Pathology of Bone, Skeletal Muscle, and Tooth

  • Stacey L. FosseyEmail author
  • D. Greg Hall
  • Andrew W. Suttie
  • Martin Guillot
  • Aurore Varela


The musculoskeletal system provides vital functions such as protection of fragile tissues, support, contribution to mineral homeostasis, and locomotion. In this chapter, we cover toxicologic pathology of importance to the nonpathologist in three major tissues comprising this system: bone and joints, skeletal muscle, and teeth. This chapter reviews the anatomy, physiology, and histology of these tissues. Best practices for study design, tissue collection and handling, and special procedures and ancillary evaluations such as biomarkers and imaging modalities are addressed. Common background lesions in nonclinical species are presented and mechanisms of toxicity and response to injury are discussed. Finally, types of animal models, risk assessment considerations, and determination of adversity are examined.

Key words

Musculoskeletal Bone Joint Skeletal muscle Tooth Toxicologic pathology Nonclinical 



The authors thank Dr. John Vahle for his review of the bone and joint section of this chapter and David Sabio for preparation of Fig. 1.


  1. Albassam MA, Wojcinski ZW, Barsoum NJ, Smith GS (1991) Spontaneous fibro-osseous proliferative lesions in the sternums and femurs of B6C3F1 mice. Vet Pathol 28:381–388PubMedCrossRefGoogle Scholar
  2. Allen MJ (2003) Biochemical markers of bone metabolism in animals: uses and limitations. Vet Clin Pathol 32(3):101–113PubMedCrossRefGoogle Scholar
  3. Allen MR, Burr DB (2014) Bone modeling and remodeling. In: Burr DB, Allen MR (eds) Basic and applied bone biology. Academic, San Diego, pp 75–90CrossRefGoogle Scholar
  4. Armstrong RB, Phelps RO (1984) Muscle fiber type composition of the rat hindlimb. Am J Anat 171:259–272PubMedCrossRefGoogle Scholar
  5. Armstrong RB, Saubert CW 4th, Seeherman HJ, Taylor CR (1982) Distribution of fiber types in locomotory muscles of dogs. Am J Anat 163:87–98PubMedCrossRefGoogle Scholar
  6. Bendele A, McComb J, Gould T, McAbee T, Sennello G, Chlipala E, Guy M (1999) Animal models of arthritis: relevance to human disease. Toxicol Pathol 27:134–142PubMedCrossRefGoogle Scholar
  7. Blankenship B, Eighmy JJ, Hoffmann G, Schroeder M, Sharma AK, Sorden SD (2016) Findings in historical control Harlan RCCHan™:WIST rats from 104-week oral gavage studies. Toxicol Pathol 44:947–961PubMedCrossRefGoogle Scholar
  8. Bonetto A, Andersson DC, Waning DL (2015) Assessment of muscle mass and strength in mice. Bonekey Reports 4:732PubMedPubMedCentralCrossRefGoogle Scholar
  9. Bonewald LF (2006) Mechanosensation and transduction in osteocytes. Bonekey Osteovision 3:7–15PubMedPubMedCentralCrossRefGoogle Scholar
  10. Bonewald LF (2011) The amazing osteocyte. J Bone Miner Res 26:229–238PubMedCrossRefGoogle Scholar
  11. Boskey AL (2002) Connective tissues of the musculoskeletal system. In: Slatter D (ed) Textbook of small animal surgery, 3rd edn, vol 2. Saunders, Philadelphia, pp 1774–1784Google Scholar
  12. Boss JH, Misselevich I (2003) Osteonecrosis of the femoral head of laboratory animals: the lessons learned from a comparative study of osteonecrosis in man and experimental animals. Vet Pathol 40:345–354PubMedCrossRefGoogle Scholar
  13. Boyce RW, Varela A, Chouinard L, Bussiere JL, Chellman GJ, Ominsky MS, Pyrah IT (2014) Infant cynomolgus monkeys exposed to denosumab in utero exhibit an osteoclast-poor osteopetrotic-like skeletal phenotype at birth and in the early postnatal period. Bone 64:314–325PubMedCrossRefPubMedCentralGoogle Scholar
