was ~0.5% for group A. The A’e of formulations 1–4 taken fasted was 0.220% (90% confidence interval 0.124–0.389), 0.298% (0.122–0.730), 0.154% (0.090–0.264), and 0.108% (0.051–0.231), respectively. With food, the A’e of formulation 1 decreased least versus fasted (−27%) compared with the A’e of formulations 2, 3, and 4 (−73%, −80%, and −65%, respectively). Formulations 1–3 disintegrated in the small intestine, formulation 4 closer to the large intestine. All GR formulations were well tolerated and in line with the known safety profile for IR risedronate. Formulation 2 had the highest absorption when taken fasted, whereas the absorption of formulation 1 was least affected by food.

Statement of the Problem: Alveolar bone resorption associated with periodontal disease is a common finding and generally irreversible. It impairs mastication and causes esthetic problems for patients. Bisphosphonates are the most commonly used antiresorptive agents for bone diseases. Purpose: Considering the risk of bisphosphonate-related osteonecrosis of the jaw, this study aimed to assess the effect of 2% risedronate gel on calvarial bone defects in rabbits. Materials and Method: In this animal study, critical-size defects of 8mm were created in the calvaria of 20 New Zealand white rabbits. In group 1 (n=10), 2% risedronate gel was applied into the right side defect while the left side defect remained empty and served as control. In group 2 (n=10), placebo gel was applied into the right side defect, while the left side defect remained empty and served as control. Five rabbits in each group were sacrificed at 1month and the remaining five at 2 month, post-operatively, and tissue samples were collected for histomorphometric analysis. Histomorphometric assessments included bone fill, degree of inflammation, number of osteoblasts, number of osteoclasts, and foreign body reaction at the site. Data were statistically analysed using SPSS version 25 via the Dunn test and Kruskal-Wallis test. Results: No bone remodeling was noted in any group at 1 month. The risedronate group showed significantly higher bone fill than the other groups after 2 months (p= 0.016). At 2 months, the number of osteoblasts was significantly higher in the risedronate group (p< 0.05). The groups were not significantly different in terms of inflammation score at 1 (p= 0.31) or 2 (p=0.69) months. Foreign body reaction was not observed in any group at any time point. No osteoclast was detected in any group at any time point. Conclusion: Risedronate gel showed superior efficacy with regard to regeneration of rabbit calvarial bone defects compared to the placebo and control groups.

Purpose: This randomized controlled trial compared changes in bone mineral density (BMD) and bone turnover in postmenopausal women with low bone mass randomized to 12 months of either risedronate, exercise, or a control group. Methods: Two hundred seventy-six women with low bone mass, within 6 years of menopause, were included in analysis. Treatment groups were 12 months of (a) calcium and vitamin D supplements (CaD) (control), (b) risedronate + CaD (risedronate), or (c) bone-loading exercises + CaD (exercise). BMD and serum markers for bone formation (Alkphase B) and resorption (Serum Ntx) were analyzed at baseline, 6, and 12 months. Results: Using hierarchical linear modeling, a group by time interaction was found for BMD at the spine, indicating a greater improvement in the risedronate group compared to exercise (p ≤.010) or control groups (p ≤.001). At 12 months, for women prescribed risedronate, changes in BMD at the spine, hip, and femoral neck from baseline were + 1.9%, + 0.9%, and +.09%; in exercise group women, + 0.2%, + 0.5%, and − 0.4%; and in control group women, − 0.7%, + 0.5%, and − 0.5%. There were also significant differences in reductions in Alkphase B (RvsE, p <.001, RvsC, p <.001) and Serum Ntx (RvsE, p =.004, RvsC, p =.007) in risedronate women compared to exercise and control groups. For risedronate, 12-month changes in Alkphase B and Serum Ntx were − 20.3% and − 19.0%; for exercise, − 6.7% and − 7.0%; and for control, − 6.3% and − 9.0%. Conclusion: Postmenopausal women with low bone mass should obtain adequate calcium and vitamin D and participate in bone-loading exercises. Additional use of BPs will increase BMD, especially at the spine. [ABSTRACT FROM AUTHOR]