The coupling of bone formation and resorption is mediated through the OPG/RANK/RANKL system. OPG and RANKL are mainly produced by osteoblasts but also a variety of other tissues. The binding of RANKL to RANK, its natural receptor which is expressed by osteoclasts, accelerates bone resorption. OPG acts as decoy receptor and prevents the interaction of RANKL with RANK and therefore leads to a decrease in activity, survival and proliferation of osteoclasts. Since assays for measurements of serum OPG and RANKL have become commercially available, intense research focused on serum OPG/RANKL levels in context with underlying disease, age, co-morbidities, bone density, and fractures has derived. This review aims to provide an overview if and to which extent serum OPG and RANKL levels may reflect bone metabolism in patients with osteoporosis and metabolic bone disease.