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)

Effects of ergosteroside combined risedronate on fracture healing and BMP-2, BMP-7 and VEGF expression in rats

Purpose To evaluate the effect of ergosterol combined with risedronate on fracture healing. Methods Sixty male Sprague Dawley fracture model rats were assigned into group A (n=20), group B (n=20), and group C (n=20) at random. All rats were fed by gavage until their sacrifice as it follows: group A with ergosteroside and risedronate, group B with risedronate, and group C with saline solution. At weeks 2 and 4, 10 rats of each group were sacrificed. Healing effect and bone tissue changes in the fractures site were assessed by using hematoxylin and eosin stain histology. Enzyme-linked immunosorbent assay was used to detect the expression of serum bone morphogenetic protein-2 (BMP-2), bone morphogenetic protein-7 (BMP-7), and vascular endothelial growth factor (VEGF). Reverse transcriptase polymerase chain reaction was applied to detect the expression of osteoprotegerin (OPG) mRNA, osteocalcin (OCN) mRNA and core-binding factor subunit-?1 (CBF-?1) mRNA. Results In terms of serum BMP-2, BMP-7, and VEGF expression at weeks 2 and 4 after gavage, group A < group B < group C (P<0.05). At week 4 after gavage, serum VEGF expression in the three groups harbored positive relationship with serum BMP-2 and BMP-7 expression (P<0.05). Regarding serum OPG, OCN and CBF-?1 mRNA expression at weeks 2 and 4 after gavage, group A

Eficácia e segurança da Teriparatida comparada aos bifosfonados orais e Raloxifeno para prevenção de fraturas em osteoporose: revisão rápida de evidências / Effectiveness, safety and cost-effectiveness of Teriparatide compared to oral biposphonates or Raloxifene for osteoporotic fracture prevention: rapid review of evidence

Tecnologia: Teriparatida, comparada a bifosfonados orais ou Raloxifeno. Indicação: prevenção de fraturas em pessoas com osteoporose. Pergunta: A Teriparatida é mais eficaz e segura que os bifosfonados orais ou o Raloxifeno para tratamento da osteoporose e prevenção de fraturas secundárias à osteoporose? Métodos: Levantamento bibliográfico foi realizado na base de dados PUBMED, seguindo estratégias de buscas predefinidas. Foi feita avaliação da qualidade metodológica das revisões sistemáticas com a ferramenta Assessing the Methodological Quality of Systematic Reviews version 2 (AMSTAR-2). Resultados: Foram selecionadas 2 revisões sistemáticas, que atendiam aos critérios de inclusão. Conclusão: Para a população em geral com osteoporose, a Teriparatida evita mais fraturas vertebrais que o Alendronato de sódio ou Risedronato de sódio, mas efeito similar para fraturas não vertebrais. Teriparatida previne mais fraturas vertebrais e não vertebrais que Raloxifeno. Teriparatida tem maior efeito sobre a massa óssea corporal que o Risedronato de sódio e o Raloxifeno, mas tem efeito similar ao Alendronato de sódio. Na população masculina com osteoporose, a terapia com bifosfonados orais é mais eficaz que suplementação nutricional ou placebo para prevenir fraturas. Já o tratamento com Teriparatida não é mais eficaz que a suplementação nutricional ou placebo

Teriparatide compared to oral bisphosphonates or Raloxifene. Indication: prevention of fractures in people with osteoporosis. Question: Is Teriparatide more effective and safer than oral bisphosphonates or Raloxifene for treating osteoporosis and preventing fractures secondary to osteoporosis? Methods: Bibliographic survey was carried out in the PUBMED database, following predefined search strategies. Evaluation of the methodological quality of systematic reviews was carried out using the tool Assessing the Methodological Quality of Systematic Reviews version 2 (AMSTAR-2). Results: Two systematic reviews were selected, which met the inclusion criteria. Conclusion: For the general population with osteoporosis, Teriparatide prevents more vertebral fractures than Alendronate or Risedronate sodium, but has similar effect for non-vertebral fractures. Teriparatide prevents more vertebral and non-vertebral fractures than Raloxifene. Teriparatide has a greater effect on body bone mass than Risedronate sodium and Raloxifene, but it has a similar effect to Alendronate sodium. In the male population with osteoporosis, oral bisphosphonates is more effective than nutritional supplementation or placebo to prevent fractures. Treatment with teriparatide is no more effective than nutritional supplementation or placebo

