Elsevier

Bone

Volume 147, June 2021, 115907
Bone

“The use of bisphosphonates to treat skeletal complications in solid tumours”

https://doi.org/10.1016/j.bone.2021.115907Get rights and content

Highlights

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    Metastasis to the skeleton is a major complication of solid tumours, including breast, prostate, lung and renal cancers.

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    Bisphosphonates have revolutionized the treatment and clinical outcomes of patients with metastatic bone disease.

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    Bisphosphonates can prevent/delay onset of skeletal related events (SREs), including hypercalcaemia.

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    Bisphosphonates improve patient quality of life, including reduction of bone pain.

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    Current research aims to use the bisphosphonate group to target anti-cancer drugs to bone.

Abstract

The skeleton is the most common site of secondary disease in breast cancer and prostate cancer, with up to 80% of patients with advanced disease developing bone metastases (BM). The proportion is also substantial in advanced lung cancer (20%–40%). Because of the high prevalence of cancers of the breast, prostate and lung, these cancers account for more than 80% of cases of metastatic bone disease occurring in solid tumours.

Metastatic bone disease is associated with greatly increased bone resorption by osteoclasts, leading to moderate to severe pain and other skeletal complications, with major impact on quality of life (QoL). Skeletal Related Events (SREs) have been defined as: pathological long bone or vertebral fractures; spinal cord compression; need for radiation for pain relief or to prevent fracture/spinal cord compression, need for surgery to bone and hypercalcaemia. More recently, Symptomatic Skeletal Events (SSEs) have been defined to monitor QoL.

Although there are currently no curative treatments for metastatic bone disease, patients with breast or prostate cancer and BM are now surviving for several years and sometimes longer, and prevention of SREs is the key aim to optimization of QoL. Since their discovery 50 years ago and their introduction more than 30 years ago into the field of metastatic bone disease, a range of oral and intravenous bisphosphonate drugs have made a major contribution to prevention of SREs.

Large trials have clearly demonstrated the clinical value of different bisphosphonate-based drugs (including the oral drugs ibandronate and clodronate and intravenous agents such as zoledronate and pamidronate), in treatment of hypercalcaemia of malignancy and the reduction of SREs and SSEs in a range of cancers. Despite the success of denosumab in reducing osteolysis, bisphosphonates also remain mainstay drugs for treatment of metastatic bone disease. Recognizing the 50th Anniversary of the discovery of bisphosphonates, this review focuses on their continuing value in BM treatment and their future potential, for example in providing a bone-targeting vehicle for cytotoxic drugs.

Section snippets

Background and introduction

The skeleton is the most common site of secondary disease in breast cancer and prostate cancer, with up to 80% of patients with advanced disease developing bone metastases (BM). The proportion is also substantial in advanced lung cancer (20%–40%) (Table 1). Because of the high prevalence of cancers of the breast, prostate and lung, these cancers account for more than 80% of cases of metastatic bone disease occurring in solid tumours [1]. Recognizing the 50th Anniversary of the discovery of

Skeletal related events (SREs)

Patients with BM are subject to a range of potentially debilitating skeletal complications which challenge QoL in subjects whose survival is potentially measured in years. Most often patients report moderate to severe bone pain but, in addition, they may suffer from pathological fractures. The impact of a fracture depends upon the site, for example a fractured neck of the femur can have a major impact whereas a vertebral fracture may sometimes be asymptomatic and may only be identified on

Systemic treatment of metastatic bone disease

The currently used treatment options for patients with BM are aimed at symptom palliation and SRE prevention, while concurrent systemic anti-cancer therapies are employed for disease control at both skeletal and extra-skeletal sites [20]. The most commonly applied treatments for BM are the bisphosphonate class of bone-targeted antiresorptive agents, e.g. clodronate, ibandronate, pamidronate and zoledronate depending upon the cancer type [21,22]. Newer antibody-based therapies targeting specific

Bisphosphonate – drug conjugates

The bone targeting properties of the bisphosphonate moiety provide an attractive means to ensure that anti-cancer drugs are delivered to bone, specifically released there, thus providing reduced side effects. To date most studies of bisphosphonate-drug conjugates have been performed in vitro but they show promise – (this area is also reviewed in [110]).

In one pre-clinical study, paclitaxel was conjugated to alendronate via a cathepsin-K sensitive linker. This conjugate naturally assembled into

Guidelines on bisphosphonate use in metastatic bone disease

Current ASCO [119] and ESMO guidelines [119] recommend the addition of bone-targeting agents, namely bisphosphonates or denosumab, to disease-specific anti-cancer treatments in order to manage skeletal metastases in patients with solid tumours.

In particular, among the various agents, both zoledronate and denosumab are approved for use in solid malignancies, whereas pamidronate and ibandronate can be considered only in the breast cancer setting. As stated earlier, clodronate is approved in the

Conclusions

The discovery of bisphosphonate drugs 50 years ago and their subsequent application in patients with BM has had a transformational clinical benefit. Prior to this, patients with skeletal complications had very poor prospects for ensuing QoL. Whilst cure of metastatic bone disease remains elusive, the reduced bone pain, decreased frequency of SREs, better treatment of hypercalcaemia and reduced need for surgery has benefitted hundreds of thousands of patients worldwide and continues to do so.

The

CRediT authorship contribution statement

All authors (SD, SLW and JEB) provided significant input into the sections of this article, in terms of authoring, content selection and editing.

Acknowledgements

This work was funded by the University of Sheffield (SLW, JEB) and the University of Bari Aldo Moro (SD).

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