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Lancet (London, England) Jan 2018No clinical trials have compared osteoporosis drugs with incident fractures as the primary outcome. We compared the anti-fracture efficacy of teriparatide with... (Randomized Controlled Trial)
Randomized Controlled Trial
Effects of teriparatide and risedronate on new fractures in post-menopausal women with severe osteoporosis (VERO): a multicentre, double-blind, double-dummy, randomised controlled trial.
BACKGROUND
No clinical trials have compared osteoporosis drugs with incident fractures as the primary outcome. We compared the anti-fracture efficacy of teriparatide with risedronate in patients with severe osteoporosis.
METHODS
In this double-blind, double-dummy trial, we enrolled post-menopausal women with at least two moderate or one severe vertebral fracture and a bone mineral density T score of less than or equal to -1·50. Participants were randomly assigned to receive 20 μg of teriparatide once daily plus oral weekly placebo or 35 mg of oral risedronate once weekly plus daily injections of placebo for 24 months. The primary outcome was new radiographic vertebral fractures. Secondary, gated outcomes included new and worsened radiographic vertebral fractures, clinical fractures (a composite of non-vertebral and symptomatic vertebral), and non-vertebral fractures. This study is registered with ClinicalTrials.gov (NCT01709110) and EudraCT (2012-000123-41).
FINDINGS
We enrolled 680 patients in each group. At 24 months, new vertebral fractures occurred in 28 (5·4%) of 680 patients in the teriparatide group and 64 (12·0%) of 680 patients in the risedronate group (risk ratio 0·44, 95% CI 0·29-0·68; p<0·0001). Clinical fractures occurred in 30 (4·8%) of 680 patients in the teriparatide group compared with 61 (9·8%) of 680 in the risedronate group (hazard ratio 0·48, 95% CI 0·32-0·74; p=0·0009). Non-vertebral fragility fractures occurred in 25 (4·0%) patients in the teriparatide group and 38 (6·1%) in the risedronate group (hazard ratio 0·66; 95% CI 0·39-1·10; p=0·10).
INTERPRETATION
Among post-menopausal women with severe osteoporosis, the risk of new vertebral and clinical fractures is significantly lower in patients receiving teriparatide than in those receiving risedronate.
FUNDING
Lilly.
Topics: Aged; Aged, 80 and over; Americas; Bone Density; Bone Density Conservation Agents; Double-Blind Method; Europe; Female; Humans; Incidence; Middle Aged; Osteoporosis, Postmenopausal; Osteoporotic Fractures; Radiography; Risedronic Acid; Teriparatide
PubMed: 29129436
DOI: 10.1016/S0140-6736(17)32137-2 -
Bone Aug 2020Herein we review the discovery, development, commercial history and legacy of risedronate or NE-58095, a potent N-containing bisphosphonate developed by scientists at... (Review)
Review
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) and a pyridyl-methylene substituent (R) 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.
Topics: Alendronate; Bone Density; Bone Density Conservation Agents; Diphosphonates; Etidronic Acid; Female; Humans; Male; Osteoporosis, Postmenopausal; Risedronic Acid
PubMed: 32387834
DOI: 10.1016/j.bone.2020.115407 -
Archives of Internal Medicine Feb 2001Risedronate sodium has recently been approved for the prevention and treatment of postmenopausal and corticosteroid-induced osteoporosis. (Review)
Review
BACKGROUND
Risedronate sodium has recently been approved for the prevention and treatment of postmenopausal and corticosteroid-induced osteoporosis.
METHODS
Studies of risedronate were obtained from the MEDLINE database (1966 to the present) of references using risedronate, risedronic acid, osteoporosis, and human subject as keywords. Additional references were sought from the reference lists of the articles obtained.
RESULTS
Nine randomized controlled trials and 7 other clinical trials were obtained. In postmenopausal women with normal bone density, risedronate increases lumbar spine bone density and preserves femoral neck density. In postmenopausal women with prior vertebral fracture, risedronate decreases new vertebral and nonvertebral fracture incidence. In patients who experienced breast cancer and who have chemotherapy-induced menopause, risedronate preserves bone. Risedronate prevents vertebral bone loss in patients beginning long-term corticosteroid therapy. Risedronate decreases pagetic bone pain and induces radiological improvement in pagetic lesions. Risedronate induces normalization of biochemical abnormalities and may be more effective than etidronate disodium for Paget disease. Only one study, a trial in patients with postmenopausal osteoporosis using a low dose (2.5 mg) of risedronate, did not have a positive result. Adverse effects in patients with postmenopausal osteoporosis, breast cancer, and Paget disease and in those taking corticosteroids are similar to those of patients taking placebo, and do not include notable upper gastrointestinal tract adverse event rates or serious adverse events.
