title: Influence of early zoledronic acid administration on bone marrow fat in ovariectomized rats.
abstract: Although the primary target cell of bisphosphonates is the osteoclast, increasing attention is being given to other effector cells influenced by bisphosphonates, such as osteoblasts and marrow adipocytes. Early zoledronic acid (ZA) treatment to ovariectomized (OVX) rats has been found to fully preserve bone microarchitecture over time. However, little is known regarding the influence of ZA on marrow adipogenesis. The purpose of this study was to monitor the ability of early administration of ZA in restoring marrow adiposity in an estrogen-deficient rat model. Thirty female Sprague-Dawley rats were randomly divided into sham-operated (SHAM), OVX + vehicle, and OVX + ZA groups (n=10/group). Dual-energy x-ray absorptiometry and water/fat magnetic resonance imaging were performed at baseline, 6 weeks, and 12 weeks after treatment to assess bone mineral density and marrow fat fraction. Serum biochemical markers, bone remodeling, and marrow adipocyte parameters were analyzed using biochemistry, histomorphometry, and histopathology, respectively. The expression levels of osteoblast, adipocyte, and osteoclast-related genes in bone marrow were assessed using RT-PCR. The OVX rats showed marked bone loss, first detected at 12 weeks, but estrogen deficiency resulted in a remarked increase in marrow fat fraction, first detected at 6 weeks compared with the SHAM rats (all P < .001). Similarly, the OVX rats had a substantially larger percent adipocyte area (+163.0%), mean diameter (+29.5%), and higher density (+57.3%) relative to the SHAM rats. Bone histomorphometry, levels of osteoclast-related gene expression, and a serum resorption marker confirmed that ZA significantly suppressed bone resorption activities. Furthermore, ZA treatment returned adipocyte-related gene expression and marrow adipocyte parameters toward SHAM levels. These data suggest that a single dose of early ZA treatment acts to reverse marrow adipogenesis occurring during estrogen deficiency, which may contribute to its capacity to reduce bone loss.
authors.affiliation: Departments of Radiology (G.-W.L., S.-X.C., L.Z., X.-Y.W.), Pharmacy (H.N.), and Gerontology (X.S.), Yueyang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China; and Medico-Technical Department (Z.X.), Xin-Zhuang Community Health Service Center, Shanghai 201199, China.
authors.forename: Guan-Wu
authors.initials: GW
authors.lastname: Li
authors.forename: Zheng
authors.initials: Z
authors.lastname: Xu
authors.forename: Shi-Xin
authors.initials: SX
authors.lastname: Chang
authors.forename: Lei
authors.initials: L
authors.lastname: Zhou
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Wang
authors.forename: Hua
authors.initials: H
authors.lastname: Nian
authors.forename: Xiao
authors.initials: X
authors.lastname: Shi
mesh_terms: D017667:Adipocytes / Q000187:drug effects; D050156:Adipogenesis / Q000187:drug effects*; D050154:Adiposity / Q000187:drug effects*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D001853:Bone Marrow / Q000187:drug effects*; D016723:Bone Remodeling / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology*; D005260:Female; D007093:Imidazoles / Q000494:pharmacology*; D008137:Longitudinal Studies; D010052:Ovariectomy; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D014599:Uterus / Q000187:drug effects; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid