Background
Steroids (glucocorticosteroids) are widely used to treat inflammation. Bone loss (osteoporosis) and spinal fractures are serious side effects of this therapy. Bisphosphonates are considered a first-line treatment for osteoporosis and have been used since the 1990s.
Methods
We examined the research published up to April 2016 and found a total of 27 eligible trials, which included 3075 adults with inflammatory diseases that required steroid treatment for at least one year. People were randomly assigned to receive either bisphosphonate treatment (alone or with calcium or vitamin D, or both) or 'no treatment' (given calcium or vitamin D or a placebo). Our objective was to determine the benefits and harms of bisphosphonates for adults on long-term steroid therapy.
Main Results
New spinal fractures (12 to 24 months)
There were 12 trials with 1343 people for this analysis. We found that 77 per 1000 people with no treatment experienced new spinal fracture compared to 44 per 1000 (range 27 to 70) people taking bisphosphonates; an absolute benefit of 2% fewer people (5% fewer to 1% more) sustaining spinal fractures when taking bisphosphonates.
Approximately 31 people (range 20 to 145) would need to be treated with bisphosphonates to prevent spinal fractures in one person.
New non-spinal fractures (12 to 24 months)
There were nine trials with 1245 people for this analysis. We found that 55 per 1000 people with no treatment experienced new non-spinal fractures compared to 42 per 1000 (range 25 to 69) people taking bisphosphonates; an absolute benefit of 1% fewer people (4% fewer to 1% more) sustaining non-spinal fractures when taking bisphosphonates.
Lumbar spine bone mineral density (BMD) at 12 months
There were 23 trials with 2042 people for this outcome. We found that the BMD of the lumbar spine of people taking bisphosphonates was 3.50% higher (2.90% to 4.10% higher) than in people who had no treatment.
Approximately three people (range 2 to 3) would need to be treated with bisphosphonates for 12 months for one person to see a minimally important difference in BMD at the lumbar spine.
Femoral neck (top of thigh bone) BMD at 12 months
There were 18 trials with 1665 people for this outcome. We found that the BMD of the femoral neck was 2.06% higher in the bisphosphonate group (1.45% to 2.68% more) than in people with no treatment.
Approximately five people (range 4 to 7) would need to be treated with bisphosphonates for 12 months for one person to see a minimally important difference in BMD at the femoral neck.
Serious adverse events (requiring hospitalisations, life threatening or fatal)
There were 15 trials with 1703 people for this outcome. We found that 162 per 1000 people with no treatment experienced serious adverse events compared to 147 per 1000 (range 120 to 181) taking bisphosphonates; an absolute increased harm of 0% more serious adverse events (2% fewer to 2% more) with bisphosphonates.
Withdrawals due to adverse events
There were 15 trials with 1790 people for this outcome. We found that 73 per 1000 people with no treatment withdrew compared to 77 per 1000 (range 56 to 107) people taking bisphosphonates; an absolute increased harm of 1% more withdrawals due to adverse events (1% fewer to 3% more) with bisphosphonates.
Authors' conclusions
Based on moderate- to high-certainty evidence, we found that bisphosphonates are beneficial in preventing new spinal fractures and preventing and treating steroid-induced bone loss at the lumbar spine and femoral neck. For preventing non-spinal fractures, we found that there was little or no difference whether patients used bisphosphonates or not, although this evidence was low-certainty because the methods used to assess non-spinal fractures were subject to bias.
We found that there was little or no difference in the number of serious adverse events or withdrawals due to adverse events when comparing bisphosphonates to no treatment. The evidence for these outcomes was of low certainty and we are cautious in making firm conclusions about the harm of bisphosphonates based only on these measures.
Overall, our review supports the use of bisphosphonates to reduce the risk of spinal fractures and in the prevention and treatment of steroid-induced bone loss.
There was high-certainty evidence that bisphosphonates are beneficial in reducing the risk of vertebral fractures with data extending to 24 months of use. There was low-certainty evidence that bisphosphonates may make little or no difference in preventing nonvertebral fractures. There was moderate-certainty evidence that bisphosphonates are beneficial in preventing and treating corticosteroid-induced bone loss at both the lumbar spine and femoral neck. Regarding harm, there was low-certainty evidence that bisphosphonates may make little or no difference in the occurrence of serious adverse events or withdrawals due to adverse events. We are cautious in interpreting these data as markers for harm and tolerability due to the potential for bias.
Overall, our review supports the use of bisphosphonates to reduce the risk of vertebral fractures and the prevention and treatment of steroid-induced bone loss.