CONCLUSIONS
Risedronate prevents postmenopausal bone loss, decreases fracture in those with established postmenopausal osteoporosis, effectively treats Paget disease, and prevents corticosteroid-induced bone loss. Long-term toxic effects and efficacy, particularly fracture end point data, are unknown. Also undefined are optimal duration of therapy, potential for use in combination with other agents, and direct comparison with other bisphosphonates used for osteoporosis.
Topics: Animals; Bone Density; Bone and Bones; Breast Neoplasms; Calcium Channel Blockers; Etidronic Acid; Female; Glucocorticoids; Humans; Osteitis Deformans; Osteoporosis; Osteoporosis, Postmenopausal; Risedronic Acid
PubMed: 11176760
DOI: 10.1001/archinte.161.3.353 -
Modern Rheumatology May 2021No evidence has shown the efficacy of Sodium Risedronate (Risedronate) for glucocorticoid-induced osteoporosis (GIO) in patients with Rheumatoid arthritis (RA). The aim... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and safety of sodium RISedronate for glucocorticoid-induced OsTeoporosis with rheumaTOid arthritis (RISOTTO study): A multicentre, double-blind, randomized, placebo-controlled trial.
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], < .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.
Topics: Aged; Arthritis, Rheumatoid; Bone Density; Bone Density Conservation Agents; Double-Blind Method; Female; Glucocorticoids; Humans; Lumbar Vertebrae; Male; Middle Aged; Osteoporosis; Risedronic Acid
PubMed: 32820698
DOI: 10.1080/14397595.2020.1812835 -
Journal of Clinical Rheumatology :... Jun 2010In most cases bisphosphonates are the first choice therapy for osteoporosis. We present a case of acute arthritis associated with once-weekly risedronate in a...
In most cases bisphosphonates are the first choice therapy for osteoporosis. We present a case of acute arthritis associated with once-weekly risedronate in a 58-year-old woman with osteoporosis. She developed arthritis 48 hours after the second dose of oral risedronate with elevated serum acute-phase reactants. There was no evidence of rheumatoid arthritis or seronegative arthritis. Her symptoms resolved rapidly with rest, however, recurred after the patient was rechallenged with the same drug 1 week later. Although the mechanism of this potential side effect remains speculative, it is thought to be as a result of the proinflammatory properties of aminobisphosphonates. With the increasing use of bisphosphonates in the treatment and prevention of osteoporosis, physicians should be well aware of this possible side effect of these drugs.
Topics: Bone Density Conservation Agents; Etidronic Acid; Female; Humans; Middle Aged; Osteoarthritis; Osteoporosis, Postmenopausal; Risedronic Acid
PubMed: 20414126
DOI: 10.1097/RHU.0b013e3181dfbb15 -
Drug Delivery Dec 2023Sugarcane bagasse-derived nanofibrillated cellulose (NFC), a type of cellulose with a fibrous structure, is potentially used in the pharmaceutical field. Regeneration of...
Sugarcane bagasse-derived nanofibrillated cellulose (NFC), a type of cellulose with a fibrous structure, is potentially used in the pharmaceutical field. Regeneration of this cellulose using a green process offers a more accessible and less ordered cellulose II structure (amorphous cellulose; AmC). Furthermore, the preparation of cross-linked cellulose (NFC/AmC) provides a dual advantage by building a structural block that could exhibit distinct mechanical properties. 3D aerogel scaffolds loaded with risedronate were prepared in our study using NFC or cross-linked cellulose (NFC/AmC), then combined with different concentrations of chitosan. Results proved that the aerogel scaffolds composed of NFC and chitosan had significantly improved the mechanical properties and retarded drug release compared to all other fabricated aerogel scaffolds. The aerogel scaffolds containing the highest concentration of chitosan (SC-T3) attained the highest compressive strength and mean release time values (415 ± 41.80 kPa and 2.61 ± 0.23 h, respectively). Scanning electron microscope images proved the uniform highly porous microstructure of SC-T3 with interconnectedness. All the tested medicated as well as unmedicated aerogel scaffolds had the ability to regenerate bone as assessed using the MG-63 cell line, with the former attaining a higher effect than the latter. However, SC-T3 aerogel scaffolds possessed a lower regenerative effect than those composed of NFC only. This study highlights the promising approach of the use of biopolymers derived from agro-wastes for tissue engineering.
