Elsevier

Bone

Volume 47, Issue 1, July 2010, Pages 131-139
Bone

Denosumab improves density and strength parameters as measured by QCT of the radius in postmenopausal women with low bone mineral density

https://doi.org/10.1016/j.bone.2010.04.594Get rights and content

Abstract

Background

Bone strength is determined by both cortical and trabecular bone compartments and can be evaluated radiologically through measurement of bone density and geometry. Quantitative computed tomography (QCT) separately assesses cortical and trabecular bone reliably at various sites, including the distal radius where there is a gradation of cortical and trabecular bone. We evaluated the effect of denosumab, a fully human monoclonal antibody that inhibits RANK ligand, on distal radius QCT in women with low bone mass to assess the impact of this novel therapy separately on trabecular and cortical bone.

Methods

Postmenopausal women (n = 332) with spine areal bone mineral density (BMD) T-scores between −1.0 and −2.5 received denosumab 60 mg or placebo every 6 months during the 24-month study. QCT measurements along the distal radius were made using a whole-body computed tomography scanner and were used to determine the percentage change from baseline in volumetric BMD; volumetric bone mineral content (BMC); cortical thickness; volume; circumference; and density-weighted polar moment of inertia (PMI), a derived index of bone strength.

Results

Denosumab treatment significantly increased total BMD and BMC along the radius (proximal, distal, and ultradistal sections). At 24 months, the ultradistal region had the greatest percentage increase in total BMD (4.7% [95% CI, 3.6–5.7]; P < 0.001) and total BMC (5.7% [95% CI, 4.8–6.6]; P < 0.001) over placebo. When cortical and trabecular bone at the proximal and distal regions were separately assessed, cortical bone had significant (P < 0.001) increases in BMD, BMC, and thickness, and trabecular bone had a significant increase in BMD relative to placebo (P < 0.05). Bone strength, estimated by density-weighted PMI, significantly increased compared with placebo after 6 months of treatment, with the largest percentage increase occurring at 24 months in the ultradistal region (6.6% [95% CI, 5.6–7.6]; P < 0.0001).

Conclusions

QCT measurements demonstrated that denosumab significantly increased BMD, BMC, and PMI along the radius over 24 months. Additionally, denosumab prevented the decrease in QCT-measured cortical thickness observed in the placebo group. These data extend the evidence from previous dual-energy X-ray absorptiometry studies for a positive effect of denosumab on both the cortical and trabecular bone compartments and propose a possible mechanism for the reduction in fracture risk achieved with denosumab therapy.

Introduction

Osteoporosis is a skeletal condition characterized by decreased bone strength that predisposes affected individuals to an increased risk for fracture [1], [2]. Nonvertebral fractures account for the majority of fractures associated with low bone mass and are a major cause of morbidity and mortality [3]. The wrist is the most common nonvertebral fracture site in postmenopausal women [4], [5], and wrist fractures represent a significant clinical and economic burden.

Bone strength is influenced by several factors, including density, microstructure, and geometry of cortical and trabecular bone [6], [7], [8]. Trabecular bone is more metabolically active than cortical bone, and skeletal locations with a high percentage of trabecular bone commonly fracture in osteoporosis. Consequently, trabecular bone has been a major focus in osteoporosis research. However, cortical bone has also been identified as a major contributor to bone strength [8], [9], [10], [11], and the relative influence of cortical and trabecular bone remains a subject of continuing investigation. For specific skeletal locations, such as the hip, cortical bone may be largely responsible for bone strength [9], and therapy-associated changes in femoral neck strength are influenced by cortical as well as trabecular changes [9].

