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], 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.

Efficacy of combined medication of risedronate sodium and selective estrogen receptor modulator on the postmenopausal osteoporosis.

To evaluate the efficacy of combined medication of risedronate sodium and raloxifene, a selective estrogen receptor modulator (SERM) on the postmenopausal osteoporosis (PMOP). PMOP patients underwent the combined medication of risedronate sodium and raloxifene (SERM, Treatment group), or only medication of risedronate sodium (Control group). After medication, more significant increases were observed in the bone densities of the lumber vertebra (L1-4) and the neck of left femur of patients in the treatment group. Simultaneously, the levels of estrogen and progesterone in serum decreased sharply in the treatment group. After treatment, P1NP and ß-CTX levels in serum decreased significantly in two groups in comparison with the levels prior to treatment, with evident elevations in the levels of BAP and BGP; similarly, ameliorations in the treatment group were much more evident than those in the control group. In addition, significant declines were identified in the VAS scores of two groups after treatment when comparing to the scores prior to the treatment, and the decline in the treatment group was more evident than that in the control group. Combined medication of risedronate sodium and SERM (raloxifene) performs better in treatment of osteoporosis than the single use of risedronate sodium, without the deterioration of adverse effect of medication.

Novel combinatorial transdermal drug delivery of alendronate with risedronate for the treatment of osteoporosis.

The presented investigation explores the efficiency of novel transdermal drug delivery system of combination of two drugs i.e risedronate and alendronate in the treatment of osteoporosis. The nanoparticulate transdermal patch was prepared using PLGA as principle polymer which has been found to be suitable for drug delivery. The novel formulation system was found to be more efficient in lowering and maintaining the plasma calcium at a normal level when compared to a pure drug in a study carried out on an excised rat skin.

QbD Approach for Novel Crosslinker-Free Ionotropic Gelation of Risedronate Sodium-Chitosan Nebulizable Microspheres: Optimization and Characterization.

Risedronate sodium (RS) is a potent inhibitor of bone resorption, having an extreme poor permeability and limited oral bioavailability (0.62%). RS should be orally administered under fasting conditions while keeping in an upright posture for at least 30 min to diminish common gastroesophageal injuries. To surmount such limitations, novel risedronate-chitosan (RS-CS) crosslinker-free nebulizable microspheres were developed adopting the quality by design (QbD) approach and risk assessment (RA) thinking. RS:CS ratio, surfactant (Pluronic® F127) concentration, homogenization duration, speed, and temperature were identified using Ishikawa diagrams as the highest formulation and process risk factors affecting the critical quality attributes (CQAs), average particle size (PS), and entrapment efficiency (EE%). The risk factors were screened using the Plackett-Burman design, and the levels of the most significant factors were optimized using a multilevel factorial design to explore the optimized system with the least PS, maximum EE%, and a prolonged drug release profile. The optimized system (B6) was developed at a RS:CS ratio of 1:7, a surfactant concentration of 2% (w/v), and a homogenization speed of 14,000 rpm. It revealed good correlation with QbD theoretical prediction, where positively charged (47.9 ± 3.39 mV) discrete, spherical microspheres (3.47 ± 0.16 µm) having a high EE% (94.58 ± 0.19%) and prolonged RS release over 12 h (Q12 h, 89.70 ± 0.64%) were achieved. In vivo lung deposition after intratracheal instillation of B6 confirmed the delivery of high RS percentage to rat lung tissues (87 ± 3.54%) and its persistence for 24 h. This investigation demonstrated the effectiveness of QbD philosophy in developing RS-CS crosslinker-free nebulizable microspheres.

Efficacy of risedronate with cholecalciferol on bone mineral density in Korean patients with osteoporosis.

