A Patient's Guide to Managing Hormone-Refractory Prostate Cancer  

Chapter 11.  Protect your bones from deterioration
 

Hormone therapy puts you at risk for osteoporosis

Dealing with prostate cancer involves a double risk to your bones. First, the treatment intended to stop the cancer—hormone blockade—also interferes with the process that keeps your bones strong. Secondly,  prostate cancer which begins in the prostate, prefers to spread into your bones creating bone metastases.

Hormone therapy takes many forms -- there are the LH-RH agonists such as Lupron and Zoladex; there is the combined hormone therapy of an LH-RH agonist and an anti-androgen and then there is total or complete hormone blockade consisting of an LH-RH agonist + an anti-androgen such as flutamide or casodex + a 5-alpha reductase inhibitor such as proscar.

All the above suppress testosterone in these combinations. Suppression of testosterone frequently leads to bone loss.  Sometimes casodex is used as a monotherapy. In this case, testosterone is not suppressed as the anti-androgen blocks the uptake of testosterone by the cancer cells preventing their continued growth. Studies are showing that Casodex monotherapy does not lead to osteoporosis -- testosterone may actually increase and the excess testosterone will be converted into estrogen which helps to maintain bone mineral density.

Your skeleton is constantly undergoing a process called “remodeling.” That means that its calcium and phosphorus content are constantly being resorbed into your blood then redeposited in the same or another place. When you exercise vigorously, you enhance the redeposition of calcium to points of stress. Testosterone controls the rate at which bone is lost due to resorption.

On a technical level, remodeling is managed by two sets of bone cells called osteoclasts and osteoblasts. Osteoclasts are activated by parathyroid hormone to dissolve bone calcium and phosphate. At the other end of this process is the osteoblast, a cell that synthesizes collagen and glycoproteins into solid bone cells, called osteocytes. Collagen itself is a protein that forms tendons and cartilage, as well as bone. Calcification of cartilage produces hard bone.

Why prostate cancer has such an affinity for the bone is not understood. But 70% of the PCa mets are to the bone, predominantly the pelvic area and the spine. Other common spots for metastases are the ribs, skull, femur, humerus, and shoulder. Interestingly, bone tumors attract calcium and become more dense (sclerotic) than normal bone; but that calcium is stolen from areas surrounding the tumor, and those areas are weakened. The weakened areas are susceptible to fracture, which may be the first hint that there is a problem in the bone.

You can diagnose these problems by using the tests described in Chapter 19. Bone density can be measured, as can excessive loss of calcium.

The loss of bone density due to lack of testosterone leads to osteoporosis—or its precursor, osteopenia. If you have not been treating this and are not aware of the problem, the first warning you will get is a broken bone—pelvis, leg, arm, back. Unfortunately, there are still some doctors who are not fully aware of this danger and how to prevent it. If you are on hormone therapy and not on a bisphosphonate, you need to get this message through to your doctor. This is too important to ignore.

Whether or not you have bone mets, you also need bisphosphonates to prevent them or to suppress them. Fortuitously, the same drug that prevents/cures osteoporosis might also prevent and suppress bone metastases -- although preventing bone metastases has not yet been proven in clinical trials.

Although there is a tendency to see bone tumors as fundamentally different from the tumor in the prostate, they are in fact alike. Bone tumors are soft-tissue tumors growing in the spaces in the bony network. Bone tumors are also fed by blood vessels in the bone and marrow. Unfortunately, these bone tumors also replace the marrow that produces red and white blood cells.

Several other issues are involved in the maintenance of bone integrity. Vitamin D, calcium and phosphorus levels in your body are important. Additionally, the parathyroid gland is involved in controlling the levels of those elements. These are discussed below.

Bisphosphonates

The bisphosphonate drug of choice for HRPCa is Zometa (given by IV), also called zoledronic acid. Clinical trials have shown that Zometa is the most effective of the group. If you can’t get Zometa, then Aredia (pamidronate) is the next best choice; it is also given by IV. Next in line is Fosamax (alendronate) and Actonel, both pills. The doses are those recommended by the manufacturer, although you may wish to consider a high dose of Fosamax (as much as 40 mg/day). 

