Analysis of bone morphology – including the micro-architecture of
trabecular bone, and the Haversian and lacuno-canalicular ultrastructure of
cortical bone – is critical in understanding bone mechanics, assessing fracture
risk, and evaluating responses to disease, age, joint degeneration such as in
osteoarthritis. Improved predictions of biomechanical properties have been found
as a result of including measures of trabecular micro-architecture in
statistical regressions (1,
2). Trabecular micro-architecture is
also critical in the evaluation of therapeutic interventions, enabling
researchers to explain a greater proportion of the effect of drugs on fracture
risk than BMD alone (3,
4). Similarly, the
ultrastructure of cortical bone is an important determinant of bone strength (5, 6), is
critical in fracture initiation and propagation (7),
and known to change with aging (8),
disease (9),
and therapy (10). In
the context of joint degeneration and osteoarthritis, the interaction between
the bone-cartilage complex is an important determinant of disease progression,
and may provide unique targets for therapeutic interventions. Therefore the development of
technology that delivers quantitative assessment of these bone quality factors
represents an important goal to advance the understanding of skeletal health. Quantitative
imaging techniques to evaluate the three-dimensional micro-architecture of
trabecular and cortical bone have been developed using two primary modalities: X-ray
computed tomography (CT), high resolution peripheral computed tomography
(HRpQCT), and magnetic resonance imaging (MRI).
There is a growing body of literature featuring HR-pQCT assessment of
bone quality. The first cross-sectional studies by Boutroy et al. and Khosla et al.
reported gender specific, age-related differences in trabecular bone
micro-architecture (11, 12). Several centers have observed
age-related differences in µFE estimates of bone strength in normative
cross-sectional cohorts (13-15). Furthermore, Burghardt et al. (14) and Macdonald et al. (15) have demonstrated the ability of
HR-pQCT to detect dramatic age-related differences in cortical porosity in
females using new techniques for the analysis of cortical ultrastructure (16). Boutroy et al. showed that µFEA mechanical measures provided additional
discriminatory power between osteopenic women with and without distal radius
fractures (17). Data from the first HR-pQCT
single- and multi-center longitudinal trials have been published (18-21).
Magnetic resonance imaging is an attractive modality for acquiring
high-resolution images of cortical and trabecular bone in vivo. MRI is a non-invasive imaging technique that does not
require the use of ionizing radiation and is therefore well suited for
assessing in vivo images in a
clinical setting. The technological development over the
past few years have made quantitative MRI of bone clinically practical (22-33). A
substantial improvement in fracture discrimination by including structural
information in addition to BMD has been well established (23, 24, 26). The effect
of salmon calcitonin on bone structure was investigated at the distal radius
and calcaneous of 91 postmenopausal women during a period of 2 years (34). The
treatment group showed improved trabecular structure compared to the placebo
group but no significant change in BMD was detected. Topological changes of the
trabecular bone network after menopause and the protective effect of estradiol
were recently reported (35). The effect of testosterone replacement on trabecular architecture
in hypogonadal men was investigated in the distal tibial metahpysis of 10
severely testosterone-deficient hypogonadal men (32). Dramatic topological changes in the bone were found suggesting
that antiresorptive treatment results in improved structural integrity. No
significant changes in estimated elastic moduli and morphological parameters
were detected in the eugonadal group over 24 months but a significant increase
in four estimated elastic moduli was found in hypogonadal men.
Although OA
has been considered a disease primary characterized by cartilage degeneration,
the accompanying bone changes are critical in the pathogenesis of OA. The
pathologic bone changes in OA include joint space narrowing, osteophytes,
increased turnover in subchondral bone, thinning of the trabecular structure,
bone marrow lesions, subchondral bone sclerosis, and bony cysts. The changes in
bone remodeling, trabecular microstructure, mechanical properties, and bone
mineral density in OA will be discussed.
Numerous cross-sectional studies indicated that OA is associated with
increased BMD(36-40).
In a study of 1,154 cohort subjects, mean femoral BMD of proximal femur
was 5-9% higher in patients with either Kellgren and Lawrence (KL) grade 1,
grade 2, or grade 3 knee OA, compared with those with no knee OA (36). Similarly a study of 979 women
showed a small but significant increase in BMD in middle-aged women with OA
defined on the basis of osteophytes of the hand, knee and lumbar spine(37).
The findings of a study by Nevitt et al.(38) showed the same positive
relationship between OA and increased BMD in hip OA. Several studies have not only evaluated the
relationship between BMD and the incidence of OA but have also assessed the
relationship between BMD and the progression of OA (41-44).
Changes in trabecular bone architecture of osteoarthritic joints are
evident in OA(45-47).
Increased trabecular thickness and decreased trabecular spacing is
common in OA bone. One study found
increased trabecular thickness in the principal compressive stress regions of
the femoral head from human femoral specimens with OA(45).
