Pamidronate Administration During Pregnancy and Lactation Induces Temporal Preservation of Maternal Bone Mass in a Mouse Model of Osteogenesis Imperfecta.

During pregnancy and lactation, the maternal skeleton undergoes significant bone loss through increased resorption to provide the necessary calcium supply to the developing fetus and suckling neonate. This period of skeletal vulnerability has not been clearly associated with increased maternal fracture risk, but these physiological conditions can exacerbate an underlying metabolic bone condition like osteogenesis imperfecta. Although bisphosphonates (BPs) are commonly used in postmenopausal women, there are cases where premenopausal women taking BPs become pregnant. Given BPs' long half-life, there is a need to establish how BPs affect the maternal skeleton during periods of demanding metabolic bone changes that are critical for the skeletal development of their offspring. In the present study, pamidronate- (PAM-) amplified pregnancy-induced bone mass gains and lactation-induced bone loss were prevented. This preservation of bone mass was less robust when PAM was administered at late stages of lactation compared with early pregnancy and first day of lactation. Pregnancy-induced osteocyte osteolysis was also observed and was unaffected with PAM treatment. No negative skeletal effects were observed in offspring from PAM-treated dams despite lactation-induced bone loss prevention. These findings provide important insight into (1) a treatment window for when PAM is most effective in preserving maternal bone mass, and (2) the maternal changes in bone metabolism that maintain calcium homeostasis crucial for fetal and neonatal bone development. © 2019 American Society for Bone and Mineral Research.

Relationship between glycemic control and OPG gene polymorphisms with lower bone mineral density in patients with type 1 Diabetes mellitus

ABSTRACT The aim of the present study was to investigate the bone mineral density (BMD) of patients with type 1 Diabetes mellitus (T1DM). We also assessed the association between osteoprotegerin (OPG) genetic polymorphisms and BMD. Genotyping was performed for 1181G>C and 163A>G OPG polymorphisms by allelic discrimination in 119 patients with T1DM and 161 normoglycemic (NG) individuals, aged 6 to 20 years old. Glycemic control, serum parameters of bone metabolism and BMD were evaluated. T1DM patients showed low BMD, poor glycemic control and decreased total calcium values when compared to controls (p < 0.05). For all the polymorphisms studied, the genotype and allele frequencies in patients with T1DM were not significantly different from the controls. In patients with T1DM, carriers of OPG 1181CC showed higher concentrations of ionized calcium compared to patients with GG+GC genotypes. These results suggest that low BMD is associated with poor glycemic control in T1DM. Despite the lack of a detected association between OPG polymorphisms and BMD in these patients, the increased ionized calcium in those carrying OPG 1181CC suggests a possible increase in osteoclastogenesis, a conclusion that may be supported by the lower BMD observed in these subjects.

Prevención primaria y secundaria de la fractura de cadera por fragilidad ósea en la población del sector sanitario Teruel / Primary and secondary prevention of hip fragility fracture in Teruel health sector, Aragon, Spain

Fundamentos: La osteoporosis puede y debe prevenirse, diagnosticarse y tratarse, preferentemente antes de que aparezca la fractura por fragilidad. El objetivo fue analizar las intervenciones de prevención primaria y secundaria llevadas a cabo en las personas que sufrieron fractura de cadera por fragilidad en 2014 en el sector sanitario de Teruel. Método: Estudio descriptivo transversal. Variables analizadas: sexo, edad, zona básica de salud, residencia, situación funcional basal, antecedente de osteoporosis, fractura de fémur o vertebral, pérdida de estatura, utilización de FRAX, tratamiento al alta, exitus y su causa. Se empleó t-Student y ANOVA para variables cuantitativas por categorías y regresión para relaciones lineales. Resultados: Se incluyó a 148 personas, de las cuales 123 eran mujeres, con una mediana de edad de 87 años, 27,4% tenían dependencia grave o total para las actividades de la vida diaria, 33% estaban institucionalizados. El 10,1% tenían antecedente de fractura de cadera y 10% de fractura vertebral. Constaba diagnóstico de osteoporosis en el 13’7%. En ningún caso se había utilizado la herramienta FRAX®. Habían seguido tratamiento previo con calcio el 12,2%, con vitamina D el 11,5% y con fármacos antiosteoporóticos un 6,8%. Tras la fractura siguió tratamiento para prevención secundaria el 52,7%. A 31/12/2015 había fallecido un 25,7%, con mediana de supervivencia de los fallecidos de 64,5 días, siendo las causas de exitus más frecuentes enfermedad cardiovascular (42,3%), infección (23,1%) y neoplasias (11,5%). Conclusiones: En nuestro sector sanitario es infrecuente la valoración de la osteoporosis y del riesgo de fractura en población de riesgo así como la indicación de medidas farmacológicas de prevención primaria. Aunque la indicación de terapia para la prevención secundaria es superior a la reflejada en la literatura, debemos tomar medidas adicionales para mejorar la prevención de fracturas por fragilidad (AU)