Eficácia e segurança do ácido zoledrônico comparado aos bifosfonados orais para prevenção de fraturas na osteoporose: revisão rápida de evidências / Effectiveness and safety of zoledronic acid compared to oral bifosfonates for fracture prevention in osteoporosis: rapid review of evidence

Tecnologia: Ácido zoledrônico e bifosfonados orais (alendronato e risedronato de sódio). Indicação: Prevenção de fraturas em pessoas com osteoporose. Pergunta: Em pessoas com osteoporose, o ácido zoledrônico é mais eficaz e seguro que os bifosfonados orais para prevenção de fraturas e outros desfechos de interesse? Métodos: Levantamento bibliográfico foi realizado nas bases eletrônicas Pubmed e BVS usando estratégias de buscas predefinidas. Foi feita avaliação da qualidade metodológica das revisões sistemáticas com a ferramenta Assessing the Methodological Quality of Systematic Reviews (AMSTAR). Resultados: Foram selecionadas e incluídas 5 revisões sistemáticas. Conclusão: O ácido zoledrônico é similar aos bifosfonados orais para prevenir fraturas em mulheres com osteoporose. Seu efeito sobre a densidade mineral óssea femoral é similar ao do alendronato e superior ao do risedronato. Um tratamento por 3 anos com ácido zoledrônico ou por 5 anos com alendronato de sódio é suficiente para prevenir fraturas vertebrais e não vertebrais. Bifosfonados têm similar risco de eventos adversos que o placebo, incluindo transtornos cardiovasculares e taxa de abandono do tratamento devido a distúrbios gastrointestinais. O ácido zoledrônico tem maior incidência de sintomas influenza-like que o placebo. O ácido zoledrônico não provoca eventos adversos do tipo esofágicos, gastrointestinais sérios ou do trato gastrointestinal superior, mas tem maior risco de náuseas, que pode estar relacionada à infusão intravenosa de grandes doses

Technology: Zoledronic acid and oral bisphosphonates. Indication: Prevention of osteoporotic fractures. Question: In people with osteoporosis, is zoledronic acid more effective and safer than oral bisphosphonates for preventing fractures and other outcomes? Methods: Bibliographic search was performed on PUBMED and BVS, using predefined search strategies. Evaluation of the methodological quality of systematic reviews was done by the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) tool. Results: 5 systematic reviews were selected and included. Conclusion: Zoledronic acid is similar to bisphosphonates for preventing fractures in women with osteoporosis and his effect on femoral bone mineral density is similar to that of alendronate and superior to risedronate. A 3 years treatment with zoledronic acid or for 5 years with sodium alendronate is sufficient to prevent vertebral and non-vertebral fractures. Bisphosphonates have a similar risk of adverse events than placebo, including cardiovascular disorders and risk of attrition due to gastrointestinal events. Zoledronic acid has a higher incidence of influenza-like symptoms (myalgia and arthralgia) than placebo, limited to the first dose and lasting a few days. Zoledronic acid does not cause esophageal, serious gastrointestinal or upper gastrointestinal tract adverse events, but has a higher risk of nausea, which can be caused by large doses of intravenous infusion

Eficácia e segurança do denosumabe comparado aos bifosfonados orais para tratamento de osteoporose e prevenção de fraturas: revisão rápida de evidências / Effectiveness, safety and cost-effectiveness of denosumab compared to oral biposphonates for treating osteoporosis and fracture prevention: rapid review of evidence

Tecnologia: Denosumabe e bifosfonados. Indicação: tratamento de osteoporose para prevenção de fraturas. Pergunta: O denosumabe é mais eficaz e seguro que os bifosfonados orais para tratamento da osteoporose e prevenção de fraturas secundárias à osteoporose? Métodos: Levantamento bibliográfico realizado na PUBMED seguindo estratégia de busca predefinida. Avaliação da qualidade metodológica das revisões sistemáticas com a ferramenta AMSTAR (Assessing the Methodological Quality of Systematic Reviews). Resultados: Foram selecionadas e incluídas 3 revisões sistemáticas, com pontuação de 9 a 11 no AMSTAR. Conclusão: Denosumabe tem menor risco relativo que alendronato e risedronato de sódio para fraturas vertebrais e maior efeito sobre densidade óssea mineral femoral, com risco similar de outros tipos de fratura e eventos adversos (infecções, transtornos cardiovasculares, óbito por infecção, morte cardiovascular ou por qualquer causa). Denosumabe evita 0,00154 fraturas, previne 0,00025 institucionalizações (ou cuidados permanentes de enfermagem no domicílio) e promove um ganho de 0,0018 anos de vida a mais que o alendronato de sódio por paciente tratado. Denosumabe é um pouco mais eficaz e tão seguro quanto os bifosfonados, mas a diferença de eficácia é mínima

