Cone-Beam Computed Tomography to evaluate changes in trabecular lower jawbone microstructure caused by bone loss and antiresorptive treatment / CBCT para evaluar cambios en la microarquitectura ósea de la mandíbula por pérdida ósea y tratamiento antirresortivo

ABSTRACT For decades, conventional histomorphometry has been the gold standard for analyzing trabecular bone microarchitecture. In recent years, micro-computed tomography (μCT) devices have been validated and are now considered the gold standard for quantifying bone microstructure Aim The aim of this preliminary report is to evaluate the usefulness of CBCT to assess trabecular mandible microstructural properties in normal ewes and to compare the quantitative changes associated with ovariectomy and antiresorptive treatment Material and Method Twelve adult Corriedale ewes (n=4/group) aged 3-4 years were divided into 3 groups and studied for 28 months. Eight ewes were ovariectomized (OVX) and divided into OVX and OVX+ZOL groups (n=4/group) which were treated as follows, by jugular injection: OVX received saline solution and OVX+ZOL received zoledronate (Zol) (Gador SA, CABA, Argentina) (4 mg/month). Another four ewes were subjected to sham surgery (SHAM group) and received saline solution Results Densitometry showed that jaw mineral content (BMC) and density (BMD) were significantly lower in OVX than in SHAM and OVX+ZOL ewes; no difference was observed between OVX+ ZOL and SHAM groups. CBCT analysis showed that bone volume (BV/TV%); trabecular thickness (TbTh); connectivity density (CD) and anisotropy degree (AD) were significantly lower, and trabecular spacing (TbSp), significantly higher in OVX than in SHAM ewes. AD was significantly higher and TbSp significantly lower in OVX+ZOL than in OVX groups. BV/TV%, TbTh and CD showed a clear tendency to being higher in OVX+ZOL than in OVX groups. No statistical difference was observed between OVX+ZOL and SHAM ewes. CBCT in a nondestructive, fast, very precise procedure for measuring bone morphometric indices without biopsies, which are not indicated for morphometric evaluation in osteoporosis Conclusions The current study demonstrated the potential of the high-resolution CBCT imaging to assess in vivo quantitative bone morphometry and bone quality of lower jaw cancellous bone under normal conditions and to differentiate changes associated with excessive bone loss induced by estrogen withdrawal and antiresorptive intervention.

RESUMEN Objetivo El presente informe preliminar evaluó la utilidad de Tomografía Computada de Haz Cónico (CBCT) para analizar las propiedades microestructurales trabeculares del maxilar inferior de ovejas y comparar los cambios cuantitativos asociados con la ovariectomía y tratamiento antirresortivo. Se estudiaron dieciséis ovejas Corriedale adultas de 3-4 años Materiales y Método Doce ovejas fueron ovariectomizadas (OVX) y divididas en 2 grupos: OVX y OVX+ZOL (n=4/grupo) cuyo tratamiento por inyección endovenosa en la yugular durante 28 meses fue el siguiente: OVX con solución salina y OVX+ZOL con zoledronato (Gador S.A. CABA. Argentina) (Zol) (4 mg/mes); 4 ovejas fueron sometidas a cirugía simulada (grupo SHAM) Resultados La densitometría (Lunar DPX) mostró que el contenido mineral del hueso maxilar (CMO) y la densidad (DMO) fueron significativamente más bajos en OVX que en SHAM y OVX+ZOL; no se observaron diferencias entre los grupos OVX+ZOL y SHAM. El análisis de las imágenes por CBCT (Planmeca Promax 3D Classic) mostró que el volumen óseo (BV/TV%); el espesor trabecular (TbTh); la densidad de conectividad (CD) y el grado de anisotropía (AD) fueron significativamente menores (p<0.05), y el espaciado trabecular (TbSp), significativamente mayor en OVX que en SHAM (p<0.05). AD fue significativamente mayor (p<0.05) y TbSp, significativamente menor en OVX+ZOL que en OVX (p<0.05). BV/TV%, TbTh y CD mostró una clara tendencia a ser mayor en OVX+ZOL que en OVX. No se observaron diferencias estadísticas entre OVX+ZOL y SHAM Conclusiones En base a nuestros resultados consideramos que CBCT presenta suficiente confiabilidad y validez para evaluar in vivo la morfometría cuantitativa y la calidad del hueso esponjoso del maxilar inferior en condiciones normales, así como para diferenciar los cambios en dichos parámetros asociados a la pérdida ósea excesiva por la caída estrogénica e intervención antirresortiva. Aunque se necesitan estudios futuros, nuestros resultados agregarían una herramienta no invasiva adicional para diferenciar la microestructura del hueso trabecular mandibular en estudios preclínicos , sentando las bases para su futura aplicación en la práctica clínica.

Efecto del tratamiento con ácido zoledrónico e hidroxocobalamina sobre la microarquitectura ósea en ratones con periodontitis y osteoporosis inducida: Estudio preclínico / Effect of zoledronic acid and hydroxocobalamin treatment on bone microarchitecture in mice with induced periodontitis and osteoporosis: preclinical study

Objetivo. Evaluar el efecto del tratamiento con ácido zoledrónico e hidroxocobalamina sobre la microarquitectura ósea alveolar en ratones con periodontitis y osteoporosis inducidas. Métodos. Diseño experimental en fase preclínica. Se incluyeron 16 ratones hembras a quienes se les indujo osteoporosis mediante la ovariectomía total y también se indujo la periodontitis por inflamación por ligadura de seda negra 5/0 en el segundo molar maxilar, todos los protocolos fueron sometidos durante anestesia general. Los ratones se distribuyeron en 4 grupos: control, tratamiento con ácido zoledrónico, tratamiento con hidroxocobalamina y tratamiento combinado. A las 16 semanas, se realizó la autanasia, se realizó la disección para la evaluación mediante microtomografía; determinando la densidad mineral ósea (BMD), el volumen de hueso (BV/TV), espesor trabecular (Tb. Th), número de trabéculas (Tb.N), separación trabecular (Tb.Sp); se realizó el análisis descriptivo y bivariado mediante ANOVA de 1 vía considerando un 95% de nivel de confianza. Resultados. El grupo que recibió tratamiento combinado de ácido zoledrónico e hidroxocobalamina presentó mayor densidad mineral ósea (DMO), mayor volumen óseo (BV/TV) y menor separación trabecular (Tb.Sp) en comparación con el grupo de control (p<0,05). Conclusiones. El tratamiento combinado de ácido zoledrónico e hidroxocobalamina mejora las características microarquitectónicas óseas en ratones con osteoporosis y periodontitis inducidas.