Background: Osteoporosis should be prevented, diagnosed and treated, preferably before the fragility fracture occurs. The objective was to analyze primary and secondary interventions carried out in individuals diagnosed with femur fragility fracture at Teruel in 2014. Methods: Descriptive retrospective study. Variables assessed were sex, age, main health district, place of residence, basal functional situation, diagnosis on osteoporosis, hip or vertebral fracture, loss of height, use of FRAX tool, treatment on discharge, survival and cause of exitus. Student’s t-test and ANOVA were used for quantitative variables by categories and regression for linear relationships. Results: 148 patients were included. 123 were women median age was 87 years, 123 (76,4%) were women, 27,4% of the patients were totally or severely dependent for activities of daily living and 33% of them were living in a nursing home. There was a previous history of hip fracture in 10,1%, and one or more vertebral fractures in 10,1%. FRAX® tool was not used in any case. 12,2% of patients had been treated with calcium prior to fracture, 11,5% with vitamin D, and 6,8% of them with antiosteoporotic drugs. Only 52,7% were treated for secondary prevention after discharge. At the end of follow-up, 25,7% of hip fractured patients had died. Median survivorship of deceased patients was 64,5 days. 42,3% of exitus were caused by cardiovascular disease, 23,1% by infection and 11,5% by neoplasms. Conclusions: Primary pharmacologic prevention and assessment of osteoporosis or risk of fracture are unfrequent in our health district.. Although pharmacologic treatment is prescribed more frequently in Teruel than in other areas after a hip or vertebral fracture, additional measures should be taken in order to improve fragility fracture prevention (AU)

Counteracting bone fragility with human amniotic mesenchymal stem cells.

The impaired maturation of bone-forming osteoblasts results in reduced bone formation and subsequent bone weakening, which leads to a number of conditions such as osteogenesis imperfecta (OI). Transplantation of human fetal mesenchymal stem cells has been proposed as skeletal anabolic therapy to enhance bone formation, but the mechanisms underlying the contribution of the donor cells to bone health are poorly understood and require further elucidation. Here, we show that intraperitoneal injection of human amniotic mesenchymal stem cells (AFSCs) into a mouse model of OI (oim mice) reduced fracture susceptibility, increased bone strength, improved bone quality and micro-architecture, normalised bone remodelling and reduced TNFα and TGFß sigalling. Donor cells engrafted into bones and differentiated into osteoblasts but importantly, also promoted endogenous osteogenesis and the maturation of resident osteoblasts. Together, these findings identify AFSC transplantation as a countermeasure to bone fragility. These data have wider implications for bone health and fracture reduction.

Resultados de un modelo de prevención secundaria de fractura osteoporótica coordinado por reumatología centrado en la enfermera y el médico de atención primaria / Results of a model of secondary prevention for osteoporotic fracture coordinated by rheumatology and focused on the nurse and primary care physicians