  14. Bregman CL, Adler RR, Morton DG, Regan KS, Yano BL (2003) Recommended tissue list for histopathologic examination in repeat-dose toxicity and carcinogenicity studies: a proposal of the Society of Toxicologic Pathology (STP). Toxicol Pathol 31:252–253PubMedPubMedCentralGoogle Scholar
  15. Burch PM, Hall DG, Walker EG, Bracken W, Giovanelli R, Goldstein R, Higgs RE, King NMP, Lane P, Sauer J-M, Michna L, Muniappa N, Pritt ML, Vlasakova K, Watson DE, Wescott D, Zabka TS, Glaab WE (2015) Evaluation of the relative performance of drug-induced skeletal muscle injury biomarkers in rats. Toxicol Sci 150:247–256PubMedCrossRefGoogle Scholar
  16. Burkhardt JE, Hill MA, Carlton WW, Kesterson JW (1990) Histologic and histochemical changes in articular cartilages of immature beagle dogs dosed with difloxacin, a fluoroquinolone. Vet Pathol Online 27:162–170CrossRefGoogle Scholar
  17. Burkhardt JE, Hill MA, Turek JJ, Carlton WW (1992) Ultrastructural changes in articular cartilage of immature beagle dogs dosed with difloxacin, a fluoroquinolone. Vet Pathol Online 29:230–238CrossRefGoogle Scholar
  18. Burr DB, Akkus O (2014) Bone morphology and organization. In: Burr DB, Allen MR (eds) Basic and applied bone biology. Academic, San Diego, pp 3–25CrossRefGoogle Scholar
  19. Canalis E, Mazziotti G, Giustina A, Bilezikian JP (2007) Glucocorticoid-induced osteoporosis: pathophysiology and therapy. Osteoporos Int 18:1319–1328PubMedCrossRefGoogle Scholar
  20. Caplazi P, Baca M, Barck K, Carano RA, DeVoss J, Lee WP, Bolon B, Diehl L (2015) Mouse models of rheumatoid arthritis. Vet Pathol 52:819–826PubMedCrossRefPubMedCentralGoogle Scholar
  21. Castillo AB, Tarantal AF, Watnik MR, Martin RB (2002) Tenofovir treatment at 30 mg/kg/day can inhibit cortical bone mineralization in growing rhesus monkeys (Macaca mulatta). J Orthop Res 20:1185–1189PubMedCrossRefPubMedCentralGoogle Scholar
  22. Chamanza R, Marxfeld HA, Blanco AI, Naylor SW, Bradley AE (2010) Incidences and range of spontaneous findings in control cynomolgus monkeys (Macaca fascicularis) used in toxicity studies. Toxicol Pathol 38:642–657PubMedCrossRefGoogle Scholar
  23. Chang SC, Inui K, Lee WC, Hsuan SL, Chien MS, Chen CH, Chang SJ, Liao JW (2008) Spontaneous rhabdomyosarcoma in a young Sprague-Dawley rat. Toxicol Pathol 36:866–870PubMedCrossRefPubMedCentralGoogle Scholar
  24. Chouinard L, Felx M, Mellal N, Varela A, Mann P, Jolette J, Samadfam R, Smith SY, Locher K, Buntich S, Ominsky MS, Pyrah I, Boyce RW (2016) Carcinogenicity risk assessment of romosozumab: a review of scientific weight-of-evidence and findings in a rat lifetime pharmacology study. Regul Toxicol Pharmacol 81:212–222PubMedCrossRefPubMedCentralGoogle Scholar
  25. Cook JL, Kuroki K, Visco D et al (2010) The OARSI histopathology initiative: recommendations for histological assessments of osteoarthritis in the dog. Osteoarthr Cartil 18(suppl 3):S66–S79PubMedCrossRefPubMedCentralGoogle Scholar
  26. Costa AG, Bilezikian JP (2012) Sclerostin: therapeutic horizons based upon its actions. Curr Osteoporos Rep 10:64–72PubMedCrossRefGoogle Scholar
  27. Courtney CL, Kim SN, Walsh KM, Watkins JR, Dominick MA (1991) Proliferative bone lesions in rats given anticancer compounds. Toxicol Pathol 19:184–188PubMedCrossRefPubMedCentralGoogle Scholar
  28. Craig L, Julian M, Ferracone J (2002) The diagnosis and prognosis of synovial tumors in 16 dogs: 35 cases. Vet Pathol 39:66–73PubMedCrossRefGoogle Scholar
  29. Cui GL, Syversen U, Zhao CM, Chen D, Waldum HL (2001) Long-term omeprazole treatment suppresses body weight gain and bone mineralization in young male rats. Scand J Gastroenterol 36:1011–1015PubMedCrossRefGoogle Scholar
  30. Dalakas MC, Illa I, Pezeshkpour GH, Laukaitis JP, Cohen B, Griffin JL (1990) Mitochondrial myopathy caused by long-term zidovudine therapy. N Engl J Med 322:1098–1105PubMedCrossRefGoogle Scholar
