Lemborexant linked to fewer hip fractures than Z-drugs in older adults, though the estimate is uncertain

Sleeping pills and broken hips have been linked in study after study. A study from Japan has now asked whether a newer kind of sleeping pill carries less of that risk than the Z-drugs many older people are prescribed.

For one of the two newer drugs, lemborexant, the answer was a tentative yes: older adults who started it were hospitalized for hip fracture less often over the next year than those who started a Z-drug. For the other, suvorexant, the difference was not clear. The study, published on October 8 in the Journal of the American Geriatrics Society, was not a randomized trial, and the range around its main estimate is wide.

Why sleeping pills and hip fracture are studied together

A broken hip in old age is a serious injury. One review of the subject cites reports that a third of older people die within a year of a hip fracture, and gives a US estimate of 24% for deaths from any cause in that year. Most hip fractures follow a fall, so anything that makes an older person unsteady at night raises the stakes.

Sleeping pills are suspected of being one such thing. The older ones, benzodiazepines, were followed by a group known as Z-drugs, which a 2017 review lists as zolpidem, zopiclone, eszopiclone and zaleplon and which were widely thought to be gentler than benzodiazepines.

The pooled evidence did not bear that out. The review that gave the death figures, published the same year, found that people taking Z-drugs had a 90% higher risk of hip fracture, and concluded that Z-drugs and benzodiazepines showed little difference between their respective risks. The danger was greatest at the start, with patients newly prescribed these medicines at the greatest risk of hip fracture, the authors wrote. The review that listed the Z-drugs reached a similar result for fractures of any kind, while cautioning that the studies included were observational and susceptible to confounding, in which some other difference between the groups, such as poorer health in those given the pills, accounts for part of the result.

The suspected reason lies in how these drugs work. They act on receptors in the brain that calm it, some of which also relax muscles, and a Japanese research group wrote that binding to these receptors is thought to cause lightheadedness and falls.

The newer pills work differently. In the new paper’s description, lemborexant and suvorexant are both widely used dual orexin receptor antagonists (DORAs): drugs that block both of the brain’s receptors for orexin, a chemical that keeps people awake. Because they block a wake signal, the same Japanese group noted, they do not have muscle relaxant effects.

That makes them look safer on paper, and the new paper’s authors grant that they are generally considered safer than the older drugs, while noting that evidence from direct comparisons remains limited.

How the hip fracture study worked

The researchers, with Yuichiro Matsuo as first author and Hideo Yasunaga as last author, drew on health databases from Tochigi Prefecture, Japan, to follow groups of people forward in time and compare what happened to them.

Their design, called a target trial emulation, starts by setting out the randomized trial the researchers would ideally run and then applies its rules as closely as possible to existing records. Here the imagined trial would take people aged 65 and over who needed a sleeping pill and assign them to one drug or another.

So the study took in only people who newly initiated either lemborexant or Z-drugs and, in a separate comparison, people newly starting either suvorexant or Z-drugs. Following new users from the day of their first prescription avoids a known trap, since people who have taken a drug for years without trouble are survivors, and comparing them with new users flatters the old drug. The main result the study was designed to answer was hospitalization for hip fracture within 1 year of entering the study.

Two statistical adjustments stood in for the random assignment of a real trial. The first dealt with the fact that doctors choose different drugs for different patients, and handled it with weighting based on propensity scores. A person’s propensity score is their estimated chance of being given one drug over the other, judged from their recorded characteristics, and weighting by it makes the two groups resemble each other on those characteristics.

The second dealt with people who did not stay on their pill. The analysis estimated the effects of continuous treatment with the assigned drugs, asking what happens to people while they keep taking the drug they started. A person dropped out of the count on stopping or switching, and further weighting corrected for the possibility that those who stop differ from those who continue.

What the study found for lemborexant and suvorexant

The lemborexant comparison included 22,655 individuals, of whom 6,879 started lemborexant and 15,776 a Z-drug. After adjustment, the rate of hospitalization for hip fracture over the year was 69% lower in the lemborexant group, with a range from 41% lower to 84% lower. Because the whole range lies on the side of fewer fractures, the result counts as clear in statistical terms, but the range is also broad, which usually means the number of fractures behind it was limited.