Objective. Evaluate the effect of zoledronic acid and hydroxocobalamin treatment on alveolar bone microarchitecture in mice with induced periodontitis and osteoporosis. Methods. Experimental design in preclinical phase. Sixteen female mice were included in which osteoporosis was induced by total ovariectomy and periodontitis was also induced by inflammation by 5/0 black silk ligation of the maxillary second molar, all protocols were performed under general anesthesia. The mice were distributed into 4 groups: control, treatment with zoledronic acid, treatment with hydroxocobalamin and combined treatment. At 16 weeks, euthanasia was performed, dissection was performed for evaluation by microtomography; determining bone mineral density (BMD), bone volume (BV/TV), trabecular thickness (Tb.Th), number of trabeculae (Tb.N), trabecular separation (Tb.Sp); descriptive and bivariate analysis was performed using 1-way ANOVA with a 95% confidence level. Results. The group that received combined treatment of zoledronic acid and hydroxocobalamin presented higher bone mineral density (BMD), higher bone volume (BV/TV) and lower trabecular separation (Tb.Sp) compared to the control group (p<0.05). Conclusions. Combined treatment with zoledronic acid and hydroxocobalamin improves bone microarchitectural features in mice with induced osteoporosis and periodontitis.

Interleukin-17 plays a role in dental pulp inflammation mediated by zoledronic acid: a mechanism unrelated to the Th17 immune response?

Abstract Objective To evaluate the influence of RORγT inhibition by digoxin on inflammatory changes related to interleukin-17 (IL-17) in the pulp of rats treated with zoledronate (ZOL). Methodology Forty male Wistar rats were divided into a negative control group (NCG) treated with saline solution, a positive control group (PCG) treated with ZOL (0.20 mg/kg), and three groups treated with ZOL and co-treated with digoxin 1, 2, or 4 mg/kg (DG1, 2, and 4). After four intravenous administrations of ZOL or saline solution in a 70-day protocol, the right molars were evaluated by histomorphometry (number of blood vessels, blood vessels/µm2, cells/µm2, total blood vessel area, and average blood vessel area) and immunohistochemistry (IL-17, TNF-α, IL-6, and TGF-β). The Kruskal-Wallis/Dunn test was used for statistical analysis. Results PCG showed an increase in total blood vessel area (p=0.008) and average blood vessel area (p=0.014), and digoxin treatment reversed these changes. DG4 showed a reduction in blood vessels/µm2 (p<0.001). In PCG odontoblasts, there was an increase in IL-17 (p=0.002) and TNF-α (p=0.002) immunostaining, and in DG4, these changes were reversed. Odontoblasts in the digoxin-treated groups also showed an increase in IL-6 immunostaining (p<0.001) and a reduction in TGF-β immunostaining (p=0.002), and all ZOL-treated groups showed an increase in IL-17 (p=0.011) and TNF-α (p=0.017) in non-odontoblasts cells. Conclusion ZOL induces TNF-α- and IL-17-dependent vasodilation and ectasia, and the classical Th17 response activation pathway does not seem to participate in this process.

Intravenous zoledronate for postmenopausal women with osteopenia and osteoporosis: a systematic review and metanalysis

ABSTRACT BACKGROUND: Osteoporosis compromises bone strength and increases the risk of fractures. Zoledronate prevents loss of bone mass and reduces the risk of fractures. OBJECTIVES: To determine the efficacy and safety of zoledronate in postmenopausal women with osteopenia and osteoporosis. DESIGN AND SETTINGS A systematic review and meta-analysis was conducted within the evidence-based health program at the Universidade Federal de São Paulo. METHODS: An electronic search of the CENTRAL, MEDLINE, Embase, and LILACS databases was performed until February 2022. Randomized controlled trials comparing zoledronate with placebo or other bisphosphonates were included. Standard methodological procedures were performed according to the Cochrane Handbook and the certainty of evidence for the Grading of Recommendations Assessment, Development, and Evaluation Working Group. Two authors assessed the risk of bias and extracted data on fractures, adverse events, bone turnover markers (BTM), and bone mineral density (BMD). RESULTS: Twelve trials from 6,652 records were included: nine compared zoledronate with placebo, two trials compared zoledronate with alendronate, and one trial compared zoledronate with ibandronate. Zoledronate reduced the incidence of fractures in osteoporotic [three years: morphometric vertebral fractures (relative risk, RR = 0.30 (95% confidence interval, CI: 0.24-0.38))] and osteopenic women [six years: morphometric vertebral fractures (RR = 0.39 (95%CI: 0.25-0.61))], increased incidence of post-dose symptoms [RR = 2.56 (95%CI: 1.80-3.65)], but not serious adverse events [RR = 0.97 (95%CI: 0.91-1.04)]. Zoledronate reduced BTM and increased BMD in osteoporotic and osteopenic women. CONCLUSION: This review supports the efficacy and safety of zoledronate in postmenopausal women with osteopenia for six years and osteoporosis for three years. PROSPERO REGISTRATION NUMBER: CRD42022309708, https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=309708.

Desarrollo de un inyectable liofilizado de ácido zoledrónico 5 mg. Estudio de estabilidad / Development of a lyophilized injectable of zoledronic acid 5 mg. Stability study / Desenvolvimento de um injetável liofilizado de ácido zoledrónico de 5 mg. Estudo de estabilidade

RESUMEN Introducción: El ácido zoledrónico es un inhibidor de la resorción ósea que se utiliza en el tratamiento de la enfermedad de Paget, la prevención de la osteoporosis inducida por glucocorticoides y la osteoporosis en mujeres posmenopáusicas y hombres. Objetivo: Evaluar la estabilidad de un nuevo inyectable liofilizado de ácido zoledrónico 5 mg a través de los parámetros de calidad. Métodos: Se validó un método de HPLC con detector UV para determinar la estabilidad química de la formulación a través de la presencia de productos de degradación y la concentración del ácido zoledrónico en el producto terminado. También se midieron las características organolépticas, pH, esterilidad y endotoxinas bacterianas, partículas en inyectables y totalidad y transparencia de soluciones de este. Resultados: El método cromatográfico resultó satisfactorio para su empleo en la evaluación del producto terminado. Se elaboraron 3 lotes del inyectable de ácido zoledrónico 5 mg liofilizado, los cuales cumplieron con los límites de calidad establecidos durante los 6 meses (estabilidad acelerada) y hasta los 24 meses (vida útil).

