Journal of Endocrinological Investigation

, Volume 38, Issue 1, pp 13–29 | Cite as

Treatment of post-menopausal osteoporosis: beyond bisphosphonates

Review
First Online:
Received:
Accepted:

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.

Keywords

Denosumab Teriparatide Cathepsin K inhibitors Anti-sclerostin antibody 

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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Notes

Conflict of interest

The authors declare no conflict of interests.

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Copyright information

© Italian Society of Endocrinology (SIE) 2014

Authors and Affiliations

  1. 1.Osteoporosis Screening UnitGuy’s HospitalLondonUK
  2. 2.Department of Chemical PathologySt Thomas’ HospitalLondonUK
  3. 3.Department of Nuclear MedicineGuy’s HospitalLondonUK

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