Background-In the Denosumab and Teriparatide Administration (DATA) study, we showed that denosumab fully inhibits teriparatide-induced bone resorption while allowing for continued teriparatide-induced bone formation, resulting in larger increases in hip and spine bone mineral density (BMD) than with either drug alone. We aimed to assess whether administration of denosumab with high dose teriparatide would stimulate larger increases in bone mass than those observed in the DATA study. Methods-DATA-HD was an open-label, randomised, controlled phase 4 trial done at Massachusetts General Hospital. Eligible women were postmenopausal women (at least 36 months since last menses or since hysterectomy with a follicle-stimulating hormone concentration of ≥40 U/L) with osteoporosis. Participants were randomly assigned (1:1) to receive teriparatide 20 μg

Combined teriparatide and denosumab rapidly and substantially increases bone mineral density (BMD) at all anatomic sites. Discontinuation of denosumab however, results in high‐turnover bone loss and increased fracture risk. The optimal way to prevent this bone loss remains undefined. This study is a preplanned extension of the DATA‐HD study, where postmenopausal women with osteoporosis were randomized to receive 9 months of either 20 μg or 40 μg of teriparatide daily overlapping with denosumab (60 mg administered at months 3 and 9). At the completion of this 15‐month study, women were invited to enroll in the DATA‐HD Extension where they received a single dose of zoledronic acid (5 mg) 24 to 35 weeks after the last denosumab dose. Areal BMD and bone turnover markers were measured at month 27 and 42 (12 and 27 months after zoledronic acid, respectively) and spine and hip volumetric bone density by quantitative CT was measured at month 42. Fifty‐three women enrolled in the DATA‐HD Extension. At the femoral neck and total hip, the mean 5.6% and 5.1% gains in BMD achieved from month 0 to 15 were maintained both 12 and 27 months after zoledronic acid administration. At the spine, the mean 13.6% gain in BMD achieved from month 0 to 15 was maintained for the first 12 months but modestly decreased thereafter, resulting in a 3.0% reduction (95% CI, −4.0% to −2.0%, p < .0001) 27 months after zoledronic acid. The pattern of BMD changes between months 15 and 42 were qualitatively similar in the 20‐μg and 40‐μg groups. A single dose of zoledronic acid effectively maintains the large and rapid total hip and femoral neck BMD increases achieved with combination teriparatide/denosumab therapy for at least 27 months following the transition. Spine BMD was also largely, though not fully, maintained during this period. These data suggest that the DATA‐HD Extension regimen may be an effective strategy in the long‐term management of patients at high risk of fragility fracture. © 2021 American Society for Bone and Mineral Research (ASBMR).

In postmenopausal women at high risk of fracture, we previously reported that combined denosumab and high‐dose (HD; 40 μg) teriparatide increased spine and hip bone mineral density (BMD) more than combination with standard‐dose teriparatide (SD; 20 μg). To assess the effects of these combinations on bone microarchitecture and estimated bone strength, we performed high‐resolution peripheral quantitative computed tomography (HR‐pQCT) at the distal radius and distal tibia in these women, who were randomized to receive either teriparatide 20 μg (n = 39) or 40 μg (n = 37) during months 0 to 9 overlapped with denosumab 60 mg s.c. given at months 3 and 9, for a 15‐month study duration. The 69 women who completed at least one study visit after baseline are included in this analysis. Over 15 months, increases in total BMD were higher in the HD‐group than the SD‐group at the distal tibia (5.3% versus 3.4%, p = 0.01) with a similar trend at the distal radius (2.6% versus 1.0%, p = 0.06). At 15 months, cortical porosity remained similar to baseline, with absolute differences of −0.1% and −0.7% at the distal tibia and −0.4% and −0.1% at the distal radius in the HD‐group and SD‐group, respectively; p = NS for all comparisons. Tibial cortical tissue mineral density increased similarly in both treatment groups (1.3% [p < 0.0001 versus baseline] and 1.5% [p < 0.0001 versus baseline] in the HD‐group and SD‐group, respectively; p = 0.75 for overall group difference). Improvements in trabecular microarchitecture at the distal tibia and estimated strength by micro‐finite element analysis at both sites were numerically greater in the HD‐group compared with SD‐group but not significantly so. Together, these findings suggest that short‐term treatment combining denosumab with either high‐ or standard‐dose teriparatide improves HR‐pQCT measures of bone density, microstructure, and estimated strength, with greater gains in total bone density observed in the HD‐group, which may be of benefit in postmenopausal women with severe osteoporosis. © 2020 American Society for Bone and Mineral Research (ASBMR).