BACKGROUND: Bisphosphonates and receptor activator of nuclear factor-kappa B ligand (RANKL)-inhibitors are amongst the bone-modifying agents used as supportive treatment in women with breast cancer who do not have bone metastases. These agents aim to reduce bone loss and the risk of fractures. Bisphosphonates have demonstrated survival benefits, particularly in postmenopausal women.
OBJECTIVE: To assess and compare the effects of different bone-modifying agents as supportive treatment to reduce bone mineral density loss and osteoporotic fractures in women with breast cancer without bone metastases and generate a ranking of treatment options using network meta-analyses (NMAs).
METHODS: We identified studies by electronically searching CENTRAL, MEDLINE and Embase until January 2023. We searched various trial registries and screened abstracts of conference proceedings and reference lists of identified trials.
METHODS: We included randomised controlled trials comparing different bisphosphonates and RANKL-inihibitors with each other or against no further treatment or placebo for women with breast cancer without bone metastases.
METHODS: Two review authors independently extracted data and assessed the risk of bias of included studies and certainty of evidence using GRADE. Outcomes were bone mineral density, quality of life, overall fractures, overall survival and adverse events. We conducted NMAs and generated treatment rankings.
RESULTS: Forty-seven trials (35,163 participants) fulfilled our inclusion criteria; 34 trials (33,793 participants) could be considered in the NMA (8 different treatment options). Bone mineral density We estimated that the bone mineral density of participants with no treatment/placebo measured as total T-score was -1.34. Evidence from the NMA (9 trials; 1166 participants) suggests that treatment with ibandronate (T-score -0.77; MD 0.57, 95% CI -0.05 to 1.19) may slightly increase bone mineral density (low certainty) and treatment with zoledronic acid (T-score -0.45; MD 0.89, 95% CI 0.62 to 1.16) probably slightly increases bone mineral density compared to no treatment/placebo (moderate certainty). Risedronate (T-score -1.08; MD 0.26, 95% CI -0.32 to 0.84) may result in little to no difference compared to no treatment/placebo (low certainty). We are uncertain whether alendronate (T-score 2.36; MD 3.70, 95% CI -2.01 to 9.41) increases bone mineral density compared to no treatment/placebo (very low certainty). Quality of life No quantitative analyses could be performed for quality of life, as only three studies reported this outcome. All three studies showed only minimal differences between the respective interventions examined. Overall fracture rate We estimated that 70 of 1000 participants with no treatment/placebo had fractures. Evidence from the NMA (16 trials; 19,492 participants) indicates that treatment with clodronate or ibandronate (42 of 1000; RR 0.60, 95% CI 0.39 to 0.92; 40 of 1000; RR 0.57, 95% CI 0.38 to 0.86, respectively) decreases the number of fractures compared to no treatment/placebo (high certainty). Denosumab or zoledronic acid (51 of 1000; RR 0.73, 95% CI 0.52 to 1.01; 55 of 1000; RR 0.79, 95% CI 0.56 to 1.11, respectively) probably slightly decreases the number of fractures; and risedronate (39 of 1000; RR 0.56, 95% CI 0.15 to 2.16) probably decreases the number of fractures compared to no treatment/placebo (moderate certainty). Pamidronate (106 of 1000; RR 1.52, 95% CI 0.75 to 3.06) probably increases the number of fractures compared to no treatment/placebo (moderate certainty). Overall survival We estimated that 920 of 1000 participants with no treatment/placebo survived overall. Evidence from the NMA (17 trials; 30,991 participants) suggests that clodronate (924 of 1000; HR 0.95, 95% CI 0.77 to 1.17), denosumab (927 of 1000; HR 0.91, 95% CI 0.69 to 1.21), ibandronate (915 of 1000; HR 1.06, 95% CI 0.83 to 1.34) and zoledronic acid (925 of 1000; HR 0.93, 95% CI 0.76 to 1.14) may result in little to no difference regarding overall survival compared to no treatment/placebo (low certainty). Additionally, we are uncertain whether pamidronate (905 of 1000; HR 1.20, 95% CI 0.81 to 1.78) decreases overall survival compared to no treatment/placebo (very low certainty). Osteonecrosis of the jaw We estimated that 1 of 1000 participants with no treatment/placebo developed osteonecrosis of the jaw. Evidence from the NMA (12 trials; 23,527 participants) suggests that denosumab (25 of 1000; RR 24.70, 95% CI 9.56 to 63.83), ibandronate (6 of 1000; RR 5.77, 95% CI 2.04 to 16.35) and zoledronic acid (9 of 1000; RR 9.41, 95% CI 3.54 to 24.99) probably increases the occurrence of osteonecrosis of the jaw compared to no treatment/placebo (moderate certainty). Additionally, clodronate (3 of 1000; RR 2.65, 95% CI 0.83 to 8.50) may increase the occurrence of osteonecrosis of the jaw compared to no treatment/placebo (low certainty). Renal impairment We estimated that 14 of 1000 participants with no treatment/placebo developed renal impairment. Evidence from the NMA (12 trials; 22,469 participants) suggests that ibandronate (28 of 1000; RR 1.98, 95% CI 1.01 to 3.88) probably increases the occurrence of renal impairment compared to no treatment/placebo (moderate certainty). Zoledronic acid (21 of 1000; RR 1.49, 95% CI 0.87 to 2.58) probably increases the occurrence of renal impairment while clodronate (12 of 1000; RR 0.88, 95% CI 0.55 to 1.39) and denosumab (11 of 1000; RR 0.80, 95% CI 0.54 to 1.19) probably results in little to no difference regarding the occurrence of renal impairment compared to no treatment/placebo (moderate certainty).
CONCLUSIONS: When considering bone-modifying agents for managing bone loss in women with early or locally advanced breast cancer, one has to balance between efficacy and safety. Our findings suggest that bisphosphonates (excluding alendronate and pamidronate) or denosumab compared to no treatment or placebo likely results in increased bone mineral density and reduced fracture rates. Our survival analysis that included pre and postmenopausal women showed little to no difference regarding overall survival. These treatments may lead to more adverse events. Therefore, forming an overall judgement of the best ranked bone-modifying agent is challenging. More head-to-head comparisons, especially comparing denosumab with any bisphosphonate, are needed to address gaps and validate the findings of this review.

