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.

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.

Incidence of vertebral fractures in calcium and vitamin D-supplemented postmenopausal Brazilian women with osteopenia or osteoporosis: data from Arzoxifene Generations Trial

ABSTRACT Objective Vertebral fracture is the most common osteoporotic fracture, affecting quality of life and increasing mortality. Epidemiological data on incidence of vertebral fracture are scarce in Brazil and throughout Latin America. Our aim was to determine vertebral fracture incidence and risk factors in a female Brazilian population. Subjects and methods Postmenopausal women with low bone mass were studied from the Brazilian placebo group of Arzoxifene Generations Trial (n = 974), followed for up to 5 years. The primary endpoint was new vertebral fractures, detected by X-Ray. Experimental design defined two strata: A. Osteoporosis or previous vertebral fracture with osteopenia; B. Osteopenia without previous fracture. Previous fracture, T-score, ionized calcium, alkaline phosphatase, creatinine and glucose were analyzed at baseline. Crude and adjusted incidence rates of vertebral fractures were estimated and Poisson regression model was used. Results Incidence rate was 7.7 (95% CI of 5.4 to 10.9) per 1,000 person-years (PY), increasing as a function of age. Women with new vertebral fractures had higher prevalence of previous nonvertebral fracture after menopause, were older and had lower lumbar spine (LS) T-score. Fracture risk increased by 46% for each unit reduction in LS T-score. Variables correlated with new vertebral fracture were age (p = 0.034), LS T-score, stratum A (p = 0.001 for both) and previous nonvertebral fracture after menopause (p = 0.019). In the final model, LS T-score was the strongest predictor. Conclusions Incidence rate of vertebral fracture of 7.7 per 1,000 PY. Age and previous fractures were associated with new vertebral fracture, but LS T-score was the most important predictor.

Pharmacological management of osteogenesis

Osteogenesis and bone remodeling are complex biological processes that are essential for the formation of new bone tissue and its correct functioning. When the balance between bone resorption and formation is disrupted, bone diseases and disorders such as Paget's disease, fibrous dysplasia, osteoporosis and fragility fractures may result. Recent advances in bone cell biology have revealed new specific targets for the treatment of bone loss that are based on the inhibition of bone resorption by osteoclasts or the stimulation of bone formation by osteoblasts. Bisphosphonates, antiresorptive agents that reduce bone resorption, are usually recommended as first-line therapy in women with postmenopausal osteoporosis. Numerous studies have shown that bisphosphonates are able to significantly reduce the risk of femoral and vertebral fractures. Other antiresorptive agents indicated for the treatment of osteoporosis include selective estrogen receptor modulators, such as raloxifene. Denosumab, a human monoclonal antibody, is another antiresorptive agent that has been approved in Europe and the USA. This agent blocks the RANK/RANKL/OPG system, which is responsible for osteoclastic activation, thus reducing bone resorption. Other approved agents include bone anabolic agents, such as teriparatide, a recombinant parathyroid hormone that improves bone microarchitecture and strength, and strontium ranelate, considered to be a dual-action drug that acts by both osteoclastic inhibition and osteoblastic stimulation. Currently, anti-catabolic drugs that act through the Wnt-β catenin signaling pathway, serving as Dickkopf-related protein 1 inhibitors and sclerostin antagonists, are also in development. This concise review provides an overview of the drugs most commonly used for the control of osteogenesis in bone diseases.

