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Reportedly, nausea or vomiting after heavy exercise was associated with post-exercise increased blood calcium (Ca) levels, which was correlated with enhanced bone resorption. We conducted a randomized, double-blind, placebo-controlled trial, enrolling 104 healthy trained male members of the Japan Ground Self-Defense Forces. Risedronate (17.5 mg) or placebo was prescribed 3 and 10 days before heavy exercise lasting approximately 5 h. The primary outcome was the severity of nausea or vomiting assessed by a visual analog scale during or post-exercise. The secondary outcomes included clinical symptoms associated with heat illness, post-exercise serum total Ca (tCa), whole blood ionized Ca (iCa), and serum tartrate-resistant acid phosphatase 5b (TRACP-5b) levels. The mean age was 26 years. The exercise resulted in a 4.5% weight loss. The two groups were comparable in terms of the symptoms, including primary outcome. However, post-exercise tCa and TRACP-5b were significantly lower with risedronate. A similar result was observed for iCa. The post-exercise urinary Ca/Magnesium ratio and the incidence of hypercalcemia (defined as tCa or iCa levels ≥ each median value of all subjects) were significantly lower with risedronate (78.0% vs. 58.5%). A stronger treatment effect of risedronate on blood Ca levels was observed in participants who lost substantial body weight. Post-exercise hypercalcemia is attributed to enhanced bone resorption but not the cause of nausea., (© 2024. The Author(s).)

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., Objectives: 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)., Search 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., Selection Criteria: 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., Data Collection and Analysis: 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., Main 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)., Authors' 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., (Copyright © 2024 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

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., (© 2024. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023. Published by Elsevier B.V.)

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.

To assess the effectiveness and safety of denosumab (Prolia®) compared to bisphosphonates (alendronate, ibandronate, risedronate, zoledronate), selective estrogen receptor modulators (SERMs; bazedoxifene, raloxifene) or placebo, for the treatment of osteoporosis in postmenopausal women (PMW). Systematic searches were run in PubMed, Embase & Cochrane Library on 27-April-2022. Randomized controlled trials (RCTs) that included osteoporotic PMW allocated to denosumab, SERMs, bisphosphonates, or placebo were eligible for inclusion. RCTs were appraised using Cochrane Risk of Bias 2.0. Bayesian network and/or pairwise meta-analyses were conducted on predetermined outcomes (i.e. vertebral/nonvertebral fractures, bone mineral density [BMD], mortality, adverse events [AEs], serious AEs (SAEs), withdrawals due to AEs, AEs caused by denosumab discontinuation). A total of 12 RCTs (k = 22 publications; n = 25,879 participants) were included in the analyses. Denosumab, reported a statistically significant increase in lumbar spine (LS) and total hip (TH) BMD, compared to placebo. Similarly, denosumab also resulted in a statistically significant increase in TH BMD compared to the raloxifene and bazedoxifene. However, relative to denosumab, alendronate, ibandronate and risedronate resulted in significant improvements in both femoral neck (FN) and LS BMD. With regards to vertebral fractures and all safety outcomes, there were no statistically significant differences between denosumab and any of the comparator. Relative to placebo, denosumab was associated with significant benefits in both LS and TH BMD. Additionally, denosumab (compared to placebo) was not associated with reductions in vertebral and nonvertebral fractures. Finally, denosumab was not associated with improvement in safety outcomes, compared to placebo. These findings should be interpreted with caution as some analyses suffered from statistical imprecision., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., (© 2023. The Author(s).)

Background/objective: This study aims to evaluate ibandronate clinical effectiveness in the prevention of osteoporosis-related vertebral fractures (VFs) and nonvertebral fractures (NVFs) in the treatment of postmenopausal osteoporosis., Methods: This systematic review was conducted in accordance with the Centre for Reviews and Dissemination's guidance and reporting in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement 2020. A literature search was performed in PubMed and EMBASE since their inception until February 7, 2022. Randomized controlled trials (RCTs), meta-analysis, experimental, and observational studies evaluating adult patients treated with ibandronate and assessed to osteoporotic fractures prevention were included. The risk of bias was assessed according to study design. Data were analyzed using descriptive statistics., Results: Eight references from 4 RCTs, 7 meta-analyses, and 6 observational studies were included. In RCTs, oral ibandronate was superior to placebo in the prevention of VF. However, the doses were lower than those approved. The meta-analyses confirmed these results and showed that adequate doses of oral ibandronate reduce the risk of NVF compared with insufficient doses. In observational studies, oral ibandronate (in approved doses) reduced the risk of VF compared with no treatment or risedronate or alendronate and the risk of NVF versus risedronate or alendronate; the risk of hip fractures was similar between ibandronate and other oral bisphosphonates., Conclusions: There is strong evidence that ibandronate reduces the risk of VF in postmenopausal osteoporosis. The available evidence further suggests that ibandronate may reduce the risk of NVF versus insufficient doses of ibandronate, as well as risedronate or alendronate., Competing Interests: The authors declare no conflict of interest. The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Persistence with initial treatment was highest after 1 year, decreasing afterwards. Persistence was highest for denosumab followed by alendronate. We identified several factors associated with treatment persistence, some of which were the same irrespective of OTx agent, which could help target subgroups of patients in terms of social and healthcare support., Purpose: To describe patient characteristics, persistence, and factors associated with the persistence of new users of the bisphosphonates (alendronate, risedronate, and ibandronate) and the RANKL inhibitor denosumab in Denmark., Methods: A population-based cohort study using health registries (2010-2018). We included alendronate (n = 128,590), risedronate (n = 892), ibandronate (n = 5,855), and denosumab (n = 16,469) users, aged ≥ 50 years., Results: The 1-year persistence was 68.2% in the alendronate cohort; 39.3% in the risedronate cohort; 56.3% in the ibandronate cohort; and 84.0% in the denosumab cohort. The 2-year persistence was 58.7% in the alendronate cohort; 28.0% in the risedronate cohort; 42.9% in the ibandronate cohort; and 71.9% in the denosumab cohort. The 4-year persistence was 46.3%, 15.4%, 29.6%, and 56.9%, respectively. Later years of treatment initiation were associated with lower persistence for alendronate (adjusted odds ratio (OR) with 95% CI was 0.86 (0.81-0.91) in 2016 compared to 2010), but not for risedronate (OR was 1.56 (0.60-4.06), ibandronate (OR was 0.92 (0.71-1.19) or denosumab (OR was 1.11 (0.87-1.43). Older age was associated with higher persistence for all medications and the same goes for the female sex except for ibandronate. Dementia was associated with higher persistence for alendronate but not denosumab, whereas prior osteoporosis treatment (OT) was the opposite. Several comorbidities were associated with lower persistence for alendronate, but not denosumab., Conclusion: Persistence was highest for denosumab followed by alendronate. We identified several factors associated with treatment persistence, some of which were the same irrespective of OTx agent, which could help target subgroups of patients in terms of social and healthcare support., (© 2023. The Author(s).)

Background: Chronic obstructive pulmonary disease (COPD) is a progressive disorder that causes airway obstruction and lung inflammation. The first-line treatment of COPD is the bronchodilators of β2-agonists and antimuscarinic drugs, which can help control the airway obstruction, but the long-term use might render the drug tolerance. Bisphosphonates are widely used in osteoclast-mediated bone diseases treatment for decades. For drug repurposing, can delivery of a third generation of nitrogen-containing bisphosphonate, risedronate (RIS) ameliorate the progression of COPD?, Methods: COPD rats or mice models have been established through cigarette-smoking and elastase injection, and then the animals are received RIS treatment via nebulization. Lung deposition of RIS was primarily assessed by high-performance liquid chromatography (HPLC). The respiratory parameters of airway obstruction in COPD rats and mice were documented using plethysmography method and resistance-compliance system., Results: High lung deposition and bioavailability of RIS was monitored with 88.8% of RIS input dose. We found that RIS could rescue the lung function decline of airspace enlargement and mean linear intercept in the COPD lung. RIS could curb the airway obstruction by suppressing 60% of the respiratory resistance and elevating the airway's dynamic compliance, tidal volume and mid-expiratory flow. As an inhibitor of farnesyl diphosphate synthase (FDPS), RIS suppresses FDPS-mediated RAS and RhoA prenylation to obstruct its membrane localization in airway smooth muscle cells (ASMCs), leading to the inhibition of downstream ERK-MLCK and ROCK1-MLCP pathway to cause ASMCs relaxation. Additionally, RIS nebulization impeded pro-inflammatory cell accumulation, particularly macrophages infiltration in alveolar parenchyma. The NF-κB, tumor necrosis factor-alpha, IL-1β, IL-8, and IL-6 declined in microphages following RIS nebulization. Surprisingly, nebulization of RIS could overcome the tolerance of β2-agonists in COPD-rats by increasing the expression of β2 receptors., Conclusions: Nebulization of RIS could alleviate airway obstruction and lung inflammation in COPD, providing a novel strategy for treating COPD patients, even those with β2-agonists tolerance., (© 2022. The Author(s).)

