Zoledronate regulates osteoclast differentiation and bone resorption in high glucose through p38 MAPK pathway / 南方医科大学学报

OBJECTIVE@#To investigate the effect of zoledronate (ZOL) on osteoclast differentiation and bone resorption under high glucose, and the regulation mechanism of p38 mitogen activated kinase (p38 MAPK) signaling pathway in this process.@*METHODS@#RAW264.7 cells were divided into four groups: low group, high group, low+ZOL group and high+ZOL group after induced into osteoclasts. Cell proliferation activity was determined by MTT assay. The migration of RAW264.7 cells were examined Optical microscopy. Immunofluorescence microscopy was used to observe the cytoskeleton and sealing zones of osteoclasts. After adding group 5: high + ZOL + SB203580 group, trap staining was used to identify the number of positive osteoclasts in each group. The number and area of resorption lacunae were observed by SEM. The mRNA and protein expression of osteoclast related factors were detected by real-time PCR and Western blotting.@*RESULTS@#The cells in the 5 groups showed similar proliferative activity. High glucose promoted the migration of RAW264.7 cells (@*CONCLUSIONS@#High glucose inhibits osteoclast differentiation and bone resorption. ZOL inhibits osteoclast differentiation and bone resorption in high-glucose conditions by regulating p38 MAPK pathway, which can be a new pathway for ZOL to regulate diabetic osteoporosis.

Bone-seeking nanoplatform co-delivering cisplatin and zoledronate for synergistic therapy of breast cancer bone metastasis and bone resorption

The "vicious cycle" established between tumor growth and osteolysis aggravates the process of breast cancer bone metastasis, leading to life-threatening skeletal-related events that severely reduce survival and quality of life. To effectively interrupt the "vicious cycle", innovative therapeutic strategies that not only reduce osteolysis but also relieve tumor burden are urgently needed. Herein, a bone-seeking moiety, alendronate (ALN), functionalized coordination polymer nanoparticles (DZ@ALN) co-delivering cisplatin prodrug (DSP) and antiresorptive agent zoledronate (ZOL)

Preparation of Zoledronate liposome and its impact on apoptosis of Kupffer cells in rat liver

Abstract Purpose: To establish a method for the preparation of zoledronate liposome and to observe its effect on inducing the apoptosis of rat liver Kupffer cells. Methods: Zoledronate was encapsulated in liposomes, and then the entrapment rate was detected on a spectrophotometer. The prepared Zoledronate liposome (0.01 mg/mL) was injected into the tail vein of SD rats. Three days later, the number of Kupffer cells (CD68 positive) in rat liver tissue was detected by immunohistochemistry. Flow cytometry was used to detect the apoptosis rate of the isolated liver Kupffer cell cultured in vitro. Results: The entrapment rate of Zoledronate was 43.4±7.8%. Immunohistochemistry revealed that the number of Kupffer cells was 19.3±2.1 in PBS group and 5.5±1.7 in Zoledronate liposome group, with a significant difference (P<0.05). The apoptosis rate of Kupffer cells was 4.1±0.8% in PBS group, while it was 9±2.2% and 23.3±5.9% in Zoledronate liposomes groups with different concentrations of Zoledronate liposome (P<0.05). Conclusions: Zoledronate liposomes can effectively induce the apoptosis of Kupffer cells in vivo and in vitro, and the apoptosis rate is related to the concentration of Zoledronate liposome. To establish a rat liver Kupffer cell apoptosis model can provide a new means for further study on Kupffer cell function.