The efficacy of once-weekly risedronate with and without cholecalciferol in bone mineral density (BMD) in Korean patients with osteoporosis was compared. After 12 months, both spine and hip BMD increased significantly in both groups, but there was no significant difference between two groups. INTRODUCTION: This study investigated the efficacy and safety of once-weekly risedronate with and without cholecalciferol in BMD in Korean patients with osteoporosis. METHODS: This was a prospective, 12-month, randomized, open-labeled, actively controlled trial involving 41 hospitals. A total of 841 subjects with osteoporosis were randomized to once-weekly risedronate (35 mg) and cholecalciferol (5600 IU) in a single pill (RSD+, n = 642) or once-weekly risedronate (35 mg) alone (RSD, n = 199). BMD was measured via dual-energy X-ray absorptiometry at the lumbar spine and hip, and the serum levels of 25-hydroxy vitamin D (25(OH) D), parathyroid hormone (PTH), and alkaline phosphatase (ALP) were assayed at baseline and after 12 months of treatment. RESULTS: After 12 months, the lumbar spine, femoral neck, and total hip BMD increased significantly in both groups; there was no significant difference between two groups. Women in the RSD+ group exhibited significantly increased lumbar spine BMD, and subjects with previous fracture history in the RSD+ group had significantly increased total hip BMD compared with the RSD group. The serum 25(OH) D level increased significantly in the RSD+ group. The serum PTH level decreased in the RSD+ group but increased in the RSD group. The serum ALP level significantly decreased in both groups; there was no significant difference between two groups. CONCLUSIONS: A once-weekly pill containing risedronate and cholecalciferol had the equivalent antiresorptive efficacy on BMD compared with risedronate alone and improved 25(OH) D serum levels after 12 months of treatment without significant adverse events in Korean patients with osteoporosis.

Safety and efficacy of risedronate for patients with esophageal varices and liver cirrhosis: a non-randomized clinical trial.

Despite the high prevalence of osteoporosis in liver cirrhosis, the indication of bisphosphonates for patients with esophageal varices has been avoided due to risk of digestive mucosal damage. Therefore, this study aimed to evaluate the safety profile of risedronate treatment for patients with osteoporosis, liver cirrhosis and esophageal varices with low risk of bleeding. A total of 120 patients were allocated into two groups according to their bone mineral density measured by dual-energy X-ray absorptiometry. In the intervention group, 57 subjects with osteoporosis received oral risedronate at 35 mg weekly plus daily calcium and vitamin D supplementation. In the control group, 63 subjects with osteopenia received only calcium and vitamin D. The groups received the treatment for one year and underwent surveillance endoscopies at six and 12 months, as well as a control dual-energy X-ray absorptiometry after a 12-month follow-up. The study received Institutional Review Board approval. The groups had not only comparable Model for End-stage Liver Disease score and esophageal varices degree, but also similar incidence of digestive adverse effects. A significant improvement was achieved in the intervention group in the lumbar spine T score (p < 0.001). The results suggest that risedronate may be safely used in liver cirrhosis and esophageal varices with low bleeding risk under endoscopic surveillance, thus allowing bone mass recovery.

Reduced Bone Loss Is Associated With Reduced Mortality Risk in Subjects Exposed to Nitrogen Bisphosphonates: A Mediation Analysis.

