Osteoarthritis (OA) of the knee, a musculoskeletal disease characterized by degenerations in multiple joint tissues including the articular cartilage and subchondral bone, is a major clinical challenge worldwide that currently has no cure. Traumatic knee injuries such as anterior cruciate ligament (ACL) tear predispose subjects to early onset of post-traumatic OA (PTOA), necessitating the development of effective disease modifying therapies as total knee replacement surgeries have a limited lifetime. Significant knowledge gap remains in the pathogenesis of OA, while recent evidence suggests the important role of subchondral bone microstructure and mechanics in OA development. Subchondral bone is composed of the subchondral bone plate, a thin layer of cortical lamella, and the subchondral trabecular bone, composed of individual plate- like and rod-like trabeculae. These trabecular plates and rods determine the microstructure and mechanics of trabecular bone entirely and can be quantitatively analyzed using individual trabecula segmentation (ITS). Recent application of ITS showed that changes in the plate-and-rod microstructure of subchondral trabecular bone precede cartilage damage and are implicated to play a role in disease pathogenesis. Studies presented in this thesis aim to provide a deeper understanding of subchondral bone in knee OA scientifically and clinically, which may ultimately be used to improve diagnosis, prevention and treatment of this prevalent and disabling disease.
In the first study, we comprehensively quantified microstructural and tissue biomechanical properties of the subchondral bone and articular cartilage in human knee specimens with advanced OA and control knees without OA. We found reduced tissue modulus in trabecular plates and rods in regions with moderate OA, where cartilage is still intact, that persisted in severe OA regions, where cartilage is severely damaged. These observations suggest that tissue biomechanical changes in the subchondral trabecular bone may precede cartilage damage in OA development. Furthermore, we found strong correlations between structural and mechanical parameters of the cartilage and subchondral bone in CT knees, suggesting cross-talk at the tissue level. This coupling persisted in moderate OA regions but disappeared in severe OA regions, suggesting that loss of tissue crosstalk may be an additional indicator of disease progression.
In the second study, we quantified subchondral bone microstructural changes after ACL tear in vivo in human subjects using the second-generation high resolution peripheral quantitative computed tomography (HR-pQCT). We examined short-term longitudinal changes during the acute phase (~18 days to ~141 days) after injury, as well as long-term adaptations (~5 years post injury) in the injured knee relative to the contralateral knee in a cross-sectional cohort. We found subchondral bone loss within 1 month from injury that primarily targeted trabecular rods, especially at the distal femur. We also found increased spatial heterogeneity in subchondral trabecular microstructure within the injured knees compared to the contralateral knees in the long- term after injury. These findings indicate that ACL tear results in both short-term and long-term microstructural adaptations in the subchondral bone. ITS based on HR-pQCT knee scans may be a valuable tool to monitor disease progression in vivo.
Finally, we quantified subchondral bone microstructural changes after ACL-transection in a canine model of PTOA and investigated the effects of bisphosphonate and NSAID treatment on subchondral bone changes and OA progression. Studies were conducted in skeletally-mature and juvenile animals to investigate the effect of injury age. We found that subchondral boneadaptations after surgery and treatment effects depended on skeletal maturity of animals. In mature animals, changes in the microstructure of trabecular plates and rods occurred 1-month post-op and persisted until 8-months post-op. Bisphosphonate treatment attenuated these microstructural changes and cartilage degeneration while NSAID treatment did not. In juvenile animals that have not reached skeletal maturity, transient changes in trabecular plate and rod microstructure occurred at 3-months post-op but disappeared by 9-months post-op. Neither bisphosphonate nor NSAID treatment attenuated bone microstructural changes or cartilage damages. These findings suggest that age and skeletal maturity at time of injury may need to be considered as additional factors in studying PTOA progression and developing preventative treatments.
Taken together, these studies highlight the importance of microstructural and tissue biomechanical changes of subchondral bone in the development of OA. In vivo quantification of subchondral bone using advanced imaging modalities enable longitudinal monitoring of disease progression. Therapeutic agents targeting subchondral bone changes after traumatic injury may be effective preventative strategies for PTOA.
