Key messages
• For women with close to normal bone density (bone strength) and no previous broken spinal bones, etidronate probably makes little or no difference to the likelihood of having a hip or wrist fracture or a serious adverse (unwanted/harmful) event.
• For women who have low bone density and are at risk for or have had a previous broken spinal bone, etidronate may make little or no difference in preventing fractures in bones other than the spine.
What is osteoporosis?
Bone is a living, growing part of your body. Throughout your lifetime, new bone cells grow, and old bone cells break down to make room for new, stronger bone. When you have osteoporosis, the old bone breaks down faster than the new bone can replace it. As this happens, the bones lose minerals (such as calcium). This makes bones weaker and more likely to break, even after a minor injury, such as a slight bump or fall. Women who have gone through menopause are more likely to get osteoporosis than other people.
What is etidronate?
Etidronate belongs to the class of medicines called bisphosphonates, which slow down the cells that break down the old bone. It is given by mouth in an intermittent or cyclical schedule; for example, a 400 mg tablet daily for two weeks every 90 days, followed by calcium or no treatment for the remainder of each 90-day treatment cycle.
What did we want to find out?
We wanted to find out if etidronate was better than placebo (inactive or 'dummy' medicine) or another medicine for osteoporosis in preventing broken bones in postmenopausal women. For clinical relevance, we looked at etidronate's effects on women, as grouped by their risk of fracture (lower versus higher risk). We also wanted to find out if etidronate was associated with any unwanted effects.
What did we do?
We searched for studies comparing etidronate to placebo or another medicine for preventing osteoporosis. We compared and summarized their results, and rated our confidence in the evidence, based on factors such as study methods and sizes.
What did we find?
Overall, we found 30 studies, but 4 studies provided insufficient information about their results. Thus, we were able to analyse the results of 26 studies involving 2770 women. Nine studies were interested in 'primary prevention' of osteoporosis-based fractures, meaning they focused on women at lower fracture risk, who had bones with near-to-normal density/strength and no previous broken spinal bones. Seventeen studies were interested in 'secondary prevention' with etidronate, meaning they focused on women at higher fracture risk, who already had weak bones (low bone density), had a broken spinal bone, or both. Most studies mainly included white women. The studies lasted between 1 and 4 years. Some studies gave the women 400 mg/day of etidronate, whilst other studies gave 200 mg/day.
Main results for primary prevention studies that gave women 400 mg of etidronate/day
Compared to a placebo, etidronate:
• probably makes little or no difference to non-vertebral (non-spinal) fractures and serious adverse events;
• may make little or no difference to clinical vertebral fractures (that is, spinal fractures suggested by clinical signs and symptoms) and the number of women who left the studies due to adverse events.
The evidence is very uncertain about the effect of etidronate on hip fractures. None of the studies reported on the effect on wrist fractures.
Main results for secondary prevention studies that gave women 400 mg of etidronate/day
Compared to a placebo, etidronate may make little or no difference in preventing fractures in bones other than the spine. The evidence is very uncertain about the effect of etidronate on hip and wrist fractures, the number of women who left the studies due to adverse events, and serious adverse events. None of the studies reported on etidronate's effect on clinical vertebral fractures.
What are the limitations of the evidence?
Our confidence in the evidence ranged from very low to moderate. In general, we have little confidence in the evidence because it is possible that the women in the studies were aware of which treatment they were getting, which could influence the results, and because many of the studies were very small.
How up to date is this evidence?
The evidence is current to February 2023.
This update echoes the key findings of our previous review that etidronate probably makes or may make little to no difference to vertebral and non-vertebral fractures for both primary and secondary prevention.
Osteoporosis is an abnormal reduction in bone mass and bone deterioration, leading to increased fracture risk. Etidronate belongs to the bisphosphonate class of drugs which act to inhibit bone resorption by interfering with the activity of osteoclasts – bone cells that break down bone tissue. This is an update of a Cochrane review first published in 2008. For clinical relevance, we investigated etidronate's effects on postmenopausal women stratified by fracture risk (low versus high).
To assess the benefits and harms of intermittent/cyclic etidronate in the primary and secondary prevention of osteoporotic fractures in postmenopausal women at lower and higher risk of fracture, respectively.
We searched the Cochrane Central Register of Control Trials (CENTRAL), MEDLINE, Embase, two clinical trial registers, the websites of drug approval agencies, and the bibliographies of relevant systematic reviews. We identified eligible trials published between 1966 and February 2023.