  31. De Souza AT, Cornwell PD, Dai X, Caguyong MJ, Ulrich RG (2006) Agonists of the peroxisome proliferator-activated receptor alpha induce a fiber-type-selective transcriptional response in rat skeletal muscle. Toxicol Sci 92:578–586PubMedCrossRefGoogle Scholar
  32. Dempster DW, Cosman F, Parisien M, Shen V, Lindsay R (1993) Anabolic actions of parathyroid hormone on bone. Endocr Rev 14:690–709PubMedGoogle Scholar
  33. Dempster DW, Compston JE, Drezner MK, Glorieux FH, Kanis JA, Malluche H et al (2013) Standardized nomenclature, symbols, and units for bone histomorphometry: a 2012 update of the report of the ASBMR Histomorphometry nomenclature committee. J Bone Miner Res 28:2–17PubMedPubMedCentralCrossRefGoogle Scholar
  34. Egermann M, Goldhahn J, Schneider E (2005) Animal models for fracture treatment in osteoporosis. Osteoporos Int 16:S129–S138PubMedCrossRefGoogle Scholar
  35. EMEA (European Medicines Agency CHMP) (2006) Guideline on the evaluation of medicinal products in the treatment of primary osteoporosis. European Medicines Agency, London, UK. Accessed September 16, 2018Google Scholar
  36. Erben RG, Jolette J, Chouinard L, Boyce R (2017) Application of histopathology and bone histomorphometry for understanding test article-related bone changes and assessing potential bone liabilities. In: Smith SY, Varela A, Samadfam R (eds) Bone toxicology, Molecular and Integrative Toxicology series. Springer, Gewerbestrasse, Switzerland, pp 253–280.Google Scholar
  37. Eriksen EF (2010) Cellular mechanisms of bone remodeling. Rev Endocr Metab Disord 11:219–227PubMedPubMedCentralCrossRefGoogle Scholar
  38. Erlandson MC, Lorbergs AL, Mathur S, Cheung AM (2016) Muscle analysis using pQCT, DXA and MRI. Eur J Radiol 85:1505–1511PubMedCrossRefGoogle Scholar
  39. Erlandson MC, Wong AKO, Szabo E, Vilayphiou N, Zulliger MA, Adachi JD, Cheung AM (2017) Muscle and myotendinous tissue properties at the distal tibia as assessed by high-resolution peripheral quantitative computed tomography. J Clin Densitom 20:226–232PubMedCrossRefGoogle Scholar
  40. Eyre DR, Weis MA, Wu JJ (2006) Articular cartilage collagen: an irreplaceable framework? Eur Cell Mater 12:57–63PubMedCrossRefGoogle Scholar
  41. FDA (2016) Osteoporosis: nonclinical evaluation of drugs intended for treatment – guidance for industry (Draft guidance). Accessed 16 Sept 2018
  42. Fossey S, Vahle J, Long P, Schelling S, Ernst H, Boyce RW, Jolette J, Bolon B, Bendele A, Rinke M, Healy L, High W, Roth DR, Boyle M, Leininger J (2016) Nonproliferative and proliferative lesions of the rat and mouse skeletal tissues (bones, joints, and teeth). J Toxicol Pathol 29(3 Suppl):49S–103SPubMedPubMedCentralCrossRefGoogle Scholar
  43. Frazier KS (2017) Drug-induced physeal abnormalities in preclinical toxicity studies. Toxicol Pathol 45:869–875PubMedCrossRefGoogle Scholar
  44. Fukuda S, Cho F, Honjo S (1978) Bone growth and development of secondary ossification centers of extremities in the cynomolgus monkey (Macaca fascicularis). Exp Anim 27:387–397CrossRefGoogle Scholar
  45. Gahunia HK, Pritzker KP (2012) Effect of exercise on articular cartilage. Orthop Clin North Am 43:187–199PubMedCrossRefGoogle Scholar
  46. Gasser JA, Kneissel M (2017) Bone physiology and biology. In: Smith SY, Varela A, Samadfam R (eds) Bone toxicology, Molecular and Integrative Toxicology series. Springer, Gewerbestrasse, Switzerland, pp 27–94Google Scholar
  47. Gerwin N, Bendele AM, Glasson S et al (2010) The OARSI histopathology initiative: recommendations for histological assessments of osteoarthritis in the rat. Osteoarthr Cartil 18(suppl 3):S24–S34PubMedCrossRefGoogle Scholar