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.
OBJECTIVE: 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.
CONCLUSIONS: 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.

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.

BACKGROUND: Bisphosphonates have an inhibitory impact on osteoclastic activity, reducing bone resorption. However, the influence of risedronate on tooth movement is not well-defined.
OBJECTIVE: This systematic review assessed the effect of risedronate intake on orthodontic tooth movement. A case report was also provided.
METHODS: Two independent reviewers searched six databases (PubMed, Web of Science, Ovid, Lilacs, Scopus, and Open Grey). The searches were carried out in April/2020, and an update was set in place in June/2023. Therefore, the searches considered a timeline from the databases\' inception date until June/2023, with no publication date and/or language restrictions. The clinical question focused on evaluating the orthodontic tooth movement and relapse movement (Outcome) in animals (Population) exposed to risedronate (Exposure), compared to control groups (Comparison). The Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines were applied, and the protocol was registered in PROSPERO (CRD42020168581). The risk of bias was determined using the Systematic Review Centre for Laboratory Animal Experimentation protocol (SYRCLE).
RESULTS: Two studies in rats and one in guinea pigs were included in the systematic review. The studies reported a decrease in orthodontic tooth movement, a reduction in the relapse movement, and a reduced number of positive tartrate-resistant acid phosphatase (TRAP) cells, with a significantly reduced number of bone gaps after the administration of risedronate in rats. A case report illustrated the effects of risedronate administration in one patient.
CONCLUSIONS: Based on the systematic review, risedronate seems to impair orthodontic tooth movement and relapse due to a decrease in bone resorption cells.

BACKGROUND: 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.
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.
CONCLUSIONS: To conclude, risedronate 17.5 mg/day is safe and effective for treating patients with PDB in daily practice.

Postmenopausal osteoporosis and poor dietary habits can lead to overweightness and obesity. Bisphosphonates are the first-line treatment for osteoporosis. However, some studies show that they may increase the risk of osteonecrosis of the jaw. Considering the antimicrobial, angiogenic and vasodilatory potential of nitric oxide, this study aims to evaluate the local activity of this substance during the placement of surface-treated implants. Seventy-two Wistar rats were divided into three groups: SHAM (SHAM surgery), OVX + HD (ovariectomy + cafeteria diet), and OVX + HD + RIS (ovariectomy + cafeteria diet + sodium risedronate treatment), which were further subdivided according to the surface treatment of the future implant: CONV (conventional), TE10, or TE100 (TERPY at 10 or 100 μM concentration); n = 8 per subgroup. The animals underwent surgery for implant installation in the proximal tibia metaphysis and were euthanized after 28 days. Data obtained from removal torque and RT-PCR (OPG, RANKL, ALP, IBSP and VEGF expression) were subjected to statistical analysis at 5% significance level. For biomechanical analysis, TE10 produced better results in the OVX + HD group (7.4 N/cm, SD = 0.6819). Molecular analysis showed: (1) significant increase in OPG gene expression in OVX groups with TE10; (2) decreased RANKL expression in OVX + HD + RIS compared to OVX + HD; (3) significantly increased expressions of IBSP and VEGF for OVX + HD + RIS TE10. At its lowest concentration, TERPY has the potential to improve peri-implant conditions.

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.

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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.

Osteoporosis is a fatal bone-wearing malady and a substantial reason behind the impermanence of human life and economic burden. Risedronate Sodium along with Ursolic acid has been studied to ameliorate osteoporosis. To bypass problems associated with bioavailability, we have developed a microneedle transdermal patch loaded with optimized formulation nanotransfersomes. It was optimized using three factor, three-level Central composite design with independent variables namely, the concentration of phospholipid, surfactant, and sonication time on dependent variables (vesicle size, entrapment efficiency and Polydispersity index). Vesicles of size 271.9 ± 8.45 nm with PDI 0.184 ± 0.01, having entrapment efficiency of 86.12 ± 5.20% and 85.65 ± 4.88% for RIS and UA respectively were observed. In vitro release study showed the sustained release pattern with 78.16 ± 1.12% and 75.72 ± 1.01% release of RIS and UA respectively. Dissolving MN patch prepared from gelatin was found to have good strength and folding endurance with uniform drug content (98.68 ± 0.004%). Ex vivo permeation study revealed that up to 80% of the drug can be permeated within 24 h. CLSM analysis was also performed to show penetration of RU-NTRs. From the results obtained, we can conclude that dissolving MN patch loaded with RU-NTRs has great potential than its conventional counterpart.