Bisphosphonates, potent antiresorptive agents, have been found to be associated with mortality reduction. Accelerated bone loss is, in itself, an independent predictor of mortality risk, but the relationship between bisphosphonates, bone loss, and mortality is unknown. This study aimed to determine whether the association between bisphosphonates and mortality is mediated by a reduction in the rate of bone loss. Participants from the population-based Canadian Multicentre Osteoporosis Study were followed prospectively between1996 and 2011. Comorbidities and lifestyle factors were collected at baseline and bone mineral density (BMD) at baseline and at years 3 (for those aged 40 to 60 years), 5, and 10. Rate of bone loss was calculated using linear regression. Information on medication use was obtained yearly. Bisphosphonate users grouped into nitrogen bisphosphonates (nBP; alendronate or risedronate) and etidronate and non-users (NoRx) were matched by propensity score, including all baseline factors as well as time of treatment. Cox's proportional hazards models, unadjusted and adjusted for annual rate of bone loss, were used to determine the association between nBP and etidronate versus NoRx. For the treatment groups with significant mortality risk reduction, the percent of mortality reduction mediated by a reduction in the rate of bone loss was estimated using a causal mediation analysis. There were 271 pairs of nBP and matched NoRx and 327 pairs of etidronate and matched NoRx. nBP but not etidronate use was associated with significant mortality risk reduction (hazard ratios [HR] = 0.61 [95% confidence interval 0.39-0.96] and 1.35 [95% CI 0.86-2.11] for nBP and etidronate, respectively). Rapid bone loss was associated with more than 2-fold increased mortality risk compared with no loss. Mediation analysis indicated that 39% (95% CI 7%-84%) of the nBP association with mortality was related to a reduction in the rate of bone loss. This finding provides an insight into the mechanism of the relationship between nBP and survival benefit in osteoporotic patients. © 2019 American Society for Bone and Mineral Research.

Improved treatment efficacy of risedronate functionalized chitosan nanoparticles in osteoporosis: formulation development, in vivo, and molecular modelling studies.

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.

Anionic versus cationic bilosomes as oral nanocarriers for enhanced delivery of the hydrophilic drug risedronate.

Albeit its well known potency as a postmenopausal osteoporosis treatment, Risedronate suffers from poor oral bioavailability and high oral toxicity. This is the first work to assess the potential of bilosomes to address challenges of RS oral delivery. Furthermore, impact of integrating cationic moiety into bilosomes on intestinal digestability and toxicity of RS nanovesicles was first investigated in this article. Prepared formulations were optimized based on physicochemical properties, digestibility, intestinal permeation and local toxicity studies. Optimized preparations were prepared by reversed phase evaporation technique with three extrusion cycles and loaded by 10 mg/ml RS. Molar lipid to bile salt to cholesterol ratio was adjusted to 4:1:1 at pH 5. Addition of cholesterol had significantly improved bilosomes stability to digestive media. Results also revealed that permeation of anionic vesicles increased permeation by 1.5 times more than RS solution and reduced drug toxicity by 2 folds. On the other hand, Cationic bilosomes showed good stability in GIT fluids but their induced oral toxicity could limit their use. In conclusion, bilosomes are superior over liposomes regarding protection of delivery system from the damaging effect of external in digestive bile salts. In addition, it decreases toxicity issues of orally administered drugs.

Predictive and modifying factors of bone mineral density decline in patients with COPD.

RATIONALE: Various determinants of osteoporosis have been previously identified. However, only a few longitudinal studies have examined related factors. We aimed to investigate factors predicting and modifying rapid decline of bone mineral density in patients with chronic obstructive pulmonary disease. METHODS: We analyzed patients with chronic obstructive pulmonary disease whose bone mineral density were measured at least three times over three years (n = 111). We divided annual per cent changes of bone mineral density in different body parts into tertiles. Rapid decliners (n = 33) were defined as those with the largest decline in at least two parts; all other participants were defined as non-rapid decliners (n = 78). RESULTS: At enrollment, bone mineral density did not differ between the two groups. However, rapid decliners had a significantly greater rate of new vertebral fractures over 3 years compared with non-rapid decliners. On multivariate logistic regression analysis, age, moderate to severe emphysema, no daily exercise habits, and anemia increased the likelihood of rapid decliners. Furthermore, patients who newly started and continued bisphosphonate exhibited higher annual per cent changes of bone mineral density than did those without bisphosphonate use. CONCLUSIONS: A rapid decline in bone mineral density correlates to a higher likelihood of vertebral fracture. We clarified the predictors of bone mineral density decline and demonstrated that bisphosphonate use might modify bone mineral density in patients with chronic obstructive pulmonary disease.

Cost-effectiveness of gastro-resistant risedronate tablets for the treatment of postmenopausal women with osteoporosis in France.

