Avaliação do efeito sinérgico entre risedronato sistêmico e genisteína local sobre o reparo peri-implantar em ratas com deficiência de estrógeno e síndrome metabólica / Evaluation of the synergistic effect between systemic Risedronate and local Genistein on peri-implant repair in strogen deficient rats and metabolic syndrome

O objetivo deste estudo foi investigar a ação sinérgica do risedronato de sódio sistêmico e da genisteína administrada localmente, através da funcionalização de implantes, de ratas submetidas a ovariectomia e com hábitos de mimetizam a síndrome metabólica. A parte in vitro deste estudo foi executado em 2 etapas. Na primeira etapa, foi realizada a funcionalização da superfície de discos/implantes com genistína na concentração de 100 µM pela técnica layer by layer (lbl). Na segunda etapa foram feitos testes biológicos em culturas de células, para avaliar as propriedades da superfície funcionalizada, quanto às respostas osteogênicas. Para a cultura de células foram utilizadas células mesenquimais diferenciadas em osteoblastos, isoladas de fêmures de ratos. Após a validação pelos testes executados nas superfícies funcionalizadas, foi realizado estudo in vivo (3ª etapa). Para tanto, no dia 0, as ratas Wistar adultas jovens, fêmeas (n=64) foram divididas em 4 grupos: 1- SHAM (n= 16), animais foram submetidos à ovariectomia (OVX) fictícia e dieta balanceada. 2- SHAM Síndrome Metabólica (SM) (n=16), animais foram submetidos à ovariectomia fictícia e dieta de cafeteria. 3- OVX SM (n=16), animais foram submetidos à ovariectomia bilateral e dieta de cafeteria. 4- OVX SM Risedronato (RIS) (n=16), animais foram submetidos à ovariectomia bilateral, dieta de cafeteria e tratadas com risedronato de sódio. Em cada grupo há 2 subgrupos: A- implantes convencionais e B- implantes funcionalizados com genisteína. No dia 30, foi iniciado o tratamento medicamentoso com risedronato de sódio, na concentração de 0,35mg/kg, ou apenas solução salina, via gavagem, 1 vez por semana. Passados 60 dias da medicação (dia 90), todos os animais foram submetidos à cirurgia para exodontia dos 1os molares superiores bilateralmente e, imediatamente, no alvéolo da raiz mesial, foi instalado os implantes com superfície convencional ou funcionalizada. Os animais foram eutanasiados aos 28 dias (dia 118) após a instalação dos implantes para mensuração do torque de falha na interface osso implante em N/cm. Os dados foram submetidos ao teste de homocedasticidade (Shapiro Wilk). Houve a confirmação de distribuição normal dos dados amostrais e na sequência, foi realizado o teste paramétrico ANOVA One Way or Two Way, seguido do pós teste de Tukey, com o nível de significância de 5% (p< 0,05). Concluiu-se que, a concentração de 100 µM da genisteína manteve a viabilidade celular e resultados favoráveis quanto a genotoxicidade. A dieta de cafeteria e a ovariectomia bilateral mimetizam a síndrome metabólica e a predisposição para osteoporose por deficiência de esteroides gonadais. E, a ação sinérgica entre fármaco sistêmico (risedronato de sódio) e genisteína local foi promissora para a melhora no processo de reparo periimplantar, principalmente no grupo SHAM e OVX SM RIS(AU)

