Enfoques terapéuticos de la osteoporosis / Therapeutic approaches to osteoporosis

La finalidad del tratamiento de la osteoporosis es la prevención primaria y secundaria de fracturas. Las indicaciones para las intervenciones terapéuticas en la osteoporosis deben derivarse de la determinación del riesgo absoluto de fractura, que tiene en cuenta la evaluación de los factores de riesgo y la densidad ósea. El propósito de este estudio es comentar algunos enfoques terapéuticos empleados en la osteoporosis, destacando el mecanismo de acción del ranelato de estroncio que aumenta la formación de hueso y disminuye la resorción. La causa más común de osteoporosis en las mujeres es la disminución de los niveles de estrógeno durante la menopausia, lo que lleva a un aumento significativo en el recambio de masa ósea y el consiguiente desequilibrio entre la formación y reabsorción ósea con un aumento de la pérdida ósea y el deterioro de la estructura y fuerza óseas. El ranelato de estroncio sigue siendo una opción farmacológica eficaz y viable en la prevención de las fracturas vertebrales y del cuello femoral en mujeres posmenopáusicas y hombres adultos con osteoporosis, en cuanto a indicaciones, contraindicaciones y una cuidadosa evaluación de sus efectos y riesgos. Representa una alternativa a los medicamentos antirresortivos en caso de contraindicación, intolerancia o fracaso(AU)

The purpose of the treatment of osteoporosis is the primary and secondary prevention of fractures. The indications for therapeutic interventions in osteoporosis should be derived from the determination of the absolute risk of fracture, which takes into account the evaluation of risk factors and bone density. To comment on some therapeutic approaches used in osteoporosis, highlighting the mechanism of action of strontium ranelate that increases bone formation and reduces resorption. The most common cause of osteoporosis in women is the decrease in estrogen levels during menopause, which leads to a significant increase in the turnover of bone mass and the consequent imbalance between bone formation and resorption with an increase in bone loss and deterioration of bone structure and strength. Strontium ranelate continues to be an effective and viable pharmacological option in the prevention of vertebral and femoral neck fractures in postmenopausal women and adult men with osteoporosis, in terms of indications, contraindications and a careful evaluation of its effects and risks. It represents an alternative to antiresorptive drugs in case of contraindication, intolerance or failure(AU)

Avaliação da morfologia hepática em ratos após administração do ranelato de estrôncio / Evaluation of hepatic morphology in rats after administration of strontium ranelate

Introdução: o fármaco ranelato de estrôncio (RE) é muito utilizado na terapêutica profilática e no controle da osteoporose. Age sistemicamente diminuindo a reabsorção e aumentando a formação óssea, apresentando eventos adversos pouco esclarecidos na literatura, à exemplo a síndrome DRESS com envolvimento hepático. Objetivo: avaliar a morfologia hepática em ratos norvegicus albinus após administração do RE. Metodologia: estudo experimental com 10 ratos, divididos aleatoriamente em dois grupos, Grupo Controle (GC), sem administração do RE, e Grupo Ranelato de Estrôncio (GRE), ambos acompanhados durante 15 dias, e, em seguida, sacrificados e o fígado de cada animal colocado para fixação no solução de formaldeído a 4% durante 48 horas. Após essa etapa, foram realizados os procedimentos necessários à análise pela microscopia óptica, com lâminas coradas pela hematoxilina e eosina, e picrosirius red.Resultados: nos GC e GRE foram encontradas alterações similares, como reação ductular, dilatação sinusoidal e fibrose perissinusoidal, com intensidades distintas entre os grupos, sendo a reação ductular mais proeminente no GC, e a dilatação sinusoidal e fibrose perissinusoidal mais pronunciada no GRE. Além disso, no GC foram evidenciados achados inflamatórios, como presença de infiltrado inflamatório misto e hiperplasia de células de Kupffer, não visualizados no GRE, implicando numa possível ação anti-inflamatória do RE. Conclusão: pode-se concluir que foram visualizadas diferenças nos achados morfológicos do parênquima hepático dos ratos tratados com o RE em comparação aos não tratados, ainda que esses achados não sejam suficientes para inferir a incidência de um processo patológico característico, como cirrose ou hepatite.

Introduction: the drug strontium ranelate (SR) is widely used in prophylactic therapy and in the control of osteoporosis. It acts by reducing reabsorption and increasing bone formation systemically, presenting unclear adverse events in the literature, such as the DRESS syndrome with hepatic involvement. Objective: to evaluate hepatic morphology in norvegicus albinus rats after SR administration. Methodology: experimental group with 10 rats, divided into two groups, randomly distributed, five from the Control Group (CG), without SR administration, and the other five from the Strontium Ranelate Group (SRG), both followed for 15 days, and then sacrificed and the liver of each animal placed for fixation in 4% formalin for 48 hours. After this step, the procedures necessary for the analysis by optical microscopy were performed, with blades stained by hematoxylin e eosin, and picrosirius red. Results: in CG and SRG, similar alterations were observed, such as ductular reaction, sinusoidal dilatation and perissinusoidal fibrosis, with distinct intensities between the groups, being the ductular reaction more prominent in the CG, and sinusoidal dilation and a perissinusoidal fibrosis more pronounced in the SRG. In addition, in the CG were evidenced inflammatory findings such as the presence of mixed inflammatory infiltrate and Kupffer cell hyperplasia, not visualized in the SRG, implying a possible anti-inflammatory action of SR. Conclusion: it can be concluded that differences were observed in the morphological findings of the hepatic parenchyma of rats treated with SR compared to untreated rats, although these findings are not sufficient to infer the incidence of a characteristic pathological process, such as cirrhosis or hepatitis.

