Five Years of Cenosumab Exposure in Women With Postmenopausal Osteoporosis: Results From the First Two Years of the FREEDOM Extension

The 3‐year FREEDOM trial assessed the efficacy and safety of 60 mg denosumab every 6 months for the treatment of postmenopausal women with osteoporosis. Participants who completed the FREEDOM trial were eligible to enter an extension to continue the evaluation of denosumab efficacy and safety for up to 10 years. For the extension results presented here, women from the FREEDOM denosumab group had 2 more years of denosumab treatment (long‐term group) and those from the FREEDOM placebo group had 2 years of denosumab exposure (cross‐over group). We report results for bone turnover markers (BTMs), bone mineral density (BMD), fracture rates, and safety. A total of 4550 women enrolled in the extension (2343 long‐term; 2207 cross‐over). Reductions in BTMs were maintained (long‐term group) or occurred rapidly (cross‐over group) following denosumab administration. In the long‐term group, lumbar spine and total hip BMD increased further, resulting in 5‐year gains of 13.7% and 7.0%, respectively. In the cross‐over group, BMD increased at the lumbar spine (7.7%) and total hip (4.0%) during the 2‐year denosumab treatment. Yearly fracture incidences for both groups were below rates observed in the FREEDOM placebo group and below rates projected for a “virtual untreated twin” cohort. Adverse events did not increase with long‐term denosumab administration. Two adverse events in the cross‐over group were adjudicated as consistent with osteonecrosis of the jaw. Five‐year denosumab treatment of women with postmenopausal osteoporosis maintained BTM reduction and increased BMD, and was associated with low fracture rates and a favorable risk/benefit profile. © 2012 American Society for Bone and Mineral Research

[1]  S. Cummings,et al.  Effects of denosumab on bone turnover markers in postmenopausal osteoporosis , 2011, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[2]  Nicholas T. Longford,et al.  Random Coefficient Models , 1994, International Encyclopedia of Statistical Science.

[3]  W. Ray,et al.  The ethics of placebo in studies with fracture end points in osteoporosis. , 2010, The New England journal of medicine.

[4]  S. Khosla,et al.  Placebo-controlled trials in osteoporosis--proceeding with caution. , 2010, The New England journal of medicine.

[5]  David M. Thomas,et al.  Safety of denosumab in giant-cell tumour of bone. , 2010, The Lancet. Oncology.

[6]  S. Cummings,et al.  Estimating long‐term effects of treatment from placebo‐controlled trials with an extension period, using virtual twins , 2010, Statistics in medicine.

[7]  Claus Christiansen,et al.  Denosumab for prevention of fractures in postmenopausal women with osteoporosis. , 2009, The New England journal of medicine.

[8]  P. Kostenuik.  Osteoprotegerin and RANKL regulate bone resorption, density, geometry and strength. , 2005, Current opinion in pharmacology.

[9]  J. Rodriguez-Portales,et al.  Ten years' experience with alendronate for osteoporosis in postmenopausal women. , 2004, The New England journal of medicine.

[10]  David L. Lacey,et al.  Osteoclast differentiation and activation , 2003, Nature.

[11]  M. Hochberg,et al.  Changes in bone density and turnover explain the reductions in incidence of nonvertebral fractures that occur during treatment with antiresorptive agents. , 2002, The Journal of clinical endocrinology and metabolism.

[12]  J. Samet,et al.  Food and Drug Administration , 2007, BMJ : British Medical Journal.

[13]  M. Kenward,et al.  Small sample inference for fixed effects from restricted maximum likelihood. , 1997, Biometrics.

[14]  M. Nevitt,et al.  Vertebral fracture assessment using a semiquantitative technique , 1993, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.