text: The original bisphosphonates (first generation) were simple molecules with small groups of single atoms or alkyl chains in position R and R. They only had a rather weak inhibiting effect on bone resorption. The inclusion of an amino group marked the beginning of the second generation of bisphosphonates with higher potency. The first was pamidronate and similar analogues followed where the position of the nitrogen in the side chain was the key to a more potent drug. Later it became apparent that the nitrogen does not necessarily have to be connected to an alkyl chain but instead using a heterocyclic group. A few such drugs have been developed and placed on the market where zoledronate is the most notable one. Minodronic acid is even more potent and has been placed on the market in Japan. Their potency is such that it is effective even in picomolar concentration.
  Further development has not resulted in the placing on the market of compounds in equal potency. Arylalkyl substitutes of pamidronate are among the most recent bisphosphonates to be used clinically where the hydroxyl group in position R has been omitted to ensure stability.
  Recent research in this area has opened up an opportunity to develop new bisphosphonate drug therapies.
  Bisphosphonates with a more lipophilic character have been developed and have shown potential as a tumor suppressant. They operate by a slightly different mechanism in which they not only inhibit the key enzyme farnesyl pyrophosphate synthase (FPPS) of the mevalonate pathway but also geranylgeranyl pyrophosphate synthase (GGPS), an enzyme also located in the mevalonate pathway. They do not have the same affinity for the bone minerals.
  GGPS has since been successfully inhibited by a novel bisphosphonate compound with a triazole group within R and a methyl group in R. This may become useful in therapies against malignancies like multiple myeloma.
  In 2018, a dendritic bisphosphonate was introduced containing three bisphosphonate units. It has shown potential for bone specific delivery of large therapeutic molecules by taking advantage of the high affinity of bisphosphonates to the bone minerals