Technology: Denosumab and bisphosphonates. Indication: osteoporosis treatment for fracture prevention. Question: Denosumab is more effective and safer than oral bisphosphonates for treating osteoporosis and preventing fractures related to osteoporosis? Methods: Bibliographic search was performed on PUBMED, following predefined search strategies. Evaluation of the methodological quality of systematic reviews was carried out using the AMSTAR (Assessing the Methodological Quality of Systematic Reviews) tool. Results: We selected and included 3 systematic reviews. Their scores ranged from 9 to 11 on AMSTAR. Conclusion: Denosumab has a lower relative risk than sodium alendronate and risedronate for vertebral fractures and greater effect on femoral mineral bone density, with a similar risk for non-vertebral fractures and adverse events (infections, cardiovascular disorders, death caused by infection, cardiovascular death or any cause mortality). Denosumab avoids 0.00154 fractures, prevents 0.00025 nursing home/ residential care admissions and get 0.0018 years of life gained per treated patient more than sodium alendronate. Denosumab is slightly more effective and as safe as bisphosphonates, but the effectiveness difference is minimal

Osteoactivos en insuficiencia renal crónica avanzada: a propósito de un caso / Osteoactive in advanced chronic renal failure: a case report

El propósito de la terapia en el desorden del metabolismo óseo mineral asociado a la enfermedad renal crónica (IRC) consiste en restaurar el balance mineral, y, en la osteoporosis, mantener o aumentar la masa ósea. Ambas terapias tratan de evitar la fractura ósea. La mayoría de los osteoactivos están contraindicados en la insuficiencia renal crónica avanzada (estadios 4 y 5), y las terapias son empíricas. Algunos autores opinan que sin anomalías bioquímicas del desorden del metabolismo óseo mineral asociado a la enfermedad renal crónica avanzada se podría intentar el tratamiento estándar para la osteoporosis. Antes de intentar la terapia osteoactiva se debe corregir el desorden mineral óseo que pudiera presentarse asociado a la IRC, y en la indicación del tipo de osteoactivo se sugiere seleccionar al paciente según su estado óseo. Se aconseja que la administración de los antirresortivos se realice a dosis menores con respecto a los que tienen mejor función renal junto con aportes adecuados de calcio y vitamina D, antes y durante el tratamiento para prevenir el riesgo de severas hipocalcemias y un efecto óseo excesivo. Se presenta el caso clínico de una mujer de 65 años, con diagnóstico de osteoporosis de etiología multifactorial, fractura de pelvis, múltiples fracturas vertebrales e insuficiencia renal crónica avanzada, entre otras comorbilidades, y probable enfermedad ósea adinámica. Recibió inicialmente terapia con teriparatide y luego con denosumab, complicándose con hipocalcemia asintomática. (AU)

The purpose of therapy for the bone mineral metabolism disorder associated with chronic kidney disease is to restore the mineral balance; and to maintain or increase bone mass in osteoporosis. The goal of both types of therapy is to avoid bone fractures. Most antiosteoporotic drugs are contraindicated in advanced chronic renal failure (CRF) stages 4 and 5, and the therapies are empirical. Some authors believe that without biochemical abnormalities of the mineral bone metabolism disorder associated with advanced chronic kidney disease, standard treatment for osteoporosis could be attempted. Before attempting antiosteoporotic therapy, the bone mineral disorder that may be associated with CRF must be corrected, and in the indication of the type drug it is suggested that the patient be selected according to their bone status. It is advised that the administration of anti-resorptives be performed at lower doses in individuals with poor renal function compared to those with better renal function together with adequate calcium and vitamin D, before and during treatment to prevent the risk of severe hypocalcemia, and an excessive bone effect. We present the clinical case of a 65-year-old woman with a diagnosis of osteoporosis of multifactorial etiology, pelvic fracture, multiple vertebral fractures and advanced chronic renal failure, among other comorbidities and probable adynamic bone disease. The patient received initial therapy with teriparatide and followed by denosumab administration and exhibited asymptomatic hypocalcemia. (AU)

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.

