Efecto de la suplementación con vitamina D en los efectos secundarios musculoesqueléticos relacionados con los inhibidores de la aromatasa para el cáncer de mama: cohorte B-ABLE / Effect of vitamin D supplementation on aromatase inhibitor-related musculoskeletal side effects for breast cancer: B-ABLE cohort

Objetivo: Evaluar el efecto de la suplementación con vitamina D en las complicaciones musculoesqueléticas relacionadas con el tratamiento con inhibidores de la aromatasa (IA) en pacientes con cáncer de mama. Material y métodos: Estudio observacional prospectivo de mujeres en tratamiento con IA, reclutadas en la cohorte B-ABLE. Las pacientes con niveles séricos iniciales de 25(OH)D (25-hidroxivitamina D) <30 ng/ml recibieron una dosis de 16.000 UI de calcifediol oral cada 2 semanas. La artralgia y la pérdida ósea relacionadas con los IA se evaluaron a los 3 meses y al año de seguimiento, respectivamente. Los análisis de asociación del status de vitamina D a los 3 meses con eventos musculoesqueléticos se realizaron mediante modelos de regresión lineal multivariante ajustados. Además, se evaluó la asociación del dolor incidente, definido como pacientes sin dolor articular inicial, pero con una escala visual analógica (EVA) >0 a los 3 meses, mediante regresión logística. Resultados: La suplementación con vitamina D al inicio del tratamiento con IA disminuyó el riesgo tanto de artralgia incidente como de su empeoramiento. El umbral efectivo de 25(OH)D en suero para reducir el dolor articular se estableció en 40 ng/ml. Sin embargo, este umbral no se relacionó significativamente con los cambios óseos al año de seguimiento. No obstante, los niveles de vitamina D se correlacionaron inversamente con la pérdida ósea de la columna lumbar (CL) (β=0,177% [IC 95%: 0,014 a 0,340]). Conclusiones: La administración de suplementos de vitamina D con el objetivo de alcanzar niveles séricos de 25OHD de al menos 40 ng/ml es protectora para la artralgia. Los niveles de vitamina D a los tres meses podrían predecir el riesgo de pérdida ósea en CL al año de tratamiento con IA. Por lo tanto, se recomiendan dosis altas de vitamina D en estas pacientes, que son más propensas a sufrir afecciones musculoesqueléticas. (AU)

Objetive: To assess the effect of vitamin D supplementation on musculoskeletal complications related to aromatase inhibitor (AI) treatment in patients with breast cancer. Material and methods: Prospective observational study of women undergoing AI treatment, recruited in the B-ABLE cohort. Patients with baseline serum 25 (OH) D (25-hydroxyvitamin D) levels <30 ng/ml received a 16,000 IU dose of oral calcifediol every 2 weeks. Arthralgia and bone loss related to AIs were assessed at 3 months and 1 year of followup, respectively. The association analyzes of vitamin D status at 3 months with musculoskeletal events were carried out using adjusted multivariate linear regression models. In addition, the association of incident pain, defined as patients without initial joint pain, but with a visual analog scale (VAS) >0 at 3 months, was evaluated using logistic regression. Results: Vitamin D supplementation at the start of AI treatment decreased the risk of both incident arthralgia and its worsening. The effective threshold of 25 (OH) D in serum to reduce joint pain was established at 40 ng/ml. However, this threshold was not significantly related to bone changes at one year of follow-up. However, vitamin D levels were inversely correlated with lumbar spine bone loss (LS) (β=0.177% [95% CI: 0.014 to 0.340]). Conclusions: Vitamin D supplementation aimed at achieving serum 25(OH)D levels of at least 40 ng/ml is protective for arthralgia. Vitamin D levels at three months could predict the risk of bone loss in LS at one year of AI treatment. Therefore, high doses of vitamin D are recommended in these patients, who are more prone to musculoskeletal conditions. (AU)

Persistencia a los inhibidores de la aromatasa en la cohorte SIDIAP: mortalidad e influencia de los bifosfonatos / Persistence to aromatase inhibitors in the SIDIAP cohort: mortality and influence of bisphosphonates

OBJETIVO: Evaluar la persistencia a la terapia con inhibidores de la aromatasa (IA), la mortalidad asociada a la discontinuidad al tratamiento y la influencia de los bifosfonatos (BF) orales, en la práctica clínica habitual. MATERIAL Y MÉTODOS: Estudio prospectivo observacional de mujeres con cáncer de mama en tratamiento con IA entre enero de 2006 y diciembre de 2015, registradas en la base de datos SIDIAP. Se excluyeron aquellas tratadas previamente con tamoxifeno. Se estudió la persistencia al tratamiento con IA con un análisis de supervivencia: se calculó el estimador de Kaplan-Meier, y se realizó un modelo de los riesgos proporcionales (regresión de Cox) entre usuarias y no usuarias de BF ajustando por edad. Se llevó a cabo un análisis de sensibilidad teniendo en cuenta la mortalidad como riesgo competitivo (modelos de Fine y Gray). Se comparó la diferencia de mortalidad entre grupos mediante una prueba Chi cuadrado. RESULTADOS: Se observó una persistencia a los IA del 87% a 5 años de tratamiento, con una mortalidad global del 19,75%. Se registró un 7,7% menos de mortalidad en aquellas pacientes que completaron los 5 años de tratamiento respecto a las que no. Las pacientes con BF mostraron una disminución de la mortalidad (6,6%) y una disminución del riesgo de abandono de la terapia (SHR ajustado: 0,62 [IC 95%: 0,55 a 0,70]) respecto a las no usuarias. CONCLUSIONES: La permanencia a los IA y el uso de BF está asociada a una disminución de la mortalidad global. Además, el uso de BF resulta en un aumento de la adherencia al tratamiento con IA

