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 13 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 DMAbs 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 width (μm)||8.70||5.44||5.6||3.29|
18 May 2013 - 22 May 2013