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

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.

Clinical characteristics and recurrence-related factors of medication-related osteonecrosis of the jaw

OBJECTIVES: The purpose of this study was to investigate the demographic and clinical characteristics of patients with medication-related osteonecrosis of the jaw (MRONJ) and to elucidate factors affecting recurrence in surgical treatment. MATERIALS AND METHODS: A total of 51 patients who were diagnosed with MRONJ were analyzed according to demographic and clinical features and treatment results through a retrospective chart review from 2013 to 2017 in the Department of Oral and Maxillofacial Surgery, Korea University Anam Hospital, Seoul in Korea. RESULTS: Alendronate composed the majority of medication doses (55.6%), followed by ibandronate (20.0%), risedronate (15.6%), and zoledronate (6.7%). Forty patients (88.9%) were given oral medication, and five patients (11.1%) were intravenously treated, and the mean duration of medication use was 61.1±42.9 months. A total of 10 patients (22.2%) had a drug holiday before MRONJ-induced dental treatment lasting an average of 6.8±7.0 months. MRONJ occurred 2.7 times more in the mandible, with 41 cases (73.2%) occurring in the mandible and 15 cases (26.8%) occurring in the maxilla, and the prevalence of affected posterior parts (premolar-molar) was six times greater than that of the anterior parts (incisor-canine) (48 cases vs 8 cases, 85.7% vs 14.3%). The most common dental cause of MRONJ was tooth extraction (69.6%). Regarding recurrence, there was no statistical difference in recurrence rate according to either site or stage. However, recurrence occurred in 4 out of 34 cases (11.8%) in the primary closure group and 9 out of 20 cases (45.0%) in the secondary healing group, and there was a statistical difference with respect to closure technique. CONCLUSION: The identified risk factors in patients taking bone resorption inhibitors can aid dental clinicians in ensuring prevention and proper treatment of MRONJ.

The Effect of Postoperative Use of Teriparatide Reducing Screw Loosening in Osteoporotic Patients

OBJECTIVE: The loosening of pedicle screws (PS) is one of the frequent problems of spinal surgery in the patients with osteoporosis. Previous studies had revealed that intermittent injection of teriparatide could reduce PS loosening by improving bone mass and quality when their patients took parathyroid hormone for a considerable duration before surgery. However, although the teriparatide is usually used after spine surgery in most clinical situations, there was no report on the efficacy of teriparatide treatment started after spine surgery. The purpose of this retrospective study was to examine the efficacy of teriparatide treatment started immediately after lumbar spinal surgery to prevent pedicle screw loosening in patients with osteoporosis. METHODS: We included 84 patients with osteoporosis and degenerative lumbar disease who underwent transforaminal interbody fusion and PS fixation and received parathyroid hormone or bisphosphonate (BP) postoperatively. They were divided into teriparatide group (daily injection of 20 μg of teriparatide for 6 months, 33 patients, 172 screws) and BP group (weekly oral administration of 35 mg of risedronate, 51 patients, 262 screws). Both groups received calcium (500 mg/day) and cholecalciferol (1000 IU/day) together. The screw loosening was evaluated with simple radiographic exams at 6 and 12 months after the surgery. We counted the number of patients with PS loosening and the number of loosened PS, and compared them between the two groups. Clinical outcomes were evaluated using visual analog scale (VAS) and Oswestry disability index (ODI) preoperatively, and at 12 months after surgery. RESULTS: There was no significant difference in the age, sex, diabetes, smoking, bone mineral density, body mass index, and the number of fusion levels between the two groups. The number of PS loosening within 6 months after surgery did not show a significant difference between the teriparatide group (6.9%, 12/172) and the BP group (6.8%, 18/272). However, during 6–12 months after surgery, it was significantly lower in the teriparatide group (2.3%, 4/172) than the BP group (9.2%, 24/272) (p < 0.05). There was no significant difference in the number of patients showing PS loosening between the teriparatide and BP groups. The teriparatide group showed a significantly higher degree of improvement of the bone mineral density (T-score) than that of BP group (p < 0.05). There was no significant difference in the pre- and post-operative VAS and ODI between the groups. CONCLUSION: Our data suggest that the teriparatide treatment starting immediately after lumbar spinal fusion surgery could reduce PS loosening compared to BP.