OBJETIVE: To assess the persistence of aromatase inhibitor (AI) therapy, mortality associated with treatment discontinuation and the influence of oral bisphosphonates (BP) in routine clinical practice. MATERIAL AND METHODS: Prospective observational study of women with breast cancer undergoing AI treatment between January 2006 and December 2015, registered in the SIDIAP database. Those previously treated with tamoxifen were excluded. AI persistence was studied with a survival analysis: the Kaplan-Meier estimator was calculated, and a proportional hazards model (Cox regression) was performed between users and non-users of BP adjusting for age. A sensitivity analysis was carried out taking into account mortality as a competitive risk (Fine and Gray models). The difference in mortality between groups was compared using a Chi square test. RESULTS: A persistence to AI of 87% was observed after 5 years of treatment, with an overall mortality of 19.75%. There was 7.7% less mortality in those patients who completed the 5 years of treatment compared to those who did not. Patients with BP showed a decrease in mortality (6.6%) and a decrease in the risk of discontinuing therapy (adjusted SHR: 0.62 [95% CI: 0.55 to 0.70]) compared to non-users. CONCLUSIONS: Persistence to AI and BP use are associated with a decrease in overall mortality. Furthermore, the use of BP increases adherence to AI treatment

Puntuación de hueso trabecular. ¿Más fiable que la densitometría en pacientes con espondiloartritis? / Trabecular bone score. Is it more reliable than densitometry in patients with spondyloarthritis?

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Factores de riesgo de fractura incidente en pacientes con cáncer de mama tratadas con inhibidores de la aromatasa: cohorte B-ABLE / Risk factors for incident fracture in patients with breast cancertreated with aromatase inhibitors: B-ABLE cohort

OBJETIVO: Los inhibidores de la aromatasa (IA) se han asociado con una pérdida de masa ósea acelerada y un mayor riesgo de fracturas osteoporóticas. Con este trabajo se pretendió evaluar los factores de riesgo de fractura incidente en pacientes con cáncer de mama que reciben IA. MATERIAL Y MÉTODOS: Estudio prospectivo-observacional de cohorte de mujeres con cáncer de mama que inician tratamiento con IA (cohorte B-ABLE). Las pacientes realizaron tratamiento durante 5 años o bien 2 ó 3 años si habían recibido previamente tamoxifeno. Se les evaluó la salud ósea desde el inicio del tratamiento hasta un año después de finalizar dicho tratamiento mediante densitometría ósea, marcadores de remodelado óseo, niveles de vitamina D y una radiografía antero-posterior y otra lateral de columna. Se realizó el cálculo de riesgo de fractura mediante la herramienta FRAX® antes de iniciar IA. Se utilizaron modelos de Cox para calcular los ratios de riesgo (HR [IC 95%]) de fractura. RESULTADOS: Un total de 943 pacientes fueron incluidas en el estudio. El 5,4% sufrieron una fractura incidente, la mayoría durante el tratamiento con IA, aunque un 21,5% ocurrieron durante el primer año después de finalizar la terapia. La mayoría de las fracturas incidentes fueron vertebrales clínicas (29,4%) y de Colles (31,4%). El 86,3% de las pacientes tenían un diagnóstico de osteopenia u osteoporosis en el momento de la fractura y el 33% tenían los niveles de β-CTX (isómero β del telopéptido carboxiterminal del colágeno tipo I) por encima de la normalidad. Las pacientes diagnosticadas de osteoporosis o con riesgo de fractura al inicio del estudio fueron tratadas con antirresortivos óseos. No se encontraron diferencias significativas en el riesgo de fractura entre pacientes con y sin tratamiento antirresortivo: HR=1,75 [IC 95%: 0,88 a 3,46]. Tampoco se encontraron diferencias entre las pacientes que habían hecho tratamiento previo con tamoxifeno respecto a las que no (HR=1,00 [IC 95%: 0,39 a 2,56]). La herramienta FRAX® dio valores de media dentro del rango de riesgo intermedio, con 13 pacientes con valores de alto riesgo de fractura principal. CONCLUSIONES: El principal factor de riesgo detectado para fractura incidente en pacientes tratadas con IA es el diagnóstico de osteopenia u osteoporosis. El cálculo de la herramienta FRAX® y la determinación de los niveles de β-CTX son herramientas útiles para identificar a pacientes de alto riesgo

OBJETIVO:Aromatase inhibitors (AI) have been associated with an accelerated loss of bone mass and an increased risk ofosteoporosis fractures. This study assesses the risk factors for incident fracture in breast cancer patients receiving AI. MATERIAL AND METHODS:Prospective‐observational cohort study of women with breast cancer who begin treatment withAI (B‐ABLE cohort). Patients were treated for 5 years or 2 or 3 years if they had previously received tamoxifen. Bone healthwas assessed from the beginning of the treatment until one year post treatment by bone densitometry, bone remodelingmarkers, vitamin D levels and an anteroposterior and lateral spine radiography. The fracture risk calculation was performedusing the FRAX® tool before starting AI. Cox models were used to calculate the risk ratios (HR [95% CI]) of fracture. RESULTS: A total of 943 patients were included in the study.5.4% suffered an incident fracture, most during AI treatment,although 21.5% occurred during the first year after the end of therapy. Most of the incident fractures were clinical vertebral (29.4%) and Colles (31.4%).86.3% of the patients had a diagnosis of osteopenia or osteoporosis at the time of the fractureand 33% had the levels of β‐CTX (β isomer of the carboxyterminal telopeptide of type I collagen) above normal. Patients diagnosed with osteoporosis or at risk of fracture at the start of the study were treated with bone antiresorptives. No significant differences in fracture risk were found between patients with and without antiresorptive therapy: HR=1.75[95% CI: 0.88 to 3.46]. Nor were differences found among patients who had previously treated with tamoxifen comparedto those who did not (HR=1.00 [95% CI 0.39 to 2.56]). The FRAX®tool gave average values within the intermediate riskrange, with 13 patients with high risk of major fracture values. CONCLUSIONS:The main risk factor detected for incident fracture in patients treated with AI is the diagnosis of osteopeniaor osteoporosis. The calculation of the FRAX® tool and the determination of β‐CTX levels are useful tools to identifyhigh‐risk patients

In-vitro comparison of hydroxyapatite coatings obtained by cold spray and conventional thermal spray technologies.