Combination therapy is used to retard the selection of malaria parasite strains resistant to individual components of a combination of drugs. This approach has proved to be a success in the combination of sulphadoxine and pyrimethamine, which targets two different steps in the folate pathway of malaria parasites. However, after the success of this therapeutic combination, the efficacy of other combinations of drugs that target different enzymes in a particular metabolic pathway has, apparently, not been reported. In the current study, the antimalarial effect of a combination of risedronate (RIS), which is known for its anti-osteoporosis activity, and azithromycin (AZT) was investigated. Peter's suppression test was carried out on mice infected with 1 × 10 7 P. yoelii infected erythrocytes. Drug efficacy was analyzed by comparing the percent reduction in parasitaemia on day 4 post-infection. RIS was observed to be a blood schizonticidal agent against P. yoelii infection which showed ED 50 7.0 (4.04-12.13) mg/kg/day x 4. Normalized isobologram showed additive action between RIS 1 mg/kg/day x 4 and AZT 10 mg/kg/day x 4, and antagonistic action for the rest of the combinations (RIS 1 + AZT 20, RIS 1 + AZT 40, RIS 5 + AZT 10, RIS 5 + AZT 20, RIS 5 + AZT 40, RIS 10 + AZT 10, RIS 10 + AZT 20 and RIS 10 + AZT 40 mg/kg/day x 4). Furthermore, a combination of RIS with AZT showed inferior efficacy as compared to AZT treatment alone. This antagonistic interaction may be due to the high accumulation of AZT in WBCs, which will reduce its serum bio-availability, whereas RIS has anti-parasitic activity by increasing WBCs., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Bisphosphonates are the mainstay of osteoporosis treatment, but their use for patients with esophageal varices has been avoided due to the risk of esophagitis, which may cause variceal bleeding. Since most clinical trials assessing osteoporosis treatment last 2-3 years, this study aimed to evaluate a 2-year risedronate treatment for patients with esophageal varices and liver cirrhosis., Methods: The study received Institutional Review Board approval, and the sample was divided into two groups according to bone mineral density (BMD). Cirrhosis severity and endoscopic findings at baseline were similar between the groups. The intervention group had 51 patients with osteoporosis, who received oral risedronate 35 mg weekly plus calcium and vitamin D supplements. The control group had 51 patients with osteopenia, receiving only the supplements. Scheduled esophagogastroduodenoscopies and BMD measurements were carried out., Results: The adjusted esophagitis risk was higher in the intervention group; however, none of the subjects had digestive bleeding. Lumbar spine BMD increased in the intervention group (- 3.06 ± 0.71 to - 2.33 ± 0.90; p < 0.001) and in the control group (- 1.38 ± 0.77 to - 1.10 ± 1.05; p = 0.012). Femoral neck BMD did not change in the intervention group (- 1.64 ± 0.91 to - 1.71 ± 0.95; p = 0.220), but tended to decrease in the control group (- 1.00 ± 0.74 to - 1.09 ± 0.82; p = 0.053)., Conclusion: Oral risedronate was effective and did not cause gastrointestinal bleeding in cirrhotic patients with esophageal varices under endoscopic surveillance., (© 2022. Asian Pacific Association for the Study of the Liver.)

In older adults, polypharmacy and osteoporosis frequently occur contemporaneously. Polypharmacy is increasingly recognized as a risk factor for hip and fall-related fractures. Treatments for osteoporosis include antiresorptive (alendronate, risedronate, zoledronic acid, ibandronate, denosumab) and osteoanabolic (teriparatide, abaloparatide, romosozumab) agents. Polypharmacy is associated with worse adherence to pharmacologic therapy. Thus, the selection of osteoporosis treatment should be individualized and based on a variety of factors, including underlying fracture risk (high vs very high risk), medical comorbidities, medication burden, as well as fracture risk reduction profiles, modes of administration, and side effects of treatment options., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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., (© 2022. The Author(s).)

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.

Aminobisphosphonates are widely used in the treatment of osteoporosis. They have a high affinity for hydroxyapatite, binding primarily to resorbing surfaces, but also to forming surfaces and to some extent to resting surfaces. They inhibit osteoclasts, thereby decreasing remodelling units. Consequently, they increase bone mass and reduce stress risers. This decreases the risk of fractures. If this decrease is sufficient, they can be temporarily withdrawn (drug holidays), which prevents serious complications (atypical femoral fracture). They probably reduce mortality. Virtually all patients with osteoporosis can benefit from them at some point in the course of their disease (at the beginning of treatment or after the administration of anabolics, selective estrogen receptor modulators or denosumab). If well tolerated orally, alendronate and risedronate are preferable. Otherwise, zoledronate is preferred. Their efficacy vs. cost-safety-convenience ratio makes aminobisphosphonates reference drugs in the field of osteoporosis., (Copyright © 2022 The Authors. Published by Elsevier España, S.L.U. All rights reserved.)

Background: The efficacy of the prevention of vertebral fractures in men with osteoporosis by treatment with denosumab is debated. This study aimed to update the comparative effectiveness of denosumab and bisphosphonates for preventing vertebral fractures in men with osteoporosis., Methods: We searched PubMed, EMBASE, and Cochrane Central Register of Controlled Trials for randomized controlled trials that enrolled men with osteoporosis. Fixed-effects network meta-analysis was performed to evaluate the risk of vertebral fractures, and the relative risk (RR) and 95% confident interval (CI) values were calculated., Results: Sixteen studies were included, and the identified bisphosphonates were risedronate, alendronate, zoledronic acid, and ibandronate. Compared with placebo or control, a significant reduction in vertebral fractures was observed for denosumab (RR 0.30, 95%CI 0.13 0.68), risedronate (RR 0.39, 95%CI 0.19 0.77), and zoledronic acid (RR 0.45, 95%CI 0.21 0.98). According to the surface under the cumulative ranking curve (SUCRA), denosumab was the most effective one among the included agents for the risk reduction of vertebral fracture. However, compared with each bisphosphonate, the RR values of denosumab were not significant [RR 0.78 (95%CI 0.25 2.43) vs. risedronate, RR 0.55 (95%CI 0.18 1.75) vs. alendronate, RR 0.66 (95%CI 0.19 2.32) vs. zoledronic acid and RR 1.12 (95%CI 0.08 14.83) vs. ibandronate]., Conclusion: Denosumab effectively reduced the risk of vertebral fractures in men with osteoporosis, and this effect was comparable to that of bisphosphonates.

We assessed the survival outcomes associated with real-world bisphosphonate use, stratified by fracture site, type, administration, and duration of treatment, among patients with osteoporosis. A systematic review that incorporates our findings was conducted to provide up-to-date evidence on survival outcomes with bisphosphonate treatment in real-world settings. Patients diagnosed with osteoporosis who had been hospitalized for major fractures were identified from Taiwan's National Health Insurance Research Database 2008-2017 and followed until 2018. There were 24,390 new bisphosphonate users who were classified and compared with 76,725 nonusers of anti-osteoporosis medications in terms of survival outcomes using Cox model analysis. An inverse probability of treatment weighted Cox model and landmark analyses for minimizing immortal time bias were also performed. Bisphosphonate users vs. nonusers had a significantly lower mortality risk, regardless of fracture site (hazard ratios (95% confidence intervals) for patients with any major fracture, hip fracture, and vertebral fracture: 0.90 (0.88, 0.93), 0.83 (0.80, 0.86), and 0.86 (0.82, 0.89), respectively). Compared with nonuse, zoledronic acid (0.77 (0.73, 0.82)) was associated with the lowest mortality, followed by ibandronate (0.85 (0.78, 0.93)) and alendronate/risedronate (0.93 (0.91, 0.96)). Using bisphosphonates for ≥ 3 years had lower mortality (0.60 (0.53, 0.67)) than using bisphosphonates for < 3 years (0.98 (0.95, 1.01)). Intravenous bisphosphonates had a lower mortality than that of oral bisphosphonates. Our results are consistent with the systematic review findings among real-world populations. In conclusion, bisphosphonate use, especially persistence to intravenous bisphosphonates (e.g., zoledronic acid), may reduce post-fracture mortality among patients with osteoporosis, particularly those with hip/vertebral fractures. This supports the rational use of bisphosphonates in post-fracture care., (© 2022 The Authors. Clinical Pharmacology & Therapeutics 2022 American Society for Clinical Pharmacology and Therapeutics.)

