Protective mechanism of alendronate granule in a rat osteoporosis model based on TMT proteomic analysis / 中国组织工程研究

BACKGROUND:The mechanisms and targets of alendronate in the treatment of osteoporosis still need to be investigated in depth. OBJECTIVE:To investigate the mechanism by which alendronate regulates bone metabolism in rats with osteoporosis and to perform a bioinformatics analysis of differentially expressed proteins. METHODS:Female Sprague-Dawley rats were randomly divided into three groups(n=12 per group):model group,alendronate group and sham-operated group.Animal models of osteoporosis were prepared using ovariectomy in the model and alendronate groups.At 4 weeks after modeling,rats in the alendronate group were gavaged with alendronate;the other two groups were given the equal volume of normal saline.After 12 weeks of continuous gavage,the bone mineral density of the tibia was measured and the lumbar spine of the rats was taken for proteomic analysis using Tandem mass tag-liquid chromatography-tandem mass spectrometry technique to identify differentially expressed proteins for gene ontology,Kyoto Encyclopedia of Genes and Genomes pathway and protein-protein interaction analysis. RESULTS AND CONCLUSION:There were 32 up-regulated proteins and 51 down-regulated proteins identified between the alendronate group and model group.Gene ontology enrichment analysis showed that the differentially expressed proteins were mainly involved in molecular functions,such as binding and catalytic activity,and in biological processes,such as cellular process and metabolic process.Kyoto Encylopedia of Genes and Genomes enrichment analysis showed that the differentially expressed proteins in the alendronate group and model group were mainly involved in the biosynthesis of pantothenate and coenzyme A.Protein-protein interaction analysis indicated that among the differentially expressed proteins in the alendronate group and model group,Hspa1l,Enpp3,Unc45a,Myh9 and Cant1 were located at the nodes of the protein-protein interaction network and were closely related to bone metabolism.Overall,these findings indicate that alendronate may regulate bone metabolism in the rat model of osteoporosis by regulating the expression of differentially expressed proteins and biosynthesis of pantothenate and coenzyme A.

Mechanism by which alendronate promotes rapid mandibular distraction osteogenesis in rabbits / 中国组织工程研究

BACKGROUND:Some studies have found that local application of alendronate can promote osteogenesis,but less is reported on the process of distraction osteogenesis. OBJECTIVE:To observe the promoting effect of alendronate on rapid mandibular distraction in a rabbit model and explore its possible mechanism. METHODS:Thirty-six male New Zealand white rabbits were randomly divided into groups A,B and C(n=12 per group)after operation and rapid distraction(3-day delay period followed by 3-day distraction at 1.5 mm/12 hours).At the 1st,3rd and 7th days of the consolidation period,animal were injected with 200 μg/kg alendronate in group A and 100 μg/kg alendronate in group B,while those in group C were treated as controls.CT scanning and dual energy X-ray bone mineral density measurement were performed at 4 and 8 weeks of the consolidation period.After the radionuclide scanning was completed at the 4th week,several animals were sacrificed and the samples were collected for western blot assay and tartrate resistant acid phosphatase staining.A three-point bending test was performed after the animals were sacrificed at the 8th week. RESULTS AND CONCLUSION:CT results showed that bone formation in the distraction space of group B was significantly better than that in groups A and C.At the 4th week,the bone mineral density in group B was(0.092±0.010)g/cm2,which was 1.26 times higher than that in group A(P＜0.001)and 1.28 times higher than that in group C(P＜0.001).At the 8th week,the bone mineral density in group B was(0.175±0.029)g/cm2,which was 1.38 times higher than that in group A(P＜0.001)and 1.45 times higher than that in group C(P＜0.001).Tartrate resistant acid phosphatase staining showed that the number of osteoclast-like cells in group C were 2.83 times more than that in group A(P＜0.001)and 2.21 times more than that in group B(P＜0.001).The radionuclide intensity was higher in group C than in groups A and B.Western blot assay results showed that the expression of Runx2 was significantly stronger in group B than in groups A and C.The maximum biomechanical load in group B was(158.48±23.21)N,which was 1.26 times higher than that in group A(P=0.007)and 1.31 times higher than that in group C(P=0.003).To conclude,the low concentration of alendronate may promote rapid distraction osteogenesis of the rabbit mandible by inhibiting osteoclast signals.