Hydroxyapatite (HA) coatings onto Ti6Al4V alloy substrates were obtained by several thermal spray technologies: atmospheric plasma spray (APS) and high velocity oxy fuel (HVOF), together with the cold spray (CS) technique. A characterization study has been performed by means of surface and microstructure analyses, as well as biological performance. In-vitro tests were performed with primary human osteoblasts at 1, 7 and 14 days of cell culture on substrates. Cell viability was tested by MTS and LIVE/DEAD assays, cell differentiation by alkaline phosphatase (ALP) quantification, and cell morphology was analyzed by scanning electron microscopy. The HA coatings showed an increase of HA crystallinity from 62,4% to 89%, but also an increase of hydrophilicity from ∼32° to 0°, with the decrease of the operating temperature of the thermal spray techniques (APS > HVOF > CS). Additionally, APS HA coatings showed more surface micro-features than HVOF and CS HA coatings; cells onto APS HA coatings showed faster attachment by acquiring osteoblastic morphology in comparison with the rounded cell morphology observed onto CS HA coatings at 1 day of cell culture. HVOF HA coatings also showed proper cell adherence but did not show extended filopodia as cells onto APS HA coatings. However, at 14 days of cell culture, higher cell proliferation and differentiation was detected on HA coatings with higher crystallinity (HVOF and CS techniques). Cell attachment is suggested to be favoured by surface micro-features but also moderate surface wettability whereas cell proliferation and differentiation is suggested to be highly influenced by HA crystallinity and crystal size.

The impact of hip fracture on health-related quality of life and activities of daily living: the SPARE-HIP prospective cohort study.

PURPOSE: The medical morbidity and mortality associated with neck of femur fractures is well-documented, whereas there is limited data for patient-reported outcomes. The aim of this study was to characterize the impact of neck of femur fractures on activities of daily living and patient-reported health-related quality of life. METHODS: Design and participants: Multicentric prospective cohort study. Consecutive sample patients with fragility hip fracture over 50 years old admitted in 48 hospitals in Spain. OUTCOMES: daily living activity function (Barthel Index) and health-related quality of life (EQ-5D) pre-fracture, admission to hospital and at 1- and 4-month follow-up post-fracture. STATISTICS: Barthel and EQ-5D over time are described as mean (SD) and median (interquartile range). RESULTS: A total of 997 patients were recruited at baseline with 4-month outcomes available for, and 856 patients (89.5%). Barthel Index fell from 78.77 (23.75) at baseline to 43.62 (19.86) on admission to hospital with the fracture. Scores partially recovered to 54.89 (25.40) and 64.09 (21.35) at 1- and 4-month post-fracture, respectively. EQ-5D fell from a median of 0.75 (0.47-0.91) to - 0.01 (- 0.03 to 0.51) on admission. Partial recovery was observed again to (0.51 (- 0.06 to 0.67)) and (0.60 (0.10 to 0.80)) at 1- and 4-month post-fracture, respectively. CONCLUSIONS: Hip fracture results in a large decline in the ability to perform activities of daily living and patient-reported health-related quality of life with only partial recovery amongst survivors 4-month post-fracture.

El papel de la determinación de un marcador de resorción, el telopéptido carboxiterminal del colágeno I, en la valoración del cumplimiento terapéutico en pacientes tratadas con bifosfonatos orales / The determining role of a resorption marker,carboxyterminal telopeptide of collagen I,in assessing therapeutic compliance inpatients treated with oral bisphosphonates

Objetivo: Se estima que al año entre el 50-60% de los pacientes tratados con fármacos para la osteoporosis son incumplidores. Disponemos de diferentes métodos indirectos de valoración del cumplimiento. Nuestro objetivo es testar una única determinación del telopéptido carboxiterminal del colágeno tipo I (CTX) para valorar el cumplimiento en pacientes tratadas con bifosfonatos, de forma aislada o junto al cuestionario de Morinsky-Green. Material y método: Estudio de validación diagnóstica realizado en 10 centros de Cataluña. Mediante muestreo consecutivo se seleccionaron mujeres postmenopáusicas con osteoporosis y tratadas con un mismo fármaco antirresortivo en el último año; se excluyeron aquellas tratadas con un fármaco diferente a bifosfonato, con deterioro cognitivo, enfermedad terminal, o insuficiencia renal avanzada, o fractura en el año previo. Se recogieron datos sobre el diagnóstico de osteoporosis y tipo de tratamiento. Se solicitó analítica con determinación del CTX. Como gold-standard se utilizó la tasa de posesión de medicación (Medication Possession Ratio, MPR). Mediante metodología de la curva ROC se estableció el punto de corte teórico del CTX. Se calculó la sensibilidad, la especificidad y los valores predictivos positivos para estimar el cumplimiento terapéutico. Resultados: Se incluyeron 100 pacientes, de las cuales más de la mitad recibían alendronato. Según la MPR, un 70% eran cumplidoras. El valor medio del CTX fue de 0,193±0,146 ng/ml, siendo inferior en las pacientes cumplidoras. Se estableció como punto de corte para valorar el cumplimiento un valor de 0,196 ng/ml. La valoración conjunta del CTX junto al cuestionario de Morinsky-Green presentó mayor capacidad discriminativa. Conclusiones: La realización de una única determinación del CTX (<0,196 ng/ml) junto al cuestionario de Morinsky-Green permite valorar mejor el cumplimiento terapéutico en pacientes tratadas con bifosfonatos

Objective:It is estimated that in one year between 50‐60% of patients treated with osteoporosis drugs are non‐com‐pliant. There are different indirect methods of assessing compliance. Our objective is to test a single determination ofthe carboxyterminal telopeptide of type I collagen (CTX) to assess compliance in patients treated with bisphosphonates,either on its own or together with the Morinsky‐Green questionnaire.Material and method:A diagnostic assessment study was carried out in 10 centers in Catalonia. Through consecutivesampling, postmenopausal women with osteoporosis were selected and treated with the same antiresorptive drug inthe last year. Those treated with a drug other than bisphosphonate, with cognitive impairment, terminal illness, advancedrenal failure or fracture in the previous year, were excluded. Data were collected on the diagnosis of osteoporosis andtype of treatment. Analysis was requested with CTX determination. As a gold standard, the medication possession rate(MPR) was used. Using the ROC curve methodology, the theoretical CTX cut‐off point was established. Sensitivity, spe‐cificity and positive predictive values were calculated to estimate therapeutic compliance.Results:100 patients were included, of which more than half were being treated with alendronate. According to theMPR, 70% were compliant. The mean CTX value was 0.193±0.146 ng/ml. It was lower in the compliant patients. A valueof 0.196 ng/ml was established as a cut‐off point to assess compliance. The joint assessment of the CTX together withthe Morinsky‐Green questionnaire showed greater discriminatory capacity.Conclusions:Carrying out a single determination of CTX (<0.196 ng/ml) along with the Morinsky‐Green questionnaireallows us to more accurately assess the therapeutic compliance in patients treated with bisphosphonates

