Bisphosphonates suppress osteoclast-mediated bone resorption and are widely used in the management of osteoporosis. Daily oral administration of alendronic acid and risedronic acid have been shown to reduce the risk of vertebral and non-vertebral fractures. Once-weekly regimens with these bisphosphonates are pharmacologically equivalent to daily regimens. Regimens with treatment-free intervals longer than 1 week present an attractive therapeutic option as they may offer additional patient convenience and long-term adherence to treatment. However, until recently, such regimens, usually referred to as intermittent or cyclical, have not shown any convincing antifracture efficacy in clinical trials, probably because of the empirical manner in which the design of these regimens has been approached. Investigation of pharmacokinetics/pharmacodynamics of bisphosphonates may help in the design of effective intermittent dosage regimens. Bisphosphonates are poorly absorbed from the gastrointestinal tract and about 50% of the absorbed drug is taken up selectively by the skeleton, while the rest is excreted unaltered in urine. Bisphosphonates exert their action at the bone surface, where they are taken up by the osteoclasts during bone resorption. Therefore, when describing the pharmacokinetics of bisphosphonates in relation to the pharmacodynamics, the amount of bisphosphonate at the skeleton should be accounted for. Few of the reported clinical pharmacokinetic studies addressed this issue. This is partly due to the absence of study design elements to account for skeletal binding of the drugs. Pharmacokinetic studies have also been hampered by technical difficulties in determining the concentration of bisphosphonates in serum and urine. Moreover, most clinical pharmacokinetic (but also pharmacokinetic/pharmacodynamic) studies have primarily used noncompartmental analysis, leaving out the distinct advantages of modelling and simulation techniques. Clinically, the primary action of bisphosphonates can be assessed by the measurement of biochemical markers of bone resorption. Recent studies indicate that the pattern of these markers during bisphosphonate treatment may be predictive of antifracture efficacy; however, only limited data are available for the development of pharmacokinetic/pharmacodynamic models that are able to predict the response of these markers to different treatment regimens with bisphosphonates. Recently, pharmacokinetic/pharmacodynamic models for response to bisphosphonates have been described and, at present, some of them are being used in the design of bisphosphonate regimens with long drug-free intervals.