Effect of zoledronate on the clinical efficacy and IL-8, IL-10 and osteocalcin levels in perimenopausal with osteoporosis / 中国生化药物杂志

Objective To investigate the effect of zoledronate on the clinical efficacy and IL-8, IL-10 and osteocalcin levels in perimenopausal women with osteoporosis.Methods A total of 72 cases menopausal syndrome with osteoporosis from January 2014 to March 2015 in Hangzhou Third People's Hospital of Yuhang District were randomly divided into two groups with 36 cases in each group.Patients in the control group were treated with routine oral administration of calcium carbonate D3 and alpha D3, and the observation group was treated with zoledronate acid sodium on this basis for four weeks.Serum inflammatory factor and bone metabolism index were measured before and after treatment , VAS score and bone mineral density were measured, and the clinical effect was compared.Results Compared with before treatment, two groups of serum ALP, BGP levels and VAS score were significantly decreased (P<0.05), IL-8 and TNF-αlevels decreased (P<0.05), IL-10 level increased (P<0.05), lumbar(L1 ~4), bilateral hip and femoral neck BMD increased (P<0.05); compared with the control group, serum ALP, BGP levels and VAS score in the observation group was lower (P<0.05), IL-8, TNF-αlevels were lower (P<0.05), IL-10 level was higher (P<0.05), lumbar(L1 ~4), bilateral hip and femoral neck BMD were higher (P<0.05), the treatment effective rate was higher (P <0.05).Conclusion Zoledronate in the treatment of perimenopausal syndrome with osteoporosis is significant clinical efficacy, it can effectively relieve the inflammatory symptoms and bone and joint pain, inhibit bone reduction.

Raloxifene neutralizes bone brittleness induced by anti-remodeling treatment and increases fatigue life through non-cell mediated mechanisms / El raloxifeno invierte fragilidad ósea inducida por el tratamiento anti-remodelación y aumenta la resistencia a la fatiga a través de mecanismos mediados no celulares

Pre-clinical data have shown that tissue level effects stemming from bisphosphonateinduced suppression of bone remodeling can result in bone that is stronger yet more brittle. Raloxifene has been shown to reduce bone brittleness through non-cellular mechanisms. The goal of this work was to test the hypothesis that raloxifene can reverse the bone brittleness resulting from bisphosphonate treatment. Dog and mouse bone from multiple bisphosphonate dosing experiments were soaked in raloxifene and then assessed for mechanical properties. Mice treated with zoledronate in vivo had lower post-yield mechanical properties compared to controls. Raloxifene soaking had significant positive effects on select mechanical properties of bones from both vehicle and zoledronate treated mice. Although the effects were blunted in zoledronate bones relative to vehicle, the soaking was sufficient to normalize properties to control levels. Additional studies showed that raloxifene-soaked bones had a significant positive effect on cycles to failure (+114%) compared to control-soaked mouse bone. Finally, raloxifene soaking significantly improved select properties of ribs from dogs treated for 3 years with alendronate. These data show that ex vivo soaking in raloxifene can act through non-cellular mechanisms to enhance mechanical properties of bone previously treated with bisphosphonate. We also document that the positive effects of raloxifene soaking extend to enhancing fatigue properties of bone. (AU)

Los datos preclínicos han demostrado que los efectos a nivel de tejido que se derivan de la supresión del remodelado óseo inducida por bifosfonatos puede dar como resultado un hueso que es más fuerte pero más frágil. Está comprobado que el raloxifeno reduce la fragilidad ósea a través de mecanismos no celulares. El objetivo de este trabajo fue probar la hipótesis de que el raloxifeno puede revertir la fragilidad ósea resultante del tratamiento con bifosfonatos. Se emplearon huesos de perro y ratón de múltiples experimentos con diferentes dosis de bifosfonatos los cuales fueron sumergidos en raloxifeno y luego se evaluaron sus propiedades mecánicas. Ratones tratados con zoledronato in vivo mostraron propiedades mecánicas post-rendimiento más bajas en comparación con los controles. Luego de sumergirlos en raloxifeno se observaron efectos positivos significativos en algunas propiedades biomecánicas tanto en los huesos de ratones tratados con vehículo como con zoledronato. Aunque los efectos se atenuaron en los huesos tratados con zoledronato en relación con los tratados con vehículo, el raloxifeno fue suficiente para normalizar las propiedades a niveles basales. Estudios adicionales mostraron que los huesos sumergidos en raloxifeno tuvieron un efecto positivo significativo en los ciclos de fractura (+ 114%) en comparación con los huesos de ratón sumergido en vehículo. Finalmente, el raloxifeno mejoró significativamente las propiedades de costillas de perros tratados durante 3 años con alendronato. Estos datos muestran que la inclusión ex vivo en raloxifeno puede actuar a través de mecanismos no celulares para mejorar las propiedades mecánicas de huesos previamente tratado con bifosfonatos. También documentamos que los efectos positivos del raloxifeno mejoran las propiedades de fatiga del hueso. (AU)