Estudios funcionales de variantes de DKK1 presentes en la población general / Functional studies of DKK1 variants present in the general population

Objetivo: En las últimas décadas se han identificado genes asociados a la masa ósea y al riesgo de fractura osteoporótica, varios de los cuales pertenecen a la vía de Wnt. En este proyecto se estudió la funcionalidad de 7 mutaciones de cambio de sentido del gen DKK1 -un inhibidor de la vía de Wnt- presentes en la población general. Material y métodos: Se realizaron estudios in vitro del gen reportero luciferasa para medir la actividad de la vía de Wnt en presencia o ausencia de DKK1 silvestre o mutada, y estudios de western blot, para evaluar si las distintas mutaciones afectan a su síntesis y/o a su estabilidad. Resultados: La proteína DKK1 con la variante p.Ala41Thr presenta menor actividad inhibidora de la vía en comparación con la proteína silvestre. También se observaron diferencias significativas entre los experimentos realizados en ausencia de DKK1 y los que incluyen DKK1 con la mutación p.Ala41Thr. Los western blots mostraron que la cantidad de proteína era similar para todas las variantes, tanto las mutadas como la silvestre, por lo que la pérdida de actividad de p.Ala41Thr no parecía deberse a falta de proteína. El resto de las mutaciones no presentaron un comportamiento diferente al de la proteína DKK1 silvestre. Conclusiones: La variante de cambio de sentido p.Ala41Thr de la proteína DKK1, con una frecuencia poblacional de 0,013%, presenta una pérdida parcial de su función inhibidora, que no es debida a la falta de expresión de ésta. Esta variante génica podría conllevar un aumento de la densidad mineral ósea en las personas de la población general portadoras de esta mutación

Objective: In recent decades, genes associated with bone mass and osteoporotic fracture risk have been identified, several of which belong to the Wnt pathway. In this project, the functionality of 7 missense mutations of the gene DKK1-an inhibitor of the Wnt pathway- present in the general population was studied. Material and methods: In vitro studies of the luciferase reporter gene were carried out to measure Wnt pathway activity in the presence or absence of wild-type or mutated DKK1, and western blot studies, to evaluate if the different mutations affect its synthesis and/or stability. Results: The DKK1 protein with the p.Ala41Thr variant shows lower pathway inhibitory activity compared to the wild-type protein. Significant differences were also observed between the experiments performed in the absence of DKK1 and those that include DKK1 with the p.Ala41Thr mutation. Western blots showed that the amount of protein was similar for all variants, both mutated and "wild-type, so the loss of p.Ala41Thr activity did not seem to be due to a lack of protein. The rest of the mutations did not show different behavior from that of the wild DKK1 protein. Conclusions: The missense variant p.Ala41Thr of the DKK1 protein, with a population frequency of 0.013%, shows a partial loss of its inhibitory function, which is not due to the lack of expression. This gene variant could lead to an increase in bone mineral density in those people in the general population who carry this mutation

La resistencia mecánica tisular ósea es independiente de la edad en individuos sanos / Bone tissue mechanical strength is in dependent of age in healthy individuals

Objetivo: La microindentación de impacto (MII) es una técnica que permite medir in vivo la resistencia tisular mecánica ósea. Se ha demostrado que la MII proporciona información útil sobre la evaluación de enfermedades esqueléticas, pero se desconoce el efecto que la edad puede ejercer sobre la propiedad ósea medida. El objetivo del estudio es analizar la relación entre la edad y la MII. Material y métodos: El índice de Resistencia Mineral Ósea (BMSi), la variable de medición de MII, se midió en 69 mujeres (mediana de edad: 49 años; rango: 30-81 años) y 19 varones (mediana de edad: 34 años; rango: 24-98 años) sanos. La correlación entre BMSi y la edad se analizó mediante regresión lineal. La asociación entre BMSi y edad se evaluó mediante ANOVA tras ajustar por el índice de masa corporal. El posible efecto de depleción estrogénica postmenopáusica sobre el BMSi se estudió comparando el subgrupo de mujeres más jóvenes con las más mayores mediante la prueba t de Student. Resultados: Los análisis de regresión lineal mostraron que la BMSi no se correlaciona con la edad en varones (R2=0,0016, p=0,74) ni en mujeres (R2=0,076, p=0,25). Asimismo, el análisis ajustado de ANOVA no demostró asociación entre la BMSi y la edad ni en varones (p=0,78) ni en mujeres (p=0,73). Finalmente, no se encontraron diferencias entre la BMSi entre las mujeres más jóvenes y las mayores (p=0,8). Conclusiones: La resistencia tisular mecánica ósea en individuos sanos es independiente a la edad y a la depleción estrogénica postmenopáusica

Objective: Impact microindentation (IMI) is a technique that allows the measurement of mechanicalbone tissue resistance in vivo. IMI has proven to provide useful information on the evaluation of skeletal diseases, but the effect of age on the bone property that is measured by this technique is unknown. This study aims to analyzethe relationship between age and MIH. Material and methods: Bone Material Strength index (BMSi), IMI’s output variable, was measured in 69 healthy women (median age: 49 years, range: 30-81 years) and 19 healthy men median age: 34 years, range: 24-98 years). The correlation between BMSi and age was analyzed by linear regression. The association between BMSi and age was evaluated by ANOVA after adjusting for body mass index. The potential effect of postmenopausal estrogenic depletion on BMSi was studied by comparing the younger vs the older subset of women through a t-student test. Results: Linear regression analysis showed that BMSi was not correlated with age in either men (R2=0.0016, p=0.74) or women (R2=0.076, p=0.25). Similarly, the BMI-adjusted ANOVA model revealed a lack of asso-ciation of BMSi with age in men (p=0.78) and women (p=0.73). Finally, there were not significant differences on BMSi detected between the younger and the older subset of women (p=0.8). Conclusions: Bone tissue mechanical resistance in healthy individuals is independent of age and postmenopausal estrogenic depletion

In-vitro study of hierarchical structures: Anodic oxidation and alkaline treatments onto highly rough titanium cold gas spray coatings for biomedical applications.

