Pharmacogenetics of Osteoporosis: Towards Novel Theranostics for Personalized Medicine?

Osteoporosis is a common disease characterised by a systemic impairment of bone mass and microarchitecture that results in fragility fractures. With an ageing population, the medical and socioeconomic effect of osteoporosis, particularly postmenopausal osteoporosis, will increase further. A detailed knowledge of bone biology with molecular insights into the communication between bone-forming osteoblasts and bone-resorbing osteoclasts and the orchestrating signalling network has led to the identification of novel therapeutic targets. Novel treatment strategies have been developed that aim to inhibit excessive bone resorption and increase bone formation. The most promising novel treatments include: denosumab, a monoclonal antibody for receptor activator of NF-κB ligand, a key osteoclast cytokine; odanacatib, a specific inhibitor of the osteoclast protease cathepsin K; and antibodies against the proteins sclerostin and dickkopf-1, two endogenous inhibitors of bone formation. This overview discusses these novel therapies and explains their underlying physiology. Copyright © 2011 Elsevier Ltd. All rights reserved.

The diagnosis of osteoporosis centres on the assessment of bone mineral density (BMD). Osteoporosis is defined as a BMD 2.5 SD or more below the average value for premenopausal women (T score < -2.5 SD). Severe osteoporosis denotes osteoporosis in the presence of one or more fragility fractures. The same absolute value for BMD used in women can be used in men. The recommended site for diagnosis is the proximal femur with dual energy X-ray absorptiometry (DXA). Other sites and validated techniques, however, can be used for fracture prediction. Although hip fracture prediction with BMD alone is at least as good as blood pressure readings to predict stroke, the predictive value of BMD can be enhanced by use of other factors, such as biochemical indices of bone resorption and clinical risk factors. Clinical risk factors that contribute to fracture risk independently of BMD include age, previous fragility fracture, premature menopause, a family history of hip fracture, and the use of oral corticosteroids. In the absence of validated population screening strategies, a case finding strategy is recommended based on the finding of risk factors. Treatment should be considered in individuals subsequently shown to have a high fracture risk. Because of the many techniques available for fracture risk assessment, the 10-year probability of fracture is the desirable measurement to determine intervention thresholds. Many treatments can be provided cost-effectively to men and women if hip fracture probability over 10 years ranges from 2% to 10% dependent on age.

Coronary artery disease (CAD) is the leading cause of death worldwide and is commonly caused by a constellation of risk factors called the metabolic syndrome. We characterized a family with autosomal dominant early CAD, features of the metabolic syndrome (hyperlipidemia, hypertension, and diabetes), and osteoporosis. These traits showed genetic linkage to a short segment of chromosome 12p, in which we identified a missense mutation in LRP6, which encodes a co-receptor in the Wnt signaling pathway. The mutation, which substitutes cysteine for arginine at a highly conserved residue of an epidermal growth factor-like domain, impairs Wnt signaling in vitro. These results link a single gene defect in Wnt signaling to CAD and multiple cardiovascular risk factors.