Topics: Risedronic Acid; Cellulose; Chitosan; Saccharum; Bone Regeneration
PubMed: 36474425
DOI: 10.1080/10717544.2022.2152135 -
AAPS PharmSciTech Jul 2021Risedronate sodium (RS) is a potent nitrogen-containing bisphosphonate which is known to induce osteoclast apoptosis. As a drug repurposing approach, the current work...
Risedronate sodium (RS) is a potent nitrogen-containing bisphosphonate which is known to induce osteoclast apoptosis. As a drug repurposing approach, the current work explored the potential of nebulizable RS-chitosan (CS) microspheres to induce alveolar macrophage apoptosis. RS-CS microspheres were assessed for lung deposition, cytotoxicity, and cellular uptake percentage in Calu-3 cells. The potential of nebulizable microspheres for treating elastase-induced emphysema in rats was investigated, compared to RS marketed oral tablets®, with respect to histopathological, immunohistochemical, and flow cytometric studies. The in vitro lung deposition pattern suggested deep alveolar deposition of RS microspheres, with respect to high FPF% and suitable MMAD (66% and 1.506 μm, respectively, at a flow rate of 28.3 L min). No apparent cytotoxicity was observed, with a cell viability > 90%. The inhalation of RS-CS microspheres was suggested to inhibit airspace enlargement and lung rarefaction after elastase instillation and reduce the macrophage accumulation in alveolar parenchyma. Immunohistochemical and cytometric analyses revealed significant low expression levels of CD68 and CD11b surface markers, respectively, with significantly (P < 0.05) lower detected numbers of intact alveolar macrophages following inhalation of RS-CS microspheres. The nebulization of RS-CS microspheres could induce apoptosis in alveolar macrophages and be promisingly adopted for attenuation of pulmonary emphysema.
Topics: Animals; Apoptosis; Lung; Macrophages, Alveolar; Microspheres; Nebulizers and Vaporizers; Pulmonary Emphysema; Rats; Risedronic Acid
PubMed: 34235597
DOI: 10.1208/s12249-021-02078-8 -
Yonsei Medical Journal Mar 2010The purpose of the present study was to discuss the effects of risedronate on osteoarthritis (OA) of the knee by reviewing the existing literature. The literature was... (Review)
Review
The purpose of the present study was to discuss the effects of risedronate on osteoarthritis (OA) of the knee by reviewing the existing literature. The literature was searched with PubMed, with respect to prospective, double-blind, randomized placebo-controlled trials (RCTs), using the following search terms: risedronate, knee, and osteoarthritis. Two RCTs met the criteria. A RCT (n = 231) showed that risedronate treatment (15 mg/day) for 1 year improved symptoms. A larger RCT (n = 1,896) showed that risedronate treatment (5 mg/day, 15 mg/day, 35 mg/week, and 50 mg/week) for 2 years did not improve signs or symptoms, nor did it alter radiological progression. However, a subanalysis study (n = 477) revealed that patients with marked cartilage loss preserved the structural integrity of subchondral bone by risedronate treatment (15 mg/day and 50 mg/week). Another subanalysis study (n = 1,885) revealed that C-terminal crosslinking telopeptide of type II collagen (CTX-II) decreased with risedronate treatment in a dose-dependent manner, and levels reached after 6 months were associated with radiological progression at 2 years. The results of these RCTs show that risedronate reduces the marker of cartilage degradation (CTX-II), which could contribute to attenuation of radiological progression of OA by preserving the structural integrity of subchondral bone. The review of the literature suggests that higher doses of risedronate (15 mg/day) strongly reduces the marker of cartilage degradation (CTX-II), which could contribute to attenuation of radiological progression of OA by preserving the structural integrity of subchondral bone.
Topics: Animals; Calcium Channel Blockers; Cartilage; Diphosphonates; Etidronic Acid; Humans; Osteoarthritis, Knee; Risedronic Acid
PubMed: 20191005
DOI: 10.3349/ymj.2010.51.2.164 -
Life Sciences Nov 2022This study aims at formulating combined delivery of Risedronate sodium (RIS) and Vitamin D3 (VITD3) for augmented therapeutic outcome against osteoporosis (OP) using...
Efficient lung-targeted delivery of risedronate sodium/vitamin D3 conjugated PAMAM-G5 dendrimers for managing osteoporosis: Pharmacodynamics, molecular pathways and metabolomics considerations.
