Study Confirms Risk of Bone Loss for Patients Taking Exemestane
Women who switched to the drug exemestane (Aromasin®) after taking tamoxifen (Nolvadex®) to prevent a breast cancer relapse lost more bone density and had a higher risk of bone fractures than women who continued taking tamoxifen, an international study has concluded.
The Lancet Oncology, published online Jan. 26, 2007; in print February 2007 (see the journal abstract).
(Lancet Oncol. 2007 Feb;8(2):119-27)
Many breast tumors are “estrogen sensitive,” meaning the hormone estrogen helps them to grow. Women whose tumors are estrogen sensitive are advised to take anti-estrogen drugs for five years to reduce the risk of a relapse after their initial treatment. Tamoxifen was the first anti-estrogen drug shown to lower the risk of a breast cancer recurrence.
However, several large clinical trials have now shown that drugs called aromatase inhibitors (AIs) are more effective than tamoxifen at preventing the recurrence of estrogen-sensitive breast cancer. AIs also carry a lower risk of blood clots and endometrial cancer, both of which are possible side effects of tamoxifen.
AIs have their own side effects, however. Studies of two AIs, anastrozole (Arimidex®) and letrozole (Femara®), have shown that these drugs cause a loss of bone density and increase the risk of bone fractures. One of estrogen’s effects on the body is to protect bones from thinning. Tamoxifen, because of the way it works in the body, actually has a protective effect on bone. AIs, by contrast, block the production of estrogen, reducing the amount of the hormone in the body. The absence of estrogen leads to accelerated loss of bone density.
In 2006 a large international clinical trial showed that women who switched after two or three years of tamoxifen to an AI called exemestane lived longer and had a lower risk of breast cancer relapse than women who stayed on tamoxifen for five years. Now researchers have published data from a subgroup of the women on that trial showing exemestane’s effect on bone density and fracture risk.
In the original trial, 4,724 postmenopausal women with early breast cancer who had been taking tamoxifen for two or three years were assigned at random either to remain on tamoxifen or to switch to exemestane until they had completed five years of treatment.
A subgroup of 206 patients took part in the bone density study. Roughly half of them had been assigned to stay on tamoxifen, the other half to switch to exemestane. Their bone density (in the lumbar spine and in the hip) was measured when they entered the study and again after six months, one year, and two years. The researchers also collected blood and urine samples to measure markers of bone loss. In addition, the researchers kept a record of all patients in the main trial who suffered bone fractures.
The principal investigator for the bone study was Robert E. Coleman, M.D., of Weston Park Hospital in Sheffield in the United Kingdom.
At the two-year mark, the loss of bone density in the lumbar spine experienced by women who had switched to exemestane was 4.0 percent, compared to just 0.6 percent among women who stayed on tamoxifen. In the exemestane group, most of the bone loss occurred in the first six months.
Among women who had normal bone density when they entered the study, a higher percentage of those on exemestane were diagnosed with low bone mass, or osteopenia, after two years, compared with those on tamoxifen. The difference was statistically significant. No one in either group whose bone density was normal at the start of the study later developed osteoporosis, a disease characterized by brittle bones that break easily.
Among those women who were already showing signs of bone loss at the start of the study, five of those on exemestane developed osteoporosis by the two-year mark, compared to none of those taking tamoxifen.
Researchers have followed the 4,724 participants from the original trial for nearly five years and report that 162 women in the exemestane group (7 percent) had fractures, compared with 115 (5 percent) of those in the tamoxifen group.
“These results indicate that the increase in survival shown previously with [the switch from tamoxifen to exemestane] is achieved at the expense of some detriment to [bone] health,” Coleman and his coauthors write. They note that the rate of bone loss is about the same for patients on letrozole and anastrozole, two other AIs previously studied.
Jennifer Eng-Wong, M.D., a clinical oncologist at the National Cancer Institute’s Center for Cancer Research, agrees that this study confirms earlier research showing that AIs reduce bone density and increase the risk of fractures. In the United States, patients taking AIs should receive bone density tests every 12 to 18 months as part of standard care, she adds.
The researchers recommend that all women switching from tamoxifen to exemestane have a bone density test around the time they make the switch. Those with normal bone density, they say, may not need further testing but should be counseled about lifestyle changes that can protect them from bone loss (such as consuming adequate calcium and vitamin D and getting regular weight-bearing exercise).
The risks and benefits of AI therapy for a woman with low bone mass or osteoporosis should be considered individually, Eng-Wong says, weighing the risk of breast cancer recurrence against the risk of further loss of bone density. “If a woman has already had an osteoporotic fracture, she would not be a good candidate for AI therapy,” she says.
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