Farnesyl Diphosphate Synthase Gene Associated with Loss of Bone Mass Density and Alendronate Treatment Failure in Patients with Primary Osteoporosis.

Aminobisphosphonates (NBPs) are the first-choice medication for osteoporosis (OP); NBP treatment aims at increasing bone mineral density (BMD) by inhibiting the activity of farnesyl diphosphate synthase (FDPS) enzyme in osteoclasts. Despite its efficacy, inadequate response to the drug and side effects have been reported. The A allele of the rs2297480 (A > C) SNP, found in the regulatory region of the FDPS gene, is associated with reduced gene transcription. This study evaluates the FDPS variant rs2297480 (A > C) association with OP patients' response to alendronate sodium treatment. A total of 304 OP patients and 112 controls were enrolled; patients treated with alendronate sodium for two years were classified, according to BMD variations at specific regions (lumbar spine (L1-L4), femoral neck (FN) and total hip (TH), as responders (OP-R) (n = 20) and non-responders (OP-NR) (n = 40). We observed an association of CC genotype with treatment failure (p = 0.045), followed by a BMD decrease in the regions L1-L4 (CC = -2.21% ± 2.56; p = 0.026) and TH (CC = -2.06% ± 1.84; p = 0.015) after two years of alendronate sodium treatment. Relative expression of the FDPS gene was also evaluated in OP-R and OP-NR patients. Higher expression of the FDPS gene was also observed in OP-NR group (FC = 1.84 ± 0.77; p = 0.006) when compared to OP-R. In conclusion, the influence observed of FDPS expression and the rs2897480 variant on alendronate treatment highlights the importance of a genetic approach to improve the efficacy of treatment for primary osteoporosis.

Influence of the use of bisphosphonates on the development of postextraction sequelae: Scoping review with mapping evidence of in vivo studies.

OBJECTIVE: To map the current scientific landscape regarding the association/causality of medication-related osteonecrosis of the jaw (MRONJ) after tooth extraction under bisphosphonate (BF) therapy to identify knowledge gaps and guide future research. DATA: This review used the PCC strategy (P = Patient; C = Concept; C = Context). SOURCES: The MEDLINE/PubMed, Scopus, Web of Science/Clarivate Analytics, and gray literature databases were used. STUDY SELECTION: Searches were conducted by two independent reviewers until April 2024. Studies involving prior BF use and tooth extraction in humans or animals were included. Among the 176 studies, 73 (41.4 %) were in animals, and 103 (58.5 %) were in humans. Brazil led in animal studies (n = 14; 19.1 %), while Italy led in human studies (n = 14; 13.6 %). Zoledronic acid was the most cited BF (79.4 % in animals; 34.9 % in humans), with intravenous administration being most frequent (38.3 % in animals; 35.9 % in humans). The mandible was the main extraction site (n = 36 in animals; n = 41 in humans). In 91.7 % of the animal studies, sequelae compatible with osteonecrosis signs and symptoms were observed, with bone necrosis being most common (n = 39; 53.4 %). In humans, 93.2 % of studies presented 239 sequelae, with bone necrosis (n = 53; 22.1 %) being the most cited. The main location of sequelae was the mandible (n = 36 in animals; n = 41 in humans). CONCLUSIONS: Animal studies highlighted bone exposure, notably using murine models, with a significant Brazilian contribution. In human studies, bone necrosis was the main sequela of MRONJ, which has been reported by researchers in the Italy. CLINICAL SIGNIFICANCE: These findings underscore the importance of careful consideration and monitoring of patients who have a history of bisphosphonate use and who are undergoing tooth extraction, highlighting the potential risk of MRONJ.

Cholesterol nanoarchaeosomes for alendronate targeted delivery as an anti-endothelial dysfunction agent.

