Osteoporotic fractures: appraisal consultation document

Denosumab for the prevention of osteoporotic fractures in postmenopausal women

Appraisal consultation document

The Department of Health has asked the National Institute for Health and Clinical Excellence (NICE) to produce guidance on using denosumab for the prevention of osteoporotic fractures in postmenopausal women in the NHS in England and Wales. The Appraisal Committee has considered the evidence submitted by the manufacturer and the views of non-manufacturer consultees and commentators, and clinical specialists and patient experts.

This document has been prepared for consultation with the consultees. It summarises the evidence and views that have been considered, and sets out the draft recommendations made by the Committee. NICE invites comments from the consultees and commentators for this appraisal (see appendix B) and the public. This document should be read along with the evidence base (the evaluation report), which is available from www.nice.org.uk

The Appraisal Committee is interested in receiving comments on the following:

  • Has all of the relevant evidence been taken into account?
  • Are the summaries of clinical and cost effectiveness reasonable interpretations of the evidence?
  • Are the provisional recommendations sound and a suitable basis for guidance to the NHS?
  • Are there any aspects of the recommendations that need particular consideration to ensure we avoid unlawful discrimination against any group of people on the grounds of gender, race, disability, age, sexual orientation, religion or belief?

Note that this document is not NICE's final guidance on this technology. The recommendations in section 1 may change after consultation.

After consultation:

  • The Appraisal Committee will meet again to consider the evidence, this appraisal consultation document and comments from the consultees.
  • At that meeting, the Committee will also consider comments made by people who are not consultees.
  • After considering these comments, the Committee will prepare the final appraisal determination (FAD).
  • Subject to any appeal by consultees, the FAD may be used as the basis for NICE's guidance on using denosumab in the NHS in England and Wales.

For further details, see the 'Guide to the technology appraisal process' (available at www.nice.org.uk).

The key dates for this appraisal are:

Closing date for comments: 9th July 2010
Second Appraisal Committee meeting: 27 July 2010

Details of membership of the Appraisal Committee are given in appendix A, and a list of the sources of evidence used in the preparation of this document is given in appendix B.


Appraisal Committee's preliminary recommendations

1.1 Denosumab is recommended as a treatment option for the primary prevention of osteoporotic fragility fractures only in postmenopausal women at increased risk of fractures:

  • who are unable to comply with the special instructions for the administration of oral bisphosphonates, are intolerant of oral bisphosphonates or for whom treatment with oral bisphosphonates is contraindicated and
  • who also have a combination of T-score1, age and number of independent clinical risk factors for fracture (see section 1.3) as indicated in the following table.

T-scores (SD) at (or below) which denosumab is recommended when oral bisphosphonates are unsuitable

  Number of independent clinical risk factors for fracture
Age (years) 0 1 2
65-69 -a -4.5 -4.0
70-74 -4.5 -4.0 -3.5
75 or older -4.0 -4.0 -3.0

a Treatment with denosumab is not recommended

1.2 Denosumab is recommended as a treatment option for the secondary prevention of osteoporotic fragility fractures only in postmenopausal women at increased risk of fractures:

  • who are unable to comply with the special instructions for the administration of oral bisphosphonates, are intolerant of oral bisphosphonates or for whom treatment with oral bisphosphonates is contraindicated

1.3 For the purposes of this guidance, independent clinical risk factors for fracture are parental history of hip fracture, alcohol intake of 4 or more units per day, and rheumatoid arthritis.

1 T-score relates to the measurement of bone mineral density (BMD) using central (hip and/or spine) DXA scanning, and is expressed as the number of standard deviations (SD) below peak BMD.

The technology

2.1 Denosumab (Prolia, Amgen) is a monoclonal antibody that reduces osteoclast activity, and so reduces bone breakdown and increases bone mass and strength. Denosumab has a UK marketing authorisation for the treatment of osteoporosis in postmenopausal women at increased risk of fractures. The summary of product characteristics states in the indication that denosumab significantly reduces the risk of vertebral, non-vertebral and hip fractures.

2.2 The summary of product characteristics states that the following conditions may be associated with denosumab treatment: eczema, diverticulitis, cataracts, hypocalcaemia, and skin infections (predominantly cellulitis). The SPC states that osteonecrosis of the jaw has been reported in patients receiving denosumab or bisphosphonates with most cases occurring in cancer patients; however some have occurred in patients with osteoporosis. For full details of side effects and contraindications, see the summary of product characteristics.

