Diffuse Damage Repair Mechanism in Bone

Bone microdamage is a result of fatigue, creep or ‘wear and tear’ caused by physiological activities and largely contributes to bone fragility. Bone, unlike engineered materials, has the ability to repair the microscopic cracking or microdamage through targeted, osteoclast-mediated bone remodeling. This capability is crucial for preservation of its structural integrity and quality; failure of the skeleton to effectively repair microdamage leads to accumulation of damage, which is one of the main contributors to bone fragility. Linear microcracks (50-100 µm) and diffuse damage (Dif.Dx) (sub-micron) are the two types of microdamage. Recent studies show that Dif.Dx repairs without bone remodeling, pointing to a direct healing mechanism for these small cracks. These discoveries raise questions about the mechanism(s) by which localized matrix damage in bone undergoes self-repair and whether of overall mechanical integrity is completely restored. Thus it is reasonable to hypothesize thatsmall (“diffuse”) crack damage repairs principally through a physicochemical mechanism that restores integrity of the bone mineral and the tissue mechanical properties, with no significant change in the organic component of the bone matrix. We first tried to understand the nature of mineral and collagen changes in diffuse damage and repaired tissue. Then we tested the hypothesis that the repair of Dif.Dx regions in bone, as assessed functionally by recovery of mechanical properties, can occur ex-vivo in the absence of viable osteocytes. Then we tested whether mineral deposition is an essential component of repair of diffuse damage in vivo, in order to gain insight into the importance of physicochemical mineral deposition in repair of diffuse damage

Raman microspectroscopy studies showed no difference in mineral/matrix, carbonate/phosphate ratio and crystallinity among diffuse damage, control and repaired diffuse damage tissue or survival groups. Raman microspectroscopy studies revealed a weak shoulder at 945-950 1/cm in diffuse damage area as an amorphous or crystalographically disordered. This peak is chemically calibrated and has been reported. Small Angle X-ray scattering (SAXS) showed no change in mineral thickness between diffuse damage area compare to control. However crystal thickness in survival group increased by 2 Å compare to control group. SAXS data showed decrease in degree of crystals alignment (more isotropic) in Dif.Dx area compare to control. However, in repaired diffuse damage area bone mineral crystal became more anisotropic. Increase in bone mineral thickness and degree of bone mineral alignment in repaired diffuse damage tissue are in consistent with non-classical crystallization pathway.

The results of ex-vivo and in-vivo remineralization studies support the concept that the spontaneous recovery of mechanical and microstructural alterations caused by Dif.Dx in bone requires deposition of Ca and Pi, but does not require the direct action of osteocytes. This repair process appears to resemble physicochemical remineralization like that occurring in enamel. Nevertheless, osteocytes and their lacunar-canalicular system likely play an essential indirect role in healing of these submicron-sized cracks in bone in vivo, by maintaining the ionic bone tissue fluid required for chemical repair of bone mineral and perfusing it through the matrix to access damage sites.

We examined collagen fibril architecture and orientation in bone containing diffuse damage induced in vivo, using a combination of SEM and SHG imaging approaches. Scanning vielectron microscopy studies revealed changes in tissue collagen fibrillar structure in diffuse damage regions compared to non-loaded control bone. Surprisingly, collagen fibril bundles in diffuse damaged bone were on average ~ 10% greater in diameter than those in non-loaded control bone. In addition, there was a substantial increase in the number of large diameter (550-650nm) fibril bundles; fibril bundles of this size were not seen in control bone. Importantly, ruptured or torn collagen fibrils were not seen in Dif.Dx bone.

Recovery of tissue stiffness mediated by remineralization may involve multiple pathways. Our results in consistent with non-classical crystallization pathways that involves the arrangement of primary nanoparticles into an iso-oriented crystal via oriented attachment. Non-classical crystallization pathway is always particle facilitated and in consistent with mesoscopic transformation process, where oriented attachment of smaller building blocks is required to achieve a uniform orientation in the bulk phase.