Objetivo. Evaluar la influencia de la implantación de un programa para la prevención secundaria de fracturas osteoporóticas sobre la prescripción de bisfosfonatos y la persistencia del tratamiento a corto plazo. Pacientes y métodos. Se incluyeron pacientes con fractura por fragilidad > 50 años atendidos en el servicio de urgencias durante un año. El programa consistió en: 1) plan de formación en osteoporosis de los médicos de primaria; 2) densitometría ósea; 3) cuestionario relativo a osteoporosis y educación del paciente por la enfermera; 4) derivación al médico de primaria o, en caso de múltiples fracturas o precisar terapia parenteral, a consulta hospitalaria; y 5) seguimiento y comprobación de inicio del tratamiento prescrito a través de los registros electrónicos y encuesta telefónica. La variable principal de desenlace fue el porcentaje de pacientes que, habiéndose prescrito un bisfosfonato, cumple el tratamiento a los 3 meses. Resultados. De 532 pacientes con criterios de inclusión, 202 (38%) no aceptaron participar. Comparados con los pacientes que participaron, los que rechazaron tenían una edad promedio mayor (p < 0,01) y una mayor frecuencia de fractura de cadera (p < 0,01). Así, se incluyeron 330 pacientes con una edad media de 71 años, el 77% mujeres. Cuarenta y cinco pacientes (13%) utilizaban bisfosfonato al inicio del estudio, mientras que tras la visita basal se prescribió a 223 pacientes (67%). En el seguimiento a los 3 meses, el 78% de los pacientes a los que se aconsejó bisfosfonato estaba tomando la medicación. Conclusiones. El programa de prevención secundaria de fracturas coordinado por reumatología consigue que el número de pacientes que inicia bisfosfonato se multiplique por 4 en comparación con la visita basal (AU)

Objective: To assess the influence of the implementation of a program for secondary prevention of osteoporotic fractures on prescribing bisphosphonates and persistent short-term treatment. Patients and methods: Patients > 50 years with fragility fracture attended in the emergency department were enrolled in an observational study. The program consisted of: 1) training of primary care physicians, 2) baseline visit: questionnaire on osteoporosis, bone densitometry and patient education, 3) patient referral to primary care, except those with multiple fractures or requiring special study or therapy, who were referred to a specialist, and 4) follow-up by checking prescriptions in electronic records, and a telephone survey. The outcome variable was the percentage of patients who, on having been prescribed bisphosphonates, still adhered to the treatment at 3 months. Results: Of the 532 patients with inclusion criteria, 202 (39%) refused to participate. Those who refused to take part had a higher mean age ( P < .01) and a higher frequency of hip fracture (P < .01) compared with patients who did participate. A total of 330 patients were included for intervention, with a mean age of 71 years, and 254(77%) were female. An antiresorptive was being used by 45 patients (13%) at baseline. After the baseline visit 223 patients (67%) were recommended a bisphosphonate. In the follow-up at 3 months 78% of patients who had been prescribed bisphosphonate were still receiving treatment. Conclusions: We present a multidisciplinary program for secondary prevention of fractures coordinated by rheumatology in which the number of patients who were receiving bisphosphonate at 3 months increased by four times compared to baseline visit (AU)

IFN-γ directly inhibits TNF-α-induced osteoclastogenesis in vitro and in vivo and induces apoptosis mediated by Fas/Fas ligand interactions.

Cytokines secreted by T cells play a pivotal role in inflammatory bone destruction. Tumor necrosis factor-α (TNF-α) is a major proinflammatory cytokine produced by macrophages following T cell activation, and directly promotes osteoclast differentiation resulting in accelerated bone resorption. Interferon-γ (IFN-γ) attenuates RANKL-initiated cellular signals through osteoclast formation and counterbalances aberrant bone resorption. With respect to this crosstalk during osteoclastogenesis, the direct interruption of IFN-γ in TNF-α-induced osteoclast formation still requires elucidation. We have demonstrated that IFN-γ directly inhibits osteoclastogenesis induced by TNF-α stimulation and accelerates apoptosis mediated by Fas/Fas ligand signals. There were a decreased number of osteoclasts and reduced mRNA levels encoding Nfatc1 in cultured bone marrow macrophages. Apoptotic responses of cultured cells were observed, with accelerated nuclear fragmentation in osteoclast precursor cells and increased FasL mRNA levels in bone marrow cells stimulated with TNF-α evident. IFN-γ reduced the level of osteoclastogenesis in response to TNF-α treatment in vivo. IFN-γ inhibited TNF-α-induced osteoclastogenesis in mice with T cells that had been exposed to anti-CD4 and -CD8 antibodies. These results provide evidence that IFN-γ directly inhibits osteoclastogenesis and induces cells apoptosis by Fas/FasL signals, leading to the indirect regulation of bone resorption, which is required for protective roles in bone destruction at an inflammation site.