Ding et al.(46) examined OA bone from human tibial
specimens using micro-computed tomography and found that OA trabecular bone was
thicker and more “plate-like” than normal, healthy bone. They hypothesized that
the increase in trabecular thickness and density but decrease in connectivity
in OA trabecular bone suggest a mechanism of altered bone remodeling in early
OA. This altered bone remodeling leads
to a change of trabeculae from rod-like to plate-like which is opposite to that
of normal aging. Similarly results were
found by Fazzalari et al. who used trabecular bone samples from severe
osteoarthritic specimens taken following total hip replacement surgery(47). They also found an increase in
trabecular number and reduced trabecular spacing in OA. Lindsey et al.(48) examined patients with OA of the
knee using MRI. They found that as
cartilage was lost on the medial side of the joint, there was an increase in
bone on the medial side of the joint, and a loss of bone on the lateral side of
the joint. These results demonstrated
the response of bone to OA varies depending on location. The authors suggest that bone responses may
be due to joint malalignment. OA can be
affected by varus or valgus alignment, which distributes the forces during
stance toward the medial and lateral sides of the joint, respectively. In the case of varus alignment, the cartilage
and bone on the medial side of the joint experience more mechanical
stress. Therefore, as the cartilage
degenerates on the medial side of the joint, the bone may respond to the
increased loading, by getting stronger.
There may be an unloading effect on the lateral side of the joint, and
the bone may respond by getting weaker.
Another longitudinal study(49) found that cartilage degeneration
was related to trabecular bone loss closer to the joint line, and trabecular
bone gain farther from the joint line.
The authors hypothesize that cartilage loss is related to subchondral
plate sclerosis (greater absorption of local stresses and decreased load
transmission). Thus, osteopenia occurs
in the subarticular bone, and there is reactive bone formation farther from the
joint line, compensating for the localized bone loss. Therefore, in OA, the trabecular structure
has a varied response on the medial/lateral and proximal/distal areas of the
joint, demonstrating the importance of location when examining trabecular bone
structure in OA.
Subchondral bone changes are present prior
and during development of OA and increased bone blood flow and bone remodeling
as demonstrated by [18F]-NaF positron emission tomography
(PET)-computed tomography (CT) (50) may be
associated with patellofemoral pain and later stage morphological changes in
cartilage. Bone-cartilage interactions in the whole knee-joint in OA patients
using simultaneous PET-MR imaging may be used to understand the pathophysiology
of the disease. With simultaneous detection of early cartilage biochemical
degeneration using quantitative MR and bone remodeling in adjoining and
non-adjoining regions, we can elucidate the natural history of the disease and
assess therapeutic targets in the treatment of OA. (51, 52).
References
1. C.
L. Gordon, T. F. Lang, P. Augat, H. K. Genant, Image-based assessment of spinal
trabecular bone structure from high-resolution CT images. Osteoporos Int 8, 317
(1998).
2. T.
M. Link et al., Structure analysis of
high resolution magnetic resonance imaging of the proximal femur: in vitro
correlation with biomechanical strength and BMD. Calcif Tissue Int 72,
156 (Feb, 2003).
3. C.
H. Chesnut, 3rd, C. J. Rosen, Reconsidering the effects of antiresorptive
therapies in reducing osteoporotic fracture. J Bone Miner Res 16,
2163 (Dec, 2001).
4. B.
L. Riggs, L. J. Melton, 3rd, Bone turnover matters: the raloxifene treatment
paradox of dramatic decreases in vertebral fractures without commensurate
increases in bone density. J Bone Miner
Res 17, 11 (Jan, 2002).
5. P.
Schneider et al., Ultrastructural
properties in cortical bone vary greatly in two inbred strains of mice as
assessed by synchrotron light based micro- and nano-CT. J Bone Miner Res 22,
1557 (Oct, 2007).
6. V.
Sansalone et al., Determination of
the heterogeneous anisotropic elastic properties of human femoral bone: from
nanoscopic to organ scale. J Biomech 43, 1857 (Jul 20, 2010).
7. R.
Voide et al., Time-lapsed assessment
of microcrack initiation and propagation in murine cortical bone at submicrometer
resolution. Bone 45, 164 (Aug, 2009).
8. D.
M. Cooper et al., Age-dependent
change in the 3D structure of cortical porosity at the human femoral midshaft. Bone 40, 957 (Apr, 2007).
9. K.
L. Bell, N. Loveridge, J. Power, N. Rushton, J. Reeve, Intracapsular hip
fracture: increased cortical remodeling in the thinned and porous anterior
region of the femoral neck. Osteoporos
Int 10, 248 (1999).
10. B. Borah et al.,
Risedronate reduces intracortical porosity in women with osteoporosis. J Bone Miner Res 25, 41 (Jan, 2010).