Year	Entry
1976	Parfitt AM. The actions of parathyroid hormone on bone: relation to bone remodeling and turnover, calcium homeostasis, and metabolic bone disease: part I of IV parts: mechanisms of calcium transfer between blood and bone and their cellular basis: morphological and kinetic approaches to bone turnover. Metabolism. July 1976;25(7):809-844.
2000	Timlin JA, Carden A, Morris MD, Rajachar RM, Kohn DH. Raman spectroscopic imaging markers for fatigue-related microdamage in bovine bone. Anal Chem. May 15, 2000;72(10):2229-2236.
2010	Fung DT, Wang VM, Andarawis-Puri N, Basta-Pljakic J, Li Y, Laudier DM, Sun HB, Jepsen KJ, Schaffler MB, Flatow EL. Early response to tendon fatigue damage accumulation in a novel in vivo model. J Biomech. January 19, 2010;43(2):274-279.
1996	Landis WJ, Hodgens KJ, Arena J, Song MJ, McEwen BF. Structural relations between collagen and mineral in bone as determined by high voltage electron microscopic tomography. Microsc Res Tech. 1996;33(2):192-202.
1988	Fondrk M, Bahniuk E, Davy DT, Michaels C. Some viscoplastic characteristics of bovine and human cortical bone. J Biomech. 1988;21(8):623-630.
1966	Fleisch H, Russell RGG, Straumann F. Effect of pyrophosphate on hydroxyapatite and its implications in calcium homeostasis. Nature. November 26, 1966;212:901-903.
2003	Cotton JR, Zioupos P, Winwood K, Taylor M. Analysis of creep strain during tensile fatigue of cortical bone. J Biomech. July 2003;36(7):943-949.
2007	Miller LM, Little W, Schirmer A, Sheik F, Busa B, Judex S. Accretion of bone quantity and quality in the developing mouse skeleton. J Bone Miner Res. July 2007;22(7):1037-1045.
2000	Verborgt O, Gibson GJ, Schaffler MB. Loss of osteocyte integrity in association with microdamage and bone remodeling after fatigue in vivo. J Bone Miner Res. January 2000;15(1):60-67.
2008	Allen MR, Reinwald S, Burr DB. Alendronate reduces bone toughness of ribs without significantly increasing microdamage accumulation in dogs following 3 years of daily treatment. Calcif Tiss Int. May 2008;82(5):354-360.
1996	Gustafson MB, Martin RB, Gibson V, Storms DH, Stover SM, Gibeling J, Griffin L. Calcium buffering is required to maintain bone stiffness in saline solution. J Biomech. September 1996;29(9):1191-1194.
2003	Tong W, Glimcher MJ, Katz JL, Kuhn L, Eppell SJ. Size and shape of mineralites in young bovine bone measured by atomic force microscopy. Calcif Tiss Int. May 2003;72(5):592-598.
2009	Fritton SP, Weinbaum S. Fluid and solute transport in bone: flow-induced mechanotransduction. Annu Rev Fluid Mech. 2009;41:347-374.
1996	Fratzl P, Schreiber S, Klaushofer K. Bone mineralization as studied by small-angle x-ray scattering. Connect Tissue Res. 1996;34(4):247-254.
1992	Fratzl P, Groschner M, Vogl G, Plenk H Jr, Eschberger J, Fratzl-Zelman N, Koller K, Klaushofer K. Mineral crystals in calcified tissues: a comparative study by SAXS. J Bone Miner Res. March 1992;7(3):329-334.
2007	Vashishth D. Hierarchy of bone microdamage at multiple length scales. Int J Fatigue. June 2007;29(6):1024-1033.
1997	Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, Deguchi K, Shimizu Y, Bronson RT, Gao Y-H, Inada M, Sato M, Okamoto R, Kitamura Y, Yoshiki S, Kishimoto T. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell. May 30, 1997;89(5):755-764.
2014	Reznikov N, Shahar R, Weiner S. Bone hierarchical structure in three dimensions. Acta Biomater. September 2014;10(8):3815-3826.
2003	Carden A, Rajachar RM, Morris MD, Kohn DH. Ultrastructural changes accompanying the mechanical deformation of bone tissue: a Raman imaging study. Calcif Tiss Int. February 2003;72(2):166-175.
