Risedronate sodium is a widely used bisphosphonate for the treatment of osteoporosis and other metabolic bone disorders. This study aimed to evaluate the bioequivalence and safety of a test formulation of risedronate sodium 35 mg tablets compared with the reference formulation in healthy Chinese participants under fasting conditions. A randomized, open-label, single-dose, three-period, partial replicate crossover study was conducted in healthy participants. Forty-five participants were enrolled and 38 completed the study. Plasma concentrations of risedronic acid were measured using a validated liquid chromatography-tandem mass spectrometry method, and pharmacokinetic parameters were calculated using non-compartmental analysis. Bioequivalence was assessed using the reference-scaled average bioequivalence approach. The geometric mean values of Cmax, AUC0-t, and AUC0-∞ for the test formulation were 28.50 ng/mL, 115.40 h.ng/mL, and 129.60 h.ng/mL, respectively, compared with 26.67 ng/mL, 107.01 h.ng/mL, and 119.03 h.ng/mL for the reference formulation. The geometric mean ratios for Cmax, AUC0-t, and AUC0-∞ were 1.1077, 1.0894, and 1.0897, respectively, all within the predefined acceptance range. For the primary pharmacokinetic parameters, the point estimate of the test/reference mean ratios were within 0.80-1.25 and the upper bounds of the one-sided 95% confidence intervals for the RSABE criteria were below zero. Both formulations were generally well tolerated, and no serious adverse events were reported. These findings demonstrate that the test and reference formulations of risedronate sodium 35 mg tablets are bioequivalent under fasting conditions and exhibit comparable safety profiles. Clinical Trial Registration: CTR20201946.

Osteosarcoma faces the challenges of limited drug delivery and an immunosuppressive tumor microenvironment. M1 macrophages, a type of tumor-associated macrophage, play a pivotal role in shaping tumor immune responses. A dual enzyme-mimicking nanozyme coordinated to risedronate sodium and encapsulated in a sodium alginate gel (RZRSA) was developed to enhance the radiosensitivity of osteosarcoma. After intratumoral injection, RZRSA formed a calcium alginate hydrogel in osteosarcoma owing to the presence of Ca[2+]. Because of its peroxidase-like activity, RZRSA generated abundant toxic hydroxyl radicals in the presence of intratumoral H2O2 overexpression. Moreover, the hypoxia status of tumors was alleviated by the catalase-mimicking property of RZRSA by transforming H2O2 into O2, thereby improving the efficacy of radiotherapy. The Ru elements in RZRSA augmented the energy decomposition of ionizing irradiation in tumor regions. These properties contributed to magnifying the oxidative stress in the tumor microenvironment, which promoted M1-like polarization to kill tumor cells. In addition, radiosensitization by RZRSA triggered a robust immunogenic cell death effect and promoted dendritic cell maturation. This innovative design of RZRSA provides a promising strategy for targeted osteosarcoma treatment.

This study evaluated the structural, electronic, pharmacokinetic, and receptor-binding properties of three bisphosphonate derivatives, alendronate, risedronate, and zoledronate, to investigate their therapeutic relevance in osteoporosis and breast cancer. Density Functional Theory (DFT) calculations at the B3LYP/6-31G(d,p) level showed that risedronate exhibited the highest kinetic stability (ΔE = 6.7468 eV), whereas zoledronate displayed greater chemical reactivity (ΔE = 2.9669 eV) and the strongest nonlinear optical response (β = 1.20 × 10[-30] esu). ADMET analysis indicated acceptable safety profiles for all compounds, although high polarity and low lipophilicity may limit oral bioavailability. Molecular docking against 11 breast cancer- and bone metabolism-related targets revealed favorable binding affinities, particularly for zoledronate and risedronate. Zoledronate showed strong interactions with ESR2, VEGFR/KDR, GGPS1, and FPPS, whereas risedronate exhibited notable affinity for BRCA2 and MMP9. Bioinformatics analyses identified significant dysregulation of GGPS1, FDPS, TNFSF11, ESR1, MMP9, and BRCA2 in breast cancer tissues, while survival analysis linked elevated FDPS, MMP9, and BRCA2 expression to poor prognosis. Network analyses highlighted pathways related to mevalonate metabolism, hormone signaling, angiogenesis, extracellular matrix remodeling, and the RANK/RANKL/OPG axis. These findings support the potential repurposing of bisphosphonates, particularly zoledronate, for breast cancer-associated bone disease.