SUMMARY Introduction: Zoledronic acid is an inhibitor of bone resorption used in the treatment of Paget's disease, the prevention of glucocorticoid-induced osteoporosis, osteoporosis in postmenopausal women and in men. Aim: To evaluate the stability of a new lyophilized injection of zoledronic acid 5 mg through the quality parameters. Methods: An HPLC method with UV detector was validated for the finished product and the chemical stability of the formulation was determined through the presence of degradation products and the concentration of zoledronic acid in the finished product. In addition, the organoleptic characteristics, pH, sterility and bacterial endotoxins, particles in injectables and totality and transparency of solutions were measured. Results: The chromatographic method was satisfactory for its use in the evaluation of the finished product. 3 batches of the lyophilized 5 mg zoledronic acid injection were made which met the quality limits established during 6 months (accelerated stability) and up to 24 months (shelf life).

RESUMO Introdução: O ácido zoledrónico é um inibidor da reabsorção óssea utilizado no tratamento da doença de Paget, na prevenção da osteoporose induzida por glico-corticóides e na osteoporose em mulheres e homens na pós-menopausa. Objetivo: Avaliar a estabilidade de um novo injetável liofilizado de ácido zoledrónico 5 mg por meio de parâmetros de qualidade. Métodos: Um método de HPLC com detector UV foi validado para determinar a estabilidade química da formulação através da presença de produtos de degradação e da concentração de ácido zoledrónico no produto acabado. Também foram medidas as características organolépticas, pH, esterilidade e endotoxinas bacterianas, partículas em injetáveis e totalidade e transparência de suas soluções. Resultados: O método cromatográfico foi satisfatório para sua utilização na avaliação do produto acabado. Foram produzidos três lotes de injeção de ácido zoledrónico liofilizado de 5 mg, que atenderam aos limites de qualidade estabelecidos para 6 meses (estabilidade acelerada) e até 24 meses (prazo de validade).

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.

Effects of zoledronic acid therapy in fibrous dysplasia of bone: a single-center experience

ABSTRACT Objective: Fibrous dysplasia (FD) is a rare bone disorder that can involve any part of the skeleton, leading to bone pain, deformities, and fractures. Treatment with intravenous bisphosphonates has been used with variable results. Therefore, we aimed to evaluate the effects of zoledronic acid (ZA) therapy in patients with monostotic or polyostotic FD. Subjects and methods: The medical records of thirteen patients with FD evaluated between 2015 and 2020 were retrospectively analyzed. In the subgroup of patients treated with ZA (n = 7), data on pain relief, changes in bone turnover markers (BTMs), and adverse events following ZA infusions were retrieved. Moreover, radiological changes in response to treatment were recorded in patients who underwent radiological follow-up. Results: Of the patients, 5 (38%) presented with monostotic whereas 8 (62%) had polyostotic FD. Bone pain was a common finding (69%), and most patients (62%) exhibited elevated baseline BTMs. Partial or complete pain relief was reported in 6 of 7 patients treated with ZA. BTMs, especially C-telopeptide of type I collagen (CTX), significantly decreased after therapy (change rate: −61.8% [IQR −71, −60%]), and median CTX levels were significantly lower than at baseline (0.296 ng/mL [0.216, 0.298] vs. 0.742 ng/mL [0.549, 0.907], respectively; P = 0.04). No radiological improvement was observed in cases with radiological follow-up (n = 3). No serious adverse effects of ZA were reported. Conclusion: ZA treatment was well tolerated and provided beneficial effects in relieving bone pain and reducing BTMs, especially CTX. Our data reinforce the role of ZA in the treatment of FD-related bone pain.

Cost-utility analysis of denosumab and zoledronic acid in the treatment of postmenopausal osteoporosis / 中国药房

OBJECTIVE To evaluate the cost-effectiveness of denosumab and zoledronic acid in the treatment of postmenopausal osteoporosis ，and to provide reference for relevant decision-making. METHODS From the perspective of Chinese health system ，Excel 2003 software was used to establish Markov model ，and cost-utility analysis was used to evaluate the cost-effectiveness of denosumab or zoledronic acid combined with calcium carbonate D 3 in the treatment of postmenopausal osteoporosis. Pharmacotherapy effects were obtained from the network Meta-analysis ，and cost and health-utility value data were obtained from the published literature or network ，etc. The model cycle was 1 year，and the simulation time limit was the patient ’s lifetime. One-way sensitivity analysis and probabilistic sensitivity analysis were used to evaluate the impact of model parameter changes on the robustness of the results ；and the cost-effectiveness of changing the medication cycle of zoledronic acid were explored through scenario analysis. RESULTS Denosumab regimen was more effective than zoledronic acid regimen （12.77 QALYs vs. 11.98 QALYs），and its cost was also higher than zoledronic acid regimen （51 224.56 yuan vs. 49 221.67 yuan）， and the incremental cost-effectiveness ratio was 2 544.14 yuan/QALY. One-way sensitivity analysis showed that the cost of Zoledronic acid injection and that of Denosumab injection had great impact on the results. The results of probabilistic sensitivity analysis showed that when using 3 times of per capita gross domestic product （GDP）in China in 2021 as the threshold of willingness to pay ，the probability of Denosumab regimen being cost-effective was 85.4％. The results of the scenario analysis showed that the Denosumab regimen was still more cost-effective when the dosing cycle of zoledronic acid was changed. CONCLUSIONS Under the threshold of 1-3 times of Chinese per capita GDP in 2021，denosumab combined with calcium carbonate D 3 is more cost-effective than zoledronic acid combined with calcium carbonate D 3 in the treatment of postmenopausal osteoporosis.

