Skip to main content
SpringerLink
Log in

An Overview of Bone Toxicology

  • Living reference work entry
  • First Online:
Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays

  • 48 Accesses

Abstract

The skeleton is an active and dynamic tissue that interacts with other complex systems such as the endocrine, nervous, and immune systems. During the development of a new therapeutic agent for adult or pediatric populations, the potential for bone-related effects is assessed by a weight of evidence approach consisting of a comprehensive evaluation of data available in the literature and from relevant in vivo and in vitro studies related to the development of the new compound. If concerns are raised based on the clinical indication, pharmacology, pharmacokinetics, or potential direct and/or secondary effects, they need to be correctly addressed in safety assessment nonclinical studies. Depending on the potential expected changes and animal species selected, all or a selection of the specialized bone parameters can be evaluated in standard toxicology studies. Those specialized bone endpoints can include serum or urinary biochemical markers of bone turnover and hormones, in vivo or ex vivo densitometry (dual-energy X-ray absorptiometry, peripheral quantitative computed tomography, microcomputed tomography), radiology, development of the skeleton for juvenile animals, biomechanical strength testing, quantitative static/dynamic histomorphometry, or expanded bone qualitative histopathology.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

Similar content being viewed by others

References and Further Reading

  • Allen MJ (2003) Biochemical markers of bone metabolism in animals: uses and limitations. Vet Clin Pathol 32(3):101–113

    Article  CAS  PubMed  Google Scholar 

  • Andersen B, Straarup EM, Heppner KM, Takahashi DL, Raffaele V, Dissen GA, Lewandowski K, Bödvarsdottir TB, Raun K, Grove KL, Kievit P (2018) FGF21 decreases body weight without reducing food intake or bone mineral density in high-fat fed obese rhesus macaque monkeys. Int J Obes 42(6):1151–1160. https://doi.org/10.1038/s41366-018-0080-7

    Article  CAS  Google Scholar 

  • Andrukhova OV, Erben RG (2017) Kidney-bone. In: Smith SY, Varela A, Samadfam R (eds) Bone toxicology, molecular and integrative toxicology. Springer, Cham, pp 335–362

    Chapter  Google Scholar 

  • Bolam SM, O’Regan-Brown A, Konar S, Callon KE, Coleman B, Dalbeth N, Monk AP, Musson DS, Cornish J, Munro JT (2022) Cytotoxicity of tranexamic acid to tendon and bone in vitro: is there a safe dosage? Orthop Surg Res 17:273. https://doi.org/10.1186/s13018-022-03167-5

    Article  Google Scholar 

  • Bonnet N, Benhamou CL, Brunet-Imbault B, Arlettaz A, Horcajada MN, Richard O, Vico L, Collomp K, Courteix D (2005) Severe bone alterations under beta2 agonist treatments: bone mass, microarchitecture and strength analyses in female rats. Bone 37(5):622–633

    Article  CAS  PubMed  Google Scholar 

  • Bouxsein ML, Boyd SK, Christiansen BA, Guldberg RE, Jepsen KJ, Muller R (2010) Guidelines for assessment of bone microstructure in rodents using micro-computed tomography. J Bone Miner Res 25:1468–1486. https://doi.org/10.1002/jbmr.141

    Article  PubMed  Google Scholar 

  • Boyce RW, Varela A, Chouinard L, Bussiere JL, Chellman GJ, Ominsky M, 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 64:314–325

    Article  CAS  PubMed  Google Scholar 

  • Bradley A, Wancket LM, Rinke M et al (2021) International harmonization of nomenclature and diagnostic criteria (INHAND): nonproliferative and proliferative lesions of the rabbit. Toxicol Pathol 34(3S):183S–292S

    Article  Google Scholar 

  • 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 20:1185–1189

    Article  CAS  PubMed  Google Scholar 

  • Charles ED, Neuschwander-Tetri BA, Pablo Frias J, Kundu S, Luo Y, Tirucherai GS et al (2019) Pegbelfermin (BMS-986036), PEGylated FGF21, in patients with obesity and type 2 diabetes: results from a randomized phase 2 study. Obesity 27:41–49

    Article  CAS  PubMed  Google Scholar 

  • Cho SW, An JH, Park H, Yang JY, Choi HJ, Kim SW, Park YJ, Kim SY, Yim M, Baek WY, Kim JE, Shin CS (2013) Positive regulation of osteogenesis by bile acid through FXR. J Bone Miner Res 28(10):2109–2121. https://doi.org/10.1002/jbmr.1961

    Article  CAS  PubMed  Google Scholar 

  • Collins FL, Kim SMI, McCabe LR, Weaver CM (2017) Intestinal microbiota and bone health: the role of prebiotics, probiotics, and diet. In: Smith SY, Varela A, Samadfam R (eds) Bone toxicology, molecular and integrative toxicology. Springer, Cham, pp 417–444

