One of the most significant risks facing men on androgen deprivation therapy (ADT) for prostate cancer is osteoporosis. Representing a critical decrease in the density of bones, osteoporosis is usually associated with menopause in women. However, men with prostate cancer, particularly those on androgen deprivation therapy, are also at risk for this condition. So why do we care about osteoporosis? By making bones less dense, osteoporosis also makes them more prone to fracture. These fractures can be devastating, decreasing the ability to move around and, even worse, substantially increasing the risk of death. In fact one study demonstrated that people with osteoporosis related fractures had a risk of death two times that of similarly aged people without fractures. In addition, another study showed that fractures decreased the life expectancy of men with prostate cancer by more than 3 years. As a result, men with prostate cancer who receive ADT should make bone health a top priority. In this post, I will discuss the steps all men undergoing ADT need to take to prevent osteoporosis. In addition, I will describe the treatment options for those men found to already have low bone density.
ADT and Osteoporosis: What is the Connection?
When most people think about bones, they imagine sturdy, stable structures that really don’t change much from day to day. In reality, however, this perception could not be further from the truth. Every bone in the body represents a constant battle between two opposing classes of cells. Osteoblasts, the bone builders, work frantically to strengthen bones by incorporating calcium into them. Osteoclasts, in contrast, remove calcium from bones and, in so doing, weaken them. While most of the time, these two cells are in a stalemate called “dynamic equilibrium”, occasionally one cell type wins. For example, when there is not enough calcium circulating in the body, osteoclasts free calcium from bones into the bloodstream. In this situation, bones are weakened. When this situation continues for a prolonged period of time and bones are weakened beyond a critical point, osteoporosis occurs.
So what does ADT have to do with osteoporosis and the battle between osteoblasts and osteoclasts? These competing cells are regulated by various hormones in the body. Two of these very important hormones are estrogen and testosterone. Estrogen works to deactivate osteoclasts . As a result, the hormone works to increase the strength of bones. During menopause, estrogen levels are decreased, allowing osteoclasts to function more effectively and to weaken bones. This leads to osteoporosis associated with menopause in women. Testosterone also functions to strengthen bones through its impact on the osteoclasts and osteoblasts. This male hormone activates osteoblasts, stimulating them to strengthen bones by incorporating more calcium. In addition, in men, some testosterone gets converted to estrogen, leading to deactivation of osteoclasts and secondary strengthening of bones as well. For men with prostate cancer, the administration of ADT leads to the decrease of testosterone (and subsequently estrogen) in the body. While this decrease in testosterone is great in battling prostate cancer, it can be devastating to bone health.
Through its decrease of testosterone and estrogen, ADT secondarily shifts the balance of power to osteoclasts and leads to osteoporosis and its associated risks for many men undergoing this treatment for prostate cancer. Studies have demonstrated that ADT decreases bone density in men by 1-5% per year. As a result, one study demonstrated that 80% of men on ADT develop osteoporosis after 10 years of treatment. As a result, men on ADT have been found to be 13-30% more likely to develop a fracture as compared to their counterparts with prostate cancer not treated with ADT.
Starting ADT? Get Your Bone Density Checked
Given this propensity for ADT to decrease the density of bones, it is important for men starting this hormonal therapy to evaluate their risk of osteoporosis at the outset of treatment. This task is accomplished through a bone density scan. Also known as a DEXAscan, this simple x ray test can easily and non invasively determine the density of bones over the span of 10-30 minutes. It is no more painful than a chest x ray and its only risk is the low level of ionizing radiation that you absorb during the test.
The bone density scan is reported as a series of scores. The first score, called the T score, determines the overall bone density as compared to the maximal potential bone density. A T score of greater (more positive) than -1 is considered normal. Men with T scores ranging from -1 to -2.5 are considered to have low bone density or osteopenia. T scores of less than -2.5 indicate osteoporosis. The second score, called the Z score, compares the measured bone density to that of other people with the same age and gender. This score helps to differentiate a pathologically low bone density from a low bone density that is “normal” for a particular age and gender. Using these scores, a physician can determine whether a man about to start ADT has low bone density and who, in turn, is at higher risk for fractures. As such, the scores help determine who needs pre-emptive treatment for osteoporosis or osteopenia and what kind of treatment would best suit them.