11. S. Boutroy, M. L. Bouxsein, F. Munoz, P. D. Delmas, In vivo
assessment of trabecular bone microarchitecture by high-resolution peripheral
quantitative computed tomography. J Clin
Endocrinol Metab 90, 6508 (Dec,
2005).
12. S. Khosla et al.,
Effects of sex and age on bone microstructure at the ultradistal radius: a
population-based noninvasive in vivo assessment. J Bone Miner Res 21, 124
(Jan, 2006).
13. N. Dalzell et al.,
Bone micro-architecture and determinants of strength in the radius and tibia:
age-related changes in a population-based study of normal adults measured with
high-resolution pQCT. Osteoporos Int 20, 1683 (Oct, 2009).
14. A. J. Burghardt, G. J. Kazakia, S. Ramachandran, T. M. Link,
S. Majumdar, Age- and gender-related differences in the geometric properties
and biomechanical significance of intracortical porosity in the distal radius
and tibia. J Bone Miner Res 25, 983 (May, 2010).
15. H. M. Macdonald, K. K. Nishiyama, J. Kang, D. A. Hanley, S. K.
Boyd, Age-related patterns of trabecular and cortical bone loss differ between
sexes and skeletal sites: A population-based HR-pQCT study. J Bone Miner Res, (Jun 30, 2010).
16. A. J. Burghardt, H. R. Buie, A. Laib, S. Majumdar, S. K. Boyd,
Reproducibility of direct quantitative measures of cortical bone
microarchitecture of the distal radius and tibia by HR-pQCT. Bone,
(May 31, 2010).
17. S. Boutroy et al.,
Finite element analysis based on in vivo HR-pQCT images of the distal radius is
associated with wrist fracture in postmenopausal women. J Bone Miner Res 23, 392
(Mar, 2008).
18. E. Seeman et al.,
Microarchitectural deterioration of cortical and trabecular bone: Differing
effects of denosumab and alendronate. J
Bone Miner Res 25, 1886 (Aug,
2010).
19. A. J. Burghardt et al.,
A longitudinal HR-pQCT study of alendronate treatment in post-menopausal women
with low bone density: Relations between density, cortical and trabecular
micro-architecture, biomechanics, and bone turnover. J Bone Miner Res, (Jun 18,
2010).
20. R. Rizzoli et al.,
Strontium ranelate and alendronate have differing effects on distal tibia bone
microstructure in women with osteoporosis. Rheumatol
Int 30, 1341 (Aug, 2010).
21. H. M. Macdonald, K. K. Nishiyama, D. A. Hanley, S. K. Boyd,
Changes in trabecular and cortical bone microarchitecture at peripheral sites
associated with 18 months of teriparatide therapy in postmenopausal women with
osteoporosis. Osteoporos Int, (May 11, 2010).
22. T. M. Link et al.,
In vivo high resolution MRI of the calcaneus: differences in trabecular
structure in osteoporosis patients. J
Bone Miner Res 13, 1175 (Jul,
1998).
23. F. W. Wehrli et al.,
Cancellous bone volume and structure in the forearm: noninvasive assessment
with MR microimaging and image processing. Radiology
206, 347 (Feb, 1998).
24. S. Majumdar et al.,
Trabecular bone architecture in the distal radius using magnetic resonance
imaging in subjects with fractures of the proximal femur. Magnetic Resonance
Science Center and Osteoporosis and Arthritis Research Group. Osteoporos Int 10, 231 (1999).
25. T. M. Link et al.,
Changes in calcaneal trabecular bone structure after heart transplantation: an
MR imaging study. Radiology 217, 855 (Dec, 2000).
26. F. W. Wehrli et al.,
Digital topological analysis of in vivo magnetic resonance microimages of
trabecular bone reveals structural implications of osteoporosis. J Bone Miner Res 16, 1520 (Aug, 2001).
27. F. W. Wehrli et al.,
Role of magnetic resonance for assessing structure and function of trabecular
bone. Top Magn Reson Imaging 13, 335 (Oct, 2002).
28. T. M. Link et al.,
Changes in calcaneal trabecular bone structure assessed with high-resolution MR
imaging in patients with kidney transplantation. Osteoporos Int 13, 119
(2002).
29. M. Benito et al.,
Deterioration of trabecular architecture in hypogonadal men. J Clin Endocrinol Metab 88, 1497 (Apr, 2003).
30. L. Pothuaud, D. C. Newitt, Y. Lu, B. MacDonald, S. Majumdar,
In vivo application of 3D-line skeleton graph analysis (LSGA) technique with
high-resolution magnetic resonance imaging of trabecular bone structure. Osteoporos Int 15, 411 (May, 2004).
31. F. W. Wehrli, M. B. Leonard, P. K. Saha, B. R. Gomberg,
Quantitative high-resolution magnetic resonance imaging reveals structural
implications of renal osteodystrophy on trabecular and cortical bone. J Magn Reson Imaging 20, 83 (Jul, 2004).
