Effectiveness of bisphosphonate for alleviating tinnitus associated with otosclerosis: a prospective case-control study.

PURPOSE: To investigate the short-term efficacy of third-generation bisphosphonate in the management of tinnitus associated with otosclerosis. METHODS: A prospective case-control study included 100 patients with otosclerosis-associated bothersome tinnitus. Patients were assigned to two groups: group A (control): 25 patients who planned to receive only complementary supplements, oral vitamin D plus calcium, and group B (case): 75 patients who planned to receive oral bisphosphonate plus routine vitamin D and calcium supplements. Group B was subdivided into B1: 25 patients without any previous intervention, B2: 25 patients with persistent tinnitus for more than 6 months after a previous uncomplicated stapedotomy in the same ear, and B3: 25 patients with persistent tinnitus for more than 6 months after hearing aid fitting. The outcome was tinnitus assessment both subjectively (tinnitus intensity, frequency, and questionnaire) and objectively (tinnitus intensity and frequency). RESULTS: The female-to-male ratio was 1.6:1 with ages ranging from 40 to 61 years. The baseline revealed no statistically significant differences between the groups. After 6 months, there were statistically significant differences, both objectively and subjectively. The tinnitus questionnaire median (IQR) for group B was 16 (30), whereas control group A had 52 (24). The tinnitus severity median (IQR) for group B was 20 (30), compared to group A's 52 (42). After 6 months, 40% of the cases in group B demonstrated complete improvement, compared to 0% in control group A. CONCLUSION: We demonstrated significant tinnitus improvement in cases treated with bisphosphonate compared to the control group.

Transdermal delivery of bisphosphonates using dissolving and hydrogel-forming microarray patches: Potential for enhanced treatment of osteoporosis.

As of 2023, more than 200 million people worldwide are living with osteoporosis. Oral bisphosphonates (BPs) are the primary treatment but can cause gastrointestinal (GI) side effects, reducing patient compliance. Microarray (MAP) technology has the potential to overcome GI irritation by facilitating the transdermal delivery of BPs. This study examines the delivery of alendronic acid (ALN) and risedronate sodium (RDN) using dissolving and hydrogel-forming MAPs for osteoporosis treatment. In vivo testing on osteoporotic female Sprague Dawley rats demonstrated the efficacy of MAPs, showing significant improvements in mean serum and bone alkaline phosphatase levels, bone volume, and porosity compared to untreated bilateral ovariectomy (OVX) controls. Specifically, MAP treatment increased mean bone volume to 55.04 ± 2.25 % versus 47.16 ± 1.71 % in OVX controls and reduced porosity to 44.30 ± 2.97 % versus 52.84 ± 1.70 % in the distal epiphysis of the femur. In the distal metaphysis, bone volume increased to 43.32 ± 3.24 % in MAP-treated rats compared to 24.31 ± 3.21 % in OVX controls, while porosity decreased to 55.39 ± 5.81 % versus 75.69 ± 3.21 % in OVX controls. This proof-of-concept study indicates that MAP technology has the potential to be a novel, patient-friendly alternative for weekly osteoporosis management.

Development and Characterization of a Peptide-Bisphosphonate Nanoparticle for the Treatment of Breast Cancer.

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.

Influence of Metamizole on Antitumour Activity of Risedronate Sodium in In Vitro Studies on Canine (D-17) and Human (U-2 OS) Osteosarcoma Cell Lines.