We included randomized controlled trials that assessed the benefits and harms of etidronate in the prevention of fractures for postmenopausal women. Women in the experimental arms must have received at least one year of etidronate, with or without other anti-osteoporotic drugs and concurrent calcium/vitamin D. Eligible comparators were placebo (i.e. no treatment; or calcium, vitamin D, or both) or another anti-osteoporotic drug. Major outcomes were clinical vertebral, non-vertebral, hip, and wrist fractures, withdrawals due to adverse events, and serious adverse events. We classified a study as secondary prevention if its population fulfilled one or more of the following hierarchical criteria: a diagnosis of osteoporosis, a history of vertebral fractures, a low bone mineral density T-score (≤ -2.5), or aged 75 years or older. If none of these criteria were met, we considered the study to be primary prevention.
We used standard methodological procedures expected by Cochrane. The review has three main comparisons: (1) etidronate 400 mg/day versus placebo; (2) etidronate 200 mg/day versus placebo; (3) etidronate at any dosage versus another anti-osteoporotic agent. We stratified the analyses for each comparison into primary and secondary prevention studies. For major outcomes in the placebo-controlled studies of etidronate 400 mg/day, we followed our original review by defining a greater than 15% relative change as clinically important. For all outcomes of interest, we extracted outcome measurements at the longest time point in the study.
Thirty studies met the review's eligibility criteria. Of these, 26 studies, with a total of 2770 women, reported data that we could extract and quantitatively synthesize. There were nine primary and 17 secondary prevention studies.
We had concerns about at least one risk of bias domain in each study. None of the studies described appropriate methods for allocation concealment, although 27% described adequate methods of random sequence generation. We judged that only 8% of the studies avoided performance bias, and provided adequate descriptions of appropriate blinding methods. One-quarter of studies that reported efficacy outcomes were at high risk of attrition bias, whilst 23% of studies reporting safety outcomes were at high risk in this domain.
The 30 included studies compared (1) etidronate 400 mg/day to placebo (13 studies: nine primary and four secondary prevention); (2) etidronate 200 mg/day to placebo (three studies, all secondary prevention); or (3) etidronate (both dosing regimens) to another anti-osteoporotic agent (14 studies: one primary and 13 secondary prevention). We discuss only the etidronate 400 mg/day versus placebo comparison here.
For primary prevention, we collected moderate- to very low-certainty evidence from nine studies (one to four years in length) including 740 postmenopausal women at lower risk of fractures. Compared to placebo, etidronate 400 mg/day probably results in little to no difference in non-vertebral fractures (risk ratio (RR) 0.56, 95% confidence interval (CI) 0.20 to 1.61); absolute risk reduction (ARR) 4.8% fewer, 95% CI 8.9% fewer to 6.1% more) and serious adverse events (RR 0.90, 95% CI 0.52 to 1.54; ARR 1.1% fewer, 95% CI 4.9% fewer to 5.3% more), based on moderate-certainty evidence. Etidronate 400 mg/day may result in little to no difference in clinical vertebral fractures (RR 3.03, 95% CI 0.32 to 28.44; ARR 0.02% more, 95% CI 0% fewer to 0% more) and withdrawals due to adverse events (RR 1.41, 95% CI 0.81 to 2.47; ARR 2.3% more, 95% CI 1.1% fewer to 8.4% more), based on low-certainty evidence. We do not know the effect of etidronate on hip fractures because the evidence is very uncertain (RR not estimable based on very low-certainty evidence). Wrist fractures were not reported in the included studies.
For secondary prevention, four studies (two to four years in length) including 667 postmenopausal women at higher risk of fractures provided the evidence. Compared to placebo, etidronate 400 mg/day may make little or no difference to non-vertebral fractures (RR 1.07, 95% CI 0.72 to 1.58; ARR 0.9% more, 95% CI 3.8% fewer to 8.1% more), based on low-certainty evidence. The evidence is very uncertain about etidronate's effects on hip fractures (RR 0.93, 95% CI 0.17 to 5.19; ARR 0.0% fewer, 95% CI 1.2% fewer to 6.3% more), wrist fractures (RR 0.90, 95% CI 0.13 to 6.04; ARR 0.0% fewer, 95% CI 2.5% fewer to 15.9% more), withdrawals due to adverse events (RR 1.09, 95% CI 0.54 to 2.18; ARR 0.4% more, 95% CI 1.9% fewer to 4.9% more), and serious adverse events (RR not estimable), compared to placebo. Clinical vertebral fractures were not reported in the included studies.