Strontium ranelate improving metabolic imbalance in oim mice of osteogenesis imperfecta: The dual mechanism / 第二军医大学学报

Objective: To explore the dual effects of strontium ranelate (SrR) on primary osteoblasts and osteoclasts using an osteogenesis imperfecta (OI) model oim mouse. Methods: The osteoblasts were obtained by digesting the calvaria of one-week-old homozygote oim/oim mice and wild type (wt/wt) mice with type I collagenase. The osteoclasts were obtained by inducing the bone marrow mononuclear cells derived from the long bone of oim/oim mice and wt/wt mice aged between five and seven weeks old. SrR with different concentrations (1 mmol/L and 10 mmol/L) was used to stimulate the cells. Quantitative real-time PCR (qRT-PCR) and Western blotting were used to quantify the expression of osteoblast differentiation-related genes (Runt-related transcription factor 2 [Runx2], alkaline phosphatase [ALP] and osteocalcin [OCN]), osteoclast differentiation-related genes (calcitonin receptor [Calcr], tartrate-resistant acid phosphatase [Trap] and cathepsin K [CTSK]), and osteoclast differentiation-related transcription factors (cellular oncogene fos [c-fos] and nuclear factor of activated T-cell c1 [NFATc1]). The osteoblast differentiation and mineralization were evaluated by ALP staining and alizarin red S staining. The osteoclastogenesis and resorption activity of the osteoclasts were evaluated by Trap staining and pit formation assay. The effect of SrR on cell viability of osteoblasts and osteoclasts was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Results: qRT-PCR and Western blotting showed that the expression levels of Runx2, ALP, and OCN in oim/oim mice were significantly increased at mRNA and protein levels after stimulation with SrR in a dose-dependent manner (all P<0.05). In comparison, SrR caused significant decreases in Calcr, Trap, CTSK, c-fos, and NFATc1 expression (all P<0.05). ALP staining and alizarin red S staining demonstrated that SrR stimulation significantly increased osteoblast differentiation and mineralization of oim/oim mice (all P<0.05). Trap staining and pit formation assay showed that SrR significantly decreased the formation number of osteoclasts and inhibited the resorption activity of osteoclasts in oim/oim mice (all P<0.05). MTT assay showed that 1 mmol/L and 10 mmol/L SrR had no cell cytotoxicity on osteoblasts or osteoclasts of oim/oim mice. Conclusion: SrR can improve the imbalance of bone metabolism in OI model oim mouse, which might involve the increases in osteoblast differentiation and mineralization and decreases in formation and resorption of the osteoclasts.

Efectos del ranelato de estroncio sobre la densidad mineral ósea en hombres / Effect of strontium ranelate on bone mineral density in men

La osteoporosis afecta al 6-7% de la poblaciónmasculina. Es alta la proporción de pacientes confractura osteoporótica sin diagnóstico previo de estaenfermedad. La mortalidad luego de una fracturaes mayor en hombres que en población femenina;a pesar de esto, la mayoría de los pacientes no reciben tratamiento. Los fármacos aprobados, en nuestro medio, para tratar la osteoporosis masculina son:bifosfonatos, teriparatida y ranelato de estroncio. Elobjetivo de este estudio fue evaluar el efecto del ranelato de estroncio sobre la densidad mineral ósea enhombres después de 1 año de tratamiento. Se incluyeron los registros de 20 hombres de 67.8±3.0 años,tratados con ranelato de estroncio (2 g/día) durante 1año. Todos los pacientes presentaban un T-score inferior a -2.5 en cadera o columna vertebral o un T-scoreinferior a -2.0 y factores de riesgo de fractura. Nohubo modificación de parámetros de laboratorio luego del tratamiento (calcemia, calciuria, fósforo sérico,parathormona, 25(OH)vitamina D, fosfatasa alcalinay desoxipiridinolina). Luego de 1 año de tratamiento con ranelato de estroncio se observó incrementode la densidad mineral ósea en columna lumbar:0.953±0.029 versus 0.997±0.030 g/cm2 (p=0.0068),cuello femoral: 0.734±0.013 versus 0.764±0.016 g/cm2 (p=0.0084) y cadera total: 0.821±0.02 versus0.834±0.02 g/cm2 (p=0.0419). Conclusión: luego de1 año de tratamiento el ranelato de estroncio produjoun incremento significativo de la densidad mineralósea en columna lumbar y fémur proximal en hombres con osteoporosis (AU)

Osteoporosis affects 6-7% of the male population. The proportion of patients with fragility fractures but without diagnosis of the disease is high. Mortality after hip fracture is higherin men than in women; in spite of this, mostpatients are left without treatment for osteoporosis. Drugs approved, for the treatment ofosteoporosis in our country are bisphosphonates, teriparatide, and strontium ranelate (SrR).The objective of this study was to evaluate theeffect of SrR on axial BMD in men after one yearof treatment. We obtained pertinent data frommedical registries of 20 men aged 67,8±3,0 years,treated with oral SrR (2 g/day) for 12 months. All patients had a T-score below -2,5 at the hipor the lumbar spine, or a T-score below -2,0and one or more risk factors for fracture. Thelevels of serum calcium, phosphate, alkalinephosphatase, 25-hydroxyvitamin D, or PTH,or urinary calcium and desoxipyridinoline remained unchanged following SrR administration. After treatment with SrR there weresignificant increases in BMD at the lumbarspine: 0,953±0,029 versus 0,997±0,030 g/cm2(p=0,0068), femoral neck: 0,734±0,013 versus 0,764±0,016 g/cm2 (p=0.0084), and total hip: 0,821±0,02 versus 0,834±0,02 g/cm2(p=0,0419). Conclusion: in osteoporotic men,treatment with SrR significantly increases BMDin the lumbar spine and the proximal femur (AU)

Strontium ranelate inhibits wear particle-induced aseptic loosening in mice

The imbalance between bone formation and osteolysis plays a key role in the pathogenesis of aseptic loosening. Strontium ranelate (SR) can promote bone formation and inhibit osteolysis. The aim of this study was to explore the role and mechanism of SR in aseptic loosening induced by wear particles. Twenty wild-type (WT) female C57BL/6j mice and 20 sclerostin-/- female C57BL/6j mice were used in this study. Mice were randomly divided into four groups: WT control group, WT SR group, knockout (KO) control group, and KO SR group. We found that SR enhanced the secretion of osteocalcin (0.72±0.007 in WT control group, 0.98±0.010 in WT SR group, P=0.000), Runx2 (0.34±0.005 in WT control group, 0.47±0.010 in WT SR group, P=0.000), β-catenin (1.04±0.05 in WT control group, 1.22±0.02 in WT SR group, P=0.000), and osteoprotegerin (OPG) (0.59±0.03 in WT control group, 0.90±0.02 in WT SR group, P=0.000). SR significantly decreased the level of receptor activator for nuclear factor-κB ligand (RANKL) (1.78±0.08 in WT control group, 1.37±0.06 in WT SR group, P=0.000) and improved the protein ratio of OPG/RANKL, but these effects were not observed in sclerostin-/- mice. Our findings demonstrated that SR enhanced bone formation and inhibited bone resorption in a wear particle-mediated osteolysis model in wild-type mice, and this effect relied mainly on the down-regulation of sclerostin levels to ameliorate the inhibition of the canonical Wnt pathway.