The Effect of Postoperative Use of Teriparatide Reducing Screw Loosening in Osteoporotic Patients

OBJECTIVE: The loosening of pedicle screws (PS) is one of the frequent problems of spinal surgery in the patients with osteoporosis. Previous studies had revealed that intermittent injection of teriparatide could reduce PS loosening by improving bone mass and quality when their patients took parathyroid hormone for a considerable duration before surgery. However, although the teriparatide is usually used after spine surgery in most clinical situations, there was no report on the efficacy of teriparatide treatment started after spine surgery. The purpose of this retrospective study was to examine the efficacy of teriparatide treatment started immediately after lumbar spinal surgery to prevent pedicle screw loosening in patients with osteoporosis.METHODS: We included 84 patients with osteoporosis and degenerative lumbar disease who underwent transforaminal interbody fusion and PS fixation and received parathyroid hormone or bisphosphonate (BP) postoperatively. They were divided into teriparatide group (daily injection of 20 μg of teriparatide for 6 months, 33 patients, 172 screws) and BP group (weekly oral administration of 35 mg of risedronate, 51 patients, 262 screws). Both groups received calcium (500 mg/day) and cholecalciferol (1000 IU/day) together. The screw loosening was evaluated with simple radiographic exams at 6 and 12 months after the surgery. We counted the number of patients with PS loosening and the number of loosened PS, and compared them between the two groups. Clinical outcomes were evaluated using visual analog scale (VAS) and Oswestry disability index (ODI) preoperatively, and at 12 months after surgery.RESULTS: There was no significant difference in the age, sex, diabetes, smoking, bone mineral density, body mass index, and the number of fusion levels between the two groups. The number of PS loosening within 6 months after surgery did not show a significant difference between the teriparatide group (6.9%, 12/172) and the BP group (6.8%, 18/272). However, during 6–12 months after surgery, it was significantly lower in the teriparatide group (2.3%, 4/172) than the BP group (9.2%, 24/272) (p < 0.05). There was no significant difference in the number of patients showing PS loosening between the teriparatide and BP groups. The teriparatide group showed a significantly higher degree of improvement of the bone mineral density (T-score) than that of BP group (p < 0.05). There was no significant difference in the pre- and post-operative VAS and ODI between the groups.CONCLUSION: Our data suggest that the teriparatide treatment starting immediately after lumbar spinal fusion surgery could reduce PS loosening compared to BP.

Effectiveness of bisphosphonate combined with activated vitamin D in patients with aromatase inhibitor-induced osteoporosis after breast cancer operation

OBJECTIVES: We compared the effectiveness of bisphosphonates combined with activated vitamin D administered for therapy of aromatase inhibitor-induced osteoporosis after a breast cancer operation and primary postmenopausal osteoporosis through propensity score matching. METHODS: Forty-eight postmenopausal patients with estrogen receptor-positive early breast cancer, who had postoperative adjuvant treatment with aromatase inhibitors and whose T-score of bone mineral density (BMD) decreased below −2.5 (AI group), and 48 patients of primary postmenopausal osteoporosis (PO group) enrolled in this retrospective observational study. They were administered monthly risedronate or minodronate, and daily alfacalcitol or eldecalcitol were combined. Their BMD (L2–4, L-BMD), serum-corrected calcium, serum phosphate, tartrate-resistant acid phosphatase 5b (TRACP-5b), bone alkaline phosphatase (BAP), estimated glomerular filtration rate, urine calcium/creatinine ratio, intact-parathyroid hormone, and 25-hydroxy vitamin D were measured before treatment and until 24 months. RESULTS: L-BMD values increased with time compared with the baseline values in each group, and there was no significant difference in the groups. Percentage value of TRACP-5b decreased rapidly after 6 months and maintained low level until 24 months in both groups. Percentage value of BAP in the AI group decreased continuously until 24 months. In contrast, the percentage change in the PO group plateaued after 6 months. CONCLUSIONS: It is suggested that monthly oral bisphosphonate combined with activated Vitamin D is an effective therapy to increase BMD in the aromatase inhibitor-induced osteoporosis after breast cancer operation. Monitoring of kidney function and concentration of Ca in blood and urine may be necessary.

