Paula A. Chmielewski

Three-dimensional microimaging (MRμI and μCT), finite element modeling, and rapid prototyping provide unique insights into bone architecture in osteoporosis

With the proportion of elderly people increasing in many countries, osteoporosis has become a growing public health problem, with rising medical, social, and economic consequences. It is well recognized that a combination of low bone mass and the deterioration of the trabecular architecture underlies osteoporotic fractures. A comprehensive understanding of the relationships between bone mass, the three‐dimensional (3D) architecture of bone and bone function is fundamental to the study of new and existing therapies for osteoporosis. Detailed analysis of 3D trabecular architecture, using high‐resolution digital imaging techniques such as magnetic resonance microimaging (MRμI), micro‐computed tomography (μCT), and direct image analysis, has become feasible only recently. Rapid prototyping technology is used to replicate the complex trabecular architecture on a macroscopic scale for visual or biomechanical analysis. Further, a complete set of 3D image data provides a basis for finite element modeling (FEM) to predict mechanical properties. The goal of this paper is to describe how we can integrate three‐dimensional microimaging and image analysis techniques for quantitation of trabecular bone architecture, FEM for virtual biomechanics, and rapid prototyping for enhanced visualization. The integration of these techniques provide us with an unique ability to investigate the role of bone architecture in osteoporotic fractures and to support the development of new therapies. Anat Rec (New Anat) 265:101–110, 2001.

Risedronate Preserves Trabecular Architecture and Increases Bone Strength in Vertebra of Ovariectomized Minipigs as Measured by Three‐Dimensional Microcomputed Tomography

Risedronate reduces the risk of new vertebral fractures up to 70% within 1 year of treatment in patients with osteoporosis. Both increases in bone mass and preservation of bone architecture are thought to contribute to antifracture effects. Our objectives were to determine the effects of risedronate on trabecular bone mass and architecture and to determine the relative contributions of mass and architecture to strength in the vertebra of ovariectomized (OVX) minipigs. The minipigs were OVX at 18 months of age and were treated daily for 18 months with either vehicle or risedronate at doses of 0.5 mg/kg per day or 2.5 mg/kg per day. The three‐dimensional (3D) bone architecture of the L4 vertebral cores of Sinclair S1 minipigs was evaluated by 3D microcomputed tomography (μCT). Compared with the OVX control, the vertebral bone volume (bone volume/tissue volume [BV/TV]) was higher in both treated groups (p < 0.05). The architectural changes were more significant at the 2.5‐mg/kg dose and were more prevalent at the cranial‐caudal ends compared with the midsection. At the higher dose, the trabecular thickness (Tb.Th), trabecular number (Tb.N), and connectivity were higher, and marrow star volume (Ma.St.V) and trabecular separation (Tb.Sp) were lower (p < 0.05). The trabecular separation variation index(TSVI), a new measure to approximate structural variations, was smaller in the 2.5‐mg/kg‐treated group (p < 0.05). In this group, a significant preservation of trabeculae orthogonal to the cranial‐caudal axis was confirmed by a decrease in the degree of anisotropy (DA) and an increase in the percent Cross‐strut (%Cross‐strut; p < 0.05). Both normalized maximum load (strength) and normalized stiffness of the same vertebral cores were higher in the 2.5‐mg/kg risedronate group compared with the OVX group (p < 0.05). BV/TV alone could explain 76% of the variability of the bone strength. The combination of bone volume and architectural variables explained >90% of the strength. The study showed that risedronate preserved trabecular architecture in the vertebra of OVX minipigs, and that bone strength is tightly coupled to bone mass and architecture.

Risedronate Preserves Bone Architecture in Early Postmenopausal Women In 1 Year as Measured by Three-Dimensional Microcomputed Tomography

