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  • Review Article
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Emerging insights into the comparative effectiveness of anabolic therapies for osteoporosis

Nature Reviews Endocrinology volume 17, pages 31–46 (2021)Cite this article

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Abstract

Over the past three decades, the mainstay of treatment for osteoporosis has been antiresorptive agents (such as bisphosphonates), which have been effective with continued administration in lowering fracture risk. However, the clinical landscape has changed as adherence to these medications has declined due to perceived adverse effects. As a result, decreases in hip fracture rates that followed the introduction of bisphosphonates have now levelled off, which is coincident with a decline in the use of the antiresorptive agents. In the past two decades, two types of anabolic agents (including three new drugs), which represent a novel approach to improving bone quality by increasing bone formation, have been approved. These therapies are expected to lead to a new clinical paradigm in which anabolic agents will be used either alone or in combination with antiresorptive agents to build new bone and reduce fracture risk. This Review examines the mechanisms of action for these anabolic agents by detailing their receptor-activating properties for key cell types in the bone and marrow niches. Using these advances in bone biology as context, the comparative effectiveness of these anabolic agents is discussed in relation to other therapeutic options for osteoporosis to better guide their clinical application in the future.

Key points

  • Antiresorptive agents, such as bisphosphonates, have been the mainstay of treatment for osteoporosis, but concerns regarding perceived adverse effects have resulted in a reduction in adherence.

  • Anabolic agents represent a novel approach to improving bone quality by increasing bone formation.

  • Alone, or in combination with antiresorptive agents, anabolic agents are expected to lead to a new clinical paradigm.

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Fig. 1: Cellular mechanisms of PTH signalling in bone.
Fig. 2: Key actions of PTH anabolic agents on cell types of the bone and marrow niche.
Fig. 3: Paradigm of synergistic effect of hormonal and mechanical stimulation on bone.
Fig. 4: Canonical WNT signalling pathway in bone cells, its inhibition by sclerostin and its restoration by sclerostin inhibition via romosozumab.
Fig. 5: Key actions of romosozumab-stimulated WNT signalling on cell types of the bone and marrow niche.

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    Eben G. Estell & Clifford J. Rosen

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Glossary

T-score

A metric indicating the number of standard deviations or units of measurement by which a patient’s bone density differs from the average for a young, healthy adult of the same sex.

Bone remodelling units

A multicellular biological unit composed of bone cells including osteocytes, osteoclasts and osteoblasts, whose coordinated function removes and replaces bone in a given structural volume in the process of maintaining bone microarchitecture.

RG

The G protein-dependent conformation of PTH1R, distinguished from the G protein-independent R0 conformation by its sensitivity to GTPγS.

Cell non-autonomous

A cellular process that relies on a signalling factor or synthesis of a signalling factor, i.e. communication between multiple cells, as opposed to the independent action of a single cell.

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Estell, E.G., Rosen, C.J. Emerging insights into the comparative effectiveness of anabolic therapies for osteoporosis. Nat Rev Endocrinol 17, 31–46 (2021). https://doi.org/10.1038/s41574-020-00426-5

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