AIMS
This study aims at formulating combined delivery of Risedronate sodium (RIS) and Vitamin D3 (VITD3) for augmented therapeutic outcome against osteoporosis (OP) using deep lung targeted PAMAM-G5-NH dendrimers to minimize RIS gastrointestinal side effects and enhance both drugs bioavailability through absorption from the alveoli directly to the blood.
METHODS
RIS-PAMAM-G5-NH, VITD3-PAMAM-G5-NH, and RIS/VITD3-PAMAM-G5-NH were prepared and evaluated in vitro for particle size (PS), zeta potential (ZP), %loading efficiency (%LE), morphology and FTIR. The efficacy of the RIS/VITD3-PAMAM-G5-NH compared to oral RIS was evaluated in OP-induced rats by comparing serum calcium, phosphorus, and computed bone mineral density (BMD) pre- and post-treatment. Additionally, a comprehensive metabolomics and molecular pathways approach was applied to find serum potential biomarkers for diagnosis and to evaluate the efficacy of inhaled RIS/VITD3-PAMAM-G5-NH.
KEY FINDINGS
RIS/VITD3-PAMAM-G5-NH was successfully prepared with a %LE of 92.4 ± 6.7 % (RIS) and 83.2 ± 4.4 % (VIT-D3) and a PS of 252.8 ± 34.1 adequate deep lung delivery. RIS/VITD3-PAMAM-G5-NH inhalation therapy was able to restore serum calcium, phosphorus, and BMD close to normal levels after 21 days of treatment in OP-induced rats. The WNT-signalling pathway and changes in the metabolite levels recovered to approximately normal levels upon treatment. Moreover, histone acetylation of the WNT-1 gene and miR-148a-3p interference proved to play a role in the regulation of the WNT-signalling pathway during OP progression and treatment.
SIGNIFICANCE
Pulmonary delivery of RIS/VITD3-PAMAM-G5-NH offers superior treatment for OP treatment compared to the oral route. Molecular and Metabolic pathways represents key indicators for OP diagnosis and progression.
Topics: Rats; Animals; Dendrimers; Risedronic Acid; Cholecalciferol; Calcium; Histones; Osteoporosis; Metabolomics; Lung; Phosphorus; MicroRNAs
PubMed: 36174709
DOI: 10.1016/j.lfs.2022.121001 -
Materials Science & Engineering. C,... Jun 2016Targeting of superior osteogenic drugs to bone is an ideal approach for treatment of osteoporosis. Here, we investigated the potential of using...
Targeting of superior osteogenic drugs to bone is an ideal approach for treatment of osteoporosis. Here, we investigated the potential of using risedronate/zinc-hydroxyapatite (ZnHA) nanoparticles based formulation in a rat model of experimental osteoporosis. Risedronate, a targeting moiety that has a strong affinity for bone, was loaded to ZnHA nanoparticles by adsorption method. Prepared risedronate/ZnHA drug formulation was characterized by field-emission scanning electron microscopy, X-ray diffraction analysis and fourier transform infrared spectroscopy. In vivo performance of the prepared risedronate/ZnHA nanoparticles was tested in an experimental model of postmenopausal osteoporosis. Therapy with risedronate/ZnHA drug formulation prevented increase in serum levels of bone-specific alkaline phosphatase and tartrate-resistant acid phosphatase 5b better than risedronate/HA or risedronate. With respect to improvement in the mechanical strength of the femoral mid-shaft and correction of increase in urine calcium and creatinine levels, the therapy with risedronate/ZnHA drug formulation was more effective than risedronate/HA or risedronate therapy. Moreover, risedronate/ZnHA drug therapy preserved the cortical and trabecular bone microarchitecture better than risedronate/HA or risedronate therapy. Furthermore, risedronate/ZnHA drug formulation showed higher values of calcium/phosphorous ratio and zinc content. The results strongly implicate that risedronate/ZnHA drug formulation has a therapeutic advantage over risedronate or risedronate/HA therapy for the treatment of osteoporosis.
Topics: Alkaline Phosphatase; Animals; Bone Density Conservation Agents; Bone and Bones; Calcium; Creatinine; Disease Models, Animal; Drug Carriers; Durapatite; Nanomedicine; Nanoparticles; Osteoporosis; Rats; Rats, Wistar; Risedronic Acid; Tartrate-Resistant Acid Phosphatase; X-Ray Diffraction; X-Ray Microtomography; Zinc
PubMed: 27040198
DOI: 10.1016/j.msec.2016.02.062