The availability of metamizole varies greatly around the world. There are countries such as the USA, UK, or Australia where the use of metamizole is completely forbidden, and there are also countries where this drug is available only on prescription (e.g., Greece, Italy, Spain, etc.) and those in which it is sold OTC-over the counter (e.g., most Asian and South American countries). Metamizole, as a drug with a strong analgesic effect, is used as an alternative to other non-steroidal anti-inflammatory drugs, alone or in combination with opioid drugs. Risedronate sodium is a third-generation bisphosphonate commonly used in orthopaedic and metabolic diseases of the musculoskeletal system, including hypercalcemia, postmenopausal osteoporosis, Paget's disease, etc. The aim of this study was to check whether there were any pharmacological interactions between metamizole and risedronate sodium in in vitro studies. Cell viability was assessed using the MTT method, the number of apoptotic cells was assessed using the labelling TUNEL method, and the cell cycle assessment was performed with a flow cytometer and propidium iodide. This was a pilot study, which is why only two cancer cell lines were tested: D-17 of canine osteosarcoma and U-2 OS of human osteosarcoma. Exposure of the canine osteosarcoma cell line to a combination of risedronate sodium (100 µg/mL) and metamizole (50, 5, and 0.5 µg/mL) resulted in the complete abolition of the cytoprotective activity of metamizole. In the human osteosarcoma cell line, the cytotoxic effect of risedronate sodium was entirely eliminated in the presence of 50 µg/mL of metamizole. The cytoprotective and anti-apoptotic effect of metamizole in combination with risedronate sodium in the tested human and canine osteosarcoma cell lines indicates an urgent need for further in vivo studies to confirm or disprove the potential dose-dependent undesirable effect of such a therapy.

In Situ Hydrogel with Immobilized Mn-Porphyrin for Reactive Oxygen Species Scavenging, Oxygen Generation, and Risedronate Delivery in Bone Defect Treatment.

We propose a hydrogel immobilized with manganese porphyrin (MnP), a biomimetic superoxide dismutase (SOD), and catalase (CAT) to modulate reactive oxygen species (ROS) and hypoxia that impede the repair of large bone defects. Our hydrogel synthesis involved thiolated chitosan and polyethylene glycol-maleimide conjugated with MnPs (MnP-PEG-MAL), which enabled in situ gelation via a click reaction. Through optimization, a hydrogel with mechanical properties and catalytic effects favorable for bone repair was selected. Additionally, the hydrogel was incorporated with risedronate to induce synergistic effects of ROS scavenging, O2 generation, and sustained drug release. In vitro studies demonstrated enhanced proliferation and differentiation of MG-63 cells and suppressed proliferation and differentiation of RAW 264.7 cells in ROS-rich environments. In vivo evaluation of a calvarial bone defect model revealed that this multifunctional hydrogel facilitated significant bone regeneration. Therefore, the hydrogel proposed in this study is a promising strategy for addressing complex wound environments and promoting effective bone healing.

Gelatin-Zinc Carrier as a New Method of Targeted and Controlled Release of Risedronate.

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.

Risedronate-Induced Chronic Drug Fever in a Case of Parkinson's Disease.

We present an atypical case of risedronate-induced chronic fever in an 85-year-old woman with Parkinson's disease, with a dosage regimen of 17.5 mg/week. Our patient had been administered an analgesic/antipyretic drug, acetaminophen, at a rate of 600 mg/day for treatment of a vertebral fracture that occurred relatively frequently, which might have masked the fever caused by risedronate. We noted two clinically significant indications. Firstly, blood test results do not necessarily show the cause of risedronate-induced fever, as white blood cell counts and C-reactive protein levels vary. A simple way to diagnose risedronate-induced fever is to suspend risedronate for a certain period and observe if the patient's fever lowers. Secondly, in general, cases receiving polypharmacy tend to include an analgesic antipyretic agent, which may mask the drug-induced fever. Even in patients with Parkinson's disease whose body temperature is generally unstable due to autonomic nerve system disorder, if they are administered risedronate and experience chronic fever of unknown cause, the possibility of drug fever may be considered. This study concludes that risedronate-induced chronic fever, as observed in our case, represents a rare phenomenon, and it may be necessary to reconsider treatment methods for osteoporosis.

Denosumab vs. bisphosphonates in primary osteoporosis: a meta-analysis of comparative safety in randomized controlled trials.