Strontium ranelate as a possible disease-modifying osteoarthritis drug: a systematic review

Considering that osteoarthritis (OA) is the most prevalent joint disease worldwide, multiple pharmacological treatments have been proposed to alter the articular structure with potential benefit in the progression of the disease. The so-called disease-modifying OA drugs have been frequently investigated but conclusive findings are rare. Strontium ranelate (SrRan) is a drug usually prescribed to treat osteoporosis, with proven effects in decreasing the risk of fractures and possible effect in reducing the progression of OA. The objective of this review was to demonstrate the current panorama of knowledge on the use of SrRan in clinical and experimental models, clarifying its mechanisms of action and describing possible anti-nociceptive and anti-inflammatory effects. The systematic review was based on the PRISMA statement and included articles that are indexed in scientific databases. Fifteen studies were included: seven pre-clinical and eight clinical studies. Despite the limited number of studies, the results suggest a positive effect of SrRan in patients with OA, through changes in functional capacity and reduction of progression of morphological parameters and joint degradation, with moderate quality of evidence for those clinical outcomes. Novel studies are necessary to elucidate the molecular targets of SrRan, focusing on anti-inflammatory effects and histological changes promoted by SrRan, which seemed to reduce the progression of OA in the experimental and clinical studies.

Effects of strontium ranelate on alveolar ridge morphology augmentation / Efectos del ranelato de estroncio en el aumento del rebforde alveolar

SUMMARY: The objective of this study was to compare the Primary and Secondary stability of immediate implant placement with Alveolar Ridge Augmentation (ARA) and Strontium Ranelate (SR) as aids to enhance the stability using Resonance Frequency Analysis (RFA). Fifty eight subjects ideal for immediate implants were assigned to two groups to compare the primary and secondary stability of the implant using Alveolar Ridge Augmentation and oral strontium ranelate. They were tested for primary stability on placement of the implant and after eight weeks of placement for secondary stability. The stability was measured using resonance frequency analysis. Both the procedures showed an improvement in the stability but the Alveolar Ridge Augmentation procedure showed a significantly better primary stability (P< .03) and the secondary stability (P<.00). The means of the implant stability quotient value (ISQ) for the Alveolar ridge augmentation procedure was 74.2 for primary stability, and 83.34 for secondary stability. With the enhancement of stability with both the procedures Alveolar Ridge Augmentation proved to be a better procedure to achieve successful results of an immediately placed implant.

RESUMEN: El objetivo de este estudio fue comparar la estabilidad primaria y secundaria de la colocación inmediata del implante con el aumento de reborde alveolar (ARA) y el ranelato de estroncio (SR) como ayudas para mejorar la estabilidad mediante el análisis de frecuencia de resonancia (RFA). Cincuenta y ocho sujetos, ideales para implantes inmediatos, fueron asignados a dos grupos para comparar las estabilidades primaria y secundaria del implante usando el aumento del reborde alveolar y el ranelato de estroncio oral. Se efectuaron pruebas de estabilidad primaria en la colocación del implante, y después de ocho semanas para la estabilidad secundaria. La estabilidad se midió utilizando análisis de frecuencia de resonancia. Ambos procedimientos mostraron una mejora en la estabilidad, sin embargo el procedimiento del aumento del reborde alveolar mostró una estabilidad primaria significativamente mejor (P <0,03) que la estabilidad secundaria (P <0,00). Las medias del valor de cociente de estabilidad del implante (ISQ) para el procedimiento de aumento de reborde alveolar fueron 74,2 para la estabilidad primaria y 83,34 para la estabilidad secundaria. Se observó una mejora de la estabilidad en ambos procedimientos, el aumento del reborde alveolar demostró ser un mejor procedimiento para lograr resultados exitosos del posicionamiento de implante inmediato.

Efecto del ranelato de estroncio sobre la densidad mineral ósea en hombres con osteoporosis / Effect of strontium ranelate on bone mineral density in men with osteoporosis

La osteoporosis afecta al 6-7% de la población masculina. Es alta la proporción de pacientes con fracturas sin diagnóstico previo de esta enfermedad. La mortalidad luego de una fractura es mayor en hombres que en población femenina; a pesar de esto, la mayoría de los pacientes no reciben tratamiento. Los fármacos aprobados, en nuestro medio, para tratar la osteoporosis masculina son: bifosfonatos, teriparatida y ranelato de estroncio. El objetivo de este estudio fue evaluar el efecto del ranelato de estroncio sobre la densidad mineral ósea en hombres después de 1 año de tratamiento. Se incluyeron los registros de 20 hombres de 67,8±3,0 años, tratados con ranelato de estroncio (2 g/día) durante 1 año. Todos los pacientes presentaban un T-score inferior a -2,5 en cadera o columna vertebral o un T-score inferior a -2,0 y factores de riesgo de fractura. No hubo modificación de parámetros de laboratorio luego del tratamiento (calcemia, calciuria, fósforo sérico, parathormona, 25(OH)vitamina D, fosfatasa alcalina y desoxipiridinolina) en relación a los basales. Luego del tratamiento con ranelato de estroncio se observó incremento de la densidad mineral ósea en columna lumbar: 0,953±0,029 versus 0,997±0,030 g/cm2 (p=0,0068), cuello femoral: 0,734±0,013 versus 0,764±0,016 g/cm2 (p=0,0084) y cadera total: 0,821±0,02 versus 0,834±0,02 g/cm2 (p=0,0419). Conclusión: el tratamiento con ranelato de estroncio produjo un incremento significativo de la densidad mineral ósea en columna lumbar y fémur proximal en hombres con osteoporosis. (AU)

