Emerging therapeutic opportunities for skeletal restoration

Abstract

Osteoporosis, a syndrome characterized by thin bones and fractures, has become more prevalent in both women and men. Established therapies for treating this disorder consist primarily of drugs that prevent bone loss, such as the bisphosphonates and selective oestrogen receptor modulators. Although these drugs have been shown to reduce fractures in randomized trials, there is an urgent need for treatments that could lower fracture risk further without additional adverse effects. The introduction of parathyroid hormone (teriparatide), which significantly increases bone mineral density, albeit for a relatively short duration, raised expectations that drugs that stimulate bone formation might cure osteoporosis. After outlining current approaches for treating osteoporosis, this Review focuses on emerging therapeutic opportunities for osteoporosis that are based on recent insights into skeletal physiology. Such novel strategies offer promise not only for reducing age-related bone loss and the associated risk of fractures but also for restoring bone mineral density to healthy levels.

Figure 1. Regulation of osteoclast development by RANKL and other cytokines in the bone marrow microenvironment

Modified from Riggs et al. with permission . Remodeling begins with the elaboration of cytokines from osteoblast precursors leading to the recruitment and differentiation of multinucleated osteoclasts that subsequently attach to the endosteal bone surface. Resorption of the skeletal matrix releases growth factors such as IGF-I and TFG-beta which recruit lining cells and early osteoblast precursors that eventually form new bone. Osteoblasts that do not undergo programmed cell death are entombed within the skeletal matrix and become osteocytes that can signal lining cells and respond to gravitary forces to initiate remodeling.]

Figure 2. Osteoblast lineage specification, expansion, and terminal differentiation as well as the central role of canonical (ca) Wnts in regulating these processes

Osteoblasts are derived from multi-potent mesodermal or neural crest progenitors. Activation of the caWnt pathway through β-catenin stabilization prevents chondrogenesis. Wnt10b prevents adipogenesis. The caWnt pathway promotes survival of all cells of the osteoblast lineage and induces proliferation of preosteoblasts. Reproduced from Khosla et al. with permission .

Figure 3. Sclerostin monoclonal antibody treatment in osteopenic rats restores trabecular BMD and bone volume back to sham levels at the distal femur

Shown is the distal femur region of analysis (top left panel) and representative 3D μCT images of a 1-mm central section (with attached cortices) from sham operated, ovariectomized rates treated with vehicle, and ovariectomized rats treated with the sclerostin antibody. Reproduced from Li et al. with permission .

Figure 4. Proposed effect of PPARγ antagonist in the bone marrow milieu

Bone remodeling is fine tuned by the balance between bone formation by osteoblasts and bone resorption by osteoclasts. PPARγ is involved in the cell fate determination of mesenchymal stem cells (MSCs) toward the adipogenic lineage and away from osteogenic lineage. In addition, PPARγ may be the positive regulator for osteoclastogenesis although this tenet needs to be clarified. Therefore, PPARγ antagonist may increase bone mass by switching the cell fate of MSCs toward osteogenic lineage and suppressing osteoclastogenesis. HSCs: hematopoietic stem cells, PPARγ: Peroxisome proliferator-activated receptor-gamma. C/EBP: CCAAT enhancer binding protein. Runx2: Runt-related transcription factor 2. Msx2: Muscle segment homeobox homolog of 2.