  48. Glass DA, Bialek P, Ahn JD, Starbuck M, Patel MS, Clevers H, Taketo MM, Long F, McMahon AP, Lang RA, Karsenty G (2005) Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell 8:751–764PubMedCrossRefGoogle Scholar
  49. Goldring MB, Marcu KB (2009) Cartilage homeostasis in health and rheumatic diseases. Arthritis Res Ther 11:224PubMedPubMedCentralCrossRefGoogle Scholar
  50. Gopinath C, Mowat V (2014) Atlas of toxicological pathology. Springer, New YorkCrossRefGoogle Scholar
  51. Greaves P (2012) Musculoskeletal system. In: Greaves P (ed) Histopathology of preclinical toxicity studies, interpretation and relevance in drug safety evaluation, 4th edn. Academic, AmsterdamGoogle Scholar
  52. Greaves P, Chouinard L, Ernst H, Mecklenburg L, Pruimboom-Brees IM, Rinke M, Rittinghausen S, Thibault S, von Erichsen J, Yoshida T (2013) Proliferative and non-proliferative lesions of the rat and mouse soft tissue, skeletal muscle and mesothelium. J Toxicol Pathol 26(3 Suppl):1S–26SPubMedCrossRefPubMedCentralGoogle Scholar
  53. Gropp KE (2017) Effects on cancellous bone in the metaphysis. Toxiol Pathol 45:876–878CrossRefGoogle Scholar
  54. Gunson D, Gropp KE, Varela A (2013) Bone and joints. In: Haschek WM, Rousseaux CG, Wallig MA (eds) Haschek and Rousseaux’s Handbook of Toxicologic Pathology, 3rd edn. Elsevier Inc/Academic, London, pp 2761–2858Google Scholar
  55. Hall AP, Westwood FR, Wadsworth PF (2006) Review of the effects of anti-angiogenic compounds on the epiphyseal growth plate. Toxicol Pathol 34:131–147PubMedCrossRefGoogle Scholar
  56. Hartke J (1996) Have you seen this? Bone anti-resorptive properties of bisphosphonates. Toxicol Pathol 24:799–800PubMedCrossRefGoogle Scholar
  57. Hartmann K, Koenen M, Schauer S, Wittig-Blaich S, Ahmad M, Baschant U, Tuckermann JP (2016) Molecular actions of glucocorticoids in cartilage and bone during health, disease, and steroid therapy. Physiol Rev 96:409–447PubMedCrossRefGoogle Scholar
  58. Hrvacic B, Situm K, Duric K, Bosnjak B, Ferencic Z, Brajsa K, Markovic S, Glojnaric I (2014) Relative potencies of three glucocorticoids to induce hypoplasia of the physis and concomitant biochemical alterations in the rat. Drug Chem Toxicol 38:272–277PubMedCrossRefGoogle Scholar
  59. Hui AY, McCarty WJ, Masuda K et al (2012) A systems biology approach to synovial joint lubrication in health, injury, and disease. Wiley Interdiscip Rev Syst Biol Med 4:15–37PubMedCrossRefGoogle Scholar
  60. Huiskes R (2000) If bone is the answer, then what is the question? J Anat 197:145–156PubMedPubMedCentralCrossRefGoogle Scholar
  61. Institute of Medicine (1997) Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D, and fluoride. The National Academies Press, Washington, D.C.Google Scholar
  62. Jee WSS, Yao W (2001) Overview: animal models of osteopenia and osteoporosis. J Musculoskelet Neuronal Interact 1:193–207PubMedGoogle Scholar
  63. Jerome CP, Peterson PE (2001) Nonhuman primate models in skeletal research. Bone 29:1–6PubMedCrossRefGoogle Scholar
  64. JMHW (1999) Guideline concerning the clinical evaluation method for anti-osteoporosis agents, pharmaceutical examination No. 742. In Management BoH, ed.: issued by the Prefectural Bureau Chief, Bureau of Health Management, Section of Examination and Control, Bureau of Drug Safety, Japanese Ministry of Health and WelfareGoogle Scholar
  65. Jolette J, Wilker CE, Smith SY, Doyle N, Hardisty JF, Metcalfe AJ, Marriott TB, Fox J, Wells DS (2006) Defining a noncarcinogenic dose of recombinant human parathyroid hormone 1-84 in a 2-year study in Fischer 344 rats. Toxicol Pathol 34:929–940PubMedCrossRefGoogle Scholar