Sinais e sintomas de doença da superfície ocular em usuários de hipotensores oculares tópicos / Signs and symptoms of ocular surface disease in patients on topical intraocular pressure-lowering therapy

OBJETIVO: determinar a prevalência de sinais e sintomas de doença da superfície ocular (OSD) em pacientes em uso crônico de hipotensores oculares tópicos. MÉTODOS: Neste estudo transversal, foram recrutados 40 pacientes consecutivos, provenientes do ambulatório de glaucoma de um hospital público localizado no Rio de Janeiro, Brasil. Os mesmos deveriam apresentar: idade maior ou igual a 18 anos, diagnóstico de hipertensão ocular ou glaucoma primário de ângulo aberto e deveriam estar em uso da mesma terapia hipotensora ocular há pelo menos seis meses. Foram considerados: sexo, idade, medicação utilizada e duração do tratamento. Todos os pacientes foram submetidos à avaliação da superfície ocular que incluiu: entrevista por meio do questionário Ocular Surface Disease Index® (OSDI®), tempo de rotura do filme lacrimal, biomicroscopia, avaliação da superfície ocular com fluoresceína e com rosa Bengala. RESULTADOS: A média de pontuação do OSDI® foi 24,6 ± 20,7. A maioria dos pacientes (67,5%) apresentou uma pontuação anormal no questionário do OSDI®. Em 25% dos pacientes, a pontuação foi compatível com sintomas leves, em 12,5% com sintomas moderados e em 30% com sintomas graves. Blefarite e ceratite ponteada foram diagnosticadas em 42,5% e 20% dos pacientes respectivamente. Instabilidade do filme lacrimal foi observada em 75% dos pacientes, enquanto que alteração da superfície ocular foi evidenciada pelo teste de rosa bengala em 35% dos pacientes. Foi encontrada correlação positiva (r=0,4) estatisticamente significativa (p=0,01) entre a pontuação do OSDI® e o tempo de duração do tratamento com hipotensores oculares tópicos. CONCLUSÃO: Pacientes em uso crônico de hipotensores oculares tópicos apresentam alta prevalência de sinais e sintomas de OSD. Existe correlação significativa entre a duração do tratamento e a gravidade dos sintomas de OSD.

PURPOSE: To determine the prevalence of signs and symptoms of ocular surface disease (OSD) in patients using topical intraocular pressure-lowering therapy. METHODS: In this cross-sectional study, 40 patients were consecutively recruited from the glaucoma clinic of a public hospital located in Rio de Janeiro, Brazil. Eligible patients were 18 years of age or older, with primary open-angle glaucoma or ocular hypertension and on the same topical ocular therapy for at least 6 months. The following data were considered: sex, age, medication history and number of years on topical intraocular pressure-lowering therapy. All patients underwent an evaluation of the ocular surface which included: an interview using the Ocular Surface Disease Index® (OSDI®) questionnaire, break-up time, biomicroscopy, fluorescein corneal staining and rose Bengal ocular surface staining. RESULTS: The mean OSDI® score was 24.6 ± 20.7. Most patients (67.5%) had an abnormal score on the OSDI® questionnaire. In 25% of patients, the score was consistent with mild symptoms, 12.5% ​​with moderate symptoms and 30% with severe symptoms. Blepharitis and punctate keratitis were diagnosed in 42.5% and 20% of patients respectively. Tear film instability was observed in 75% of patients and ocular surface staining with rose Bengal in 35%. A positive statistically significant correlation (r=0.4; p=0.01) was found between OSDI® scores and the duration of topical intraocular pressure-lowering therapy. CONCLUSION: Patients with primary open-angle glaucoma or ocular hypertension on topical intraocular pressure-lowering therapy have high prevalence of OSD. Longer duration since diagnosis is significantly correlated with worsening of OSD symptoms.

P2Y12 inhibitors in acute coronary syndromes: Which and when.

Acute coronary syndromes (ACS) are the commonest acute manifestation of coronary artery disease and a major cause of hospitalization and death. Plaque rupture and subsequent platelet activation are the key factors in its pathogenesis. Platelet inhibitors are crucial in the management of ACS. Aspirin remains the standard antiplatelet but use of dual antiplatelet drugs is beneficial in ACS. Platelet P2Y12 receptor inhibitors are an important group of antiplatelet compounds that can be combined with aspirin in the management of ACS. P2Y12 inhibitors may belong to the thienopyridine or nonthienopyridine group of compounds. The former (clopidogrel, prasugrel) combine irreversibly with the receptor and therefore have a prolonged duration of action. On the other hand, the non-thienopyridine compounds (ticagrelor, elinogrel) have a reversible action and hence a shorter duration of action. Several new compounds in this group have become or are likely to become available. The newer agents have a more uniform and complete antiplatelet effect and are much less likely to be affected by genetic variability of CYP2C19 enzyme activity compared with that of clopidogrel. Large phase 3 trials have shown that ticagrelor and prasugrel reduce major cardiovascular events in ACS compared to clopidogrel when given in addition to aspirin. This is accompanied by some increase in bleeding. This review discusses the properties, clinical profile and possible place of P2Y12 receptor inhibitors in clinical practice.

