Biomechanical testing is considered the ultimate test of bone quality and as such is one of the most important end-points yet also the least precise. As a single time-point there is no room for error. It also requires the knowledge of a biomedical engineer as part of the team to ensure this important end-point is performed to meet accepted standards using established techniques and appropriate data capture methods.

Measures of bone strength are performed at standardized sites and normally include a long bone (femur or tibia) and vertebrae; femoral neck (or hip) strength is also often measured in mature populations. Data from these sites reflect sites typically at risk for fracture in humans: the spine, hip and forearm. The basic tests include 3 or 4-point bending of long-bones, vertebral compression, and shear at the femoral neck. More refined tests to assess the material quality of trabecular and cortical bone rather than the whole bone structure can be performed using vertebral cores and cortical beams, respectively. The selection of which test to use will depend upon several factors including the study objectives, species, and age of the test system. Quality control specimens and rigorous procedures for specimen preparation and storage are critical in order to obtain consistent data.

To appropriately interpret bone strength data, it is important to have information on the specimens’ mass and size, both of which can be derived using the imaging techniques, DXA and/or pQCT. The relationship between bone strength and bone mass is also normally explored since higher bone mass should result in correspondingly greater bone strength. If this relationship is disturbed, it implies factors other than bone mass may have affected bone quality. This could be because of effects on the non-collagenous bone matrix, or the strength of the collagen cross-links, for example. Additional investigations can be performed to further characterize such effects on bone quality.

It is important to know when biomechanical testing will be required in a study. Testing is typically included in pharmacology and efficacy studies (fracture and intact models), especially in small animal species where the populations can be adequately powered. Large scale studies are required using large animal species for osteoporosis drug testing, where measures of bone strength are required to establish lack of adversity (as a minimum), or superiority relative to controls or standard of care. These bone quality studies are normally powered sufficiently to permit meaningful biomechanical testing. On the other hand, most large-animal safety studies have few animals per group (3 to 5) and as such are essentially under-powered for biomechanical testing. However, in a safety assessment setting, these data normally provide sufficient information to assess overall bone safety and are being requested more and more frequently by regulatory authorities.

Biomechanics data, integrated with biomarker, bone densitometry and histomorphometry data, provide a comprehensive assessment of drug effects on bone. The densitometry data should correlate with the biomechanical outcome measures, while the biomarkers and histomorphometry data provide useful mechanistic information to understand how changes in densitometry were effected. Importantly, the biomarkers provide information on the chronology of skeletal activity during the in vivo phase of the study.

To make the decision to perform biomechanical testing or not, and which biomechanics tests 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 data available, and the known mechanism of action of the compound under test, among others. Implications of changes in body weight are also a factor. Establishing whether effects on bone strength are secondary to effects on body weight/size, or a direct effect on bone, remains one of the most challenging conclusions to establish.

Selected Publications:

Biomechanics, Chapter 7 in Bone Toxicology. 2017 Lin ASP, Boyd G, Varela A, Guldberg RE. Eds: SY Smith, A Varela, R Samadfam, Springer: Molecular and Integrative Toxicology series.

Abaloparatide, a novel PTH receptor agonist, increased bone mass and strength in ovariectomized cynomolgus monkeys by increasing bone formation without increasing bone resorption. Doyle N, Varela A, Haile S, Guldberg R, Kostenuik PJ, Ominsky MS, Smith SY, Hattersley G. Osteoporos Int. 2018 Mar;29(3):685-69.

One year of abaloparatide, a selective peptide activator of the PTH1 receptor, increased bone mass and strength in ovariectomized rats. Varela A, Chouinard L, Lesage E, Guldberg R, Smith SY, Kostenuik PJ, Hattersley G. Bone. 2017 Feb;95:143-150.