Does Discontinuing Teriparatide Treatment and Replacing It with Bisphosphonate Maintain the Volume of the Bone Fusion Mass after Lumbar Posterolateral Fusion in Women with Postmenopausal Osteoporosis?

STUDY DESIGN: Retrospective case series. PURPOSE: The purpose of this study was to determine whether discontinuing teriparatide treatment and replacing it with bisphosphonate treatment maintains the volume of the fusion mass after posterolateral fusion (PLF) in women with postmenopausal osteoporosis. OVERVIEW OF LITERATURE: Clinical data support the efficacy of parathyroid hormone (PTH) for lumbar PLF. However, the use of PTH is limited to 2 years. METHODS: We treated 19 women diagnosed with osteoporosis and degenerative spondylolisthesis with teriparatide (20 µg daily subcutaneously). All patients underwent one-level instrumented PLF. Teriparatide was used during 2 months prior to surgery and more than 8 months after surgery. After discontinuing teriparatide treatment, all patients used bisphosphonate (17.5 mg risedronate weekly, oral administration). Area of the fusion mass across the transverse processes at one segment was determined on an anteroposterior radiograph at 1, 2, and 3 years after surgery. RESULTS: We followed 19 patients for 3 years. The average duration of teriparatide treatment was 11.5 months. The bone union rate was 95%. The average area of the bone fusion mass was not significantly different between the right and left sides at 1, 2, or 3 years after surgery (p>0.05). CONCLUSIONS: This study showed that replacing teriparatide treatment with bisphosphonate maintained the bone fusion mass volume after PLF in women with postmenopausal osteoporosis.

Can Alarming Improve Compliance with Weekly Bisphosphonate in Patients with Osteoporosis?

BACKGROUND: Although bisphosphonate is effective for the prevention and treatment of osteoporosis, poor medication compliance is a key-limiting factor. We determined whether alarm clock could improve compliance with weekly bisphosphonate in patients with osteoporosis, by comparing with age- and gender-matched control group. METHODS: Fifty patients with osteoporosis were recruited and participated in alarm clock group. Patients were asked to take orally weekly risedronate for 1 year, and received alarm clock to inform the time of taking oral bisphosphonate weekly. Using the propensity score matching with age and gender, 50 patients were identified from patients with osteoporosis medication. We compared the compliance with bisphosphonate using medication possession ratio (MPR) between two groups. RESULTS: Although there was no significant difference of baseline characteristics between both groups, the mean MPR (0.80±0.33) of alarm clock group was higher than that (0.56±0.34) of control group (P<0.001). CONCLUSIONS: Alarming could improve the compliance with weekly oral bisphosphonate in patients with osteoporosis.

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.

Pamidronate Down-regulates Tumor Necrosis Factor-alpha Induced Matrix Metalloproteinases Expression in Human Intervertebral Disc Cells

BACKGROUND: N-containing bisphosphonates (BPs), such as pamidronate and risedronate, can inhibit osteoclastic function and reduce osteoclast number by inducing apoptotic cell death in osteoclasts. The aim of this study is to demonstrate the effect of pamidronate, second generation nitrogen-containing BPs and to elucidate matrix metallo-proteinases (MMPs) mRNA expression under serum starvation and/or tumor necrosis factor alpha (TNF-α) stimulation on metabolism of intervertebral disc (IVD) cells in vitro. METHODS: Firstly, to test the effect of pamidronate on IVD cells in vitro, various concentrations (10⁻¹², 10⁻¹⁰, 10⁻⁸, and 10⁻⁶ M) of pamidronate were administered to IVD cells. Then DNA and proteoglycan synthesis were measured and messenger RNA (mRNA) expressions of type I collagen, type II collagen, and aggrecan were analyzed. Secondly, to elucidate the expression of MMPs mRNA in human IVD cells under the lower serum status, IVD cells were cultivated in full serum or 1% serum. Thirdly, to elucidate the expression of MMPs mRNA in IVD cells under the stimulation of 1% serum and TNF-α (10 ng/mL) In this study, IVD cells were cultivated in three dimensional alginate bead. RESULTS: Under the lower serum culture, IVD cells in alginate beads showed upregulation of MMP 2, 3, 9, 13 mRNA. The cells in lower serum and TNF-α also demonstrated upregulation of MMP-2, 3, 9, and 13 mRNA. The cells with various doses of pamidronate and lower serum and TNF-α were reveled partial down-regulation of MMPs. CONCLUSIONS: Pamidronate, N-containing second generation BPs, was safe in metabolism of IVD in vitro maintaining chondrogenic phenotype and matrix synthesis, and down-regulated TNF-α induced MMPs expression.

