Pam Harrison

September 18, 2016

ATLANTA — Current use of a bisphosphonate — alendronate in particular — is associated with a reduction in all-cause mortality in both women and men, and the protective effect remains after adjustment for important baseline variables, according to results from a new prospective, epidemiological cohort study.

"Bisphosphonate use was associated with a reduced mortality risk in both women and in men," Dana Bliuc, PhD, Garvan Institute of Medical Research, Sydney, Australia, told attendees here at the American Society of Bone and Mineral Research 2016 Annual Meeting.

"However, the effect was largely attributable to alendronate, where alendronate had a significant benefit, risedronate had a possible benefit, and etidronate had no benefit," she added, noting that the apparent survival advantage associated with bisphosphonate use was not related to a decline in subsequent fractures in this large Canadian Multicentre Osteoporosis study (CaMos).

Nevertheless, she noted, given the magnitude of the effect, the findings indicate that bisphosphonate treatment should be started immediately after someone has had a fracture.

Session cochair Michael McClung, MD, Oregon Osteoporosis Center, Portland, Oregon, told Medscape Medical News that a reduction in mortality risk has actually been observed both in prospective randomized trials of the bisphosphonates as well as in previous observational studies.

"[However,] this effect appears to be specific to nitrogen-containing bisphosphonates, since reducing bone remodeling with estrogen and etidronate did not alter the risk of death," Dr McClung added.

"So these analyses are very important, and this particular study is consistent with previous observations," he said.

Bisphosphonate Use Reduced Mortality by 40% or More

CaMos enrolled women and men 50 years of age and older between 1995 and 2012. Follow-up occurred from the time treatment was initiated, but on average, participants took alendronate for about 5 years.

Risedronate was introduced later than alendronate, and uptake of the former was not robust until about 2005, so far fewer numbers of participants were on risedronate and follow-up was considerably shorter, Dr Bliuc noted.

A total of 2173 bisphosphonate users were included in the whole cohort, while 1265 female hormone-replacement-therapy (HRT) users served as a healthy-user group. Furthermore, some 1889 participants did not receive any type of treatment.

"Comorbidities, medication, and lifestyle factors were collected yearly," Dr Bliuc noted.

Baseline characteristics between bisphosphonate users, those taking HRT, and those not on treatment were predictably somewhat different.

For example, 35% of women in the bisphosphonate group had experienced a prior fracture compared with 17% in the HRT group.

Women taking bisphosphonates also had important risk factors that could be associated with a higher mortality risk, including a lower body weight, but their lifestyle profile was somewhat better than it was for the group who received no treatment. Women in the HRT group also had factors associated with a better outcome.

The number of men in the whole cohort on bisphosphonates was considerably smaller than it was for women, but similar to women, prior fracture rates were higher among men prescribed alendronate — at 27% compared with 13% for men not on any treatment.

Again, similar to women, men on treatment had several risk factors that might be associated with a higher mortality risk, including a lower body weight and a higher prevalence of cancer, but they, too, had a better lifestyle profile than men not on any treatment, Dr Bliuc noted.

After adjustment for important variables, the risk of mortality among women was reduced by 42% among current bisphosphonate users and by 47% in past bisphosphonate users compared with women who had never used bisphosphonates.

In contrast, treatment with HRT had no effect on mortality risk among women, as Dr Bliuc indicated.

Among men, multivariate analysis indicated that the risk of mortality was reduced by 30% among current bisphosphonate users compared with nonusers.

Protective Effect "Even Stronger" in Fracture Cohort

Dr Bliuc and colleagues then analyzed a subset cohort from the same CaMos study, all of whom had experienced a prior fracture.

In this, investigators wanted to examine the protective benefit that different types of bisphosphonates had on mortality risk; they separated out women who only took alendronate, risedronate, or etidronate exclusively.

Treatment was initiated within 2 years of experiencing a fracture, and only females in the fracture cohort were analyzed, because bisphosphonate therapy was initiated in too few men to provide any statistical power.

Again adjusted for all factors that might increase mortality risk in general, "the protective effect from the bisphosphonates became even stronger," Dr Bliuc told Medscape Medical News.

Overall, bisphosphonate use reduced mortality risk in the fracture cohort by approximately 35% compared with the no-treatment group, she noted.

However, among women, alendronate was associated with an approximately 45% reduction in mortality risk compared with the nontreatment group and risedronate by a nonsignificant reduction of about 20%.

Etidronate was not associated with any reduction in mortality risk.

"I think our study should highlight the need to initiate treatment immediately after someone has had a fracture," Dr Bliuc reiterated.

She added, however, that the mechanisms behind how bisphosphonate use might enhance survival independent of fracture prevention require further explanation.

Dr Bliuc has no relevant financial relationships. McClung reports receiving consulting fees from Amgen, Merck, and Radius.

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American Society of Bone and Mineral Research 2016 Annual Meeting. September 16, 2016; Atlanta, Georgia. Abstract 1007.


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