Sodium alendronate (ALN) is a very hydrosoluble and poorly permeable molecule used as an antiresorptive agent and with vascular anticalcifying capacity. Loaded into targeted nanovesicles, its anti-inflammatory activity may be amplified towards extra-osseous and noncalcified target cells, such as severely irritated vascular endothelium. Here cytotoxicity, mitochondrial membrane potential, ATP content, and membrane fluidity of human endothelial venous cells (HUVECs) were determined after endocytosis of ALN-loaded nanoarchaeosomes (nanoARC-Chol(ALN), made of polar lipids from Halorubrum tebenquichense: cholesterol 7:3 w/w, 166 ± 5 nm, 0.16 ± 0.02 PDI, -40.8 ± 5.4 mV potential, 84.7 ± 21 µg/mg ALN/total lipids, TL). The effect of nanoARC-Chol(ALN) was further assessed on severely inflamed HUVECs. To that aim, HUVECs were grown on a porous barrier on top of a basal compartment seeded either with macrophages or human foam cells. One lighter and one more pronounced inflammatory context was modelled by adding lipopolysaccharide (LPS) to the apical or the apical and basal compartments. The endocytosis of nanoARC-Chol(ALN), was observed to partly reduce the endothelial-mesenchymal transition of HUVECs. Besides, while 10 mg/mL dexamethasone, 7.6 mM free ALN and ALN-loaded liposomes failed, 50 µg/mL TL + 2.5 µg/mL ALN (i.e., nanoARC-Chol(ALN)) reduced the IL-6 and IL-8 levels by, respectively, 75% and 65% in the mild and by, respectively, 60% and 40% in the pronounced inflammation model. This is the first report showing that the endocytosis of nanoARC-Chol(ALN) by HUVECs magnifies the anti-inflammatory activity of ALN even under conditions of intense irritation, not only surpassing that of free ALN but also that of dexamethasone.

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.

Estrogen Deficiency Impairs Osseointegration in Hypertensive Rats Even Treated with Alendronate Coated on the Implant Surface.

Hypertension and estrogen deficiency can affect bone metabolism and therefore increase the risk of osseointegration. Antihypertensive drugs such as losartan not only control blood pressure but also enhance bone healing. In addition, alendronate sodium is widely used to treat postmenopausal osteoporosis. Hence, we evaluated the effect of systemic antihypertensive and local alendronate coted on implants on osseointegration under hypertensive and estrogen-deficiency conditions. A total of 64 spontaneously hypertensive rats (SHRs) treated with losartan were randomly divided according to the estrogen-deficiency induction by ovariectomy (OVX) or not (SHAM), and whether the implant surface was coated with sodium alendronate (ALE) or not, resulting in four groups: SHR SHAM, SHR SHAM ALE, SHR OVX, and SHR OVX ALE. The removal torque, microcomputed tomography, and epifluorescence microscopy were the adopted analyses. The hypertensive and estrogen-deficiency animals presented a lower removal torque even when treated with alendronate on implant surface. The microcomputed tomography revealed a higher bone volume and bone-to-implant contact in the SHRs than the SHR OVX rats. Epifluorescence showed a decreased mineral apposition ratio in the SHR OVX ALE group. The data presented indicate that estrogen deficiency impairs osseointegration in hypertensive rats; in addition, alendronate coated on the implant surface does not fully reverse this impaired condition caused by estrogen deficiency.

Alendronate induces skeletal alterations in the chicken embryonic development model.

Alendronate, a nitrogen-containing bisphosphonate, has reported long-term clinical success in the management of distinct bone-related conditions, particularly in the modulation of post-menopausal osteoporosis. Nonetheless, whether the inhibitory activity over osteoclastic cells' functionality is widely acknowledged, contradictory evidence arises from the assessment of alendronate activity over osteoblastic populations. This may be of particular relevance in situations in which bone formation exceeds bone resorption, with further emphasis on embryonic development, since alendronate can cross the placental barrier and alendronate-based therapies are being extended into women of reproductive age. Accordingly, the present study aims to assess the effects of alendronate, at distinct concentrations (1.5E-10M to 1.5E-7M) on bone tissue development, within a translational animal model - the embryonic chicken development model. Embryos, at the beginning of osteogenesis (day 7) were exposed to different alendronate concentrations for 4 days. Embryos were following characterized for skeletal development by histomorphometric analysis upon histochemical staining, microtomographic analysis, and gene expression assessment of genes related to osteoclastogenic/osteoclastic and osteoblastogenic/osteogenic differentiation, as well as to the immuno-inflammatory activation. The findings revealed that exposure to alendronate had a dose-dependent impact on skeletal growth and mineralization. This effect was evidenced by diminished bone volume and reduced bone surface parameters, with the 1.5E-7M concentration leading to a remarkable reduction of over 50%. Additionally, a decreased osteoclastogenic/osteoclastic gene expression was verified, associated with a diminished osteoblastogenic/osteogenic program - within the 30-50% range for 1.5E-7 M, supporting the diminished bone formation process. An increased inflammatory activation may contribute, at least in part, to the attained outcomes. Overall present findings suggest a negative influence of alendronate on the embryonic bone development process in a dose-dependent manner, highlighting the potential risk of alendronate use during embryonic development.