Literature Review of Using Bisphosphonates in the Treatment of Calciphylaxis / 罕见病研究

Objective To analyze the effectiveness and safety of bisphosphonates in the treatment of patients with calcification defense. Methods PubMed, Embase databases, CNKI and Wanfang were searched to collect the case reports and clinical studies of bisphosphonates for calcification defense. Then, the relevant information of patients was extracted for statistical analysis. Results A total of 18 case reports were selected involving 20 patients. Thirteen patients (65.0%) were treated with pamidronate, four (20.0%) were treated with etidronate, two (10.0%) were treated with alendronate, and one (5.0%) was treated with zoledronic acid. Thirteen patients (65.0%) recovered completely, the recovery time of whom ranged from half month to nine months. The tolerance of bisphosphonates in most patients(90.0%)was good, while one patient who did not tolerate pamidronate recovered after the frequency of administration was adjusted and one patient with high dosage of etidronate returned to normal after the discontinuation of the usage. Conclusions Bisphosphonates, an inhibitor of bone resorption, is effective and safe in the treatment of patients with calcification defense.

The effects of sodium alendronate on socket healing after tooth extraction: a systematic review of animal studies

Abstract The aim of this systematic review was to answer the following question: "Does alendronate, a nitrogen-containing bisphosphonate, improve or impair alveolar socket healing after tooth extraction in animal models"? To this end, a systematic review of the literature was carried out in PubMed, Scopus, LILACS, Web of Science, as well as in the gray literature up to May 2023. Preclinical studies that evaluated alveolar healing after tooth extraction and the intake of sodium alendronate compared with placebo were included. Two investigators were responsible for screening the articles independently, extracting the data, and assessing their quality through the SYRCLE's RoB tool for randomized trials in animal studies. The study selection process, study characteristics, risk of bias in studies, impact of alendronate on bone healing, and certainty of evidence were described in text and table formats. Methodological differences among the studies were restricted to the synthesis methods. The synthesis of qualitative results followed the Synthesis Without Meta-analysis (SWiM) reporting guideline. From the 19 included studies, five were considered to have low risk, three were of unclear risk, and eleven presented a high risk of bias. The studies were considered heterogeneous regarding alendronate posology, including its dosage and route of administration. Furthermore, a variety of animal species, different age ranges, diverse teeth extracted, and exposure or not to ovariectomy contributed to the lack of parity of the selected studies. Our results indicated that alendronate monotherapy negatively affects the early phase of wound healing after tooth extraction in preclinical studies, suggesting that the bone resorption process after tooth extraction in animals treated with alendronate might impair the bone healing process of the extraction socket. In conclusion, alendronate administration restrains bone resorption, thereby delaying alveolar socket healing . Future studies should be conducted to validate these findings and to better understand the effects of alendronate therapy on oral tissues.

Effect of alendronate tablets combined with calcitonin therapy on IGF-1, PINP and S-CTX levels in patients with T2DM combined with osteoporosis / 中华内分泌外科杂志

Objective:To investigate the effect of combined treatment with alendronate tablets and calcitonin on insulin like growth factor-1 (IGF-1), procollagen type Ⅰ amino terminal lengthening peptide (PINP) and c-terminal telopeptide of type Ⅰ collagen (S-CTX) levels in patients with type 2 diabetes mellitus (T2DM) combined with osteoporosis (OP) .Methods:Using the principle of randomized controlled experiment, 130 patients in Xiyuan Hospital, China Academy of Chinese Medical Sciences from Feb. 2021 to Feb. 2022 were selected as study subjects and divided into control group and observation group according to the randomized envelope method in the ratio of 1:1, 65 cases each. The control group was treated with calcitonin and the observation group was treated with alendronate tablets combined with calcitonin, both were treated continuously for 6 months. The therapeutic effect, bone mineral density, blood glucose related indexes [fasting blood glucose (FPG), 2 h postmeal blood glucose (2 hPG), glycosylated hemoglobin content (HAb1c) ], 25 hydroxyvitamin D[25 (OH) D], IGF-1, PINP, S-CTX, and adverse reactions were statistically compared between the two groups.Results:The total effective rate of the observation group was 98.46%, higher than that of the control group 86.15% ( P < 0.05) ; After 6 months of treatment, the bone mineral density of left femoral neck, hip, lumbar spine L1-L4 and Wards triangle in the observation group was higher than that in the control group ( P < 0.05) ( P < 0.05) ; After 6 months of treatment, the levels of PINP (38.36 ± 3.44 vs 42.77 ± 3.86, t=6.88, P<0.001) and S-CTX (0.36 ± 0.13 vs 0.52 ± 0.13, t=7.02, P<0.001) in the observation group were lower than those in the control group, while the levels of 25 (OH) D (31.28 ± 5.96 vs 27.46± 5.18, t=3.90, P<0.001) and IGF-1 (167.82 ± 39.46 vs 150.86 ± 40.27, t=2.43, P=0.017) were higher than those in the control group; FPG, 2 hPG and HAb1c levels in the observation group were lower than those in the control group after 6 months of treatment ( P < 0.05) ; The difference was not statistically significant when comparing the incidence of adverse reactions between the two groups ( P>0.05) . Conclusion:The combined treatment of T2DM combined with osteoporosis with alendronate tablets sodium and osteopontin can further increase bone mineral density, regulate bone metabolism and improve osteoporosis symptoms, and also have a positive effect on blood glucose control.

