Mitigating aging and doxorubicin induced bone loss in mature mice via mechanobiology based treatments.

Aging leads to a reduced anabolic response to mechanical stimuli and a loss of bone mass and structural integrity. Chemotherapy agents such as doxorubicin exacerbate the degeneration of aging skeleton and further subject older cancer patients to a higher fracture risk. To alleviate this clinical problem, we proposed and tested a novel mechanobiology-based therapy. Building upon prior findings that i) Yoda1, the Piezo1 agonist, promoted bone growth in young adult mice and suppressed bone resorption markers in aged mice, and ii) moderate tibial loading protected bone from breast cancer-induced osteolysis, we hypothesized that combined Yoda1 and moderate loading would improve the structural integrity of adult and aged skeletons in vivo and protect bones from deterioration after chemotherapy. We first examined the effects of 4-week Yoda1 (dose 5 mg/kg, 5 times/week) and moderate tibial loading (4.5 N peak load, 4 Hz, 300 cycles for 5 days/week), individually and combined, on mature mice (∼50 weeks of age). Combined Yoda1 and loading was found to mitigate age-associated cortical and trabecular bone loss better than individual interventions. As expected, the non-treated controls experienced an average drop of cortical polar moment of inertia (Ct.pMOI) by -4.3 % over four weeks and the bone deterioration occurred in the majority (64 %) of the samples. Relative to no treatment, loading alone, Yoda1 alone, and combined Yoda1 and loading increased Ct.pMOI by +7.3 %, +9.5 %, +12.0 % and increased the % of samples with positive Ct.pMOI changes by +32 %, +26 %, and +43 %, respectively, suggesting an additive protection of aging-related bone loss for the combined therapy. We further tested if the treatment efficacy was preserved in mature mice following two weeks (six injections) of doxorubicin at the dose of 2.5 or 5 mg/kg. As expected, doxorubicin increased osteocyte apoptosis, altered bone remodeling, and impaired bone structure. However, the effects induced by DOX were too severe to be rescued by Yoda1 and loading, alone or combined, although loading and Yoda1 individually, or combined, increased the number of mice showing positive responsiveness by 0 %, +15 %, and +29 % relative to no intervention after doxorubicin exposure. Overall, this study supported the potentials and challenges of the Yoda1-based strategy in mitigating the detrimental skeletal effects caused by aging and doxorubicin.

A Bisphosphonate With a Low Hydroxyapatite Binding Affinity Prevents Bone Loss in Mice After Ovariectomy and Reverses Rapidly With Treatment Cessation.

Bisphosphonates (BPs) are a mainstay of osteoporosis treatment; however, concerns about bone health based on oversuppression of remodeling remain. Long-term bone remodeling suppression adversely affects bone material properties with microdamage accumulation and reduced fracture toughness in animals and increases in matrix mineralization and atypical femur fractures in patients. Although a "drug holiday" from BPs to restore remodeling and improve bone quality seems reasonable, clinical BPs have long functional half-lives because of their high hydroxyapatite (HAP) binding affinities. This places a practical limit on the reversibility and effectiveness of a drug holiday. BPs with low HAP affinity and strong osteoclast inhibition potentially offer an alternative approach; their antiresorptive effect should reverse rapidly when dosing is discontinued. This study tested this concept using NE-58025, a BP with low HAP affinity and moderate osteoclast inhibition potential. Young adult female C57Bl/6 mice were ovariectomized (OVX) and treated with NE-58025, risedronate, or PBS vehicle for 3 months to test effectiveness in preventing long-term bone loss. Bone microarchitecture, histomorphometry, and whole-bone mechanical properties were assessed. To test reversibility, OVX mice were similarly treated for 3 months, treatment was stopped, and bone was assessed up to 3 months post-treatment. NE-58025 and RIS inhibited long-term OVX-induced bone loss, but NE-58025 antiresorptive effects were more pronounced. Withdrawing NE-58025 treatment led to the rapid onset of trabecular resorption with a 200% increase in osteoclast surface and bone loss within 1 month. Cessation of risedronate treatment did not lead to increases in resorption indices or bone loss. These results show that NE-58025 prevents OVX-induced bone loss, and its effects reverse quickly following cessation treatment in vivo. Low-HAP affinity BPs may have use as reversible, antiresorptive agents with a rapid on/off profile, which may be useful for maintaining bone health with long-term BP treatment. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Niveles de cuidados en pacientes ingresados en hospitales de media y larga estancia / Levels of care in medium and long-stay hospital patients

Objetivo: determinar los niveles de cuidados en pacientes ingresados en hospitales de media y larga estancia de la Comunidad de Madrid. Material y método: estudio descriptivo longitudinal en los hospitales de media estancia de la Comunidad de Madrid (La Fue fría y Guadarrama), sobre el total de pacientes ingresados del año 2000 al 2010 (n= 23.595). La herramienta utilizada para la clasificación de los enfermos fue la parrilla de Montesinos. Se clasificaron las necesidades de cuidados en nueve de las once acciones cuidadoras propuestas por SIGNO II, adjudicándoseles un valor del1 al 4 (1: menor nivel de dependencia), lo que se traducía en necesidad de tiempo de enfermera o de auxiliar de Enfermería. El índice de complejidad de cuidados resultaba de la media aritmética de las puntuaciones registradas para cada una de las nueve acciones cuidadoras. Resultados: no se han mostrado cambios relevantes a lo largo de los años estudiados en lo que respecta a los niveles de dependencia, aunque se ha podido observar un incremento de pacientes dependientes y muy dependientes desde el año 2005. Sin embargo, el peso en otros aspectos estudiados tiene como consecuencia que no se produzca un cambio de nivel. Conclusiones: la herramienta utilizada para la clasificación de enfermos resulta insuficiente para medir las necesidades de cuidados, ya que no recoge muchos aspectos que son relevantes para el cuidado en el momento actual. Se propone la aplicación de una nueva herramienta que mida la atención directa y que incluya intervenciones sistemáticas, seguridad, trabajo en equipo, función administrativa y docente, y cuidados de trazabilidad (AU)

Objective: to determine the levels of care in patients admitted in medium and long-stay hospitals in the Comunidad de Madrid. Materials and method: Longitudinal descriptive study in medium-stay hospitals in the Comunidad de Madrid (La Fuenfría and Guadarrama), over the total number of patients hospitalized from 2000 to 2010 (n= 23.595). The tool used for patient classification was the Parrilla de Montesinos method. Care needs were classified into nine of the eleven care actions put forward by SIGNO II, and they were assigned a value from 1 to 4 (1 = lower level of dependence), which translated into the need for nurse or nursing assistant time. The rate of care complexity resulted from the arithmetical median of those registered scores for each one of the nine care actions. Results: no relevant changes regarding dependence levels have been shown throughout the years studied, though an increase in the number of dependent and very dependent patients has been observed since 2005. However, the weight in other aspects studied has no change of level as a consequence. Conclusions: the tool used for patient classification is insufficient to measure the needs for care, because it does not collect many aspects which are currently relevant for care. It is recommended to apply a new tool which measures direct care and includes systematic interventions, safety, team work, administrative and teaching functions, and traceability care (AU)