Relationship between bone mineral density changes with denosumab treatment and
risk reduction for vertebral and nonvertebral fractures.
Author(s): Austin M, Yang YC, Vittinghoff E, Adami S, Boonen S, Bauer DC, Bianchi G,
Bolognese MA, Christiansen C, Eastell R, Grauer A, Hawkins F, Kendler DL, Oliveri
B, McClung MR, Reid IR, Siris ES, Zanchetta J, Zerbini CA, Libanati C, Cummings
SR; FREEDOM Trial.
Affiliation(s): Amgen Inc., Thousand Oaks, CA 91320, USA. maustin@amgen.com
Publication date & source: 2012, J Bone Miner Res. , 27(3):687-93
Dual-energy X-ray absorptiometric bone mineral density (DXA BMD) is a strong
predictor of fracture risk in untreated patients. However, previous patient-level
studies suggest that BMD changes explain little of the fracture risk reduction
observed with osteoporosis treatment. We investigated the relevance of DXA BMD
changes as a predictor for fracture risk reduction using data from the FREEDOM
trial, which randomly assigned placebo or denosumab 60 mg every 6 months to 7808
women aged 60 to 90 years with a spine or total hip BMD T-score < -2.5 and not <
-4.0. We took a standard approach to estimate the percent of treatment effect
explained using percent changes in BMD at a single visit (months 12, 24, or 36).
We also applied a novel approach using estimated percent changes in BMD from
baseline at the time of fracture occurrence (time-dependent models). Denosumab
significantly increased total hip BMD by 3.2%, 4.4%, and 5.0% at 12, 24, and 36
months, respectively. Denosumab decreased the risk of new vertebral fractures by
68% (p < 0.0001) and nonvertebral fracture by 20% (p = 0.01) over 36 months.
Regardless of the method used, the change in total hip BMD explained a
considerable proportion of the effect of denosumab in reducing new or worsening
vertebral fracture risk (35% [95% confidence interval (CI): 20%-61%] and 51% [95%
CI: 39%-66%] accounted for by percent change at month 36 and change in
time-dependent BMD, respectively) and explained a considerable amount of the
reduction in nonvertebral fracture risk (87% [95% CI: 35% - >100%] and 72% [95%
CI: 24% - >100%], respectively). Previous patient-level studies may have
underestimated the strength of the relationship between BMD change and the effect
of treatment on fracture risk or this relationship may be unique to denosumab.
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