The suvorexant comparison covered 22,377 people, of whom 6,699 started suvorexant and 15,678 a Z-drug. Hip fracture incidence was lower in the suvorexant group too, by 43%, but the range ran from 77% lower to 44% higher, and an estimate whose range includes both a large benefit and a sizable harm cannot be told apart from no difference.

Both results are relative: they say how the rate in one group compared with the rate in the other, not how many people in each group broke a hip. Hip fracture in any single year affects a small minority of older people, so a large relative difference can correspond to a small difference in the number of fractures.

The authors word their conclusion with care, writing that the two drugs, particularly lemborexant, may be safer alternatives to Z-drugs where hip fracture is concerned.

What earlier research on orexin blockers and fractures showed

For suvorexant, earlier Japanese studies disagreed with each other, and one, from Shizuoka Prefecture in 2023, pointed the opposite way from the new study. Its suvorexant group comprised 6860 patients, set against 50,203 people on benzodiazepines or Z-drugs. Because the suvorexant patients were older and had more other illnesses before any adjustment, the researchers paired each with a similar patient from the comparison group, and in the matched groups the rate of hip fracture was 48% higher with suvorexant, with a range from 20% to 82% higher.

The Shizuoka authors concluded that among sleep-drug users in that regional Japanese population, patients on suvorexant could be at higher risk of hip fracture. They acknowledged that unmeasured differences may remain despite efforts to align the groups.

A second study that year, which compared 389 older adults hospitalized with hip fracture against 1,509 without, found no increase in the risk of hip fracture in patients treated with suvorexant.

The designs differ in ways that could matter. The Shizuoka comparison group mixed benzodiazepines with Z-drugs, whereas the new study compared against Z-drugs alone and counted people only while they stayed on their first drug. None of the three studies settles which approach comes closer to the truth.

For the class as a whole, a pooled analysis appeared in the same journal less than two weeks before the new study. It combined 19 studies, 10 of them randomized trials, with 183,595 participants, and compared people taking orexin blockers with people not taking them. It observed no association with fractures and concluded that the drugs do not appear to raise the risk of falls or fractures in adults, though the authors added that limited data in older adults call for caution.

That fits the new result loosely: if Z-drugs raise fracture risk and orexin blockers do not, people on orexin blockers would be expected to have fewer fractures than people on Z-drugs.

Safety in trials has not been spotless. A 2026 analysis of trials in older patients found more unwanted effects emerging after treatment began with lemborexant and suvorexant than with placebo, though without an increase in serious adverse events. A large comparison of insomnia drugs in The Lancet in 2022 judged that lemborexant worked over the long term but that safety data on lemborexant were inconclusive.

What the hip fracture study cannot show

Patients were not assigned at random. Doctors chose each person’s pill, and weighting can balance the two groups only on what the records hold. Frailty, unsteadiness, memory problems and a history of falls are often poorly recorded, and any of them could sway both the choice of pill and the chance of a fracture.

A wide range. The lemborexant estimate could mean a fracture rate anywhere from about a sixth to about three fifths of the rate with Z-drugs.

No absolute numbers in the headline result. A relative reduction does not say how many fewer fractures there were per thousand people treated.

Same direction, different certainty. Lemborexant and suvorexant act on the same receptors, both estimates point toward fewer fractures, and the suvorexant range overlaps the lemborexant one, so the study does not show that the two drugs differ from each other.

It conflicts with one earlier study. The Shizuoka analysis found more hip fractures with suvorexant, not fewer.

No untreated group. Everyone in the study started a sleeping pill, so the results compare one pill with another and say nothing about how either compares with taking none.

One prefecture, one year. The data come from a single region of Japan, where prescribing habits and doses may differ from those elsewhere, and follow-up stopped at 12 months. Only hip fractures that led to a hospital stay were counted, not falls or other fractures.

People who stayed on their drug. The main analysis describes continuous treatment, yet many people stop or switch sleeping pills, and the statistical correction for that depends on assumptions.

Do not stop or change a prescribed medicine without talking to your doctor.

Whether a particular sleeping pill suits a particular older person is assessed by their doctor.

The study offers a sign that lemborexant goes with fewer hip fractures than Z-drugs in older adults, and leaves the size of the difference to be confirmed.