This is an update of a Cochrane Review first published in 1999. Corticosteroids are widely used in inflammatory conditions as an immunosuppressive agent. Bone loss is a serious side effect of this therapy. Several studies have examined the use of bisphosphonates in the prevention and treatment of glucocorticosteroid-induced osteoporosis (GIOP) and have reported varying magnitudes of effect.
To assess the benefits and harms of bisphosphonates for the prevention and treatment of GIOP in adults.
We searched CENTRAL, MEDLINE and Embase up to April 2016 and International Pharmaceutical Abstracts (IPA) via OVID up to January 2012 for relevant articles and conference proceedings with no language restrictions. We searched two clinical trial registries for ongoing and recently completed studies (ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal). We also reviewed reference lists of relevant review articles.
We included randomised controlled trials (RCTs) satisfying the following criteria: 1) prevention or treatment of GIOP; 2) adults taking a mean steroid dose of 5.0 mg/day or more; 3) active treatment including bisphosphonates of any type alone or in combination with calcium or vitamin D; 4) comparator treatment including a control of calcium or vitamin D, or both, alone or with placebo; and 4) reporting relevant outcomes. We excluded trials that included people with transplant-associated steroid use.
At least two review authors independently selected trials for inclusion, extracted data, performed ‘risk of bias’ assessment and evaluated the certainty of evidence using the GRADE approach. Major outcomes of interest were the incidence of vertebral and nonvertebral fractures after 12 to 24 months; the change in bone mineral density (BMD) at the lumbar spine and femoral neck after 12 months; serious adverse events; withdrawals due to adverse events; and quality of life. We used standard Cochrane methodological procedures.
We included a total of 27 RCTs with 3075 participants in the review. Pooled analysis for incident vertebral fractures included 12 trials (1343 participants) with high-certainty evidence and low risk of bias. In this analysis 46/597 (or 77 per 1000) people experienced new vertebral fractures in the control group compared with 31/746 (or 44 per 1000; range 27 to 70) in the bisphosphonate group; relative improvement of 43% (9% to 65% better) with bisphosphonates; absolute increased benefit of 2% fewer people sustaining fractures with bisphosphonates (5% fewer to 1% more); number needed to treat for an additional beneficial outcome (NNTB) was 31 (20 to 145) meaning that approximately 31 people would need to be treated with bisphosphonates to prevent new vertebral fractures in one person.
Pooled analysis for incident nonvertebral fractures included nine trials with 1245 participants with low-certainty evidence (downgraded for imprecision and serious risk of bias as a patient-reported outcome). In this analysis 30/546 (or 55 per 1000) people experienced new nonvertebral fracture in the control group compared with 29/699 (or 42 per 1000; range 25 to 69) in the bisphosphonate group; relative improvement of 21% with bisphosphonates (33% worse to 53% better); absolute increased benefit of 1% fewer people with fractures with bisphosphonates (4% fewer to 1% more).
Pooled analysis on BMD change at the lumbar spine after 12 months included 23 trials with 2042 patients. Eighteen trials with 1665 participants were included in the pooled analysis on BMD at the femoral neck after 12 months. Evidence for both outcomes was moderate-certainty (downgraded for indirectness as a surrogate marker for osteoporosis) with low risk of bias. Overall, the bisphosphonate groups reported stabilisation or increase in BMD, while the control groups showed decreased BMD over the study period. At the lumbar spine, there was an absolute increase in BMD of 3.5% with bisphosphonates (2.90% to 4.10% higher) with a relative improvement of 1.10% with bisphosphonates (0.91% to 1.29%); NNTB 3 (2 to 3). At the femoral neck, the absolute difference in BMD was 2.06% higher in the bisphosphonate group compared to the control group (1.45% to 2.68% higher) with a relative improvement of 1.29% (0.91% to 1.69%); NNTB 5 (4 to 7).
Pooled analysis on serious adverse events included 15 trials (1703 participants) with low-certainty evidence (downgraded for imprecision and risk of bias). In this analysis 131/811 (or 162 per 1000) people experienced serious adverse events in the control group compared to 136/892 (or 147 per 1000; range 120 to 181) in the bisphosphonate group; absolute increased harm of 0% more serious adverse events (2% fewer to 2% more); a relative per cent change with 9% improvement (12% worse to 26% better).
Pooled analysis for withdrawals due to adverse events included 15 trials (1790 patients) with low-certainty evidence (downgraded for imprecision and risk of bias). In this analysis 63/866 (or 73 per 1000) people withdrew in the control group compared to 76/924 (or 77 per 1000; range 56 to 107) in the bisphosphonate group; an absolute increased harm of 1% more withdrawals with bisphosphonates (95% CI 1% fewer to 3% more); a relative per cent change 6% worse (95% CI 47% worse to 23% better).
Quality of life was not assessed in any of the trials.