The aim of this study was to investigate the synergistic action of systemic risedronate sodium and locally administered genistein, through implant functionalization, of rats submitted to ovariectomy and with habits mimicking the metabolic syndrome. The in vitro part of this study was performed in 2 steps. In the first step, the surface functionalization of discs/implants was performed with genistein at a concentration of 100 µM by the layer by layer (lbl) technique. In the second step biological tests were performed in cell cultures to evaluate the properties of the functionalized surface for osteogenic responses. For the cell culture, mesenchymal cells differentiated into osteoblasts, isolated from rat femurs, were used. After validation by tests performed on the functionalized surfaces, the in vivo study (third test) was performed. For this purpose, on day 0, young adult female Wistar rats (n=64) were divided into 4 groups: 1- SHAM (n=16), animals were submitted to sham ovariectomy (OVX) and balanced diet. 2- SHAM Metabolic Syndrome (MS) (n=16), animals were submitted to sham ovariectomy and cafeteria diet. 3- OVX SM (n=16), animals underwent bilateral ovariectomy and cafeteria diet. 4- OVX SM Risedronate (RIS) (n=16), animals underwent bilateral ovariectomy, cafeteria diet and treated with risedronate sodium. In each group there are 2 subgroups: A- conventional implants and B- implants functionalized with genistein. On day 30, drug treatment was started with risedronate sodium, at a concentration of 0.35 mg/kg, or just saline solution, via gavage, once a week. After 60 days of medication (day 90), all animals underwent surgery to extract the 1st upper molars bilaterally, and implants with conventional or functionalized surfaces were immediately installed in the mesial root alveolus. The animals were euthanized at 28 days (day 118) after implant installation to measure the failure torque at the implant-bone interface in N/cm. The data were submitted to the homoscedasticity test (Shapiro Wilk). The normal distribution of the sample data was confirmed and then the parametric One Way or Two Way ANOVA test was performed, followed by Tukey's post-test, with a significance level of 5% (p< 0.05). It was concluded that, the concentration of 100 µM of genistein maintained cell viability and favorable results regarding genotoxicity. The cafeteria diet and bilateral ovariectomy mimic the metabolic syndrome and predisposition to osteoporosis by gonadal steroid deficiency. And, the synergistic action between systemic drug (risedronate sodium) and local genistein was promising for the improvement in the periimplant repair process, especially in the SHAM and OVX SM RIS groups(AU)

Protective effect of glucosamine and risedronate (alone or in combination) against osteoarthritic changes in rat experimental model of immobilized knee / 대한해부학회지

Risedronate inhibits rat bone marrow adipogenesis and reduces RANKL expression in adipocytes / 南方医科大学学报

OBJECTIVE@#To investigate the effects of risedronate on bone marrow adipogenesis and the expression of the receptor activator of nuclear factor κB ligand (RANKL) in adipocytes in the bone marrow micro-environment.@*METHODS@#Primary cultured rat mesenchymal stem cells (BMSCs) with or without adipogenic induction for 14 days were treated with 1, 5, 10, and 25 μmol/L risedronate. The droplets of the differentiated adipocytes were analyzed, and Western blotting was performed to detect the expression level of RANKL. Female SD rats (24-week-old) were randomly divided into sham-operated group and ovariectomy (OVX) group, and 12 weeks after the operation, the OVX rats were further divided into control group and risedronate group (2.4 μg/kg, injected subcutaneously for 3 times a week). Eight weeks later, the bone mineral density (BMD) of the rats and bone marrow histopathology of the femurs was examined to evaluate the effect of risedronate on the fat fraction in the bone marrow.@*RESULTS@#Risdronate significantly inhibited adipogenic differentiation of rat BMSCs and suppressed RANKL expression in the adipocytes derived from the BMSCs in a concentration-dependent manner. In OVX rats, risdronate treatment significantly increased the BMD and decreased the fat content in the bone marrow.@*CONCLUSIONS@#Risdronate can effectively inhibit the adipogenic differentiation of rat BMSCs, decrease fat content in the bone marrow, and suppress the generation and function of osteoclasts by down-regulating the expression of RANKL, which can be an important mechanism underlying the therapeutic effect of risedronate against osteoporosis.

Plasmodium falciparum parasites overexpressing farnesyl diphosphate synthase/geranylgeranyl diphosphate synthase are more resistant to risedronate

Farnesyl diphosphate synthase/geranylgeranyl diphosphate synthase (FPPS/GGPPS) is a key enzyme in the synthesis of isoprenic chains. Risedronate, a bisphosphonate containing nitrogen (N-BP), is a potent inhibitor of blood stage Plasmodium. Here, we show that P. falciparum parasites overexpressing FPPS/GGPPS are more resistant to risedronate, suggesting that this enzyme is an important target, and bisphosphonate analogues can be used as potential antimalarial drugs.