A Interventional Study in a Real Life Setting to Assess the Clinical Efficacy and Effect on Fracture in the 1 Year after Injection of Zoledronic Acid in Osteoporotic Patients with Long Bone or Spine, Pelvic Fractures / 대한정형외과학회잡지

PURPOSE: We studied the improvement of back pain in vertebral fracture and fracture healing in non-vertebral fracture after treatment with zoledronate in postmenopausal patients. MATERIALS AND METHODS: Postmenopausal women with bone mineral density (BMD) T-score of -2.5 or less and existing vertebral fractures or non-vertebral fractures between January 2011 and June 2012 were included. Patients received a single intravenous infusion of zoledronate within 3 days after diagnosis of fractures. The primary outcome was BMD and secondary outcomes were visual analogue scale (VAS) for back pain, fracture healing, and new clinical fracture. RESULTS: T-score increased significantly in the vertebral fracture group (n=97) and non-vertebral fracture group (n=31) at 1 year (p<0.05). The average VAS for back pain decreased significantly in the vertebral fracture group (p<0.05) and there was no delayed union, nonunion in the non-vertebral fracture group. There was no re-fracture and 3 new clinical fractures (2.34%) occurred during the follow-up period. CONCLUSION: Zoledronate, as treatment in postmenopausal osteoporosis patients can improve BMD, reduce back pain in vertebral fracture, and has no negative effect on bone healing after fracture in non-vertebral fracture.

Efficacy of zoledronate in patients with osteoporosis and its influence on the indicators of bone metabolism / 中国生化药物杂志

Objective To observe the clinical effect of zoledronate in patients with osteoporosis and its influence on the indicator of bone metabolism.Methods 120 cases osteoporosis patients were randomly divided into treatment group (66 cases) and control group (54 cases).Control group were given calcium carbonate vitamin D3 ,patients in treatment group were also treated with zoledronate by intravenous injection.The pain score, bone density and the indicators of bone metabolism one year after the treatment were analyzed and compared.Results After one year of treatment, the pain score of treatment group was significantly lower than that of the control group, showing significant difference between the two group(P<0.05). Bone density of L1-L4, neck were higher than those of control group, serum concentrations of BALP,β-CTX, DPD/Cr were lower than that of control group(all P<0.05), but hCT was lower than that of control group(P<0.05), and the treatment of serum Ca,P,BGP were not significant statistically before and after treatment.In treatment group, serum TRACP-5b was remarkably decreased, but was increased remarkably in control group(P<0.05) .Conclusion Zoledronate combined with calcium carbonate vitamin D3 in treatment of patients with osteoporosis can be effective in improving the symptom of pain associated with bone metabolism indicators, decrease bone absorb, increase the bone mineral density, with less adverse reaction and patient compliance is good.

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.

Effect of Zoledronate on the Expression of Vascular Endothelial Growth Factor-A by Articular Chondrocytes and Synovial Cells: An in Vitro Study

BACKGROUND: The aim of this in vitro study was to determine the effect of zoledronate, which is frequently used to treat osteoporosis, on osteoarthritis by analyzing zoledronate-induced expression of vascular endothelial growth factor-A (VEGF-A) in chondrocytes and synovial cells. METHODS: After chondrocytes and synovial cells were separated and cultured, zoledronate was added, and VEGF-A and pigment epithelium-derived factor (PEDF) expression were quantified by real-time polymerase chain reaction and Western blotting. RESULTS: There was no significant difference in the expression of VEGF-A mRNA in chondrocytes between the zoledronate group and the control group on the 8th day of culture. The expression of both VEGF-A and PEDF mRNA in synovial cells was significantly decreased in the zoledronate group (P<0.05). CONCLUSIONS: Zoledronate decreases the expression of VEGF-A in synovial cells and may affect the development and progression of osteoarthritis.