    Chapter  Google Scholar 

  • Colman K, Andrews RN, Atkins H, Boulineau T, Bradley A, Braendli-Baiocco A, Capobianco R, Caudell D, Cline M, Doi T, Ernst R, van Esch E, Everitt J, Fant P, Gruebbel MM, Mecklenburg L, Miller AD, Nikula KJ, Satake S, Schwartz J, Sharma A, Shimoi A, Sobry C, Taylor I, Vemireddi V, Vidal J, Wood C, Vahle JL (2021) International harmonization of nomenclature and diagnostic criteria (INHAND): non-proliferative and proliferative lesions of the non-human primate (M. Fascicularis). Toxicol Pathol 34(3S):1S–182S. https://doi.org/10.1293/tox.34.1S

    Article  Google Scholar 

  • Cui GL, Syversen U, Zhao CM, Waldum HL (2001) Long-term omeprazole treatment suppresses body weight gain and bone mineralization in young male rats. Scand J Gastroenterol 36:1011–1015

    Article  CAS  PubMed  Google Scholar 

  • Cui A, Jian L, Shaohui J, Fengguang M, Genbei W, Yaqian X, Zhengshuai L, Jing G, Jun H, Ping T, Tony W, Jianxun C, Xiaohui M, Yu L (2020) The effects of B1344, a novel fibroblast growth factor 21 analog, on nonalcoholic steatohepatitis in nonhuman primates. Diabetes 69(8):1611–1623. https://doi.org/10.2337/db20-0209

    Article  PubMed  Google Scholar 

  • 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 28:2–17

    Article  PubMed  Google Scholar 

  • Donnelly E (2011) Methods for assessing bone quality: a review. Clin Orthop Relat Res 469(8):2128–2138

    Article  PubMed  Google Scholar 

  • Doyle N, Varela A, Haile S, Guldberg R, Kostenuik PJ, Ominsky MS, Smith SY, Hattersley G (2018) Abaloparatide, a novel PTH receptor agonist, increased bone mass and strength in ovariectomized cynomolgus monkeys by increasing bone formation without increasing bone resorption. Osteoporos Int 29(3):685–697. https://doi.org/10.1007/s00198-017-4323-6

    Article  CAS  PubMed  Google Scholar 

  • Eastell R, Vittinghoff E, Lui LY et al (2022) Validation of the surrogate threshold effect for change in bone mineral density as a surrogate endpoint for fracture outcomes: the FNIH-ASBMR SABRE project. J Bone Miner Res 37(1):29–35. https://doi.org/10.1002/jbmr.4433

    Article  CAS  PubMed  Google Scholar 

  • Edin ML, Miclau T, Lester GE, Lindsey RW, Dahners LE (1996) Effect of cefazolin and vancomycin on osteoblasts in vitro. Clin Orthop Relat Res 333:245–251

    Article  Google Scholar 

  • Erben RG (1997) Embedding of bone samples in methylmethacrylate: an improved method suitable for bone histomorphometry, histochemistry, and immunohistochemistry. J Histochem Cytochem 45:307–313

    Article  CAS  PubMed  Google Scholar 

  • Erben RG (2003) Bone labeling techniques. In: An YH et al (eds) Handbook of histology methods for bone and cartilage. Humana Press, Totowa, pp 99–117

    Google Scholar 

  • Erben RG, Glösmann M (2012) Histomorphometry in rodents. Methods Mol Biol 816:279–303

    Article  CAS  PubMed  Google Scholar 

  • 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. Springer, Cham, pp 253–278

    Chapter  Google Scholar 

  • European Medicines Agency (EMA) (2007) Guideline on the evaluation of medical products in the treatment of primary osteoporosis. CPMP/EWP/552/95 Rev. 2. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-evaluation-medicinal-products-treatment-primary-osteoporosis_en.pdf. Accessed 16 Dec 2022

  • European Medicines Agency (EMA) (2008) Guideline on the need for nonclinical testing in juvenile animals of pharmaceuticals for pediatric indications. Doc. Ref. EMEA/CHMP/SWP/169215/2005. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-need-non-clinical-testing-juvenile-animals-pharmaceuticals-paediatric-indications_en.pdf. Accessed 16 Dec 2022

  • Feteih R, Tassinari MS, Lian JB (1990) Effect of sodium warfarin on vitamin K-dependent proteins and skeletal development in the rat fetus. J Bone Miner Res 5:885–894

    Article  CAS  PubMed  Google Scholar 

  • Food and Drug Administration (FDA) (2006) Guidance for industry – nonclinical safety evaluation of pediatric drug products. https://www.fda.gov/media/119658/download. Accessed 16 Dec 2022

  • Food and Drug Administration (FDA) (2019) Osteoporosis: nonclinical evaluation of drugs intended for treatment https://www.fda.gov/media/129899/download. Accessed 16 Dec 2022