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.

The effect of black cohosh extract and risedronate coadministration on bone health in an ovariectomized rat model.

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.

Bisphosphonate alternative regimens for the prevention of osteoporotic fragility fractures: BLAST-OFF, a mixed-methods study.

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: 1. Explore patient, clinician and stakeholder views, experiences and preferences of alendronate compared to alternative bisphosphonates. 2. Update and refine the 2016 systematic review and cost-effectiveness analysis of bisphosphonates, and estimate the value of further research into their benefits. 3. 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.

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. 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. 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. 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. 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.

Risedronate-functionalized manganese-hydroxyapatite amorphous particles: A potent adjuvant for subunit vaccines and cancer immunotherapy.

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.

Safety and effectiveness of risedronate in Paget's disease of bone: postmarketing surveillance study in Japan.

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.

Micronanoparticled risedronate exhibits potent vaccine adjuvant effects.

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.

BBD Driven Fabrication of Hydroxyapatite Engineered Risedronate Loaded Thiolated Chitosan Nanoparticles and Their In Silico, In Vitro, and Ex Vivo Studies.

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).

Enhancing Osteoporosis Treatment through Targeted Nanoparticle Delivery of Risedronate: In Vivo Evaluation and Bioavailability Enhancement.

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.

Cost-effectiveness of weekly gastro-resistant risedronate 35 mg, compared with weekly alendronate 70 mg tablets, in the treatment of postmenopausal osteoporosis in Spain.

Aim: To estimate the cost-effectiveness of treating postmenopausal osteoporosis (PMO) with weekly gastro-resistant risedronate 35 mg gastro-resistant tablets (RIS-GR), compared with weekly alendronate 70 mg tablets (ALN) in Spain. Methods: A probabilistic analysis (second-order Monte Carlo simulation) was performed with a time horizon of 5 years, from the perspective of the Spanish National Health System. The bone fracture probabilities were obtained from a cohort study of 3614 women from USA with PMO treated with RIS-GR (1807) or ALN (1807) (Thomasius, 2022). The pharmacological cost and the cost of fractures were obtained from Spanish sources (€ 2022). The utilities of patients with and without fracture (quality-adjusted life years [QALYs]) were obtained from the medical literature. Results: Compared with ALN, treatment with RIS-GR can avoid 79 fractures (between 75 and 82) every 1000 patients treated, and 0.0119 QALYs would be gained (between 0.0098 and 0.0140) per patient. Additionally, GR-RIS would generate a cost saving per patient of €1994 (€1437-2904) with a probability of 99.7%. The scenario analyses confirmed the stability of the base case results. Conclusion: According to this study, RIS-GR would be the dominant treatment (lower costs with QALY gain) compared with ALN.

Surface Modification of Ti6Al4V ELI Titanium Alloy by Poly(ethylene-alt-maleic anhydride) and Risedronate Sodium.

With the simultaneous increase in the number of endoprostheses being performed, advances in the field of biomaterials are becoming apparent-whereby the materials and technologies used to construct implants clearly improve the implants' quality and, ultimately, the life of the patient after surgery. The aim of this study was to modify the titanium alloy Ti6Al4V ELI used in the construction of hip joint endoprostheses. This is why the continuous development of biomaterials is so important. This paper presents the results of research for a new application of polymer poly(ethylene-alt-maleic anhydride) as a drug release layer, placed on the surface of a titanium alloy. The obtained layers were analyzed using Raman spectroscopy (spectra and maps), Fourier transform infrared spectroscopy (spectra and maps), contact angle measurements as well as scanning electron microscopy and energy dispersive spectroscopy imaging and topography analysis. The results confirmed that the polymer layer obtained on the plate surface after the alkali heat treatment process is much better-it binds much more polymer and thus the applied drug. In addition, a longer and more gradual release of the drug was observed for the alkali heat treatment modification than for H2O2 solution.