Comparative bone histomorphometry effects of combined denosumab and teriparatide vs monotherapy in postmenopausal women with osteoporosis: a randomized controlled trial

Combined treatment with parathyroid hormone (PTH) receptor stimulation (teriparatide 20-μg) and RANKL inhibition (denosumab 60-mg) increases spine and hip bone mineral density (BMD) and improves estimates of bone strength to a greater extent than either monotherapy. The mechanisms underlying the enhanced efficacy of this combination, however, are not fully defined. In this randomized, three-arm interventional trial, postmenopausal women with osteoporosis were randomized to receive denosumab 60-mg (n=9), teriparatide 20-μg (n=13), or both (n=12) for 3 months. Participants received double fluorochrome labeling and underwent a single iliac crest bone biopsy at month 3. A total of 26 bone biopsies were suitable for histomorphometry. Fluorescence microscopy was utilized to differentiate remodeling-based from modeling-based bone formation in the cancellous and endocortical envelopes by identifying the morphology of underlying cement lines as either scalloped or smooth, respectively. Within-subject three-month changes from baseline were compared among the three treatment groups using one way ANOVA. At 3 months, teriparatide significantly increased histomorphometric indices of bone formation (BFR/BS, MS/BS, and dLS/BS) compared to denosumab or combination therapy, consistent with its greater effect on bone formation markers. Although both remodeling- and modeling-based bone formation increased in the combination group, denosumab attenuated the teriparatide-induced increases bone in formation, except for modeling-based bone formation in the endocortical envelope. These findings suggest that the greater increases in BMD observed with combined denosumab and teriparatide in the DATA study may result from the net effect of denosumab-mediated remodeling suppression which leads to a reduction in cortical porosity and enables secondary mineralization of the preserved bone volume and teriparatide-induced bone formation.