We have used isothermal titration calorimetry (ITC) to study the thermodynamics of binding of 12 bisphosphonates to human bone. The ITC results show that there are two binding sites. Site A is the weak, highly populated site seen by NMR and is characterized by an average Delta G of binding of -5.2 kcal. Site B is a strong binding site characterized by a Delta G of binding of -8.5 kcal. Binding to both sites is overwhelmingly entropy driven. Using a thermodynamic group approach and a linear regression method, we predict the Delta G of binding of all 12 compounds with an R-2 = 0.95 (a 0.19 kcal error variance estimate, similar to 3% of the total Delta G range), opening up the way to designing novel chemotherapy, immunotherapy, and anti-infectious disease drugs having weak bone binding affinity.