Abstract and Introduction
Abstract
Objective. The aim of this study was to report the effects of denosumab on radius cortical and trabecular bone density, mass, and strength, and wrist fracture incidence in the FREEDOM (Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months) study.
Methods. In the FREEDOM study, postmenopausal women with osteoporosis (N = 7,808) received placebo or 60 mg of denosumab every 6 months for 36 months. Radius bone mineral density (BMD), bone mineral content, and strength (polar moment of inertia) were evaluated in two prespecified substudies using dual-energy x-ray absorptiometry (placebo, n = 209; denosumab, n = 232) or quantitative CT (placebo, n = 48; denosumab, n = 62). Prespecified analysis assessed wrist fracture incidence in all FREEDOM participants (placebo, N = 3,906; denosumab, N = 3,902), and post hoc subgroup analyses evaluated those with higher fracture risk (baseline femoral neck T-score ≤−2.5; placebo, N = 1,406; denosumab, N = 1,384).
Results. Denosumab significantly increased areal BMD (assessed by dual-energy x-ray absorptiometry) and volumetric BMD, bone mineral content, and polar moment of inertia (assessed by quantitative CT), compared with placebo, in radius cortical and trabecular bone at all time points evaluated (all P < 0.05). Wrist fracture incidence was 2.9% for placebo and 2.5% for denosumab (relative risk reduction, 16%; P = 0.21) on month 36. Participants with a femoral neck T-score of −2.5 or lower were at increased risk for wrist fracture, and denosumab significantly reduced wrist fracture incidence compared with placebo (placebo, 4.0%; denosumab, 2.4%; relative risk reduction, 40%; absolute risk reduction, 1.6%; P = 0.03).
Conclusions. Denosumab significantly improves radius bone density, mass, and strength compared with placebo. In higher-risk women, denosumab significantly reduces wrist fracture risk.
Introduction
Nonvertebral fractures are the fractures most frequently associated with low bone mass and account for considerable morbidity and mortality. Among nonvertebral fractures in postmenopausal women with osteoporosis, the wrist is the most common site, accounting for around one third of all osteoporotic fractures.
Bone mineral density (BMD) is an important determinant of fracture risk. Regardless of age, wrist fractures are more common in individuals with a documented deficit in BMD at either the distal forearm or the femoral neck (FN). Therefore, FN BMD is a strong risk factor that can be used to identify individuals with reduced bone strength who are at increased risk for wrist and other fractures.
Bone strength is influenced by several factors, including bone density, bone microarchitecture, and the geometry of cortical and trabecular bone. For a better understanding of therapeutic impact on a particular skeletal site, it is important to assess both cortical and trabecular bone compartments.
Dual-energy x-ray absorptiometry (DXA) is widely used to diagnose osteoporosis, estimate fracture risk, and assess bone loss, as well as to evaluate response to therapy. Measurement of BMD is routine at the lumbar spine and hip but can also be easily measured at the radius. Forearm BMD evaluations are recommended by many guidelines, particularly in individuals with hyperparathyroidism or when lumbar spine and/or hip BMD cannot be measured because of artifacts, anatomic abnormalities, or excessive body weight. DXA provides a measure of areal BMD (aBMD) only and is therefore limited in its ability to assess bone geometry. Quantitative CT (QCT) can complement DXA by enabling the separation of cortical and trabecular bone and by measuring volumetric BMD (vBMD) three-dimensionally at different sites, including the distal radius, where there is gradation of cortical and trabecular bone from proximal to more distal locations, with the proximal and distal third sites comprising entirely cortical bone. In addition, QCT measurements can be used to evaluate functional bone strength by determining parameters such as the polar moment of inertia (PMI), which estimates the ability of an object to resist torsion and bending.
Denosumab (Prolia; Amgen Inc., Thousand Oaks, CA) is a fully human monoclonal antibody that inhibits RANKL, a key modulator of osteoclast formation, function, and survival. In postmenopausal women with osteoporosis, denosumab acts to rapidly reduce bone resorption, increase BMD, and reduce the risk of new vertebral, hip, and nonvertebral fractures over 36 months compared with placebo. In 12- and 24-month studies of postmenopausal women with low BMD, denosumab significantly increased BMD, bone mineral content (BMC), and PMI along the radius.
We report new analyses from two substudies of the larger phase 3 FREEDOM (Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months) study. We describe the effect of denosumab on bone parameters (using DXA and QCT scans of the radius) and on the wrist fracture reductions observed during the 36 months of the overall study.