Osteoporosis affects 6-7% of the male population. The proportion of patients with fragility fractures but without diagnosis of the disease is high. Mortality after hip fracture is higher in men than in women; in spite of this, most patients are left without treatment for osteoporosis. Drugs approved, for the treatment of osteoporosis in our country are bisphosphonates, teriparatide, and strontium ranelate (SrR). The objective of this study was to evaluate the effect of SrR on axial BMD in men after one year of treatment. We obtained pertinent data from medical registries of 20 men aged 67,8±3,0 years, treated with oral SrR (2 g/day) for 12 months. All patients had a T-score below -2,5 at the hip or the lumbar spine, or a T-score below -2,0 and one or more risk factors for fracture. The levels of serum calcium, phosphate, alkaline phosphatase, 25-hydroxyvitamin D, or PTH, or urinary calcium and desoxipyridinoline remained unchanged following SrR administration. After treatment with SrR there were significant increases in BMD at the lumbar spine: 0,953±0,029 versus 0,997±0,030 g/cm2 (p=0,0068), femoral neck: 0,734±0,013 versus 0,764±0,016 g/cm2 (p=0.0084), and total hip: 0,821±0,02 versus 0,834±0,02 g/cm2 (p=0,0419). Conclusion: in osteoporotic men, treatment with SrR significantly increases BMD in the lumbar spine and the proximal femur. (AU)

Evaluación de la respuesta densitométrica en pacientes con osteoporosis posmenopáusica tratadas con ranelato de estroncio o denosumab / Densitometric response in postmenopausal osteoporosis treated with strontium ranelate or denosumab

Tanto el ranelato de estroncio (RSr) como el denosumab (Dmab) son eficaces en el tratamiento de la osteoporosis (OP) posmenopáusica (PM). El efecto de cada fármaco por separado sobre la densidad mineral ósea (DMO) ha sido estudiado recientemente. Con ambas drogas se observó, al año de tratamiento, un aumento significativo de la DMO en columna lumbar (CL), cuello femoral (CF) y cadera total (CT). En este trabajo comparamos la respuesta densitométrica al año de tratamiento con una y otra droga. Utilizamos los registros de 425 pacientes PMOP tratadas con Dmab y 441 tratadas con RSr. En cada paciente analizamos el porcentaje de cambio; se clasificaron como respondedoras aquellas que mostraron un cambio ≥3%. Adicionalmente se comparó la respuesta en pacientes no previamente tratadas con bifosfonatos (BF-naïve) en comparación con pacientes que habían recibido previamente un BF. Al analizar el grupo completo para Dmab, el porcentaje de pacientes respondedoras fue de 68,4% en CL, 63,3% en CF y 49,3% en CT. Por otro lado, en el grupo de pacientes tratadas con RSr, el porcentaje de respondedoras (53,8% en CL, 40,0% en CF y 35,6% en CT) fue estadísticamente menor. Cuando comparamos la respuesta entre las pacientes BF-naïve que recibieron RSr o Dmab, el Dmab indujo mayor respuesta en CL y CF que el grupo RSr, sin diferencias en CT. Cuando se analizaron los subgrupos BF-previo, las tratadas con Dmab mostraron mayor respuesta en todas las regiones. Conclusión: en pacientes con OP-PM, el tratamiento con Dmab produjo mayores incrementos densitométricos que el RSr, siendo el porcentaje de pacientes respondedoras mayor con Dmab que con RSr. (AU)

Both strontium ranelate (SrR) and denosumab (Dmab) are effective in the treatment of postmenopausal osteoporosis (PMOP). The effect of each drug on bone mineral density (BMD) has been studied separately by us. With both treatments, there was a significant increase after one year of treatment at the lumbar spine (LS) and hip. In this paper we compared the densitometric response after one year of treatment with both drugs used separately. We used the clinical records of 425 PM patients treated with Dmab and 441 treated with SrR. For each patient we analyzed the percentage of change; those who showed a change ≥3% were classified as responders. Additionally, the response was compared in patients not previously treated with bisphosphonates (BP-naïve) compared to patients who had previously received a BP. When analyzing the complete group for Dmab, the percentage of "responders" was 65.2% at the LS, 62.9% at the femoral neck (FN) and 47.4% at the total hip (TH). On the other hand, in the group of patients treated with SrR the percentage of responders (53.8% at the LS, 40.0% at the FN and 35.6% at the TH) was statistically lower. When comparing the response between in BF-naïve patients receiving RSr or Dmab, Dmab induced a greater response at the LS and FN than the RSr group, with no statistical differences at the TH. When the subgroups with prior BP treatment were analyzed, those treated with Dmab showed greater response in all regions. Conclusion: in patients with PMOP treatment with Dmab produced greater densitometric increments than SrR, and the percentage of responders was higher with Dmab than with SrR. (AU)

Effect of strontium ranelate on pain behavior in an experimental model of osteoarthritis

Strontium ranelate (SrRan) is a drug usually prescribed to treat osteoporosis, with proven effects of decreasing the risk of fractures and an indication of reducing the progression of osteoarthritis (OA). This study aimed to investigate the effects of SrRan as either a prophylactic or a treatment drug, using an OA rat model to assess pain behavior. A monoiodoacetate (MIA)-induced knee joint OA model in Wistar rats was used. Thirty Wistar rats (both sexes, 60 days old) were distributed in five groups of 6 rats each: the control group, that received no intervention; a prophylactic group, that received oral administration of 25 mg·kg-1·day-1 of SrRan for 28 days before induction of OA; a group treated with 25 mg·kg-1·day-1 of SrRan for 28 days after OA induction; a group treated with 50 mg·kg-1·day-1 during 28 days after OA induction; and a group that received oral saline for 28 days after induction. The assessment of pain behavior was performed considering articular incapacitation (weight-bearing test), mechanical hyperalgesia (Randall Selitto test) and motor activity (rotarod test), on days 0, 7, 14, 21, and 28. This experiment did not yield a significant difference when comparing the group that received SrRan prophylactically with the groups treated with 25 or 50 mg·kg-1·day-1 and the group that received oral saline. Thus, SrRan did not provide analgesia in either treated rats or as a prophylactic drug with the tested doses. Higher doses should be tested further to achieve possible significant results.