This study evaluated the cost-effectiveness of 1 year of romosozumab followed by alendronate versus oral bisphosphonates alone in women with postmenopausal osteoporosis at very high risk for fracture in Canada. Results showed that romosozumab sequenced to alendronate is a cost-effective treatment option, dominating both alendronate and risedronate alone., Purpose: To demonstrate the value of romosozumab sequenced to alendronate compared to alendronate or risedronate alone, for the treatment of osteoporosis in postmenopausal women with a history of osteoporotic fracture and who are at very high risk for future fracture in Canada., Methods: A Markov model followed a hypothetical cohort of postmenopausal osteoporotic women at very high risk for future fractures, to estimate the cost-effectiveness of romosozumab and alendronate compared to oral bisphosphonates alone. A total treatment period of 5 years was assumed. Quality-adjusted life years and costs were estimated for each comparator across health states defined by different types of fragility fractures., Results: Romosozumab/alendronate was associated with a lifetime gain of 0.103 and 0.127 QALYs and a cost reduction of $343 and $3805, relative to alendronate and risedronate, respectively. These results were driven by a reduction of the number of fractures (2561 per 1000 patients, versus 2700 for alendronate and 2724 for risedronate over lifetime). Romosozumab/alendronate had the highest probability of being cost-effective, relative to alendronate and risedronate, at any willingness to pay threshold value., Conclusion: Romosozumab/alendronate was associated with reduced costs and greater benefit relative to other comparators. Probabilistic, deterministic, and scenario analyses indicate that romosozumab/alendronate represents the best value for money; the uncertainty analyses are robust, and therefore romosozumab should be considered for reimbursement by public drug plans in Canada ., (© 2022. The Author(s).)

BACKGROUND Numerous randomized controlled trials (RCTs) have evaluated pharmacological therapies for osteoporosis. The aim of this Bayesian network meta-analysis was to compare the efficacy and safety of pharmacological therapies for osteoporosis patients. MATERIAL AND METHODS The electronic databases of PubMed, Embase, and Cochrane Library were systematically searched for eligible RCTs from their inception up to January 2021. The primary endpoints were all fractures, vertebral fractures, and non-vertebral fractures, while the secondary endpoints were fractures at hip or peripheral locations, bone mineral density (BMD) at various sites, and potential adverse events. RESULTS We included 79 RCTs reporting a total of 108 797 individuals in the final quantitative analysis. The results of network analysis indicated that romosozumab (92.1%) was the most effective in reducing the risk for all fractures, with the best therapeutic effects on vertebral fracture (97.2%) and non-vertebral fracture (88.0%). Romosozumab (92.5%) provided better therapeutic effects for the reduction of hip fracture. The best treatment agents for improving whole-body BMD (100.0%), spine BMD (95.7%), hip BMD (92.4%), femoral neck BMD (86.7%), and trochanter BMD (95.5%) were alendronate, strontium ranelate, ibandronate, risedronate, and ibandronate, respectively. Finally, the use of bazedoxifene was associated with the highest incidence of any upper-gastrointestinal event, nasopharyngitis, and back pain, while risedronate was associated with higher incidence of abdominal pain and dyspepsia. CONCLUSIONS This study found that romosozumab yielded the best effects for preventing fracture risk, while abaloparatide was the most effective in reducing the risk of vertebral fracture and non-vertebral fracture.

This meta-analysis and systematic review investigated the efficacy of bisphosphonates on the incidence of hip fracture (IHF) in patients of different ages with osteoporosis or osteopenia. We searched Web of Science, Embase, the Cochrane Database, and PubMed from inception to January 10, 2021, for trials reporting the effects of bisphosphonates on the IHF. We included only randomized, double-blind, placebo-controlled clinical trials. We pooled data using a random-effects meta-analysis with risk ratios (RRs) and reported 95% CIs. We also used the Cochran Q and I² statistics to assess the heterogeneity in the results of individual studies. The primary endpoints were the total numbers of people in the bisphosphonates and placebo groups and the numbers of IHFs during the follow-up periods. Bisphosphonates reduced the IHF with an overall effect (RR: 0.66; 95% CI: 0.56 to 0.77; zoledronic acid: RR: 0.60; 95% CI: 0.46 to 0.78; risedronate: RR: 0.74; 95% CI: 0.59 to 0.94, and alendronate: RR: 0.61; 95% CI: 0.40 to 0.95). The result of the heterogeneity assessment was I²=0, p=0.97. In all age groups (all ages, ≥55 years old, ≥65 years old), bisphosphonates reduced the IHF. In the ≥55 years old and ≥65 years old age groups, the RR and 95% CI were 0.63 and 0.43 to 0.93, and 0.60 and 0.44 to 0.81, respectively. Bisphosphonate reduced the IHF in the general population and all age groups (≥55 years old and ≥65 years old). Zoledronic acid, risedronate and alendronate reduced the IHF in osteoporosis or osteopenia populations. The association between bisphosphonate and the IHF does not appear to be influenced by age., Competing Interests: Competing interests: None declared., (© American Federation for Medical Research 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (© 2021. International Osteoporosis Foundation and National Osteoporosis Foundation.)

Patients with osteoporosis prescribed risedronate gastro-resistant had a lower incidence of fractures versus those prescribed other oral bisphosphonates. Administration of risedronate gastric-resistant does not require fasting, and this more convenient dosing administration may explain its improved efficacy., Purpose: Up to half of patients do not follow complex dosing instructions of immediate-release bisphosphonates used for the prevention of osteoporotic fractures, which can result in suboptimal effectiveness. Risedronate gastro-resistant (GR) offers a more convenient dosing option by eliminating the need for fasting. This study compares fracture rates and outcomes between osteoporosis women treated with risedronate GR (GR cohort) versus other oral bisphosphonates (other cohort)., Methods: Claims from women with osteoporosis in the USA were analyzed. Patients were classified into the two cohorts based on the first oral bisphosphonate observed (index date) and matched 1:1 based on patient characteristics. Patients were observed for ≥ 2 years following the index date. Fracture rates, health care resource utilization and costs, and treatment persistence were compared., Results: In total, 2,726 patients were selected in each cohort (median age: 60.0 years). The incidence of fractures was lower in the GR versus the other cohort for any fracture sites (incidence rate ratio, 95% CI: 0.83, 0.70-0.97) and spine fractures (0.71, 0.54-0.95), although the respective rate of medication discontinuation at 2 years was 80.5% and 74.4%. Time to first fracture was delayed for the GR cohort, reaching statistical significance after 36 months. The GR cohort incurred fewer hospitalizations (incidence rate per 1,000 patient-years: GR = 106.74; other = 124.20, p < 0.05) translating into lower hospitalization costs per patient per year (GR = $3,611; other = $4,603, p < 0.05)., Conclusions: Patients prescribed risedronate GR versus other bisphosphonates had a lower incidence of fractures, which may be explained by the fact that the GR formulation is absorbed even when taken with food., (© 2021. The Author(s).)

Anorexia nervosa is complicated by low bone mineral density (BMD) and increased fracture risk associated with low bone formation and high bone resorption. The lumbar spine is most severely affected. Low bone formation is associated with relative insulin-like growth factor 1 (IGF-1) deficiency. Our objective was to determine whether bone anabolic therapy with recombinant human (rh) IGF-1 used off-label followed by antiresorptive therapy with risedronate would increase BMD more than risedronate or placebo in women with anorexia nervosa. We conducted a 12-month, randomized, placebo-controlled study of 90 ambulatory women with anorexia nervosa and low areal BMD (aBMD). Participants were randomized to three groups: 6 months of rhIGF-1 followed by 6 months of risedronate ("rhIGF-1/Risedronate") (n = 33), 12 months of risedronate ("Risedronate") (n = 33), or double placebo ("Placebo") (n = 16). Outcome measures were lumbar spine (1° endpoint: postero-anterior [PA] spine), hip, and radius aBMD by dual-energy X-ray absorptiometry (DXA), and vertebral, tibial, and radial volumetric BMD (vBMD) and estimated strength by high-resolution peripheral quantitative computed tomography (HR-pCT) (for extremity measurements) and multi-detector computed tomography (for vertebral measurements). At baseline, mean age, body mass index (BMI), aBMD, and vBMD were similar among groups. At 12 months, mean PA lumbar spine aBMD was higher in the rhIGF-1/Risedronate (p = 0.03) group and trended toward being higher in the Risedronate group than Placebo. Mean lateral lumbar spine aBMD was higher, in the rhIGF-1/Risedronate than the Risedronate or Placebo groups (p < 0.05). Vertebral vBMD was higher, and estimated strength trended toward being higher, in the rhIGF-1/Risedronate than Placebo group (p < 0.05). Neither hip or radial aBMD or vBMD, nor radial or tibial estimated strength, differed among groups. rhIGF-1 was well tolerated. Therefore, sequential therapy with rhIGF-1 followed by risedronate increased lateral lumbar spine aBMD more than risedronate or placebo. Strategies that are anabolic and antiresorptive to bone may be effective at increasing BMD in women with anorexia nervosa. © 2021 American Society for Bone and Mineral Research (ASBMR)., (© 2021 American Society for Bone and Mineral Research (ASBMR).)

