Odanacatib, a New Drug for the Treatment of Osteoporosis: Review of the Results in Postmenopausal Women

Osteoclasts are specialized cells that initiate the process of bone resorption, which has two phases, dissolution of the mineral component and degradation of the organic matrix, in which cathepsin K plays a key role. Cathepsin K inhibitors, which block the activity of cathepsin on bone resorption lacunae, may be a new therapeutic option in osteoporosis. Odanacatib is a nonpeptidic biaryl inhibitor of cathepsin K. Two studies have evaluated the efficacy and safety of odanacatib, a phase I study to determine the dose and a phase II study of safety and efficacy. Due to the long half-life of odanacatib and the similar effects of different doses on bone remodeling markers, a weekly dosage was chosen for the phase II trail, with the best results being obtained with a dose of 50 mg. At 36 months, increases in bone mineral density similar to those produced by other powerful antiresorptive drugs (zoledronate and denosumab) were observed but there were differences in the behaviour of bone remodeling markers. Data on fractures from the phase III trial currently in development are required to confirm these possible advantages

Vitamin D Levels and Lipid Response to Atorvastatin

Adequate vitamin D levels are necessary for good vascular health. 1,25-dihydroxycholecalciferol activates CYP3A4, an enzyme of the cytochrome P450 system, which metabolizes atorvastatin to its main metabolites. The objective of this study was to evaluate the response of cholesterol and triglycerides to atorvastatin according to vitamin D levels. Sixty-three patients with acute myocardial infarction treated with low and high doses of atorvastatin were included. Levels of total cholesterol, triglycerides, HDL cholesterol, and LDL cholesterol were measured at baseline and at 12 months of follow-up. Baseline levels of 25-hydroxyvitamin D (25-OHD) were classified as deficient (<30 nmol/L), insufficient (30–50 nmol/L), and normal (>50 nmol/L). In patients with 25-OHD <30 nmol/L, there were no significant changes in levels of total cholesterol (173 ± 47 mg/dL versus 164 ± 51 mg/dL), triglycerides (151 ± 49 mg/dL versus 177 ± 94 mg/dL), and LDL cholesterol (111 ± 48 mg/dL versus 92 45 ± mg/dL); whereas patients with insufficient (30–50 nmol/L) and normal vitamin D (>50 nmol/L) had a good response to atorvastatin. We suggest that vitamin D concentrations >30 nmol/L may be required for atorvastatin to reduce lipid levels in patients with acute myocardial infarction

Clinical Study Vitamin D Levels and Lipid Response to Atorvastatin

Adequate vitamin D levels are necessary for good vascular health. 1,25-dihydroxycholecalciferol activates CYP3A4, an enzyme of the cytochrome P450 system, which metabolizes atorvastatin to its main metabolites. The objective of this study was to evaluate the response of cholesterol and triglycerides to atorvastatin according to vitamin D levels. Sixty-three patients with acute myocardial infarction treated with low and high doses of atorvastatin were included. Levels of total cholesterol, triglycerides, HDL cholesterol, and LDL cholesterol were measured at baseline and at 12 months of follow-up. Baseline levels of 25-hydroxyvitamin D (25-OHD) were classified as deficient (&lt;30 nmol/L), insufficient (30-50 nmol/L), and normal (&gt;50 nmol/L). In patients with 25-OHD &lt; 30 nmol/L, there were no significant changes in levels of total cholesterol (173 ± 47 mg/dL versus 164 ± 51 mg/dL), triglycerides (151 ± 49 mg/dL versus 177 ± 94 mg/dL), and LDL cholesterol (111 ± 48 mg/dL versus 92 45± mg/dL); whereas patients with insufficient (30-50 nmol/L) and normal vitamin D (&gt;50 nmol/L) had a good response to atorvastatin. We suggest that vitamin D concentrations &gt;30 nmol/L may be required for atorvastatin to reduce lipid levels in patients with acute myocardial infarction