Sodium alendronate is an effective adjunctive therapy for treating periodontitis in male rats treated with anticancer chemotherapy.

OBJECTIVES: To assess sodium alendronate as a local adjunctive therapy for treating experimental periodontitis in male rats treated with chemotherapy. DESIGN: One-hundred-eighty male rats were randomly divided into two groups (n = 90) based on the systemic treatments: PSS, physiological saline solution; and 5-Fluorouracil, and then, subdivided into three subgroups (n = 30): NT, no treatment; scaling and root planing; and sodium alendronate. Treatments were performed 7 days after induction of experimental periodontitis. Specimens were collected at 14, 22, and 37 days after induction. Alveolar bone level, percentage of bone in the furcation, percentage of non-vital bone in the furcation, histopathologic features, and immunolabeling pattern for tartrate-resistant acid phosphatase (TRAP) and osteocalcin (OCN) were evaluated. RESULTS: The lowest amount of alveolar bone and highest amount of non-vital bone was found in group 5-Fluorouracil when no treatment was performed. In animals receiving 5-Flurouracil and subjected to periodontal treatment, adjunctive sodium alendronate resulted in higher percentage of bone in the furcation and higher alveolar bone loss, when compared with scaling and root planing alone. Better structural and cellularity patterns were found in the periodontal tissues when sodium alendronate was used, regardless of systemic treatment. Higher TRAP-expression was found when no treatment was performed. Sodium alendronate didn't affect the immunolabeling pattern of osteocalcin in the presence of 5-Fluorouracil. CONCLUSION: Adjunctive therapy with local sodium alendronate prevented alveolar bone loss and improved the histopathological features of the periodontal tissues following scaling and root planing in male rats with experimental periodontitis receiving anticancer chemotherapy with 5-Fluorouracil.

Influence of the Osteogenomic Profile in Response to Alendronate Therapy in Postmenopausal Women with Osteoporosis: A Retrospective Cohort Study.

BACKGROUND: Postmenopausal osteoporosis is a multifactorial disease. Genetic factors play an essential role in contributing to bone mineral density (BMD) variability, which ranges from 60 to 85%. Alendronate is used as the first line of pharmacological treatment for osteoporosis; however, some patients do not respond adequately to therapy with alendronate. AIM: The aim of this work was to investigate the influence of combinations of potential risk alleles (genetic profiles) associated with response to anti-osteoporotic treatment in postmenopausal women with primary osteoporosis. METHODS: A total of 82 postmenopausal women with primary osteoporosis receiving alendronate (70 mg administered orally per week) for one year were observed. The bone mineral density (BMD; g/cm2) of the femoral neck and lumbar spine was measured. According to BMD change, patients were divided into two groups: responders and non-responders to alendronate therapy. Polymorphic variants in CYP19, ESR1, IL-6, PTHR1, TGFß, OPG and RANKL genes were determined and profiles were generated from the combination of risk alleles. RESULTS: A total of 56 subjects were responders to alendronate and 26 subjects were non-responders. Carriers of the G-C-G-C profile (constructed from rs700518, rs1800795, rs2073618 and rs3102735) were predisposed to response to alendronate treatment (p = 0.001). CONCLUSIONS: Our findings highlight the importance of the identified profiles for the pharmacogenetics of alendronate therapy in osteoporosis.

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.

Vascular response to stress: Protective action of the bisphosphonate alendronate.