2.3 Denosumab is administered as a single subcutaneous injection into the thigh, abdomen or back of the arm. The recommended dosage is 60 mg once every 6 months.

2.4 The manufacturer's submission states that the cost for one pre-filled syringe is £183, which is equivalent to £366 for 1 year of treatment. Costs may vary in different settings because of negotiated procurement discounts.

The manufacturer's submission

The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of denosumab and a review of this submission by the Evidence Review Group (ERG; appendix B).

3.1 The manufacturer's submission presented data on clinical effectiveness from one main randomised controlled trial. The FREEDOM (fracture reduction evaluation of denosumab in osteoporosis every 6 months) study was a multicentre, double-blind, placebo-controlled trial that enrolled 7868 postmenopausal women aged between 60 and 90 years. The T-score relates to the measurement of bone mineral density (BMD) using central (hip and/or spine) DXA scanning and is expressed as the number of standard deviations (SD) below the mean BMD of young, healthy adults of the same gender at their peak bone mass. Lower T-scores indicate lower BMD. The FREEDOM trial only included women with BMD T-scores of less than ?2.5 SD and greater than ?4.0 SD. Women were randomly assigned to receive a subcutaneous injection of either 60 mg denosumab or placebo twice a year for 3 years. All participants also took daily calcium and vitamin D supplements.

3.2 The primary outcome was the incidence of new radiographically diagnosed vertebral fractures. Secondary outcomes were time to first non-vertebral fracture and time to first hip fracture. Health-related quality of life was assessed in terms of change from baseline in patient-reported outcomes using both the osteoporosis assessment questionnaire-short version (OPAQ-SV; physical function, emotional status and back pain score), and the EUROQOL-5D (EQ-5D) questionnaire.

3.3 The results of the FREEDOM study demonstrated that the 36 month incidence of new radiographically diagnosed vertebral fractures was 2.3% (86 of 3702 women) in the denosumab group compared with 7.2% (264 of 3691 women) in the placebo group (relative risk [RR] 0.32, 95% confidence interval [CI] 0.26 to 0.41; p < 0.001). The reduction in risk was similar during each year of the trial. Similar reductions were seen for incidences of clinically diagnosed vertebral fracture (0.8% for women receiving denosumab compared with 2.6% for women receiving placebo; hazard ratio [HR] 0.31, 95% CI 0.20 to 0.47; p < 0.001) and multiple new radiographically diagnosed vertebral fractures (0.6% for women receiving denosumab compared with 1.6% for women receiving placebo; RR 0.39, 95% CI 0.24 to 0.63; p < 0.001). Denosumab also reduced the risk of non-vertebral fracture (6.5% for women receiving denosumab compared with 8.0% for women receiving placebo; HR 0.80, 95% CI 0.67 to 0.95; p = 0.01) and hip fracture (0.7% for women receiving denosumab compared with 1.2% for women receiving placebo; HR 0.60, 95% CI 0.37 to 0.97; p = 0.04).

3.4 Health-related quality of life was assessed using the OPAQ-SV and EQ-5D questionnaire at baseline and every 6 months for 3 years. Among women who completed the study, completion rates for measures of health-related quality of life at year 3 were 83% for OPAQ-SV and 82% for EQ-5D. No significant differences were seen between treatment groups in measures of health-related quality of life at baseline compared with year 3, or when comparing women without any fractures with women with incident clinical fractures. Decreases in scores for two OPAQ-SV dimensions (physical function and emotional status) and in EQ-5D health index and visual analogue scale scores (all p < 0.001) were reported at year 3 regardless of treatment group. Changes from baseline to year 3 for each OPAQ-SV dimension and EQ-5D scores were positively correlated (all p < 0.0001).

