The integration of musculoskeletal end-points into standard toxicology studies brings the worlds of toxicology and bone research together and was a natural progression for me based on my years of experience in both fields. Preclinical skeletal safety assessments and mechanistic studies have become pivotal in the development of numerous therapeutic drug classes, most notably for metabolic diseases such as diabetes and obesity. An assessment of skeletal adversity in the context of toxicology testing requires a fundamental knowledge of bone biology and an understanding of the cross-talk bone has with other major organ systems. Knowing what to look for and using optimal tools is critical. The earlier in drug development that signs of adversity are detected the better, ensuring an early termination of development and optimal use of resources, including funds.

Musculoskeletal end-points can be included in all safety assessments: acute, sub-chronic, chronic toxicity studies, and carcinogenicity testing, in all standard species, irrespective of the route of administration, in young adult, juvenile and aged population. Biomarkers are the most useful tool in early drug development and can be applied to any study type. Understanding what is known of the mechanism of action of the drug, and the drug class, can help to focus on specific markers of interest to establish essential pharmacodynamic parameters that can then be included in subsequent studies. Combining markers with bone densitometry measures adds important safety information when applied appropriately. In rodent studies, ex vivo bone densitometry measurements are particularly given that studies are normally well powered and these species are generally more sensitive to determine skeletal effects relative to large animal species based on their higher bone turnover and more rapid skeletal growth.

Use of markers and bone densitometry data in early, short-term studies is often adequate to identify any skeletal effects. These data are valuable to determine the appropriate end-points to incorporate into longer-term studies. The study design should include specimen and sample retention to ensure more in-depth evaluations can be performed, as needed.  Retaining bones for possible biomechanical testing is critical since the regulatory agencies are requesting bone strength assessments more and more frequently. Bones can also be retained for histomorphometry, if injecting fluorochrome labels during the study is feasible. In the context of a toxicology study, bone labelling may not be advantageous and should be included with caution so as not to compromise the toxicology end-points; study objectives must be clearly stated.

With more than 20 years of experience in musculoskeletal research and safety testing, I can help you to navigate through the required safety assessments and provide guidance as to how/when and what bone-endpoints to include in your studies.  Ensuring appropriate integration and interpretation of these critical end-points into the study report or submission documents is also a strength. I have experience with many drug classes and therapeutic areas, and with large and small molecules.

Selected publications:

Introduction and Considerations in Bone Toxicology, Chapter 1 in Bone Toxicology. 2017 Smith SY, Doyle, N and Felx M. Eds: SY Smith, A Varela, R Samadfam, Springer: Molecular and Integrative Toxicology series.

Bone Physiology and Biology, Chapter 2 in Bone Toxicology. 2017 Gasser JA, Kneissel M. Eds: SY Smith, A Varela, R Samadfam, Springer: Molecular and Integrative Toxicology series.

Specific Considerations for Bone Evaluations for Pediatric Therapies, Chapter 3 in Bone Toxicology. 2017 Robinson K. Eds: SY Smith, A Varela, R Samadfam, Springer: Molecular and Integrative Toxicology series.

Bone as an Endocrine Organ, Part III, Chapters 9 to 15 in Bone Toxicology. 2017 Eds: SY Smith, A Varela, R Samadfam, Springer: Molecular and Integrative Toxicology series.

Studies on articular and general toxicity of orally administered ozenoxacin in juvenile rats and dogs. Borroto JIG, Awori MS, Santillan D, Chouinard L, Smith SY, Asamara CT, Blazquez T, Gargallo-Viola D, Zsolt I. Future Microbiology, Chapter 3. Chondrotoxicity of Ozenoxacin. Accepted March 2018.

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.  Regulatory Toxicology and Pharmacology. 2016 Nov81:212-222.

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]

Effects of pioglitazone and fenofibrate co-administration on bone biomechanics and histomorphometry in ovariectomized rats.  Smith SY, Samadfam R, Chouinard L, Awori M, Bénardeau A, Bauss F, Guldberg RE, Sebokova E, Wright MB. J Bone Miner Metab. 2015 Nov;33(6):625-41.

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.

The effect of rosiglitazone on bone mass and fragility is reversible and can be attenuated with alendronate.  Kumar S, Hoffman SJ, Samadfam R, Mansell P, Jolette J, Smith SY, Guldberg RE, Fitzpatrick LA. J Bone Miner Res. 2013 Jul;28(7):1653–65.

Combination treatment with pioglitazone and fenofibrate attenuates pioglitazone-mediated acceleration of bone loss in ovaroectimized rats.  Samadfam R, Awori M, Benardeau A, Bauss F, Sebokova E, Wright M, Smith SY, J Endocrinol. 2012 Feb;212(2):179-86.

Two Doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength.  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.  J Bone Miner Res. 2010 May;25(5):948-59.

Instilled or injected purified natural capsaicin has no adverse effects on rat hindlimb sensory-motor behaviour or osteotomy repair.  Kramer SM, May JR, Patrick DJ, Chouinard L, Boyer M, Doyle N, Varela A, Smith SY, Longstaff E.  Anesth Analg. 2009 Jul:109 (1) 249-57.

The RANKL inhibitor OPG-Fc increases cortical and trabecular bone mass in young gonad-intact cynomolgus monkeys.  Ominsky MS, Kostenuik PJ, Cranmer P, Smith SY, Atkinson JE. Osteoporos Int. 2007 Aug;18(8):1073-82.

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.

A toxicity profile of osteoprotegerin in the cynomolgus monkey.  Smith BB, Cosenza ME, Mancini A, Dunstan C, Gregson R, Martin SW, Smith SY, Davis H. Int.  J. Toxicol. 2003 Sept-Oct: 22(5) 403-12.

Increases in adipose and total body weight, but not in lean body mass, associated with subcutaneous administration of sonic hedgehog-Ig fusion protein in mice.  Martin PL, Lane J, Pouliot L, Gains M, Stejskal R, Smith SY, Galdes A, Green J.  Drug Development Research. 2002 57:107-14.

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