Objectives: An open-label, randomized trial was conducted to examine the effects of risedronate versus menopausal hormone therapy (MHT) in postmenopausal women with recent hip fracture., Methods: Among 1165 eligible women, 281 were recruited and randomly assigned to receive oral risedronate (35 mg/week) or percutaneous estradiol gel (1.5 mg/day) plus oral micronized progesterone (100 mg/day) for 4 years. The primary end point was recurrent fracture and the secondary end points were mortality and bone mineral density (BMD)., Results: Kaplan-Meier analyses showed no significant differences in fracture recurrence and mortality between the two groups. The incidence of any new fracture per 100 person-years (PY) was 8.63 in the risedronate group and 12.86 in the MHT group ( p  = 0.180); that of clinical fracture was 4.75 and 6.99, respectively ( p  = 0.265); and that of asymptomatic vertebral fracture was 4.87 and 5.58, respectively ( p  = 0.764). The respective incidence of death per 100 PY was 3.58 and 4.40 ( p  = 0.503). BMD increased comparably at the lumbar spine in both groups. BMD at the total hip did not change in the risedronate group, but increased significantly by 2.8% in the MHT group., Conclusions: MHT might not differ from risedronate in the prevention of secondary fractures and death among postmenopausal women with recent hip fracture.

Objective: No evidence has shown the efficacy of Sodium Risedronate (Risedronate) for glucocorticoid-induced osteoporosis (GIO) in patients with Rheumatoid arthritis (RA). The aim of this study was to explore the effectiveness and safety of Risedronate for GIO complicated with RA., Methods: This was a six-month randomized, double-blind, placebo-controlled trial of 95 patients with GIO complicated with RA from 19 centers. The primary endpoint was the change from baseline in lumbar spine bone mineral density (L-BMD). Secondary endpoints included changes in femoral neck and total hip BMD and bone turnover markers, as well as rheumatoid arthritis Disease Activity Score with 28-joint counts. Incident of non-traumatic spine fractures and adverse events were tracked as safety endpoints., Results: Increase in L-BMD was significantly greater in the Risedronate group compared to the Placebo group (Risedronate: 3.49% [95% CI: 1.92-5.05] vs Placebo: 0.12% [95% CI: -2.07 to 2.30], p  < .0001). No significant difference was found in the femoral neck and total hip BMD. Although adverse events were observed in 28 patients, none were considered serious. Non-traumatic vertebral fractures were identified in 10 patients., Conclusion: Risedronate was effective in increasing L-BMD and was well tolerated in patients with GIO complicated with RA.

Metabolic activities are closely correlated with bone remodeling and long-term anti-resorptive bisphosphonate treatment frequently causes atypical femoral fractures through unclear mechanisms. To explore whether metabolic alterations affect bone remodeling in femurs and lumbar vertebrae and whether anti-osteoporotic bisphosphonates perturb their reconstruction, we studied three mouse strains with different fat and lean body masses (BALB/c, C57BL6, and C3H mice). These mice displayed variable physical activity, food and drink intake, energy expenditure, and respiratory quotients. Following intraperitoneal calcein injection, double calcein labeling of the femoral diaphysis, as well as serum levels of the bone-formation marker procollagen type-I N-terminal propeptide and the bone-resorption marker C-terminal telopeptide of type-I collagen, revealed increased bone turnover in mice in the following order: C3H > BALB/c ≥ C57BL6 mice. In addition, bone reconstitution in femurs was distinct from that in lumbar vertebrae in both healthy control and estrogen-deficient osteoporotic mice with metabolic perturbation, particularly in terms of femoral trabecular and cortical bone remodeling in CH3 mice. Interestingly, subcutaneous administration of bisphosphonate risedronate to C3H mice with normal femoral bone density led to enlarged femoral cortical bones with a low bone mineral density, resulting in bone fragility; however, this phenomenon was not observed in mice with ovariectomy-induced femoral cortical bone loss. Together, these results suggest that diverse metabolic activities support various forms of bone remodeling and that femur remodeling differs from lumbar vertebra remodeling. Moreover, our findings imply that the adverse effect of bisphosphonate agents on femoral cortical bone remodeling should be considered when prescribing them to osteoporotic patients.

Oral bisphosphonates are effective medications for the prevention of fractures in people suffering from osteoporosis. They are associated with gastrointestinal adverse reactions the most severe being an esophageal ulcer. It is unclear if oral bisphosphonates have a similar gastrointestinal safety profile in the hospital setting as in the community setting because hospitalized patients are often bedridden which may hinder proper drug administration., Introduction: To evaluate the incidence of upper gastrointestinal symptoms in hospitalized patients taking oral bisphosphonate., Methods: This single-center prospective cohort study included hospitalized adult patients actively taking risedronate or alendronate. Upper gastrointestinal symptoms were actively assessed at the baseline and 1 to 5 h following the administration of the oral bisphosphonate., Results: A total of 298 patients were included in the study. The mean age was 64 ± 15 years. During the follow-up period, gastric and esophageal symptoms affected 32 patients (10.7%). Epigastric burning, dysphagia, and regurgitation were reported in 4.4% (n = 13), 3% (n = 9), 2.7 (n = 8), and 2.3% (n = 7) patients, respectively. Heartburn, retro-sternal pain, and odynophagia were observed in 1.7% (n = 5), 1.7% (n = 5), and 0.3% (n = 1) patients., Conclusion: The incidence of adverse reaction was similar to that reported in community trials. The administration of oral bisphosphonate in hospitalized patients does not represent an additional risk for upper gastrointestinal adverse events. Treatment should be optimized during the hospital stay to improve the pharmacological management of osteoporosis.