Strontium Ranelate Effect on the Repair of Bone Defects and Molecular Components of the Cortical Bone of Rats

Abstract This study was conducted to evaluate the effects of treatment with strontium ranelate (SR) on the repair of bone defects and molecular components of bones in femurs. Adult female rats (n=27) were subjected to ovariectomy (OVX) or Sham surgery. Thirty days after surgery, a defect was made in the femur and the animals were then divided into three groups: OVX, SHAM and OVX+SR. Euthanasia was performed four weeks after the bone defect surgery. Repair in bone defect was assessed by computed microtomography (μCT) and chemical composition of cortical bone was analyzed by Fourier transform infrared (FTIR) spectroscopy and energy dispersive X-ray spectroscopy (EDS). The trabecular thickness (Tb.Th) of the newly formed bone in the OVX+SR group was significantly higher than that for the OVX group. The collagen maturity in the OVX+SR group was smaller than in the other two groups. In this group, a significant increase in the amount of strontium (Sr) and a decrease in the amount of calcium (Ca) embedded to bone tissue were also observed. Systemic treatment with SR improved microarchitecture of the newly formed bone inside the defect, but decreased cross-linking of mature collagen in cortical bone.

Resumo Este estudo foi conduzido para avaliar os efeitos do tratamento com ranelato de estrôncio (RE) na reparação de defeitos ósseos e componentes moleculares de ossos nos fêmures. Ratas adultas (n = 27) foram submetidas a ovariectomia (OVX) ou cirurgia Sham. Trinta dias após a cirurgia, um defeito foi feito no fêmur e os animais foram então divididos em três grupos: OVX, SHAM e OVX+RE. A eutanásia foi realizada quatro semanas após a cirurgia de preparo do defeito ósseo. A reparação do defeito ósseo foi avaliada por microtomografia computorizada (μCT) e a composição química do osso cortical foi analisada por espectroscopia de infravermelho de transformada de Fourier (FTIR) e espectroscopia por energia dispersiva de raios X (EDS). A espessura do osso trabecular (Tb.Th) recém formado no grupo OVX+SR foi significativamente maior que a do grupo OVX. A maturidade do colágeno no grupo OVX+SR foi menor do que nos outros dois grupos. Neste grupo, observou-se também um aumento significativo na quantidade de estrôncio (Sr) e uma diminuição na quantidade de cálcio (Ca) no tecido ósseo. O tratamento sistêmico com RE melhorou a microarquitetura do osso recém formado dentro do defeito, mas diminuiu a reticulação do colágeno maduro no osso cortical.

Efectos in vivo del ranelato de estroncio sobre células progenitoras de médula ósea de ratas diabéticas / In vivo effects of strontium ranelate on bone marrow progenitor cells of diabetic rats

La diabetes mellitus (DM) crónica se asocia con reducción en el contenido mineral óseo (osteopenia y osteoporosis). El objetivo de este trabajo fue evaluar la acción del ranelato de estroncio (RaSr) administrado por vía oral a animales control y diabéticos, sobre el potencial osteogénico de células progenitoras de médula ósea (CPMO). Dieciséis ratas Wistar macho jóvenes se dividieron en dos grupos: controles (C) y diabéticas (D) con destrucción parcial de células b-pancreáticas mediante inyecciones intraperitoneales consecutivas de nicotinamida y estreptozotocina. Siete días después de la inyección, cada grupo se subdividió: sin tratamiento, o tratadas oralmente con RaSr (625 mg/kg/día) durante seis semanas, luego de lo cual los animales fueron sacrificados. Las CPMO se obtuvieron de ratas de los cuatro grupos, por lavados del canal diafisario medular (húmero o fémur o ambos) y cultivo hasta confluencia en DMEM-10% FBS. La proliferación celular se evaluó mediante el ensayo de MTT. Luego las CPMO se replaquearon e incubaron en un medio osteogénico durante 14 días (fosfatasa alcalina [FAL] y colágeno tipo 1) o 21 días (mineralización). Las CPMO del grupo C+RaSr mostraron un aumento significativo versus control en la proliferación (133%) y en la diferenciación osteogénica (colágeno 143%, FAL 168%, mineralización 117%). La DM (grupo D) disminuyó significativamente la proliferación y diferenciación osteoblástica de las CPMO. El tratamiento con RaSr (grupo D+RaSr) previno completamente estos efectos antiosteogénicos de la DM. Así, en nuestro modelo experimental in vivo, la DM disminuye el potencial osteogénico de CPMO, efecto que puede ser prevenido por un tratamiento oral con RaSr. (AU)

Chronic diabetes mellitus (DM) is associated with a reduction in bone mineral content (osteopenia and osteoporosis). The object of this study was to evaluate the in vivo effect of he anti-osteoporotic drug strontium ranelate (SrRa) administered orally to control and diabetic animals, on the osteogenic potential of bone marrow progenitor cells (BMPC). Sixteen young male Wistar rats were divided into two groups: control (C) and diabetic with partial beta-cell destruction via consecutive intra-peritoneal injections of nicotinamide and streptozotocin (D). Seven days postinjection, each group was sub-divided: without treatment, or oral treatment with SrRa (625 mg/kg/day) for six weeks, after which the animals were euthanised (groups C, C+SrRa, D, D+SrRa). BMPC were obtained from rats of all four groups by flushing of the diaphysary canal (humerus and/or femur). Adherent cells were then cultured until confluence in DMEM10% FBS. Cell proliferation was evaluated with the MTT mitogenic bioassay. BMPC were replated and incubated in an osteogenic medium for 14 days (determination of alkaline phosphatase [ALP] and type-1 collagen) or 21 days (evaluation of mineralisation). BMPC from C+SrRa rats showed a significant increase versus control in proliferation (133%) and in osteogenic differentiation (collagen 143%, ALP 168%, mineralisation 117%). Induction of diabetes (group D) significantly decreased the proliferation and osteoblastic differentiation of BMPC. Treatment of diabetic animals with SrRa (group D+SrRa) completely prevented these anti-osteogenic effects of Diabetes. Thus, in our experimental in vivo model, Diabetes decreases the osteogenic potential of BMPC, an effect that can be prevented by oral treatment with strontium ranelate. (AU)