The use of gastro-resistant risedronate, a convenient dosing regimen for oral bisphosphonate therapy, seems a cost-effective strategy compared with weekly alendronate, generic risedronate, and no treatment for the treatment of postmenopausal women with osteoporosis in France. INTRODUCTION: Gastro-resistant (GR) risedronate tablets are associated with improved persistence compared to common oral bisphosphonates but are slightly more expensive. This study assessed its cost-effectiveness compared to weekly alendronate and generic risedronate for the treatment of postmenopausal women with osteoporosis in France. METHODS: A previously validated Markov microsimulation model was used to estimate the lifetime costs (expressed in €2017) per quality-adjusted life-years (QALY) of GR risedronate compared with weekly alendronate, generic risedronate, and no treatment. Pooled efficacy data for bisphosphonates derived from a previous meta-analysis were used for all treatment options, and persistence data (up to 3 years) were obtained from a large Australian longitudinal study. Evaluation was done for high-risk women 60-80 years of age, with a bone mineral density (BMD) T-score ≤ - 2.5 and/or prevalent vertebral fractures. RESULTS: In all of the simulated populations, GR risedronate was cost-effective compared to alendronate, generic risedronate, and no treatment at a threshold of €60,000 per QALY gained. In women with a BMD T-score ≤ - 2.5 and prevalent vertebral fractures, the cost per QALY gained of GR risedronate compared to alendronate, generic risedronate, and no treatment falls below €20,000 per QALY gained. In women aged 75 years and older, GR risedronate was even shown to be dominant (more QALYs, less costs) compared to alendronate, generic risedronate, and no treatment. CONCLUSION: This study provides the first economic results about GR risedronate, suggesting that it represents a cost-effective strategy compared with weekly alendronate and generic risedronate for the treatment of postmenopausal women with osteoporosis in France.

Risedronate-Loaded Macroporous Gel Foam Enriched with Nanohydroxyapatite: Preparation, Characterization, and Osteogenic Activity Evaluation Using Saos-2 Cells.

The application of minimally invasive surgical techniques in the field of orthopedic surgery has created a growing need for new injectable synthetic materials that can be used for bone grafting. In this work, novel injectable thermosensitive foam was developed by mixing nHAP powder with a thermosensitive polymer with foaming power (Pluronic F-127) and loaded with a water-soluble bisphosphonate drug (risedronate) to promote osteogenesis. The foam was able to retain the porous structure after injection and set through temperature change of PF-127 solution to form gel inside the body. The effect of different formulation parameters on the gelation time, porosity, foamability, injectability, and in vitro degradation in addition to drug release from the prepared foams were analyzed using a full factorial design. The addition of a co-polymer like methylcellulose or sodium alginate into the foam was also studied. Results showed that the prepared optimized thermosensitive foam was able to gel within 1 min at 37°C, and sustain the release of drug for 72 h. The optimized formulation was further tested for any interactions using DSC and IR, and revealed no interactions between the drug and the used excipients in the prepared foam. Furthermore, the ability of the pre-set foam to support osteoblastic-like Saos-2-cell proliferation and differentiation was assessed, and revealed superior function on promoting cellular proliferation as confirmed by fluorescence microscope compared to the plain drug solution. The activity of the foam treated cells was also assessed by measuring the alkaline phosphatase activity and calcium deposition, and confirmed that the cellular activity was greatly enhanced in foam treated cells compared to those treated with the plain drug solution only. The obtained results show that the prepared risedronate-loaded thermosensitive foam would represent a step forward in the design of new materials for minimally invasive bone regeneration.

Bioactive injectable triple acting thermosensitive hydrogel enriched with nano-hydroxyapatite for bone regeneration: in-vitro characterization, Saos-2 cell line cell viability and osteogenic markers evaluation.