Efectividad y seguridad del ácido risedrónico para prevenir y tratar la osteoporosis secundaria en pacientes expuestos a tratamiento sistémico prolongado con corticosteroides / Effectiveness and safety of risedronic acid to prevent and treat secondary osteoporosis in patients exposed to prolonged systemic corticosteroid treatment

Introducción: osteoporosis inducida por Glucocorticoides (OIG) es la osteoporosis (OP) más frecuente dentro de la categoría de las OP secundarias, todos los pacientes en tratamiento prolongado con GC pueden desarrollar osteoporosis, debido a una mayor pérdida de hueso trabecular (5), las prevalencias de fractura secundaria a OIG están entre 30% y 50%. Objetivo: evaluar la efectividad y la seguridad del ácido risendronico en la prevención y tratamiento de la osteoporosis secundaria a tratamiento sistémico prolongado con corticosteroides, como uno de los criterios para informar la toma de decisiones relacionada con la posible inclusión de tecnologías en el Plan Obligatorio. Metodología: la evaluación fue realizada de acuerdo al protocolo definido previamente por el grupo desarrollador el cual incluye una revisión sistemática de la literatura en MEDLINE, EMBASE, LILACS, COCHRANE, Google, WHO y clinicaltrias.gov para dar respuesta a la pregunta de investigación desarrollada. Resultados: La comparación entre ácido risedronico y zoledrónico como tratamiento para prevención de la OIG con un uso de glucocorticoides menor a 3 meses , reportó un porcentaje de cambio en la densidad mineral ósea (DMO) con ácido zoledrónico de 2.46 (DE:0.84), versus −0.24 (DE:0.90) del risedronato y una diferencia a favor de zoledrónico de 2.70 (IC 95%: 0.99, 4.42), estadísticamente significativo; mientras para tratamiento de la OIG (tratamiento reciente con GC > 3 meses), reportó un porcentaje de cambio en la DMO con ácido zoledrónico de 4.69 (DE:0.52), versus 3.27 (DE: 0.52) del risedronato y una diferencia a favor de zoledrónico de 1.42 (IC 95%: 0.20, 2.64), es estadísticamente significativo. Los dos estudios referencian una diferencia a favor del ácido zoledrónico en el efecto sobre marcadores bioquímicos para resorción y formación ósea después de 12 meses de tratamiento, pero ninguno de los dos aportó los datos respecto al tamaño del efecto. Respecto a la seguridad del risedronato el estudio publicado por Reid, 2009 (29) reportó una frecuencia de cualquier evento adverso en los pacientes intervenidos en el esquema de prevención del 77% (111/272 pacientes) en el grupo de ácido zoledrónico, mientras que en el grupo de risedronato fue del 65% (93/273 pacientes), con un valor de p= 0.0272, una diferencia estadísticamente significativa, a favor del risedronato. El estudio Reid, 2009 (29) reporto una frecuencia de cualquier evento adverso del 78% (211 pacientes) para el grupo de zoledronato, comparado con un 68% (186 pacientes) para el grupo de risedronato, con una p estadísticamente significativa de 0.0159, a favor del risedronato. El empeoramiento de la artritis reumatoidea fue el evento adverso serio más frecuente con un 8% para el ácido zoledronico comparado con un 6% en pacientes tratados con risedronato (p=0.5067), diferencia no estadísticamente significativa. Conclusiones: Efectividad: Para el desenlace del cambio en la densidad mineral ósea medida en espina lumbar, se evidencia que el ácido zoledronico es más efectivo que el risedronato, tanto para prevenir como para tratar la osteoporosis secundaria en pacientes expuestos a tratamiento sistémico prolongado con corticosteroides. Seguridad: El reporte de eventos adversos fue más frecuente en el grupo que recibió ácido zoledronico comparado con el grupo de pacientes que recibió risedronato para tratamiento y prevención de la osteoporosis secundaria al tratamiento sistémico prolongado con corticoides.(AU)