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Treatment of bone disease with bisphosphonates

Prostate cancer is today an important public health problem in the world and particularly in Europe. Its incidence is increasing and appears at younger and younger ages. It is estimated that the probability that a man will suffer from this disease throughout his life is around 17%. Despite being the most common cancer in males, it is only the third leading cause of cancer death, which means an effective medical approach, both in the increasingly early diagnosis and in the increasingly effective treatment. In fact, the introduction of PSA (prostate specific antigen) in the early 1990s made it possible to bring the diagnosis forward by about 10 years, that is, at a still curable stage. On the other hand, advances in the various therapeutic modalities have significantly increased survival.

However, it is important to bear in mind that, despite efforts, the percentage of prostate cancers that are diagnosed at a more advanced stage, of disseminated disease, is still considerable. On the other hand, the increase in the life expectancy of the population and the therapeutic improvements allow patients to live longer with their prostate cancer and therefore have more time to develop metastatic bone disease.

Prostate cancer, in terms of its natural history, metastasizes to many organs, but predominantly to bones. In other words, it is one of the cancers, along with breast cancers of the kidney and lung, that most metastasizes to the bones. In fact, about 75% of men with advanced prostate cancer have bone metastases. These metastases are located essentially in the axial skeleton, that is, in the skull, spine, ribs, and pelvis. The special predilection for bone results from the expression, by circulating neoplastic cells, of adhesion molecules that specifically identify glycoproteins on the endothelial surface of bone capillaries. Once in the bone tissue, there is an activation of osteoclasts and indirectly of osteoblasts, which results in a deregulation of bone metabolism with increased bone resorption, but also in the formation of new fragile and unstable bone tissue with loss of skeletal integrity (osteoblastic metastases). .

This is a fundamental issue because, in addition to being frequent, bone metastases carry significant morbidity associated with important complications usually called skeletal-related events (SRE):
– Bone pain – pain is the most common symptom of bone metastases and is usually the first to manifest and is often severe.
– Fractures – metastases weaken bones, increasing the risk of pathological fractures, especially in the limbs and spine.
– Spinal cord compression – when the cancer metastasizes to the spine, spinal cord compression can cause not only pain, but also various types of neurological symptoms.
– Hypercalcemia – results from the release of bone calcium and is associated with symptoms such as anorexia, nausea, thirst, constipation, confusion and coma.

These complications result in a significant loss of the patient's quality of life, either due to pain, loss of autonomy, or even the anxiety and depression caused.
On the other hand, the appearance of these complications is directly associated with a shortening of patient survival, as well as an increase in treatment costs, which can almost double.

Until recently, the treatment of patients with advanced prostate cancer was purely palliative, in an attempt to control pain and other complications.

This scenario has changed and for a few years now we have at our disposal two major therapeutic weapons to treat these patients.

One of them is the use of chemotherapy with taxanes (docetaxel), which has shown a statistically significant increase in survival.

The other is bisphosphonates, such as zoledronic acid, the only one approved for use in prostate cancer. These are osteoclast inhibitors, thus preventing bone resorption typical of prostate carcinoma metastases. They also have a direct antineoplastic and antiproliferative activity, as well as anti-invasive and antimetastatic activity. In fact, they have the great advantage of significantly reducing the incidence of bone complications (SRE), delaying their appearance by about five months, thus improving, in a real way, the quality of life of patients. On the other hand, they effectively control bone pain with an efficiency of about 70%. They also seem to prevent the development and recurrence of bone metastases. They are also very effective drugs in preventing and delaying bone demineralization, iatrogenically caused by hormonal treatment. (Hormone therapy is responsible for a loss of bone mineral density that is four to five times greater than in a postmenopausal woman.)

Ultimately, we now have something to offer these patients, which was not the case before. The fact that we are facing an advanced stage of prostate cancer, which has no cure, does not necessarily mean that we cannot improve the patient's quality of life and even increase his survival.

In conclusion, prostate cancer metastasized to the skeleton can currently be treated with bisphosphonates, which have shown important efficacy not only in controlling pain, but also in preventing and delaying the onset of SRE, which are highly compromising the quality of life of these patients.

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