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Treatment of post-menopausal osteoporosis: beyond bisphosphonates

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Abstract

Osteoporosis is a highly prevalent condition, characterized by compromised bone strength and fragility fractures and with an important associated socio-economic burden. Bisphosphonates are well established as the first line treatment for osteoporosis. However, while randomized control trials have in general demonstrated reasonable anti-fracture efficacy at the spine, they have shown moderate reduction in fracture incidence for non-vertebral sites. Furthermore, oral bisphosphonates are commonly associated with adverse gastrointestinal effects and both oral and parenteral bisphosphonates have been linked with osteonecrosis of the jaw and atypical femoral fracture, two rare but debilitating side effects. In addition, bisphosphonates are not recommended in patients with GFR <35 ml/min/1.73 m2. Hence, there is a clear requirement for newer agents, which are able to reduce fracture risk further, whilst overcoming the limitations of bisphosphonates. Over the past 20 years, knowledge and a deeper understanding of the various signalling pathways involved in bone remodelling has increased, enabling identification of additional targets for therapy. This review focuses on these newer therapies and includes anti-resorptive agents such as raloxifene and other selective oestrogen receptor modulators, the monoclonal antibody denosumab (which inhibits the RANKL pathway), odanacatib, a cathepsin K inhibitor and the anabolic agents, PTH analogue; PTH (1–34) and anti-sclerostin antibodies (activator of the Wnt pathway). Strontium ranelate will not be reviewed as recent reports highlight concerns surrounding its cardiovascular safety and together with an apparent increased risk of thrombosis, its future use remains uncertain. Some of these agents such as raloxifene, denosumab and teriparatide are already in clinical use whilst others are at varying stages of development. This review will provide an overview of the mechanisms of action of these therapeutic agents on the skeleton and assess their efficacy in osteoporosis and fracture prevention.

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Abbreviations

BRC:

Bone remodelling compartment

RANKL:

Receptor activator of nuclear factor kappa-B ligand

OPG:

Osteoprotegerin

BMU:

Basic multicellular unit

VEGF:

Vascular endothelial growth factor

M-CSF:

Macrophage colony stimulating factor

LRP 5/6:

Low-density lipoprotein receptor-related protein 5 or 6

GSK:

3beta-glycogen synthase kinase

Tcf/Lef:

T cell factor/lymphoid enhancer factors

RUNX2:

Runt-related transcription factor 2

PMW:

Postmenopausal women

PTHR1:

Parathyroid hormone receptor

PKA:

Protein kinase A

PKC:

Protein kinase C

SOST:

Sclerostin gene

ER-alpha:

Oestrogen receptor-alpha

FasL:

Fas-ligand

MAPK:

Mitogen-activated protein kinase

AFF:

Atypical femoral fracture

ONJ:

Osteonecrosis of the jaw

SRE:

Skeletal-related events

GIOP:

Glucocorticoid-induced osteoporosis

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Authors and Affiliations

  1. Osteoporosis Screening Unit, Guy’s Hospital, London, UK

    S. Ishtiaq, I. Fogelman & G. Hampson

  2. Department of Chemical Pathology, St Thomas’ Hospital, 5th Floor, North Wing, Lambeth Palace Road, London, SE1 7EH, UK

    S. Ishtiaq & G. Hampson

  3. Department of Nuclear Medicine, Guy’s Hospital, London, UK

    I. Fogelman

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  1. S. Ishtiaq
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Ishtiaq, S., Fogelman, I. & Hampson, G. Treatment of post-menopausal osteoporosis: beyond bisphosphonates. J Endocrinol Invest 38, 13–29 (2015). https://doi.org/10.1007/s40618-014-0152-z

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