  66. Jones L, Allen M (2011) Animal models of osteonecrosis. Clin Rev Bone Miner Metabol 9:63–80CrossRefGoogle Scholar
  67. Kerlin R, Bolon B, Burkhardt J, Francke S, Greaves P, Meador V, Popp, J (2016) Scientific and regulatory policy committee: recommended (“best”) practices for determining, communicating, and using adverse effect data from nonclinical studies. Toxicol Pathol 44(2):147–162Google Scholar
  68. Khalatbari H, Parisi MT, Kwatra N, Harrison DJ, Shulkin BL (2019) Pediatric musculoskeletal imaging: the indications for and applications of PET/computed tomography. PET Clin 14:145–174PubMedCrossRefGoogle Scholar
  69. Kiebzak GM, Smith R, Gundberg CC, Howe JC, Sacktor B (1988a) Bone status of senescent male rats: chemical, morphometric, and mechanical analysis. J Bone Miner Res 3:37–45PubMedCrossRefGoogle Scholar
  70. Kiebzak GM, Smith R, Howe JC, Gundberg CM, Sacktor B (1988b) Bone status of senescent female rats: chemical, morphometric, and biomechanical analyses. J Bone Miner Res 3:439–446PubMedCrossRefGoogle Scholar
  71. Kramer K, Kinter LB (2003) Evaluation and applications of radiotelemetry in small laboratory animals. Physiol Genomics 13:197–205PubMedCrossRefGoogle Scholar
  72. Krishnan V, Bryant HU, Macdougald OA (2006) Regulation of bone mass by Wnt signaling. J Clin Invest 116:1202–1209PubMedPubMedCentralCrossRefGoogle Scholar
  73. Kumar S, Hoffman SJ, Samadfam R, Mansell P, Jolette J, Smith SY, Guldberg RE, Fitzpatrick LA (2013) The effect of rosiglitazone on bone mass and fragility is reversible and can be attenuated with alendronate. J Bone Miner Res 28:1653–1665PubMedCrossRefGoogle Scholar
  74. Lambert RGW, Østergaard M, Jaremko JL (2018) Magnetic resonance imaging in rheumatology. Magn Reson Imaging Clin N Am 26:599–613PubMedCrossRefGoogle Scholar
  75. Lamperth L, Dalakas MC, Dagani F, Anderson J, Ferrari R (1991) Abnormal skeletal and cardiac muscle mitochondria induced by zidovudine (AZT) in human muscle in vitro and in an animal model. Lab Invest 65:742–751PubMedGoogle Scholar
  76. Laverty S, Girard CA, Williams JM et al (2010) The OARSI histopathology initiative: recommendations for histological assessments of osteoarthritis in the rabbit. Osteoarthr Cartil 18(suppl 3):S53–S65PubMedCrossRefGoogle Scholar
  77. Leininger JR, Schutten M (2017) Oral cavity, teeth, and gingiva. In: Suttie AW, Leininger JR, Bradley AE (eds) Boorman’s pathology of the rat reference and atlas, 2nd edn. Elsevier, LondonGoogle Scholar
  78. Lelovas PP, Xanthos TT, Thoma SE, Lyritis GP, Dontas IA (2008) The laboratory rat as an animal model for osteoporosis research. Comp Med 58:424–430PubMedPubMedCentralGoogle Scholar
  79. Lin ASP, Boyd G, Varela A, Guldberg RE (2017) Biomechanics. In: Smith SY, Varela A, Samadfam R (eds) Bone toxicology, Molecular and Integrative Toxicology series. Springer, Gewerbestrasse, Switzerland, pp 229–252Google Scholar
  80. Little CB, Zaki S (2012) What constitutes an “animal model of osteoarthritis”: the need for consensus? Osteoarthr Cartil 20:261–267PubMedCrossRefGoogle Scholar
  81. Loberg LI, Logan M, Barnhart K, Fossey S, Whitney K (2017) Bone marrow findings secondary to antineoplastic compounds: hematopoietic, bone, and cytokine cross talk. Toxicol Pathol 45:879–883PubMedCrossRefGoogle Scholar
  82. Lui JC, Baron J (2011) Effects of glucocorticoids on the growth plate. Endocr Dev 20:187–193PubMedCrossRefGoogle Scholar
  83. Mahler JE, Flagler ND, Malarkey DE, Mann PC, Haseman JK, Eastin W (1998) Spontaneous and chemically induced proliferative lesions in Tg.AC transgenic and p53-heterozygous mice. Toxicol Pathol 26:501–511PubMedCrossRefGoogle Scholar