Análisis costo-efectividad de alternativas de tratamiento para osteoporosis en mujeres postmenopáusicas en México / Cost-effectiveness analysis of treatment alternatives for osteoporosis in postmenopausal women in Mexico

Resumen Objetivo: Identificar el tratamiento de osteoporosis más costo- efectivo en la prevención de fracturas de cadera en mujeres mexicanas postmenopáusicas sin seguridad social en el primer nivel de atención. Material y Métodos: Se realizó un análisis de costo-efectividad para tres esquemas de tratamiento de osteoporosis seleccionados por sus diferentes vías de aplicación y dosificación. Los tratamientos se estimaron para el periodo de un año. Los costos de cada intervención se estimaron desde la perspectiva del proveedor y se tomaron los precios del mercado mexicano disponibles en julio de 2021. La efectividad se determinó a partir de estudios previos sobre el efecto de los medicamentos sobre la fractura de cadera. Se determinó el coeficiente costo-efectividad de cada tratamiento. Resultados: La intervención con mayor costo-efectividad fue el tratamiento con alendronato de 10 mg, medicamento de administración diaria por vía oral, para el cual se obtuvo un costo de $188,482.40 USD, una tasa de efectividad de 55% y un coeficiente de efectividad de 0.0343. El tratamiento con denosumab fue el más costoso ($725,625.05 USD) y el menos costo- efectivo (Coeficiente C-E 0.1814), mientras que el ácido zoledrónico tuvo un costo de $377,291.92 USD y un coeficiente C-E de 0.0920. Conclusiones: El alendronato es el tratamiento de la osteoporosis más costo-efectivo para la prevención de fracturas de cadera en mujeres postmenopáusicas, por lo cual debería recomendarse como primera opción en estas pacientes.

Abstract Objective: To identify the most cost-effective treatment for osteoporosis in the prevention of hip fractures in postmenopausal Mexican women without social security in the first level of care. Material and Methods: A cost-effectiveness analysis was performed for three osteoporosis treatment schemes selected for their different administration routes and dosage. The treatments were estimated for a one-year period. The costs of each intervention were estimated from the provider's perspective and the prices from the Mexican market available for July 2021 were considered. Treatment effectiveness was determined from previous studies on the effect of each treatment on the prevention of hip fractures. The cost-effectiveness coefficient was calculated for each treatment. Results: The most cost-effective treatment was 10 mg alendronate, a daily oral treatment, with a $188,548.61 USD cost, a 55% effectiveness and a 0.0377 cost-effectiveness coefficient. Treatment with denosumab was the most expensive ($725,625.05 USD) and the least effective (C-E coefficient 0.1814), zoledronic acid had a $377,291.92 USD cost and a 0.0920 C-E coefficient. Conclusions: Alendronate is the most cost-effective treatment of osteoporosis for the prevention of hip fractures in postmenopausal women and should be recommended as the first-line treatment in these patients.