BACKGROUND: Since several additional actions of bone bisphosphonates have been proposed, we studied the effect of the bisphosphonate alendronate (ALN) on the vascular response to environmental stress. METHODS: Primary cultures of endothelial cells (EC) and vascular smooth muscle cells (VSMC) exposed to strained conditions were employed for experimental evaluation. After ALN treatment, cell migration, proliferation, and angiogenesis assays were performed. The participation of signal transduction pathways in the biochemical action of ALN was also assessed. RESULTS: In VSMC cultures, ALN counteracted the stimulation of cellular migration elicited by the proinflammatory agent lipopolysaccharide (LPS) or by high levels of calcium and phosphorus (osteogenic medium). Indeed, ALN reduced the increase of VSMC proliferation evoked by the stressors. When LPS and osteogenic medium were added simultaneously, the enhancement of cell proliferation dropped to control values in the presence of ALN. The mechanism of action of ALN involved the participation of nitric oxide synthase, mitogen-activated protein kinase (MAPK), and protein kinase C (PKC) signaling pathways. The study revealed that ALN exhibits a proangiogenic action. On EC, ALN enhanced vascular endothelial growth factor (VEGF) synthesis, and induced capillary-like tube formation in a VEGF-dependent manner. The presence of vascular stress conditions (LPS or osteogenic medium) did not modify the proangiogenic action elicited by ALN. CONCLUSION: The findings presented suggest an extra-bone biological action of ALN, which could contribute to the maintenance of vascular homeostasis avoiding cellular damage elicited by environmental stress.

Inhibition of osteoclastogenesis after bisphosphonate therapy discontinuation: an in vitro approach.

Osteoclasts are specialized cells that degrade and resorb bone. Bisphosphonates (BPs) are drugs with well-known capacity to inhibit the resorption of mineralized tissues. Nitrogen-containing BPs, like alendronate (ALN) and zoledronic acid (ZA), inactivate osteoclast activity mostly by alterations on the cytoskeleton architecture of the cell. In this study, we used an in vitro model to test the hypothesis that bisphosphonates may have inhibitory effects on the osteoclastogenesis and osteoclast activity after the therapy was discontinued. Primary osteoclasts were generated from mouse bone marrow in media supplemented with 1,25-dihydroxyvitamin D3 and cultivated over bones pre-treated with ALN and ZA. The pre-saturation of the bone slices with bisphosphonates did not affect cell viability. We found, however, that by disrupting the gene expression of RANKL and OPG the osteoclastogenesis and resorption activity of osteoclasts was significantly disturbed. These inhibitory effects were confirmed by scanning electron microscopy resorption assay, assessment of osteoclast ultrastructure, and by gene expression analysis of TRAP and Cathepsin K. In conclusion, ALN and ZA adhered to the bone matrix reduced the osteoclast activity in vitro.

Histomorphometry of Bone Microarchitecture in Rats Treated with Vitamin D and Bisphosphonate in the Management of Osteoporosis.

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 + 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.

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.

Orbital Inflammation Caused by Aminobisphosphonates.

The aim of this review was to describe orbital inflammation secondary to aminobisphosphonates by analyzing demographic data, clinical presentation, and treatment of the disease. This is a narrative literature review. The search was performed using databases such as Ovid/MEDLINE and COCHRANE. The searches were limited to papers in the English language. We found 43 cases of orbital inflammation due to aminobisphosphonates. Zoledronate was the drug most associated with orbital side effects. Clinical presentation was evident by unilateral involvement (89%), palpebral edema (88%), conjunctival congestion (81%), chemosis (79%), ocular pain (77%), ocular motility impairment (65%), proptosis (56%), and blurred vision (39%). It can affect both eyes (11%) and is accompanied by anterior uveitis (23%). Orbital inflammation secondary to aminobisphosphonates is a severe side effect. Clinically, it cannot be distinguished from idiopathic inflammation of the orbit. Therefore, it is important to rule out previous drug exposure. Timely treatment is vital to expect a favorable outcome, with systemic corticosteroids being the treatment of choice.

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.

Effects of Alendronate and Dexamethasone on Osteoclast Gene Expression and Bone Resorption in Mouse Marrow Cultures.