Hierarchical structures were obtained applying two different nanotexturing surface treatments onto highly rough commercial pure titanium coatings by cold spray: (i) anodic oxidation and (ii) alkaline treatments. An extended surface characterization in terms of topography, composition, and wettability has been performed to understand how those parameters affect to cell response. Primary human osteoblasts extracted from knee were seeded onto the as-sprayed titanium surface before and after the nanotexturing treatments. Cell viability was tested by using MTS and LIVE/DEAD assays, as well as osteoblasts differentiation by alkaline phosphatase (ALP) quantification at 3 and 10 days of cell culture. The combination of micro-/nano-roughness results in a significantly increase of cell proliferation, as well as cell differentiation after 10 days of cell culture in comparison with the non-treated coatings.

Real-world antidiabetic drug use and fracture risk in 12,277 patients with type 2 diabetes mellitus: a nested case-control study.

We conducted a nested case-control study to study the association between antidiabetic treatments (alone or in combination) use and fracture risk among incident type 2 Diabetes mellitus patients. We found an increased risk of bone fracture with insulin therapy compared to metformin monotherapy. INTRODUCTION: Patients with type 2 diabetes mellitus (T2DM) have an increased risk of fragility fractures, to which antidiabetic therapies may contribute. We aimed to characterize the risk of fracture associated with different antidiabetic treatments as usually prescribed to T2DM patients in actual practice conditions. METHODS: A case-control study was nested within a cohort of incident T2DM patients registered in 2006-2012 in the Information System for Research Development in Primary Care (Catalan acronym, SIDIAP), a database which includes records for > 5.5 million patients in Catalonia (Spain). Each case (incident major osteoporotic fracture) was risk-set matched with up to five same-sex controls by calendar year of T2DM diagnosis and year of birth (± 10 years). Study exposure included previous use of all antidiabetic medications (alone or in combination), as dispensed in the 6 months before the index date, with metformin (MTF) monotherapy, the most commonly used drug, as a reference group (active comparator). RESULTS: Data on 12,277 T2DM patients (2049 cases and 10,228 controls) were analyzed. Insulin use was associated with increased fracture risk (adjusted OR 1.63 (95% CI 1.30-2.04)), as was the combination of MTF and sulfonylurea (SU) (adjusted OR 1.29 (1.07-1.56)), compared with MTF monotherapy. Sensitivity analyses suggest possible causality for insulin therapy but not for the MTF + SU combination association. No significant association was found with any other antidiabetic medications. CONCLUSIONS: Insulin monotherapy was associated with an increased fracture risk compared to MTF monotherapy in T2DM patients. Fracture risk should be taken into account when starting a glucose-lowering drug as part of T2DM treatment.

Estudio de la base genética de la reducción del Trabecular Bone Score relacionada con los inhibidores de la aromatasa / Study of the genetic basis of Trabecular Bone Score reduction related to aromatase inhibitors

Objetivos: Los inhibidores de la aromatasa (AI) son terapias endocrinas adyuvantes eficaces para pacientes con cáncer de mama, aunque se han asociado a un mayor riesgo de fractura osteoporótica. Previamente se ha demostrado una pérdida en el Trabecular Bone Score (TBS) que puede variar entre las pacientes tratadas con IA. El estudio pretendió identificar la base genética asociada al cambio en el TBS mediante el estudio de genes de la vía esteroidogénica. Material y métodos: La cohorte B-ABLE estudia de forma prospectiva a mujeres postmenopáusicas con cáncer de mama en tratamiento con IA. Se calculó el TBS a partir de los datos adquiridos en la densitometría mediante absorciometría radiológica dual (DXA) realizada al inicio y al final del tratamiento con IA. El cambio relativo del TBS se calculó como la variación porcentual del valor de TBS al final de tratamiento respecto al TBS basal. Para estudiar la posible asociación genética se genotiparon los polimorfismos de cambio de un nucleótido (SNPs) en los genes CYP11A1, CYP17A1, HDE3B2, HDE17B3, CYP19A1, CYP2C19, CYP2C9, ESR1, GC, CYP27B1, VDR y CYP24A1. Se estudió mediante regresión lineal múltiple la posible relación entre genes y cambios en TBS contemplando los modelos de herencia genética dominante, recesivo y aditivo. Resultados: Se incluyeron en el estudio un total de 212 mujeres no tratadas con bisfosfonatos en las que pudo calcularse el TBS. La mitad de las pacientes habían recibido tratamiento previo con tamoxifeno. El porcentaje de cambio intra-individual del TBS fue del -0,04% [IC del 95%: -0,05 a -0,03; p<0,001] al final de tratamiento con IA. El SNP rs6013897 en el gen CYP24A1 mostró una asociación significativa con la reducción del TBS [p=0,03565; coeficiente Beta (IC del 95%) = -1,55 (-2,98 a -0,11)]. Conclusiones: El gen CYP24A1 podría estar implicado en la variabilidad fenotípica encontrada en el deterioro de la microarquitectura ósea durante el tratamiento con IA

