title: Sustained Modeling-Based Bone Formation During Adulthood in Cynomolgus Monkeys May Contribute to Continuous BMD Gains With Denosumab.
abstract: Denosumab (DMAb) administration to postmenopausal women with osteoporosis is associated with continued bone mineral density (BMD) increases and low fracture incidence through 8 years, despite persistently reduced bone turnover markers and limited fluorochrome labeling in iliac crest bone biopsies. BMD increases were hypothesized to result from additional accrual of bone matrix via modeling-based bone formation-a hypothesis that was tested by examining fluorochrome labeling patterns in sections from ovariectomized (OVX) cynomolgus monkeys (cynos) treated with DMAb for 16 months. Mature OVX or Sham cynos were treated monthly with vehicle for 16 months, whereas other OVX cynos received monthly 25 or 50 mg/kg DMAb. DMAb groups exhibited very low serum bone resorption and formation biomarkers and near-absent fluorochrome labeling in proximal femur cancellous bone. Despite these reductions, femoral neck dual-energy X-ray absorptiometry (DXA) BMD continued to rise in DMAb-treated cynos, from a 4.6% increase at month 6 to 9.8% above baseline at month 16. Further examination of cortical bone in the proximal femur demonstrated consistent and prominent labeling on the superior endocortex and the inferior periosteal surface, typically containing multiple superimposed labels from month 6 to 16 over smooth cement lines, consistent with continuous modeling-based bone formation. These findings were evident in all groups. Quantitative analysis at another modeling site, the ninth rib, demonstrated that DMAb did not alter the surface extent of modeling-based labels, or the cortical area bound by them, relative to OVX controls, while significantly reducing remodeling-based bone formation and eroded surface. This conservation of modeling-based formation occurred concomitantly with increased femoral neck strength and, when coupled with a reduction in remodeling-based bone loss, is likely to contribute to increases in bone mass with DMAb treatment. Thus, this study provides preclinical evidence for a potential mechanism that could contribute to the clinical observations of continued BMD increases and low fracture rates with long-term DMAb administration.
authors: Metabolic Disorders, Amgen Inc., Thousand Oaks, CA, USA.
authors: Michael S
authors: MS
authors: Ominsky
authors: Clinical Development, Amgen Inc., Thousand Oaks, CA, USA.
authors: Cesar
authors: C
authors: Libanati
authors: Metabolic Disorders, Amgen Inc., Thousand Oaks, CA, USA.
authors: Qing-Tian
authors: QT
authors: Niu
authors: Comparative Biology & Safety Sciences, Amgen Inc., Thousand Oaks, CA, USA.
authors: Rogely W
authors: RW
authors: Boyce
authors: Metabolic Disorders, Amgen Inc., Thousand Oaks, CA, USA.
authors: Paul J
authors: PJ
authors: Kostenuik
authors: Clinical Development, Amgen Inc., Thousand Oaks, CA, USA.
authors: Rachel B
authors: RB
authors: Wagman
authors: Harvard Medical School, Endocrine Unit, Massachusetts General Hospital, Boston, MA, USA.|Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, USA.
authors: Roland
authors: R
authors: Baron
authors: Clinical Pathology and Cell Biology, College of Physicians and Surgeons of Columbia University, New York, NY, USA.|Regional Bone Center, Helen Hayes Hospital, New York State Department of Health, West Haverstraw, NY, USA.
authors: David W
authors: DW
authors: Dempster
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D015519:Bone Density / Q000187:drug effects*; D016723:Bone Remodeling / Q000187:drug effects*; D000069448:Denosumab / Q000494:pharmacology*; D005260:Female; D005272:Femur Neck / Q000187:drug effects / Q000502:physiology; D005456:Fluorescent Dyes / Q000378:metabolism; D008252:Macaca fascicularis; D010012:Osteogenesis / Q000187:drug effects*; D010052:Ovariectomy; D013194:Staining and Labeling
chemical_list: D005456:Fluorescent Dyes; D000069448:Denosumab
keywords: ANTIRESORPTIVES; BONE HISTOMORPHOMETRY; BONE MODELING AND REMODELING; OSTEOPOROSIS; PRECLINICAL STUDIES