  • Fossey S, Vahle J, Long P, Schelling S, Ernst H, Waite Boyce R, 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 tissue (bones, joints and teeth). Toxicol Pathol 29(3S):49S–103S

    Article  CAS  Google Scholar 

  • Fossey SL, Hall DG, Suttie AW, Guillot M, Varela A (2019) Pathology of bone, skeletal muscle, and tooth. In: Steinbach TJ, Patrick DJ, Cosenza ME (eds) Toxicologic pathology for non-pathologists. Humana, New York, pp 571–618. https://doi.org/10.1007/978-1-4939-9777-0_14

    Chapter  Google Scholar 

  • Fox J, Newman MK, Turner CH, Guldberg RE, Varela A, Smith SY (2008) Effects of treatment with parathyroid hormone 1–84 on quantity and biomechanical properties of thoracic vertebral trabecular bone in ovariectomized rhesus monkeys. Calcif Tissue Int 82:212–220

    Article  CAS  PubMed  Google Scholar 

  • Frazier KS (2017) Drug-induced physeal abnormalities in preclinical toxicity studies. Toxicol Pathol 45:869–875

    Article  CAS  PubMed  Google Scholar 

  • Frazier KS, Thomas RA, Scicchitano MS, Mirabile RC, Zimmerman DA, Grygielko E et al (2007) Inhibition of ALK5 signaling induces physeal hypertrophy in rats. Toxicol Pathol 35:284–295

    Article  CAS  PubMed  Google Scholar 

  • Gasser JA, Kneissel M (2017) Bone physiology and biology. In: Smith SY, Varela A, Samadfam R (eds) Bone toxicology, molecular and integrative toxicology. Springer, Cham, pp 27–94

    Chapter  Google Scholar 

  • Grol MW, Lee BH (2018) Gene therapy for repair and regeneration of bone and cartilage. Curr Opin Pharmacol 40:59–66. https://doi.org/10.1016/j.coph.2018.03.005

    Article  CAS  PubMed  Google Scholar 

  • 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. Elsevier Inc./Academic, pp 2761–2858

    Chapter  Google Scholar 

  • Hartke J (1996) Have you seen this? Bone antiresorptive properties of bisphosphonates. Toxicol Pathol 24:799–800

    Article  CAS  PubMed  Google Scholar 

  • Hernandez CJ, Keaveny TM (2006) A biomechanical perspective on bone quality. Bone 39(6):1173–1181. https://doi.org/10.1016/j.bone.2006.06.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Holtom PD, Pavkovic SA, Bravos PD, Patzakis MJ, Shepherd LE, Frenkel B (2005) Inhibitory effects of the quinolone antibiotics trovafloxacin, ciprofloxacin, and levofloxacin on osteoblastic cells in vitro. J Orthop Res 18(5):721–727. https://doi.org/10.1002/jor.1100180507

    Article  Google Scholar 

  • Hotchkiss C (1999) Use of peripheral quantitative computed tomography for densitometry of the femoral neck and spine in cynomolgus monkeys (Macaca fascicularis). Bone 24:101–107

    Article  CAS  PubMed  Google Scholar 

  • Hotchkiss C, Stavisky R, Nowak J, Brommage R, Lees CJ, Kaplan J (2001) Levormeloxifene prevents increased bone turnover and vertebral bone loss following ovariectomy in cynomolgus monkeys. Bone 29:7–15

    Article  CAS  PubMed  Google Scholar 

  • Innocenti M, Baldrighi C (2018) Growth considerations in pediatrics upper extremity trauma and reconstruction. In: Plastic surgery: volume 6: hand and upper extremity (30). Elsevier Inc, pp 670–687

    Google Scholar 

  • International Council for Harmonisation (ICH) (2020) Nonclinical safety testing in support of development of paediatric pharmaceuticals S11. https://database.ich.org/sites/default/files/S11_Step4_FinalGuideline_2020_0310.pdf. Accessed 16 Dec 2022

  • International Organization for Standardization (ISO) 10993-6 (2016) Biological evaluation of medical device part 6: Tests for local effects after implantation

    Google Scholar 

  • Isefuku S, Joyner CJ, Simpson AH (2001) Toxic effect of rifampicin on human osteoblast-like cells. J Orthop Res 19(5):950–954. https://doi.org/10.1016/S0736-0266(01)00022-5

    Article  CAS  PubMed  Google Scholar 

  • Ivaska KK, Gerdhem P, Akesson K et al (2007) Effect of fracture on bone turnover markers: a longitudinal study comparing marker levels before and after injury in 113 elderly women. J Bone Miner Res 22:1155–1164