Objectives: Aromatase inhibitors (AI) are effective adjuvant endocrine therapies for breast cancer patients, although they have been associated with an increased risk of osteoporotic fracture. Trabecular Bone Score (TBS) loss has been previously demonstrated, although it may vary among AI-treated patients. This study aims to identify the genetic basis associated with TBS change by studying steroidogenic pathway genes. Material and methods: The B-ABLE cohort studies prospectively postmenopausal women with breast cancer under treatment with AI. TBS is calculated from the raw data acquired in dual-energy x-ray absorptiometry (DXA) scan at the outset of the study and at the end of AI-treatment. The relative TBS change was calculated as the percentage variation of the TBS value at the end of treatment from baseline. To study the possible genetic association, nucleotide polymorphisms (SNPs) were genotyped in genes CYP11A1, CYP17A1, HDE3B2, HDE17B3, CYP19A1, CYP2C19, CYP2C9, ESR1, GC, CYP27B1, VDR and CYP24A1. The possible relationship between genes and TBS changes was studied by multiple linear regression, considering models of dominant, recessive and additive genetic inheritance. Results: The study included 212 women that had not been treated with bisphosphonates and had available TBS data. Half of the patients had been treated previously with tamoxifen. The percentage of intra-individual TBS change was -0.04% [95% CI: -0.05 to -0.03; p<0.001] at the end of AI treatment. The SNP rs6013897 in the gene CYP24A1 showed a significant association with TBS reduction [p=0.03565; coefficient Beta (95% CI) = -1.55 (-2.98 to -0.11)]. Conclusions: The CYP24A1 gene could be involved in the phenotypic variability found in bone microarchitecture deterioration during AI treatment

Functionalized coatings by cold spray: An in vitro study of micro- and nanocrystalline hydroxyapatite compared to porous titanium.

Three different surface treatments on a Ti6Al4V alloy have been in vitro tested for possible application in cementless joint prosthesis. All of them involve the novelty of using the Cold Spray technology for their deposition: (i) an as-sprayed highly rough titanium and, followed by the deposition of a thin hydroxyapatite layer with (ii) microcrystalline or (iii) nanocrystalline structure. Primary human osteoblasts were extracted from knee and seeded onto the three different surfaces. Cell viability was tested by MTS and LIVE/DEAD assays, cell differentiation by alkaline phosphatase (ALP) quantification and cell morphology by Phalloidin staining. All tests were carried out at 1, 7 and 14 days of cell culture. Different cell morphologies between titanium and hydroxyapatite surfaces were exhibited. At 1 day of cell culture, cells on the titanium coating were spread and flattened, expanding the filopodia actin filaments in all directions, while cells on the hydroxyapatite coatings showed round like-shape morphology due to slower attachment. Higher cell viability was detected at all times of cell culture on titanium coating due to a better attachment at 1 day. However, from 7 days of cell culture, cells on hydroxyapatite showed good attachment onto surfaces and highly increased their proliferation, mostly on nanocrystalline, achieving similar cell viability levels than titanium coatings. ALP levels were significantly higher in titanium, in part, because of greatest cell number. Overall, the best cell functional results were obtained on titanium coatings whereas microcrystalline hydroxyapatite presented the worst cellular parameters. However, results indicate that nanocrystalline hydroxyapatite coatings may achieve promising results for the faster cell proliferation once cells are attached on the surface.

Osteoblastic cell response on high-rough titanium coatings by cold spray.

Highly rough and porous commercially pure titanium coatings have been directly produced for first time by the cold spray technology, which is a promising technology in front of the vacuum plasma spray for oxygen sensitive materials. The wettability properties as well as the biocompatibility evaluation have been compared to a simply sand blasted Ti6Al4V alloy substrate. Surface topographies were analysed using confocal microscopy. Next, osteoblast morphology (Phalloidin staining), proliferation (MTS assay), and differentiation (alkaline phosphatase activity) were examined along 1, 7 and 14 days of cell culture on the different surfaces. Finally, mineralization by alizarin red staining was quantified at 28 days of cell culture. The contact angle values showed an increased hydrophilic behaviour on the as-sprayed surface with a good correlation to the biological response. A higher cell viability, proliferation and differentiation were obtained for highly rough commercial pure titanium coatings in comparison with sand blasted substrates. Cell morphology was similar in all coatings tested; at 14 days both samples showed extended filopodia. A higher amount of calcium-rich deposits was detected on highly rough surfaces. In summary, in-vitro results showed an increase of biological properties when surface roughness increases.

Spanish consensus on treat to target for osteoporosis.

To reach a Spanish expert consensus on a treat-to-target strategy in osteoporosis, a Delphi Consensus Study has been developed. Most of the experts (59.8%) were rheumatologist with a mean clinical experience of 21.3 years (SD 8.5). Consensus was achieved for 70% of the items. Therapeutic objectives, patient follow-up scheme, treatment failure criteria, and appropriate treatment choice for use in T2T strategy in Spain have been defined. INTRODUCTION: The paper aims to achieve a Spanish expert consensus on a treat-to-target (T2T) strategy in osteoporosis. METHODS: A scientific committee led the project and was involved in expert panel identification and Delphi questionnaire development. Two Delphi rounds were completed. The first-round questionnaire included 24 items and assessed, using a seven-point Likert scale, the experts' wish (W) and prognosis (P) in 5 years for each topic (applicability, therapeutic objectives, patient follow-up, and possible treatment to be prescribed). Items for which there was no consensus in the first round were included in the second round. Consensus was defined as ≥75% agreement (somewhat/mostly/entirely agree) or disagreement (somewhat/mostly/entirely disagree) responses. RESULTS: Of the experts, 112 and 106 completed the first and second rounds, respectively. 59.8% were rheumatologists with a mean clinical experience of 21.3 years (SD 8.5). Consensus was achieved for 70% of the items, and was established regarding the utility of a T2T strategy to define therapeutic objectives, optimal follow-up, and therapeutic algorithm. Participants agreed on the utility of the bone mineral density (BMD) value (T-score >-2.5 SD for spine and >-2.5/-2.0 SD for femoral neck), lack of fractures, and fracture risk (FRAX) as therapeutic objectives. For measuring BMD changes, consensus was achieved on the suitability of hip and femoral neck locations. Experts agreed to consider treatment failure as when a significant BMD gain could not be achieved, or when a new fracture occurs within 2-3 years. There was consensus that all proposed therapies should achieve a therapeutic target through T2T strategy (treatments with the highest consensus scores were denosumab and teriparatide). CONCLUSION: The therapeutic objectives, patient follow-up scheme, treatment failure criteria, and appropriate treatment choice for use in T2T strategy in Spain have been established by a panel of experts. Some aspects nevertheless still require further analysis.