2000	Mashiba T, Hirano T, Turner CH, Forwood MR, Johnston CC, Burr DB. Suppressed bone turnover by bisphosphonates increases microdamage accumulation and reduces some biomechanical properties in dog rib. J Bone Miner Res. April 2000;15(4):613-620.
2001	Mashiba T, Turner CH, Hirano T, Forwood MR, Johnston CC, Burr DB. Effects of suppressed bone turnover by bisphosphonates on microdamage accumulation and biomechanical properties in clinically relevant skeletal sites in beagles. Bone. May 2001;28(5):524-531.
1994	Schaffler MB, Pitchford WC, Choi K, Riddle JM. Examination of compact bone microdamage using back-scattered electron microscopy. Bone. September–October 1994;15(5):483-488.
1995	Schaffler MB, Choi K, Milgrom C. Aging and matrix microdamage accumulation in human compact bone. Bone. December 1995;17(6):521-525.
2008	Ritchie RO, Koester KJ, Ionova S, Yao W, Lane NE, Ager JW III. Measurement of the toughness of bone: a tutorial with special reference to small animal studies. Bone. November 2008;43(5):798-812.
2004	Fratzl P, Gupta HS, Paschalis EP, Roschger P. Structure and mechanical quality of the collagen–mineral nano-composite in bone. J Mater Chem. 2004;14(14):2115-2123.
2008	Lenart BA, Lorich DG, Lane JM. Atypical fractures of the femoral diaphysis in postmenopausal women taking alendronate. NEJM. March 20, 2008;358(12):1304-1306.
2005	Gupta HS, Wagermaier W, Zickler GA, Aroush DR-B, Funari SS, Roschger P, Wagner HD, Fratzl P. Nanoscale deformation mechanisms in bone. Nano Lett. October 2005;5(10):2108-2111.
2008	Russell RGG, Watts NB, Ebetino FH, Rogers MJ. Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int. June 2008;19(6):733-759.
1996	Wenzel TE, Schaffler MB, Fyhrie DP. In vivo trabecular microcracks in human vertebral bone. Bone. August 1996;19(2):89-95.
2010	Herman BC, Cardoso L, Majeska RJ, Jepsen KJ, Schaffler MB. Activation of bone remodeling after fatigue: differential response to linear microcracks and diffuse damage. Bone. October 2010;47(4):766-772.
2006	Nancollas GH, Tang R, Phipps RJ, Henneman Z, Gulde S, Wu W, Mangood A, Russell RGG, Ebetino FH. Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite. Bone. May 2006;38(5):617-627.
2008	Yerramshetty JS, Akkus O. The associations between mineral crystallinity and the mechanical properties of human cortical bone. Bone. March 2008;42(3):476-482.
1990	Mosekilde L. Consequences of the remodelling process for vertebral trabecular bone structure: a scanning electron microscopy study (uncoupling of unloaded structures). Bone Miner. July 1990;10(1):13-35.
1998	Bentolila V, Boyce TM, Fyhrie DP, Drumb R, Skerry TM, Schaffler MB. Intracortical remodeling in adult rat long bones after fatigue loading. Bone. September 1998;23(3):275-281.
2014	Bajaj D, Geissler JR, Allen MR, Burr DB, Fritton JC. The resistance of cortical bone tissue to failure under cyclic loading is reduced with alendronate. Bone. July 2014;64:57-64.
1998	Zioupos P, Currey JD. Changes in the stiffness, strength, and toughness of human cortical bone with age. Bone. January 1998;22(1):57-66.
2001	Zioupos P, Currey JD, Casinos A. Tensile fatigue in bone: are cycles-, or time to failure, or both, important? J Theo Biol. June 7, 2001;210(3):389-399.
2001	Cowin SC, ed. Bone Mechanics Handbook. 2nd ed. Boca Raton, FL: CRC Press; 2001.
2005	Hansma PK, Fantner GE, Kindt JH, Thurner PJ, Schitter G, Turner PJ, Udwin SF, Finch MM. Sacrificial bonds in the interfibrillar matrix of bone. J Musculoskel Neuron Interact. October–December 2005;5(4):313-315.
1994	Finlay JB, Hardie WR. Anisotropic contraction of cortical bone caused by dehydration of samples of the bovine femur in vitro. Proc Inst Mech Eng Part H-J Eng Med. 1994;208(1):27-32.
