Pharmacogenomics of osteoporosis-related bone fractures

Abstract

Osteoporosis is a systemic skeletal disease characterised by low bone mass and deterioration in the microstructure of bone tissue, which causes bone fragility and consequent increase in fracture risk. The lifetime fracture risk of a patient with osteoporosis is as high as 40%, and fractures most commonly occur in the hip, spine or wrist. From a patient’s perspective, a fracture and the subsequent loss of mobility and autonomy often represent a major drop in the quality of life. Additionally, osteoporotic fractures of the hip and spine carry a 12-month excess mortality of up to 20%, because they require hospitalisation and they subsequently present enhanced risk of other complications, such as pneumonia or thromboembolic disease due to chronic immobilisation. On the other hand, osteoporosis is a multifactorial and polygenic disease, so the individual likelihood of having a fracture depends on the combination of several risk factors such as low bone mineral density (BMD) and genetic predisposition. This chapter will present the most interesting concerns related to phar macogenetics of the pathologies most prevalent in the elderly population. It will identify fracture risk and estimation of the probability of major osteoporotic fracture by assessment tools. The genetics of osteoporosis will be approached by showing general pathways involved in bone homeo stasis and polymorphisms of genes related with BMD and osteoporotic fractures. Genetic or genomic screening approaches that have been used and also potential benefits from other existing or emerging technologies/approaches will be discussed. In addition, the pharmacogenetics of osteo porosis will be discussed, in particular antiresorptive medications, reviewing efficacy limitations and adverse drug reactions associated with current osteoporosis treatments and how these could be attributed to genetic factors. Additionally, it will analyse the therapeutic targets in osteoporosis (bone anabolic and bone resorptive) and the development of new antiresorptive therapies. Furthermore, gene-environment, age and gender differences interactions known to affect response to osteoporosis treatment will be considered. Finally, the translation of pharmacogenetic findings to the clinical practice will be discussed.