Risedronate reduces the risk of vertebral fractures by up to 70% within the first year of treatment. Increases in bone mineral density or decreases in bone turnover markers explain only a portion of the anti-fracture effect, suggesting that other factors, such as changes in trabecular bone architecture, also play a role. Our objective was to determine the effects of risedronate on bone architecture by analyzing iliac crest bone biopsy specimens using three-dimensional microcomputed tomography (3-D µCT). Biopsy specimens were obtained at baseline and after 1 year of treatment from women enrolled in a double-blind, placebo-controlled study of risedronate 5 mg daily for the prevention of early postmenopausal bone loss. Trabecular architecture deteriorated in the placebo group (n = 12), as indicated by a 20.3% decrease in bone volume (25.1% vs. 20.0%, P = 0.034), a 13.5% decrease in trabecular number (1.649 vs. 1.426 mm−1, P = 0.052), a 13.1% increase in trabecular separation (605 vs. 684 µm, P = 0.056), and an 86.2% increase in marrow star volume (3.251 vs. 6.053 mm3, P = 0.040) compared with baseline values. These changes in architectural parameters occurred in the presence of a concomitant decrease from baseline in lumbar spine bone mineral density (−3.3%, P = 0.002), as measured by dual energy x-ray absorptiometry. There was no statistically significant (P < 0.05) deterioration in the risedronate-treated group (n = 14) over the 1-year treatment period. Comparing the actual changes between the two groups, the placebo group experienced decreases in bone volume (placebo, −5.1%; risedronate, +3.5%; P = 0.011), trabecular thickness (placebo, −20 µm; risedronate, +23 µm; P = 0.032), and trabecular number (placebo, −0.223 mm−1; risedronate, +0.099 mm−1; P = 0.010), and increases in percent plate (placebo, +2.79%; risedronate, −3.23%; P = 0.018), trabecular separation (placebo, +79 µm; risedronate, −46 µm; P = 0.010) and marrow star volume (placebo, +2.80 mm3 ; risedronate, −2.08mm3; P = 0.036), compared with the risedronate group. These data demonstrate that trabecular architecture deteriorated significantly in this cohort of early postmenopausal women, and that this deterioration was prevented by risedronate. Although there is no direct link in this study between fracture and preservation of architecture, it is reasonable to infer that the preservation of bone architecture may play a role in risedronate’s anti-fracture efficacy.

Architecture Is One of the Determinants of Bone Strength

In our recent publication in JBMR, we assessed the effects of risedronate on trabecular architecture and compressive strength of lumbar vertebrae from ovariectomized (OVX) minipigs. Regression analysis showed that trabecular bone volume (BV/TV) explained 76% of the variability of compressive strength. Adding architectural parameters to BV/TV in a three-parameter multiple linear regression model increased the R value to 91%. We concluded that risedronate improves the three-dimensional trabecular architecture in the vertebra of OVX minipigs in a way that contributes to an increase in bone strength. In their letter to the editor, Drs Kiebzak and Miller commented that our data lacked critical information, namely, ash weight or mineral content. Our decision not to include bone mineral content (BMC) or ash weight was based on data from a previous study on minipig vertebral cores in which there was a strong correlation between BV/TV and BMC (R 0.82). For completeness, however, we now report dual-energy X-ray absorptiometry (DXA) data that we collected from the minipig vertebral cores before microcomputed tomography measurements. After 18 months of treatment, risedronate significantly increased bone mineral density (BMD) compared with OVX controls (0.303 0.040 vs. 0.248 0.037 g/cm). Trabecular BV/TV (measured by microcomputed tomography) and BMD (measured by DXA) correlated strongly (R 0.96). In a simple linear regression model, BMD correlated strongly (R 0.80) with strength. Adding the architectural parameters TSVI and Tb.N to BMD in a three-parameter multiple linear regression model increased R to 0.91. The conclusion, therefore, is that although BV/TV and BMD correlate strongly with compressive strength, neither explains all the variance in bone strength. Although the contribution of trabecular architecture to bone strength, as indicated by change in R, was less than 15% in these minipigs, trabecular bone volume was high ( 25–33%). Architecture is likely to contribute more to bone strength and fracture risk in low bone mass conditions, and this is supported by data from several studies. Key architectural parameters have an exponential relationship with BV/TV. Furthermore, there were larger changes in architectural parameters when BV/TV was less than 11%, a value that has been suggested as threshold for spontaneous vertebral fracture. For trabecular bone in human biopsy specimens from different skeletal sites, BV/TV explained only 37–67% of the variance in elastic constants, especially at low bone volume. The prediction of the mechanical properties was significantly improved when architectural indices were included with bone volume. These data show that the relative contribution of architecture to strength increases as the bone mass decreases. It was not our intention to downplay the importance of BMD. Low BMD is clearly associated with a high risk of fragility fracture. However, there is now strong clinical evidence that an increase in BMD does not fully explain the fracture benefits of antiresorptive agents. It is appropriate, therefore, that we revisit the paradigm that BMD alone is an adequate surrogate for bone strength. We agree with Drs Kiebzak and Miller that the effectiveness of antiresorptive therapies for osteoporosis may be related to increase in BMD as well as to changes in one or several other factors that contribute to better bone quality. Our focus on the role of architecture does not preclude the importance of other components such as decreased bone turnover and osteocyte viability. Continued investigation into the effects of treatments on bone quality will improve our understanding of the pathophysiology and treatment of bone diseases.