Cost-effectiveness of Pharmaceutical Interventions to Prevent Osteoporotic Fractures in Postmenopausal Women with Osteopenia

BACKGROUND: To assess the cost-effectiveness of drug therapy to prevent osteoporotic fractures in postmenopausal women with osteopenia in Korea. METHODS: A Markov cohort simulation was conducted for lifetime with a hypothetical cohort of postmenopausal women with osteopenia and without prior fractures. They were assumed to receive calcium/vitamin D supplements only or drug therapy (i.e., raloxifene or risedronate) along with calcium/vitamin D for 5 years. The Markov model includes fracture-specific and non-fracture specific health states (i.e. breast cancer and venous thromboembolism), and all-cause death. Published literature was used to determine the model parameters. Local data were used to estimate the baseline incidence rates of fracture in those with osteopenia and the costs associated with each health state. RESULTS: From a societal perspective, the estimated incremental cost-effectiveness ratios (ICERs) for the base cases that had T-scores between -2.0 and -2.4 and began drug therapy at the age of 55, 60, or 65 years were $16,472, $6,741, and -$13,982 per quality-adjusted life year (QALY) gained, respectively. Sensitivity analyses for medication compliance, risk of death following vertebral fracture, and relaxing definition of osteopenia resulted in ICERs reached to $24,227 per QALY gained. CONCLUSIONS: ICERs for the base case and sensitivity analyses remained within the World Health Organization's willingness-to-pay threshold, which is less than per-capita gross domestic product in Korea (about $25,700). Thus, we conclude that drug therapy for osteopenia would be a cost-effective intervention, and we recommend that the Korean National Health Insurance expand its coverage to include drug therapy for osteopenia.

Difference in Bone Mineral Density Change at the Lateral Femoral Cortices according to Administration of Different Bisphosphonate Agents

BACKGROUND: To retrospectively assess whether the response of subtrochanteric lateral cortex (STLC) is different according to the bisphosphonate agents in terms of bone mineral density (BMD) change. METHODS: A total of 149 subjects, who had 2- to 4-year interval follow-up of BMD using dual energy X-ray absorptiometry (DXA), were included in this retrospective study divided into following 3 groups: control group (no consumption of any anti-osteoporotic drugs, n=38), alendronate group (naïve alendronate users, n=48), risedronate group (naïve risedronate users, n=63). BMD was measured at the STLC and subtrochanteric medial cortex (STMC) in each patient by drawing rectangular ROIs at the bone cortices. The percent change of BMD at the STLC were compared between the aforementioned 3 groups by using analysis of covariance model to control five independent variables of age, body mass index, percent change of STMC, hip axis length, time interval between DXA examinations. RESULTS: The least square mean values±standard deviation of the percent change of BMD in the control, alendronate, and risedronate groups were 1.46±1.50, 2.23±1.26, and 6.96±1.11, respectively. The risedronate group showed significantly higher change of BMD percentage compared with the control (adjusted P=0.012) or alendronate (adjusted P=0.016) groups. CONCLUSIONS: The percent change of BMD at the STLC in the risedronate user group was greater than the alendronate and control groups. The implication of these changes needs to be further verified.

Monthly minodronate inhibits bone resorption to a greater extent than does monthly risedronate

As a bisphosphonate, minodronate (MIN) is one of the strongest inhibitors of bone resorption. However, there have been no reports directly comparing the antiresorptive effects of monthly MIN with those of monthly risedronate (RIS). We enrolled 30 cases of osteoporosis (OP; 16 in the MIN group [mean age: 68.2 years] and 14 in the RIS group [mean age: 68.1 years]) to investigate the early effects of treatment by monthly MIN or RIS over a 4-month period using bone turnover marker values. Only female patients were enrolled to avoid gender bias. Urinary cross-linked N-telopeptide of type I collagen (NTX) before treatment and at 1, 2, and 4 months of therapy, as well as serum bone alkaline phosphatase and alkaline phosphatase before treatment and at 4 months afterwards, were evaluated. All bone turnover marker values were significantly decreased at 4 months in both groups. The changes in urinary NTX at the study end point for RIS and MIN were -30.1% and -63.1%, respectively. From 2 months of treatment, the antiresorptive effects on urinary NTX by MIN were significantly higher than those by RIS, indicating that MIN more immediately and strongly inhibited bone absorption. Thus, monthly MIN seems to suppress bone resorption faster and more strongly than RIS in OP treatment.