Hydrogels forming in-situ have gained great attention in the area of bone tissue engineering recently, they were also showed to be a good and less invasive alternative to surgically applied ones. The primal focus of this study was to prepare chitosan-glycerol phosphate thermosensitive hydrogel formed in-situ and loaded with risedronate (bone resorption inhibitor) in an easy way with no requirement of complicated processes or large number of equipment. Then we investigated its effectiveness for bone regeneration. In-situ forming hydrogels were prepared using chitosan cross-linked with glycerol phosphate and loaded with risedronate and nano-hydroxyapatite as bone cement. The prepared hydrogels were characterized by analyzing their gelation time at 37 °C, % porosity, swelling index, in-vitro degradation, rheological properties, and in-vitro drug release. Results showed that the in-situ hydrogels prepared using 2.5% (w/v) chitosan cross-linked with 50% (w/v) glycerol phosphate in the ratio (9:1, v/v) reinforced with 20 mg/mL and nano-hydroxyapatite possessed the most sustained drug release profile. This optimized formulation was further evaluated using DSC and FTIR studies, in addition to their morphological properties using scanning electron microscopy. The effect on Saos-2 cell line viability was evaluated also using MTT assay on the optimized hydrogel formulation in addition to their action on cell proliferation using fluorescence microscope. Moreover, calcium deposition on the hydrogel and alkaline phosphatase activity were evaluated. Risedronate-nano-hydroxyapatite loaded hydrogels significantly enhanced the Saos-2 cell proliferation in addition to enhanced alkaline phosphatase activity and calcium deposition. Such results suggest that risedronate-nano-hydroxyapatite loaded hydrogels present great biocompatibility for bone regeneration. Proliferation of cells, as well as deposition of mineral on the hydrogel, was an evidence of the biocompatible nature of the hydrogel. This hydrogel formed in-situ present a good less invasive alternative for bone tissue engineering.

Prevalence and Characteristics of Atypical Periprosthetic Femoral Fractures.

Bisphosphonate use has been associated with atypical femoral fractures (AFFs), defined by the American Society of Bone and Mineral Research (ASBMR) Task Force criteria, which currently exclude periprosthetic fractures. The objectives of this study were to establish the prevalence of atypical periprosthetic femoral fractures (APFFs) in patients with hip and knee arthroplasties and to determine the clinical and radiological risk factors associated with these fractures. We performed a retrospective radiological review of all femoral fractures between January 1, 2006, and March 31, 2015, in Quebec City, Canada. Patients who sustained a periprosthetic femoral fracture (PFF) were identified and included in this study. We used the ASBMR Task Force criteria to identify atypical fractures and establish their prevalence. Data from medical records and radiological assessments of the femoral anatomy, the characteristics of the fracture, and the positioning of the prosthesis were collected. The prevalence of APFFs among PFFs was 8.3% (11/133). A strong association with bisphosphonates (p = 0.007) was observed, as well as an increased risk of APFFs among alendronate users compared to risedronate users (p = 0.04). A transverse fracture (p < 0.0001), a periosteal thickening of the lateral cortex at the fracture (p < 0.0001), a unicortical fracture (p = 0.02), and prodromal symptoms (p = 0.03) were associated with APFFs. The type of implant, its positioning, and the femoral geometry did not appear to be risk factors for APFFs compared to PFFs. © 2018 American Society for Bone and Mineral Research.

Long-term control of Paget's disease of bone with low-dose, once-weekly, oral bisphosphonate preparations, in a "real world" setting.

