Genetic and acquired factors influencing the effectiveness and toxicity of drug therapy in osteoporosis

ABSTRACT

Introduction: Osteoporosis is a highly prevalent skeletal disorder characterized by compromised bone strength, usually related to decreased bone mass and microstructural alterations of bone tissue, predisposing a person to an increased risk of fracture. As other prevalent disorders, osteoporosis is the result of a complex interplay of genetic and acquired factors.

Areas covered: We provide an update of recent studies aimed at identifying the clinical and genetic factors that influence the response to drugs used to treat osteoporosis, as well as those determining the risk of two intriguing adverse effects of antiresorptives: osteonecrosis of the jaw (ONJ) and atypical femoral fractures (AFF).

Expert opinion: Several clinical factors have been suggested to increase the risk of a poor drug response, such as advanced age and frailty. Candidate gene studies suggest that some common polymorphisms of the Wnt pathway and farnesyl diphosphate synthase (FDPS), the target enzyme for bisphosphonates, also influence the response to antiresorptives. However, they await for replication in large independent cohorts of patients. Similarly, some genetic and acquired factors may influence the risk of ONJ and AFF. Preliminary data suggest that the risk of suffering these adverse effects may have a polygenic basis.

KEYWORDS:

• Atypical femoral fractures
• bisphosphonates
• denosumab
• fractures
• osteonecrosis of the jaw
• osteoporosis
• pharmacogenetics

Article highlights

• Osteoporosis compromises bone strength and predisposes to fragility fractures.

• Both acquired and genetic factors influence the response to drug therapy.

• Genetic variants of the Wnt and mevalonate pathways are appealing candidates to influence drug response.

• ONG and AFF are intriguing adverse effects of antiresorptives likely to have a polygenic predisposition basis.

• Genome-wide studies including a large number of patients are needed to identify the genetic mechanisms determining drug response and adverse effects.

• Obtaining pharmacogenetic data from osteoporosis clinical trials is essential to advance in this field.

Declaration of Interest

The authors were supported by research grants from Instituto de Salud Carlos III (PI 12/615), potentially funded by FEDER funds from EU, and IDIVAL. The authors have no other 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 apart from those disclosed.