Therapeutic effect of proximal femoral nail antirotation treatment combined with risedronate sodium on intertrochanteric fractures in elderly patients / 中华老年医学杂志

Objective To compare the clinical outcomes between proximal femoral nail antirotation (PFNA) combined with risedronate sodium and isolated PFNA for the treatment of intertrochanteric fractures in elderly patients.Methods Clinical data of 62 elderly patients with intertrochanteric fracture from January 2011 to April 2013 were prospectively studied.Patients were randomly divided into two treatment groups:risedronate sodium group (the combined PFNA and risedronate) and control group (isolated PFNA).According to AO classification,32 patients in risedronate sodium group (15 males and 17 females,with an average age of 78 years) were divided into type A1 (n=10),type A2 (n=18) and type A3 (n=4).30 patients in control group (13 males and 17 females,with an average age of 77.5 years) were divided into type A1 (n=9),type A2 (n=16) and type A3 (n=5).Bone mineral density (BMD) was measured by dual energy X-ray absorptiometry before and 1 year after operation.The hip joint function was assessed by Harris hip score.Complications and subsequent fragility fractures were evaluated postoperatively.Results 60 patients (30 patients in risedronate sodium group and 30 patients in control group) were followed up for at least one year.All fractures were healed at 6 months after surgery.No significant difference was found between the two groups in BMD in contra-lateral hip before treatment [(-2.58±0.41)kg/m2 vs.(-2.56±0.36)kg/m2,P＞0.05].BMD in contra-lateral hip had significant difference between the risedronate sodium and control groups one year after surgery [(-0.66±0.37)kg/m2 vs.(-1.13 ±0.28)kg/m2,P=0.000].There was no significant difference between the two groups in Harris hip score (P=0.238).During the follow-up,no patient in risedronate group suffered from subsequent fragility fracture after surgery,while lumbar compression fracture occurred in 1 case,distal radius fracture occurred in 1 case,the contralateral hip fractures occurred in 2 cases,postoperatively.Conclusions PFNA treatment combined with risedronate sodium can effectively improve BMD and reduce the risk for refracture,and has a good effect on intertrochanteric fracture in elderly patients.

Determination method of related substances in risedronate sodium tablets / 药学实践杂志

Objective To establish a HPLC method for determination of related substances of risedronate sodium tab‐lets .Methods The C18 column ,5 μm ,150 mm × 4 .6 mm ,the buffer solution (3 .22 g tetrabutyl ammonium bromide was added to a buffer solution of 1 000 ml 0 .05 mol/L ammonium chloride ,then adjusted pH to 7 .8 ± 0 .05 by ammonia)‐methanol‐aceto‐nitrile =250:50:25 as mobile phase ,column temperature:room temperature ,flow rate:1 .0 ml/min ,detection length:254 nm . Results Determined by HPLC at high temperature ,acid ,alkali degradation ,the main peak and the impurity peaks were separa‐ted well ,and the peaks had a linear relationship ,Y=1 .28 × 107 X-1 .62 × 105 (r=0 .999 9) .Conclusion The method was rap‐id ,simple ,accurate and sensitive ,and suitable for determination of risedronate sodium tablets related substances .

Long-term risks of bisphosphonate therapy / Riscos do tratamento a longo prazo com bisfosfonatos

The objective this study was to summarize long-term risks associated with bisphosphonate therapy. Search of relevant medical publications for data from clinical trials, trial extensions, observational studies and post-marketing reports. Trial extensions and modifications did not reveal significant long-term safety issues. Observational data suggest at least as many benefits as risks. Post-marketing reports of musculoskeletal pain, osteonecrosis of the jaw and atypical femur fractures have been widely circulated in the lay press. Most focus on long-terms risks has been on osteonecrosis of the jaw and atypical femur fractures which occur in patients who have not received bisphosphonate therapy but may be more frequent (though still uncommon) in patients who have been on treatment for 5 years or longer. Lower-risk patients may be able to stop treatment after 3-5 years for a “drug holiday,” which mitigates these long-term risks; for higher risk patients, therapy through 6-10 years appears to be advisable and offers more benefits than risks.