    Article  CAS  PubMed  Google Scholar 

  • Japanese Ministry of Health, Labour and Welfare (MHLW) (2012) Guideline on the nonclinical safety study in juvenile animals for pediatric drugs. https://www.pref.kagawa.lg.jp/documents/7476/161_241015.pdf. Accessed 16 Dec 2022

  • Johansson S, Lind PM, Hakansson H, Oxlund H, Orberg J, Melhus H (2002) Subclinical hypervitaminosis a causes fragile bones in rats. Bone 3:685–689

    Article  Google Scholar 

  • Jolette J, Wilker CE, Wells DS et al (2006) Defining a noncarcinogenic dose of recombinant human parathyroid hormone 1–84 in a 2-year study in Fischer 344 rats. Toxicol Pathol 34(7):929–940. https://doi.org/10.1080/01926230601072301

    Article  CAS  PubMed  Google Scholar 

  • Jolette J, Attalla B, Varela A, Long GG, Mellal N, Trimm S, Smith SY, Ominsky MS, Hattersley G (2017) Comparing the incidence of bone tumors in rats chronically exposed to the selective PTH receptor agonist abaloparatide or PTH(1-34). Regul Toxicol Pharmacol 86:356–365

    Article  CAS  PubMed  Google Scholar 

  • Kahn M (2014) Can we safely target the WNT pathway? Nat Rev Drug Discov 13(7):513–532

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):147–162. https://doi.org/10.1177/2F0192623315623265

    Article  PubMed  Google Scholar 

  • 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 14:145–174

    Article  PubMed  Google Scholar 

  • Kim AM, Somayaji VR, Dong JQ, Rolph TP, Weng Y, Chabot JR et al (2017) Once-weekly administration of a long-acting fibroblast growth factor 21 analogue modulates lipids, bone turnover markers, blood pressure and body weight differently in obese people with hypertriglyceridaemia and in non-human primates. Diabetes Obes Metab 19:1762–1772

    Article  CAS  PubMed  Google Scholar 

  • Kimmel DB (2017) Animal models in bone research. In: Smith SY, Varela A, Samadfam R (eds) Bone toxicology, molecular and integrative toxicology. Springer, Cham, pp 129–171

    Chapter  Google Scholar 

  • Kinoshita Y, Mohamed FF, Amadeu de Oliveira F, Narisawa S, Miyake K, Foster BL, Millán JL (2021) Gene therapy using adeno-associated virus serotype 8 encoding TNAP-D10 improves the skeletal and dentoalveolar phenotypes in Alpl−/− mice. J Bone Miner Res 36(9):1835–1849. https://doi.org/10.1002/jbmr.4382

    Article  CAS  PubMed  Google Scholar 

  • Klinck RJ, Campbell GM, Boyd SK (2008) Radiation effects on bone architecture in mice and rats resulting from in vivo micro-computed tomography scanning. Med Eng Phys 30:888–895

    Article  PubMed  Google Scholar 

  • Komm BS, Vlasseros F, Samadfam R, Chouinard L, Smith SY (2011) Skeletal effects of bazedoxifene paired with conjugated estrogens in ovariectomized rats. Bone 49:376–386

    Article  CAS  PubMed  Google Scholar 

  • Kostenuik PJ, Smith SY, Jolette J, Schroeder J, Pyrah I, Ominsky MS (2011) Decreased bone remodeling and porosity are associated with improved bone strength in ovariectomized cynomolgus monkeys treated with denosumab, a fully human RANKL antibody. Bone 49:151–161

    Article  CAS  PubMed  Google Scholar 

  • Kramer SM, May JR, Patrick DJ, Chouinard L, Boyer M, Doyle N, Varela A, Smith SY, Longstaff E (2009) Instilled or injected purified natural capsaicin has no adverse effects on rat hindlimb sensory-motor behaviour or osteotomy repair. Anesth Analg 109(1):249–257

    Article  PubMed  Google Scholar 

  • Kulkarni RN, Baldock PA (2017) Bone and the central nervous system. In: Smith SY, Varela A, Samadfam R (eds) Bone toxicology, molecular and integrative toxicology. Springer, Cham, pp 399–416

    Chapter  Google Scholar 

  • Kumar S, Hoffman SJ, Samadfam R, Mansell P, Jolette J, Smith SY, Guldberg RE et al (2013) The effect of rosiglitazone on bone mass and fragility is reversible and can be attenuated with alendronate. J Bone Miner Res 28:1653–1665

    Article  CAS  PubMed  Google Scholar 

  • Kwak HB, Kim HS, Lee MS, Kim KJ, Choi EY, Choi MK, Kim JJ et al (2009) Pyridone 6, a pan-Janus-activated kinase inhibitor, suppresses osteoclast formation and bone resorption through downregulation of receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL)-induced c-Fos and nuclear factor of activated T cells (NFAT) c1 expression. Biol Pharm Bull 32:45–50