Sequential administration of alendronate and strontium ranelate: histomorphometry and bone biomechanics in ovariectomized animals

Bisphosphonates are the first choice therapy for the pharmaco logical treatment of osteoporosis. Following reports of cases of bisphosphonaterelated osteonecrosis of the jaw and atypical femur fracture, the safety of longterm use of bisphosphonates has been evaluated, resulting in the proposal of strontium as an alternative drug. No experimental study using a sequential administration design has been reported to date. Hence, the aim of this study was to evaluate the effect on bone tissue of ovariectomized rats of administration of alendronate followed by strontium ranelate. Fortyeight female Wistar rats were ovariectomized on day 1 of the experiment. Beginning on day 30, they were administered 0.3 mg/kg/week of alendronate (ALN) or vehicle (VEH) for 8 weeks. Two groups (ALN and corresponding control) were euthanized at this time, and the remaining animals were divided into 4 groups and given 290 mg/kg/day of strontium ranelate (SR) in their drinking water (TW) or only water for 4 months. Experimental groups were: ALN+SR, ALN+TW, VEH+SR, VEH+TW, ALN and VEH. The tibiae and hemimandibles were resected for histomorphometric evaluation, and the right femur was used to perform biomechanical studies. ANOVA and Bonferroni test were applied. Diaphyseal stiffness, maximum elastic load and fracture load increased in animals that received alendronate, regardless of whether or not they received subsequent SR treatment. Fracture load also increased in VEH+ SR versus control (VEH+TW). Subchondral and interradicular bone volumes were significantly higher in animals that received ALN than in those that received vehicle. No difference was observed in cortical area or thickness of the tibia among treatments. The results obtained with the model presented here, evaluating tibial and mandibular interradicular bone, showed that the combination of ALN and SR and administration of ALN alone are equally effective in preventing bone loss associated with ovariectomyinduced estrogen depletion.

Si bien la primera opción terapéutica para el tratamiento farmacológico de la osteoporosis son los bisfosfonatos (BPs), luego de los primeros reportes en 2003 de los casos de osteone crosis de mandíbula asociada al uso de dichas drogas y las fracturas atípicas de fémur, se ha evaluado su seguridad a largo plazo. Además, en aquellos pacientes que no responden al tratamiento con BPs y mantienen elevado el riesgo de fractura, es necesario suspender su administración y alternar con otras drogas. Una de las que se ha utilizado en la clínica luego del tratamiento con BPs es el ranelato de estroncio (SR). Existen varios trabajos clínicos que reportan los efectos de la administra ción secuencial de ambas drogas, aunque estudios experi men tales con un diseño secuencial aun no se han reportado. Por ello el objetivo de este trabajo ha sido evaluar el efecto de la administración secuencial de alendronato, seguido de ranelato de estroncio sobre el tejido óseo de ratas ovariectomizadas. Se utilizaron 48 ratas Wistar hembras de dos meses de edad divididas en 6 grupos de 8 animales cada uno. El día 1 de experiencia todas fueron ovariectomizadas. El día 30 se comenzó con la administración de alendronato (ALN) en una dosis de 0.3 mg/kg/semana o vehículo (VEH) durante 8 semanas. Luego de este período se sacrificaron dos grupos (uno que recibió ALN y su correspondiente control (sólo vehículo). Los cuatro grupos restantes continuaron con ranelato de estroncio (SR) en el agua de bebida durante 4 meses en una dosis de 290 mg/kg/día o sólo agua corriente( TW) Luego de ese período fueron eutanasiados. Así, los grupos experimentales conformados fueron: ALN+SR, ALN+TW, VEH+SR, VEH+TW, ALN y VEH. Para los estudios histomorfométricos se extrajeron ambas tibias y hemimandíbulas; para el estudio biomecánico se utilizó el fémur derecho. Los resultados fueron analizados mediante el test de ANOVA y el test de Bonferroni. Incrementaron significativamente la rigidez diafisaria, la carga elástica límite y la carga de fractura aquellos grupos que recibieron alendronato versus aquellos que no lo recibieron, independientemente del tratamiento posterior con SR. La carga de fractura además fue mayor en el grupo VEH+SR versus el control (VEH+TW). En cuanto al volumen óseo subcondral e interradicular evaluado histomorfométricamente fue significativamente mayor en aquellos animales que recibieron ALN versus aquellos que recibieron vehículo. No se detectaron diferencias entre aquellos grupos que recibieron SR y sus controles. El área y espesor cortical de la tibia no mostraron diferencias entre grupos. Los resultados obtenidos en el modelo estudiado tanto a nivel del volumen óseo subcondral y cortical de la tibia como a nivel del hueso interradicular del maxilar inferior, mostraron que la combinación de ALN con SR y la administración aislada de ALN son igualmente efectivas para prevenir la pérdida ósea causada por la depleción estrogénica de la ovariectomía.

Comparison of the Effects of Strontium Ranelate and PTH (1-34)on Bone Quality of Ovariectomized Rats / 中国药房

OBJECTIVE:To compare the effects of strontium ranelate and PTH(1-34)on bone quality of ovariectomized rats. METHODS:80 SD rats were randomly divided into sham operation group(group A,n=10)and dual ovariectomy(group B,n=70). 3 months after operation,group B were randomly divided into 7 groups,with 10 rats in each group. B0 group were given nor-mal saline [0.9 g/(kg·d)] subcutaneously;B1-B3 groups were given low-dose,medium-dose and high-dose of strontium ranelate [0.45,0.9,1.35 g/(kg·d)] intragastrically;B4-B6 groups were given low-dose,medium-dose and high-dose of PTH(1-34)[30, 60,90 μg/(kg·d),treated for 5 days,rested for 2 days] subcutaneously. Group A was same to group B0 in therapy regimen. All rats were sacrificed 8 weeks later. The contents of P1NP and CTX-1 in serum of rats were determined by ELISA assay;bone densi-ty of 4th lumbar vertebrae was detected by bone densitometer;BV/TV,Tb.Th,Tb.N and Tb.Sp were detected by CT;maximal load and elastic modulus of 5th lumbar vertebrae were measured by compression test. RESULTS:Compared with group A,the se-rum levels of P1NP and CTX-1 in B0-B6 groups increased significantly,while bone density of 4th lumbar vertebrae,maximal load and elastic modulus of 5th lumbar vertebrae decreased significantly in B0-B3 groups(P0.05). CONCLUSIONS:PTH(1-34) is better than strontium ranelate in inhibiting bone loss,improving vertebral bone micro-structure and biomechanical properties of ovariectomized rats.