PURPOSE: Bisphosphonates are the mainstay of the treatment of Paget's disease of bone (PDB). Clinical practice guidelines recommend treatment with intravenous zoledronic acid or high-dose oral nitrogen bisphosphonates (N-BPs). We present our long-term experience treating PDB patients with lower than recommended oral doses of N-BPs, equivalent to once-weekly doses used for treating osteoporosis. METHODS: PDB patients were seen, between 1990 and 2015 at the endocrine clinic of an academic medical center. Diagnosis was established according to accepted criteria. Patients were initially treated with alendronate 70 mg/week or risedronate 35 mg/week. Whenever the initial dose failed to produce remission, the dosage was increased to twice a week the respective dose. RESULTS: Patients were followed for a mean of 11.9 years (range: 1.7-24.8). Out of 96 treatment courses with N-BPs, 89% were with alendronate and 11% with risedronate. Remission was achieved in 84% of the courses with alendronate 70 mg/week. 90% of those who did not achieve remission subsequently responded to 140 mg/week. Out of the 8 treatment courses with risedronate 35 mg/week, 87% achieved remission, and the 2 patients who did not achieve remission subsequently responded to 70 mg/week. The median duration of remissions following 3-4 months courses of alendronate 70 mg/week or risedronate 35 mg/week was 8.8 months (IQR: 5.5, 14.8). CONCLUSION: In a large proportion of "real world" PDB patients, remission can be achieved with once-weekly, "osteoporosis doses" of alendronate or risedronate.

Comparison of the efficacy between once-monthly oral ibandronate and risedronate among Korean women with osteoporosis: a nationwide population-based study.

Using a nationwide database from the Korean National Health Insurance Service, this study showed that once-monthly oral ibandronate (150 mg) had better anti-fracture efficacy than once-monthly oral risedronate (150 mg), as seen on assessing overall and non-vertebral fractures among Korean elderly women with osteoporosis. INTRODUCTION: Once-monthly oral bisphosphonates have been used widely without appropriate comparison. Therefore, we aimed to compare the anti-fracture efficacy of once-monthly ibandronate (150 mg) and once-monthly risedronate (150 mg). METHODS: We conducted a retrospective cohort study among Korean women aged ≥ 60 years from 2006 to 2015 using a nationwide database from the National Health Insurance Service Senior Cohort. The primary outcome was the first occurrence of fracture related to osteoporosis after the initial prescription of bisphosphonates. A Cox proportional model was used to estimate the incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for overall and site-specific fractures between the two treatments, after adjusting for possible confounding factors. RESULTS: After propensity score matching, the ibandronate and risedronate groups, with 3454 patients each, were assembled from 36,701 new once-monthly ibandronate or risedronate users. After 4 years of follow-up, the ibandronate group had significantly lower incidence rates of overall and non-vertebral fractures than the risedronate group (IRR 0.822, 95% CI 0.698-0.968, P = 0.919 and IRR 0.798, 95% CI 0.647-0.985, P = 0.036, respectively). CONCLUSIONS: Once-monthly ibandronate (150 mg) shows better anti-fracture efficacy than once-monthly risedronate (150 mg). However, further large-scale studies are required to confirm our findings and to determine site-specific differences, especially regarding the vertebral and hip areas.

Efficacy and safety of once-monthly risedronate in osteoporosis subjects with mild-to-moderate chronic kidney disease: a post hoc subgroup analysis of a phase III trial in Japan.

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 m2). 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.

Decreased intramuscular calcium hydroxyapatite implant resorption in a murine model of osteoporosis.

OBJECTIVE: Calcium hydroxyapatite (CaHA) is a common material for vocal fold injection augmentation. Durability is variable, and factors involved in implant longevity are not understood. Animal models of osteoporosis show decreased bone density and increased mineral liberation, suggesting CaHA retention may be altered in these conditions. STUDY DESIGN: Prospective murine investigation. METHODS: Fourteen skeletally mature, 10-month-old female Sprague-Dewley rats were treated by one of three interventions: oophorectomy, laparotomy without oophorectomy (sham), or monthly risedronate injection (90 µg/kg, subcutaneous). CaHA was implanted into the right lateral thigh muscle in all animals at the time of procedure or first risedronate injection. After 17 weeks, all rats were sacrificed, and the residual CaHA isolated from excised lateral thigh muscle through incubation in a 900 °C calcinator for 9 hours. RESULTS: Mean CaHA mass remaining in the oophorectomy group was 65.9 (standard deviation ± 16.1) mg, compared to 44.4 ± 10.0 mg CaHA in the risedronate group and 48.6 ± 7.5 mg in the sham group. One-way analysis of variance found a statistically significant difference between the oophorectomy and risedronate groups but not between the sham and other groups, F(2,11) = 4.404, P = 0.039. CONCLUSION: Persistent estrogen deficiency in a murine model of osteoporosis demonstrated decreased rate of CaHA resorption. This suggests that hormone alterations associated with osteoporosis may alter the longevity of CaHA implant resorption through an uncertain mechanism. LEVEL OF EVIDENCE: NA. Laryngoscope, 2576-2580, 2018.

