Odanacatib in postmenopausal women with low bone mineral density: a review of current clinical evidence

Abstract

Human bones are in a continuous process of remodeling that ensures renovation and maintenance of the skeletal mass. Bone remodeling has two phases that are normally coupled and balanced: bone resorption mediated by osteoclasts and bone formation mediated by osteoblasts. An increase in bone resorption over bone formation results in a progressive loss of bone mass and impairment of bone microarchitecture leading to osteoporosis and its associated fractures. Recent advances in the understanding of the molecular and cellular mechanisms involved in the remodeling process have allowed the development of new targets for osteoporosis treatment. Cathepsin K, a cysteine protease, is found in osteoclasts along the bone resorption surfaces and very efficiently degrades type I collagen, the major component of the organic bone matrix. Inhibition of cathepsin K reduces bone resorption but does not impair bone formation particularly at cortical sites. Odanacatib, a potent and highly selective cathepsin K inhibitor, showed prevention of bone loss without reduction of bone formation in preclinical and clinical trials (phase I and II). Odanacatib is currently in a phase III fracture outcome international trial for the treatment of postmenopausal osteoporosis.

Keywords: animal models; bone demineralization; bone density conservation agents; bone remodeling; cathepsin K; osteoporosis postmenopausal; pathologic.

Figure 1.

Mechanism of bone resorption by osteoclasts. A sealing zone is created when osteoclasts attach to the bone surface through integrin αVβ3. Secretion of H⁺ and acidic proteases such as cathepsin K and metalloproteinases (MMP9, MMP13) mediate bone degradation, creating a resorptive lacunae.

Figure 2.

Cathepsins: a family of lysosomal proteases. Cathepsins are lysosomal proteases found in many types of cells. They are differentiated by their structure, catalytic mechanism and the kind of proteins they cleave (cysteine, aspartyl or serine proteases). Cathepsin K, a cysteine protease, is abundantly expressed in osteoclasts along the bone resorption surfaces, in transcytotic vesicles and intracellular lysosomes. Cathepsin K has optimal activity at the acidic pH found in lysosomes and efficiently degrades collagen.

Figure 3.

Chemical structure of odanacatib (MK-0822).

Figure 4.

Mean percentage change from baseline over time for the full-analysis-set population (LOCF) in lumbar spine BMD (primary endpoint) (a) and femoral neck BMD (b) at 5 years for three of the randomization groups. 50 mg, odanacatib 50 mg once weekly; BMD, bone mineral density; LOCF, last observation carried forward; PBO, placebo once weekly; SE, standard error. (Adapted from Langdahl et al. [2012].)

Figure 5.

Effects of odanacatib versus placebo on percentage change from baseline in BMD (least square mean ± standard error) at 24 months in postmenopausal women previously treated with alendronate. BMD, bone mineral density; ODN, odanacatib; OW, once weekly.