Effects of polydopamine-coated porous titanium alloy scaffolds loaded with zoledronic acid-gelatin nanoparticles for topical sustained drug release on osteoclasts: an in vitro study / 中华创伤骨科杂志

Objective:To analyze the effects of a novel type of polydopamine (PDA)-coated porous titanium alloy scaffolds loaded with zoledronic acid-gelatin nanoparticles (ZOL-GNPs) for topical sustained drug release on osteoclasts in vitro. Methods:After porous titanium alloy scaffolds were fabricated using electron beam melting technique and ZOL-GNPs with different ZOL concentrations (0, 1, 10, 50, 100, 500 μmol/L) were prepared by desolvation method, PDA-coated porous titanium alloy scaffolds loaded with ZOL-GNPs were constructed by combining the two. The characteristics of the scaffolds were analyzed. The biomechanics of 3 different scaffolds (bare porous titanium alloy scaffolds, PDA-coated porous titanium alloy scaffolds, and PDA-coated porous titanium alloy scaffolds loaded with ZOL-GNPs) were investigated. Drug release detection was carried out by high performance liquid chromatography on the 1st, 4th, 7th, 14th, 21st, and 28th days respectively. The osteoclasts were inoculated into the novel scaffolds with different ZOL concentrations. The expression of osteoclast-related genes was detected by real-time quantitative (RT)-polymerase chain reaction (PCR); the expression of osteoclast-related proteins was detected by Western-blot.Results:The PDA-coated porous titanium alloy scaffolds loaded with ZOL-GNPs were successfully constructed. Electron microscope scanning showed that the GNPs were well spheroidized, smooth in surface, and uniformly dispersed, with a particle size of (243.6±63.4) nm. The ZOL-GNPs were uniformly compounded on the surface and in the pores of the scaffolds, and the spheres were regular in shape with no adhesion. The biomechanical experiments showed that the elastic moduli of the porous titanium alloy scaffolds under 3 different conditions were (1.81±0.12) GPa, (1.80±0.23) GPa and (1.81±0.15) GPa, showing no significant difference ( P> 0.05). The drug release percentage in the porous titanium alloy scaffolds was obviously high on the first day, and increased gradually and slowly in the subsequent 27 days. In the scaffolds with a low concentration ZOL, more osteoclasts adhered and proliferated; in the 50 μmol/L scaffolds, spheroid cells appeared; the spheroid cells increased and even apoptosis occurred with an increase in the ZOL concentration. RT-PCR showed that the expression of Ctsk gene and TRAP gene increased with the increased ZOL concentration, peaked in the 50 μmol/L scaffolds, and then decreased with the increased concentration, showing statistically significant differences ( P < 0.05). Western-blot showed that the expression pattern of Ctsk and TRAP was similar to that of their related genes. Conclusions:The novel PDA-coated porous titanium alloy scaffolds loaded with ZOL-GNPs demonstrate good mechanical properties and an anti-osteoporosis effect via their topical sustained drug release. The scaffolds with a ZOL concentration of 50 μmol/L may exert the best effect on inhibition of osteoclasts.

Clinical efficacy of zoledronic acid combined with calcium in the treatment of primary osteoporosis / 国际生物医学工程杂志

Objective:To investigate the clinical efficacy of zoledronic acid combined with calcium in the treatment of primary osteoporosis (OP).Methods:A total of 180 patients with OP were selected and randomly divided into study group and control group. The two groups of patients were given oral calcium carbonate D3 tablets (Ⅱ), on this basis, the patients in the study group were given zoledronic acid injection. The clinical efficacy was observed after 12 months of the treatment, and the total effective rate was calculated. The bone mineral density, visual analog scale (VAS) of pain, and bone biochemical indexes, including blood calcium (Ca), blood phosphorus (P), bone γ-carboxyglutamate protein (BGP), calcitonin (hCT), collagen type I amino-terminal peptide (P1NP) and collagen type I cross-linked carboxy-terminal peptide (β-specific sequence) (β-CTX) were collected before and after the treatment.Results:The clinical efficacy of the study group was better than that of the control group ( P<0.05). After the treatment, the bone mineral density in the study group was higher ( P<0.05), and the VAS score was lower than that in the control group ( P<0.05). After the treatment, there was no significant difference in serum calcium, serum phosphorus and BGP between the control group and the study group (all P>0.05), the hCT and P1NP levels in the study group were significantly higher than those before the treatment (all P<0.01), and the β-CTX level was significantly lower than that before the treatment ( P<0.01). Conclusions:Zoledronic acid combined with calcium has a good therapeutic effect on OP.

Therapeutic value of zoledronic acid in the prevention of osteoporotic hip sequential fracture / 中华内分泌代谢杂志

Objective:To investigate the clinical value of zoledronic acid in improving the prognosis of osteoporotic hip fracture and preventing its sequential contralateral hip fracture.Methods:A retrospective study of 206 patients diagnosed with hip fragile fractures in China Medical University Affiliated Shengjing Hospital and treated with anti-osteoporotic drugs after surgery was conducted. The prognosis of patients with hip fracture using survival rate analysis and the risk factors of acute febrile complications with multivariate analysis after zoledronic acid treatment were evaluated. Furthermore, chi-square test and multivariate analysis was used to explore whether zoledronic acid decreases the occurrence of the contralateral sequential fracture.Results:The 3-year survival rate of patients with overall hip fracture was higher in zoledronic acid treatment group compared with control group( P=0.026), with the incidence of fever at 53.3%. The age [ OR=0.786, P=0.027, the area under receiver operating characteristic (ROC) curve was 0.724] and cardiopulmonary complications ( OR=0.043, P=0.025, the area under ROC curve was 0.628) were significantly correlated with the occurrence of acute febrile response. The incidence of sequential contralateral fractures in zoledronic acid treatment group was significantly lower than that in control group ( χ2=4.356, P=0.037). The application of zoledronic acid ( OR=0.160, P=0.007, the area under ROC curve is 0.586) and the type of femoral neck fracture ( OR=0.196, P=0.001, the area under ROC curve is 0.607) were statistically associated with the occurrence of sequential fractures. Conclusion:Zoledronic acid treatment improves the outcome of patients with osteoporotic hip fracture and reduces the incidence of sequential hip fractures, especially femoral neck fracture. Senile age and cardiopulmonary complications might be associated with lower risk of acute febrile reactions after zoledronic acid treatment.