O objetivo deste estudo foi resumir os riscos associados ao tratamento a longo prazo com bisfosfonatos. Foram pesquisadas as publicações médicas relevantes incluindo ensaios clínicos, extensões de ensaios clínicos, estudos observacionais e relatórios pós-comercialização (vigilância farmacológica). As extensões e modificações de ensaios clínicos não indicaram nenhuma situação de alarme quanto à segurança dos bisfosfonatos a longo prazo. Dados observacionais sugerem pelo menos tantos benefícios quanto riscos. Entretanto, relatos pós-comercialização de dor musculoesquelética, osteonecrose da mandíbula e fraturas de fêmur atípicas foram amplamente divulgados na imprensa leiga. O foco nos riscos a longo prazo do tratamento com bisfosfonatos tem sido pincipalmente a osteonecrose da mandíbula e as fraturas atípicas de fêmur. Essas últimas, embora mais frequentes (ainda que pouco comuns) em pacientes que receberam tratamento com bisfosfonatos por 5 anos ou mais, podem ocorrer em indivíduos não tratados com esses medicamentos. Pacientes com baixo risco de fratura podem potencialmente parar o tratamento depois de 3 a 5 anos (“drug holiday”). Esse procedimento reduz os riscos desses medicamentos a longo prazo. Não obstante, nos pacientes de maior risco a terapia por 6 a 10 anos parece ser aconselhável e oferece mais benefícios do que riscos.

Comparison of the efficacy of three once-weekly bisphosphonates on bone mineral density gains in Korean women

OBJECTIVE: To assess the efficacies of once-weekly bisphosphonates on bone mineral density (BMD) gains in Korean women aged 50 years or more. METHODS: We selected 166 patients who received: alendronate 70 mg (n=48), alendronate 70 mg + cholecalciferol 2,800 IU (n=31) or risedronate 35 mg (n=87) for one year. The baseline BMD and the % changes of BMD at one-year were compared among the three medication groups. RESULTS: The menopausal status and number of women with osteoporosis was not different among the three groups, but mean age of women was significantly lower in alendronate group. Baseline BMD at L1-4 and femur neck (FN) was similar, but baseline BMD at femur total (FT) was significantly lower in alendronate group. After one-year use, the median % changes of BMD at three sites were similar among the three groups; however, the median values were highest in alendronate + cholecalciferol group (L1-4: 4.48%, 6.74%, and 4.50%; FT: 2.09%, 3.70%, and 2.31%; FN: 3.05%, 3.79%, and 2.03%). CONCLUSION: Among three once-weekly bisphosphonates, BMD gains were highest after one-year use of alendronate+cholecalciferol, although statistically not significant.

Estudo de biodisponibilidade relativa/bioequivalência de duas formulações de risedronato de sódio em voluntários sadios de ambos os sexos / Study of relative bioavailability/bioequivalence of two formulations of risendronate sodium in healthy volunteers of both sexes

O estudo foi realizado para comparar a biodisponibilidade de duas formulações de risedronato de sódio 35 mg comprimido revestido (risedronato de sódio do Aché Laboratórios Farmacêuticos S/A, formulação teste, e Actonel® da Sanofi-Aventis Farmacêutica Ltda., formulação referência, Brasil) em 80 voluntários de ambos os sexos. O estudo foi aberto, aleatorizado, 2-sequências, 2-períodos, cruzado, dose única com dois tratamentos, nos quais um grupo de voluntários recebeu a formulação teste e outro a formulação referência. As amostras de sangue foram obtidas ao longo de um intervalo de 96 horas. As concentrações de risedronato de sódio foram determinadas através de espectrometria de massa (UPLC-MS-MS), utilizando ácido risedrônico-D4 (risedronato deuterado) como padrão interno. A partir dos dados obtidos se calcularam os seguintes parâmetros farmacocinéticos: ASC0-t, ASC0-¥ e Cmax. A média geométrica de Risedronato de Sódio/Actonel® 35 mg foi de 101,90 % para ASC0-t, 97,95 % para ASC0-¥ e 100,70 % para Cmax. Os intervalos de confiança de 90% foram de 86,43%-120,14%, 83,04%-115,54% e 85,50%-118,61%, respectivamente. Uma vez que os intervalos de confiança de 90% para Cmax e ASC0-t estiveram dentro da faixa de 80%-125% proposta pelo FDA e pela ANVISA (Agência Nacional de Vigilância Sanitária do Brasil), conclui-se que o comprimido de risedronato de sódio de 35 mg foi bioequivalente ao comprimido de Actonel® de 35 mg e, dessa forma, o produto teste pode ser considerado intercambiável na prática médica.

