期刊
JBMR PLUS
卷 5, 期 4, 页码 -出版社
WILEY
DOI: 10.1002/jbm4.10476
关键词
ANALYSIS/QUANTITATION OF BONE; ANTIRESORPTIVES; BONE HISTOMORPHOMETRY; BONE MICRO-COMPUTED TOMOGRAPHY (mu CT); BONE MODELING AND REMODELING; BONE QUANTITATIVE (QCT); DISEASES AND DISORDERS OF/RELATED TO BONE; OSTEOPOROSIS; THERAPEUTICS
资金
- National Institute of Arthritis and Musculoskeletal and Skin Diseases [AR041210, AR070547]
- National Institutes of Aging [AG056397]
- Wallace Coulter Foundation
- City College of New York
- Seymour & Pearl Moskowitz Foundation
Bisphosphonates are effective in treating osteoporosis but long-term use may have negative effects on bone health. BPs with low hydroxyapatite binding affinity may offer a reversible, antiresorptive alternative, which can quickly reverse their effects upon cessation of treatment, potentially maintaining bone health with long-term use.
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. (C) 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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