Dual-energy X-ray absorptiometry (DXA) is currently the standard method for measuring bone density for the diagnosis and follow-up treatment of osteoporosis. However, owing to limitations in the technology, DXA is unable to reliably differentiate between cortical and trabecular bone and only provides a measure of areal bone mineral density (aBMD) using a 2-dimensional approach [6], [12]. Quantitative computed tomography (QCT), which is used less frequently than DXA, allows separation of cortical and trabecular bone and measures bone mineral density (BMD) 3-dimensionally (g/cm3) [12], [13]. QCT is increasingly used in basic and clinical research to assess BMD and bone geometry [14], [15], [16]. Primary scan locations are the spine, hip, and forearm. At the forearm, dedicated computed tomography (CT) scanners are typically used [17], [18], but we have recently demonstrated the advantages of using whole-body clinical CT scanners to evaluate the radius [7]. In addition, QCT measurements can be used to evaluate functional bone strength, measuring parameters such as the density-weighted polar moment of inertia (PMI), which relates to the ability of an object to resist torsion [7], [19], [20], [21], or can be used as a basis for finite element analysis [8], [22], [23].

Denosumab is a novel, fully human monoclonal antibody that inhibits RANK ligand (RANKL), a key modulator of osteoclast development and action. Administered subcutaneously every 6 months, it causes a rapid and significant reduction of bone turnover associated with a significant increase in DXA aBMD in postmenopausal women with low bone mass [24], [25], [26], [27], [28], [29] and a significant reduction in vertebral, nonvertebral, and hip fracture risk in women with postmenopausal osteoporosis [30]. Denosumab increases aBMD at all skeletal sites, including the radius, which is a non-weight-bearing long bone with both cortical- and trabecular-rich regions [25], [26], [27], [28], [29]. Because of the gradation of cortical and trabecular bone across and along the radius, there is an opportunity to evaluate the effect of therapy on both cortical and trabecular regions within the same bone [31]. Until now, changes in the cortical bone compartment in response to antiresorptive therapies have typically been modest or nonexistent [32], [33], [34]. Because the radius is a common site of osteoporotic fractures [5] and cortical bone is relevant to mechanical strength, it is important to understand the effects of RANKL inhibition on individual trabecular and cortical bone compartments.

We recently reported a method using standard, whole-body, spiral QCT to evaluate densitometric changes at the radius with good accuracy and precision [7]. In addition to assessing total, cortical, and trabecular BMD, this method allows the evaluation of important parameters that contribute to bone strength, such as bone mineral content (BMC), cortical thickness, circumference, and density-weighted PMI along the radius. Using this QCT method, we assessed the effect of denosumab on the cortical, trabecular, and total bone compartments at the radius in postmenopausal women with low BMD. We hypothesize that both trabecular and cortical compartments are positively affected and that the changes are relevant to bone strength.

Section snippets

Participants

The Denosumab Fortifies Bone Density (DEFEND) trial, a randomized, phase 3, double-blind, placebo-controlled study of denosumab conducted at 21 centers in the United States and Canada (ClinicalTrials.gov identifier: NCT00091793) [25], enrolled postmenopausal women with the following eligibility criteria: ambulatory with lumbar spine aBMD T-scores between −1.0 and −2.5, not currently receiving medication for or experiencing conditions that would affect bone metabolism, and without a fracture

Participants

This study enrolled 332 postmenopausal women who were randomized to receive placebo or denosumab 60 mg subcutaneously every 6 months for 24 months. The results of the primary efficacy endpoint, aBMD, and safety data have been previously reported [25]. Participant demographics were balanced between treatment groups. Most women were white (83% in both groups), with a mean age of 58.9 years in the placebo group and 59.8 years in the denosumab-treated group (Table 1). Baseline QCT measurements of the

Discussion

This study demonstrates that treatment with denosumab, administered as a 60-mg dose every 6 months for 24 months, resulted in significant increases in total, cortical, and trabecular BMD along the radius as assessed by QCT. Differences in bone circumference between the groups were not significant at the proximal and ultradistal locations and were rather small in the distal location. In addition, differences in total volume were significant only at the distal and ultradistal sites and were much

Acknowledgments

The authors thank Susan DeRocco, PhD, and Sue Myers, MSc, of Complete Healthcare Communications, Inc., for their assistance in providing editorial and formatting support, collating and coordinating authors' input, and figure preparations. Editorial support was funded by Amgen Inc.

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    Funding Statement: This study was funded by Amgen Inc., Thousand Oaks, CA, USA.

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