This summary of a Cochrane Review presents what we know from the evidence up to 24 March 2021 about the effect of risedronate for preventing fractures (broken bones) caused by osteoporosis.
What is osteoporosis and what is risedronate?
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 the 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, like a little bump or fall. Women who have gone through menopause are more likely to get osteoporosis than other people.
Risedronate belongs to the class of drugs called bisphosphonates. It is a type of medication that slows down the cells that break down the old bone.
In postmenopausal women whose bone density is closer to normal or who may not yet have had a fracture in the bones of their spine therefore putting them at lower risk for fractures:
- there is insufficient evidence to tell us if risedronate leads to any reduction in the number of women sustaining bone fractures;
- based on limited data there is no evidence of an increase in adverse events for postmenopausal women at lower risk for fractures.
In postmenopausal women who have already been diagnosed with osteoporosis (who have low bone density, or who have already had a fracture in the bones of their spine) putting them at higher risk for fractures, risedronate:
- probably prevents fractures in the bones of the hip and in bones other than in the spine;
- may not lead to any difference in preventing wrist fractures;
- does not have enough evidence to show if it may prevent fractures in the bones of the spine suggested by clinical signs and symptoms;
- might make little or no difference in adverse events for postmenopausal women at higher risk for fractures.
Best estimate of what happens to postmenopausal women at lower risk for fractures who take risedronate or placebo:
- for spine fractures suggested by clinical signs and symptoms and hip fractures, it was not possible to calculate the effect because none of these fractures were reported in any of the studies;
- compared to placebo, there is not enough information to tell if risedronate prevents fractures in wrist and bones other than in the spine.
Best estimate of what happens to postmenopausal women at higher risk for fractures who take risedronate or placebo:
Fractures of the spine suggested by clinical signs and symptoms were not reported in any of the studies.
Fractures in bones other than the spine:
- 10 out of 100 women had a fracture when taking a placebo;
- 8 out of 100 women had a fracture when taking risedronate;
Fractures of the hip
- 3 out of 100 women had a fracture when taking a placebo;
- 2 out of 100 women had a fracture when taking risedronate.
Fractures of the wrist:
- there is not enough information to tell if risedronate prevents wrist fractures.
This update recaps the key findings from our previous review that, for secondary prevention, risedronate 5 mg/day probably prevents non-vertebral fracture, and may reduce the risk of hip fractures. We are uncertain on whether risedronate 5mg/day reduces clinical vertebral and wrist fractures. Compared to placebo, risedronate probably does not increase the risk of serious adverse events.
For primary prevention, the benefit and harms of risedronate were supported by limited evidence with high uncertainty.
Osteoporosis is an abnormal reduction in bone mass and bone deterioration leading to increased fracture risk. Risedronate belongs to the bisphosphonate class of drugs which act to inhibit bone resorption by interfering with the activity of osteoclasts. This is an update of a Cochrane Review that was originally published in 2003.
We assessed the benefits and harms of risedronate in the primary and secondary prevention of osteoporotic fractures for postmenopausal women at lower and higher risk for fractures, respectively.
With broader and updated strategies, we searched the Cochrane Central Register of Control Trials (CENTRAL), MEDLINE and Embase. A grey literature search, including the online databases ClinicalTrials.gov, International Clinical Trials Registry Platform (ICTRP), and drug approval agencies, as well as bibliography checks of relevant systematic reviews was also performed. Eligible trials published between 1966 to 24 March 2021 were identified.
We included randomised controlled trials that assessed the benefits and harms of risedronate in the prevention of fractures for postmenopausal women. Participants must have received at least one year of risedronate, placebo or other anti-osteoporotic drugs, with or without concurrent calcium/vitamin D. Major outcomes were clinical vertebral, non-vertebral, hip and wrist fractures, withdrawals due to adverse events, and serious adverse events. In the interest of clinical relevance and applicability, we classified a study as secondary prevention if its population fulfilled more than one of the following hierarchical criteria: a diagnosis of osteoporosis, a history of vertebral fractures, low bone mineral density (BMD)T score ≤ -2.5, and age ≥ 75 years old. If none of these criteria was met, the study was considered to be primary prevention.
We used standard methodology expected by Cochrane. We pooled the relative risk (RR) of fractures using a fixed-effect model based on the expectation that the clinical and methodological characteristics of the respective primary and secondary prevention studies would be homogeneous, and the experience from the previous review suggesting that there would be a small number of studies. The base case included the data available for the longest treatment period in each placebo-controlled trial and a >15% relative change was considered clinically important. The main findings of the review were presented in summary of findings tables, using the GRADE approach.
In addition, we looked at benefit and harm comparisons between different dosage regimens for risedronate and between risedronate and other anti-osteoporotic drugs.
Forty-three trials fulfilled the eligibility criteria, among which 33 studies (27,348 participants) reported data that could be extracted and quantitatively synthesized. We had concerns about particular domains of risk of bias in each trial. Selection bias was the most frequent concern, with only 24% of the studies describing appropriate methods for both sequence generation and allocation concealment. Fifty per cent and 39% of the studies reporting benefit and harm outcomes, respectively, were subject to high risk. None of the studies included in the quantitative syntheses were judged to be at low risk of bias in all seven domains. The results described below pertain to the comparisons for daily risedronate 5 mg versus placebo which reported major outcomes. Other comparisons are described in the full text.
For primary prevention, low- to very low-certainty evidence was collected from four studies (one to two years in length) including 989 postmenopausal women at lower risk of fractures. Risedronate 5 mg/day may make little or no difference to wrist fractures [RR 0.48 ( 95% CI 0.03 to 7.50; two studies, 243 participants); absolute risk reduction (ARR) 0.6% fewer (95% CI 1% fewer to 7% more)] and withdrawals due to adverse events [RR 0.67 (95% CI 0.38 to 1.18; three studies, 748 participants); ARR 2% fewer (95% CI 5% fewer to 1% more)], based on low-certainty evidence. However, its preventive effects on non-vertebral fractures and serious adverse events are not known due to the very low-certainty evidence. There were zero clinical vertebral and hip fractures reported therefore the effects of risedronate for these outcomes are not estimable.
For secondary prevention, nine studies (one to three years in length) including 14,354 postmenopausal women at higher risk of fractures provided evidence. Risedronate 5 mg/day probably prevents non-vertebral fractures [RR 0.80 (95% CI 0.72 to 0.90; six studies, 12,173 participants); RRR 20% (95% CI 10% to 28%) and ARR 2% fewer (95% CI 1% fewer to 3% fewer), moderate certainty], and may reduce hip fractures [RR 0.73 (95% CI 0.56 to 0.94); RRR 27% (95% CI 6% to 44%) and ARR 1% fewer (95% CI 0.2% fewer to 1% fewer), low certainty]. Both of these effects are probably clinically important. However, risedronate's effects are not known for wrist fractures [RR 0.64 (95% CI 0.33 to 1.24); three studies,1746 participants); ARR 1% fewer (95% CI 2% fewer to 1% more), very-low certainty] and not estimable for clinical vertebral fractures due to zero events reported (low certainty). Risedronate results in little to no difference in withdrawals due to adverse events [RR 0.98 (95% CI 0.90 to 1.07; eight studies, 9529 participants); ARR 0.3% fewer (95% CI 2% fewer to 1% more); 16.9% in risedronate versus 17.2% in control, high certainty] and probably results in little to no difference in serious adverse events [RR 1.00 (95% CI 0.94 to 1.07; six studies, 9435 participants); ARR 0% fewer (95% CI 2% fewer to 2% more; 29.2% in both groups, moderate certainty).