Prevención y tratamiento de la osteoporosis en pacientes con Mieloma múltiple, estadios iniciales de Carcinoma de mama y Cáncer de próstata / Prevention and treatment of osteoporosis in multiple myeloma, early stages of breast cancer and prostate cancer

Se ha efectuado una revisión de los trabajos sobre la fisiopatología del MM y sobre el tratamiento de las lesiones osteoporóticas que se presentan en casi todos los casos. Es sabido que los bifosfonatos son sumamente efectivos por lo que se comentan los actuales esquemas de tratamiento tomando en cuenta los recientes consensos. Hay un acuerdo prácticamente unánime en la eficacia del pamidronato y el zoledronato endovenosos aplicados mensualmente durante dos años, siendo aceptado el uso del clodronato oral en Europa pero no en EE.UU. Aunque mejorarían la calidad de la sobrevida, los bifosfonatos no la prolongarían. Se refieren las precauciones que habría que tomar para evitar la osteonecrosis de mandíbula, una complicación de las dosis altas de bifosfonatos que se ha comunicado con mayor frecuencia durante los últimos años. Se destaca la importancia de la consulta odontológica frecuente y del permanente cuidado dental.

The aim of this review is to discuss recent findings in the physiopathology and treatment of osteoporotic lesions present in almost all patients with MM. The efficacy of bisphosphonates is well known, so we summarize the current treatment schedules according to the most recent consensus. Pamidronate and Zoledronate are equally effective and universally accepted. They should be administered intravenously on a monthly basis for two years. Oral clodronate is accepted in Europe but not in USA. Even if bisphosphonates provide a better quality of life, they do not increase survival. Because osteonecrosis of the jaw has been repeatedly reported after high doses of bisphosphonates, we discuss the necessary precautions to prevent this condition emphasizing frequent dental care and examinations.

EFFECT OF SHORT ADMINISTRATION BISPHOSPHONATE TO PERIOSTEUM AND SINUS MEMBRANE AFTER ILIAC BONE GRAFT INTO MAXILLARY SINUS IN RABBIT

The effects of bisphosphonates on differentiation of human amniotic fluid-derived mesenchymal stem cells into osteoblast / 대한산부인과학회지

OBJECTIVE: It has been known that amniotic fluid (AF) is rich source of mesenchymal stem cells (MSCs). Bisphosphonates are widely used in clinical treatment of various metabolic bone diseases and their primary action is the inhibition of osteoclastic bone resorption. However, litter is known about whether bisphosphonates affect the differentiation into osteoblast, especially from AF-derived MSCs (AFMSCs). Therefore, the purpose of this study is to investigate whether these bisphosphonates influence in the process of AFMSCs differentiation into osteoblast. METHODS: AF samples were obtained by second trimester amniocentesis for fetal karyotyping from 6 pregnant women. Cells were treated with various concentration (0, 10(-10), 10(-8), 10(-6) M) of zoledronate and alendronate and analyzed over 21 days of culture. Differentiation into osteoblast was determined by cell staining and RT-PCR for alkaline phosphatase (ALP). RESULTS: It was observed that AFMSCs could differentiate into osteoblast. Alendronate had more potent effect than zoledronate in osteoblastic differentiation. ALP expression was increased with increasing concentration of zoledronate and it was highest in 10(-8) M alendronate. However, no effect of bisphosphonates was found in 14 days of culture. CONCLUSION: This study shows that AFMSCs can be differentiated into osteoblast. The induction of these differentiation following bisphosphonate treatment was appear to be drug type-, dose-, and culture time-dependent. However, further studies are needed to conclude a consistent outcome for the effects of bisphosphonate on differentiation potential of AFMSCs.