3.5 Only one serious adverse effect of denosumab was reported in the FREEDOM study. A statistically significant difference was noted in skin infections, which occurred in 12 women receiving denosumab compared with one woman receiving placebo (p = 0.002). However, when all studies of denosumab were pooled in a meta-analysis by the manufacturer, no statistically significant difference in adverse effects was observed. Further safety data were available from 30 studies, giving a total of 14,000 patients, 11,000 of whom were postmenopausal women. These data came from clinical trials of other indications for denosumab, such as for preventing bone loss in people with breast cancer or prostate cancer. A review of these data by the US Food and Drug Administration concluded that patients receiving denosumab had a slightly higher incidence of serious infections of the skin, ear, urinary tract and abdomen, and more non-serious skin infections. The Food and Drug Administration considered denosumab to be safe, but had a concern about bone structure, since biopsies showed suppression of dynamic bone formation parameters, which raised theoretical risks of delayed fracture healing and of atypical fracture. However, no statistically significant differences were observed for delayed fracture healing in the FREEDOM study (with two cases in women receiving denosumab and four in women receiving placebo).


3.6 The manufacturer stated that it was mindful of the need to make efficient use of NHS resources, and that, given the wide availability of generic bisphosphonates, denosumab was expected to be an option for women in whom oral bisphosphonates are unsuitable. Therefore denosumab was not expected to compete with oral bisphosphonates in clinical practice. In the absence of head-to-head clinical trials comparing denosumab with all relevant comparators, the manufacturer carried out a random-effects meta-analysis of the relative risks (RRs) for all fracture endpoints directly comparing each treatment against placebo. The fracture incidence data (and RRs) for strontium ranelate for hip and wrist fracture were taken from the publication by Reginster et al. 2008 which reported the 5-year data from the TROPOS study. The results of the manufacturer's meta-analysis showed that all treatments (denosumab, strontium ranelate, raloxifene, teriparatide and zoledronate) were associated with statistically significant decreases in the risk of morphometric vertebral fractures compared with placebo (RRs of 0.33, 0.72, 0.65, 0.35 and 0.30 respectively). Denosumab, strontium ranelate and zoledronate were associated with statistically significant decreases in the risk of clinical vertebral fractures (RRs of 0.32, 0.65 and 0.23, respectively), but raloxifene was not (RR of 0.45; no data were available for teriparatide). Similarly, denosumab, strontium ranelate, teriparatide and zoledronate were associated with statistically significant decreases in the risk of non-vertebral fractures (RRs of 0.81, 0.88, 0.47 and 0.75 respectively), but raloxifene was not (RR of 0.66). Denosumab and zoledronate were associated with statistically significant decreases in the risk of hip fractures (RRs of 0.61 and 0.59 respectively) but strontium ranelate, and teriparatide were not (RRs of 0.89 and 0.25 respectively; no data were available for raloxifene). None of the treatments were associated with a statistically significant decrease in the risk of wrist fracture (RR of 0.84 for denosumab, 0.98 for strontium ranelate and 0.29 for teriparatide; no data were available for zoledronate or raloxifene).

3.7 The manufacturer's submission included a systematic review of the cost-effectiveness evidence for denosumab. The manufacturer carried out Markov cohort modelling to assess the cost effectiveness of denosumab against a range of comparators (divided into primary and secondary comparators). Primary comparators were strontium ranelate, raloxifene and no treatment (placebo). Secondary comparators were intravenous ibandronate, zoledronate and teriparatide. The manufacturer had stated that denosumab is expected to be a treatment option for women with osteoporosis for whom oral bisphosphonates are unsuitable (reasons for unsuitability are that the woman is unable to comply with the special instructions for the administration of bisphosphonates, or has a contraindication to or is intolerant of bisphosphonates). Therefore comparisons with oral bisphosphonates were not directly relevant to this appraisal and were included in the appendices to the manufacturer's submission. The manufacturer stated that 71.6% of women receiving treatment for osteoporosis in England and Wales receive alendronate, 15.8% receive risedronate, 1.5% receive etidronate and 4.3% receive ibandronate (oral), which together account for 93.2% of women receiving oral bisphosphonates (2009 figures). Thus an estimated 6.8% of women receiving treatment for osteoporosis in England and Wales receive drugs other than oral bisphosphonates (3% strontium ranelate, 2% raloxifene, 0.6% ibandronate, 0.7% zoledronate, 0.2% calcitonin, 0.2% calcitriol and 0.1% teriparatide).It is this latter group of women that is expected to be eligible for denosumab treatment.