Comparison of the Efficacy and Safety of Alfacalcidol and Strontium Ranelate in the Treatment of Senile Menopausal Osteoporosis / 中国药房

OBJECTIVE:To compare the efficacy and safety of alfacalcidol and strontium ranelate in the treatment of senile menopausal osteoporosis. METHODS:158 elderly menopausal patients with osteoporosis were randomly divided into control group (79 cases)and observation group(79 cases). All patients were orally given 1 Calcium carbonate D3 tablet,once a day. Based on it, control group was given 2 Alfacalcidol soft capsules,once a day. Observation group was additionally given 1 bag of Strontium ranelate dry suspension,orally before bedtime,once a day. The treatment course for both groups was 12 months. L2-4 and BMD of femoral neck,osteocalcin,TPINP and VAS and ADR before and after 6 and 12 months in 2 groups were observed. RESULTS:Before treatment,there were significant differences in the BMD of L2-4 and femoral neck,osteocalcin,TPINP and VAS scores be-tween 2 groups(P>0.05). BMD of L2-4 and femoral neck in control group after 12 months and in observation group after 6 and 12 months were significantly higher than before,and it gradually increased be time in observation,observation group was higher than control group;TPINP and VAS scores in control group after 12 months and in observation group after 6 and 12 months were significantly lower than before,and it gradually decreased be time,observation group was lower than control group,the differenc-es were statistically significant(P0.05). There were no ADR during treatment. CONCLUSIONS:Based on the conventional treatment,the efficacy of alfacal-cidol and strontium ranelate is superior to alfacalcidol alone in the treatment of senile menopausal osteoporosis,with similar safety.

Effects of strontium ranelate on the rats' palatal suture after rapid maxillary expansion / 华西口腔医学杂志

<p><b>OBJECTIVE</b>This study investigated the effects of strontium ranelate (SrR) on the rats' palatal suture after rapid maxillary expansion (RME).</p><p><b>METHODS</b>Thirty-six male 6-week-old Wistar rats were randomly divided into three groups: control group (A), expansion only group (B), and expansion plus SrR group (C). Each group comprised 12 rats. Neither expansion nor SrR was given to group A. Each rat in groups B and C was set an orthodontic appliance with an initial expansive force of 1 N. The rats in group C were administered with SrR (600 mg·kg⁻¹ body weight) at the same time every day after RME. All the rats were then euthanized in batches on days 4, 7, and 10. The width of the rats' upper jaw was measured. Histological observation was used to section the rats and count the osteoblasts.</p><p><b>RESULTS</b>After the RME, no statistical difference was observed on the rats' upper jaw width in group A (P>0.05). However, the change of upper jaw width in groups B and C presented a statistical significance (P<0.05). By contrast, no statistical difference was observed between groups B and C (P>0.05). The rats' sections were placed under a microscope, and some red fibrous tissues, mesenchymal cells, chondrocytes, and osteoblasts were observed in group A. More red fibrous tissues, mesenchymal cells, and chondrocytes were observed in groups B and C. In addition, more osteoblasts were observed on the edge of mid-palatal suture of the rats. Group C contains more osteoblasts than group B.</p><p><b>CONCLUSIONS</b>RME can expand the mid-palatal suture of rats, which were in the growth development period, and increase the width of dental arch. SrR may promote osteoblast differentiation and hasten new bone formation in the expanded mid-palatal suture. Both conditions accelerate new bone formation and bone deposition calcification, which may be therapeutically beneficial to prevent relapse after RME.</p>

Effect of Strontium ranelate on stress-absence induced osteoporosis / 天津医药

Objective To investigate the preventive effect of Strontium ranelate on stress-absence induced osteoporo?sis in tail-suspended rat. Methods A total of 30 SD rats with average age of 6 month were randomly divided into 3 groups (n=10 in each group):Group A was normal control group while rats in group B and C were subjected to tail suspension test to establish stress absence models. Rats in group C were administered with Strontium ranelate [1 g/(kg·d)]. All rats were sacri?ficed 4 weeks later. Left femurs were harvested for bone mineral density (BMD) test and prepared for undecalcified tissue sec?tion and thereby bone histomorphometry assessment. Bone marrow from right femurs and tibias were cultured and induced to?wards osteogenic-differentiation. The expression levels of osteocalcin in the fourth-passage cultured bone marrow cells and in blood serum were detected separately. Results Rats in group B showed markedly decreased BMD comparing to those in group A and C(P<0.05). Trabecular volume (BV/TV), number (Tb.N) and thickness (Tb.Th) in group B were lower than those in group A and C;erosion percentage (Er.Pm) and osteoclast number (Oc.N) in group B and C were higher than those in group A;comparing to those in group B, bone formation rate (BFR/BV), labeled percentage (L.Pm), were higher in group C, coupled with decreased Er.Pm and Oc.N(P<0.05). mRNA expression levels of OCN in group B and C were higher than those of group A. But its level in plasma were lower in group B than those in group A and C(P<0.05). Conclusion Tail suspension could induce osteosporosis. Strontium ranelate prevent bone loss in stress-absence osteoporosis in rat induced by tail-suspension for 4 weeks, which might be partially through upregulating the expression of OCN, thereby promoting bone formation.

