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Most of the bone modifications observed during metastases (and especially osteolysis) appear to be related to stimulation of osteoclasts after interaction with cancer cells. Two main arguments are in favour of this cellular stimulation. Histological argument: there are almost always osteoclasts inside metastatic osteolysis zones. Most of the lacunae are of the size of osteoclasts and not of the adjacent tumour cells. Therapeutic argument: all molecules which act on osteoclast bone resorption (in particular diphosphonate, gallium nitrate) are also excellent treatment for hypercalcemia induced by bone metastases.

Very many physiological and pathological mechanisms are implied during this stimulation.

Diphosphonates are synthetic analogues of endogenous pyrophosphate. The carbon atom replaces the oxygen atom and allows the fixation of two radicals which prevent the destruction of diphosphonates by the osteoclasts. The diphosphonates are bound to the bone hydoxyapatite crystals and block their growth and their dissolution.

Pyrophosphate	General diagram of diphosphonates

Marketing

Many disphosphates are available on the market:

• clodronate (Clastoban ™, Lytos™, Bonefos™, Ostac™),
  
• etidronate (Didronel™),
  
• ibandronate (Bondronat™, Boniva™),
  
• pamidronate (Aredia™),
  
• zoledronate (Zometa™).

Mechanism of action

Their mechanism of action is based on the inhibition of bone resorption by osteoclasts. They have a high affinity for mineralised bone and reduce the activity and the number of osteoclasts at the bone surface. They are metabolised in an analogue of ATP and thus disturb the mechanisms of osteoclasts. Moreover, recent products may also possess an activity on signal proteins (alteration of prenylation), thus inducing apoptosis.

When administered over a long period, they do not appear to have a negative influence on bone formation and mineralization, or on mechanical properties of the bone (they do have a very small influence on osteoblasts).

An alteration of the medullar micro-environment may also exist, in particular due to reduced angiogenesis, thus rendering tumour invasion more difficult. This may also explain the analgesic effect of such drugs. Other examples of direct action on tumour cells have been described in vitro, but involving high dosages and which are probably not clinically significant.

Indications

The main therapeutic indications of these drugs are:

• malignant hypercalcaemia,
  
• Paget's disease,
  
• Prevention of hypercalcaemia,
  
• Osteolytic manifestations of multiple myeloma,
  
• Prevention of osteolytic bone metastases.

In the last indication, diphosphonate might be able to reduce the number of pathological fractures which are so often observed in metastatic patients (for instance: breast cancer) and reduce the diffuse bone pains caused by dense bone metastases.