Fragilidad de la mujer posmenopáusica pobre / No disponible

No disponible

Genetics: what's it got to do with family health care?

Genetics is an important contributory factor in many medical conditions. Having an understanding of the genetic basis of diseases can therefore be helpful in identifying and supporting people who have, or are at risk of having, a genetic condition. Most of the current practical applications relate to conditions which are known to have a definite mode of inheritance (for instance cystic fibrosis or familial hypercholesterolaemia) or which are due to chromosomal anomalies (such as Down syndrome). Current research projects are attempting to identify and understand the genetic factors associated with common diseases (such as diabetes and Crohn's disease) but it will be some time before these are likely to be useful clinically. Key skills in the delivery of a holistic family practice service include being able to collect a genetic family history, identifying people at risk and knowing how to refer to specialist services.

Evolución de mujeres con osteoporosis tratadas durante más de tres años / Evolution of women with osteoporosis treated for more than three years

Presentamos la evolución de 41 pacientes con osteoporosis posmenopáusica que han seguido tratamiento durante más de tres años (86 meses de media). Treinta y cinco pacientes (85%) presentaron incrementos de la densidad mineral ósea (DMO) en columna, con una ganancia media del 21%, siendo los cambios estadísticamente significativos (p < 0,005); el 63% mostró incrementos en cadera, pero no fueron significativos. Trece pacientes presentaron alguna fractura por fragilidad y 6 de ellas sufrieron más de un evento. Por orden de frecuencia fueron 8 fracturas vertebrales (19,5%), 5 de la extremidad distal de radio (12%), 3 de húmero (7,5%) y 2 de cadera (5%). El tratamiento más utilizado fue alendronato (71%), seguido de raloxifeno (58%) y risedronato (54%). Utilizando el test de Morisky, el 48% de las pacientes era buena cumplidora. Hemos encontrado correlación entre los aumentos de la DMO y la aparición de fractura, pero no con otros factores de riesgo analizados(AU)

We are going to show the progress of 41 postmenopausal patients who have followed treatment for more than three years (86 months). Assessing several factors such as: development of the bone mineral density (BMD), adherence to therapeutic treatment, incidence of fractures and risk factors. Thirty five patients (85%) showed increases of the BMD in the spine with an average increase of 21%, and presented statistic changes (p < 0.005); 63% presented statistic changes in the hip but with not significant increases. Thirteen patients showed some fracture through fragility and 6 of them suffered more than one episode. By order of frequency: vertebral (spinal) fractures 8 (19.5%), radius 5 (12%), epiphysis of humerus 3 (7, 5%) and hip 2 (5%). The most used treatment was alendronate (71%), followed by raloxifene (58%) and risedronate (54%). Using the Morisky test, the 48% of the patients were reliable. We have found correlation between increases of the BMD and risk of fracture, not being found related to other risk factors(AU)

In utero transplantation of adult bone marrow decreases perinatal lethality and rescues the bone phenotype in the knockin murine model for classical, dominant osteogenesis imperfecta.

Autosomal dominant osteogenesis imperfecta (OI) caused by glycine substitutions in type I collagen is a paradigmatic disorder for stem cell therapy. Bone marrow transplantation in OI children has produced a low engraftment rate, but surprisingly encouraging symptomatic improvements. In utero transplantation (IUT) may hold even more promise. However, systematic studies of both methods have so far been limited to a recessive mouse model. In this study, we evaluated intrauterine transplantation of adult bone marrow into heterozygous BrtlIV mice. Brtl is a knockin mouse with a classical glycine substitution in type I collagen [alpha1(I)-Gly349Cys], dominant trait transmission, and a phenotype resembling moderately severe and lethal OI. Adult bone marrow donor cells from enhanced green fluorescent protein (eGFP) transgenic mice engrafted in hematopoietic and nonhematopoietic tissues differentiated to trabecular and cortical bone cells and synthesized up to 20% of all type I collagen in the host bone. The transplantation eliminated the perinatal lethality of heterozygous BrtlIV mice. At 2 months of age, femora of treated Brtl mice had significant improvement in geometric parameters (P < .05) versus untreated Brtl mice, and their mechanical properties attained wild-type values. Our results suggest that the engrafted cells form bone with higher efficiency than the endogenous cells, supporting IUT as a promising approach for the treatment of genetic bone diseases.