Effects of drug discontinuation after short-term daily alendronate administration on osteoblasts and osteocytes in mice

In order to determine whether osteoclastic bone resorption is restarted after withdrawn of bisphosphonates, we conducted histological examinations on murine osteoclasts, osteoblasts and osteocytes after discontinuation of a daily regimen of alendronate (ALN) with a dosage of 1 mg/kg/day for 10 days. After drug discontinuation, metaphyseal trabecular number and bone volume remained unaltered for the first 4 days. Osteoclast number did not increase, while the number of apoptotic osteoclasts was elevated. On the other hand, tissue non-specific alkaline phosphatase-immunoreactive area was markedly reduced after ALN discontinuation. In addition, osteocytes showed an atrophic profile with empty lacunar areas during and after ALN treatment. Interestingly, as early as 36 h after a single ALN injection, osteocytes show signs of atrophy despite the presence of active osteoblasts. Structured illumination microscopy system showed shortening of osteocytic cytoplasmic processes after drug cessation, suggesting a possible morphological and functional disconnection between osteocytes and osteoblasts. Taken together, it appears that osteoclastic bone resorption is not resumed after ALN discontinuation; also, osteoblasts and osteocytes hardly seem to recover once they are inactivated and atrophied by ALN. In summary, it seems that one must pay more attention to the responses of osteoblasts and osteocytes, rather focusing on the resuming of osteoclastic bone resorption after the ALN discontinuation

都市近郊の里山地域における地域協働型デザイン教育モデルの実践的構築

　本研究は、都市近郊に活用されないまま偏在する緩衝緑地、圃場、里山をフィールドとして、環境デザイン、プロダクト・インテリアデザイン、ソーシャルアートの見地から、持続可能な地域協働型のデザイン教育モデルを構築することを目的としている。　具体的には、研究学園都市周辺地域の荒廃した保安林や緑地、共生ゾーン集落の里山、国営明石海峡公園神戸地区、キーナの森公園、神出里づくり地域などの活用されないまま残る緑地、里山、圃場地等において、自然生態、歴史、文化、環境、空間、素材などの調査活動および、立地環境や整備派生材を生かしたワークショップの企画・運営を実践し、地域協働型のデザイン教育モデルを試行した 。　令和3年度においては、調査対象地における、①地理的・歴史的・文化的側面からのランドスケープおよび建造物調査、②樹木や希少植物などの植生調査を中心に、既存資料などの集約を行い、対象地の利用価値について検討する基礎資料を作成した。実証実験では、地域の教育機関と連携した体験学習会を実施したほか、大学・大学院授業において里山をテーマとした制作を行った。また、調査や実験のプロセス、結果をリアルタイムに映像化・可視化し、SNS等によって情報公開を行った。　The purpose of this research is to construct a sustainable collaborative regional design education model from the perspectives of environmental design, product and interior design, and social art, using buffer green spaces, fields, and satoyama, which remain unutilized and unevenly distributed in the urban suburbs, as fields.　In 2021, the project focused on (1) landscape and building surveys from geographical, historical, and cultural perspectives, (2) vegetation surveys of trees and rare plants,　and compiled existing materials to create basic data for　considering the us e value of the target sites. In the　demonstration experiment, hands on learning sessions were　conducted in collaboration with local educational institutions,　and satoyama themed productions were conducted in university and graduate school classes. In addition, the process and results of the surveys and experiments were visualized in real time and made public through SNS and other means

Deficient of a Clock Gene, Brain and Muscle Arnt-Like Protein-1 (BMAL1), Induces Dyslipidemia and Ectopic Fat Formation

A link between circadian rhythm and metabolism has long been discussed. Circadian rhythm is controlled by positive and negative transcriptional and translational feedback loops composed of several clock genes. Among clock genes, the brain and muscle Arnt-like protein-1 (BMAL1) and circadian locomotor output cycles kaput (CLOCK) play important roles in the regulation of the positive rhythmic transcription. In addition to control of circadian rhythm, we have previously shown that BMAL1 regulates adipogenesis. In metabolic syndrome patients, the function of BMAL1 is dysregulated in visceral adipose tissue. In addition, analysis of SNPs has revealed that BMAL1 is associated with susceptibility to hypertension and type II diabetes. Furthermore, the significant roles of BMAL1 in pancreatic β cells proliferation and maturation were recently reported. These results suggest that BMAL1 regulates energy homeostasis. Therefore, in this study, we examined whether loss of BMAL1 function is capable of inducing metabolic syndrome. Deficient of the Bmal1 gene in mice resulted in elevation of the respiratory quotient value, indicating that BMAL1 is involved in the utilization of fat as an energy source. Indeed, lack of Bmal1 reduced the capacity of fat storage in adipose tissue, resulting in an increase in the levels of circulating fatty acids, including triglycerides, free fatty acids, and cholesterol. Elevation of the circulating fatty acids level induced the formation of ectopic fat in the liver and skeletal muscle in Bmal1 -/- mice. Interestingly, ectopic fat formation was not observed in tissue-specific (liver or skeletal muscle) Bmal1 -/- mice even under high fat diet feeding condition. Therefore, we were led to conclude that BMAL1 is a crucial factor in the regulation of energy homeostasis, and disorders of the functions of BMAL1 lead to the development of metabolic syndrome

Short-term efficacy and safety of zoledronate acid or denosumab in Japanese patients with postmenopausal osteoporosis

