Abstract
Osteoporosis is a chronic disease and requires long-term treatment with pharmacologic therapy to ensure sustained antifracture benefit. Denosumab reduced the risk for new vertebral, nonvertebral, and hip fractures over 36 months in the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial. Whereas discontinuation of denosumab has been associated with transient increases in bone remodeling and declines in bone mineral density (BMD), the effect on fracture risk during treatment cessation is not as well characterized. To understand the fracture incidence between treatment groups after cessation of investigational product, we evaluated subjects in FREEDOM who discontinued treatment after receiving two to five doses of denosumab or placebo, and continued study participation for ≥7 months. The off-treatment observation period for each individual subject began 7 months after the last dose and lasted until the end of the study. This subgroup of 797 subjects (470 placebo, 327 denosumab), who were evaluable during the off-treatment period, showed similar baseline characteristics for age, prevalent fracture, and lumbar spine and total hip BMD T-scores. During treatment, more placebo-treated subjects as compared with denosumab-treated subjects sustained a fracture and had significant decreases in BMD. During the off-treatment period (median 0.8 years per subject), 42% versus 28% of placebo- and denosumab-treated subjects, respectively, initiated other therapy. Following discontinuation, similar percentages of subjects in both groups sustained a new fracture (9% placebo, 7% denosumab), resulting in a fracture rate per 100 subject-years of 13.5 for placebo and 9.7 for denosumab (hazard ratio [HR] 0.82; 95% confidence interval [CI], 0.49–1.38), adjusted for age and total hip BMD T-score at baseline. There was no apparent difference in fracture occurrence pattern between the groups during the off-treatment period. In summary, there does not appear to be an excess in fracture risk after treatment cessation with denosumab compared with placebo during the off-treatment period for up to 24 months. © 2013 American Society for Bone and Mineral Research.
Highlights
Sustained benefit of a therapeutic agent for a chronic condition generally requires continued treatment
The fractures were analyzed as recurrent events using the Andersen–Gill formulation of the Cox proportional hazards model adjusting for baseline age and total hip bone mineral density (BMD) T-score.[29]. The hazard ratio (HR) between the treatment groups during the off-treatment period and the 95% confidence intervals (CI) were calculated using the robust sandwich variance estimate
Placebo- and denosumab-treated subjects included in the off-treatment analysis showed similar baseline characteristics at FREEDOM study entry with respect to age, prevalent fracture, and lumbar spine and total hip BMD T-scores as subjects who had discontinued investigational product (IP) but did not meet criteria for this assessment of fracture risk (Table 1)
Summary
Sustained benefit of a therapeutic agent for a chronic condition generally requires continued treatment. Effects of therapeutic agents often are not sustained once treatment is discontinued, including in chronic diseases, such as hypertension and diabetes mellitus. Reversibility of treatment effect has been observed with some, but not all, pharmacologic interventions, as judged by bone mineral density (BMD) and biochemical markers of bone turnover, or bone. Gradual increases in BTMs and declines in BMD have been observed 12 months after discontinuation of risedronate[22] compared with gradual changes over a few years after discontinuation of alendronate or zoledronic acid.[23,24] Discontinuation may affect bone turnover in trabecular and cortical compartments and microarchitecture, which are important for bone strength and fracture risk. The 36-month data from the randomized, double-blind, placebo-controlled, phase 3 Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 months (FREEDOM) trial in women with postmenopausal osteoporosis demonstrated that denosumab treatment reduced the incidence of new vertebral fractures, nonvertebral fractures, and hip fractures when compared with placebo.[25]
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