Osteoclasts are cells whose main function is the resorption of bone matrix. However, several factors, including medications, can interfere with the resorption process. Alendronate (ALN), a nitrogen-containing type of bisphosphonate, and dexamethasone (DEX), a glucocorticoid, are drugs that may affect the resorption activity. The aim of this study is to investigate the effects of ALN, and/or DEX on osteoclast gene expression and resorption activity in primary mouse marrow cultures stimulated with 1,25-dihydroxyvitamin D3, a model for the bone microenvironment. Cultures were treated only with ALN (10-5 M), DEX (10-6 M), and with a combination of both agents. Viability assays performed at days 5, 7, and 9 showed the highest number of viable cells at day 7. All the following assays were then performed at day 7 of cell culture: tartrate resistant acid phosphatase (TRAP) histochemistry, receptor activator of nuclear factor kappa B ligand (RANKL) immunofluorescence, osteoprotegerin (OPG), and RANKL gene expression by qPCR and resorption analysis by scanning electron microscopy. Treatment with ALN, DEX, and the combination of both did not promote significant changes in the number of TRAP+ cells, although larger giant cells were detected in groups treated with DEX. DEX treatment increased the gene expression of RANKL and reduced OPG. The treatment with ALN reduced the depth of the resorption pits, but their inhibitory effect was less effective when administered with DEX.

Potential Alendronate Sodium drug carrier by preparation and characterization of sodium alginate cross-linked Montmorillonite

Abstract In drug therapy, it is important to provide therapeutic levels of drug to the site of action and maintain them during the treatment. This work describes the in vitro release of alendronate from sodium alginate cross-linked Montmorillonite (MMT) composite beads. Effect of crosslinking cation, concentration of montmorillonite and media on encapsulation efficiencies, and release profiles of alendronate were studied. Beads were characterized using equilibrium swelling ability study, Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), Energy-dispersive x-ray spectroscopy (EDX) and scanning electron microscopy (SEM). Results indicate that addition of montmorillonite increases the encapsulation efficiencies and slows down the release rates significantly.

Alendronato de sódio tópico associado ao osso bovino liofilizado no reparo ósseo / Topical alendronate associated with lyophilized bovine bone in bone repair

Introdução: O osso bovino inorgânico é o enxerto mais utilizado na Odontologia, tendo como desvantagem longo tempo de integração ao leito receptor. Os bifosfonatos têm sido utilizados para modular a quantidade e a qualidade do osso regenerado e diminuir o tempo de integração do enxerto. Objetivo: Avaliar o efeito do bifosfonato alendronato de sódio (ALN) 0,5%, associado ou não ao osso bovino inorgânico, na reparação de defeitos ósseos. Material e método: Dois defeitos ósseos foram confeccionados na calvária de 12 coelhos, sendo a cavidade esquerda/experimental preenchida com: GI = osso bovino inorgânico (Bio-Oss®); GII = Bio-Oss® + ALN 0,5%; GIII = ALN 0,5%; e a cavidade direita por coágulo sanguíneo (controle). Os animais foram mortos aos 60 dias pós-operatórios. Por meio de análise histomorfométrica calculou-se o percentual de osso neoformado e remanescente do biomaterial em relação à área total do defeito. Resultado: Osso neoformado: GI = 38,16 ± 15,44%; GII = 55,77 ± 16,75%; GII I = 60,28 ± 11,45%. Controle = 45,11 ± 11,09%. Remanescente do enxerto: GI = 7,02 ± 5,36% e GII = 16,59 ± 9,56%. Não houve diferença quanto ao percentual de osso neoformado entre os grupos (ANOVA p = 0,15512; teste de Tukey F = 2,089). O percentual de remanescente do enxerto também foi estatisticamente semelhante entre os grupos GI e GII (teste de Tukey F = 5,019). Conclusão: O uso tópico da solução de ALN 0,5% isoladamente ou associado ao osso bovino liofilizado não alterou o percentual de neoformação óssea nem a degradação dos grânulos do enxerto.