The bisphosphonates inhibit that process of bone resorption, which would otherwise dissolve your skeleton into your body and blood stream. When the level of calcium in the blood falls below a certain level, the parathyroid hormone stimulates osteoclasts to secrete enzymes that break down the bone. According to the PDR, the bisphosphonate adheres to calcium phosphate in the bone and prevents its dissolution.

The bisphosphonates also have the fortunate characteristic of suppressing bone tumors(specifically, zometa has been shown to delay the onset of skeletal related events or SREs). See the writeup on Zometa in the main pages for more detail.  It is equally important to use this drug as part of the battle against the cancer. If you have no bone mets, the bisphosphonates may prevent their onset -- but this has only been seen in  pre-clinical models.  There are clinical trials being run to evaluate this possibility. 

This anti-cancer effect of the bisphosphonates may also result in a reduction of bone pain, which is associated with bone resorption.


Calcium, phosphorus, and vitamin D

Loss of calcium is the main culprit behind weakening of bones. We have seen that resorption of calcium into the system can deplete calcium and phosphate from the bones.

At the other side of this dual system is the redeposition of calcium and phosphate back onto the bone. If the amount of blood calcium is above a certain level, the hormone calcitonin stimulates the osteoblasts to use some of the calcium and phosphate in the blood to create new bone.

It is important to have a sufficient intake of dietary calcium to permit the creation of new bone.

You can see that these two processes—resorption and redeposition—are competing processes. When there is a lack of testosterone, a deficiency of calcium, or inadequate exercise, the resorption outpaces the rebuilding, and osteoporosis begins.

Another potential problem with HRPCa is a deficiency of vitamin D. This vitamin enhances calcium absorption and promotes bone growth. A deficiency in vitamin D can result in bone softening (osteomalacia). Once again, this vitamin seems to be unusually important in the battle against PCa. Epidemiological studies have shown that men in areas of less sunshine have a greater incidence of PCa.

One can take vitamin D plus calcium as supplements in the diet. Or you can take calcitriol, which is an activated form of vitamin D. A dose of 0.25 - .5 microgram/day plus 1,000 mg of calcium is recommended. It is desirable to monitor the blood calcium level because vitamin D—if used excessively—can be toxic. (The chapter on chemotherapy discusses the use of an extremely high dose of calcitriol as an adjuvant therapy to enhance the efficacy of certain chemotherapies. That is a totally different situation. In no case should an individual use a continuing high dose of vitamin D, due to the potential toxicity.) The use of vitamin D—in any form—as part of your cancer therapy should be done with the involvement of your physician.

Although high doses of vitamin D carry the risk of toxicity, called hypercalcemia, it is possible to increase the calcitriol dose to 1.0 to 1.5 microgram/day so long as your doctor concurs. In this case, you must not take supplemental calcium, and you must avoid foods heavy in calcium, such as milk and cheese. Additionally, you will need to get a monthly urine test to ensure that you are not hypercalcemic. The urine test is for calcium and creatinine (not creatine). So long as the calcium is 35% or less of the creatinine level, you are fine. If the calcium rises above that level, stop the calcitriol.

The parathyroid gland

The level of calcium circulating in your system is regulated by the parathyroid hormone (PTH). Control of calcium is critical to your life.

The parathyroid glands (four of these are located against the thyroid gland in your neck) produce a hormone that stimulates the osteoclast cells in the bone to begin the process of resorption. The result is that the blood level of calcium and phosphate rises. PTH also stimulates the kidneys to absorb those released molecules.

Calcium is important to muscle contraction and blood clotting, among other things. The parathyroid glands are part of the endocrine system, by definition, because they produce a hormone. The thyroid gland produces the calcitionin helps to lower the level of calcium in the blood, thus completing this chemical balancing act.

PTH also activates vitamin D—another hormone—that causes increased absorption of calcium from the intestines.

If too much PTH is released (hyperparathyroidism), then there is too much bone resorption. The result may be kidney stones. The interruption of calcium homeostasis in the body can also seriously affect the nervous system.


Continue to Chapter 12



Reviewed and updated 2/11/04