Uso de fármacos para la osteoporosis en pacientes con diabetes mellitus tipo 2: estudio de cohortes de base poblacional / Use of drugs for osteoporosis treatment in patients with type 2 diabetes mellitus: population-based cohort study

Objetivo: Determinar si existen diferencias en la prevalencia del uso de fármacos para la osteoporosis entre pacientes diabéticos tipo 2 (DM2) y no diabéticos. Material y método: Estudio de cohortes retrospectivas con datos del Sistema de Información para el Desarrollo de la Investigación en Atención Primaria (SIDIAP), que contiene información clínica anonimizada de más de 5 millones de pacientes de Cataluña. Se seleccionaron todos los pacientes de ≥50 años de edad con diagnóstico de DM2, que fueron apareados con dos sujetos sin diabetes. Se recogió información sobre variables descriptivas, fracturas prevalentes y el uso de fármacos para la osteoporosis agrupados en bifosfonatos (BF), suplementos calcio y vitamina D (CaD), y cualquier fármaco para la osteoporosis (FPO). Mediante regresión logística se calculó la asociación entre la presencia de DM2 y el uso de FPO, ajustando por variables confusoras. Resultados: Se identificaron 166.106 pacientes con DM2 y 332.212 no diabéticos. Los DM2 tenían mayor prevalencia de fractura que los no diabéticos (1,3% vs. 0,3%). El uso de BF en los pacientes con DM2 era del 6,6%, frente al 9,3% en los no diabéticos (p<0,001); de CaD, 9,7% vs. 12,3% (p<0,001); y de FPO, 7,6% vs. 10,7% (p<0,001). Tras ajustar por variables confusoras, los pacientes con DM2 presentaban menor probabilidad de ser tratados con BF (OR=0,67; IC95%: 0,64-0,68), con CaD (OR=0,71; IC95%: 0,70-0,73) o con FPO (OR=0,66; IC95%: 0,64-0,67) que los no diabéticos. Conclusiones: A pesar de presentar una mayor prevalencia de fracturas previas, los pacientes con DM2 tienen más del 30% de probabilidad de no recibir un FPO que los no diabéticos. Esto podría ser debido a una infravaloración del riesgo en estos pacientes (AU)

Objective: Ascertain whether there are differences in the prevalence of osteoporosis drugs in patients with type 2 diabetes (DM2) and non-diabetic patients. Material and methods: Retrospective cohort study with data from the Information System for the Development of Primary Care Research (SIDIAP), which contains anonymous clinical information from more than 5 million patients in Catalonia. All 50-year-old patients diagnosed with DM2, who were matched with two subjects without diabetes, were selected. Information on descriptive variables, prevalent fractures and the use of osteoporosis drugs grouped in bisphosphonates (BF), calcium and vitamin D supplements (CaD), and any osteoporosis drug (OD) were collected. Through logistic regression, the association between the presence of DM2 and the use of OD was calculated, adjusting for confounding variables. Results: A total of 166,106 patients with DM2 and 332,212 non-diabetics. The DM2 group presented a higher prevalence of fracture than did diabetics (1.3% vs 0.3%). The use of BF in patients with DM2 was 6.6%, compared to 9.3% in non-diabetics (p<0.001). Of CaD, 9.7% vs 12.3% (p<0.001) and OD, 7.6% vs 10.7% (p<0.001). After adjusting for variable confounders, the patients with DM2 presented a lower probability of being treated with BF (OR=0.67, 95% CI: 0.64-0.68), with CaD (OR=0.71, 95% CI: 0.70-0.73) or with OD (OR=0.66, 95% CI: 0.64-0.67) than non-diabetics. Conclusions: Despite having a higher prevalence of fractures in patients with DM2, they have more than 30% chance of not having received an OD than non-diabetic patients. This may be attributed to an underestimation of risk in these patients (AU)

Discrepancy between bone density and bone material strength index in three siblings with Camurati-Engelmann disease.

Camurati-Engelmann (CE) is a very rare disease affecting one in every million persons worldwide. It is characterized by an enlargement of long bones. We aimed to assess bone characteristics in three siblings with different tools. Even if there was an excess of bone density, quality seemed to be deteriorated. INTRODUCTION: CE disease is a rare monogenic disorder affecting approximately one in every million persons worldwide. It is mainly characterized by a progressive hyperostosis of the periosteum and endosteum of the diaphysis of long bones. Limited data are available about bone characteristics in these patients. In three siblings with CE disease, we aimed to assess bone mineral density (BMD) and trabecular bone score (TBS) by dual-energy X-ray absorptiometry (DXA) and material characteristics at tissue level using bone impact reference point indentation. METHODS: Clinical data were collected and a general laboratory workup was performed. At the lumbar spine and hip, BMD and TBS were measured using DXA imaging. Bone material strength index (BMSi) was measured by bone impact microindentation using an Osteoprobe instrument. RESULTS: All three cases had densitometric values consistent with high bone mass (sum of Z-score at the lumbar spine and hip > 4). Hip BMD was extremely high in all three siblings at both total hip and femoral neck, while at the lumbar spine, two of them had normal values but the third again had very high BMD. TBS values were in the normal range. In contrast, BMSi measurements were at low or very low levels, compared with normal controls. CONCLUSION: Despite strikingly increased BMD and normal microarchitecture, BMSi is affected in patients with CE. Microindentation could be an appropriate tool for assessing bone fragility in these patients. Bone disease in this group of patients requires further study to better understand the underlying regulatory mechanisms and their alterations.

Excess of all-cause mortality after a fracture in type 2 diabetic patients: a population-based cohort study.

