All treatments were associated with beneficial effects relative to placebo with HRs for fracture varying from 0.41 to 0.92 depending on treatment and fracture site. For vertebral fractures and percentage change in BMD, the treatment effects were also statistically significant for all treatments. For non-vertebral fractures, the treatment effects were statistically significant at a conventional 5% level for risedronic acid, alendronic acid and zoledronic acid. For the outcomes of hip fracture and wrist fracture, all treatments were associated with beneficial treatment effects relative to placebo, although the treatment effects were not statistically significant at a conventional 5% level. Pairwise comparisons between treatments indicated that no active treatment was significantly more effective than other active treatments for fracture outcomes. For vertebral fractures and percentage change in BMD, the greatest effect was for zoledronic acid, although, in general, the ranking of treatments varied for the different outcomes, with the treatments providing broadly similar effects.
For the majority of AEs reported in RCTs no significant difference was found between active treatment and placebo, suggesting that bisphosphonates are generally well tolerated in patients enrolled within clinical trials. Prescription event monitoring study data suggest a high level of reporting of a number of conditions in the first month of therapy with alendronic acid or risedronic acid, particularly those affecting the upper GI tract, suggesting that oral bisphosphonates may be less well tolerated in clinical practice. A significant difference in the incidence of influenza-like symptoms was identified from the RCTs for zoledronic acid compared with placebo, although clinical advice was that these symptoms are generally limited to the first dose and usually last only a few days.
Continuance and concordance data were limited for the RCT evidence evaluated. Supplementary review evidence of observational data indicates that, although patients using weekly bisphosphonate medication follow their prescribed regimens better than those using daily therapy, overall compliance and persistence rates are suboptimal for postmenopausal women.
The de novo economic model estimates that when using QFracture to estimate absolute risk, a strategy of no treatment is predicted to have the greatest net benefit, when valuing a QALY at £20,000, in the lowest-risk patients (QFracture absolute risk < 1.5%), with oral bisphosphonates (alendronic acid, risedronic acid, ibandronic acid) having the greatest INB at higher levels of absolute risk. However, the absolute costs and QALY gains are small in patients with low absolute risk and the PSA suggested that there is considerable uncertainty regarding whether or not no treatment is the optimal strategy until the QFracture score is approximately 5.5% (the mean absolute risk for the eighth risk category for QFracture). Therefore, it is possible that patients and clinicians may not consider treatment worthwhile in the lowest-risk patients even though it may be cost-effective.
The mean INBs compared with no treatment (when valuing a QALY at £20,000) were positive for all oral bisphosphonate treatments across all FRAX risk categories. However, in the base-case scenario the INBs of bisphosphonate treatments compared with no treatment were generally higher for FRAX than for QFracture for risk categories with similar absolute fracture risk. We would expect from the way the model is structured that the threshold for cost-effective treatment would be broadly similar across the two risk scores. The results of two structural sensitivity analyses suggest that the base-case analysis may have overestimated the INBs of treatment in the model based on FRAX because of the assumption that the proportion of major osteoporotic fractures that occur at the hip is the same for FRAX and QFracture. Given this possible bias in the estimates generated by the model using the FRAX absolute risk estimates, and our belief that the results should be broadly similar across the two risk scores, it would be reasonable to assume that the absolute risk thresholds estimated in the QFracture model could be applied to patients whose score had been calculated using either QFracture or FRAX.
The de novo economic model suggests that the cost-effectiveness of i.v. bisphosphonates (ibandronic acid and zoledronic acid) is less favourable than for oral bisphosphonates with a negative INB (when valuing a QALY at £20,000) than no treatment estimated for both i.v. bisphosphonates across all 10 risk categories for both FRAX and QFracture.
Implications for service provision
The prescribing of oral bisphosphonates in patients who have already received risk assessment under CG146 is not anticipated to have any major implications for service provision as these can be prescribed in primary care. If i.v. bisphosphonates were to be widely prescribed across the population eligible for risk assessment under CG146, it is likely that additional capacity would be required in existing services to administer these treatments in secondary care.
Suggested research priorities
Given that the cost-effectiveness results are sensitive to the assumptions regarding the rate of AEs for oral bisphosphonates, further research to quantify both the incidence of AEs and the impact of those AEs on HRQoL and treatment persistence would allow patients and clinicians to make better-informed decisions regarding the balance of costs, benefits and AEs. Although further RCTs evaluating efficacy and tolerability of bisphosphonates as well as assessing HRQoL and persistence could be recommended, data on the relationships between AEs and HRQoL alongside persistence could also be evaluated through observational study design.
We identified only a limited number of RCTs in men. There was evidence from single RCTs in men which showed a significant increase in upper GI AEs and withdrawals because of AEs than those receiving placebo. Further research to assess efficacy and tolerability of bisphosphonate treatment in men may be beneficial.
The existing economic model could be extended to include non-bisphosphonate treatments, as these are potential alternatives to bisphosphonate therapy in some patients. Non-bisphosphonates were not included as comparators in the economic model, as the scope for this NICE MTA stated that non-bisphosphonates licensed for the prevention of fragility fractures in women and men would be considered in a separate MTA. The economic model could also be extended to consider the cost-effectiveness of second-line treatments in patients who experience fractures while being treated with a bisphosphonate.
Given that an individual’s risk usually increases with age, and bisphosphonate treatment is not usually continued indefinitely, it is currently unclear whether or not treatment should be given as soon as an individual’s increased fracture risk is identified or whether treatment should be delayed so that the patient has the full benefit of treatment during the period that they are at greatest risk. The economic model could also be adapted to assess the optimal timing of bisphosphonate therapy in patients whose life expectancy exceeds the anticipated duration of treatment effect.
The economic analysis presented here focused on examining how cost-effectiveness varies with absolute fracture risk. This was done in order to meet the requirement laid out in the scope to link absolute fracture risk with intervention thresholds, based on cost-effectiveness. However, further work could be done to explore how cost-effectiveness varies across the cohort of patients at risk of fragility fracture and whether or not any factors other than absolute fracture risk could be used to select patients who can be treated cost-effectively.