Introduction We aimed to compare the efficacy after switching from either bisphosphonates (BPs) or non-BPs (NBPs) to combination therapies of denosumab (DMAb) or zoledronic acid (Zol) with eldecalcitol (ELD) in bone mineral density (BMD) and bone metabolism and investigate the prognostic and risk factors of side effects of this therapy. Materials and methods One-hundred forty-eight patients with postmenopausal osteoporosis were recruited; their therapy was switched from BPs or NBPs to Zol or DMAb plus ELD (BP-Zol: 43, NBP-Zol: 32, BP-DMAb: 35, and NBP-DMAb: 38). Longitudinal changes in bone metabolic markers (P1NP and TRACP-5b) and BMD were evaluated. Results In the BP-Zol group, P1NP did not change after 6 months and increased by 38.9% after 12 months. TRACP-5b decreased 15.8% after 6 months, but came back to baseline values 12 months after administration. In the rest of the groups, the bone metabolic markers remained suppressed after 6 and 12 months. Compared with baseline, all groups showed increase in BMD after 6 and 12 months. Bone metabolic markers at baseline were correlated with %change in lumbar spine BMD from baseline to 12 months. P1NP and 25-hydroxy vitamin D levels at baseline were identified as potential predictors of development of acute-phase reactions. Conclusions The combination therapy of Zol or DMAb and ELD may increase BMD at 12 months after the first administration in Japanese patients with postmenopausal osteoporosis, regardless of BPs pretreatment. Bone metabolic markers at baseline may be useful predictors for reaction to the therapy and side effects caused by these combination therapies in postmenopausal osteoporosis

Vitamin K-dependent carboxylation of osteocalcin affects the efficacy of teriparatide (PTH1-34) for skeletal repair

Teriparatide (PTH1-34) promotes skeletal repair and increases bone mass. Vitamin K is involved in bone mineralization as a coenzyme of gamma-carboxylase for Gla proteins, and therefore vitamin K insufficiency caused by malnutrition or therapeutic intake of the vitamin K antagonist warfarin could affect the efficacy of PTH1-34 therapy for bone repair. In the present study, we investigated whether vitamin K influences the efficacy of PTH1-34 therapy for bone repair in a rat osteotomy model. Female 12-week-old Sprague-Dawley rats were subjected to a closed midshaft osteotomy of the femur and randomized into four groups (n = 10 per group): vehicle, PTH1-34 (daily 30 mu g/kg/day subcutaneous injection) + solvent (orally, three times a week), PTh1-34 + warfarin (0.4 mg/kg/day orally, three times a week), and PTH1-34 + vitamin K-2 (menatetrenone, 30 mg/kg/day orally, three times a week). Serum gamma-carboxylated and uncarboxylated osteocalcin (Gla-OC and Glu-OC) levels and radiographic healing were monitored every 2 weeks. Skeletal repair was assessed by micro-computed tomography, mechanical testing, and histology at 8 weeks after surgery. PTH1-34 amplified the osteotomy-induced increase in Gla-OC and improved the mechanical properties as well as the volumetric bone mineral tissue density of the fracture callus. Concurrent use of warfarin decreased the response to PTH1-34 therapy in terms of mechanical recovery, probably by impairing mineralization due to the lack of Gla-OC. Although the effects of combination therapy with PTH1-34 and vitamin K-2 on bone repair did not significantly exceed those of PTH1-34 monotherapy in rats fed sufficient dietary vitamin K, postoperative Gla-OC levels were correlated with the mechanical properties of the osteotomized femur in PTH1-34-treated rats regardless of the use of warfarin or vitamin K-2. These findings suggest the importance of vitamin K dependent gamma-carboxylation of DC for realizing the full effects of PTH1-34 on skeletal repair. (C) 2014 Elsevier Inc. All rights reserved

Effects after starting or switching from bisphosphonate to romosozumab or denosumab in Japanese postmenopausal patients

Purpose We aimed to investigate the longitudinal changes in bone metabolic markers and bone mineral density (BMD) after starting or switching from bisphosphonate (BP) to romosozumab (ROMO) or denosumab (DENO) therapies over 12 months and to determine predictors that establish associations with changes in BMD among the patients received the ROMO therapy. Methods Postmenopausal osteoporosis patients with a high risk of fracture-154 in total-were recruited; their therapies were switched to ROMO or DENO from BP/naive or vitamin D (ND) (ND-ROMO: 43, BP-ROMO: 38, ND-DENO: 38, and BP-DENO: 35). Longitudinal changes in bone metabolic markers and BMD were evaluated. Results ROMO groups showed significant increases in BMD of the lumbar spine at 6 and 12 months and femoral neck at 12 months compared to the DENO groups. Although BP-ROMO showed significant increase in the lumbar spine BMD compared to BP-DENO, there were no significant differences in femoral neck and total hip BMDs between BP-ROMO and BP-DENO. Among the ROMO groups, % changes of BMD from baseline to 12 months were associated with bone metabolic markers at baseline and changes in TRACP-5b from baseline to 3 months. Conclusions ROMO continuously increased BMD for 12 months and performed better than DENO. On the other hand, effects of ROMO switched from BP on BMD of femoral neck and total hip were almost same with DENO. Bone metabolic markers at baseline and changes in TRACP-5b from baseline to 3 months may predict the efficacy of ROMO after 12 months of administration