  84. Mazziotti G, Canalis E, Giustina A (2010) Drug-induced osteoporosis: mechanisms and clinical implications. Am J Med 123:877–884PubMedCrossRefGoogle Scholar
  85. McCoy AM (2015) Animal models of osteoarthritis: comparisons and key considerations. Vet Pathol 52:803–818PubMedCrossRefGoogle Scholar
  86. McLaughlin F, Mackintosh J, Hayes BP, McLaren A, Uings IJ, Salmon P, Humphreys J, Meldrum E, Farrow SN (2002) Glucocorticoid-induced osteopenia in the mouse as assessed by histomorphometry, microcomputed tomography, and biochemical markers. Bone 30:924–930PubMedCrossRefGoogle Scholar
  87. Melli G, Chaudhry V, Cornblath DR (2005) Rhabdomyolysis - an evaluation of 475 hospitalized patients. Medicine 84:377–385PubMedCrossRefGoogle Scholar
  88. Nathwani RA, Pais S, Reynolds TB, Kaplowitz N (2005) Serum alanine aminotransferase in skeletal muscle diseases. Hepatology 41:380–382PubMedCrossRefPubMedCentralGoogle Scholar
  89. National Toxicology Program (1990) Toxicology and carcinogenesis studies of sodium fluoride (CAS No. 781-49-4) in F344/N rats and B6C3F1 mice (drinking water studies). Natl. Toxicol Program Tech Rep Ser 393:1–448Google Scholar
  90. Nyska A, Maronpot RR, Long PH, Roycroft JH, Hailey JR, Travlos GS, Ghanayem BI (1999) Disseminated thrombosis and bone infarction in female rats following inhalation exposure to 2-butoxyethanol. Toxicol Pathol 27:287–294PubMedCrossRefPubMedCentralGoogle Scholar
  91. Palazzi X, Burkhardt JE, Caplain H, Dellarco V, Fant P, Foster JR, Francke S, Germann P, Groters S, Harada T, Harleman J, Inui K, Kaufmann W, Lenz B, Nagai H, Pohlmeyer-Esch G, Schulte A, Skydsgaard M, Tomlinson L, Wood CE, Yoshida M (2016) Characterizing “adversity” of pathology findings in nonclinical toxicity studies: results from the 4th ESTP international expert workshop. Toxicol Pathol 44:810–824PubMedCrossRefGoogle Scholar
  92. Parfitt AM, Drezner MK, Glorieux FH, Kanis JA, Malluche H, Meunier PJ, Ott SM et al (1987) Bone histomorphometry: standardization of nomenclature, symbols, and units. J Bone Miner Res 2:595–610PubMedCrossRefPubMedCentralGoogle Scholar
  93. Pelletier JP, Troncy E, Bertaim T, Thibaud D, Goulet AC, Abram F, Caron J, Boileau C, d'Anjou MA, Moreau M, Lussier B, Martel-Pelletier J (2011) Treatment with tiludronic acid helps reduce the development of experimental osteoarthritis lesions in dogs with anterior cruciate ligament transection followed by reconstructive surgery: a 1-year study with quantitative magnetic resonance imaging. J Rheumatol 38:118–128PubMedCrossRefPubMedCentralGoogle Scholar
  94. Pratesi A, Tarantini F, Di Bari M (2013) Skeletal muscle: an endocrine organ. Clin Cases Miner Bone Metab 10:11–14PubMedPubMedCentralGoogle Scholar
  95. Pritt ML, Hall DG, Recknor J, Credille KM, Brown DD, Yumibe NP, Schultze AE, Watson DE (2008) Fabp3 as a biomarker of skeletal muscle toxicity in the rat: comparison with conventional biomarkers. Toxicol Sci 103:382–396PubMedCrossRefGoogle Scholar
  96. Prysor-Jones RA, Jenkins JS (1980) Effect of excessive secretion of growth hormone on tissues of the rat, with particular reference to the heart and skeletal muscle. J Endocrinol 85:75–82PubMedCrossRefGoogle Scholar
  97. Renberg WC (2005) Pathophysiology and management of arthritis. Vet Clin North Am Small Anim Pract 35:1073–1091PubMedCrossRefGoogle Scholar
  98. Sato J, Doi T, Kanno T, Wako Y, Tsuchitani M, Narama I (2012a) Histopathology of incidental findings in cynomolgus monkeys (Macaca Fascicularis) used in toxicity studies. J Toxicol Pathol 25:63–101PubMedPubMedCentralCrossRefGoogle Scholar
  99. Sato J, Doi T, Wako Y, Hamamura M, Kanno T, Tsuchitani M, Narama I (2012b) Histopathology of incidental findings in beagles used in toxicity studies. J Toxicol Pathol 25:103–134PubMedPubMedCentralCrossRefGoogle Scholar