Risedronate-related Localized Amnesia in an Elderly Patient with Osteoporosis

Osteoporosis is the most common metabolic bone disease that results in an increased risk of fragility fractures. Bisphosphonates are commonly used in the treatment of osteoporosis. Concerns about their association with several possible adverse effects have been raised. Here, we experienced a rare case regarding a 63-year-old female patient who had localized amnesia related to once-monthly oral risedronate. A clear cause-and-effect relationship between the treatment of risedronate and this event has not been established and the mechanism behind the adverse effect is unknown. As clinical uses of bisphosphonates continue to expand, clinicians should be aware of the rare but potential adverse effects associated with bisphosphonates including neuropsychiatric problems.

Prevention of New Vertebral Fractures after Treatment with Risedronate, Alendronate or Calcium Carbonate in Patients with Osteoporotic Compression Fracture Treated with Cement Augmentation / 대한정형외과학회잡지

PURPOSE: To evaluate the rate of new fractures of the spine after risedronate, alendronate or calcium carbonate in patients who had vertebroplasty or kyphoplasty due to compression fracture. MATERIALS AND METHODS: We studied 292 patients with osteoporotic compression fractures who had received vertebroplasty or kyophoplasty between June 2003 and October 2007. Of these, 199 were evaluated for new fractures of the spine after treatment with risedronate, alendronate or calcium carbonate. Patients (n=199) were assigned to 1 of 4 groups: No treatment (n=71), risendronate (n=64), alendronate (n=42) or calcium carbonate group (n=22). RESULTS: New fractures of the spine were morphogenically found in 19 patients (26.8%) in the no treatment group, in 11 (17.2%) in the risendronate group, in 8 (19.1%) in the alendronate group, in 5 (22.8%) in the calcium carbonate group. Symptomatically, they were found in 6 patients (8.5%) in the no treatment group, in 4 (6.3%) in the risendronate group, in 3 patients (7.1%) in the alendronate group, and in 2 patients (9.1%) in the calcium carbonate group. CONCLUSION: At one year follow up none of the differences between groups in new fracture rates of the spine were statistically significant.

The Effect of Risedronate on Posterior Lateral Spinal Fusion in a Rat Model

OBJECTIVE: To evaluate the potential effects of risedronate (RIS) which shows a higher anti-resorptive effect among bisphosphonates, after a posterolateral lumbar intertransverse process spinal fusion using both autograft and allograft in a rat model. METHODS: A totoal of 28 Sprague-Dawley rats were randomized into 2 study groups. A posterolateral lumbar intertransverse process spinal fusion was peformed using both autograft and allograft in a rat model. Group I (control) received 0.1 mL of steril saline (placebo) and Group II (treatment) received risedronate, equivalent to human dose (10 microgram/kg/week) for 10-weeks period. RESULTS: The fusion rates as determined by manual palpation were 69% in the group I and 46% in the group II (p = 0.251). According to radiographic score, the spinal segment was considered to be fused radiographically in 7 (53%) of the 13 controls and 9 (69%) of the 13 rats treated with RIS (p = 0.851). The mean histological scores were 5.69 +/- 0.13 and 3.84 +/- 0.43 for the control and treatment groups, respectively. There was a significant difference between the both groups (p = 0.001). The mean bone density of the fusion masses was 86.9 +/- 2.34 in the control group and 106.0 +/- 3.54 in the RIS treatment group. There was a statistical difference in mean bone densities of the fusion masses comparing the two groups (p = 0.001). CONCLUSION: In this study, risedronate appears to delay bone fusion in a rat model. This occurs as a result of uncoupling the balanced osteoclastic and osteoblastic activity inherent to bone healing. These findings suggest that a discontinuation of risedronate postoperatively during acute fusion period may be warranted.

