Osteoporosis: now and the future

Abstract

Osteoporosis is a common disease characterised by a systemic impairment of bone mass and microarchitecture that results in fragility fractures. With an ageing population, the medical and socioeconomic effect of osteoporosis, particularly postmenopausal osteoporosis, will increase further. A detailed knowledge of bone biology with molecular insights into the communication between bone-forming osteoblasts and bone-resorbing osteoclasts and the orchestrating signalling network has led to the identification of novel therapeutic targets. Novel treatment strategies have been developed that aim to inhibit excessive bone resorption and increase bone formation. The most promising novel treatments include: denosumab, a monoclonal antibody for receptor activator of NF-κB ligand, a key osteoclast cytokine; odanacatib, a specific inhibitor of the osteoclast protease cathepsin K; and antibodies against the proteins sclerostin and dickkopf-1, two endogenous inhibitors of bone formation. This overview discusses these novel therapies and explains their underlying physiology.

Conflict of interest statement

Conflict of interest

Tilman Rachner has received reimbursement of travel and accommodation expenses from Novartis. Sundeep Khosla has received honoraria for serving on advisory boards for Bone Therapeutics and Pfizer. Lorenz Hofbauer has received honoraria and speakers fees including reimbursement of travel and accommodation expenses from Amgen, Daiichi Sankyo, Merck, Novartis, Nycomed, and Servier.

Copyright © 2011 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Osteoporosis at a glance

Osteoporosis is a systemic skeletal disease where bone resorption exceeds bone formation and results in microarchitectural changes. (A) Fragility fractures typically involve the wrist, vertebrae, and the hip. (B) Micro-computed tomography demonstrates marked thinning of bone in a mouse model of osteoporosis. (C) Microscopic view of bone-resorbing osteoclasts and bone-forming osteoblasts; 1- Picture of an Osteoclast, with its distinctive morphology; 2- Tartrate-resistant Acidic Phosphatase (TRAP) staining of multinucleated osteoclasts; 3- Picture of multiple osteoblasts (white arrowheads) on a mineralized matrix; 4- Alizarin red staining, showing the mineralization of osteoblast secreted extracellular matrix.

Figure 2. Osteoclast physiology and potential therapeutic targets

With the help of αvβ3 integrin the osteoclast attaches to the bone surface and forms a sealing zone. Proton pumps and chloride channels produce a highly acidic microenvironment that is essential for the catalytic activity of osteoclastic enzymes such as cathepsin K. Odanacatib inhibits cathepsin K, a lysosomal protease that degrades collagens. The tyrosine Src kinase plays a critical role in osteoclast activity and can be inhibited by saracatinib. RANKL acts as an essential regulator of osteoclast differentiation and activity. The fully human monoclonal antibody denosumab prevents RANKL binding to its receptor RANK. Abbreviations used: FAK, focal adhesion kinase; NF-κB, nuclear factor-κB; PI3K, phosphatidylinositol 3-kinase, RANK, receptor activator of NF-κB; RANKL, RANK ligand; TRAF-6, tumor necrosis factor receptor associated factor-6

Figure 3. Osteoblast physiology and potential therapeutic targets

The calcium-sensing receptor is antagonised by MK-5442 and triggers a short burst of PTH secretion. Binding of PTH to its receptor enhances osteoblast functions and bone formation. The presence of the Wnt antagonists Dkk-1 and sclerostin inhibit Wnt signalling. Dkk-1 needs to form a complex with kremen, whereas sclerostin binds LRP5/6 directly. BHQ-880 and AMG-785 are antibodies directed against Dkk-1 and sclerostin, respectively. After neutralising Dkk-1 and sclerostin, Wnt can bind to LRP5/6, which results in the degradation GSK-3β. As a consequence, β-catenin is stabilised, accumulates, and translocates into the nucleus where it regulates the transcription of osteoblastic genes. Abbreviations used: APC, adenomatosis polyposis coli; cAMP, cyclic adenosine monophosphate; CaSR, calcium sensing receptor; Dkk-1, dickkopf-1, GSK, glycogen synthase kinase 3; LRP, low-density lipoprotein receptor-related protein; PKA, protein kinase A; PTH, parathyroid hormone; PTH1R, PTH 1 receptor.

Figure 4. Potential mechanisms of anti-resorptives

This theoretical concept is based on cellular, preclinical and early clinical data that require clinical validation (A) Physiologically, osteoclastic and osteoblastic functions are coupled with bidirectional communication. (B) Classic anti-resorptives act by reducing osteoclast viability. As a consequence, osteoclastic signalling and subsequently osteoblastic bone formation is suppressed. (C) Uncoupling anti-resorptives inhibit osteoclast activity rather than osteoclast viability, thus allowing physiological communication between osteoclasts and osteoblasts with maintained osteoblastic bone formation. Abbreviations used: OB, osteoblast; OC, osteoclast.