An inconvenient status in anti-osteoporotic treatment process: corticosteroid use

SUMMARY OBJECTIVE: There are limited studies investigating the comparison of the efficacy of anti-osteoporotic drugs in different conditions resulting in osteoporosis in older adults. This study aimed to compare the effectiveness of anti-osteoporotic agents in older adults with or without glucocorticoid-induced osteoporosis. METHODS: This retrospective study included 364 patients with osteoporosis, aged 65 years and older. Bone mineral density measurement was performed, and the percent change from baseline was calculated at month 24. RESULTS: Of the 364 patients, 80 were glucocorticoid users. Similar changes in the bone mineral density of the lumbar spine and femoral neck and fracture risk were found in patients with or without glucocorticoid-induced osteoporosis. There was no significant difference in bone mineral density changes between the groups in terms of anti-osteoporotic agents used. CONCLUSIONS: This study demonstrated that the response to anti-osteoporotic agents was similar in older adults with glucocorticoid-induced osteoporosis and those without glucocorticoid-induced osteoporosis. The results of our study may guide osteoporosis treatment in older individuals with glucocorticoid-induced osteoporosis.

Histomorphometry of Bone Microarchitecture in Rats Treated with Vitamin D and Bisphosphonate in the Management of Osteoporosis / Histomorfometria da microarquitetura óssea em ratas tratadas com vitamina D e bisfosfonato no manejo da osteoporose

Abstract Objective To verify how the combined administration of alendronate (ALN) and vitamin D3 (VD) acts on the bone microarchitecture in rats with glucocorticoid-induced osteoporosis. Methods The experiment used 32 90-day-old female Wistar rats weighing between 300 and 400g. The induction of osteoporosis consisted of intramuscular administration of dexamethasone at a dose of 7.5 mg/kg of body weight once a week for 5 weeks, except for the animals in the control group. The animals were separated into the following groups: G1 (control group without osteoporosis), G2 (control group with osteoporosis without treatment), G3 (group with osteoporosis treated with ALN 0.2 mg/kg), G4 (group with osteoporosis treated with VD 10,000UI/500μL), and G5 (group with osteoporosis treated with ALN þ VD). The right femurs of the rats were fixed in 10% buffered formaldehyde, decalcified, and processed for inclusion in paraffin. Histological sections were stained with hematoxylin-eosin for histomorphometric analysis. Cortical thickness and medullary cavity were measured in cross-sections. Results There was a statistical difference (p< 0.05) between groups G3 and G5 compared with the positive control group (G2), both related to the measurement of cortical thickness and to the total diameter of the bone. In the evaluation of the spinal area, only the G3 group has shown to be statistically different from the G2 group. Conclusion Concomitant treatment with daily ALN and weekly VD is effective in preventing glucocorticoid-induced bone loss. However, there was no difference between the therapy tested and treatment with ALN alone.

Resumo Objetivo Verificar como a administração conjunta de alendronato de sódio (ALN) e vitamina D3 (VD) atua na microarquitetura óssea em ratas com osteoporose induzida por glicocorticoide. Métodos O experimento utilizou 32 ratas da linhagem Wistar, com peso médio de 300 a 400g, com 90 dias de vida. A indução da osteoporose consistiu na administração de dexametasona na dose de 7,5 mg/kg de peso corporal, por via intramuscular, 1 vez por semana durante 5 semanas, à exceção dos animais do grupo controle. Os animais foram distribuídos nos seguintes grupos: G1 (grupo controle sem osteoporose), G2 (grupo controle com osteoporose sem tratamento), G3 (grupo com osteoporose tratado com ALN 0,2 mg/kg), G4 (grupo com osteoporose tratado com VD 10.000UI/500μL) e G5 (grupo com osteoporose tratado com ALN þ VD). Os fêmures direitos das ratas foram fixados em formol a 10% tamponado, descalcificados e processados para inclusão em parafina. Os cortes histológicos foram corados com hematoxilina-eosina para análise histomorfométrica. A espessura cortical e a cavidade medular foram medidas em cortes transversais. Resultados Houve diferença estatística (p< 0,05) entre os grupos G3 e G5 em relação ao grupo controle positivo (G2), tanto em relação à medida da espessura cortical quanto em relação ao diâmetro total do osso. Na avaliação da área medular, apenas o grupo G3 se mostrou estatisticamente diferente do grupo G2. Conclusão O tratamento concomitante com ALN diário e VD semanal é eficaz para prevenir a perda óssea induzida por glicocorticoide. No entanto, não houve diferença entre esta terapia testada e o tratamento apenas com o ALN.