Background: Different bone-modifying agents like bisphosphonates and receptor activator of nuclear factor-kappa B ligand (RANKL)-inhibitors are used as supportive treatment in men with prostate cancer and bone metastases to prevent skeletal-related events (SREs). SREs such as pathologic fractures, spinal cord compression, surgery and radiotherapy to the bone, and hypercalcemia lead to morbidity, a poor performance status, and impaired quality of life. Efficacy and acceptability of the bone-targeted therapy is therefore of high relevance. Until now recommendations in guidelines on which bone-modifying agents should be used are rare and inconsistent., Objectives: To assess the effects of bisphosphonates and RANKL-inhibitors as supportive treatment for prostate cancer patients with bone metastases and to generate a clinically meaningful treatment ranking according to their safety and efficacy using network meta-analysis., Search Methods: We identified studies by electronically searching the bibliographic databases Cochrane Controlled Register of Trials (CENTRAL), MEDLINE, and Embase until 23 March 2020. We searched the Cochrane Library and various trial registries and screened abstracts of conference proceedings and reference lists of identified trials., Selection Criteria: We included randomized controlled trials comparing different bisphosphonates and RANKL-inihibitors with each other or against no further treatment or placebo for men with prostate cancer and bone metastases. We included men with castration-restrictive and castration-sensitive prostate cancer and conducted subgroup analyses according to this criteria., Data Collection and Analysis: Two review authors independently extracted data and assessed the quality of trials. We defined proportion of participants with pain response and the adverse events renal impairment and osteonecrosis of the jaw (ONJ) as the primary outcomes. Secondary outcomes were SREs in total and each separately (see above), mortality, quality of life, and further adverse events such as grade 3 to 4 adverse events, hypocalcemia, fatigue, diarrhea, and nausea. We conducted network meta-analysis and generated treatment rankings for all outcomes, except quality of life due to insufficient reporting on this outcome. We compiled ranking plots to compare single outcomes of efficacy against outcomes of acceptability of the bone-modifying agents. We assessed the certainty of the evidence for the main outcomes using the GRADE approach., Main Results: Twenty-five trials fulfilled our inclusion criteria. Twenty-one trials could be considered in the quantitative analysis, of which six bisphosphonates (zoledronic acid, risedronate, pamidronate, alendronate, etidronate, or clodronate) were compared with each other, the RANKL-inhibitor denosumab, or no treatment/placebo. By conducting network meta-analysis we were able to compare all of these reported agents directly and/or indirectly within the network for each outcome. In the abstract only the comparisons of zoledronic acid and denosumab against the main comparator (no treatment/placebo) are described for outcomes that were predefined as most relevant and that also appear in the 'Summary of findings' table. Other results, as well as results of subgroup analyses regarding castration status of participants, are displayed in the Results section of the full text. Treatment with zoledronic acid probably neither reduces nor increases the proportion of participants with pain response when compared to no treatment/placebo (risk ratio (RR) 1.46, 95% confidence interval (CI) 0.93 to 2.32; per 1000 participants 121 more (19 less to 349 more); moderate-certainty evidence; network based on 4 trials including 1013 participants). For this outcome none of the trials reported results for the comparison with denosumab. The adverse event renal impairment probably occurs more often when treated with zoledronic acid compared to treatment/placebo (RR 1.63, 95% CI 1.08 to 2.45; per 1000 participants 78 more (10 more to 180 more); moderate-certainty evidence; network based on 6 trials including 1769 participants). Results for denosumab could not be included for this outcome, since zero events cannot be considered in the network meta-analysis, therefore it does not appear in the ranking. Treatment with denosumab results in increased occurrence of the adverse event ONJ (RR 3.45, 95% CI 1.06 to 11.24; per 1000 participants 30 more (1 more to 125 more); high-certainty evidence; 4 trials, 3006 participants) compared to no treatment/placebo. When comparing zoledronic acid to no treatment/placebo, the confidence intervals include the possibility of benefit or harm, therefore treatment with zoledronic acid probably neither reduces nor increases ONJ (RR 1.88, 95% CI 0.73 to 4.87; per 1000 participants 11 more (3 less to 47 more); moderate-certainty evidence; network based on 4 trials including 3006 participants). Compared to no treatment/placebo, treatment with zoledronic acid (RR 0.84, 95% CI 0.72 to 0.97) and denosumab (RR 0.72, 95% CI 0.54 to 0.96) may result in a reduction of the total number of SREs (per 1000 participants 75 fewer (131 fewer to 14 fewer) and 131 fewer (215 fewer to 19 fewer); both low-certainty evidence; 12 trials, 5240 participants). Treatment with zoledronic acid and denosumab likely neither reduces nor increases mortality when compared to no treatment/placebo (zoledronic acid RR 0.90, 95% CI 0.80 to 1.01; per 1000 participants 48 fewer (97 fewer to 5 more); denosumab RR 0.93, 95% CI 0.77 to 1.11; per 1000 participants 34 fewer (111 fewer to 54 more); both moderate-certainty evidence; 13 trials, 5494 participants). Due to insufficient reporting, no network meta-analysis was possible for the outcome quality of life. One study with 1904 participants comparing zoledronic acid and denosumab showed that more zoledronic acid-treated participants than denosumab-treated participants experienced a greater than or equal to five-point decrease in Functional Assessment of Cancer Therapy-General total scores over a range of 18 months (average relative difference = 6.8%, range -9.4% to 14.6%) or worsening of cancer-related quality of life., Authors' Conclusions: When considering bone-modifying agents as supportive treatment, one has to balance between efficacy and acceptability. Results suggest that Zoledronic acid likely increases both the proportion of participants with pain response, and the proportion of participants experiencing adverse events However, more trials with head-to-head comparisons including all potential agents are needed to draw the whole picture and proof the results of this analysis., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: The goal of this study was to review relevant randomized controlled trials or case-control studies to determine the clinical efficacy of minodronate in the treatment of osteoporosis., Method: The relevant studies were identified on PubMed, Cochrane, and Embase databases using appropriate keywords. Pertinent sources in the literature were also reviewed, and all articles published through October 2019 were considered for inclusion. For each study, we assessed odds ratios, mean difference, and 95% confidence interval (95% CI) to evaluate and synthesize outcomes., Result: Thirteen studies comprising 3740 patients were included in this study. Compared with other drugs, minodronate significantly decreased N-telopeptide of type I collagen/creatinine (weighted mean difference [WMD]: -13.669, 95% confidence interval [CI]: -23.108 to -4.229), bone alkaline phosphatase (BAP) (WMD: -1.26, 95% CI: -2.04 to -0.47) and tartrate-resistant acid phosphatase 5b (WMD: -154.11, 95% CI: -277.85 to -30.37). Minodronate combined with other drugs would significantly decrease BAP (WMD: -3.10, 95% CI: -5.20 to -1.00) than minodronate. Minodronate-naïve would significantly decrease BAP (WMD: -3.00, 95% CI: -5.47 to 0.53) and tartrate-resistant acid phosphatase 5b (WMD: -128.20, 95% CI: -198.11 to -58.29) than minodronate-switch. The incidence of vertebral fracture was significantly decreased in the minodronate group than the other drugs (relative risk: 0.520, 95% CI: 0.363-0.744)., Conclusion: Minodronate has better clinical efficacy in the treatment of osteoporosis than other drugs (alendronate, risedronate, raloxifene, or eldecalcitol).

FRAX ® calculates the 10-year probability of major osteoporotic fractures (MOF), which are considered to have a greater clinical impact than other fractures. Our results suggest that, in postmenopausal women with severe osteoporosis, those treated with teriparatide had a 60% lower risk of FRAX ® -defined MOF compared with those treated with risedronate., Introduction: The VERO trial was an active-controlled fracture endpoint clinical trial that enrolled postmenopausal women with severe osteoporosis. After 24 months, a 52% reduction in the hazard ratio (HR) of clinical fractures was reported in patients randomized to teriparatide compared with risedronate. We examined fracture results restricted to FRAX ® -defined major osteoporotic fractures (MOF), which include clinical vertebral, hip, humerus, and forearm fractures., Methods: In total, 1360 postmenopausal women (mean age 72.1 years) were randomized to receive subcutaneous daily teriparatide (20 μg) or oral weekly risedronate (35 mg). Patient cumulative incidence of ≥ 1 FRAX ® -defined MOF and of all clinical fractures were estimated by Kaplan-Meier analyses, and the comparison between treatments was based on the stratified log-rank test. Additionally, an extended Cox model was used to estimate HRs at different time points. Incidence fracture rates were estimated at each 6-month interval., Results: After 24 months, 16 (2.6%) patients in the teriparatide group had ≥ 1 low trauma FRAX ® -defined MOF compared with 40 patients (6.4%) in the risedronate group (HR 0.40; 95% CI 0.23-0.68; p = 0.001). Clinical vertebral and radius fractures were the most frequent FRAX ® -defined MOF sites. The largest difference in incidence rates of both FRAX ® -defined MOF and all clinical fractures between treatments occurred during the 6- to 12-month period. There was a statistically significant reduction in fractures between groups as early as 7 months for both categories of clinical fractures analyzed., Conclusion: In postmenopausal women with severe osteoporosis, treatment with teriparatide was more efficacious than risedronate, with a 60% lower risk of FRAX ® -defined MOF during the 24-month treatment period. Fracture risk was statistically significantly reduced at 7 months of treatment., Clinical Trial Information: ClinicalTrials.gov Identifier: NCT01709110 EudraCT Number: 2012-000123-41.