2013	Thi MM, Suadicani SO, Schaffler MB, Weinbaum S, Spray DC. Mechanosensory responses of osteocytes to physiological forces occur along processes and not cell body and require αᵥβ₃ integrin. Proc Natl Acad Sci USA. December 24, 2013;110(52):21012-21017.
1994	Zioupos P, Currey JD, Sedman AJ. An examination of the micromechanics of failure of bone and antler by acoustic emission tests and laser scanning confocal microscopy. Med Eng Phys. May 1994;16(3):203-212.
2003	Martin RB. Fatigue microdamage as an essential element of bone mechanics and biology. Calcif Tiss Int. August 2003;73(2):101-107.
2007	Allen MR, Burr DB. Three years of alendronate treatment results in similar levels of vertebral microdamage as after one year of treatment. J Bone Miner Res. November 2007;22(11):1759-1765.
2006	Allen MR, Iwata K, Phipps R, Burr DB. Alterations in canine vertebral bone turnover, microdamage accumulation, and biomechanical properties following 1-year treatment with clinical treatment doses of risedronate or alendronate. Bone. October 2006;39(4):872-879.
1998	Martin RB, Burr DB, Sharkey NA. Skeletal Tissue Mechanics. New York, NY: Springer-Verlag; 1998.
2000	Vashishth D, Koontz J, Qiu SJ, Lundin-Cannon D, Yeni YN, Schaffler MB, Fyhrie DP. In vivo diffuse damage in human vertebral trabecular bone. Bone. February 2000;26(2):147-152.
2013	Lambers FM, Bouman AR, Rimnac CM, Hernandez CJ. Microdamage caused by fatigue loading in human cancellous bone: relationship to reductions in bone biomechanical performance. PLoS One. December 2013;8(12):e83662.
1996	Pattin CA, Caler WE, Carter DR. Cyclic mechanical property degradation during fatigue loading of cortical bone. J Biomech. January 1996;29(1):69-79.
2006	Orgel JPRO, Irving TC, Miller A, Wess TJ. Microfibrillar structure of type I collagen in situ. Proc Natl Acad Sci USA. June 13, 2006;103(24):9001-9005.
2002	Boskey AL, Spevak L, Paschalis E, Doty SB, McKee MD. Osteopontin deficiency increases mineral content and mineral crystallinity in mouse bone. Calcif Tiss Int. August 2002;71(2):145-154.
2006	Diab T, Condo KW, Burr DB, Vashishth D. Age-related change in the damage morphology of human cortical bone and its role in bone fragility. Bone. March 2006;38(3):427-431.
2007	Diab T, Vashishth D. Morphology, localization and accumulation of in vivo microdamage in human cortical bone. Bone. March 2007;40(3):612-618.
1983	Carter DR, Caler WE. Cycle-dependent and time-dependent bone fracture with repeated loading. J Biomech Eng. May 1983;105(2):166-170.
1985	Carter DR, Caler WE. A cumulative damage model for bone-fracture. J Orthop Res. 1985;3(1):84-90.
1996	McKee MD, Nanci A. Osteopontin at mineralized tissue interfaces in bone, teeth, and osseointegrated implants: ultrastructural distribution and implications for mineralized tissue formation, turnover, and repair. Microsc Res Tech. February 1996;33(2):141-164.
2012	Qing H, Ardeshirpour L, Pajevic PD, Dusevich V, Jähn K, Kato S, Wysolmerski J, Bonewald LF. Demonstration of osteocytic perilacunar/canalicular remodeling in mice during lactation. J Bone Miner Res. May 2012;27(5):1018-1029.
2010	Shane E, Burr D, Ebeling PR, Abrahamsen B, Adler RA, Brown TD, Cheung AM, Cosman F, Curtis JR, Dell R, Dempster D, Einhorn TA, Genant HK, Geusens P, Klaushofer K, Koval K, Lane JM, McKiernan F, McKinney R, Ng A, Nieves J, O'Keefe R, Papapoulos S, Sen HT, van der Meulen MCH, Weinstein RS, Whyte M. Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. November 2010;25(11):2267-2294.
1999	Plotkin LI, Weinstein RS, Parfitt AM, Roberson PK, Manolagas SC, Bellido T. Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin. J Clin Invest. November 1999;104(10):1363-1374.
2002	Tarnowski CP, Ignelzi MA Jr, Morris MD. Mineralization of developing mouse calvaria as revealed by Raman microspectroscopy. J Bone Miner Res. June 2002;17(6):1118-1126.