Post-fracture mortality in type 2 diabetes mellitus (T2DM) patients has been poorly studied. We report an absolute and relative excess all-cause mortality following a fracture in these patients compared to non-diabetic patients. INTRODUCTION: T2DM and osteoporotic fractures are independently associated with a reduced lifespan, but it is unknown if T2DM confers an excess post-fracture mortality compared to non-diabetic fracture patients. We report post-fracture all-cause mortality according to T2DM status. METHODS: This is a population-based cohort study using data from the SIDIAP database. All ≥50 years old T2DM patients registered in SIDIAP in 2006-2013 and two diabetes-free controls matched on age, gender, and primary care center were selected. Study outcome was all-cause mortality following incident fractures. Participants were followed from date of any fracture (AF), hip fracture (HF), and clinical vertebral fracture (VF) until the earliest of death or censoring. Cox regression was used to calculate mortality according to T2DM status after adjustment for age, gender, body mass index, smoking, alcohol intake, and previous ischemic heart and cerebrovascular disease. RESULTS: We identified 166,106 T2DM patients and 332,212 non-diabetic, of which 11,066 and 21,564, respectively, sustained a fracture and were then included. Post-fracture mortality rates (1000 person-years) were (in T2DM vs non-diabetics) 62.7 vs 49.5 after AF, 130.7 vs 112.7 after HF, and 54.9 vs 46.2 after VF. Adjusted HR (95% CI) for post-AF, post-HF, and post-VF mortality was 1.30 (1.23-1.37), 1.28 (1.20-1.38), and 1.20 (1.06-1.35), respectively, for T2DM compared to non-diabetics. CONCLUSIONS: T2DM patients have a 30% increased post-fracture mortality compared to non-diabetics and a remarkable excess in absolute mortality risk. More research is needed on the causes underlying such excess risk, and on the effectiveness of measures to reduce post-fracture morbi-mortality in T2DM subjects.

Circuitos de atención médica de la paciente con osteoporosis postmenopáusica en España / Medical care circuits for postmenopausal patients in Spain

Objetivos: Alcanzar un consenso sobre los circuitos de atención médica de la paciente con osteoporosis postmenopáusica (OPM), incluyendo los circuitos de derivación y manejo (herramientas de evaluación y pruebas médicas), identificando perfiles de acuerdo con la opinión de expertos en metabolismo óseo pertenecientes al Sistema de Salud Español. Material y métodos: Se empleó la técnica Delphi con dos rondas de consulta sucesivas. Participaron 38 expertos en el manejo de OPM pertenecientes a 14 sociedades científicas. La revisión de la literatura y la opinión del comité científico nutrieron el cuestionario. Los expertos expresaron su "deseo" (1=rechazo total; 9=deseo más fuerte) y "pronóstico" (1=no ocurrirá en absoluto; 9=ocurrirá con máxima probabilidad) acerca de las cuestiones planteadas. Se alcanzó consenso cuando el 75% o más de los participantes puntuaron 1-3 (desacuerdo) o 7-9 (acuerdo). Adicionalmente, los expertos se dividieron en 3 grupos de discusión para complementar la información según los perfiles de pacientes previamente hallados en el método Delphi. Resultados: Se alcanzó consenso en el 75% de las preguntas. Los expertos establecieron tres perfiles de pacientes con OPM: sin fractura, con fractura vertebral y con fractura no vertebral, así como los recursos diagnósticos y terapéuticos que conviene emplear en estas pacientes. La paciente sin fractura debería ser manejada por Atención Primaria o Reumatología y se utilizarán escalas para valorar el riesgo de fractura en fases tempranas de la enfermedad. La paciente con fractura vertebral crónica debería referirse a Reumatología y Rehabilitación, y se derivará a Reumatología; mientras que la paciente con fractura vertebral aguda debería ser tratada por Cirugía Ortopédica, y así es como posiblemente ocurrirá. El diagnóstico de la paciente con fractura vertebral estará basado principalmente en la radiografía. Para la evaluación de la progresión se deberían utilizar cuestionarios sobre la capacidad funcional y escalas del dolor. Sin embargo, no se utilizarán en la práctica habitual debido a la falta de tiempo. La paciente con fractura no vertebral debería ser y será referida a Cirugía Ortopédica, recomendando realizar 3-4 radiografías anuales para asegurar la consolidación de la fractura. Conclusiones: Los resultados del método Delphi muestran los circuitos de derivación de la paciente con OPM, que se concentran en Atención Primaria y Reumatología, cuando no existe fractura, y Cirugía Ortopédica, en caso de fractura (AU)

Objectives: To reach a consensus on the medical care circuits of patients with postmenopausal osteoporosis (PMO), including derivation and management (assessment tools and medical tests), identifying profiles according to the opinion of bone metabolism experts, from Spain’s Health Service. Material and methods: The Delphi technique was used with two successive consultation rounds, with 38 experts in PMO management belonging to 14 scientific societies taking part in the study. Review of literature and the opinion of the scientific committee rounded out the questionnaire. The experts expressed their "desire" (1=total rejection, 9=stronger desire) and "forecast" (1=will absolutely not occur; 9=will occur with maximum probability) about the issues raised. A consensus was reached when 75% or more of the participants scored 1-3 (disagreement) or 7-9 (agreement). In addition, experts were divided up into 3 discussion groups to complement the information according to patient profiles found previously in the Delphi method. Results: Consensus was reached on 75% of the questions. The experts established three profiles of PMO patients: no fracture, vertebral fracture and non-vertebral fracture, as well as the diagnostic and therapeutic resources recommended for these patients. The patient without a fracture should be managed in Primary Care or Rheumatology and scales will be used to evaluate fracture risk in early stages of the disease. The patient with chronic vertebral fracture should refer to Rheumatology and Rehabilitation, and will be Rheumatology, whereas the patient with acute vertebral fracture should be treated in Orthopedic Surgery, and this is how it will possibly happen. Diagnosis of vertebral fracture patients will be based mainly on x-rays. To assess progress, questionnaires on the functional capacity and pain scales are recommended. However, these will not be used due to the lack of time involved. The patient with non-vertebral fracture should be and will be referred to Orthopedic Surgery, with 3-4 radiographs recommended to ensure fracture consolidation. Conclusions: Delphi method results indicate that referral of PMO patients are concentrated in Primary Rheumatology, when there is no fracture, and Orthopedic Surgery, in the case of fracture (AU)