Objective: Bone marrow lesions (BMLs) contribute to pain and progression of knee OA. Bisphosphonates may be a potential disease-modifier through amelioration of BMLs. We sought to determine the effect of oral bisphosphonates on BML volume over 12 months., Design: Women in the Osteoarthritis Initiative who newly initiated an oral bisphosphonate were propensity-score matched to non-initiators. BML volume was assessed using sagittal turbo spin echo fat-suppressed intermediate-weighted MR images at the index date and 12 months later. A validated semi-automated process was used to segment subchondral OA-related BMLs to determine total volume of BMLs based on number of voxels within the outlined area of interest. Mean change in BML volume over 12 months among bisphosphonate initiators was compared with non-initiators using multiple linear regression., Results: 145 bisphosphonate initiators were identified, who were well-matched to their comparators. The difference in mean change in total BML volume between the two groups, regardless of presence of baseline BMLs, was not significant (P = 0.4, 95% CI -156.6 to +354.2). The proportion of participants with decreased, increased, or unchanged BML volumes over the 12 months were similar in both groups. Among those with baseline BMLs, bisphosphonate initiators had a greater proportion with a decrease in BML volume compared with stable or increased BML volume than non-initiators (P = 0.03)., Conclusions: In this 'real-world' setting of women starting bisphosphonates, we found no clear evidence of benefit on BML volume over a 12-month period, though a trend towards a decrease in BML volume was noted., (Copyright © 2020 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Herein we review the discovery, development, commercial history and legacy of risedronate or NE-58095, a potent N-containing bisphosphonate developed by scientists at the Cincinnati Miami Valley Laboratories and the Norwich Eaton Laboratories of Procter and Gamble. It is characterized by a hydroxyl substituent (R 1 ) and a pyridyl-methylene substituent (R 2 ) at the carbon bridging two phosphonate moieties. It was shown to have greater potency than alendronate in cell-based systems while binding affinity to bone matrix was lower than alendronate, accounting for the relatively rapid offset of bone turnover inhibition when therapy is discontinued. Risedronate was shown to significantly reduce serum alkaline phosphatase and clinical features in patients with Paget's disease and was approved for this indication, at a dose of 30 mg daily for 2 months, in 1998. Formal dose response testing for treatment of osteoporosis was not performed. In large Phase 3 studies, 5 mg risedronate daily increased bone mineral density more than did the 2.5 mg dose. As a result, the 2.5 mg dose was dropped from most of the Phase 3 studies after 12 months. The 5 mg daily dose was approved for treating and preventing postmenopausal osteoporosis and glucocorticoid-induced osteoporosis in 2000. The drug was subsequently approved for treating men with osteoporosis. Following the leads of other companies, weekly and monthly preparations were developed and approved, based on non-inferiority BMD studies vs the 5 mg daily oral dose as was a unique dosing regimen of 75 mg given on 2 consecutive days each month. Finally, to overcome the effect of food on limiting the already poor gastrointestinal absorption of the drug, a once-weekly oral preparation containing the chelating agent EDTA and with an enteric coating delaying dissolution until the tablet was in the small intestine was approved in 2010 to be administered after breakfast. The Alliance for Better Bone Health, a collaboration between Procter & Gamble Pharmaceuticals and sanofi-aventis U.S. was formed to market risedronate as Actonel® and, subsequently, Actonel-EC® or Atelvia®. These drugs are still marketed by sanofi-aventis in some countries. The sale of the pharmaceutical division of Procter & Gamble to Warner Chilcott (US) was based, in large part, on the perceived value and marketability of the risedronate drugs. When marketing targets of Warner-Chilcott were not met, the rights of risedronate were sold to Allergan USA, Inc. which never actively promoted the drug. Generic forms of risedronate were introduced into the United States in 2015 but are rarely used, although several generic forms are actively marketed in other countries., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: High-turnover bone disease is a major consequence of SHPT and may explain the high risk for fracture in patients with advanced chronic kidney disease (CKD). Bisphosphonates suppress bone turnover and improve bone strength, but their effects have not been fully characterized in advanced CKD with severe SHPT. Bisphosphonates also increase 1,25-dihydroxyvitamin D levels in normal and uremic rats, but the underlying mechanism remains to be determined., Materials and Methods: We investigated the skeletal and mineral metabolic effects of RIS, a pyridinyl bisphosphonate, in rats with severe SHPT induced by 5/6 nephrectomy plus a high phosphate diet., Results: Nephrectomized rats developed severe SHPT, along with hyperphosphatemia, low 1,25-dihydroxyvitamin D, and markedly increased FGF23. Moreover, these rats exhibited characteristic features of high-turnover renal osteodystrophy, including increased indices of trabecular bone turnover, decreased cortical bone thickness, inferior cortical biomechanical properties, and a prominent increase in peritrabecular fibrosis. RIS treatment increased bone volume and partially attenuated trabecular bone remodeling, cortical bone loss, and mechanical properties, whereas it produced a marked improvement in peritrabecular fibrosis along with a corresponding decrease in osteogenic gene markers. RIS treatment also suppressed the elevation of FGF23, which was associated with increased 1,25-dihydroxyvitamin D., Conclusions: In a rat model of severe SHPT, treatment with RIS partially attenuated histological manifestations of high-turnover bone disease. RIS treatment also suppressed the elevation of FGF23, which may explain the increased 1,25-dihydroxyvitamin D production during the treatment.

Vertebral fractures (VFx) occur most frequently in the mid-thoracic and thoraco-lumbar regions, which experience the highest mechanical loading along the spine. The prevalence and incidence of VFx by their location and severity, and their relationship with bone mineral density (BMD), are seldom reported in randomized clinical trial cohorts. The VERO trial randomized 1360 postmenopausal women with at least two moderate or one severe VFx to receive either teriparatide or risedronate for up to 24 months. In this post hoc analysis, we describe the centrally read distribution and severity of prevalent and incident VFx, and the association of their location with the baseline BMD. At baseline, 21.4% of all evaluable vertebral bodies had a prevalent VFx; most commonly at L 1 , T 12 , L 2 and T 11 (38.5%, 37.4%, 25.3% and 23.5% of patients, respectively). Patients with prevalent VFx only at T 12 /L 1 showed a higher baseline BMD compared to patients with VFx at other levels. At month 24, 100 patients had 126 incident VFx (teriparatide: 35; risedronate: 91). The most frequent incident VFx occurred at T 12 (n = 17, 1.6% of patients), followed by L 1 and T 11 (n = 14, 1.3% both). The frequency of incident VFx was lower at all vertebral levels in patients given teriparatide. These results confirm prior reports that VFx occurs more frequently at mid-thoracic and thoraco-lumbar regions of the spine. Patients with these VFx locations have higher BMD than those who fracture at other sites, suggesting a role for mechanical stress in the etiology of VFx. Teriparatide is superior to risedronate in the prevention of VFx at these common fracture locations.Trial registration ClinicalTrials.gov Identifier: NCT01709110.

Introduction: In terms of the balance between benefits and risks of long-term treatment with bisphosphonate, uncertainties remain regarding the optimal treatment duration. We investigated effects of continuous long-term treatment for 10 years with bisphosphonate in postmenopausal osteoporosis patients., Materials and Methods: Fifty five patients in the outpatient clinic of our hospital have been continuously treated with alendronate or risedronate for 10 years. All data were retrospectively collected. The age, height, weight, total muscle volume, total fat volume, and BMD at the lumbar spine, total hip and distal 1/3 radius, alkaline phosphatase (ALP), urinary type I collagen cross-linked N-telopeptide (uNTX) and tartrate-resistant acid phosphatase-5b (TRAP5b), calcium (Ca) and phosphate (P) levels were measured pre- and after the start of 10-year continuous treatment., Results: BMD at the lumbar spine increased continuously over the 10-year period, while BMD at the total hip slightly but significantly decreased, and that at the 1/3 radius did not show any significant change over the 10 years. Serum Ca value was significantly decreased after the start of treatment, and became stable within the reference range from the second year. Bone resorption markers such as uNTX and TRAP5b significantly decreased from the second year after the start of treatment and no significant changes were observed thereafter. There were no serious medical adverse events including atypical femoral fractures and osteonecrosis of the jaw., Conclusion: We believe that the continuous use of alendronate and risedronate for 10 years could be an option for the treatment of postmenopausal osteoporosis patients.

Background: This meta-analysis was conducted to compare the effects and safety of teriparatide with risedronate in the treatment of osteoporosis., Material and Methods: PubMed, Embase, Web of Science and Cochrane library database were systematically reviewed for studies published up to February 24, 2019. Eligible studies that compared the effects of teriparatide with risedronate in osteoporosis were included in this meta-analysis. The outcomes included percentage change in bone mineral density (BMD) of lumbar spine, femoral neck, and total hip, the incidence of clinical fractures, serum bone markers, and adverse events. A random-effects or fixed-effects model was used to pool the estimate, according to the heterogeneity among the included studies., Results: Seven studies were included in this meta-analysis. Compared with risedronate, teriparatide was associated with a significant increase in lumbar spine BMD [weight mean difference (WMD)=4.24, 95%CI: 3.11, 5.36; P < .001], femoral neck BMD (WMD=2.28, 95%CI: 1.39, 3.18; P < .001), and total hip BMD (WMD = 1.19, 95%CI: 0.47, 1.91; P = .001). Moreover, patients in teriparatide group had significantly lower incidences of clinical fracture (risk ratio [RR] = 0.48, 95%CI: 0.32, 0.72; P < .001), new vertebral fracture (RR = 0.45, 95%CI: 0.32, 0.63; P < .001), and non-vertebral fracture (RR = 0.63, 95%CI: 0.40, 0.98; P = .042) than those in risedronate group. There were significant differences between the 2 groups in serum change, including P1NP (WMD = 122.34, 95%CI: 68.89, 175.99; P < .001), CTx (WMD = 0.62, 95%CI: 0.29, 0.96; P < .001), and iPTH (WMD = -13.18, 95%CI: -15.04, -11.33; P < .001). The incidence of adverse events was similar between the 2 groups (RR = 0.93, 95%CI: 0.69, 1.25; P = .610)., Conclusion: This study suggested that teriparatide was more effective than risedronate for increasing the BMD in lumbar spine, femoral neck, and total hip, as well as reducing the incidences of clinical fracture, new vertebral fracture and non-vertebral fracture. There was no significant difference in incidence of adverse events between the 2 drugs. Considering the potential limitations in the present study, further large-scale, well-performed randomized trials are needed to verify our findings.

Tacrolimus, a calcineurin inhibitor, affects bone metabolism and increases the risk of fracture due to marked bone loss. Bisphosphonates increase the bone mineral density (BMD) in osteoporosis patients. Menatetrenone has less positive effects on BMD but reduces the risk of fracture by improving bone quality. In this study, we investigated the effectiveness of the combined administration of risedronate and menatetrenone against bone loss induced by tacrolimus. Wistar rats were divided into four groups: [1] control, [2] tacrolimus at 1.5 mg/kg, [3] tacrolimus + risedronate at 1.0 mg/kg, and [4] tacrolimus + risedronate + menatetrenone at 20 mg/kg. After the drugs were administered for 4 weeks, bone histomorphometric analysis was performed and bone strength was evaluated using a three point bending method. BMD was measured using quantitative computed tomography. Tacrolimus significantly reduced the BMD and strength properties of the lower limb bones. These tacrolimusinduced decreases were suppressed by risedronate treatment. The combined administration of risedronate and menatetrenone more significantly improved bone strength properties than risedronate alone. Bone histomorphometric analysis revealed a significant increase in bone resorption with tacrolimus. Risedronate alone significantly suppressed the tacrolimus-induced increase in bone resorption but simultaneously reduced bone formation. On the other hand, the combined administration of risedronate and menatetrenone suppressed the tacrolimus-induced increase in bone resorption, in addition to the significant risedronate-induced decrease in bone formation. This study suggests that the combined administration of risedronate and menatetrenone improves bone strength in tacrolimus-treated rats by preventing and ameliorating the risedronate-induced suppression of bone formation.