2004	Akkus O, Adar F, Schaffler MB. Age-related changes in physicochemical properties of mineral crystals are related to impaired mechanical function of cortical bone. Bone. March 2004;34(4):443-453.
1998	Penel G, Leroy G, Rey C, Bres E. MicroRaman spectral study of the PO₄ and CO₃ vibrational modes in synthetic and biological apatites. Calcif Tiss Int. December 1998;63(6):475-481.
2003	Schaffler MB. Role of bone turnover in microdamage. Osteoporos Int. September 2003;14(suppl 5):S73-S80.
2003	Akkus O, Polyakova‐Akkus A, Adar F, Schaffler MB. Aging of microstructural compartments in human compact bone. J Bone Miner Res. June 2003;18(6):1012-1019.
1974	Currey JD, Brear K. Tensile yield in bone. Calcif Tiss Res. December 1974;15(1):173-179.
2003	Bouxsein ML. Bone quality: where do we go from here? Osteoporos Int. September 2003;14(suppl 5):S118-S127.
1991	Rey C, Renugopalakrishman V, Collins B, Glimcher MJ. Fourier transform infrared spectroscopic study of the carbonate ions in bone mineral during aging. Calcif Tiss Int. October 1991;49(4):251-258.
2012	Kennedy OD, Herman BC, Laudier DM, Majeska RJ, Sun HB, Schaffler MB. Activation of resorption in fatigue-loaded bone involves both apoptosis and active pro-osteoclastogenic signaling by distinct osteocyte populations. Bone. May 2012;50(5):1115-1122.
2005	Nalla RK, Kruzic JJ, Kinney JH, Ritchie RO. Mechanistic aspects of fracture and R-curve behavior in human cortical bone. Biomaterials. January 2005;26(2):217-231.
1960	Frost HM. Presence of microscopic cracks in vivo in bone. Henry Ford Hosp Med Bull. 1960;8(1):25-35.
2014	Kennedy OD, Laudier DM, Majeska RJ, Sun HB, Schaffler MB. Osteocyte apoptosis is required for production of osteoclastogenic signals following bone fatigue in vivo. Bone. July 2014;64:132-137.
2000	Vashishth D, Tanner KE, Bonfield W. Contribution, development and morphology of microcracking in cortical bone during crack propagation. J Biomech. September 2000;33(9):1169-1174.
1999	Fondrk MT, Bahniuk EH, Davy DT. Inelastic strain accumulation in cortical bone during rapid transient tensile loading. J Biomech Eng. December 1999;121(6):616-621.
2015	Seref-Ferlengez Z, Kennedy OD, Schaffler MB. Bone microdamage, remodeling and bone fragility: how much damage is too much damage? BoneKEy Rep. March 2015;4:644.
1998	Weiner S, Wagner HD. The material bone: structure-mechanical function relations. Ann Rev Mater Sci. August 1998;28:271-298.
2010	Donnelly E, Boskey AL, Baker SP, van der Meulen MCH. Effects of tissue age on bone tissue material compositionand nanomechanical properties in the rat cortex. J Biomed Mater Res. March 1, 2010;A92(3):1048-1056.
1992	Weiner S, Traub W. Bone structure: from ȧngstroms to microns. FASEB J. February 1992;6(3):879-885.
1991	Weiner S, Arad T, Traub W. Crystal organization in rat bone lamellae. FEBS Lett. July 1991;285(1):49-54.
2012	Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, Preibisch S, Rueden C, Saalfeld S, Schmid B, Tinevez J-Y, White DJ, Hartenstein V, Eliceiri K, Tomancak P, Cardona A. Fiji: an open-source platform for biological-image analysis. Nat Methods. June 28, 2012;9(7):676-682.
2016	Georgiadis M, Müller R, Schneider P. Techniques to assess bone ultrastructure organization: orientation and arrangement of mineralized collagen fibrils. J R Soc Interface. June 1, 2016;13(119):20160088.
2014	Schaffler MB, Cheung W-Y, Majeska R, Kennedy O. Osteocytes: master orchestrators of bone. Calcif Tiss Int. January 2014;94(1):5-24.
2001	Freeman JJ, Wopenka B, Silva MJ, Pasteris JD. Raman spectroscopic detection of changes in bioapatite in mouse femora as a function of age and in vitro fluoride treatment. Calcif Tiss Int. March 2001;68(3):156-162.