Comparison of the Effect of Vitamin K2 and Risedronate on Trabecular Bone in Glucocorticoid-Treated Rats: A Bone Histomorphometry Study

PURPOSE: To compare the effect of vitamin K2 and risedronate on trabecular bone in glucocorticoid (GC)-treated rats. MATERIALS AND METHODS: Forty-eight Sprague-Dawley female rats, 3 months of age, were randomized by the stratified weight method into 5 groups according to the following treatment schedule: age-matched control, GC administration, and GC administration with concomitant administration of vitamin K2, risedronate, or vitamin K2 + risedronate. GC (methylprednisolone sodium succinate, 5.0 mg/kg) and risedronate (10 microgram/kg) were administered subcutaneously three and five times a week, respectively. Vitamin K2 (menatetrenone, 30 mg/kg) was administered orally three times a week. At the end of the 8-week experiment, bone histomorphometric analysis was performed on trabecular bone of the tibial proximal metaphysis. RESULTS: GC administration decreased trabecular bone mass compared with age-matched controls because of decreased bone formation (mineralizing surface, mineral apposition rate, and bone formation rate) and increased bone erosion. Vitamin K2 attenuated GC-induced trabecular bone loss by preventing GC-induced decrease in bone formation (mineralizing surface) and subsequently reducing GC-induced increase in bone erosion. Risedronate prevented GC-induced trabecular bone loss by preventing GC-induced increase in bone erosion although it also suppressed bone formation (mineralizing surface, mineral apposition rate, and bone formation rate). Vitamin K2 mildly attenuated suppression of bone formation (mineralizing surface) and bone erosion caused by risedronate without affecting trabecular bone mass when administered in combination. CONCLUSION: The present study showed differential effect of vitamin K2 and risedronate on trabecular bone in GC-treated rats.

Farmacoterapia de raloxifeno y de risedronato en el proceso de reparación ósea en ratones machos con osteopenia / Pharmacotherapy of raloxifene and risedronate in the process of bone repair in male mice with osteopenia

El objetivo del estudio era el de analizar radiográficamente los efectos del risedronato de sodio (OSG Norwich Pharmaceticals, U. S. UN.) y del raloxifeno clorhidrato (Eli Lirio & Compañía Ltda, ING. ) En la reparación ósea en ratones osteopénicos. Se utilizó cincuenta ratones divididos en cinco grupos de 10 animales: (I) SHAM, (II) Castrado, (III) Castrados y tratados con risedronato 1mg/kg/dia, (IV) Castrados y tratados con raloxifeno 1mg/kg/día y (V) Castrados y tratados con raloxifeno 3mg/kg/día. Después de treinta días de la castración se les produjo heridas en el hueso de 3 mm de en las de tibias derechas. Entre 7 y 28 días de tratamiento los ratones fueron sacrificados y las tibias evaluadas considerando la densidad óptica radiográfica de la región de la reparación del defecto óseo por medio del sistema digital RVG Trophy y Programa de Imagen Tool® 2,03. Los resultados fueron sometidos al ANOVA y al Test de Tukey (p?0,05). Los datos mostraron que a los 7 días de observación los grupos I y II fueron estadísticamente semejantes en relación al grado de densidad radiográfica, así como los demás grupos entre sí. A los 28 días el grupo V presentó los valores de densidad radiográfica superior y estadísticamente significativos con respecto a los grupos II, III y IV y semejante al grupo I. Los grupos III y IV fueron semejantes entre sí y estadísticamente superior al grupo II. Se concluyó que el raloxifeno en dosis de 3mg/kg/dia presentó mejor desempeño en el proceso de reparación ósea, siendo semejante al grupo SHAM a los 28 días. El efecto del raloxifeno se mostró dosis dependiente, a los 28 días, en las posologias testadas

The aim of this study was to analyse radiographically the effects of sodium risedronate (OSG Norwich Pharmaceticals, EUA) and raloxifene hydrochloride (Eli Lilly & Company Ltd; ING.) in bone repair of male rats with osteopenia. 50 animals were divided in 5 groups of 10: (I) SHAM, (II) Castrated rats, (III) Castrated rats treated with 1mg/kg/day risedronate, (IV) Castrated rats treated with 1mg/kg/day raloxifene and (V) Castrated rats treated with 3mg/kg/day raloxifene. 30 days after castration, a 3 mm bone defect was made in the right tibia of the animals. After 7 and 28 days of treatment, the animals were sacrificed and the tibias were removed for analysis of radiographic optical density by the digital system RVG Trophy and the Image Programme Tool 2.03®. All data collected were analysed by ANOVA and the Tukey´s Test (p?0.05). The results showed that at 7 days of bone repair, groups I and II had similar and statistically significant values of optical density while the other groups had similar values among themselves. At 28 days of bone repair, group V showed greater and statistically significant values of optical density compared to groups II, III and IV, but similar values to group I. Groups III and IV had similar values between themselves but greater and statistically significant values than group II. It could be concluded that 3 mg/kg/day raloxifene had a better performance in bone repair when compared to the other groups, similar results to group I and a dose-dependent relation at 28 days