Treatments to Maximize Bone Density in Men Starting ADT
Once bone density and strength is determined via a DEXA scan, a man starting ADT can begin protecting his bones with various treatment options. While some treatment options should be undertaken by all men starting ADT, others should be reserved for those with documented osteoporosis. All men undergoing ADT, for example, should undergo lifestyle modifications to maximize their bone health. Simple steps such as exercising more, stopping smoking, and limiting caffeine and alcohol can significantly prevent the onset and progression of osteoporosis. In addition, most men starting ADT should begin supplementation with Calcium and Vitamin D. These supplements serve as the building blocks with which the osteoblast cells build up bones. The usual dosage is 1500 milligrams of calcium and 800 units of Vitamin D per day in divided doses. Certain medical conditions (such as kidney stones) prevent men from taking these supplements at full or even decreased doses. As a result, all men contemplating taking these supplements should first seek guidance from a physician.
While such treatments are applicable to all men undergoing ADT, some therapies are reserved only for men with confirmed osteoporosis. One such treatment involves a class of drugs called bisphosphonates. Available in oral or intravenous forms, bisphosphonates improve bone density and fight against osteoporosis by blocking the bone destroying activity of osteoclast cells. Numerous studies have evaluated this class of drugs in men with prostate cancer undergoing ADT. These studies have demonstrated that while bisphosphonates do prevent loss of bone density over time (some studies demonstrate that these drugs can even increase bone density), they have yet to demonstrate that these drugs can prevent fractures in these men. However, a decrease in fracture risk has been demonstrated in postmenopausal women taking bisphosphonates. While this class of drugs can, indeed, be helpful in protecting the bones of men on ADT, they are not without risks. Oral bisphosphonates, like Alendronate (Fosamax), often produce upset stomachs as well as other gastrointestinal side effects. As a result, many patients often do not stick with the therapy. In fact, one study of postmenopausal women demonstrated that less than 60% actually continued the once monthly oral therapy long term.
Intravenous bisphosphonates, like Zolendronic Acid (Zometa) and Pamidronate (Aredia), are usually better tolerated. Some patients do experience flu like symptoms during the first intravenous infusion but this reaction is usually mild. A much more serious potential side effect is kidney toxicity, sometimes leading to kidney failure requiring dialysis. As a result, men undergoing treatment with these drugs need to have their kidney function closely monitored with periodic blood tests. Another very serious, although thankfully rare, side effect of these IV drugs is osteonecrosis or destruction of the jaw bone. Because of this potential side effect, all men starting these drugs should have dental work completed prior to the start of therapy, maintain good oral hygiene, and get periodic dental checkups.
As I mentioned previously, the female hormone, estrogen, potently blocks the bone destroying activities of osteoclast cells, making bones stronger. Not surprisingly then, estrogen has been tried in the treatment of osteoporosis. While, indeed, successful in increasing bone density, estrogen unfortunately comes with the associated risks of heart attack as well as blood clots. Because healthy bones are of no use to people dead from heart disease, estrogen is not routinely used to treat osteoporosis in men on ADT. Instead, a related class of drugs called selective estrogen receptor modulators (SERM) have been successfully used to fight osteoporosis while avoiding the heart risks. Including drugs such as Raloxifene and Toremifine, SERMs have been demonstrated to significantly increase the bone density of men on ADT. A recent study of 1389 men on ADT also demonstrated that Toremifine reduced vertebral (spine) fractures by 53%.
Another new method of tackling osteoporosis in men on ADT for prostate cancer is the creation of antibodies against a compound called RANKL. In the body, RANKL binds to osteoclast cells, activating them and prolonging their survival. As you may remember from earlier in this post, osteoclasts resorb bone, making it less dense and promoting osteoporosis. Drugs that serve as antibodies against RANKL, in turn de-activate it. As a result, its ability to activate osteoclasts is diminished, preventing bone resorption and subsequent osteoporosis. One such drug called Denosumab(Xgeva) was recently studies in 1468 men with nonmetastatic prostate cancer who were undergoing ADT. The study reported that Denosumab, given as an injection once every 6 months, significantly improved bone density throughout the body and decreased the risk of fracture by 62% over a 3 year period. This success was even more impressive given that the drug was extremely well tolerated with minimal adverse side effects.
Take Home Message
Osteoporosis is a serious problem facing men with prostate cancer treated with ADT. All men starting ADT should undergo bone density testing to determine how strong and dense their bones are. Depending on the results, men should undergo one of the various treatments to increase or maintain bone density. At the very least, barring any contraindications, all men undergoing ADT should take Calcium and Vitamin D in addition to making some lifestyle modifications. In addition, those men diagnosed with osteoporosis prior to or during ADT should begin one of the many excellent treatment options available. Of course, all men considering treatment for this and any other medical conditions should carefully discuss the options with their physician prior to embarking on any treatment plan. Through such measures, men undergoing ADT for prostate cancer can enjoy good bone health and prevent the dreaded fractures associated with osteoporosis.
