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  • Review Article
  • Published:

Antiresorptive and anabolic agents in the prevention and reversal of bone fragility

Abstract

Bone volume, microstructure and its material composition are maintained by bone remodelling, a cellular activity carried out by bone multicellular units (BMUs). BMUs are focally transient teams of osteoclasts and osteoblasts that respectively resorb a volume of old bone and then deposit an equal volume of new bone at the same location. Around the time of menopause, bone remodelling becomes unbalanced and rapid, and an increased number of BMUs deposit less bone than they resorb, resulting in bone loss, a reduction in bone volume and microstructural deterioration. Cortices become porous and thin, and trabeculae become thin, perforated and disconnected, causing bone fragility. Antiresorptive agents reduce fracture risk by reducing the rate of bone remodelling so that fewer BMUs are available to remodel bone. Bone fragility is not abolished by these drugs because existing microstructural deterioration is not reversed, unsuppressed remodelling continues producing microstructural deterioration and unremodelled bone that becomes more mineralized can become brittle. Anabolic agents reduce fracture risk by stimulating new bone formation, which partly restores bone volume and microstructure. To guide fracture prevention, this Review provides an overview of the structural basis of bone fragility, the mechanisms of remodelling and how anabolic and antiresorptive agents target remodelling defects.

Key points

  • Slowness of the formation phases of bone remodelling produces a systemically ever-present deficit in bone volume that is transient and focally reversible.

  • The size of the reversible deficit in bone volume is remodelling-rate-dependent.

  • During early menopause, the rapid increase in remodelling rate enlarges the reversible deficit, causing a rapid decrease in bone mineral density (BMD).

  • Remodelling imbalance occurs around the ages of 45–50 years, producing irreversible deficits in bone volume, microstructural deterioration and bone fragility.

  • Antiresorptive agents slow remodelling, thereby reducing the reversible deficit in bone volume, resulting in an early rapid increase in BMD, but the irreversible deficit in bone volume responsible for microstructural deterioration is not corrected.

  • Restoring bone microstructure requires anabolic therapy, which produces net remodelling-based and modelling-based bone formation.

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Fig. 1: Bone anatomy.
Fig. 2: Reversible and irreversible deficits in bone volume.
Fig. 3: Menopause, bone loss and structural deterioration.
Fig. 4: Antiresorptive agents, BMD and microstructure.

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Acknowledgements

The authors thank X. Wang (Austin Health, University of Melbourne, Australia) for invaluable assistance in the preparation and critical reading of this manuscript.

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Nature Reviews Rheumatology thanks F. Marin and the other anonymous reviewer(s), for their contribution to the peer review of this work.

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Both authors researched the data for the article, provided substantial contributions to discussions of its content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Ego Seeman.

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E.S. declares that he has received research support from Amgen and Merck, Sharp and Dohme (MSD) and lecture fees from Allergan, Amgen and Eli Lilly. E.S. also declares that he is a director and board member of StraxCorp. T.J.M. declares no competing interests.

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Glossary

Fragility fractures

The result of minimal trauma, a fall from no greater than the standing position or spontaneous vertebral fractures that may occur during normal daily activity without any apparent trauma.

Periosteal surface

The external or outer surface of bone.

Medullary canal

The central canal of a long bone, which contains extracellular fluid and bone marrow cells.

Metaphysis

The end of a long bone between the joint and the diaphysis (shaft), serving to transfer loads from the joint to the diaphysis.

Diaphysis

The midsection of the shaft of a long bone, such as the femur or radius, which provides a lever for mobility and load bearing.

Endosteal surface

An internal surface of bone that has three components, the intracortical surface lining the Haversian canals, the endocortical surface lining the medullary canal and the trabecular surface on either side of the trabeculae.

Haversian canals

Central canals of osteons orientated along the long axis of a bone. They contain extracellular fluid, blood vessels, nerves and lymphatics.

Trabeculae

Thin plates of mineralized bone forming the so-called cancellous or spongy bone present at the ends of long bones and the vertebral body.

Remodelling balance

During remodelling in young adults, the same volumes of bone are resorbed by osteoclasts and deposited by osteoblasts at points upon the internal surfaces of bone; thus, there is no focal loss of bone volume or microstructural deterioration.

Osteoid

Bone matrix of type 1 collagen deposited by the osteoblast, which becomes bone when it mineralizes.

Primary mineralization

The deposition of calcium hydroxyapatite mineral within a newly deposited osteoid, which is then referred to as bone.

Secondary mineralization

The enlargement of crystal of calcium hydroxyapatite mineral deposited within a fibre of type-1 collagen during primary mineralization.

Reversal phase

A phase of remodelling that follows the resorptive phase and precedes the formation phase.

Osteons

Basic structural units of cortical bone formed by bone remodelling, which have a central fluid-filled canal, circumferential lamellae of mineralized collagen and a cement line.

Hemiosteons

Basic structural units of trabecular bone that are formed by refilling of an excavated cavity upon trabecular surfaces.

Remodelling imbalance

After the ages of 45–50 years, each bone multicellular unit deposits a smaller volume of new bone than the volume of older bone it resorbed, leaving a net focal deficit in bone volume and microstructural deterioration.

Cement line

A line delineating osteons from the interosteonal bone and other osteons. It contains less calcium and phosphorus than the surrounding bone matrix.

Stress concentrator

Stress is force per unit area. When bone is lost, stress rises or is concentrated, as it is distributed upon a smaller area.

Peak bone mass

The maximum bone mass achieved by the completion of growth.

T-score

The number of standardized deviations an individual’s bone mineral density (BMD) is above or below the mean value in healthy premenopausal women or healthy young adult men. A T-score less than –2.5 SD denotes osteoporosis, between –2.5 and –1.0 SD denotes osteopenia and greater than –1 denotes normal BMD.

Remodelling suppression

Antiresorptive agents reduce the number of bone multicellular units (BMUs) turning over bone, that is, replacing older with younger bone at a given location. Bone loss slows because there are fewer BMUs eroding the skeleton.

Crenated surfaces

Teams of osteoclasts resorb bone, producing a resorption cavity that has an irregular or crenated surface. Bone formation upon a crenated surface is remodelling-based. Bone formation upon a smooth surface is modelling-based.

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Seeman, E., Martin, T.J. Antiresorptive and anabolic agents in the prevention and reversal of bone fragility. Nat Rev Rheumatol 15, 225–236 (2019). https://doi.org/10.1038/s41584-019-0172-3

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