Effects of long term treatment with high doses of odanacatib on bone mass, bone strength, and remodeling/modeling in newly ovariectomized monkeys.  Duong LT, Pickarski M, Cusick T, Chen CM, Zhuo Y, Scott K, Samadfam R, Smith SY, Pennypacker BL. Bone. 2016 Jul;88:113-24.

Odanacatib increases mineralized callus during fracture healing in a rabbit ulnar osteotomy model.  Pennypacker BL, Gilberto D, Gatto NT, Samadfam R, Smith SY, Kimmel DB, Duong le T.  J Orthop Res. 2016 Jan;34(1):72-80.

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.

Effects of denosumab, alendronate, or denosumab following alendronate on bone turnover, calcium homeostasis, bone mass and bone strength in ovariectomized cynomolgus monkeys.  Kostenuik PJ, Smith SY, Samadfam R, Jolette J, Zhou L, Ominsky MS. J Bone Miner Res. 2015 Apr;30(4):657-69.

The effects of bazedoxifene in the ovariectomized aged cynomolgus monkey.  Smith SY, Jolette J, Chouinard L, Komm BS. J Bone Miner Metab. 2015 Mar;33(2):161-72.

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.  Takeda S, Smith SY, Tamura T, Saito H, Takahashi F, Samadfam R, Haile S, Doyle N, Endo K. Calcif Tissue Int. 2015 Jan;96(1):45-55.

Eldecalcitol, a vitamin D analog, reduces bone turnover and increases trabecular and cortical bone mass, density, and strength in ovariectomized cynomolgus monkeys.  SY Smith, N Doyle, M Boyer, L Chouinard, H Saito. Bone. 2013 57:116–22.

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.

Skeletal effects of bazedoxifene paired with conjugated estrogens in ovariectomized rats.  Komm BS, Vlasseros F, Samadfam R, Chouinard L, Smith SY.  Bone. 2011 49:376-86.

Denosumab, a fully human RANKL antibody, reduced bone turnover markers and increased trabecular and cortical bone mass, density, and strength in ovariectomized cynomolgus monkeys.  Ominsky MS, Stouch B, Schroeder J, Pyrah I, Stolina M, Smith SY, Kostenuik PJ.  Bone. 2011 49:162-73.

Decreased bone remodeling and porosity are associated with improved bone strength in ovariectomized cynomolgus monkeys treated with denosumab, a fully human RANKL antibody.  Kostenuik PJ, Smith SY, Jolette J, Schroeder J, Pyrah, I,  Ominsky MS.  Bone. 2011 49:151-61.

Inhibition of sclerostin by monoclonal antibody enhances bone healing and improves bone density and strength of non-fractured bones.  Ominsky MS, Li C, Li X, Tan HL, Lee E, Barrero M, Asuncion FJ, Dwyer D, Han C-Y, Vlasseros F, Samadfam R, Jolette J, Smith SY, Stolina M, Lacey DL, Simonet WS, Paszty C, Li G,  Ke HZ.  J Bone Miner Res. 2011 May;26(5):1012-21.

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

Effects of treatment with parathyroid hormone 1-84 on quantity and biomechanical properties of thoracic vertebral trabecular bone in ovariectomized rhesus monkeys.  Fox J, Newman MK, Turner CH, Guldberg RE, Varela A, Smith SY.  Calcif Tissue Int. 2008 Mar;82(3):212-20.

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.

Daily treatment of aged ovariectomized rats with human parathyroid hormone (1-84) for 12 months reverses bone loss and enhances trabecular and cortical bone strength.  Fox J, Miller MA, Newman MK, Metcalfe AF, Turner CH, Recker RR, Smith SY.  Calcif Tissue Int. 2006 Oct;79(4):262-72.

Intermittent ibandronate preserves bone quality and bone strength in the lumbar spine after 16 months of treatment in the ovariectomized cynomolgus monkey. Müller R, Hannan M, Smith SY, Bauss F.  J Bone Miner Res. 2004 Nov;19(11):1787-96.

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

Home