A patent review of bisphosphonates in treating bone disease

ABSTRACT

Introduction: Bisphosphonates (BPs) are widely used to manage a variety of bone disorders, including osteoporosis, metastatic bone disease and myeloma bone disease. The nitrogen-containing BPs (NBPs) target osteoclast activity by disrupting protein prenylation via inhibition of farnesyl diphosphate synthase (FDPS).

Areas covered: This review summarizes the recent advances in BPs with a focus on the latest patents (2015–2018). Patents involving novel BPs, new modes of BP delivery, as well as use of BPs to deliver other drugs to bone are discussed. A review of phosphonate-based drugs targeting geranylgeranyl diphosphate synthase (GGDPS) or geranylgeranyl transferase II (GGTase II) as alternative strategies to disrupt protein geranylgeranylation is provided.

Expert opinion: While the NBPs remain the mainstay of treatment for most bone disorders, further understanding of their pharmacological properties could lead to further refinement of their chemical structures and optimization of efficacy and safety profiles. In addition, the development of NBP analogs or drug delivery mechanisms that allow for nonbone tissue exposure could allow for the use of these drugs as direct anticancer agents. The development of GGDPS and GGTase II inhibitors represents alternative heterocycle phosphonate-based strategies to disrupt protein geranylgeranylation and may have potential as anticancer agents and/or as bone-targeted therapies.

KEYWORDS:

• Bisphosphonate
• farnesyl diphosphate synthase
• lytic bone disease
• osteoporosis

Article highlights

• Bisphosphonates are currently widely used for the treatment of a variety of bone diseases including osteoporosis, Paget disease, metastatic bone disease, myeloma bone disease and hypercalcemia of malignancy.

• The mechanism of action of the nitrogen-containing bisphosphonates is to inhibit the enzyme farnesyl diphosphate synthase (FDPS), resulting in disruption of protein prenylation in osteoclasts.

• The use of BPs coupled to other drugs as a means to deliver bone-directed therapy is being explored.

• The clinically used NBPs have limited tissue distribution and efforts are ongoing to develop NBP analogs or drug delivery methods that would increase non-bone tissue exposure, thereby disrupting protein prenylation in other target tissues.

• Geranylgeranyl diphosphate synthase (GGDPS) and geranylgeranyl transferase (GGTase) II inhibitors represent alternative heterocycle phosphonate-based strategies to disrupt protein geranylgeranylation.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they are a co-author on a patent for a novel bisphosphonate. All other peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.