ESA-SRB-AOTA 2019

Skeletal benefit/risk of long-term denosumab therapy: A virtual twin analysis of fractures prevented to skeletal safety events observed (#532)

Serge Ferrari 1 , E Michelle Lewiecki 2 , P W Butler 3 , David L Kendler 4 , Nicola Napoli 5 , S Huang 3 , Daria B Crittenden 3 , Nico Pannacciulli 3 , Ethel Siris 6 , Neil C Binkley 7 , Jeffrey Hassall 8
  1. Geneva University Hospital, Geneva, Switzerland
  2. New Mexico Clinical Research & Osteoporosis Center, Albuquerque, NM, USA
  3. Amgen Inc., Thousand Oaks, CA, USA
  4. University of British Columbia, Vancouver, BC, Canada
  5. Università Campus Bio-Medico di Roma, , Rome, Italy
  6. Columbia University Medical Center, New York, NY, USA
  7. University of Wisconsin-Madison, Madison, WI, USA
  8. Amgen Australia, North Ryde, NSW, Australia

Purpose: Osteoporosis is a chronic disease, but atypical femoral fracture (AFF) and osteonecrosis of the jaw (ONJ) remain a concern with long-term treatment. Ten years of denosumab (DMAb) therapy in postmenopausal women with osteoporosis has previously demonstrated sustained and low fracture rates, with low adverse event rates. Here, we generated a DMAb skeletal benefit/risk ratio derived from observed data and model-based estimates.

Methods: Exposure-adjusted subject incidence per 100,000 subject-years of clinical, major osteoporotic, vertebral, nonvertebral, and hip fractures was calculated for long-term (LT) subjects randomized to DMAb in the 3-year FREEDOM trial and enrolled in the 7-year Extension (follow-up time 3–10 years). Due to the lack of a long-term placebo group, fracture rates in a hypothetical cohort of placebo controls (virtual twins [VT]) were estimated using a regression model. The number of fractures prevented per 100,000 subject-years was calculated as (VT rate – LT rate). AFF and ONJ incidences on DMAb were based on observed cases in the LT group during the Extension; the VT group was assumed to have no AFF or ONJ in the absence of treatment. A skeletal benefit/risk ratio was calculated from fractures prevented per AFF or ONJ observed.

Results: This analysis included 2343 subjects. An estimated 1403 clinical fractures were prevented per 100,000 subject-years (Table). There was 1 case of AFF and 7 ONJ (mild and moderate), corresponding to rates of 5 (AFF) and 35 (ONJ) per 100,000 subject-years. Hence, there were 281 and 40 clinical fractures prevented per AFF and ONJ observed, respectively. The benefit/risk ratio for other fracture endpoints is shown below (Table).

Conclusions: As long-term placebo-controlled fracture outcome studies in postmenopausal OP are not ethical, the virtual twin model provides a reasonable estimate of untreated fracture rates. Using this model, long-term DMAb therapy has a highly favorable benefit/risk profile.

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