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Emerging therapeutic opportunities for skeletal restoration

Key Points

  • There have been major advances in our understanding of skeletal remodelling. Consequently, new therapeutic opportunities have the potential to not only prevent further bone loss but also to augment skeletal mass.

  • Conventional therapies (for example, oestrogens, selective oestrogen receptor modulators, bisphosphonates and calcitonin) for osteoporosis are centred on inhibiting bone resorption, thereby slowing turnover and enhancing mineralization. Fracture-risk reduction is in the order of 30% for non-vertebral sites. The introduction of anabolic agents, such as parathyroid hormone administered intermittently, set the stage for newer approaches for treatment, which focus on bone formation.

  • The emergence of the WNT–β-catenin pathway as a key regulatory network in the process of bone formation has led to novel targets for osteoporosis prevention and treatment.

  • Sclerostin, a protein produced by osteocytes, has been shown to naturally inhibit WNT signalling by binding to the WNT family co-receptors lipoprotein receptor-related protein 5 (LRP5) and LRP6. A monoclonal antibody to sclerostin is in Phase II trials. Animal and Phase I clinical studies show tremendous promise for enhancing bone mineral density. However, the full context of adverse events with this agent or others that target this pathway has not yet been elucidated.

  • This Review explores the rationale for drug discovery of novel osteoporosis therapies — with a background on limitations of current approaches, enumeration of potential new targets for drug development and the many roads to regulatory approval for these agents.

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.

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Figure 1: Regulation of osteoclast development by RANKL and other cytokines in the bone marrow microenvironment.
Figure 2: Osteoblast lineage specification, expansion and terminal differentiation, as well as the central role of canonical WNTs in regulating these processes.
Figure 3: Sclerostin monoclonal antibody treatment in osteopenic rats restores trabecular bone mineral density and bone volume back to sham levels at the distal femur.
Figure 4: Proposed effect of PPARγ antagonists in the bone marrow milieu.

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Acknowledgements

This work is supported by United States National Institutes of Health grants AR45433-13, AG004875, AG028936 and AR027965.

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FURTHER INFORMATION

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Glossary

Bone mineral density

(BMD). Areal bone mass as measured by dual energy X-ray absorptiometry.

Basic multicellular units

The single physiological unit of skeletal remodelling, including osteoblasts, osteoclasts and osteocytes.

Stromal cells

Connective tissue cells in the bone marrow that are multipotent stem cells.

Microcanaliculi

Small channels that connect the osteocyte with resting cells on the endosteal surface.

Women's Health Initiative (WHI)

A large observational and randomized controlled trial performed in the United States.

WNTs

A family of growth factors that bind to lipoprotein receptor-related protein 5 (LRP5), LRP6 and their own frizzled receptor.

β-catenin

An intracellular transcription factor activated by extracellular ligands such as the WNTs, as well as other intracellular signalling peptides.

Phosphatase and tensin homologue

(PTEN). a lipid phosphatase that inhibits insulininsulin-like growth factor 1 (IGF1) signalling by dephosphorylating phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) to phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2).

TPH1

(Tryptophan hydoxylase enzyme 1). The rate-limiting enzyme in the generation of serotonin.

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Kawai, M., Mödder, U., Khosla, S. et al. Emerging therapeutic opportunities for skeletal restoration. Nat Rev Drug Discov 10, 141–156 (2011). https://doi.org/10.1038/nrd3299

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