J Bone Metab.  2014 Feb;21(1):8-20.

Bone Biology and Anabolic Therapies for Bone: Current Status and Future Prospects

• Martin TJ

Abstract

Bone is continuously remodelled at many sites asynchronously throughout the skeleton, with bone formation and resorption balanced at these sites to retain bone structure. Negative balance resulting in bone loss and osteoporosis, with consequent fractures, has mainly been prevented or treated by anti-resorptive drugs that inhibit osteoclast formation and/or activity, with new prospects now of anabolic treatments that restore bone that has been lost. The anabolic effectiveness of parathyroid hormone has been established, and an exciting new prospect is presented of neutralising antibody against the osteocyte protein, sclerostin. The cellular actions of these two anabolic treatments differ, and the mechanisms will need to be kept in mind in devising their best use. On present evidence it seems likely that treatment with either of these anabolic agents will need to be followed by anti-resorptive treatment in order to maintain bone that has been restored. No matter how effective anabolic therapies for the skeleton become, it seems highly likely that there will be a continuing need for safe, effective anti-resorptive drugs.

Keyword

Anabolic agents; Bone and bones; Bone density conservation agents

MeSH Terms

Anabolic Agents
Bone and Bones
Bone Density Conservation Agents
Osteoclasts
Osteocytes
Osteogenesis
Osteoporosis
Parathyroid Hormone
Skeleton
Anabolic Agents
Bone Density Conservation Agents
Parathyroid Hormone

Figure

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  Fig. 1 Cellular events in the basic multicellular unit (BMU). Under the canopy generated by bone lining cells, osteoclasts are formed from hemopoietic precursors supplied by marrow and the bloodstream, and from partially differentiated osteoclasts termed quiescent osteoclast precursors (QoP). On the right side of the diagram, precursors of osteoblasts come from mesenchymal stem cells in the marrow and from blood, and from pericytes, and differentiate within the BMU through the osteoblast precursor stage to fully functional synthesizing osteoblasts; lining cells may also differentiate into active osteoblasts. Osteocytes communicate with the surface cells, particularly osteoblasts, through their canaliculae.

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  Fig. 2 Anabolic action of parathyroid hormone (PTH) through remodelling. PTH promotes differentiation of committed osteoblast precursors, activation of osteoclasts that produce coupling activities (see text for details), promotes survival of osteomlasts, and osteocytes, and inhibits sclerostin production by osteocytes.

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  Fig. 3 Possible mechanisms of parathyroid hormone (PTH) anabolic action in presence of resorption inhibition. PTH inhibits sclerostin production by osteocytes, promotes survival of osteoblasts and osteocytes, and promotes osteoblast differentiation in partly filled basic multicellular units (see text for details).

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  Fig. 4 Wnt signaling as a pathway to increase bone formation. (A) Wnt signalling pathway in the inactive state, showing a ligand Wnt inhibited by a decoy secreted frizzled-related protein (sFRP), the co-receptor, lipoprotein receptor-related protein (LRP)5/6, bound by either inhibitory protein, sclerostin or dickkopf (Dkk), and glycogen synthase kinase (GSK)-3β in the active state, resulting in proteasomal degradation of β-catenin (see text for details). (B) Active Wnt signalling, with LRP5/6 engaging in receptor complex after Wnt binding, disruption of GSK-3β inhibitory complex, stabilization of β-catenin and its translocation to nucleus where it activates transcription. Letters 1 to 5 indicate possible target sites for drug development (see text).

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  Fig. 5 Anabolic action of anti-sclerostin. Blockade of sclerostin acts predominantly through modelling-increasing bone on quiescent surfaces (left). On pre-resorbed surfaces (remodelling), it overfills resorbed sites and extends to adjacent quiescent surfaces (right). See text for details.

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