  100. Schiaffino S, Reggiani C (2011) Fiber types in mammalian skeletal muscles. Physiol Rev 91:1447–1531PubMedCrossRefPubMedCentralGoogle Scholar
  101. Scott JE, Stockwell RA (2006) Cartilage elasticity resides in shape module decoran and aggrecan sumps of damping fluid: implications in osteoarthrosis. J Physiol 574:643–650PubMedPubMedCentralCrossRefGoogle Scholar
  102. Shea JE, Miller SC (2005) Skeletal function and structure: implication for tissue-targeted therapeutics. Adv Drug Deliv Rev 57:945–957PubMedCrossRefPubMedCentralGoogle Scholar
  103. Shelton GD, Engvall E (2005) Canine and feline models of human inherited muscle diseases. Neuromuscul Disord 15:127–138PubMedCrossRefPubMedCentralGoogle Scholar
  104. Siebel M, Robins SP, Bilezikian JP (2006) Dynamics of bone and cartilage metabolism, 2nd edn. Elsevier, BurlingtonGoogle Scholar
  105. Smith SY, Samadfam R (2017) Biochemical markers of bone turnover. In: Smith SY, Varela A, Samadfam R (eds) Bone toxicology, Molecular and Integrative Toxicology series. Springer, Gewerbestrasse, Switzerland, pp 175–202Google Scholar
  106. Smith S, Varela A, Jolette J (2011) Nonhuman primate models of osteoporosis. In: Duque G and Watanabe K (eds) Osteoporosis research, Animal models series. Springer, London, pp 135–157Google Scholar
  107. Smith SY, Doyle N, Felx M (2017) Introduction and considerations in bone toxicology. In: Smith SY, Varela A, Samadfam R (eds) Bone toxicology, Molecular and Integrative Toxicology series. Springer, Gewerbestrasse, Switzerland, pp 3–26.Google Scholar
  108. Thompson RC (1973) Heparin osteoporosis: an experimental model using rats. J Bone Joint Surg 55:606–612PubMedCrossRefPubMedCentralGoogle Scholar
  109. Vahle JL (2017) Role of anatomic pathology in skeletal evaluations: applying INHAND diagnostic criteria. Toxicol Pathol 45:845–850PubMedCrossRefPubMedCentralGoogle Scholar
  110. Vahle JL, Sato M, Long GG, Yound JK, Francis PC, Engelhardt JA, Westmore MS, Ma YL, Nold JB (2002) Skeletal changes in rats given daily subcutaneous injections of recombinant human parathyroid hormone (1-34) for 2 years and relevance for human safety. Toxicol Pathol 30:312–321PubMedCrossRefGoogle Scholar
  111. Vahle JL, Long GG, Sandusky G, Westmore M, Ma YL, Sato M (2004) Bone neoplasms in F344 rats give teriparatide [rhPTH(1-34)] are dependent on duration of treatment and dose. Toxicol Pathol 32:426–438PubMedCrossRefGoogle Scholar
  112. Vahle JL, Zuehlke U, Schmidt A, Westmore M, Chen P, Sato M (2008) Lack of bone neoplasms and persistence of bone efficacy in cynomolgus macaques after long-term treatment with teriparatide [rhPTH(1-34)]. J Bone Miner Res 23:2033–2039PubMedCrossRefGoogle Scholar
  113. Vahle JL, Leininger JR, Long PH, Hall DG, Ernst H (2013) Bone, muscle, and tooth. In: Sahota PS, Popp JA, Hardisty JF, Gopinath C (eds) Toxicologic pathology: nonclinical safety assessment. CRC Press, Boca RatonGoogle Scholar
  114. Vahle JL, Ma YL, Burr D (2015) Skeletal assessments in the nonhuman primate. In: Bluemel J, Korte S, Schenck E, Weinbauer G (eds) The nonhuman primate in nonclinical drug development and safety assessment. Elsevier/Academic Press, Amsterdam, pp 606–627Google Scholar
  115. Varela A (2017) Skeletal Imaging. In: Smith SY, Varela A, Samadfam R (eds) Bone toxicology, Molecular and Integrative Toxicology series. Springer, Gewerbestrasse, Switzerland/New York, pp 203–228Google Scholar
  116. Varela A, Jolette J (2018) Bone toolbox: biomarkers, imaging tools, biomechanics and histomorphometry. Toxicol Pathol 46:511–529PubMedCrossRefGoogle Scholar