Avaliação dos tecidos ao redor de implantes osseointegrados com e sem peri-implantite induzida e a relação com a ocorrência de osteonecrose dos maxilares associada à terapia medicamentosa / Tissue evaluation around osseointegrated implants with and without induced peri-implantitis and the relation with the occurrence of medication-related osteonecrosis of the jaw

Objetivo: O objetivo deste trabalho foi avaliar a resposta dos tecidos periimplantares em condições de normalidade e com peri-implantite induzida por ligadura, em implantes osseointegrados na maxila de ratas senescentes submetidas ao tratamento posterior com dosagem oncológica de zoledronato. Material e métodos: Foram utilizadas 28 ratas Wistar (Rattus novergicus) iniciando o experimento com aproximandamente 14 meses de idade e pesando entre 350 e 450g. Os animais foram submetidos à exodontia do incisivo superior direito e instalação imediata de um implante de titânio com 2,5 mm de diâmetro por 5,7 mm de comprimento, onde após quase 2 meses, foi realizada a cirurgia de reabertura dos implantes e instalação de um cicatrizador. Após uma semana, os animais foram divididos de acordo com os seguintes tratamentos: veículo, administração de solução salina estéril 0,9% intraperitoneal (Grupo VEI); zoledronato, com administração de 100 µg/Kg de zoledronato (Grupo ZOL); veículo com peri-implantite experimental (Grupo VEI-PIE) e; zoledronato com peri-implantite experimental (Grupo ZOL-PIE), com a indução da peri-implantite experimental (PIE) por meio de uma ligadura de algodão 5 semanas após o início do tratamento medicamentoso. A porcentagem de tecido ósseo total (PTO-T) e porcentagem de tecido ósseo não vital (PTO-NV) foram analisadas histometricamente, e foram realizadas imunomarcações para fosfatase ácida resistente ao tartarato (TRAP), fator de necrose tumoral alfa (TNFα), interleucina 1 beta (IL1-ß), fator de crescimento endotelial vascular (VEGF) e osteocalcina (OCN). Os dados foram submetidos à análise estatística. Resultados: O grupo ZOL mostrou persistência de inflamação no tecido conjuntivo peri-implantar e uma quantidade considerável de PTO-NV ao redor do implante quando comparado com VEI. A inflamação peri-implantar foi mais exacerbada em ZOL-PIE, assim como, o comprometimento da vitalidade do tecido ósseo ao redor dos implantes quando comparado com VEI-PIE. Conclusão: Conclui-se que o tratamento com altas doses de zoledronato ocasiona alterações ao nível periimplantar, dentre elas, um aumento da inflamação local, e da PTO-NV ao redor do implante osseointegrado, o que pode representar um possível fator de risco para o surgimento da osteonecrose dos maxilares associada à terapia medicamentosa relacionada ao implante odontológico (ONMM-IO). Na presença da PIE há uma exacerbação da inflamação e um aumento ainda maior da PTO-NV, o que implica em um importante fator de risco agravante para o surgimento da ONMM-IO no modelo experimental estudado(AU)

Aim: The aim of this study was to evaluate the response of peri-implant tissues under normal conditions and with ligature-induced peri-implantitis, in osseointegrated implants in the maxilla of senescent rats submitted to subsequent treatment with oncological dosage of zoledronate. Material and methods: Twenty-eight female Wistar rats (Rattus novergicus) were used, starting the experiment at approximately 14 months of age and weighing between 350 and 450g. The animals underwent extraction of the upper right incisor and immediate installation of a titanium implant 2.5 mm wide by 5.7 mm long, where after almost 2 months, surgery to reopen the implants and installation of a healer was performed. After one week, the animals were divided according to the following treatments: vehicle, administration of 0.9% sterile saline intraperitoneally (VEI Group); zoledronate, with administration of 100 µg/Kg of zoledronate (ZOL Group); vehicle with experimental peri-implantitis (VEIPIE Group) and; zoledronate with experimental peri-implantitis (ZOL-PIE Group), with the induction of experimental peri-implantitis (PIE) by means of a cotton suture 5 weeks after the start of drug treatment. The percentage of total bone tissue (PBT-T) and percentage of non-vital bone tissue (PBT-NV) were analyzed histometrically, and immunostaining for tartrate-resistant acid phosphatase (TRAP), tumor necrosis factor alpha (TNFα), interleukin 1 beta (IL1-ß), vascular endothelial growth factor (VEGF) and osteocalcin (OCN). Data were subjected to statistical analysis. Results: The ZOL group showed persistence of inflammation in the peri-implant connective tissue and a considerable amount of PBT-NV around the implant when compared to VEI. Peri-implant inflammation was more exacerbated in ZOL-PIE, as well as compromised bone tissue vitality around the implants when compared to VEI-PIE. Conclusion: It is concluded that treatment with high doses of zoledronate causes changes at the peri-implant level, among them, an increase in local inflammation, and in PBT-NV around the osseointegrated implant, which may represent a possible risk factor for the emergence of medication-related osteonecrosis of the jaws implant- associated (MRONJ-IA). In the presence of PIE, there is an exacerbation of inflammation and an even greater increase in PBT-NV, which implies an important aggravating risk factor for the emergence of MRONJ-IA in the experimental model studied(AU)

Absence of medication-related jaw osteonecrosis after treatment with strontium ranelate in ovariectomized rats

Abstract This study aimed to evaluate the potential of strontium ranelate (SR) in medication-related jaw osteonecrosis (MRONJ) after tooth extraction in ovariectomized rats. Thirty ovariectomized rats were divided into three groups (n = 10): bisphophonate (BP) group (zoledronic acid; 0.4 mg/kg/week), SR group (625 mg/kg/day), and control group (saline solution). The lower first molars were extracted after 60 days of drug therapy. Drug administration was continued for another 30 days after tooth extraction. The mandibles were subjected to clinical, histological, radiographic, and microtomographic evaluations. Only the BP group showed clinical changes, characterized by the presence of 70% (n = 7) and 20% (n = 2) of ulcers and extraoral fistulas. Radiographic evaluation demonstrated bone sequestration only in the BP group (n = 7, 70%). Microtomographic analysis revealed increased bone porosity after ovariectomy, particularly in the the control group (p < 0.05). The BP group showed a higher bone surface density, bone volume, and trabecular number than SR and control groups, but with less trabecular separation (p < 0.05). All the animals in the BP group demonstrated histological osteonecrosis. There was no evidence of osteonecrosis in the control and SR groups, which was characterized by the absence of empty osteocyte gaps and associated with the gradual healing of the extraction area. Also, an increased number of blood vessels and a reduced number of osteoclasts were observed in the SR group (p < 0.05). Therefore, SR treatment increased angiogenesis and osteoclastogenesis in the healing socket and was not associated with MRONJ development after tooth extraction in ovariectomized rats.