32. M. Benito et al.,
Effect of testosterone replacement on trabecular architecture in hypogonadal
men. J Bone Miner Res 20, 1785 (Oct, 2005).
33. A. Techawiboonwong, H. K. Song, M. B. Leonard, F. W. Wehrli,
Cortical bone water: in vivo quantification with ultrashort echo-time MR
imaging. Radiology 248, 824 (Sep, 2008).
34. C. H. Chesnut, 3rd et
al., Effects of salmon calcitonin on trabecular microarchitecture as
determined by magnetic resonance imaging: results from the QUEST study. J Bone Miner Res 20, 1548 (Sep, 2005).
35. F. W. Wehrli et al.,
In vivo magnetic resonance detects rapid remodeling changes in the topology of
the trabecular bone network after menopause and the protective effect of
estradiol. J Bone Miner Res 23, 730 (May, 2008).
36. M. T. Hannan, J. J. Anderson, Y. Zhang, D. Levy, D. T. Felson,
Bone mineral density and knee osteoarthritis in elderly men and women. The
Framingham Study. Arthritis Rheum 36, 1671 (Dec, 1993).
37. D. J. Hart, I. Mootoosamy, D. V. Doyle, T. D. Spector, The
relationship between osteoarthritis and osteoporosis in the general population:
the Chingford Study. Ann Rheum Dis 53, 158 (Mar, 1994).
38. M. C. Nevitt et al.,
Radiographic osteoarthritis of the hip and bone mineral density. The Study of
Osteoporotic Fractures Research Group. Arthritis
Rheum 38, 907 (Jul, 1995).
39. H. Burger et al.,
Association of radiographically evident osteoarthritis with higher bone mineral
density and increased bone loss with age. The Rotterdam Study. Arthritis Rheum 39, 81 (Jan, 1996).
40. M. Sowers et al.,
The associations of bone mineral density and bone turnover markers with
osteoarthritis of the hand and knee in pre- and perimenopausal women. Arthritis Rheum 42, 483 (Mar, 1999).
41. A. P. Bergink et al.,
Bone mineral density and vertebral fracture history are associated with
incident and progressive radiographic knee osteoarthritis in elderly men and
women: the Rotterdam Study. Bone 37, 446 (Oct, 2005).
42. Y. Zhang et al.,
Bone mineral density and risk of incident and progressive radiographic knee
osteoarthritis in women: the Framingham Study. J Rheumatol 27, 1032
(Apr, 2000).
43. D. J. Hart et al.,
The relationship of bone density and fracture to incident and progressive
radiographic osteoarthritis of the knee: the Chingford Study. Arthritis Rheum 46, 92 (Jan, 2002).
44. M. C. Hochberg, M. Lethbridge-Cejku, J. D. Tobin, Bone mineral
density and osteoarthritis: data from the Baltimore Longitudinal Study of
Aging. Osteoarthritis Cartilage 12 Suppl A, S45 (2004).
45. N. L. Fazzalari, J. Darracott, B. Vernon-Roberts,
Histomorphometric changes in the trabecular structure of a selected stress
region in the femur in patients with osteoarthritis and fracture of the femoral
neck. Bone 6, 125 (1985).
46. M. Ding, A. Odgaard, I. Hvid, Changes in the three-dimensional
microstructure of human tibial cancellous bone in early osteoarthritis. J Bone Joint Surg Br 85, 906 (Aug, 2003).
47. N. L. Fazzalari, I. H. Parkinson, Fractal properties of
subchondral cancellous bone in severe osteoarthritis of the hip. J Bone Miner Res 12, 632 (Apr, 1997).
48. C. T. Lindsey et al.,
Magnetic resonance evaluation of the interrelationship between articular
cartilage and trabecular bone of the osteoarthritic knee. Osteoarthritis Cartilage 12,
86 (Feb, 2004).
49. G. Blumenkrantz et al.,
A pilot, two-year longitudinal study of the interrelationship between
trabecular bone and articular cartilage in the osteoarthritic knee. Osteoarthritis Cartilage 12, 997 (Dec, 2004).
50. C. E. Draper et al.,
Comparison of MRI and (1)(8)F-NaF PET/CT in patients with patellofemoral pain. J Magn Reson Imaging 36, 928 (Oct, 2012).
51. M. A. Karsdal et al.,
Should subchondral bone turnover be targeted when treating osteoarthritis? Osteoarthritis Cartilage 16, 638 (Jun, 2008).
52. M. A. Karsdal, B. C. Sondergaard, M. Arnold, C. Christiansen,
Calcitonin affects both bone and cartilage: a dual action treatment for
osteoarthritis? Annals of the New York
Academy of Sciences 1117, 181
(Nov, 2007).