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 ΔG of binding of −5.2 kcal. Site B is a strong binding site characterized by a ΔG 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 ΔG of binding of all 12 compounds with an R 2 = 0.95 (a 0.19 kcal error variance estimate, ∼3% of the total ΔG range), opening up the way to designing novel chemotherapy, immunotherapy, and anti-infectious disease drugs having weak bone binding affinity.