Recent studies on the mechanism of action (MOA) of bone-active drugs have rekindled interest in how to present and interpret dynamic histomorphometric parameters of bone remodeling. We compared the effects of an established anabolic agent, teriparatide (TPTD), with those of a prototypical antiresorptive agent, zoledronic acid (ZOL). This was a 12-month, randomized, double-blind, active-comparator controlled, cross-sectional biopsy study. The study was conducted at 12 U.S. and Canadian centers. Healthy postmenopausal women with osteoporosis participated in the study. Subjects received TPTD 20 μg once daily by sc injection (n = 34) or ZOL 5 mg by iv infusion at baseline (n = 35). The primary end point was mineralizing surface/bone surface (MS/BS), a dynamic measure of bone formation, at month 6. A standard panel of dynamic and static histomorphometric indices was also assessed. When specimens with missing labels were encountered, several methods were used to calculate mineral apposition rate (MAR). Serum markers of bone turnover were also measured. Among 58 subjects with evaluable biopsies (TPTD = 28; ZOL = 30), MS/BS was significantly higher in the TPTD group (median: 5.60 vs. 0.16%, P < 0.001). Other bone formation indices, including MAR, were also higher in the TPTD group (P < 0.05). TPTD significantly increased procollagen type 1 N-terminal propeptide (PINP) at months 1, 3, 6, and 12 and carboxyterminal cross-linking telopeptide of collagen type 1 (CTX) from months 3 to 12. ZOL significantly decreased PINP and CTX below baseline at all time points. TPTD and ZOL possess fundamentally different mechanisms of action with opposite effects on bone formation based on this analysis of both histomorphometric data and serum markers of bone formation and resorption. An important mechanistic difference was a substantially higher MS/BS in the TPTD group. Overall, these results define the dynamic histomorphometric characteristics of anabolic activity relative to antiresorptive activity after treatment with these two drugs.
