Pharmacogenetics and Bone Disease Therapy
Abstract
Drug response is known to be highly variable among treated patients. Today is well established that sequence variants in the human genome are one of the main causes of individual drug response. Pharmacogenetics is a novel discipline that represents the intersection between pharmacology and genetics. Analysis of genetic data could predict the individual response to drugs both in terms of beneficial and adverse effects. An ever-increasing number of pharmacogenetic studies have been performed in the last decade but, to date, only a few of them have had clinical application, especially in the field of bone disorders in which pharmacogenetic studies are still in their infancy. This article will offer an overview on pharmacogenetics with a special focus on the studies performed in the area of osteoporosis and other bone diseases.Acknowledgements: This work was supported by unrestricted grants from Fondazione Ente Cassa di Risparmio di Firenze and Fondazione Fondazione Italiana Ricerca sulle Malattie dell'Osso. Raffaella Becagli to Maria Luisa Brandi. Francesca Marini received the Amgen-Dompè fellowship, dedicated to Professor Isa Coghi, from the Osservatorio Nazionale Salute della Donna.
Drug response, pharmacogenetics, pharmacogenomics, genetic tests, polymorphisms, bone diseases
Today, it is well recognised that when a drug is given to a patient it can present with the four following possibilities:
- normal drug effect;
- no or reduced drug effect;
- pronounced or excessive drug effect; or
- adverse drug reactions (ADRs).
The lack of efficacy in all treated patients and the development of ADRs in a percentage of them represent today a limit of all prescribed drugs, with negative implications in terms of reduction of patient quality of life and high costs for healthcare systems and patients, both for the use of ineffective expensive drugs and for the treatment of ADRs.
Individual drug response can be affected by many factors, such as age, sex, ethnicity, disease severity, concomitant diseases, environmental influence, adherence to the therapy and prescription and interaction with concomitant drug therapy. However, polymorphic variants in genes that regulate drug transport and metabolism (pharmacokinetics) or in genes that codify drug targets (pharmacodynamics) are now considered the most important cause of individual variable drug responses. Today the terms pharmacogenetics and its whole-genome application, pharmacogenomics, are defined as the study of genetic factors affecting drug response. These disciplines represent the use of individual genetic data to predict the outcome of drug treatment with respect to both beneficial and adverse events. Potentially, pharmacogenetics could be very useful for refining and optimising drug treatments, allowing the identification of the most effective drug and the most beneficial dose for each patient, based on the genotype.
A major challenge of personalised medicine in complex disorders that require long-term drug treatments, such as bone diseases, is the development of specific genetic tests to distinguish responders from non-responders as well as to recognise subjects at higher risk of developing ADRs, in order to make individual dose adjustments or to choose an alternative drug therapy, when available. The last five years have seen considerable progress in understanding the role of gene variations in inter-individual drug response to several commonly used drugs, through various pharmacogenetic single-gene association studies and genome-wide association studies. Nevertheless, to date, the opportunity to apply pharmacogenetic approaches to drug response and the possibility of using genetic screenings to tailor decisions about pharmacological treatments have not yet significantly changed common therapeutic practices.
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