title: Increased numbers of nonattached osteoclasts after long-term zoledronic acid therapy in mice.
abstract: Osteoclasts are key players in the maintenance of bone, which is an endocrine target and organ. Bisphosphonates, used for the management of metastatic bone diseases and osteoporosis, suppress osteoclasts. However, the impact of continuously suppressed osteoclasts is unknown. In this study, mice received zoledronic acid (ZA) for 13 months, nearly half the lifespan of mice, and the effects of continual osteoclast suppression on the bone environment and oral wound healing were determined. ZA therapy suppressed osteoclasts, resulting in significantly more bone mass compared with control. Despite continuous and intense suppression of bone loss in mice receiving ZA, serum calcium levels were maintained in the normal range. No differences were noted in serum tartrate-resistant acid phosphatase (TRAP) 5b levels between ZA-treated and control mice. Histomorphometric analyses of bones revealed that ZA therapy significantly decreased osteoclasts on the bone surface but, instead, substantially increased TRAP(+) mononuclear cells and osteoclasts that were not on the bone surface. When oral trauma was induced, such TRAP(+) mononuclear and nonattached osteoclasts increased considerably with increased inflammatory cell infiltration in the wounds. As a result, oral wound healing was hindered at the connective tissue level. Healing of the epithelium was unaffected. These findings indicate that the continual suppression of osteoclasts does not affect serum calcium levels and that long-term ZA therapy stimulates nonattached osteoclast and TRAP(+) mononuclear cell formation that are expanded rapidly in response to oral trauma. Caution should be exercised when using the serum TRAcP5b to estimate the efficacy of antiresorptive therapy.
authors: Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, 1011 North University Avenue, Ann Arbor, Michigan 48109-1078, USA.
authors: Shinichiro
authors: S
authors: Kuroshima
authors: Virginia-Arlene A
authors: VA
authors: Go
authors: Junro
authors: J
authors: Yamashita
mesh_terms: D000135:Acid Phosphatase / Q000097:blood; D000818:Animals; D015519:Bone Density / Q000187:drug effects / Q000502:physiology; D050071:Bone Density Conservation Agents / Q000008:administration & dosage*; D002118:Calcium / Q000097:blood; D002448:Cell Adhesion / Q000187:drug effects; D004164:Diphosphonates / Q000008:administration & dosage*; D007093:Imidazoles / Q000008:administration & dosage*; D007527:Isoenzymes / Q000097:blood; D008297:Male; D008437:Maxilla / Q000187:drug effects / Q000293:injuries; D051379:Mice; D008810:Mice, Inbred C57BL; D009061:Mouth Mucosa / Q000098:blood supply / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D000071681:Tartrate-Resistant Acid Phosphatase; D013977:Tibia / Q000187:drug effects / Q000293:injuries; D013997:Time Factors; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology; D055114:X-Ray Microtomography; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D007527:Isoenzymes; D000077211:Zoledronic Acid; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase; D002118:Calcium