Analysis of Bone Histomorphometry in Rat and Guinea Pig Animal Models Subject to Hypoxia

Hypoxia may be associated with alterations in bone remodeling, but the published results are contradictory. The aim of this study was to characterize the bone morphometry changes subject to hypoxia for a better understanding of the bone response to hypoxia and its possible clinical consequences on the bone metabolism. This study analyzed the bone morphometry parameters by micro-computed tomography (?CT) in rat and guinea pig normobaric hypoxia models. Adult male and female Wistar rats were exposed to chronic hypoxia for 7 and 15 days. Additionally, adult male guinea pigs were exposed to chronic hypoxia for 15 days. The results showed that rats exposed to chronic constant and intermittent hypoxic conditions had a worse trabecular and cortical bone health than control rats (under a normoxic condition). Rats under chronic constant hypoxia were associated with a more deteriorated cortical tibia thickness, trabecular femur and tibia bone volume over the total volume (BV/TV), tibia trabecular number (Tb.N), and trabecular femur and tibia bone mineral density (BMD). In the case of chronic intermittent hypoxia, rats subjected to intermittent hypoxia had a lower cortical femur tissue mineral density (TMD), lower trabecular tibia BV/TV, and lower trabecular thickness (Tb.Th) of the tibia and lower tibia Tb.N. The results also showed that obese rats under a hypoxic condition had worse values for the femur and tibia BV/TV, tibia trabecular separation (Tb.Sp), femur and tibia Tb.N, and BMD for the femur and tibia than normoweight rats under a hypoxic condition. In conclusion, hypoxia and obesity may modify bone remodeling, and thus bone microarchitecture, and they might lead to reductions in the bone strength and therefore increase the risk of fragility fracture.Funding: The present study was supported by grant reference BFU2015-70616-R from MINECOFEDER (Spain Government) and Programa Estratégico IBGM, Escalera de Excelencia, Ref. CCVC8485, Consejería de Educacion, JCyL (Spain)

Multiple vertebral fractures after suspension of denosumab. A series of 56 cases

Background: Denosumab is a monoclonal antibody approved for the treatment of postmenopausal osteoporosis. The withdrawal of denosumab produces an abrupt loss of bone mineral density and may cause multiple vertebral fractures (MVF). Objective: The objective of this study is to study the clinical, biochemical, and densitometric characteristics in a large series of postmenopausal women who suffered MVF after denosumab withdrawal. Likewise, we try to identify those factors related to the presence of a greater number of vertebral fractures (VF). Patients and methods: Fifty-six patients (54 women) who suffered MVF after receiving denosumab at least for three consecutive years and abruptly suspended it. A clinical examination was carried out. Biochemical bone remodelling markers (BBRM) and bone densitometry at the lumbar spine and proximal femur were measured. VF were diagnosed by magnetic resonance imaging MRI, X-ray, or both at dorsal and lumbar spine. Results: Fifty-six patients presented a total of 192 VF. 41 patients (73.2%) had not previously suffered VF. After discontinuation of the drug, a statistically significant increase in the BBRM was observed. In the multivariate analysis, only the time that denosumab was previously received was associated with the presence of a greater number of VF (P = .04). Conclusions: We present the series with the largest number of patients collected to date. 56 patients accumulated 192 new VF. After the suspension of denosumab and the production of MVF, there was an increase in the serum values of the BBRM. The time of denosumab use was the only parameter associated with a greater number of fractures

Calcifediol is superior to cholecalciferol in improving vitamin D status in postmenopausal women: a randomized trial

Vitamin D has shown to play a role in multiple diseases due to its skeletal and extraskeletal actions. Furthermore, vitamin D deficiency has become a worldwide health issue. Few supplementation guidelines mention calcifediol treatment, despite being the direct precursor of calcitriol and the biomarker of vitamin D status. This 1-year, phase III-IV, double-blind, randomized, controlled, multicenter clinical trial assessed the efficacy and safety of calcifediol 0.266 mg soft capsules in vitamin D-deficient postmenopausal women, compared to cholecalciferol. Results reported here are from a prespecified interim analysis, for the evaluation of the study's primary endpoint: the percentage of patients with serum 25-hydroxyvitamin D (25(OH)D) levels above 30 ng/ml after 4 months. A total of 303 patients were enrolled, of whom 298 were included in the intention-to-treat (ITT) population. Patients with baseline levels of serum 25(OH)D <20 ng/ml were randomized 1:1:1 to calcifediol 0.266 mg/month for 12 months, calcifediol 0.266 mg/month for 4 months followed by placebo for 8 months, and cholecalciferol 25,000 IU/month for 12 months. At month 4, 35.0% of postmenopausal women treated with calcifediol and 8.2% of those treated with cholecalciferol reached serum 25(OH)D levels above 30 ng/ml (p < 0.0001). The most remarkable difference between both drugs in terms of mean change in serum 25(OH)D levels was observed after the first month of treatment (mean ± standard deviation change = 9.7 ± 6.7 and 5.1 ± 3.5 ng/ml in patients treated with calcifediol and cholecalciferol, respectively). No relevant treatment-related safety issues were reported in any of the groups studied. These results thus confirm that calcifediol is effective, faster, and more potent than cholecalciferol in raising serum 25(OH)D levels and is a valuable option for the treatment of vitamin D deficiency

Perfil de los pacientes que acuden al médico internista para valoración de osteoporosis: registro OSTEOMED

Producción CientíficaAntecedentes y objetivo: La osteoporosis se considera un trastorno generalizado del esqueleto en el que existe una alteración de la resistencia ósea que predispone a la persona a un mayor riesgo de fractura. Este estudio transversal pretende recoger y presentar las principales características clínicas de los pacientes que acuden a la consulta de los médicos internistas en Espa˜na. Conocer estas características podría facilitar la puesta en marcha de planes de actuación para mejorar la atención de estos pacientes de manera más eficaz y eficiente. Material y métodos: A través del análisis del registro OSTEOMED (Osteoporosis en Medicina Interna), este trabajo presenta las principales características clínicas de los pacientes con osteoporosis que acudieron a las consultas de Medicina Interna en 23 centros hospitalarios espa˜noles entre 2012 y 2017. Se han analizado los motivos de consulta, los valores densitométricos, la presencia de comorbilidades, el tratamiento prescrito y otros factores relacionados con el estilo de vida. Resultados: En total se evaluó a 2.024 pacientes con osteoporosis (89,87% mujeres, 10,13% hombres). La edad media de los pacientes fue de 64,1 ± 12,1 a˜nos (mujeres, 64,7 ± 11,5 a˜nos; hombres, 61,2 ± 14,2 a˜nos). No hubo diferencia entre sexos en la historia de caídas recientes (9,1-6,7%), mientras que sí se apreció en la ingesta diaria de calcio de lácteos (553,8 ± 332,6 mg en mujeres vs. 450,2 ± 303,3 mg en hombres; p < 0,001) y en causas secundarias de osteoporosis(13% de hombres vs. 6,5% de mujeres; p < 0,001). En la muestra se observaron un total de 404fracturas (20%), destacando el número de fracturas vertebrales confirmadas (17,2%, 35,6% enhombres vs. 15,2% de las mujeres; p < 0,001). Una gran parte de los pacientes no recibía eltratamiento indicado y presentaba bajos niveles de actividad física y exposición solar. Un por-centaje importante de pacientes presentó comorbilidades asociadas, siendo las más frecuentesla hipertensión (32%) y la dislipidemia (28%).Conclusiones: Estos resultados definen el perfil del paciente con osteoporosis que acude a laconsulta de Medicina Interna en Espa˜na. Además, ponen de manifiesto el carácter multisistémicode esta entidad que junto con su elevada prevalencia determinan que las consultas específicasde Medicina Interna dedicadas a su manejo son el lugar adecuado para la atención de estos pacientes