2017	Lloyd AA, Gludovatz B, Riedel C, Luengo EA, Saiyed R, Marty E, Lorich DG, Lane JM, Ritchie RO, Busse B, Donnelly E. Atypical fracture with long-term bisphosphonate therapy is associated with altered cortical composition and reduced fracture resistance. Proc Natl Acad Sci USA. August 15, 2017;114(33):8722-8727.
2005	Ager JW III, Nalla RK, Breeden KL, Ritchie RO. Deep-ultraviolet Raman spectroscopy study of the effect of aging on human cortical bone. J Biomed Opt. May–June 2005;10(3):034012.
2003	Gluhak-Heinrich J, Ye L, Bonewald LF, Feng JQ, MacDougall M, Harris SE, Pavlin D. Mechanical loading stimulates dentin matrix protein 1 (DMP1) expression in osteocytes in vivo. J Bone Miner Res. May 2003;18(5):807-817.
2010	Gamsjaeger S, Masic A, Roschger P, Kazanci M, Dunlop JWC, Klaushofer K, Paschalis EP, Fratzl P. Cortical bone composition and orientation as a function of animal and tissue age in mice by raman spectroscopy. Bone. August 2010;47(2):392-399.
2014	Carriero A, Zimmermann EA, Paluszny A, Tang SY, Bale H, Busse B, Alliston T, Kazakia G, Ritchie RO, Shefelbine SJ. How tough is brittle bone? investigating osteogenesis imperfecta in mouse bone. J Bone Miner Res. June 2014;29(6):1392-1401.
1990	Currey JD, Brear K. Hardness, Young's modulus and yield stress in mammalian mineralized tissues. J Mater Sci Mater Med. June 1990;1(1):14-20.
2004	Nalla RK, Kruzic JJ, Ritchie RO. On the origin of the toughness of mineralized tissue: microcracking or crack bridging? Bone. May 2004;34(5):790-798.
2009	McNamara LM, Majeska RJ, Weinbaum S, Friedrich V, Schaffler MB. Attachment of osteocyte cell processes to the bone matrix. Anat Rec. March 2009;292(3):355-363.
1996	Landis WJ, Hodgens KJ, Song MJ, Arena J, Kiyonaga S, Marko M, Owen C, McEwen BF. Mineralization of collagen may occur on fibril surfaces: evidence from conventional and high-voltage electron microscopy and three-dimensional imaging. J Struct Biol. July 1996;117(1):24-35.
1997	Burr DB, Forwood MR, Fyhrie DP, Martin RB, Schaffler MB, Turner CH. Bone microdamage and skeletal fragility in osteoporotic and stress fractures. J Bone Miner Res. January 1997;12(1):6-15.
2003	Vashishth D, Tanner KE, Bonfield W. Experimental validation of a microcracking-based toughening mechanism for cortical bone. J Biomech. January 2003;36(1):121-124.
1990	Burr DB, Stafford T. Validity of the bulk-staining technique to separate artifactual from in vivo bone microdamage. Clin Orthop Relat Res. November 1990;260:305-308.
2000	Carden A, Morris MD. Application of vibrational spectroscopy to the study of mineralized tissues (review). J Biomed Opt. July 2000;5(3):259-268.
1998	Burr DB, Turner CH, Naick P, Forwood MR, Ambrosius W, Hasan MS, Pidaparti R. Does microdamage accumulation affect the mechanical properties of bone? J Biomech. April 1998;31(4):337-345.
1998	Rho J-Y, Kuhn-Spearing L, Zioupos P. Mechanical properties and the hierarchical structure of bone. Med Eng Phys. 1998;20(2):92-102.
1999	Rinnerthaler S, Roschger P, Jakob HF, Nader A, Klaushofer K, Fratzl P. Scanning small angle X-ray scattering analysis of human bone sections. Calcif Tiss Int. May 1999;64(5):422-429.
1994	Torrance AG, Mosley JR, Suswillo RFL, Lanyon LE. Noninvasive loading of the rat ulna in vivo induces a strain-related modeling response uncomplicated by trauma or periostal pressure. Calcif Tiss Int. March 1994;54(3):241-247.
2003	Nalla RK, Kinney JH, Ritchie RO. Mechanistic fracture criteria for the failure of human cortical bone. Nat Mater. 2003;2(3):164-168.
2009	Cardoso L, Herman BC, Verborgt O, Laudier D, Majeska RJ, Schaffler MB. Osteocyte apoptosis controls activation of intracortical resorption in response to bone fatigue. J Bone Miner Res. April 2009;24(4):597-605.
