ECTS2013 Poster Presentations Osteoporosis: treatment (64 abstracts)
Bone histology and histomorphometry: effects of 5 years of denosumab in the FREEDOM Extension
Jacques P Brown 1 , Rachel Wagman 2 , David W Dempster 3, , David Kendler 5 , Paul Miller 6 , Michael Bolognese 7 , Ivo Valter 8 , Jens-Erik Beck Jensen 9 , Cristiano Zerbini 10 , Jose R Zanchetta 11 , Nadia Daizadeh 2 & Ian Reid 12
1Laval University and CHUQ, Quebec City, QC, Canada; 2Amgen Inc., Thousand Oaks, CA, USA; 3Columbia University, New York, NY, USA; 4Helen Hayes Hospital, West Haverstraw, NY, USA; 5University of British Columbia, Vancouver, BC, Canada; 6Colorado Center for Bone Research, Lakewood, CO, USA; 7Bethesda Health Research Center, Bethesda, MD, USA; 8Center for Clinical and Basic Research, Tallinn, Estonia; 9Hvidovre Hospital, Hvidovre, Denmark; 10Hospital Heliopolis, Sao Paulo, Brazil; 11Instituto de Investigaciones Metabólicas, Buenos Aires, Argentina; 12University of Auckland, Grafton, New Zealand.
DMAb increases BMD and reduces bone resorption and risk of vertebral, nonvertebral and hip fractures in women with PMO. Transiliac crest bone biopsies in 47 subjects treated with DMAb for 1–3 years showed reduced bone turnover vs 45 Pbo-treated subjects, which reversed on treatment cessation. Since bone turnover reduction is sustained and fracture incidence low over 6 years’ DMAb treatment, we evaluated DMAb’s effects on tissue-level remodelling in the FREEDOM Extension. Demographics for the 13 cross-over (CO) and 28 long-term (LT) subjects in the bone biopsy substudy to 5 years were comparable with those of the overall Extension population. Mean (SD) time from last DMAb dose to first tetracycline dose was 5.7 (0.5) months. Qualitative bone histology in all samples showed normally mineralized lamellar bone. Of five LT subjects without visualizable osteoid, four had intact samples showing normal mineralization. Structural indices were similar between CO and LT groups. Median (Q1, Q3) eroded surface/bone surface (i.e., resorption) was decreased in both CO (0.15% (0, 0.44%)) and LT subjects (0.1% (0, 0.25%)) vs FREEDOM Pbo-treated subjects (1.04% (0.55%, 1.88%)). Ten CO and 14 LT subjects had specimens with double-tetracycline label in trabecular and/or cortical compartments. Median (Q1, Q3) dynamic remodelling indices were low in five CO and ten LT subjects: mineral apposition rate 0.59 (0.51, 0.65) and 0.40 (0.30, 1.05) μm/d; bone formation rate 1.20 (0.66, 1.26) and 2.18 (0.20, 4.67)%/year; activation frequency 0.02 (0.01, 0.02) and 0.03 (0, 0.07)/year; mineralizing surface 0.28 (0.22, 0.37)% and 0.66 (0.28, 1.07)%. DMAb treatment over 5 years results in normal bone quality with reduced bone turnover, consistent with its mechanism of action.
Bone histomorphometry in FREEDOM and its study extension (Table 1)
| FREEDOM | Extension (24 months) | |||
| Median | Pbo (n=45) | DMAb (n=47) | CO (n=13) | LT (n=25) |
| Bone volume/tissue volume | 12.50% | 13.52% | 13.94% | 14.24% |
| Osteoid surface | 6.81% | 0.38% | 0.45% | 0.14% |
| Osteoid width (μm) | 8.70 | 5.44 | 5.6 | 3.29 |
| Osteoid volume | 0.83% | 0.05% | 0.03% | 0.01% |
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