The Comparision of Mitigative Effect of Alendronate and Risedronate on Particle-Induced Osteolysis: in Mouse Calvarian Model / 대한정형외과연구학회지

PURPOSE: The purpose of this study was to compare the mitigative effect of alendronate and risedronate on osteolysis in the mouse calvarian model by using titanium (Ti) and polymethylmethacrylate (PMMA) particles. MATERIALS AND METHODS: Experimental mice (male C57/BL6) are divided into three groups; control, Ti particle-treated and PMMA particle-treated group. Each Ti and PMMA particle-treated group was divided into three subgroups which received no bisphosphonates, which received alendronate, and which received risedronate. We measured number of osteoclast, area of osteolysis, bone and soft tissue thickness, ratio of bone and total tissue on mid-sagittal suture area (MSSA) and compared between two groups. RESULTS: Both alendronate and risedronate had significant inhibitory effect on Ti or PMMA particle-induced osteolysis in mouse calvarian model (p<0.05). Furthermore, bisphosphonates prevented formation of particleinduced osteolysis as RANK/Fc. Risedronate had better capability for preserving bone thickness in PMMA treated mice and also showed decreased soft tissue thickness in Ti treated mice than alendronate (p<0.05). CONCLUSION: Both alendronate and risedronate may be an effective agents on mitigation of Ti and PMMA particle-induced osteolysis. However, risedronate showed better structual bone preserving capacity than alendronate in particle-treated mouse calvariae.

The Effect of Vitamin K2 in Addition to Risedronate on the Patients with Postmenopausal Osteoporosis

OBJECTIVE: To assess the effect of vitamin K2 in addition to risedronate on postmenopausal osteoporosis METHOD: We enrolled 21 postmenopausal osteoporosis women (age: 65.2+/-7.8 years). Ten subjects received risedronate (35 mg, weekly) and vitamin K2 (45 mg, daily) and eleven subjects only received risedronate. They all received calcium citrate 2,130 mg and vitamin D 600 IU daily. The duration of treatment was 7.7+/-1.4 months. Bone mineral density (BMD) of lumbar spine and both femurs, serum osteocalcin and urine deoxypyridinoline were examined at baseline and after treatment. RESULTS: After treatment, BMD, serum osteocalcin and urine deoxypyridinoline were improved in each group but there was no statistical difference between the groups. CONCLUSION: There was no evidence of the benefit of vitamin K2 in addition to risedronate in bone metabolism on postmenopausal osteoporosis.

Efficacy and Safety of Risedronate Sodium in Treatment of Postmenopausal Osteoporosis / 华中科技大学学报（医学）（英德文版）

To evaluate the efficacy and safety of risedronate sodium in treatment of postmenopausal osteoporosis, one-year randomized, double blind clinical trial was performed among 54 women with postmenopausal osteoporosis. The changes were compared in bone mineral density (BMD), bone metabolism markers and adverse events after 12 months oral administration of risedronate sodium.BMD was measured by dual energy X-ray absorptionmetry (DEXA) and bone turnover marker was detected. The results showed that there was a significant increase in BMD of the lumbar spine (3.29 % ± 1.18 %, 4. 51% ±1.64 % respectively) after 6 and 12 months in the risedronate treatment group versus placebo control group (-0.62 % ±0.24 %, 0.48 % ±0.18 % respectively).Bone turnover was decreased to a stable nadir over 6 and 12 months for resorption markers [N-Telopeptide (NTx), P＜0. 05] and over 12 months for formation marker (ALP, P＜0.05; BGP, P＜0.05). The safety profile of risedronate sodium was similar to that of placebo. There were no trends toward increased frequency of any adverse experience except for gastrointestinal symptoms (7.1%), rash (7.1%) and hematuria (3.6 %), which were usually mild, transient, and resolved with continued treatment. It was concluded that risedronate was an efficacious and safe drug in treatment of postmenopausal osteoporosis.