1985	Burr DB, Martin RB, Schaffler MB, Radin EL. Bone remodeling in response to in vivo fatigue microdamage. J Biomech. 1985;18(3):189-200.
2012	Poundarik AA, Diab T, Sroga GE, Ural A, Boskey AL, Gundberg CM, Vashishth D. Dilatational band formation in bone. Proc Natl Acad Sci USA. November 20, 2012;109(47):19178-19183.
2001	Parsamian GP, Norman TL. Diffuse damage accumulation in the fracture process zone of human cortical bone specimens and its influence on fracture toughness. J Mater Sci Mater Med. September 2001;12(9):779-783.
1998	Boyce TM, Fyhrie DP, Glotkowski MC, Radin EL, Schaffler MB. Damage type and strain mode associations in human compact bone bending fatigue. J Orthop Res. May 1998;16(3):322-329.
2016	Turunen MJ, Kaspersen JD, Olsson U, Guizar-Sicairos M, Bech M, Schaff F, Tägil M, Jurvelin JS, Isaksson H. Bone mineral crystal size and organization vary across mature rat bone cortex. J Struct Biol. September 2016;195(3):337-344.
2014	Schwarcz HP, McNally EA, Botton GA. Dark-field transmission electron microscopy of cortical bone reveals details of extrafibrillar crystals. J Struct Biol. December 2014;188(3):240-248.
1989	Caler WE, Carter DR. Bone creep-fatigue damage accumulation. J Biomech. 1989;22(6-7):625-635.
1993	Rimnac CM, Petko AA, Santner TJ, Wright TM. The effect of temperature, stress and microstructure on the creep of compact bovine bone. J Biomech. March 1993;26(3):219-228.
2004	Kotha SP, Hsieh Y-F, Strigel RM, Müller R, Silva MJ. Experimental and finite element analysis of the rat ulnar loading model: correlations between strain and bone formation following fatigue loading. J Biomech. April 2004;37(4):541-548.
1997	Paschalis EP, Betts F, DiCarlo E, Mendelsohn R, Boskey AL. FTIR microspectroscopic analysis of normal human cortical and trabecular bone. Calcif Tiss Int. December 1997;61(6):480-486.
1977	Ascenzi A, Benvenuti A. Evidence of a state of initial stress in osteonic lamellae. J Biomech. 1977;10(8):447-453.
2001	Thompson JB, Kindt JH, Drake B, Hansma HG, Morse DE, Hansma PK. Bone indentation recovery time correlates with bond reforming time. Nature. December 13, 2001;414(6865):773-776.
1993	Burr DB, Martin RB. Calculating the probability that microcracks initiate resorption spaces. J Biomech. April–May 1993;26(4-5):613-616.
1995	Norman TL, Vashishth D, Burr DB. Fracture toughness of human bone under tension. J Biomech. March 1995;28(3):309-320.
2003	Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg. September 2003;61(9):1115-1117.
2011	Morris MD, Mandair GS. Raman assessment of bone quality. Clin Orthop Relat Res. August 2011;469:2160-2169.
2012	Thompson WR, Rubin CT, Rubin J. Mechanical regulation of signaling pathways in bone. Gene. July 25, 2012;503(2):179-193.
1993	Marotti G. A new theory of bone lamellation. Calcif Tiss Int. February 1993;53(suppl 1):S47-S56.
2005	Fantner GE, Hassenkam T, Kindt JH, Weaver JC, Birkedal H, Pechenik L, Cutroni JA, Cidade GAG, Stucky GD, Morse DE, Hansma PK. Sacrificial bonds and hidden length dissipate energy as mineralized fibrils separate during bone fracture. Nat Mater. August 2005;4(8):612-616.
2007	Fantner GE, Adams J, Turner P, Thurner PJ, Fisher LW, Hansma PK. Nanoscale ion mediated networks in bone: osteopontin can repeatedly dissipate large amounts of energy. Nano Lett. August 2007;7(8):2491-2498.
2003	Gao H, Ji B, Jäger IL, Arzt E, Fratzl P. Materials become insensitive to flaws at nanoscale: lessons from nature. Proc Natl Acad Sci USA. May 13, 2003;100(10):5597-5600.
2001	Lucchinetti E. Composite models of bone properties. In: Cowin SC, ed. Bone Mechanics Handbook. 2nd ed. Boca Raton, FL: CRC Press; 2001:12-1–12-19.