Effect of zoledronate to bone healing process after iliac bone graft into maxillary sinus in rabbit

OBJECTIVE : Recently, we are interested in bisphosphonate related osteonecrosis of the jaw (BRONJ). Most of patients with osteonecrosis have taken medicine bisphosphonate for a long time. But the mechanism of osteonecrosis in BRONJ was not clarified yet. The aim of this study is to evaluate the difference of bone healing effect after bone graft from ilium to maxillary sinus in rabbits between zoledronate-treated and zoledronate-not treated groups. METHOD : The subjects was divided into two groups. The experimental group was 9 rabbits, treated with intraperitoneal administration of zoledronate( 0.06mg/kg) once per week for 3 weeks. In control group, same procedure was applied but administerd saline instead of zoledronate. After 4 weeks, surgical operation under local anesthesia (ketamine 3.0cc, xylazine 1.0cc) was done. At postoperative 1, 2, 4, 8 weeks later, each rabbits were sacrificed and removed the bone grafted area. Gross, radiologic and histopathologic exminations of bone grafted area were performed. RESULT : There were no conspicuous differences of radiological findings between experimental and control groups in any experimental weeks. In experimental group, new bone formation appeared earlier than control group at 1 week after operation, and maturation of bony tissue were more conspicuous at 2 and 4 weeks after operation, compared with control group. In 8 weeks after operation, similar microscopic findings were noted in both groups. CONCLUSION : In the bisphosphonate-treated rabbits, new bone formation in the bone grafted area appeared earlier and bony maturation was more concpicuous, even though there were no significant differences of gross and radiological findings. These findings suggest that bisphosphonate might be promotive effect in the healing process in early stage after administration.

The Effect of Zoledronate on the Differentiation of Human Amniotic Fluid-Derived Mesencymal Stem Cells into Adipocytes / 대한수혈학회지

BACKGROUND: Amniotic fluid is a rich source of fetal mesenchymal stem cells (MSCs). However, little is known about whether bisphosphonates affect the differentiation into adipocytes. Therefore, this study was aimed to investigate whether zoledronate influences the differentiation of AFMSCs into adipocytes. METHODS: Amniotic fluid cells samples were obtained from 6 pregnant women by second trimester amniocentesis for performing fetal karyotyping. The cells were treated with various concentration (10(-10), 10(-8), 10(-6) M) of zoledronate and the cells were analyzed over 21 days of culture. Differentiation into adipocytes was determined by oil-red O staining and for fatty acid synthase (FAS), acetyl CoA carboxylase 1 (ACC1) and sterol regulatory elementary binding protein-1 (SREBP-1). RESULTS: Differentiation of AFMSCs into adipocytes was found by oil-red O staining. Zoledronate influenced the differentiation of AFMSCs into adipocytes in a dose- and time-dependent manner. At 7 days of culture, the expressions of FAS and SREBP-1 showed no significant differences compared to that of the control regardless of the dose of zoledronate. Very little ACC1 expression was found. However, the expressions of these three markers were remarkably increased at 14 days of culture. Of them, the ACC1 expression was significantly increased by 10(-8) M and 10(-6) M of zoledronate. At 21 days of culture, there were no effects of zoledronate on the expressions of FAS and SREBP-1. However, the ACC1 expression was decreased with an increasing dose of zoledronate (P<.05). CONCLUSION: This study shows that AFMSCs can be differentiated into adipocytes. The induction of this differentiation following zoledronate treatment appears to be dose dependent and time-of-culture dependent.

Effects of Zoledronate on Thoracic Vertebral Fracture in an Ankylosing Spondylitis Patient: A case report

Patients with ankylosing spondylitis are more susceptible to spine fractures than healthy people. Because of their underlying back pain, vertebral fracture induced pain is not easily controlled by bed rest, physical therapy and medications. Thus, new treatment methods should be introduced. We report a 63 year-old man with ankylosing spondylitis who fell down 4 weeks ago and suffered a fracture of T6 spine. He complained of a mid thoracic pain. Although he was treated with bed rest, physical therapy, second-line bisphosphonate agents, the pain persisted. Therefore, intravenous zoledronate which was approved for palliative treatment of bone metastases in patients with breast cancer, 4 mg was administrated. The severity of pain was decreased by half within 2 days and sustained over 4 weeks.