Sclerostin Inhibition in the Management of Osteoporosis

Abstract

The recognition of the importance of the Wnt-signaling pathway in bone metabolism and studies of patients with rare skeletal disorders characterized by high bone mass identified sclerostin as target for the development of new therapeutics for osteoporosis. Findings in animals and humans with sclerostin deficiency as well as results of preclinical and early clinical studies with sclerostin inhibitors demonstrated a new treatment paradigm with a bone building agent for the management of patients with osteoporosis, the antifracture efficacy, and long-term tolerability of which remain to be established in on-going phase III clinical studies. In this article we review the currently available preclinical and clinical evidence supporting the use of sclerostin inhibitors in osteoporosis.

Keywords: Blosozumab; Bone modeling; Bone remodeling; Osteoporosis; Romosozumab; Sclerostin.

Fig. 1

Schematic presentation of the canonical Wnt-signaling pathway and of the effect of sclerostin on bone cells. a Wnts bind to the receptor complex of frizzled (FZD) and LRP5/6, prevent the degradation of beta-catenin, and increase its accumulation in the cytoplasm; beta-catenin is translocated to the nucleus where it associates with transcription factors to control transcription of target genes in osteoblasts. b Osteocyte-produced sclerostin is transported to the bone surface and acts on osteoblasts to reduce bone formation by disabling the association of Wnts with their co-receptors and inhibiting the Wnt pathway in osteoblasts, an action facilitated by LRP4; sclerostin also stimulates the production of RANKL by neighboring osteocytes and osteoclastic bone resorption

Fig. 2

Upper panel Trabecular surfaces (L2) of OVX rats treated with vehicle or Scl-Ab. Surfaces were characterized as modeling-based bone formation (MBF), remodeling-based bone formation (RBF), quiescent (QS) or osteoclastic (OCs), and expressed as % of the total surface. Lower panel Endocortical surfaces (proximal diaphysis) of male cynomolgus monkeys. Bone surfaces are characterized as modeling-based bone formation (MBF), remodeling-based bone formation (RBF), quiescent (QS) or eroded surfaces (ES), and expressed as  % of the total surface. (From Ref. [51])

Fig. 3

Bone remodeling and modeling under physiological conditions, in osteoporosis, and during treatment with sclerostin inhibitors. a Within an active BMU bone is constantly removed by osteoclasts (OCs) and new bone matrix is produced by osteoblasts (OBs), at sites where bone resorption has occurred with the amount of bone formed being equal to the amount of bone resorbed. Once the BMU is completed, osteoblasts become entrapped as osteocytes (OCYs) into the newly formed matrix, remain on the bone surface as lining cells (LCs), or undergo apoptosis. Bone then remains in the quiescent phase until a new BMU is initiated. b In osteoporosis, bone resorption is increased and bone formation is decreased, resulting in a loss of bone. c Inhibition of osteocyte-produced sclerostin decreases bone resorption but mostly increases both remodeling-based and modeling-based bone formation, thereby causing a striking increase in bone formation, particularly in areas that were not previously resorbed (modeling). (Modified from original Fig. 1 of Ref. [52])

Fig. 4

Percent changes of lumbar spine and total hip BMD during treatment of postmenopausal women with low bone mass with romosozumab (ROMO) 210 mg once-monthly sc, teriparatide (TPTD) 20 μg daily sc, alendronate (ALN) 70 mg once-weekly orally, or placebo. a = p < 0.05 between ROMO and placebo, b = p < 0.02 between ROMO and ALN, c = p < 0.02 between ROMO and TPTD (From Ref. [58])

Fig. 5

Schematic presentation of changes in the levels of serum biochemical markers of bone formation (P1NP) and bone resorption (CTX) during treatment with subcutaneous injections of either romosozumab 210 mg once-monthly or teriparatide 20 μg daily for 1 year. (From Ref. [59]; original data for romosozumab from Ref. [58] and for teriparatide from Ref. [66])

Fig. 6

Percent changes of lumbar spine and femoral neck BMD during and after treatment of postmenopausal women with low bone mass with 3 different doses of blosozumab. (From Ref. [63]). ***p < 0.001, **p < 0.01, *p < 0.05