Year

Entry

1976

Parfitt AM. The actions of parathyroid hormone on bone: relation to bone remodeling and turnover, calcium homeostasis, and metabolic bone disease: part I of IV parts: mechanisms of calcium transfer between blood and bone and their cellular basis: morphological and kinetic approaches to bone turnover. Metabolism. July 1976;25(7):809-844.

2000

Timlin JA, Carden A, Morris MD, Rajachar RM, Kohn DH. Raman spectroscopic imaging markers for fatigue-related microdamage in bovine bone. Anal Chem. May 15, 2000;72(10):2229-2236.

2010

Fung DT, Wang VM, Andarawis-Puri N, Basta-Pljakic J, Li Y, Laudier DM, Sun HB, Jepsen KJ, Schaffler MB, Flatow EL. Early response to tendon fatigue damage accumulation in a novel in vivo model. J Biomech. January 19, 2010;43(2):274-279.

1996

Landis WJ, Hodgens KJ, Arena J, Song MJ, McEwen BF. Structural relations between collagen and mineral in bone as determined by high voltage electron microscopic tomography. Microsc Res Tech. 1996;33(2):192-202.

1988

Fondrk M, Bahniuk E, Davy DT, Michaels C. Some viscoplastic characteristics of bovine and human cortical bone. J Biomech. 1988;21(8):623-630.