Effect of atorvastatin combined with alendronate in the treatment of T2DM with osteoporosis on bone metabolism, TNF-α, IL-6, and 25- (OH) D levels / 中华内分泌外科杂志

Objective:To investigate the effects of atorvastatin combined with alendronate in the treatment of type 2 diabetes mellitus (T2DM) with osteoporosis (OP) on bone metabolism, tumor necrosis factor alpha (TNF-α) , interleukin 6 (IL-6) , and 25-hydroxyvitamin D[25- (OH) D] level.Methods:A total of 152 patients with T2DM and OP who were diagnosed and treated in our hospital from Jul. 2017 to Jul. 2020 were selected. According to the different treatment methods, they were divided into control group (73 cases with alendronate treatment) and study group (79 cases receiving atova Statins combined with alendronate sodium treatment) . The two groups were compared in terms of bone metabolism indexes, bone mineral density, changes in serum TNF-α, IL-6, 25- (OH) D levels, and adverse reactions before and after treatment.Results:After treatment, osteocalcin (BGP) , bone-specific alkaline phosphatase (BAP) , lumbar spine L1-4 bone mineral density, femoral neck bone mineral density, and 25- (OH) D of the two groups increased ( P< 0.001) , and the study group was significantly higher than the control group (BGP: 7.68±0.89 vs 6.88±0.93; BAP: 18.62±3.97 vs 16.82±3.24; lumbar spine L1-4: 0.95±0.08 vs 0.92±0.05; femoral neck: 0.79±0.07 vs 0.75±0.06; 25- (OH) D: 31.35±10.1 vs 26.54±7.14; all P<0.05) . After treatment, the serum type I collagen C-terminal peptide (s-CTX) , human tartrate acid phosphatase (TRAP-5b) , TNF-α, IL-6 were decreased for both groups ( P<0.001) , and they were significantly lower in the study group than those in the control group (s-CTX:0.37±0.12 vs 0.55±0.12; TRAP-5b: 2.43±0.66 vs 2.99±0.75; TNF-α: 9.93±1.91 vs 11.77±2.69; IL-6: 10.65±1.26 vs 12.91±1.21; all P<0.001) . The incidence of adverse reactions in the study group was significantly lower than that in the control group (16.46% vs 39.73%, P=0.001) . Conclusion:Atorvastatin combined with alendronate in the treatment of T2DM patients with OP can effectively increase 25- (OH) D levels, reduce inflammation, and promote bone metabolism and bone density.

Alendronate combined with Lactobacillus rhamnosus to combat bone loss in ovariectomized mice / 中华创伤骨科杂志

Objective:To study the protective effect of alendronate combined with Lactobacillus rhamnosus on bone loss in ovariectomized mice.Methods:Fifty female C57BL/6 mice were divided into 5 equal groups ( n=10). Ovariotomy was performed in groups A, B, C and D while a sham operation was performed in group E. Group A was subjected to combined administration of alendronate and Lactobacillus rhamnosus, group B to administration of alendronate, group C to administration of Lactobacillus rhamnosus, and groups D and E to administration of physiological saline only. At 3 months after operation, all the mice were sacrificed to harvest their femurs. Micro CT scanning was performed to detect the bone mineral density (BMD), trabecular relative volume, bone surface area/bone volume, and trabecular thickness and number of trabecular bone. Three-point bending test was used to detect the maximum load, stiffness, ultimate load, Young＇s modulus, and fracture energy. Osteocalcin and alkaline phosphatase levels were measured using blood samples from the mice eyeballs. The 2 groups were compared in terms of all the above indexes. Results:The BMD [(669.87±67.87) mg/cm 3], maximum load [(14.35±0.75) N] and fracture energy [(1,497.43±38.29) J/m 2] in group A were significantly higher than those in group B [(520.07±9.01) mg/cm 3, (11.94±0.82) N and(1,277.61±35.12) J/m 2] and group C [(388.15±25.61) mg/cm 3, (11.10±0.93) N and (1,115.27±63.24) J/m 2] (all P<0.05). The osteocalcin level in group A [(22.25±1.78) ng/mL] was significantly higher than that in group B [(19.08±1.45) ng/mL] and group D [(19.33±1.66) ng/mL] (both P<0.05). The alkaline phosphatase level in group A [(83.21±9.69) ng/mL] was significantly lower than that in group C [(113.16±14.44) ng/mL] and group D [(137.96±14.01) g/mL] (both P<0.05). Conclusion:Alendronate combined with Lactobacillus rhamnosus may play a synergistic role in prevention of bone loss in ovariectomized mice, because combined administration of the two is more effective than administration of either of the two.