Bisphosphonates in the treatment of prostatic cancer:
Trying to target a forgotten enemy

Advanced Prostatic cancer is known for its extremely high incidence of bone metastasis (75-80%) which causes substantial morbidity in terms of severe pains, pathological fractures and cord compression with subsequent need for repeated courses of radiation therapy and surgical intervention i.e. Skeletal Related Events (SRE)
For many decades, it was evident that the osteosclerotic nature of prostatic bone metastasis is attributed to excess osteoblastic activity leading to aberrant new bone formation. Recently, there has been accumulating evidence suggesting the role of tumor associated factors which are known to directly (or indirectly) stimulate a disorganized bone formation at the sites of metastasis. Endotheline-1 -which is secreted by the prostate cancer cells- may stand as the most significant molecular component responsible for the pathogenesis of osteoblastic metastasis.
On the other hand, osteoclastic activity in Prostatic cancer was rather denied by virtue of the constantly osteosclerotic appearance of such bone metastasis. However, during the last two decades, advances made in the field of molecular biology and clinical research could unequivocally demonstrate the significant role of osteoclasts in aggrevation of SRE experienced by those patients.
At least three different pathways have been described to explain the excess osteoclastic activity in metastatic prostate cancer.

 1.      Prostatic cancer cells express RANK ligand which is an extremely potent physiological and pathological inducer of osteoclastic activation (also called osteoclastic differentiation factor). RANK ligand directly stimulates osteocalsts leading to excess bone resorption even before the full evolution of osteosclerotic metastasis.

2.      The classic osteoblastic metastasis are known to entrap excess calcium in the newly formed bones. This may lead to the so called Bone Hunger Syndrome with subsequent hypocalcaemia and secondary hyperparathyroidism that would further stimulate osteoclastic activity.

3.      Hormonal therapy classically used to treat Prostatic cancer are known to increase osteoclastic activity ending up with extensive osteoporosis which further contributes to bony pains and fractures.

The above mentioned explanations of osteoclastic over-activity in Prostatic cancer were further confirmed by excessive biochemical studies on bone turnover markers which demonstrated a very significant increase of bone resorption markers in patients with classic osteosclerotic metastasis.
Accordingly, a number of clinical studies have been designed to evaluate the role of different classes of bisphosphonates in reducing SRE in Prostatic cancer. Unfortunately, all studies using Etidronate, Clodronate and Pamidronate have failed to show a significant improvement in SRE compared to placebo. Recently a large randomized study could show a very significant (36%) reduction in SRE in metastatic prostate patients treated by Zoledronic acid compared to placebo with a long term significant reduction of bone pain in the treated patients (up to 2 years).
In conclusion, the osteoclastic over-activity in metastatic prostate cancer has been proven on molecular and biochemical grounds. The success of Zoledronic acid-being the most potent bisphosphonates so far to reduce the SRE in such patients- is extremely promising to improve the quality of life in such patients who usually live long (median 30-36 months) with marked symptoms related to their osseous metastasis.