MONTREAL, QUEBEC — Women age 65 years and older who had osteopenia and received an injection of zoledronate every 18 months for 6 years had a 37% lower rate of fractures than those who received placebo in a new study.
There were no increased risks of prespecified adverse events; instead, the trial suggests that rates of myocardial infarction, death, and cancer may be lower with zoledronate, also known as zoledronic acid, but this needs to be confirmed in future trials.
"We conclude that zoledronate prevents fractures in osteopenic women aged over 65 and giving it every 18 months is adequate," Ian R. Reid, MD, University of Auckland, New Zealand, reported here at the American Society for Bone and Mineral Research (ASBMR) 2018 Annual Meeting.
The trial was simultaneously published in the New England Journal of Medicine (NEJM).
The US Food and Drug Administration approved yearly injections of zoledronate to treat osteoporosis in postmenopausal women in 2007.
"If we really want to decrease the total number of fractures," Reid told Medscape Medical News, "we need to treat the osteopenic women because that's where [80%] of the fractures occur."
However, the findings only apply to older women, he cautioned. "We can't generalize this to the 52 year olds," he stressed. "That is absolutely not what we're looking at."
The reductions in heart attack, cancer, and death, Reid said, need to be explored in large studies "because if those are real and if they're at the magnitude that we're finding — and one previous study has found — then that could be much more significant than the fracture effects."
"But that's another study and another decade I suspect."
"Should Affect Clinical Practice"
The new trial shows that "this treatment can certainly be added to our armamentarium for treating osteoporosis [and] should have an effect on clinical practice," NEJM Associate Editor Clifford J. Rosen, MD, Maine Medical Center Research Institute in Scarborough, writes in an accompanying editorial.
It reminds clinicians that "risk assessment and treatment decisions go well beyond bone mineral density and should focus particularly on age and a history of previous fractures."
Like Reid, he cautioned that "the results...should not be extrapolated to younger postmenopausal women (50 to 64 years of age) with osteopenia."
"I think this is one of the studies we have been waiting for," session comoderator Kristina Akesson, MD, PhD, Lund University, Malmo, Sweden, told Medscape Medical News.
"This shows that you can treat [older women]...at earlier stages [of osteoporosis] and still have an effect on fractures."
"Who on Earth Do We Give It To?"
"The issue is, who on earth do we give it to?" a physician in the audience wanted to know, "because just about everybody over the age of 70 has osteopenia."
Reid replied that the treatment decision needs to consider the patient's risk and opinions about taking the drug, as well as cost.
"I think we should be targeting the drug according to perceived fracture risk, rather than specific things like bone density or history of fractures," he elaborated to Medscape Medical News.
Most white women over age 70 years probably have a fracture risk that qualifies them for this drug, he noted.
Clinicians can tell patients, "If you accept and agree that osteoporotic fractures are a major issue for you that is likely to interfere with your well-being, then we have something that we can offer you."
"It won't make you bulletproof, but it will reduce your likelihood of having fractures by about a third."
Number Needed to Treat to Prevent One Fracture Is 15
To assess whether zoledronate would prevent fractures in older women who were osteopenic, Reid and colleagues mailed letters to more than 100,000 women in and around Auckland, New Zealand, inviting them to participate in the study; more than 4500 women replied.
Of these, 2000 women met the inclusion criteria, which included those age 65 years and older with osteopenia (total hip or femoral neck T score -1.0 to -2.5). They were randomized in a double-blinded fashion to zoledronate 5 mg or saline IV infusion every 18 months for 6 years (so four study doses).
All participants received monthly vitamin D supplements and were recommended, but not required, to take calcium.
The women were a mean age of 71 years and 94% were of European origin. At baseline, a quarter had a history of nonvertebral fractures after age 45 years.
Based on median FRAX scores, their 10-year risk of osteoporotic fracture was 12% and hip fracture was 2.3%.
At 6 years, the researchers had complete data from 93% and 94% of patients in both groups, and 68 women had died.
Most women (806 in the intervention group and 825 in the placebo group) had received all four doses of study drug or placebo, but a few (86 in the intervention group and 42 in the placebo group) had received only one dose.
The primary endpoint — nonvertebral fractures (except for fingers, toes, skull, facial bones, or jaw) or morphometric vertebral fractures (determined from lateral spine X-rays) — occurred in 122 women in the zoledronate group versus 190 women in the placebo group, which was a significant reduction in favor of active drug (hazard ratio [HR], 0.63; P < .001).
The number needed to treat over 6 years to prevent one woman from having one fracture was 15.
Zoledronate also lowered the risks of a nonvertebral fragility fracture by 34%, symptomatic fracture by 27%, and spine fracture by 55% (all P ≤ .003).
Fewer women had hip fractures in the zoledronate versus placebo groups (8 vs 12 women, respectively), but this was not significant (HR, 0.66; 95% CI, 0.27 - 1.16), possibly because of the small number of events.
"The Nice Thing About Zolendronate Is Its Long Duration of Action"
The number of serious adverse events were similar in the zoledronate (1017 events in 443 participants) and placebo groups (820 events in 400 participants).
And there were no significant increased risks of 10 prespecified adverse events that were chosen "in light of previous findings with zoledronate": death, sudden death, myocardial infarction, coronary artery revascularization, stroke, transient ischemic attack, cancer, osteonecrosis of the jaw (ONJ), atrial fibrillation, and a composite of vascular events (sudden death, myocardial infarction, coronary artery revascularization, or stroke).
There were fewer deaths (27 vs 41; odds ratio [OR], 0.65) and myocardial infarctions (25 vs 43; OR, 0.61) in the zoledronate versus placebo group, but these differences were not significant.
There were also fewer cases of cancer with zolendronate than placebo (87 vs 127; OR, 0.67), which was significant.
There were no cases of ONJ or atypical femur fractures, but the trial was underpowered to assess these rare events.
A total of 58 women did not have a second infusion of zoledronate because they had an acute phase response (temporary flu-like symptoms) after the first infusion.
"The nice thing about zoledronate," Reid summarized, "is that it has such a long duration of action. So even if you only took one infusion, you still, I believe, get a significant benefit because the duration of effect is at least 5 years."
"Within my own clinical practice," he said, "since I've been aware of these results, I am much more relaxed now about giving zoledronate to people whose bone densities look quite good but whose fracture risks are high for other reasons."
The study was funded by the Health Research Council of New Zealand and study medication was supplied by Novartis. Reid has reported receiving research funding from Merck and Amgen. He is a consultant for Amgen, Merck, Novartis, and Lilly, and gives lectures for Amgen and Lilly.
American Society of Bone and Mineral Research Annual Meeting. September 28 - October 01, 2018. Montreal, Quebec.
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Cite this: Zoledronate Reduces Fractures in Older Women With Osteopenia - Medscape - Oct 04, 2018.