Introduction: Inorganic bovine bone is the most used graft in dentistry, with the disadvantage of long integration time into the receptor bed. Bisphosphonates have been used to modulate the quantity and quality of regenerated bone and decrease graft integration time. Objective: To evaluate the effect of alendronate sodium bisphosphonate (ALN) 0.5%, associated or not with Inorganic bovine bone, in the repair of bone defects. Material and method Two bone defects were made in the calvaria of 12 rabbits, and the left/experimental cavity was filled with: GI = Inorganic bovine bone (Bio-Oss®); GII = Bio-Oss® + 0.5% ALN; GIII = 0.5% ALN; and the right cavity/blood clot control. The animals were killed at 60 days after surgery. Through histomorphometric analysis, the percentage of newly formed bone and remnant biomaterial relative to the total area of the defect was calculated. Result: Neoformed bone: GI = 38.16 ± 15.44%, GII = 55.77 ± 16.75%; GIII= 60.28 ± 11.45%; Control=45,11 ± 11,09%. Graft remnant: GI = 7.02 ± 5.36% and GII = 16.59 ± 9.56%. There was no difference in the percentage of newly formed bone between the groups (ANOVA p = 0.15512; Tukey's test F = 2.089). The percentage of graft remnant was also statistically similar between groups GI and GII (Tukey's test F = 5019). Conclusion: Topical use of 0.5% ALN solution alone or associated with lyophilized bovine bone did not change the percentage of bone neoformation, nor the degradation of graft granules.

Sodium alendronate: proposal and reliability of indicators

Abstract The present study proposes and evaluates the test-retest reliability of indicators of the correct use of sodium alendronate in elderly patients. This is a test-retest reliability study for use of sodium alendronate. Six questions to evaluate the correct use of this medicine were elaborated after analysis of information in the literature. Data collection was performed through questionnaires in face-to-face in-home interviews by previously trained interviewers. The participants were initially interviewed (test) when they agreed to participate in the study, and secondly (retest), after a period of 7 to 14 days from the first interview. The reliability of the questions was evaluated by means of the agreement percentage and the Kappa coefficient. Fifty-seven pairs (test-retest) were obtained. The mean age was 69.3 (SD = 6.9) years, the majority (92.5%) completed elementary education, and declared themselves white (50.9%). All the questions presented high concordance ranging from 79.0% to 98.3%. The Kappa values ranged from 0.1 (low) to 0.83 (very good). The agreement percentage and the Kappa values suggest adequate reliability of the proposed questions. We suggest that they can be used as a simple and quick way to evaluate the quality of sodium alendronate use among the elderly.

Alendronato de sódio e vitamina D na osteoporose pós-menopausa: revisão sistemática / Alendronate sodium and vitamin D in postmenopausal osteoporosis: a systematic review

Objetivo: avaliar a eficácia da utilização da terapia combinada de alendronato de sódio e vitamina D no metabolismo ósseo de mulheres em tratamento de osteoporose pós-menopausa. Métodos: trata-se de uma revisão sistemática, a qual foram pesquisados ensaios clínicos randomizados (ECR) indexados nas bases de dados BVS, ISI Web of Science, PubMed, SciELO, ScienceDirect e Scopus que comparavam a associação de alendronato sódico e vitamina D com a monoterapia de alendronato de sódio. Resultados: um total de seis ECR contemplou os critérios para serem inclusos nesse estudo, compreendendo um total de 4164 participantes e seus respectivos dados. Os estudos avaliaram diferentes domínios do metabolismo ósseo, como níveis séricos de vitamina D, paratormônio, densidade mineral óssea e marcadores de turnover ósseo. A terapia combinada produziu melhora significativa nos marcadores metabólicos ósseos. Conclusão: a terapia combinada de alendronato de sódio com vitamina D promove melhora no metabolismo ósseo de mulheres com osteoporose pós-menopausa.

Aim: to evaluate the effectiveness of using the combined therapy of sodium alendronate and vitamin D on bone metabolism in women undergoing postmenopausal osteoporosis. Methods: this is a systematic review. The studies included were Randomized Controlled Trials (RCT) indexed in the BVS, ISI Web of Science, PubMed, SciELO, ScienceDirect and Scopus Databases which compared the association of sodium alendronate and vitamin D to monotherapy of sodium alendronate. Results: a total of six RCT met the criteria to be included in this study, comprising a total of 4164 participants and their respective data. The studies evaluated different domains of bone metabolism, such as serum levels of vitamin D, parathyroid hormone, bone mineral density and bone turnover markers. Combination therapy produced significant improvement in bone metabolic markers. Conclusion: combined therapy of sodium alendronate with vitamin D promotes improved bone metabolism in women with postmenopausal osteoporosis.