As head of a bone research department, the successful integration of imaging techniques into a GLP-regulated facility was one of my primary objectives and resulted in the establishment of an imaging facility with a world-class reputation for precise evaluations and consistent high quality. As world leaders in preclinical contract bone research my team has set the industry standard for bone densitometry assessments.

Imaging techniques are a fundamental requirement in preclinical skeletal evaluations and are normally applied in most study types in one form or another. Basic techniques such as radiography remain the tool of choice to identify abnormalities, establish skeletal age and size, and monitor bone growth.  Radiological evaluations are critical in bone healing studies. Measurement of bone density is, however, quantified using more specialized bone densitometers including dual energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT).

DXA-derived bone mineral density (areal BMD) remains the only FDA clinically-approved measurement used for the diagnosis of osteoporosis and provides important measures at the whole body level, as well other large areas including the spine, hip and forearm. As such, DXA bone densitometry is often recommended in preclinical studies. It is important, however, to recognize the limitations of DXA technology and how other techniques, such as pQCT and high resolution micro-CT, can help to overcome some of these limitations in preclinical research. DXA and pQCT are often used together to provide complementary information on bone mass, and can also be used to measure lean and fat mass important when body composition measures are required. Both techniques measure bone area, mineral content and density, however, pQCT has the advantage of providing additional information on the different bone compartments, including estimates of bone diameter and cortical thickness, and surrogate end-points describing bone strength. Micro-CT is a powerful tool that can be used at site-specific locations to provide a rapid, high through-put read-out to characterize bone micro-architecture. It can also be used to derive information on end-points describing bone quality such as tissue level mineralization and porosity.

With several choices as to which imaging technique to use, it helps to have an informed opinion to guide this process. With my background and expertise this is exactly what I can promise to do. Many factors need to be taken into consideration, such as the species, age of the test system, duration of the study, in vivo (and the need for anesthesia) or ex vivo assessments, and the mechanism of action of the compound under test, among others. Implications of changes in body weight or body composition also weigh in. Establishing whether changes in bone density are secondary to effects on body weight or a direct effect on bone remains one of the most challenging conclusions to tease out of the data. The application of the appropriate technique at relevant sites is critical to obtaining the data to achieve this end-point.

Selected Publications:

Skeletal Imaging, Chapter 6 in Bone Toxicology. 2017 Varela A. Eds: SY Smith, A Varela, R Samadfam, Springer: Molecular and Integrative Toxicology series.

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

Carcinogenicity risk assessment of romosozumab: a review of scientific weight-of-evidence and findings in a rat lifetime pharmacology study.  Boyce RW, Chouinard L, Felx M, Mellal N, Varela A, Mann P, Jolette J, Samadfam R, Smith SY, Locher K, Buntich S, Ominsky MS, Pyrah I.  Regul Toxicol Pharmacol. 2016 Nov 81:212-222.

Does activin receptor blockade by bimagrumab (BYM338) pose detrimental effects on bone healing in a rat fibula osteotomy model?  Tankó LB, Goldhahn J, Varela A, Lesage E, Smith SY, Pilling A, Chivers S.  Calcif Tissue Int. 2016 May 11. [Epub ahead of print]

Assessment of a nonsteroidal aromatase inhibitor, letrozole, in juvenile rats.  Pouliot L, Schneider M, DeCristofaro M, Samadfam R, Smith SY, Beckman DA.  Birth Defects Research B Dev Reprod Toxicol. 2013 Oct 98(5):374–90.

Non-Human Primate Models of Osteoporosis, Chapter 12 in Osteoporosis Research. 2011 Smith SY, Varela, A, Jolette J.  G. Duque and K. Watanabe (eds.), Springer-Verlag London Limited

Skeletal health: primate model of postmenopausal osteoporosis. Smith SY, Jolette J, Turner CH. Am J Primatol. 2009 Sep;71(9):752-65.

Cancellous and cortical bone architecture and turnover at the iliac crest of postmenopausal osteoporotic women treated with parathyroid hormone 1-84. Recker RR, Bare SP, Smith SY, Varela A, Miller MA, Morris SA, Fox J. Bone. 2009 Jan;44(1):113-9.

Effects of treatment of ovariectomized adult rhesus monkeys with parathyroid hormone 1-84 for 16 months on trabecular and cortical bone structure and biomechanical properties of the proximal femur.  Fox J, Miller MA, Recker RR, Turner CH, Smith SY.  Calcif Tissue Int. 2007 Jul;81(1):53-63.

Effects of daily treatment with parathyroid hormone 1-84 for 16 months on density, architecture and biomechanical properties of cortical bone in adult ovariectomized rhesus monkeys.  Fox J, Miller MA, Newman MK, Recker RR, Turner CH, Smith SY.  Bone. 2007 Sep;41(3):321-30.

Treatment of skeletally mature ovariectomized rhesus monkeys with PTH(1-84) for 16 months increases bone formation and density and improves trabecular architecture and biomechanical properties at the lumbar spine.  Fox J, Miller MA, Newman MK, Turner CH, Recker RR, Smith SY.  J Bone Miner Res. 2007 Feb:22(2) 260-73.

Defining a noncarcinogenic dose of recombinant human parathyroid hormone 1-84 in a 2-year study in Fischer 344 rats.  Jolette J, Wilker CE, Smith SY, Doyle N, Hardisty JF, Metcalfe AJ, Marriott TB, Fox J, Wells DS.  Toxicol Pathol. 2006;34(7):929-40.

Treatment of postmenopausal osteoporotic women with parathyroid hormone 1-84 for 18 months increases cancellous bone formation and improves cancellous architecture: a study of iliac crest biopsies using histomorphometry and micro computed tomography. Fox J, Miller MA, Recker RR, Bare SP, Smith SY, Moreau I. J Musculoskelet Neuronal Interact. 2005 Oct-Dec; 5(4):356-7.

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