Decreased bone remodeling and porosity are associated with improved bone strength in ovariectomized cynomolgus monkeys treated with denosumab, a fully human RANKL antibody

Kostenuik, Paul J.; Smith, Susan Y.; Jolette, Jacquelin; Schroeder, Joseph A.; Pyrah, Ian; Ominsky, Michael S.

doi:10.1016/j.bone.2011.03.769

Cited by 92 publications

(71 citation statements)

References 32 publications

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“…Basal periosteal MS/BS and MAR have been measured to be ≤ 10% and ≤ 1 μm/day, respectively, at multiple cortical bone sites within nonhuman primates [39][40][41], as well as in human iliac crest biopsies [46], similar to measurements in this study. Rabbits are also well-suited for preclinical investigations of osteopenia and pharmaceutical interventions as rabbits experience cortical bone loss after ovariectomy [29], and respond to PTH [25,26], bisphosphonates [28,29], and cathepsin K inhibitors [29].…”

Section: Discussionmentioning

confidence: 92%

Development of an in vivo rabbit ulnar loading model

Baumann

Aref

Turnbull

et al. 2015

Bone

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Section: Discussionmentioning

confidence: 92%

Development of an in vivo rabbit ulnar loading model

Baumann

Aref

Turnbull

et al. 2015

Bone

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“…This evidenced an increase in both bone mass and density, likely due to the large effect of denosumab treatment on cortical bone. Kostenuik et al examined the effects of denosumab, on bone histomorphometry in adult ovariectomized cynomolgus monkeys, and demonstrated that remodeling inhibition with denosumab improved structural strength without altering material properties, that can be primarily explained by the combined effects of increased trabecular and cortical bone mass, and reductions in trabecular eroded surfaces and particularly cortical porosity (38). Genant et al analyzing QCT scans of the radius of patients enrolled in DEFEND trial, obtained data about bone strength parameters such as the density-weighted polar moment of inertia (PMI), which relates to the ability of a bone to resist torsion.…”

Section: Actions Of Denosumab On Cortical and Trabecular Bonementioning

confidence: 99%

The contribution of cortical and trabecular tissues to bone strength: insights from denosumab studies

Iolascon¹,

Napolano²,

Gioia³

et al. 2013

CCMBM

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SummaryAll materials undergo an aging process which is characterized essentially by changes of the rigidity (stiffness), of the ability to absorb the stresses (toughness) and then ultimately in the mechanical resistance (strength). Both cortical and trabecular bone undergo a continuous process of structural remodeling with the main aim to preserve their biomechanical properties. An imbalance in this process, which promotes bone resorption, results in a quantitative loss of bone tissue and in a qualitative alteration of the skeletal microarchitecture, as you can see in osteoporosis, rheumatoid arthritis or bone metastases. Cortical component has a prominent role on strength therefore loss of cortical bone that is prevalent in elderly may explain the higher frequency of fractures of bones composed mainly of cortical bone such as the proximal femur. Remodeling inhibition with denosumab improved structural strength without altering material properties, that can be primarily explained by the combined effects of increased trabecular and cortical bone mass, and reductions in trabecular eroded surfaces and particularly cortical porosity. Denosumab for its mechanism of action and pharmacokinetics results in a significant, early and continued increase in BMD with enhanced bone strength improving both cortical and trabecular bone.

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“…The increased strength may be explained by a decreased remodeling and cortical porosity and increased cortical thickness [Kostenuik et al 2011;Ominsky et al 2011].…”

Section: Hipmentioning

confidence: 99%

Effects of denosumab on bone density, mass and strength in women with postmenopausal osteoporosis

Törring

2015

Therapeutic Advances in Musculoskeletal

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Denosumab is a human monoclonal antibody which specifically blocks receptor activator of nuclear factor κB ligand and is a very potent antiresorptive drug. Its efficacy in reducing the risk of vertebral, hip and nonskeletal fracture has been proven in a large prospective, randomized multicenter study of 7808 postmenopausal women with osteoporosis [Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial]. Denosumab causes somewhat greater increases in bone mineral density (BMD) than the class of bisphosphonate antiresorptives. Denosumab also causes an increase in bone mass and bone strength in the spine, ultradistal and diaphysis of the radius, proximal tibia and the hip. Recently long-term treatment with denosumab has been shown to cause a continued almost linear increase in total hip and femoral neck BMD beyond 3 years up to 8 years. In this respect, denosumab seems to differ from the bisphosphonate group in which the rate of improvement of BMD diminishes and for some drugs becomes negative after 3-4 years when the process of secondary mineralization flattens out. This unique property of an antiresorptive drug points towards mechanisms of action which differ from the bisphosphonate group. Both types of antiresorptives decrease cortical porosity but contrary to bisphosphonates the reduction in cortical porosity continues with denosumab which, in addition, also seems to cause a slight continuous modeling-based formation of new bone despite suppression of bone remodeling. The net effect is an increase in cortical thickening and bone mass, and increased strength of cortical bone. This may contribute substantially to the significant further reduction of the nonvertebral fracture risk which was found in the long-term denosumab arm of the FREEDOM extension trial during years 4-7.

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Decreased bone remodeling and porosity are associated with improved bone strength in ovariectomized cynomolgus monkeys treated with denosumab, a fully human RANKL antibody

Cited by 92 publications

References 32 publications

Development of an in vivo rabbit ulnar loading model

Development of an in vivo rabbit ulnar loading model

The contribution of cortical and trabecular tissues to bone strength: insights from denosumab studies

Effects of denosumab on bone density, mass and strength in women with postmenopausal osteoporosis

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