One of the key parameters for a successful treatment with any drug is the use of an optimal dose regimen. Bisphosphonates (BPs) have been in clinical use for over five decades and during this period clinical pharmacokinetic (PK) and pharmacodynamic (PD) evaluations have been instrumental for the identification of optimal dose regimens in patients. Ideal clinical PK and PD studies help drug developers explain variability in responses and enable the identification of a dose regimen with an optimal effect. PK and PD studies of the unique and rather complex pharmacological properties of BPs also help determine to a significant extent ideal dosing for these drugs.

Clinical PK and PD evaluations of BPs preferably use study designs and assays that enable the assessment of both short- (days) and long-term (years) presence and effect of these drugs in patients. BPs are mainly used for metabolic bone diseases because they inhibit osteoclast-mediated bone resorption and the best way to quantify their effects in humans is therefore by measuring biochemical markers of bone resorption in serum and urine. In these very same samples BP concentrations can also be measured. Short-term serum and urine data after both intravenous (IV) and oral administration enable the assessment of oral bioavailability as well as the amount of BP delivered to the skeleton. Longer-term data provide information on the anti-resorptive effect as well as the elimination of the BP from the skeleton.

Using PK-PD models to mathematically link the anti-resorptive action of the BPs to the amount of BP at the skeleton provides a mechanism-based explanation of the pattern of bone resorption during treatment. These models have been used successfully during the clinical development of BPs. Newer versions of such models, which include systems pharmacology and disease progression models, are more comprehensive and include additional PD parameters such as BMD and fracture risk.

Clinical PK and PD studies of BPs have been useful for the identification of optimal dose regimens for metabolic bone diseases. These analyses will also continue to be important for newer research directions, such as BP use in the delivery of other drugs to the bone to better treat bone metastases and bone infections, as well as the potential benefit of BPs at non-skeletal targets for the prevention and treatments of soft tissue cancers, various fibroses, and other cardiovascular and neurodegenerative diseases, and reduction in mortality and extension of lifespan.