Tratamiento de la osteonecrosis de los maxilares asociada a medicamentos: Enfoque médico-quirúrgico de estadios II y III

Resumen Introducción: La osteonecrosis de los maxilares asociada a medicamentos (OMAM) se define como la presencia de hueso necrótico expuesto de los maxilares en pacientes con historia de tratamiento farmacológico antirresortivo o antiangiogénico. Se describen diferentes estadios se severidad, con tratamiento conservador para estadios 0 y I, y tratamiento médico-quirúrgico para II-III. Objetivo: Describir los factores desencadenantes, opciones de tratamiento médico-quirúrgico y resultados en pacientes con OMAM estadios II-III. Material y Método: Estudio retrospectivo, descriptivo, de pacientes diagnosticados con OMAM estadios II y III que requirieron manejo médico-quirúrgico en la Red de Salud UC-Christus entre los años 2007 y 2018. Resultados: Todos los pacientes presentaron historia de tratamiento con bifosfonatos intravenosos. La mayoría de los registros de seguimiento de pacientes estuvo disponible para su análisis. El tratamiento consistió en aseo quirúrgico, decorticación y secuestrectomía. Se reportó disminución de la sintomatología con resolución parcial en la mitad de los casos y cierre completo de la exposición ósea en los restantes. Conclusión: Sugerimos que el tratamiento médico-quirúrgico en pacientes con OMAM en etapas II y III es efectivo en términos de disminución de sintomatología y control de infección. Sin embargo, es necesario realizar nuevos estudios prospectivos, con mayor cantidad de pacientes y tiempo de seguimiento.

Abstract Introduction: Medication-associated osteonecrosis of the jaws (MRONJ) is defined as the presence of exposed necrotic bone of the jaws in patients with a history of antiresorptive or antiangiogenic drug treatment. Different stages of severity are described, with conservative treatment for stages 0 and I, and medical-surgical treatment for II-III. Aim: To describe the triggers, medical-surgical treatment options and outcomes in patients with stage II-III MRONJ. Material and Method: Retrospective, descriptive study of patients diagnosed with MRONJ stages II and III that required medical-surgical management in the UC-Christus Health Network between 2007 and 2018. Results: All patients had a history of treatment with intravenous bisphosphonates. Most of the patient follow-up records were available for analysis. Treatment consisted of surgical grooming, decortication, and sequestrectomy. A decrease in symptoms was reported with partial resolution in half of the cases, and complete closure of bone exposure in the remainder. Conclusion: We suggest that medical-surgical treatment in patients with MRONJ in stages II and III is effective in terms of reducing symptoms and controlling infection. However, it is necessary to carry out new prospective studies, with a greater number of patients and follow-up time.

Calidad de vida en pacientes con metástasis óseas por cáncer de próstata tratados con ácido zoledrónico / Quality of life in patients suffering from bone metastasis due to prostate cancer treated with zoledronic acid

Introducción: El ácido zoledrónico mejora la calidad de vida en pacientes con metástasis óseas por cáncer prostático. Objetivo: Evaluar la calidad de vida relacionada con la salud con el cuestionario EORTC QLQ-BM22 en pacientes con metástasis óseas por cáncer prostático tratados con ácido zoledrónico. Métodos: Se realizó un estudio prospectivo-descriptivo de 71 pacientes con cáncer prostático metastásico a hueso tratados en el servicio de oncología del Hospital Clínico Quirúrgico "Hermanos Ameijeiras" con: edades 18-80 años, ECOG<3, expectativa de vida >6 meses, y seguimiento de al menos doce meses. Se administró ácido zoledrónico cada 21-28 días. Se aplicó la escala visual análoga y el módulo EORTC QLQ-BM22. Resultados: Los pacientes tenían una mediana de 71 años de edad, Gleason ≥ 8: en 57,7 % de los pacientes, PSA al diagnóstico ≥ 20 ng/mL: 70,4 por ciento, ECOG 1: 67,6 por ciento, y estadio IV como presentación inicial: 50,7 por ciento. Metástasis óseas sin toma visceral: 84,5 por ciento, en vértebras 36,6 por ciento, <3 sitios 66,2 por ciento, y metástasis óseas blásticas 60,6 por ciento. Eventos esqueléticos relacionados previos al ácido zoledrónico 7,9 por ciento (fractura), y posteriores, 5,6 por ciento (radioterapia anti-álgica). A doce meses, acorde a la escala visual análoga, se alcanzó respuesta completa: 71 por ciento, y parcial: 29 por ciento (p<0,05). Luego de la aplicación del módulo EORTC QLQ-BM22, se comprobó disminución significativa tanto en la escala de síntomas como en la funcional, independientemente de otros factores. Conclusiones: Los tratamientos específicos para cáncer prostático combinado a zoledrónico mejoran significativamente el dolor y calidad de vida relacionada con la salud en pacientes con metástasis óseas(AU)

Introduction: Zoledronic Acid improves the quality of life of patients suffering from prostate cancer. Objectives: To assess the health-related quality of life using EORTC QLQ-BM22 questioner in patients suffering from prostate cancer, treated with zoledronic acid. Method: A prospective-descriptive study was carried out in 71 patients suffering from prostate cancer involving bones, with ages ranging between 18 and 80 years, and who were treated in the oncology service at Hermanos Ameijeiras Hospital. The ECOG was less than 3, life expectancy> 6 months, and follow-up of at least twelve months. Zoledronic acid was administered every 21-28 days. The visual analog scale and EORTC QLQ-BM22 module were applied. Results: The patients had median age of 71 years, Gleason ≥ 8: in 57.7% of the patients, PSA at diagnosis ≥ 20 ng / mL: 70.4%, ECOG 1: 67.6 percent, and stage IV as initial presentation: 50.7 percent. Bone metastases without visceral intake: 84.5 percent, in vertebrae 36.6 percent, <3 sites 66.2 percent, and blast bone metastases 60.6 percent. Skeletal events related to zoledronic acid before 7.9 percent (fracture), and after 5.6 percent (anti-allergic radiotherapy). At twelve months, according to the visual analog scale, a complete response was achieved, 71 percent, and a partial response, 29 percent (p <0.05). After the application of EORTC QLQ-BM22 module, a significant decrease was found in both the symptom and functional scales, regardless of other factors. Conclusions: Specific treatments for prostate cancer combined with zoledronic significantly improve pain and health-related quality of life in patients with bone metastases(AU)

Comparative study of percutaneous kyphoplasty combined with zoledronic acid at different times in the treatment of osteoporotic vertebral compression fractures / 中国医师进修杂志