Background: VERO is a fracture endpoint study in women with established osteoporosis that showed reduction in the risks of new vertebral fractures (VFx) and clinical fractures in women randomized to teriparatide compared with risedronate. Patients on psychotropic drugs (hypnotics, benzodiazepines and antidepressants [selective serotonin- and norepinephrine-reuptake inhibitors: SSRIs and SNRIs]) and proton pump inhibitors (PPIs) may be at a higher risk of fractures. We studied the association of exposure to these medications with the risk of fractures in the VERO study cohort, including an assessment of their potential interactions with the assigned clinical trial drugs., Methods: A total of 1360 postmenopausal women with at least 2 moderate or 1 severe VFx and bone mineral density T-score ≤-1.50 were randomized to subcutaneous daily teriparatide (20μg) or oral weekly risedronate (35mg) in a double-blind, double-dummy, 2-year trial. In thispost-hoc analysis, multivariable log-binomial and Cox proportional hazards regression models were used to estimate adjusted risk ratios (RR) or hazard ratios (HR) for the exposure to these concomitant medications with the occurrence of incident fractures. We also assessed treatment effect modifications on anti-fracture efficacy driven by the use of these medications., Results: There were 406 (29.9 %), 347 (25.5 %) and 176 (12.9 %) subjects taking PPIs, benzodiazepines/hypnotics, and SSRIs/SNRIs during the study, respectively. For all fracture endpoints, the greater risk reduction of teriparatide versus risedronate did not significantly differ within the categories of psychotropic drugs and PPIs. Multivariable analysis showed that the risk of pooled new and worsened VFx was higher in PPI users than in non-PPI users (RR: 1.57; p=0.032), regardless of the study treatment. Benzodiazepine/hypnotic drug users showed an increased risk of clinical fractures (HR: 1.71; p=0.026) and non-vertebral fragility fractures (NVFFx, HR: 1.89; p=0.017), regardless of the study treatment. Increases in the risk of clinical fractures (HR: 1.93; p=0.018) and NVFFx (HR: 2.16; p=0.011) were also observed in SSRI/SNRI users, regardless of the study treatment., Conclusion: In postmenopausal women with severe osteoporosis, the superior anti-fracture efficacy of teriparatide compared with risedronate was consistent regardless of psychotropic or PPI drugs use. Patients taking psychotropic drugs and PPIs showed a higher risk for NVFFx and VFx respectively, compared to those not on these medications., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Absorption of oral immediate-release (IR) risedronate tablets is reduced by food intake, thus a delayed-release (DR) tablet has been developed to overcome the necessity of taking IR tablets under fasting conditions. This randomized, double-blind, phase II/III study compared efficacy and safety of risedronate IR once-daily (QD) and DR once-monthly (QM) tablets in Japanese patients with involutional osteoporosis. Patients received 2.5 mg IR on awakening QD, or 25 or 37.5 mg DR on awakening, following breakfast, or 30 min after breakfast, QM for 12 months. Primary endpoint was non-inferiority in mean percent change from baseline to end of study (month 12, last observation carried forward [M12, LOCF]) in mean lumbar spine (L 2 -L 4 ) bone mineral density (BMD) between risedronate IR on awakening and DR following breakfast. Mean percent changes in (L 2 -L 4 ) BMD at M12, LOCF were 5.07% (IR at awakening, n = 190), 3.36% (25 mg DR following breakfast, n = 194), and 4.11% (37.5 mg DR following breakfast, n = 181). Mean percent change in (L 2 -L 4 ) BMD was numerically lower in the DR following breakfast groups versus the respective on awakening and 30 min after breakfast DR groups. Overall incidences of treatment-emergent adverse events (TEAEs) were comparable between groups. In the DR groups, 1.5-4.0% of patients reported TEAEs potentially associated with acute-phase reactions versus 0% in the IR group. In this study, non-inferiority could not be declared for 37.5 or 25 mg DR following breakfast QM (p = 0.1346 or p = 0.6711, respectively) versus 2.5 mg IR on awakening QD.

Purpose: To investigate the comparative efficacies of the five most commonly used bisphosphonates for the secondary prevention of osteoporotic fractures in a Bayesian network meta-analysis., Methods: Five databases and the reference lists of all acquired articles from inception to July 2017 were searched. A Bayesian random-effects model was employed, and vertebral, hip and nonvertebral nonhip fractures were assessed by odds ratios (ORs) and 95%credible intervals. Furthermore, with respect to each endpoint, rank probabilities for each bisphosphonate were evaluated using the surface under the cumulative ranking curve (SUCRA) value., Results: Thirteen eligible studies were identified involving 11,822 patients with osteoporotic fractures. Overall in the pairwise meta-analyses, bisphosphonate use significantly reduced the risk of new vertebral, hip, and nonvertebral nonhip fractures, with ORs and 95% confidence intervals of 0.56 (0.49-0.64), 0.69 (0.48-0.98), and 0.82 (0.70-0.97), respectively. In network meta-analyses, significant differences were found between placebo and any one of the five bisphosphonates for new vertebral fractures. The rank probability plot and the SUCRA calculation results suggested that alendronate was the best intervention (14.6%) for secondary prevention of vertebral fractures, followed by zoledronate (15.3%) and etidronate (22.1%). In terms of the incidence of new hip fractures, alendronate was associated with the lowest incidence (18.5%), followed by zoledronate (43.1%) and risedronate (52.5%). However, zoledronate ranked lowest (16.6%) regarding the incidence of new nonvertebral nonhip fractures, followed by risedronate (23.8%) and alendronate (44.1%)., Conclusions: Bisphosphonates show significant efficacy for secondary prevention of new vertebral fractures, and alendronate is most likely to be successful at secondary prevention of vertebral and hip fractures compared with the other four bisphosphonates., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2019 Lei Shi et al.)

Characteristics of patients starting oral bisphosphonate therapy changed over time, reflecting trends in osteoporosis management (e.g., new drugs to market), and general healthcare delivery (e.g., benzodiazepine use declined, statin use increased). When designing studies that examine osteoporosis drug effects, potential time-related biases must be considered., Introduction: To describe the type of oral bisphosphonate initiated and characteristics of patients starting oral bisphosphonate therapy over time., Methods: We identified community-dwelling older adults (ages ≥ 66 years) initiating oral bisphosphonate therapy from April 1996 to March 2016 (1996 to 2015 fiscal years) using healthcare administrative data in Ontario. Patients with conditions other than osteoporosis that may impact bisphosphonate prescribing were excluded. The bisphosphonate initiated and patient characteristics were summarized by fiscal year and stratified by sex., Results: We identified 560,817 eligible patients (81% women). Most patients initiated cyclical etidronate from 1996 until 2005, and then weekly regimens became dominant. In 2008, risedronate became the main oral bisphosphonate (46% risedronate, 43% alendronate, 11% etidronate); with its use increasing after availability of monthly and delayed-release risedronate formulations. In 2015, 71% of patients started risedronate, 28% started alendronate, and less than 2% started etidronate. Characteristics of patients changed over time, reflecting changes in osteoporosis management and general healthcare delivery. Over time, a larger proportion of men (9% to 28%) and patients with diabetes (women 10% to 17%, men 14% to 22%) initiated therapy; benzodiazepine (women 22% to 13%, men 20% to 10%) and estrogen-based hormone replacement therapy (12% to 15% of women 1996-2002 to 3% since 2008) decreased, while statin use increased (women 15% to 39%, men 14% to 52%)., Conclusions: The characteristics of patients starting oral bisphosphonate therapy have changed over time. Consideration must be given to these time trends when designing studies that examine osteoporosis drug effects.