    Article  CAS  PubMed  Google Scholar 

  • Lee DC, Varela A, Kostenuik PJ, Ominsky MS, Keaveny TM (2016) Finite element analysis of Denosumab treatment effects on vertebral strength in ovariectomized cynomolgus monkeys. J Bone Miner Res 31(8):1586–1595. https://doi.org/10.1002/jbmr.2830

    Article  CAS  PubMed  Google Scholar 

  • Li X, Ominsky MS, Warmington KS, Morony S, Gong J, Cao J, Gao Y et al (2009) Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J Bone Miner Res 24:578–588

    Article  CAS  PubMed  Google Scholar 

  • Lin ASP, Boyd G, Varela A, Guldberg RE (2017) Biomechanics. In: Smith SY, Varela A, Samadfam R (eds) Bone toxicology, molecular and integrative toxicology. Springer, Cham, pp 229–252

    Chapter  Google Scholar 

  • Mazziotti G, Canalis E, Giustina A (2010) Drug-induced osteoporosis: mechanisms and clinical implications. Am J Med 123:877–884

    Article  CAS  PubMed  Google Scholar 

  • McLaughlin F, Mackintosh J, Hayes BP, McLaren A, Uings IJ, Salmon P, Humphreys J et al (2002) Glucocorticoid-induced osteopenia in the mouse as assessed by histomorphometry, microcomputed tomography, and biochemical markers. Bone 30:924–390

    Article  CAS  PubMed  Google Scholar 

  • Miclau T, Edin ML, Lester GE, Lindsey RW, Dahners LE (1995) Bone toxicity of locally applied aminoglycosides. J Orthop Trauma 9(5):401–406. https://doi.org/10.1097/00005131-199505000-00007

    Article  CAS  PubMed  Google Scholar 

  • Miclau T, Edin ML, Lester GE, Lindsey RW, Dahners LE (1998) Effect of ciprofloxacin on the proliferation of osteoblast-like MG-63 human osteosarcoma cells in vitro. J Orthop Res 16(4):509–512. https://doi.org/10.1002/jor.1100160417

    Article  CAS  PubMed  Google Scholar 

  • Mo C, Wang Z, Bonewald L, Brotto M (2017) Bone and muscle. In: Smith SY, Varela A, Samadfam R (eds) Bone toxicology, molecular and integrative toxicology. Springer, Cham, pp 281–316

    Chapter  Google Scholar 

  • Ohlsson C, Bengtsson BA, Isaksson OG, Andreassen TT, Slootweg MC (1998) Growth hormone and bone. Endocr Rev 19(1):55–79. https://doi.org/10.1210/edrv.19.1.0324

    Article  CAS  PubMed  Google Scholar 

  • Ominsky MS, Vlasseros F, Jolette J, Smith SY, Stouch B, Doellgast G, Gong J, Gao Y, Cao J, Graham K, Tipton B, Cai J, Deshpande R, Zhou L, Hale MD, Lightwood DJ, Henry AJ, Popplewell AG, Moore AR, Robinson MK, Lacey DL, Simonet WS, Paszty C (2010) Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength. J Bone Miner Res 25:948–959. https://doi.org/10.1002/jbmr.14

    Article  CAS  PubMed  Google Scholar 

  • Ominsky MS, Niu QT, Li C, Li X, Ke HZ (2014) Tissue-level mechanisms responsible for the increase in bone formation and bone volume by sclerostin antibody. J Bone Miner Res 29:1424–1430

    Article  CAS  PubMed  Google Scholar 

  • Ominsky MS, Boyd SK, Varela A, Jolette J, Felx M, Doyle N, Mellal N, Smith SY, Locher K, Buntich S, Pyrah I, Boyce RW (2017) Romosozumab improves bone mass and strength while maintaining bone quality in Ovariectomized Cynomolgus monkeys. J Bone Miner Res 32(4):788–801. https://doi.org/10.1002/jbmr.3036

    Article  CAS  PubMed  Google Scholar 

  • Onuora S (2019) Gene therapy counteracts bone loss in osteoporosis. Nat Rev Rheumatol 15:513. https://doi.org/10.1038/s41584-019-0288-5

    Article  PubMed  Google Scholar 

  • Orimo H, Nakamura T, Hosoi T, Iki M, Uenishi K, Endo N, Ohta H, Shiraki M, Sugimoto T, Suzuki T, Soen S, Nishizawa Y, Hagino H, Fukunaga M, Fujiwara S (2012) Japanese 2011 guidelines for prevention and treatment of osteoporosis – executive summary. Arch Osteoporos 7(1):3–20. https://doi.org/10.1007/s11657-012-0109-9

    Article  PubMed  PubMed Central  Google Scholar 

  • Osborne DR, Kuntner C, Berr S, Stout D (2017) Guidance for efficient small animal imaging quality control. Mol Imaging Biol 19(4):485–498. https://doi.org/10.1007/s11307-016-1012-3

