Bezafibrate attenuates immobilization-induced muscle atrophy in mice

Abstract Muscle atrophy due to fragility fractures or frailty worsens not only activity of daily living and healthy life expectancy, but decreases life expectancy. Although several therapeutic agents for muscle atrophy have been investigated, none is yet in clinical use. Here we report that bezafibrate, a drug used to treat hyperlipidemia, can reduce immobilization-induced muscle atrophy in mice. Specifically, we used a drug repositioning approach to screen 144 drugs already utilized clinically for their ability to inhibit serum starvation-induced elevation of Atrogin-1, a factor related to muscle atrophy, in myotubes in vitro. Two candidates were selected, and here we demonstrate that one of them, bezafibrate, significantly reduced muscle atrophy in an in vivo model of muscle atrophy induced by leg immobilization. In gastrocnemius muscle, immobilization reduced muscle weight by an average of ~ 17.2%, and bezafibrate treatment prevented ~ 40.5% of that atrophy. In vitro, bezafibrate significantly inhibited expression of the inflammatory cytokine Tnfa in lipopolysaccharide-stimulated RAW264.7 cells, a murine macrophage line. Finally, we show that expression of Tnfa and IL-1b is induced in gastrocnemius muscle in the leg immobilization model, an activity significantly antagonized by bezafibrate administration in vivo. We conclude that bezafibrate could serve as a therapeutic agent for immobilization-induced muscle atrophy

Cost analysis of leuprorelin acetate in Japanese prostate cancer patients: comparison between 6-month and 3-month depot formulations

<p><b>Aims:</b> This study aimed to evaluate the economic value for leuprorelin acetate 6-month depot compared with leuprorelin acetate 3-month depot from a societal perspective in Japanese prostate cancer patients.</p> <p><b>Methods:</b> The cost analysis estimated the reduction in direct and indirect costs as well as intangible costs saved by having one less injection. Claims data were used for the analyses of direct and indirect costs reduction. A discrete choice experiment based on a web-based survey estimated the monetary value of the intangible costs for one injection. Another web-based survey of prostate cancer patients, who had received treatment with leuprorelin acetate injections, was carried out to calibrate the results of the discrete choice experiment.</p> <p><b>Results:</b> Reductions in medical costs and loss of productivity for having one less injection in prostate cancer patients receiving leuprorelin acetate were JPY 5,670 and JPY 1,723, respectively. Intangible costs saved by using a 6-month depot formulation instead of a 3-month depot formulation for the injection of leuprorelin acetate were estimated to be JPY 19,872, including the values for a reduction in pain (JPY 3,131), injection site reactions (JPY 11,545), waiting time (JPY 9,479), and subtracting the value of medical consultation (JPY 4,283). The total cost reduction for having one less injection was JPY 27,265.</p> <p><b>Limitations:</b> The respondents from the internet panel provided by a survey company are not necessarily a representative population of Japanese society.</p> <p><b>Conclusions:</b> Leuprorelin acetate 6-month depot has an advantage in monetary value in the reduction in medical costs, loss of productivity, and intangible costs for having one less injection in prostate cancer patients compared with leuprorelin acetate 3-month depot. In the costs for treating with leuprorelin acetate, the percentage of intangible costs might not be negligible. The intangible costs will probably be actively evaluated to proceed to patient-centered healthcare in society.</p

Pronounced femur malunion after pathological bone fracture due to a simple bone cyst in the shaft of the femur, treated using Ilizarov fixation: a case report

Abstract Background Although a simple bone cyst carries the risk of pathological fractures, it rarely causes severe deformity. Here we report a case of severe femoral deformity after multiple pathological fractures due to simple bone cysts, and consider the reason for the progression of malunion despite multiple previous treatments. Finally, we propose a treatment option for malunion correction. Case presentation A 9-year, 7-month-old Japanese girl was referred to our facility with obvious deformity of her right femur, caused by multiple simple bone cyst-related pathological fractures. The deformity included bowing of approximately 90° and an internal rotation of 60° in the middle third of the femoral shaft. To correct this deformity, we excised the lesion, thus shortening the femur, then corrected the alignment and applied an Ilizarov fixator to extend the bone. At present, 3 years after surgery, the deformity has not recurred and our patient is living without any limitations in daily activities or regular exercise. Conclusions When a long bone is in a prolonged state of deformation, the deformity not only progresses as the bone grows, but the soft tissues remain unbalanced and treatment becomes increasingly difficult. To prevent increasing bone deformity and fragility, the deformity should be corrected as quickly as possible using intramedullary nailing or other fixation techniques. We believe that our shortening-distraction method is effective for the treatment of severe deformity with unbalanced soft tissues

Hao1 Is Not a Pathogenic Factor for Ectopic Ossifications but Functions to Regulate the TCA Cycle In Vivo

Ossification of the posterior longitudinal ligament (OPLL), a disease characterized by the ectopic ossification of a spinal ligament, promotes neurological disorders associated with spinal canal stenosis. While blocking ectopic ossification is mandatory to prevent OPLL development and progression, the mechanisms underlying the condition remain unknown. Here we show that expression of hydroxyacid oxidase 1 (Hao1), a gene identified in a previous genome-wide association study (GWAS) as an OPLL-associated candidate gene, specifically and significantly decreased in fibroblasts during osteoblast differentiation. We then newly established Hao1-deficient mice by generating Hao1-flox mice and crossing them with CAG-Cre mice to yield global Hao1-knockout (CAG-Cre/Hao1flox/flox; Hao1 KO) animals. Hao1 KO mice were born normally and exhibited no obvious phenotypes, including growth retardation. Moreover, Hao1 KO mice did not exhibit ectopic ossification or calcification. However, urinary levels of some metabolites of the tricarboxylic acid (TCA) cycle were significantly lower in Hao1 KO compared to control mice based on comprehensive metabolomic analysis. Our data indicate that Hao1 loss does not promote ectopic ossification, but rather that Hao1 functions to regulate the TCA cycle in vivo