Objective:To compare the effect of percutaneous kyphoplasty (PKP) combined with zoledronic acid at different times in the treatment of osteoporotic vertebral compression fractures (OVCF).Methods:The clinical data of 110 patients with OVCF from January 2018 to June 2019 in the Hospital of Shunyi District Beijing were retrospectively analyzed. All patients were treated with PKP. Among them, 55 patients were given zoledronic acid on the second day after surgery (synchronization group), and 55 patients were given zoledronic acid 1 month after surgery (non-synchronization group). X-Ray examination was performed before and 1 year after surgery, and the vertebral recovery related indexes of compression fracture vertebral body were measured, including anterior border height of vertebral body, posterior border height of vertebral body, kyphotic angle and local Cobb angle; the degree of dysfunction was evaluated by Oswestry dysfunction index (ODI); the bone density of hip bone was detected; the serum alkaline phosphatase (ALP), osteocalcin and type Ⅰ collagen cross-linked C-terminal peptide (CTX-1) were detected. The patients were followed up for 1 year, and the recurrence of vertebral compression fractures was record.Results:There were no statistical differences in anterior border height of vertebral body, posterior border height of vertebral body, kyphotic angle and local Cobb angle before surgery and 1 year after surgery between 2 groups ( P>0.05). Compared with those before surgery, the anterior border height of vertebral body and posterior border height of vertebral body 1 year after surgery in 2 groups were significantly higher, the kyphotic angle and local Cobb angle were significantly lower, and there were statistical differences ( P<0.01). The ODI 1 year after surgery in synchronization group was significantly lower than that in non-synchronization group: (11.30 ± 1.53) scores vs. (14.27 ± 1.78) scores, and there was statistical difference ( P<0.01). The bone density of hip bone 1 year after surgery in synchronization group was significantly higher than that in non-synchronization group, and there was statistical difference ( P<0.01). The serum ALP and CTX-1 1 year after surgery in synchronization group were significantly lower than those in non-synchronization group: (74.93 ± 8.63) U/L vs. (78.77 ± 9.41) U/L and (0.24 ± 0.03) ng/L vs. (0.29 ± 0.03) ng/L, the osteocalcin was significantly higher than that in non-synchronization group: (9.63 ± 1.14) ng/L vs. (7.97 ± 0.85) ng/L, and there were statistical differences ( P<0.01 or <0.05). All patients were followed up for 1 year, and no recurrence of vertebral compression fractures was found. Conclusions:The synchronization zoledronic acid after PKP has more advantages in improving the condition and bone metabolism in patients with OVCF.

Prevalencia de osteonecrosis de los maxilares asociada a medicamentos en pacientes tratados con bifosfonatos intravenosos: análisis epidemiológico en Centro del Cáncer - Red de Salud UC-CHRISTUS

Resumen Introducción: La osteonecrosis de los maxilares asociada a medicamentos (OMAM) es una patología que involucra la exposición necrótica de hueso maxilar o mandibular, relacionada al uso de fármacos antirresortivos y antiangiogénicos, con una prevalencia de 0,94%-13% en pacientes oncológicos y con osteoporosis que hacen uso de ellos. Objetivo: Determinar la prevalencia de osteonecrosis de los maxilares en pacientes en tratamiento con bifosfonatos intravenosos (BFIV) en el Centro del Cáncer de la Red de Salud UC-Christus, Santiago de Chile. Material y Método: Se analizaron los datos de pacientes que recibieron tratamiento de bifosfonatos intravenoso entre marzo y septiembre de 2016, con seguimiento por los equipos tratantes. Se consideró para la extracción de datos el género, edad, diagnóstico primario, bifosfonato intravenoso utilizado, tiempo de seguimiento, presencia de metástasis óseas y diagnóstico de OMAM. Resultados: Se obtuvo una muestra de 143 pacientes, con una relación hombre:mujer de 1:2; promedio de edad de 63,2 años; 78% de ellos fueron tratados con ácido zoledrónico y un 22% con pamidronato. Del total de pacientes un 1,4% (n = 2) desarrolló OMAM. Ambos casos con diagnóstico de cáncer de mama en tratamiento con ácido zoledrónico, lo que corresponde al 1,8% de los pacientes en tratamiento con este fármaco. Conclusión: Si bien la OMAM es una patología infrecuente, esta se presenta con alta morbilidad y es de manejo complejo. La prevención y tratamiento de focos infecciosos odontogénicos de pacientes antes, durante o después del tratamiento con BFIV es fundamental para prevenir su desarrollo.

Abstract Introduction: Medication-related osteonecrosis of the jaw (MRONJ) is a disease involving exposition of necrotic maxillary and mandibular bone and it's related to antiresorptive and antiangiogenic drugs, with a prevalence that variates from 0,94%-13% in oncologic and osteoporosis patients treated with them. Aim: To determine the prevalence of MRONJ in patients that underwent treatment with intravenous bisphosphonates (IVBP) at Centro del Cancer de la Red de Salud UC-CHRISTUS of Santiago, Chile. Material and Method: Data from patients who received intravenous bisphosphonate treatment between March and September 2016 were analyzed, with follow-ups by their treating teams. Data extraction considered gender, age, primary diagnosis, intravenous bisphosphonate used, follow up time, bone metastases and diagnosis of MRONJ. Results: A sample of 143 patients was obtained with a men:women ratio of 1:2; an average age of 63,2 years, 78% of the patients were treated with zoledronic acid and 22% of the patients with pamidronate. From the total number of patients,1.4% (n = 2) developed MRONJ, both cases had breast cancer as primary diagnosis and in treatment with zoledronic acid, which corresponds to 1.8% of patients being treated with this drug. Conclusion: Although MRONJ is an infrequent disease, it presents high morbidity and complex management. Prevention and treatment of odontogenic infectious foci in patients before, during and after treatment with IVBP drugs is fundamental to prevent this pathology.