    Article  PubMed  Google Scholar 

  • Peake NJ, Hobbs AJ, Pingguan-Murphy B, Salter DM, Berenbaum F, Chowdhury TT (2014) Role of C-type natriuretic peptide signalling in maintaining cartilage and bone function. Osteoarthr Cartil 22(11):1800–1807. https://doi.org/10.1016/j.joca.2014.07.018

    Article  CAS  Google Scholar 

  • Pennypacker BL, Duong LT, Cusick TE, Masarachia PJ, Gentile MA, Gauthier J-Y, Black WC, Scott BB, Samadfam R, Smith SY, Kimmel DB (2011) Cathepsin K inhibitors prevent bone loss in estrogen-deficient rabbits. J Bone Miner Res 26:252–262. https://doi.org/10.1002/jbmr.223

    Article  CAS  PubMed  Google Scholar 

  • Pouliot L, Schneider M, DeCristofaro M, Samadfam R, Smith SY, Beckman DA (2013) Assessment of a nonsteroidal aromatase inhibitor, letrozole, in juvenile rats. Birth Defects Res B Dev Reprod Toxicol 98:374–390

    Article  CAS  PubMed  Google Scholar 

  • Raisin S, Belamie E, Morille M (2016) Non-viral gene activated matrices for mesenchymal stem cells based tissue engineering of bone and cartilage. Biomaterials 104:223–237. https://doi.org/10.1016/j.biomaterials.2016.07.017

    Article  CAS  PubMed  Google Scholar 

  • Rao DB, Hoberman AM, Brown PC, Varela A, Bolon B (2021) Regulatory perspectives on juvenile animal toxicologic pathology. Toxicol Pathol 49(8):1393–1404. https://doi.org/10.1177/01926233211046869

    Article  PubMed  Google Scholar 

  • Rathbone CR, Cross JD, Brown KV, Murray CK, Wenke JC (2011) Effect of various concentrations of antibiotics on osteogenic cell viability and activity. J Orthop Res 29(7):1070–1074. https://doi.org/10.1002/jor.21343

    Article  CAS  PubMed  Google Scholar 

  • Ren Z-Y, Machuca-Gayet I, Domenget C, Buchet R, Wu Y, Jurdic P, Mebarek S (2015) Azanitrile cathepsin K inhibitors: effects on cell toxicity, osteoblast-induced mineralization and osteoclast-mediated bone resorption. PLoS One 10(7):e0132513. https://doi.org/10.1371/journal.pone.0132513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rosen CJ (2017) Bone and energy metabolism. In: Smith SY, Varela A, Samadfam R (eds) Bone toxicology, molecular and integrative toxicology. Springer, Cham, pp 445–463

    Chapter  Google Scholar 

  • Ruehl-Fehlert C, Kittel B, Morawietz G et al (2003) Revised guides for organ sampling and trimming in rats and mice – part 1. Exp Toxicol Pathol 55(2-3):91–106

    Article  PubMed  Google Scholar 

  • Russo CR, Lauretani F, Bandinelli S, Bartali B, Di Iorio A, Volpato S, Guralnik JM, Harris T, Ferrucci L (2003) Aging bone in men and women: beyond changes in bone mineral density. Osteoporos Int 14:531–538

    Article  CAS  PubMed  Google Scholar 

  • Ryan AM, Eppler DB, Hagler KE, Bruner RH, Thomford PJ, Hall RL, Shopp GM, O’Neill CA (1999) Preclinical safety evaluation of rhuMAbVEGF, an antiangiogenic humanized monoclonal antibody. Toxicol Pathol 27(1):78–86. https://doi.org/10.1177/019262339902700115. PMID: 10367678

    Article  CAS  PubMed  Google Scholar 

  • Saito M, Grynpas MD, Burr DB, Allen MR, Smith SY, Doyle N, Amizuka N, Hasegawa T, Kida Y, Marumo K, Saito H (2015) Treatment with eldecalcitol positively affects mineralization, microdamage, and collagen crosslinks in primate. Bone 73:8–15. https://doi.org/10.1016/j.bone.2014.11.025

    Article  CAS  PubMed  Google Scholar 

  • Sanyal A, Charles ED, Neuschwander-Tetri BA, Loomba R, Harrison SA, Abdelmalek MF et al (2018) Pegbelfermin (BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 2a trial. Lancet 392:2705–2717. https://doi.org/10.1016/S0140-6736(18)31785-9

    Article  CAS  PubMed  Google Scholar 

  • Shiels SM, Cobb RR, Bedigrew KM, Ritter G, Kirk JF, Kimbler A, Baker IF, Wenke JC (2016) Antibiotic-loaded bone void filler accelerates healing in a femoral condylar rat model. Bone Joint J 98-B:1126–1131