Efficacy of discontinuing risedronate for patients with systemic lupus erythematosus: a prospective study.

Objective The objective of this study is to investigate the effectiveness of discontinuation of risedronate for patients with systemic lupus erythematosus (SLE) treated with glucocorticoid (GC). Methods The participants were patients with SLE treated with prednisolone (PSL) ≥ 2 mg/day and risedronate for at least three years. Lumbar spine and total hip bone mineral density (BMD) measurements were taken at baseline and 24 and 48 weeks after discontinuation of risedronate, and bone turnover markers were evaluated at baseline, 12, 24, 36, and 48 weeks. Results A total of 36 patients were enrolled, 25 of whom discontinued risedronate. The mean age was 46.8 ± 11.2 years, and 23 were female. The mean duration of GC treatment was 14.8 ± 11.4 years, the mean dose of PSL was 7.8 ± 3.9 mg/day, and the mean duration of risedronate was 5.8 ± 2.4 years. Seventeen patients showed decreased lumbar spine BMD at 48 weeks after discontinuation of risedronate, with a mean lumbar spine lumbar decrease of 1.42% ± 3.20% ( p = 0.034); 17 patients (71%) showed a decreased total hip BMD at 48 weeks after discontinuation of risedronate, with a mean total hip BMD decrease of 0.99% ± 2.10% ( p = 0.021). Serum tartrate-resistant acid phosphatase 5b (TRACP-5b) ≥ 309 mU/dl at baseline was a risk factor for decreased total hip BMD at 48 weeks compared with serum TRACP-5b < 309 mU/dl (56% vs 0%, p = 0.0098). One patient developed a clinical fracture of the lumbar spine at 20 weeks. Conclusions Discontinuation of risedronate treatment in patients with SLE who had received GC therapy led to decreases in lumbar spine and total hip BMD, particularly in patients with high baseline serum TRACP-5b levels.

Star-shaped poly(oligoethylene glycol) copolymer-based gels: Thermo-responsive behaviour and bioapplicability for risedronate intranasal delivery.

The aim of this work was to obtain an intranasal delivery system with improved mechanical and mucoadhesive properties that could provide prolonged retention time for the delivery of risedronate (RS). For this, novel in situ forming gels comprising thermo-responsive star-shaped polymers, utilizing either polyethylene glycol methyl ether (PEGMA-ME 188, Mn 188) or polyethylene glycol ethyl ether (PEGMA-EE 246, Mn 246), with polyethylene glycol methyl ether (PEGMA-ME 475, Mn 475), were synthesized and characterized. RS was trapped in the selected gel-forming solutions at a concentration of 0.2% w/v. The pH, rheological properties, in vitro drug release, ex vivo permeation as well as mucoadhesion were also examined. MTT assays were conducted to verify nasal tolerability of the developed formulations. Initial in vivo studies were carried out to evaluate anti-osteoporotic activity in a glucocorticoid induced osteoporosis model in rats. The results showed successful development of thermo-sensitive formulations with favorable mechanical properties at 37 °C, which formed non-irritant, mucoadhesive porous networks, facilitating nasal RS delivery. Moreover, sustained release of RS, augmented permeability and marked anti-osteoporotic efficacy as compared to intranasal (IN) and intravenous (IV) RS solutions were realized. The combined results show that the in situ gels should have promising application as nasal drug delivery systems.