Bisphosphonates (BPs; alendronate and risedronate) have been approved as a therapy for osteoporosis. While the efficacy of these drugs appears similar, differences in safety and gastrointestinal tract (GIT) adverse effects are lacking. Consequently, a systematic review and a meta-analysis were carried out reporting on the incidence rate of GIT adverse effects and the safety of alendronate versus risedronate. In this study, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used. This study collected articles from Embase, PubMed, Cochrane library, and Web of Science. Only RCTs that focused on the comparison between alendronate and risedronate in treating patients with osteoporosis were included. Risk ratios (RRs), 95% confidence intervals (CIs), and random-effects model were calculated. This meta-analysis identified 2202 studies including 4151 participants. There were six eligible RCTs. The incidence rate of GIT adverse effects in patients who received alendronate was 20.19%, while the incidence rate in patients who received risedronate was 18.30%. The rate of GIT adverse effects was not significantly different with alendronate compared to risedronate (RR: 1.11; 95% CI: 0.86-1.42; P < 0.44). In this review, the incidence rate of alendronate-associated gastrointestinal (GI) adverse effects was slightly higher than the incidence rate of risedronate-associated GI adverse effects. Although the finding is not statistically significant, switching the patient from alendronate to risedronate may nevertheless lower the incidence rate of GI side effects.

Dickkopf-1 (DKK1) mediated dysregulation of the Wnt/β-catenin signaling pathway contributes to synaptic loss in Alzheimer's disease (AD). Risedronate, a third-generation bisphosphonate, shows promise in pathologies related to the Wnt pathway, although its direct interaction with the DKK1-LRP6 complex has yet to be investigated. This study aimed to characterize risedronate as a novel small-molecule DKK1 antagonist and evaluate its capacity to restore canonical Wnt signaling and provide neuroprotection. In silico studies were performed using the Schrödinger Maestro (v2018-3) platform, utilizing molecular docking, molecular simualtion, SiteMap and WaterMap analysis to define the thermodynamic hydration energetics of the DKK1-LRP6 interface. In vitro validation was conducted using LRP6-overexpressing HEK-293T cells, with Wnt modulation quantified via immunofluorescence of membrane-associated DKK1 and β-catenin stabilization assays and neuroprotective assay in presence of glutamate in SHSY5Y cells. In silico analysis identified a high-affinity binding site on the DKK1 C-terminal domain (Dscore: 0.998). WaterMap analysis and simulation study revealed that risedronate binding is driven by the displacement of high-energy "unfavorable" water molecules (ΔG > 0) at the Arg203/Lys222 residue cluster. In HEK-293LRP6 cells, risedronate (IC50: 65.94 μM) significantly attenuated DKK1-mediated LRP6 sequestration (p < 0.0001), acting as a molecular "plug" to restore β-catenin signaling. This restoration successfully suggests a potential modulation of downstream of Wnt pathway restoration. Risedronate demonstrates potential inhibitory effects on DKK1 in in vitro and in silico models. By bridging bone pharmacology and neurobiology, this study provides a mechanistically grounded repurposing strategy to counteract Wnt signaling failure in neurodegenerative disorders.

The majority of clinical research continues to focus on evaluating the efficacy of teriparatide and bisphosphonates in the treatment of osteoporosis. This systematic review gathered data from extensive research assessing the efficacy, safety, and clinical outcomes of various medications. The objective was to determine the effectiveness and clinical implications of teriparatide and bisphosphonates in the treatment of postmenopausal osteoporosis. We analyzed 15 comprehensive studies, encompassing randomized controlled trials (RCTs), systematic reviews, and meta-analyses. The primary studies included large trials and several medium-sized trials that examined changes in bone mineral density (BMD), fracture risk, and adverse outcomes. Teriparatide significantly lowered vertebral fracture risk compared with risedronate in patients with severe osteoporosis and increased lumbar spine BMD to a comparable extent as alendronate, though via a distinct anabolic mechanism. Combination therapy with zoledronic acid resulted in greater BMD gains than either agent alone. Most adverse events were mild and transient, including injection-site reactions, nausea, and dizziness, with no significant difference in serious adverse event rates compared with bisphosphonates. Network meta-analyses indicate that romosozumab may achieve greater early spine BMD gains than teriparatide. Teriparatide is effective in lowering vertebral fracture risk and enhancing BMD in postmenopausal osteoporosis. Anabolic agents, including teriparatide, are recommended as first-line therapy for patients at very high risk of fractures (e.g., very low BMD with prevalent fractures or fractures occurring during glucocorticoid therapy), followed by a transition to antiresorptive therapy. Treatment selection should be guided by guideline-based risk stratification rather than applying a uniform stepwise approach.