    Article  CAS  PubMed  Google Scholar 

  • Skydsgaard M, Dincer Z, Haschek WM et al (2021) International harmonization of nomenclature and diagnostic criteria (INHAND): nonproliferative and proliferative lesions of the minipig. Toxicol Pathol 49(1):110–228. https://doi.org/10.1177/0192623320975373. PMID: 33393872

    Article  PubMed  Google Scholar 

  • Smith SY, Samadfam R (2017) Biochemical markers of bone turnover. In: Smith SY, Varela A, Samadfam R (eds) Bone toxicology, molecular and integrative toxicology. Springer, Cham, pp 175–202

    Chapter  Google Scholar 

  • Smith BB, Cosenza ME, Mancini A, Dunstan C, Gregson R, Martin SW, Smith SY, Davis H (2003a) A toxicity profile of osteoprotegerin in the cynomolgus monkey. Intl J Toxicol 22:403–412

    Article  CAS  Google Scholar 

  • Smith SY, Recker RR, Hannan M, Muller R, Bauss F (2003b) Intermittent intravenous administration of the bisphosphonate ibandronate prevents bone loss and maintains bone strength and quality in ovariectomized cynomolgus monkeys. Bone 32:45–55

    Article  CAS  PubMed  Google Scholar 

  • Smith SY, Doyle N, Boyer M, Chouinard L, Saito H (2013) Eldecalcitol, a vitamin D analog, reduces bone turnover and increases trabecular and cortical bone mass, density, and strength in ovariectomized cynomolgus monkeys. Bone 57(1):116–122. https://doi.org/10.1016/j.bone.2013.06.005

    Article  CAS  PubMed  Google Scholar 

  • Smith SY, Jolette J, Chouinard L, Komm BS (2015) The effects of Bazedoxifene in the ovariectomized aged cynomolgus monkey. J Bone Miner Metab 33(2):161–172. https://doi.org/10.1007/s00774-014-0580-z

    Article  CAS  PubMed  Google Scholar 

  • Smith SY, Doyle N, Felx M (2017) Introduction and consideration in bone toxicology. In: Smith SY, Varela A, Samadfam R (eds) Bone toxicology, molecular and integrative toxicology. Springer, Cham, pp 3–26

    Chapter  Google Scholar 

  • Stoffel K, Engler H, Kuster M et al (2007) Changes in biochemical markers after lower limb fractures. Clin Chem 53:131–134

    Article  CAS  PubMed  Google Scholar 

  • Takeda S, Smith SY, Tamura T, Saito H, Takahashi F, Samadfam R, Haile S, Doyle N, Endo K (2015) Long-term treatment with Eldecalcitol (1α, 25-Dihydroxy-2β-(3-hydroxypropyloxy) vitamin D3) suppresses bone turnover and leads to prevention of bone loss and bone fragility in ovariectomized rats. Calcif Tissue Int 96(1):45–55. https://doi.org/10.1007/s00223-014-9937-5

    Article  CAS  PubMed  Google Scholar 

  • Talukdar S, Zhou Y, Li D, Rossulek M, Dong J, Somayaji V, Weng Y, Clark R, Lanba A, Owen BM, Brenner MB, Trimmer JK, Gropp KE, Chabot JR, Erion DM, Rolph TP, Goodwin B, Calle RA (2016) A long-acting FGF21 molecule, PF-05231023, decreases body weight and improves lipid profile in non-human primates and type 2 diabetic subjects. Cell Metab 23:427–440

    Article  CAS  PubMed  Google Scholar 

  • Thompson K (2007) Bones and joints. In: Maxie MG (ed) Pathology of domestic animals. Elsevier Saunders, pp 1–184

    Google Scholar 

  • Thompson KE, Guillot M, Graziano MJ, Mangipudy RS, Chadwick KD (2021) Pegbelfermin, a PEGylated FGF21 analogue, has pharmacology without bone toxicity after 1-year dosing in skeletally-mature monkeys. Toxicol Appl Pharmacol 428:115673. https://doi.org/10.1016/j.taap.2021.115673. Epub 2021 Aug 6. PMID: 34364948

    Article  CAS  PubMed  Google Scholar 

  • Tomkinson A, Moores S, Adamo M, Guillot M, Bienvenu J-G, Robinson K, Burns-Naas LA (2018) Endochondral ossification in developing long bones of F1 offspring following administration of andecaliximab to F0 dams during gestation and lactation. Presented at the Society of Toxicology (SOT) 57th Annual meeting, San Antonio, Texas, USA

    Google Scholar 

  • Vahle JL (2017) Role of anatomic pathology in skeletal evaluations: applying INHAND diagnostic criteria. Toxicol Pathol 45(7):845–850. https://doi.org/10.1177/2F0192623317734511

    Article  PubMed  Google Scholar 

  • 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, 1st edn. CRC Press, Boca Raton, pp 561–586