Objective: Clinical trial results have shown that, in glucocorticoid-treated patients, treatment with denosumab 60 mg subcutaneously once every 6 months (Q6M) increased spine and hip bone mineral density (BMD) at month 12 significantly more than treatment with risedronate 5 mg orally once daily (QD). The present analysis was performed to compare efficacy and characterize safety through month 24., Methods: This phase III study enrolled men and women ≥18 years old who had received ≥7.5 mg daily prednisone or equivalent for <3 months (glucocorticoid-initiating) or for ≥3 months (glucocorticoid-continuing) before screening. All patients <50 years old had a history of osteoporotic fracture. Glucocorticoid-continuing patients ≥50 years old had T scores of -2.0 or less (or -1.0 or less with fracture history). Patients were randomized (1:1) to receive denosumab 60 mg subcutaneously Q6M or risedronate 5 mg orally QD for 24 months, with daily calcium and vitamin D., Results: Of 795 patients, 590 (74.2%) completed the study (in the glucocorticoid-initiating group, 109 of 145 patients treated with denosumab and 117 of 145 patients treated with risedronate; in the glucocorticoid-continuing group, 186 of 253 patients treated with denosumab and 178 of 252 patients treated with risedronate). Denosumab was superior to risedronate in increasing lumbar spine and total hip BMD at all time points assessed, among glucocorticoid-initiating patients (24-month lumbar spine: BMD increase of 6.2% versus 1.7%, respectively [P < 0.001]; 24-month total hip: BMD increase of 3.1% versus 0.0% [P < 0.001]) and among glucocorticoid-continuing patients (24-month lumbar spine: BMD increase of 6.4% versus 3.2% [P < 0.001]; 24-month total hip: BMD increase of 2.9% versus 0.5% [P < 0.001]). Adverse events, serious adverse events (including infections), and fractures were similar between treatment groups., Conclusion: Denosumab was superior to risedronate in terms of increases in spine and hip BMD through month 24, and the safety profile was similar between treatment groups. Denosumab may offer a new osteoporosis treatment option for glucocorticoid-treated patients., (© 2019 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

Anastrozole has been shown to prevent breast cancer in postmenopausal women at high risk of the disease, but has been associated with substantial accelerated loss of bone mineral density (BMD) and increased fractures. Here, we investigate the effect of risedronate on BMD after 5 years of follow-up in the IBIS-II prevention trial. 1410 women were enrolled in the bone sub-study and stratified into three strata according to the lowest baseline T-score at spine or femoral neck. The objective was to compare the effect of oral risedronate (35 mg weekly) versus placebo in osteopenic women in stratum II who were randomised to anastrozole in the main study. 258 osteopenic, postmenopausal women at high risk of developing breast cancer for whom baseline and follow-up bone mineral density measurements were available. 5-year mean BMD change at the lumbar spine for osteopenic women randomised to anastrozole and risedronate was -0.4% compared to -4.2% for those not on risedronate (P < 0.0001) but not significantly different between risedronate users and non-users at the hip (P = 0.2). 5-year mean PINP change was -20% for those randomised to anastrozole and risedronate compared to 3% for those not on risedronate but on anastrozole (P < 0.0001). Our results confirm the bone loss associated with the use of anastrozole and show that anastrozole-induced BMD loss in the spine can be controlled with risedronate treatment. However, our results suggest that weekly oral risedronate is unable to completely prevent anastrozole induced bone loss at the hip., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Limited data are available on the safety and efficacy of anti-resorptive agents, particularly once-monthly bisphosphonates, for use in osteoporotic patients with chronic kidney disease (CKD). We conducted a post hoc analysis of data from a 12-month, randomized, double-blind, phase III study to evaluate the safety and efficacy of once-monthly risedronate (RIS-OM) 75 mg tablets in Japanese osteoporosis patients with mild-to-moderate CKD. Patients who received RIS-OM 75 mg were stratified by baseline estimated glomerular filtration rate (eGFR; ≥ 90, ≥ 60 to < 90, or ≥ 30 to < 60 mL/min/1.73 m 2 ). Safety endpoints were incidence of adverse events (AEs) and percent change from baseline in eGFR, serum creatinine, calcium, and phosphorus. Efficacy endpoints were percent change from baseline in lumbar spine bone mineral density (BMD) and bone turnover markers (BTMs). In 420 patients included (age 67.7 ± 6.7 years, women 98.8%), the incidence of all AEs, gastrointestinal disorders, acute phase reaction, non-vertebral fractures, and renal and urinary disorders was not significantly different among subgroups. Interaction between subgroups and time was significant for eGFR (p = 0.010) and serum creatinine (p = 0.001) but considered to be regression to the mean and clinically insignificant. BMD significantly increased while BTMs significantly decreased from baseline with a similar degree of change among the subgroups. In conclusion, RIS-OM 75 mg showed consistent safety and efficacy in suppressing bone turnover and increasing BMD in Japanese primary osteoporosis patients with mild-to-moderate CKD. These results should, however, be interpreted with caution because the number of patients with moderate CKD was limited.

Delivery of bisphosphonates-like risedronate has been a major challenge till date due to its poor bioavailability and gastrointestinal tract adverse effects. In this study, we explored the prospective use of risedronate functionalised chitosan nanoparticle (RISCN) for management and treatment of osteoporosis. The prepared nanoparticle was characterised by using scanning electron microscopy, atomic force microscopy, and dynamic light scattering technique. Osteoporosis was induced on quarantined female Wistar rats and treated with RISCN. Docking studies were performed to establish the molecular mechanism of RISCN in improving the bone microarchitecture. Results indicated that there was a significant improvement in bone mineral density and healing of trabecular microarchitecture with less cortical porosity on the bone surfaces of the treatment groups. Docking studies indicated a high affinity and binding of chitosan and RISCN towards the human farnesyl diphosphate synthase (FDPS). Thus, a novel risedronate-loaded chitosan nanoparticle revealed promising results in an effective bone bridging process and osteoporosis treatment.

Objective The incidence of osteoporosis is increasing with the rapid aging of the Japanese population. Bisphosphonates are first-line agents used for the treatment of osteoporosis, but they can cause upper gastrointestinal mucosal injury. This study investigated symptoms and upper gastrointestinal mucosal injury associated with oral bisphosphonates. Methods Symptoms were evaluated using the F-scale questionnaire, and esophageal mucosal injury and gastroduodenal ulceration were assessed by endoscopy. Patients were stratified by the type of bisphosphonate (alendronate, risedronate, or minodronate), treatment schedule (once weekly or every four weeks), and the concomitant use of other medications [antithrombotic agents, nonsteroidal anti-inflammatory drugs (NSAIDs), or acid suppressants]. Patients The subjects included 221 patients treated with oral bisphosphonates for at least one month. Results The median F-scale total score was 4 (0-34), reflux score was 2 (0-20), and the mean dyspepsia score was 2 (0-16). Endoscopy showed esophageal mucosal injury of Grade A or worse (Los Angeles classification) in 22/221 patients (10.0%) and gastroduodenal ulcers in 9 patients (4.1%). The dyspepsia score in patients who took minodronate every four weeks was significantly lower (p<0.05) in comparison to patients who took other bisphosphonates. The dyspepsia score was significantly higher (p<0.05) and mucosal injury was significantly more frequent in patients who also used antithrombotic agents and NSAIDs. Conclusion Symptoms and upper gastrointestinal mucosal damage were not necessarily frequent or severe in patients treated with bisphosphonates. However, the concomitant use of bisphosphonates with antithrombotic agents and NSAIDs increased both symptoms and mucosal injury. The symptoms were milder in patients using minodronate once monthly.

In this prospective cohort of 6120 participants aged 50+, nitrogen-bisphosphonates but not non-nitrogen bisphosphonates were associated with a significant 34% mortality risk reduction compared to non-treated propensity score matched controls. These findings open new avenues for research into mechanistic pathways., Introduction: Emerging evidence suggests that bisphosphonates (BP), first-line treatment of osteoporosis, are associated with reduced risks for all-cause mortality. This study aimed to determine the association between different BP types and mortality risk in participants with or without a fracture., Methods: A prospective cohort study of users of different BPs matched to non-users by propensity score (age, gender, co-morbidities, fragility fracture status) and time to starting the BP medication from the population-based Canadian Multicentre Osteoporosis Study from nine Canadian centres followed from 1995 to 2013. Mortality risk for bisphosphonate users vs matched non-users was assessed using pairwise multivariable Cox proportional hazards models., Results: There were 2048 women and 308 men on BP and 1970 women and 1794 men who did not receive medication for osteoporosis. The relationship between BP and mortality risk was explored in three separate 1:1 propensity score-matched cohorts of BP users and no treatment (etidronate, n = 599, alendronate, n = 498, and risedronate n = 213). Nitrogen BP (n-BP) (alendronate and risedronate) was associated with lower mortality risks [pairwise HR, 0.66 (95% CI, 0.48-0.91)] while the less potent non-n-BP, etidronate, was not [pairwise HR: 0.89 (95% CI, 0.66-1.20)]. A direct comparison between n-BP and etidronate (n = 340 pairs) also suggested a better survival for n-BP [paired HR, 0.47 (95%CI, (95% CI, 031-0.70)] for n-BP vs. etidronate]., Conclusion: Compared to no treatment, nitrogen but not non-nitrogen bisphosphonates appear to be associated with better survival.