To explore how preceding treatment with a bisphosphonate (BP) and/or OPG-Fc, a RANKL inhibitor, affects early bone formation (BF) response to sclerostin antibody (Scl-Ab) in vertebral cancellous and cortical bone, we treated ovariectomized rats with various sequences of vehicle (Veh), OPG-Fc, and alendronate (Aln) or zoledronic acid (ZOL) in cycle 1 (0-12 wk) or cycle 2 (12-18 wk) before administering Scl-Ab in cycle 3 (18-24 wk). Treatment sequences included Veh/Veh/Scl-Ab (treatment naïve), OPG-Fc/OPG-Fc/Scl-Ab, OPG-Fc/ZOL/Scl-Ab, Aln/OPG-Fc/Scl-Ab, and OPG-Fc/OPG-Fc_Veh/Scl-Ab (4-wk treatment-free period preceding Scl-Ab). DXA scans and serum bone turnover markers were assessed. Cancellous and endocortical histomorphometric endpoints were quantified at weeks 18, 20, and 24. With Veh/Veh/Scl-Ab, anticipated bone responses to Scl-Ab were observed. From week 18 to week 24, Scl-Ab-mediated bone mass accrual was blunted with preceding antiresorptive sequences. In groups where OPG-Fc immediately preceded Scl-Ab, BF suppression was marked at week 20 with limited modeling-based bone formation (MBBF). In contrast, when ZOL was interposed between OPG-Fc and Scl-Ab, MBBF was modestly reduced at week 20. By week 24, BF surfaces were generally similar in all groups; the contribution of MBBF and remodeling-based bone formation (RBBF) differed. In contrast to other antiresorptive sequences, in OPG-Fc/OPG-Fc_Veh/Scl-Ab, RBBF was also a significant contributor to bone forming surfaces, reflecting a rebound in resorption and remodeling. With the other antiresorptive sequences, MBBF was the major contributor to BF, consistent with prolonged suppression of remodeling at week 24. All prior antiresorptive sequences blunted Scl-Ab effects on early BF. BP exposure (before or after OPG-Fc) improved cumulative effects across all cycles on bone mass compared with OPG-Fc alone. Interposing ZOL between OPG-Fc and Scl-Ab improved the early BF response to Scl-Ab.
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