    Google Scholar 

  • Vahle J, Leininger J, Long P et al (2019) Bone, muscle and tooth. In: Sahota PS, Popp JA, Hardisty JF, Gopinath C (eds) Toxicologic pathology: nonclinical safety assessment, 2nd edn. CRC Press, Florida, pp 715–742

    Google Scholar 

  • Varela A (2017) Skeletal Imaging. In: Smith SY, Varela A, Samadfam R (eds) Bone toxicology, molecular and integrative toxicology. Springer, Cham, pp 203–228

    Chapter  Google Scholar 

  • Varela A, Jolette J (2018) Bone toolbox: biomarkers, imaging tools, biomechanics, and Histomorphometry. Toxicol Pathol 46(5):511–529. https://doi.org/10.1177/0192623318779565

    Article  CAS  PubMed  Google Scholar 

  • Varela A, Chouinard L, Lesage E, Guldberg R, Smith SY, Kostenuik PJ, Hattersley G (2017a) One year of abaloparatide, a selective peptide activator of the PTH1 receptor, increased bone mass and strength in ovariectomized rats. Bone 95:143–150. https://doi.org/10.1016/j.bone.2016.11.027

    Article  CAS  PubMed  Google Scholar 

  • Varela A, Chouinard L, Lesage E, Smith SY, Hattersley G (2017b) One year of abaloparatide, a selective activator of the PTH1 receptor, increased bone formation and bone mass in osteopenic ovariectomized rats without increasing bone resorption. J Bone Miner Res 32(1):24–33. https://doi.org/10.1002/jbmr.3003

    Article  CAS  PubMed  Google Scholar 

  • Walsh WR, Oliver RA, Christou C, Lovric V, Walsh ER, Prado GR, Haider T (2017) Critical size bone defect healing using collagen-calcium phosphate bone graft materials. PLoS One 12(1):e0168883

    Article  PubMed  PubMed Central  Google Scholar 

  • Wei W, Dutchak PA, Wang X, Ding X, Wang X, Bookout AL, Goetz R et al (2012) Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor g. Proc Natl Acad Sci U S A 109:3143–3148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weinbauer GF, Niehoff M, Niehaud M, Srivastav S, Fuchs A, Van Esch E, Cline JM (2008) Physiology and endocrinology of the ovarian cycle in macaques. Toxicol Pathol 36:7S–23S

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weitzmann MN (2017) Bone and the immune system. In: Smith SY, Varela A, Samadfam R (eds) Bone toxicology, molecular and integrative toxicology. Springer, Cham, pp 363–398

    Chapter  Google Scholar 

  • Wiesli MG, Kaiser J-P, Gautier E, Wick P, Maniura-Weber K, Rottmar M, Wahl P (2021) Influence of ceftriaxone on human bone cell viability and in vitro mineralization potential is concentration- and time-dependent. Bone Joint Res 10(3):218–225. https://doi.org/10.1302/2046-3758.103.BJR-2020-0412

    Article  PubMed  PubMed Central  Google Scholar 

  • Woicke J, Al-Haddawi MM, Bienvenu JG et al (2021) International harmonization of nomenclature and diagnostic criteria (INHAND): nonproliferative and proliferative lesions of the dog. Toxicol Pathol 49(1):5–109. https://doi.org/10.1177/0192623320968181

    Article  PubMed  Google Scholar 

  • 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 50:232–238

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Charles River Laboratories, Senneville, QC, Canada

    N. Doyle, A. Bédard, R. Schafbuch, G. Boyd, M. Felx & A. Varela

  2. Charles River Laboratories, Harlow, UK

    J. R. White

Authors
  1. N. Doyle
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Bédard
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R. Schafbuch
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G. Boyd
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. Felx
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J. R. White
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A. Varela
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to N. Doyle .

Editor information

Editors and Affiliations

  1. CorDynamics, Dieburg, Hessen, Germany

    Franz J. Hock

  2. Cytokinetics (United States), South San Francisco, CA, USA

    Michael K. Pugsley

Section Editor information

  1. Toxicology, Cytokinetics, South San Francisco, CA, USA

    Michael K. Pugsley

Rights and permissions

Reprints and permissions

Copyright information

© 2023 Springer Nature Switzerland AG

About this entry

Check for updates. Verify currency and authenticity via CrossMark

Cite this entry

Doyle, N. et al. (2023). An Overview of Bone Toxicology. In: Hock, F.J., Pugsley, M.K. (eds) Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays. Springer, Cham. https://doi.org/10.1007/978-3-030-73317-9_119-1

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-73317-9_119-1

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-73317-9

  • Online ISBN: 978-3-030-73317-9

  • eBook Packages: Springer Reference Biomedicine and Life SciencesReference Module Biomedical and Life Sciences

Publish with us

Policies and ethics

Search

Navigation