  117. Vassallo JD, Janovitz EB, Wescott DM, Chadwick C, Lowe-Krentz LJ, Lehman-McKeeman LD (2009) Biomarkers of drug-induced skeletal muscle injury in the rat: troponin I and myoglobin. Toxicol Sci 111:402–412PubMedCrossRefGoogle Scholar
  118. Vaughan J (1981a) Bone as a tissue. In: The physiology of bone, 3rd edn. Oxford University Press, London, pp 1–26Google Scholar
  119. Vaughan J (1981b) Cellular elements of the skeleton. In: The physiology of bone, 3rd edn. Oxford University Press, London, pp 27–55Google Scholar
  120. Vonderfecht SL, Stone ML, Eversole RR, Yancey MF, Schuette MR, Duncan BA, Ware JA (2004) Myopathy related to administration of a cationic amphiphilic drug and the use of multidose drug distribution analysis to predict its occurrence. Toxicol Pathol 32:318–325PubMedCrossRefGoogle Scholar
  121. Wancket LM (2017) Bone and joint medical devices: methods, models, and regulations. Toxicol Pathol 45:925–930PubMedCrossRefGoogle Scholar
  122. Wang F, Wang J, He J, Li W, Li J, Chen S, Zhang P, Liu H, Chen X (2017) Serum miRNAs miR-23a, 206, and 499 as potential biomarkers for skeletal muscle atrophy. Biomed Res Int 2017:8361237PubMedPubMedCentralGoogle Scholar
  123. Westwood FR, Bigley A, Randall K, Marsden AM, Scott RC (2005) Statin-induced muscle necrosis in the rat: distribution, development, and fibre selectivity. Toxicol Pathol 33:246–257PubMedCrossRefGoogle Scholar
  124. Westwood FR, Scott RC, Marsden AM, Bigley A, Randall K (2008) Rosuvastatin: characterization of induced myopathy in the rat. Toxicol Pathol 36:345–352PubMedCrossRefGoogle Scholar
  125. Whittemore LA, Song K, Li X, Aghajanian J, Davies M, Girgenrath S, Hill JJ, Jalenak M, Kelley P, Knight A, Maylor R, OHara D, Pearson A, Quazi A, Ryerson S, Tan XY, Tomkinson KN, Veldman GM, Widom A, Wright JF, Wudyka S, Zhao L, Wolfman NM (2003) Inhibition of myostatin in adult mice increases skeletal muscle mass and strength. Biochem Biophys Res Commun 300:965–971PubMedCrossRefGoogle Scholar
  126. Willmann R, Possekel S, Dubach-Powell J, Meier T, Ruegg MA (2009) Mammalian animal models for Duchenne muscular dystrophy. Neuromuscul Disord 19:241–249PubMedCrossRefGoogle Scholar
  127. Yanagihara GR, de Paiva AG, Neto MP, Torres LH, Shimano AC, Louzada MJQ, Annoni R, de Oliveira Penoni AC (2015) Effects of long-term administration of omeprazole on bone mineral density and the mechanical properties of the bone. Rev Bras Ortop 50:232–238PubMedPubMedCentralCrossRefGoogle Scholar
  128. Yang Y (2013) Skeletal morphogenesis and embryonic development. In: Rosen CJ (ed) Primer on the metabolic bone diseases and disorders of mineral metabolism, 8th edn. Wiley, Ames, Iowa, pp 3–14Google Scholar
  129. Yarovaya N, Kramarova L, Borg J, Kovalenko S, Caragounis A, Linnane A (2002) Age-related atrophy of rat soleus muscle is accompanied by changes in fibre type composition, bioenergy decline and mtDNA rearrangements. Biogerontology 3:25–27PubMedCrossRefGoogle Scholar
  130. Zoetis T, Tassinari MS, Bagi C, Walthall K, Hurtt ME (2003) Species comparison of postnatal bone growth and development. Birth Defects Res B Dev Reprod Toxicol 68:86–110PubMedCrossRefGoogle Scholar
  131. Zwicker GM, Eyster RC (1996) Proliferative bone lesions in rats fed a diet containing glucocorticoid for up to two years. Toxicol Pathol 24:246–250PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Stacey L. Fossey
    • 1
    Email author
  • D. Greg Hall
    • 2
  • Andrew W. Suttie
    • 3
  • Martin Guillot
    • 4
  • Aurore Varela
    • 4
  1. 1.Abbvie, Inc.North ChicagoUSA
  2. 2.Lilly Research LaboratoriesIndianapolisUSA
  3. 3.Covance Laboratories, Inc.ChantillyUSA
  4. 4.Charles River Laboratories, Inc.SennevilleCanada

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