|1986||Mak AF. The apparent viscoelastic behavior of articular cartilage: the contributions from the intrinsic matrix viscoelasticity and interstitial fluid flows. J Biomech Eng. May 1986;108(2):123-130.|
|1997||Li B, Aspden RM. Composition and mechanical properties of cancellous bone from the femoral head of patients with osteoporosis or osteoarthritis. J Bone Miner Res. 1997;12(4):641-651.|
|2001||Day JS, Ding M, van der Linden JC, Hvid I, Sumner DR, Weinans H. A decreased subchondral trabecular bone tissue elastic modulus is associated with pre‐arthritic cartilage damage. J Orthop Res. September 2001;19(5):914-918.|
|1998||Johnson DL, Urban WP Jr, Caborn DNM, Vanarthos WJ, Carlson CS. Articular cartilage changes seen with magnetic resonance imaging-detected bone bruises associated with acute anterior cruciate ligament rupture. Am J Sports Med. May–June 1998;26(3):409-414.|
|2008||Boutroy S, Van Rietbergen B, Sornay-Rendu E, Munoz F, Bouxsein ML, Delmas PD. 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. March 2008;23(3):392-399.|
|1994||Ateshian GA, Lai WM, Zhu WB, Mow VC. An asymptotic solution for the contact of two biphasic cartilage layers. J Biomech. November 1994;27(11):1347-1360.|
|2000||Boyd SK, Matyas JR, Wohl GR, Kantzas A, Zernicke RF. Early regional adaptation of periarticular bone mineral density after anterior cruciate ligament injury. J Appl Physiol. December 2000;89(6):2359-2364.|
|2017||Kroker A, Zhu Y, Manske SL, Barber R, Mohtadi N, Boyd SK. Quantitative in vivo assessment of bone microarchitecture in the human knee using HR-pQCT. Bone. April 2017;97:43.|
|2006||Bonewald LF. Mechanosensation and transduction in osteocytes. Bonekey Osteovision. October 2006;3(10):7-15.|
|2003||Ferguson VL, Bushby AJ, Boyde A. Nanomechanical properties and mineral concentration in articular calcified cartilage and subchondral bone. J Anat. August 2003;203(2):191-202.|
|1965||Sneddon IN. The relation between load and penetration in the axisymmetric Boussinesq problem for a punch of arbitrary profile. Int J Eng Sci. May 1965;3(1):47-57.|
|1986||Farndale RW, Buttle DJ, Barrett AJ. Improved quantitation and discrimination of sulphated glycosaminoglycans by use of dimethylmethylene blue. Biochim Biophys Acta. September 4, 1986;883(2):173-177.|
|1986||Radin EL, Rose RM. Role of subchondral bone in the initiation and progression of cartilage damage. Clin Orthop Relat Res. December 1986;213:34-40.|
|1989||Mow VC, Gibbs MC, Lai WM, Zhu WB, Athanasiou KA. Biphasic indentation of articular cartilage, II: a numerical algorithm and an experimental study. J Biomech. 1989;22:853-861.|
|2016||Langdahl B, Ferrari S, Dempster DW. Bone modeling and remodeling: potential as therapeutic targets for the treatment of osteoporosis. Ther Adv Musculoskel Dis. December 2016;8(6):225-235.|
|1992||Oliver WC, Pharr GM. An improved technique for determining hardness and elastic modulus using load and displacement sensing indentation experiments. J Mater Res. 1992;7(6):1564-1583.|
|1980||Mow VC, Kuei SC, Lai WM, Armstrong CG. Biphasic creep and stress relaxation of articular cartilage in compression: theory and experiments. J Biomech Eng. February 1980;102(1):73-84.|
|2007||Lohmander LS, Englund PM, Dahl LL, Roos EM. The long-term consequence of anterior cruciate ligament and meniscus injuries: osteoarthritis. Am J Sports Med. October 2007;35(10):1756-1769.|
|1984||Mow VC, Holmes MH, Lai WM. Fluid transport and mechanical properties of articular cartilage: a review. J Biomech. 1984;17(5):377-394.|
|2008||Liu XS, Sajda P, Saha PK, Wehrli FW, Bevill G, Keaveny TM, Guo XE. Complete volumetric decomposition of individual trabecular plates and rods and its morphological correlations with anisotropic elastic moduli in human trabecular bone. J Bone Miner Res. February 2008;23(2):223-235.|
|2009||Liu XS, Zhang XH, Guo XE. Contributions of trabecular rods of various orientations in determining the elastic properties of human vertebral trabecular bone. Bone. August 2009;45(2):158-163.|
|2015||Wang J, Zhou B, Liu XS, Fields AJ, Sanyal A, Shi X, Adams M, Keaveny TM, Guo XE. Trabecular plates and rods determine elastic modulus and yield strength of human trabecular bone. Bone. March 2015;72:71-80.|
|1989||Martin RB, Ishida J. The relative effects of collagen fiber orientation, porosity, density, and mineralization on bone strength. J Biomech. 1989;22(5):419-426.|
|2020||Shiraishi K, Chiba K, Okazaki N, Yokota K, Nakazoe Y, Kidera K, Yonekura A, Tomita M, Osaki M. In vivo analysis of subchondral trabecular bone in patients with osteoarthritis of the knee using second-generation high-resolution peripheral quantitative computed tomography (HR-pQCT). Bone. March 2020;132:115155.|
|2010||Nishiyama KK, Macdonald HM, Buie HR, Hanley DA, Boyd SK. Postmenopausal women with osteopenia have higher cortical porosity and thinner cortices at the distal radius and tibia than women with normal aBMD: an in vivo HR-pQCT study. J Bone Miner Res. April 2010;25(4):882-890.|
|2004||Hayami T, Pickarski M, Wesolowski GA, Mclane J, Bone A, Destefano J, Rodan GA, Duong LT. The role of subchondral bone remodeling in osteoarthritis: reduction of cartilage degeneration and prevention of osteophyte formation by alendronate in the rat anterior cruciate ligament transection model. Arthritis Rheum. April 2004;50(4):1193-1206.|
|2002||Boyd SK, Müller R, Zernicke RF. Mechanical and architectural bone adaptation in early stage experimental osteoarthritis. J Bone Miner Res. April 2002;17(4):687-694.|
|1984||Brown TD, Radin EL, Martin RB, Burr DB. Finite element studies of some juxtarticular stress changes due to localized subchondral stiffening. J Biomech. 1984;17(1):11-24.|
|1972||Radin EL, Paul IL, Rose RM. Role of mechanical factors in pathogenesis of primary osteoarthritis. Lancet. March 4, 1972;299(7749):519-522.|
|2002||Brown SJ, Pollintine P, Powell DE, Davie MW, Sharp CA. Regional differences in mechanical and material properties of femoral head cancellous bone in health and osteoarthritis. Calcif Tiss Int. September 2002;71(3):227-234.|