Cost-effectiveness comparison between non-penetrating deep sclerectomy and maximum-tolerated medical therapy for glaucoma within the Brazilian National Health System (SUS) / Comparação de custo-efetividade entre a esclerectomia profunda não penetrante e a terapia clínica máxima tolerada para o glaucoma no Sistema Único de Saúde (SUS)

PURPOSE: Non-penetrating deep sclerectomy (NPDS) has emerged as a viable option in the surgical management of open-angle glaucoma. Our aim is to assess the cost-effectiveness of NPDS and to compare it to maximum medical treatment in a 5-year follow-up. METHODS: A decision analysis model was built. Surgical (NPDS) arm of the decision tree was observational (consecutive retrospective case series) and maximum medical treatment arm was hypothetical. Maximum medical therapy was considered a three-drug regimen (association of a fixed combination of timolol/dorzolamide [FCTD] and a prostaglandin analogue [bimatoprost, latanoprost or travoprost]). Cost-effectiveness ratio was defined as direct cost (US dollars) for each percentage of intraocular pressure (IOP) reduction. Horizon was 5 years and perspective is from the public health care service in Brazil (SUS). Incremental cost-effectiveness ratio (ICER) was calculated. RESULTS: Direct cost for each percentage of IOP reduction in 5 years (cost-effectiveness ratio) was US$ 10.19 for NPDS; US$ 37.45 for the association of a FCTD and bimatoprost; US$ 39.33 for FCTD and travoprost; and US$ 41.42 for FCTD and latanoprost. NPDS demonstrated a better cost-effectiveness ratio, compared to maximum medical therapy. The ICER was negative for all medical treatment options; therefore NPDS was dominant. CONCLUSIONS: Despite some limitations, NPDS was both less costly and more effective than maximum medical therapy. From the Brazilian public health perspective, it was the most cost-effective treatment option when compared to maximum medical therapy (FCTD and prostaglandin).

OBJETIVO: A esclerectomia profunda não penetrante (EPNP) é uma opção viável para o tratamento cirúrgico do glaucoma de ângulo aberto. O objetivo deste estudo é avaliar a relação custo-efetividade da EPNP e compará-la com terapia clínica máxima (TCM) em um acompanhamento de 5 anos. MÉTODOS: Um modelo de análise de decisão foi proposto comparando-se o tratamento cirúrgico (EPNP) versus a TCM. A avaliação da EPNP foi observacional retrospectiva de uma série consecutiva de casos e da TCM foi hipotética. A TCM foi considerada como o uso de três drogas (associação de uma combinação fixa de timolol/dorzolamida [CFTD] e um análogo de prostaglandina [bimatoprosta, latanoprosta ou travoprosta]). A relação custo-efetividade foi definida com o custo direto (em dólares) para cada porcentual de redução da pressão intraocular (PIO). A razão de custo-efetividade incremental (ICER) foi calculada. O seguimento foi de 5 anos e a perspectiva dos custos é do Sistema Único de Saúde (SUS). RESULTADOS: O custo direto para cada porcentual de redução da PIO ao final de 5 anos (relação custo-efetividade) foi de US$ 10,19 para a EPNP; US$ 37,45 para a CFTD + bimatoprosta; US$ 39,33 para CFTD + travoprosta; e US$ 41,42 para CFTD + latanoprosta. A EPNP apresentou uma melhor relação custo-efetividade, quando comparada com a TCM. O índice ICER foi negativo, portanto a EPNP foi a opção terapêutica dominante. CONCLUSÃO: A EPNP foi menos custosa e mais efetiva que a TCM. Do ponto de vista do SUS, ela foi a opção mais custo-efetiva, quando comparada com a TCM.