Strontium ranelate promotes osteogenic differentiation of rat bone mesen-chymal stem cells through Hedgehog/Gli1 signaling pathway / 中国病理生理杂志

AIM: To explore whether strontium ranelate ( Sr ) promotes osteogenic differentiation of rat bone mesenchymal stem cells (BMSCs) through the Hedgehog/Gli1 signaling pathway.METHODS:BMSCs were isolated from 4-week-old rats by adherent culture and induced to differentiate into osteoblasts .According to the experimental purposes , the cells were exposed to different concentrations of Sr , cyclopamine ( Cy, an inhibitor of Hedgehog receptor ) or Gli1-siR-NA.The expression of Gli1 and Runx2 in the cells was detected by Western blotting .The activity of alkaline phosphatase ( ALP) was measured by the method of colorimetry , and the mineralized nodules were observed under microscope with aliz-arin red staining .RESULTS:Exposure to Sr at concentrations of 0.1 to 5 mmol/L for 7 d markedly increased the expres-sion of Gli1 in the BMSCs , and the increase in Gli1 expression was the most obvious following Sr exposure at concentration of 3 mmol/L.Cy at concentration of 10 μmol/L inhibited Sr-induced up-regulation of Gli1 expression.Transfection of the BMSCs with Gli1-siRNA not only obviously inhibited Sr-induced up-regulation of Gli1 and Runx2 ( a downstream protein of Gli1) expression, but also antagonized Sr-induced enhancement of ALP activity and the formation of mineralized nodules . CONCLUSION:The Hedgehog/Gli1 pathway is involved in Sr-induced osteogenic differentiation of rat BMSCs .

Effect of strontium ranelate on bone remodeling

Osteoporosis is a disease in which the microarchitecture of bone tissue deteriorates, with consequent loss of bone mass. Strontium ranelate (SrR) is currently used for treatment of the condition. SrR may have a dual effect: anabolic (stimulating pre-osteoblast replication) and anti-catabolic (reducing osteoclastic activity). However, its mechanism of action has not yet been completely elucidated. The aim of this study is to evaluate the effect of SrR on bone remodeling in healthy Wistar rats. Two-month old female Wistar rats were administered SrR (2 g/L) in drinking water for 30 weeks. Oriented histological sections were prepared from lower jaw and tibia and stained with H&E, and the following histomorphometric parameters were evaluated: a) in interradicular bone: bone volume, and percentages of bone-formation, quiescent and bone-resorption surfaces; and b) in tibia: bone volume, total thickness of growth cartilage, thickness of hypertrophic cartilage zone and number of megakaryocytes. No significant difference was found in the parameters between the control animals and those treated with SrR. The results would therefore show that SrR does not alter the bone parameters studied in this experimental design.

La osteoporosis es una enfermedad caracterizada por el deterioro de la microarquitectura del tejido oseo y la consecuente perdida de masa osea. El ranelato de estroncio (RSr) es actualmente utilizado para su tratamiento ya que poseeria un efecto dual: anabolico (estimulando la replicacion de preosteoblastos) y anticatabolico (disminuyendo la actividad osteoclastica). Sin embargo, su mecanismo de accion aun no ha sido completamente dilucidado. El objetivo del presente trabajo es evaluar el efecto del RSr sobre la remodelacion osea en ratas Wistar sanas. Se utilizaron ratas Wistar hembras de dos meses de edad a las cuales se les administro RSr (2 gr/L) en el agua de bebida durante 30 semanas. Se realizaron cortes histologicos orientados de maxilar inferior y tibia coloreados con H&E y se evaluaron los siguientes parametros histomorfometricos: a) En hueso interradicular: volumen oseo, porcentaje de superficies en formacion, reposo y reabsorcion osea. b) En tibia: volumen oseo, espesor total del cartilago de crecimiento, espesor de la zona de cartilago hipertrofiado y numero de megacariocitos. No se observaron diferencias significativas en los parametros evaluados entre los animales control y los tratados con RSr. Por lo tanto, los resultados obtenidos indicarian que el RSr no altera los parametros oseos estudiados en el presente diseño experimental.

Short-term bone marker responses to teriparatide and strontium ranelate in patients with osteoporosis previously treated with bisphosphonates / Resposta dos marcadores de curto prazo a teriparatida e ranelato de estrôncio em pacientes com osteoporose previamente tratados com bisfosfonatos

OBJECTIVE: To evaluate the responses of serum β-CTX and osteocalcin in patients who were undergoing treatment with teriparatide or strontium ranelate (SR). SUBJECTS AND METHODS: We analyzed 14 patients (12 women and 2 men; mean age of 71 years) taking teriparatide, and 13 female patients (mean age of 70 years) taking SR; all the patients having previously been on bisphosphonates. Serum β-CTX and osteocalcin levels were determined before and after the first and third months of teriparatide treatment and up to the fourth month of treatment with SR. RESULTS: We observed an initial significant increase in osteocalcin levels during the first month (165 percent, p = 0.01) followed by a peak of β-CTX (180 percent, p = 0.02) after the third month of treatment with teriparatide. An increase in these markers was also observed with SR: 49 percent in osteocalcin (p = 0.002) and 80 percent in β-CTX (p = 0.008). CONCLUSION: SR had a predominantly short-term bone-forming effect in postmenopausal women with osteoporosis previously treated with bisphosphonates in a lesser degree than with teriparatide.

OBJETIVO: Avaliar as respostas do β-CTX e osteocalcina séricos em pacientes que foram submetidas a tratamento com teriparatida ou ranelato de estrôncio (RE). SUJEITOS E MÉTODOS: Analisaram-se 14 pacientes (12 mulheres e 2 homens; idade média 71 anos) tomando teriparatida, e 13 mulheres (idade média 70 anos) tomando RE; todos os pacientes haviam previamente tomado bisfosfonatos. Níveis séricos de β-CTX e osteocalcina foram determinados antes e após o primeiro e terceiro meses de tratamento com teriparatida e no quarto mês de tratamento com RE. RESULTADOS: Observou-se um aumento inicial significativo nos níveis de osteocalcina no primeiro mês (165 por cento, p = 0,01), seguido por um pico do β-CTX (180 por cento, p = 0,02) após o terceiro mês de tratamento com teriparatida. Aumento nesses marcadores também foi observado com RE: 49 por cento na osteocalcina (p = 0,002) e 80 por cento no β-CTX (p = 0,008). CONCLUSÃO: RE teve um efeito predominantemente na formação óssea a curto prazo em mulheres na pós-menopausa com osteoporose tratadas previamente com bisfosfonatos em menor grau que a teriparatida.