Original Full Length ArticleHigh resolution quantitative computed tomography-based assessment of trabecular microstructure and strength estimates by finite-element analysis of the spine, but not DXA, reflects vertebral fracture status in men with glucocorticoid-induced osteoporosis
Highlights
► In glucocorticoid-treated men we measured DXA-based areal BMD, QCT-based volumetric BMD, HRQCT-based BMD and microstructure and FEA-based strength. ► Both QCT- and HRQCT- but not DXA-based measures permit discrimination of GC treated men with and without vertebral fracture. ► Severity of vertebral fractures in glucocorticoid treated men was independently associated with vertebral cortical thickness and trabecular microarchitecture. ► HRQCT is a valuable clinical research tool and provides additional information on trabecular and cortical structure and high quality FEA. ► More studies are required to investigate clinical applications benefiting from the higher image quality of HRQCT compared to QCT.
Introduction
The current gold-standard for the diagnosis of osteoporosis, dual x-ray absorptiometry (DXA), measures areal projected bone mineral density (aBMD). Besides including projection artifacts, DXA does not allow assessment of the spatial distribution of BMD within the bone or aspects of bone quality, such as trabecular microstructure. Although the WHO definition of osteoporosis based on DXA correlates well with fracture risk in women with postmenopausal osteoporosis [1], the majority of fractures occur in women who are not classified as osteoporotic by this criterion [2]. Absolute fracture risk models that capture a number of independent risk factors, such as prevalent fractures or age, show that DXA has limitations in assessing bone strength and the corresponding fracture risk [3], [4].
Bone loss and fragility fractures are relatively common complications associated with glucocorticoid (GC) therapy and, indeed, this treatment is the most common cause of medication-induced osteoporosis. It has been estimated that 30–50% of patients who take GCs chronically have a fracture. The effect appears to be dose-dependent and more severe in the spine [5]. GC-induced osteoporosis (GIO) is pathophysiologically different from other forms of osteoporosis. It occurs in two phases: a rapid, early phase in which BMD declines, possibly as a result of excessive bone resorption, and a slower, more progressive phase in which BMD is further reduced because of impaired bone formation [6]. Histomorphometric studies have shown that GCs decrease bone formation indices, decrease the number of osteoid seams, lower mineral apposition rate, and reduce trabecular thickness [7], [8] but cortical bone and trabecular network are relatively well preserved [9]. GCs also induce apoptosis of osteoblasts and osteocytes that have a role as mechanosensors in the repair of bone microdamage [10].
Although substantial progress has been made in understanding the pathogenesis of GIO a direct relationship between BMD and fracture risk in GIO has not been established. The reasons for the altered relationship between BMD and risk of fracture are complex as the rapid decline in BMD is accompanied by other factors that influence bone strength, including the underlying disease and the multiple cellular events that lead to structural changes in bone, such as major reductions in trabecular connectivity and increases in trabecular perforations [11], [12]. Thus, fractures in GIO occur at higher BMDs than those associated with postmenopausal osteoporosis [13], and more sensitive diagnostic methods than DXA are desirable. These could include assessing additional aspects of bone strength, which can be achieved by imaging bone in 3-D, and analyzing trabecular microstructure either with computed tomography (CT) or magnetic resonance techniques. Also 3-D QCT-based BMD showed superior performance to DXA [11].
High-resolution quantitative CT (HRQCT), using modern clinical whole-body CT scanners, offers sufficient resolution to achieve these goals. It allows measurement of volumetric BMD for both trabecular (Tb.BMD) and cortical bone (Ct.BMD) and calculation of mechanical strength using finite-element analysis (FEA) [14]. The ability of HRQCT to reflect trabecular microstructure has been demonstrated in an ex vivo validation study [15] and its clinical feasibility in longitudinal [16] and cross-sectional [17] studies of women with postmenopausal osteoporosis.
The aim of this study was to assess associations between vertebral fracture status or severity and aBMD measured by DXA, volumetric BMD measured by QCT or HRQCT, HRQCT-based trabecular bone microstructural analyses, as well as vertebral body strength by HRQCT-based nonlinear FEA in males with GIO.
Section snippets
Study design and participants
We analyzed the baseline characteristics of the patients included in EuroGIOPS, a clinical trial of male patients with GIO (ClinicalTrials.gov Identifier: NCT00503399) conducted in 15 clinical sites in Germany, Greece, Italy, and Spain.
Men were aged 25 years and above, were ambulatory, had normal laboratory values for serum calcium, alkaline phosphatase, 25-hydroxyvitamin D and parathyroid hormone (PTH). They had a lumbar spine (L1–L4), femoral neck, or total hip BMD T-score equal to or less
Results
Of the 92 patients included in the EuroGIOPS trial, 88 patients had both a valid QCT scan and vertebral fracture assessments. Prior to analysis, a further 15 patients were excluded from the HRQCT results due to CT protocol violations.
Demographic and baseline characteristics of the 73 patients included in the present analyses are shown in Table 1. Thirty-one patients with a total of 66 osteoporotic radiological prevalent vertebral fractures were identified. Prior osteoporosis therapy had been
Discussion
This study is the first to employ HRQCT-based microstructural and FEA analyses for the discrimination of vertebral bone status in males with GIO, and it is the first to extend HRQCT to cortical measurements. Earlier HRQCT studies were carried out in postmenopausal women, first by Ito et al. [17] and later by our group in women on teriparatide treatment [16].
Of note, in our study, the fracture status of the spine was reflected by differences in Tb.BMD measured by QCT at L1–L3, and also by
Funding sources
The EuroGIOPS study was funded by Eli Lilly & Company.
Disclosures/Conflict of interest
The EuroGIOPS study was funded by Lilly Research Center, Europe (ClinicalTrials.gov identifier: NCT00503399).
Claus-C. Glüer and Philippe Zysset have received honoraria and research support from Eli Lilly & Company. Fernando Marin and Helmut Petto are employees of Eli Lilly & Company and have received Lilly stock/stock options. All other authors have no conflicts of interest.
Acknowledgements
We thank the following individuals for technical assistance: Beatriz Sanz, Anja Gentzel (central study coordination), and Nadine L. McCann (central laboratory coordination); Eli Lilly & Company; and Laura Briones (data management), ICON Clinical Research. Funding was provided by Lilly Research Center, Europe. Cambridge Medical Writing Services, UK, provided editorial support in the preparation of this manuscript.
Authors’ roles: Study design: CG, FM, PZ and C-CG. Data collection: CG, AR, OK, PZ
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Cited by (0)
- 1
Claus -C. Glüer and Philippe Zysset have received honoraria and research support from Eli Lilly & Company. Fernando Marin and Helmut Petto are employees of Eli Lilly & Company and have received Lilly stock/stock options. All other authors have no conflicts of interest.
- 2
Current address: Institute for Surgical Technologies and Biomechanics, University of Bern, Bern, Switzerland.