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.

Anti-nociceptive effect of duloxetine in mouse model of diabetic neuropathic pain.

The involvement of adenosinergic pathway in the anti-nociceptive effect of duloxetine, a balanced 5-HT/NE reuptake inhibitor, was evaluated in streptozotocin induced diabetic male albino mice of Laca strain. After four weeks of single injection of streptozotocin (200 mg/kg, ip), mice were tested in the tail immersion and hot-plate assays. Cerebral adenosine levels were measured by high-performance liquid chromatography (HPLC/PDA detector). Diabetic mice exhibited significant hyperalgesia along with increased plasma glucose, decreased body weights and reduced cerebral adenosine levels. Administration of duloxetine (5, 10 and 20 mg/kg, ip) to diabetic mice produced dose-dependent anti-nociceptive effect in both tail-immersion and hot-plate assays. Adenosine levels were also significantly and dose-dependently increased by different doses of duloxetine. The results demonstrated the involvement of adenosinergic pathway in duloxetine mediated anti-hyperalgesia in diabetic neuropathic pain.

Antidepressant behavioral effects of duloxetine and amitriptyline in the rat forced swimming test / Efeitos antidepressivos da duloxetina e da amitriptilina no teste do nado forçado em ratos

PURPOSE: To compare the effects of the antidepressant drugs duloxetine and amitriptyline on depressive behaviors in rats. METHODS: Fifteen male Wistar rats were given systemic injections of duloxetine, amitriptyline or saline prior to a Forced Swimming Test (FST). Immobility and number of stops were measured. Data were analyzed by one-way ANOVA and Kruskall-Wallis. RESULTS: Rats given injections of duloxetine displayed fewer stops than the amitriptyline and control group (p< 0.05). The control group and Amitriptyline showed no difference (p=0.8). CONCLUSION: Duloxetine reduced depressive behaviors in the Forced Swimming Test been more effective than amitriptyline.

OBJETIVO: Comparar o efeito antidepressivo da droga cloridrato de duloxetina com a amitriptilina. MÉTODOS: O teste do nado forçado, teste comportamental que avalia a atividade antidepressiva em ratos, foi utilizado em 15 ratos Wistar, machos adultos, divididos em três grupos iguais: duloxetina, amitriptilina e controle. Os dados foram analisados pelo teste One-way ANOVA e Kruskall-Wallis. RESULTADOS: Houve diferença significativa entre o número de paradas (p <0,05) entre os grupos duloxetina e amitriptilina e o grupo controle. Grupo amitriptilina e controle não apresentaram diferença (p=0,8). CONCLUSÃO: A duloxetina reduziu o comportamento depressivo sendo mais efetiva do que a amitriptilina.

Resultados da terapia antiagregante com ticlopidina em pacientes portadores de ulceraçöes tróficas de membros inferiores / Antiaggregant therapy results with ticlopidine in patients with trophic ulcerations of the lower limbs

Dezessete pacientes internados, portadores de ulceraçöes tróficas das extremidades, por arteriosclerose obliterante e/ou síndrome pós-flebítica, foram tratados durante 4 meses com ticlopidina VO, na dose de 500 mg/dia. Os pacientes foram avaliados clínica e laboratorialmente, observando-se, ao final do período de tratamento, excelente evoluçäo clínica, com reduçäo da sintomatologia dolorosa e boa cicatrizaçäo das lesöes em 64,7% dos casos. Paralelamente, houve significativa reduçäo da agregabilidade plaquetária ao ADP. Os autores concluem que a triclopidina constitui um bom recurso terapêutico nos pacientes com doenças vasculares periféricas, particularmente do tipo síndrome pós-trombótica ou pós-flebítica