Comprehensive treatment for multicentric giant cell tumors of the pelvis and spine using apatinib: A case report and literature review

Background: There are no standardized treatments for giant cell tumors of the bone (GCTB) in rare locations such as the spine and pelvis or for those that are inoperable and recurrent, let alone for multicentric GCTB. This study reports a novel case of multicentric GCTB treated with a promising antiangiogenic drug, apatinib, a small-molecule tyrosine kinase inhibitor. The efficacy of apatinib in the treatment of GCTB has not been reported previously. Patients and Methods: A 27-year-old female presented with two giant cell tumors of the spine and sacrum–ilium diagnosed on December 15, 2016. Surgery and selective arterial embolization (SAE) were not reasonable options for this patient, and denosumab was unavailable; therefore, the antiangiogenic drug apatinib and the osteoclast inhibitor zoledronic acid were administered. Apatinib was initially administered at a dose of 850 mg daily, which was decreased to 425 mg daily after 7 months, and then increased again to 635 mg after 11 months. The patient was prescribed a maintenance dose of 500 mg daily after 16 months. The patient reported side effects of Grades I–III nausea, vomiting, and Grades II–III hand–foot syndrome. The patient underwent SAE at 26 months, and at that time, she was switched to denosumab instead of zoledronic acid. Results: The patient showed noticeable symptomatic improvement and visibly reduced tumor size after the first month of treatment. Computed tomography in the 4th month identified a partial response based on the RECIST criteria. The patient has achieved an objective reduction in tumor size at 32 months. Conclusions: Comprehensive treatment including apatinib represents a potential new treatment strategy for inoperable GCTB, with tolerable side effects. However, further clinical trials are now necessary to confirm an effective dose and determine the efficacy and safety of apatinib in the treatment of GCTB

Impacto econômico da adoção de denosumabe em pacientes com metástases ósseas ou mieloma múltiplo sob a perspectiva do sistema de saúde privado brasileiro / Economic impact of denosumab adoption in cancer patients with bone metastases or multiple myeloma from the Brazilian private healthcare system's perspective

Objetivo: Estimar o custo por evento relacionado ao esqueleto (ERE) e o impacto econômico anual da adoção de denosumabe em pacientes com metástases ósseas secundárias ao câncer de mama, próstata e outros tumores sólidos ou mieloma múltiplo sob a perspectiva do sistema de saúde privado brasileiro. Métodos: Um modelo econômico foi desenvolvido para comparar os custos relacionados com denosumabe versus ácido zoledrônico na prevenção de EREs. O modelo incluiu os seguintes custos: medicamento, administração, monitoramento e manejo de ERE. O custo anual foi apresentado em reais (BRL) para 100 pacientes. Os custos do manejo de ERE [fratura vertebral (FV), fratura não vertebral (FNV), radiação óssea (RO), cirurgia óssea (CO) e compressão da medula espinhal (CME)] foram estimados a partir dos recursos e procedimentos coletados da revisão de literatura, bases de dados e painel Delphi. Dados coletados dos estudos clínicos randomizados relacionados com cada tipo de tumor na análise e de um estudo prospectivo observacional foram utilizados para estimar a eficácia clínica de denosumabe versus ácido zoledrônico. Resultados: O custo por cada tipo de ERE variou de BRL 27.246 a BRL 28.035 para FV, BRL 18.023 a BRL 18.811 para FNV, BRL 42.750 a BRL 43.538 para RO, BRL 18.023 a BRL 18.811 para CO e BRL 12.472 a BRL 13.260 para CME. A introdução de denosumabe foi estimada em economia anual por 100 pacientes de até BRL 1.072.043,14 para câncer de mama, BRL 1.212.822,79 para outros tumores sólidos, BRL 1.929.660,67 para câncer de próstata e BRL 77.965,07 para mieloma múltiplo. Conclusão: Esta análise sugere que EREs adicionam custos substanciais no manejo de pacientes com metástases ósseas. Dessa forma, o uso de denosumabe pode prevenir e retardar EREs em pacientes com câncer e pode possivelmente levar à redução do impacto econômico associado aos EREs sob a perspectiva dos pagadores de saúde privada brasileira.

Objective: To estimate the cost per SRE and annual economic impact of denosumab adoption in patients with bone metastases (BM) secondary to breast cancer, prostate cancer, other solid tumors or multiple myeloma from the Brazilian private healthcare system's perspective. Methods: An economic model was developed to compare the cost outcomes associated with denosumab instead of zoledronic acid for SRE prevention. The model included the following costs: drug, administration, monitoring and SRE management. Annual costs per 100 patients were reported in 2019 Brazilian currency (BRL). The SRE management costs (vertebral fracture (VF), non-vertebral fracture (NVF), radiation to bone (RB), surgery to bone (SB) and spinal cord compression (SCC)) were estimated from the resources and procedures collected from literature review, official database, and a Delphi panel. Data collected from randomized clinical trials related to each tumor type in the analysis and from a prospective observational study was used to estimate the clinical efficacy of denosumab vs zoledronic acid. Results: The cost per each type of SREs across all tumors ranged BRL 27,246 ­ BRL 28,035 for VF, BRL 18,023 ­ BRL 18,811 for NVF, BRL 42,750 ­ BRL 43,538 for RB, BRL 18,023 ­ BRL 18,811 for SB and BRL 12,472 ­ BRL 13,260 for SCC. The introduction of denosumab was estimated to result in annual savings per 100 patients of up to BRL 1,072,043.14 for breast cancer, BRL 1,212,822.79 for other solid tumors, BRL 1,929,660.67 for prostate cancer and BRL 77,965.07 for multiple myeloma. Conclusion: This analysis suggests that SREs add substantial costs to the management of patients with bone metastases. In this way, the use of denosumab would prevent and delay SREs in cancer patients and might possibly lead to reduce the economic burden associated with SREs, borne by Brazilian private healthcare payers.

Delayed alveolar bone repair and osteonecrosis associated with Zoledronic Acid therapy in rats: macroscopic, microscopic and molecular analysis

Abstract Objective This study aims to evaluate bone repair and the development of the medication related osteonecrosis of the jaw (MRONJ) associated with the use of zoledronic acid in Wistar rats. Methodology 48 male Wistar rats were divided into four groups: ZA, treated with intraperitoneal zoledronic acid, 0.6 mg/kg every 28 days, totaling five doses; control (C), treated with 0.9% sodium chloride; ZA-surgical (SZA) and C-surgical (SC), submitted to extraction of the right upper molars 45 days after the first application. Alveolar bone repair was evaluated by macroscopic and histological analysis. Protein expression evaluations were performed by qPCR. Results Macroscopic evaluation showed that 91.66% (11) of the animals in the SZA group and 41.66% (5) from the SC group presented solution of epithelium continuity (P<0.05). All animals in the SZA group and none in the SC group had bone sequestration. The area of osteonecrosis was higher in the SZA group than in the SC group (P<0.05). In molecular evaluation, the SZA group presented changes in the expression of markers for osteoclasts, with increased RANK and RANKL, and a decrease in OPG. Conclusion The results highlighted strong and evident interference of zoledronic acid in bone repair of the socket, causing osteonecrosis and delayed bone remodeling.