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 DEXA
scan, 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.
This blog is not a medical practice and cannot provide specific medical advice. This information should never be used to replace or discount the medical advice you receive from your physician
