Therapeutic Treatments for Osteoporosis-Which Combination of Pills Is the Best among the Bad?

Abstract

Osteoporosis is a chronical, systemic skeletal disorder characterized by an increase in bone resorption, which leads to reduced bone density. The reduction in bone mineral density and therefore low bone mass results in an increased risk of fractures. Osteoporosis is caused by an imbalance in the normally strictly regulated bone homeostasis. This imbalance is caused by overactive bone-resorbing osteoclasts, while bone-synthesizing osteoblasts do not compensate for this. In this review, the mechanism is presented, underlined by in vitro and animal models to investigate this imbalance as well as the current status of clinical trials. Furthermore, new therapeutic strategies for osteoporosis are presented, such as anabolic treatments and catabolic treatments and treatments using biomaterials and biomolecules. Another focus is on new combination therapies with multiple drugs which are currently considered more beneficial for the treatment of osteoporosis than monotherapies. Taken together, this review starts with an overview and ends with the newest approaches for osteoporosis therapies and a future perspective not presented so far.

Keywords: anabolic; biomaterial; bone mineral density; bone remodeling; catabolic; combination of treatments; osteoblast; osteoclast; osteoporosis; treatment.

Figure 1

Bone formation, activation, and differentiation of osteoblasts and osteoclasts in healthy individuals. Bone-resorbing osteoclasts derive from hematopoietic stem cells (HSCs) with an intermediate state of pre-osteoclasts. Important factors for the differentiation of HSCs towards osteoclasts are M-CSF, interleukin-3, and RANKL. Mature osteoclasts release cathepsin K and MMPs at the ruffled border into the sealing zone where bone is resorbed and factors such as insulin-like growth factor 1 and TGF-β are released. These factors are needed for osteoblastogenesis. Mesenchymal stem cells, derived from pericytes, need BMP-2/4/5/6/7/9, Wnt signaling, and TGF-β to differentiate towards pre-osteoblasts, followed by insulin-like growth factor 1 and platelet-derived growth factor release, which are necessary to form mature bone-synthesizing osteoblasts. Estrogen is necessary for the differentiation and activation of osteoblasts as well. It binds to its estrogen receptors-α/β (ERα/β) and activates collagen 1 and osteocalcin production in mature osteoblasts. Both cell types play a major role in bone homeostasis and exchange factors to activate each other. RANKL and M-CSF are produced by osteoblasts and are needed for the differentiation and activation of osteoclasts. OPG is also produced by osteoblasts but is a decoy for RANKL, therefore inhibiting osteoclast activation and differentiation. FasL, ephirins, semaphorins, and WNTs also play a role in cell communication between osteoblasts and osteoclasts, as indicated.

Figure 2

Overview of the different anabolic and catabolic treatments on osteoblasts and osteoclasts for osteoporosis. Bisphosphonates act on adenosine triphosphate and on farnesyl pyrophosphatase and lead osteoclasts into apoptosis. RANKL antibodies bind to osteoblast-produced RANKL and prevent RANKL from binding to RANK on osteoclasts and therefore inhibit activation and differentiation of osteoclasts. Cathepsin K inhibitors inactivate the mature cysteine protease cathepsin K and prevent bone resorption. Sclerostin antibodies bind to sclerostin that is produced by osteocytes, inhibit Wnt signaling and therefore osteoblast differentiation. When sclerostin antibodies are present, osteoblastogenesis is active. SERM are similar to estrogen and can bind to the estrogen receptors α/β, which leads to an activation of osteoblasts.

Figure 3

Overview of bone scaffold characteristics. Including: scaffold size and geometry, mechanical strength (stiffness and elasticity), geometry, surface hydrophilicity/hydrophobicity, surface charge, pore size, porosity, and others, modulating the host responses and bone regeneration.