3.8 The manufacturer stated that persistence and compliance with oral bisphosphonates are poor because of the strict and complex dosing regimen and side effects of treatment. The manufacturer's submission stated that the percentage of patients discontinuing treatment with oral bisphosphonates within 1 year is at least 42% and the median duration of treatment with oral bisphosphonates has been estimated to be 1.2 years.

3.9 The model assessed the cost effectiveness of denosumab against the primary and secondary comparators for two separate cohorts. The first investigated the primary prevention of fragility fractures in women (70 years and over) with osteoporosis (T-score of ?2.5 SD or below) who are unable to comply with the special instructions for the administration of bisphosphonates, or have a contraindication to or are intolerant of bisphosphonates. The second investigated the secondary prevention of subsequent fragility fractures in women (70 years and over) with osteoporosis (T-scores of ?2.5 SD or below) and prior fragility fractures who are unable to comply with the special instructions for the administration of bisphosphonates, or have a contraindication to or are intolerant of bisphosphonates. The model had a cycle length of 6 months and a lifetime horizon (defined as until time of death or age of 100 years), including a half-cycle correction.

3.10 The model included six discrete health states: well, hip fracture, clinically diagnosed vertebral fracture, wrist fracture, other types of fracture (pelvic, femur shaft, tibia, fibular, humerus, scapula, clavicle, rib or sternum), and death. It included two additional health states (post-hip fracture and post-vertebral fracture) to account for the long-term costs and effects associated with these fractures (no long-term costs or effects were assumed for women with wrist or other fractures). When a fracture occurred, women were modelled to remain in the respective fracture state for two cycles (1 year). After this period, women with a wrist fracture or other types of fracture were modelled to return to the well state. Women with a vertebral fracture or hip fracture were modelled to enter a post-fracture state. Women who had experienced a vertebral fracture could no longer incur a wrist fracture or other type of osteoporotic fracture (other than a subsequent vertebral fracture or hip fracture). Women who had experienced a hip fracture could only incur further hip fractures. The manufacturer's model was not a treatment-sequencing model because of the lack of clinical evidence for such use.

3.11 The manufacturer's base-case analysis assumed that women continued osteoporosis therapy for 5 years, and costs and quality-adjusted life years (QALYs) were tracked over the lifetime of the cohorts (consistent with economic modelling in NICE technology appraisal guidance 160, and NICE technology appraisal guidance 161: 'Alendronate, etidronate, risedronate, raloxifene, strontium ranelate and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women' [2008; amended 2010]). This assumption was examined in a sensitivity analysis.

3.12 Subgroup analysis was undertaken for women with and without prior fracture by age and T-score. The T-score distribution (below the threshold) was divided into brackets of 0.1 SD, and the relative risk attributable to each T-score bracket was estimated. The average risk below different T-score thresholds was estimated by taking the weighted average risk across all T-score brackets below the threshold (based on the proportions of the cohort in each bracket). Sensitivity analysis was conducted to assess the effect on cost effectiveness of the presence or absence of additional independent clinical risk factors for fracture in women of 70 years of age, with and without prior fragility fractures. Sensitivity analysis was also conducted to assess the effects on cost effectiveness of differences in treatment persistence and compliance.

3.13 In the manufacturer's base-case analysis, fracture risks were estimated on the basis of epidemiological literature, and were based on three main elements: general population fracture risk, increased fracture risk associated with osteoporosis, and risk reduction, if any, attributed to treatment. A systematic review of the literature was undertaken to identify appropriate UK studies or systematic reviews for all three model parameters. Age-specific fracture risks were estimated for women in the general population (using a study by Singer et al. [1998] to estimate risk of wrist and hip fractures, and a study by Kanis et al. [2000] to derive estimates for the incidence of clinically diagnosed vertebral and other fractures). Next, age-matched Z-scores (that is, the estimate of the number of SD below the mean BMD of the general population for the patient's age and sex) were estimated for a cohort with osteoporosis using the National Health and Nutrition Examination Survey (NHANES) III database. Evidence from the systematic review was then used to attribute age-specific relative risks for the different types of fracture. Treatment was modelled to continue for 5 years by applying relative risks to the estimated baseline risks of fracture in the cohort with osteoporosis. Following the termination of treatment after 5 years, an assumption was made that women would return in a linear fashion to baseline risk levels over 1 year (a return to baseline levels over the course of 5 years was assumed in NICE technology appraisal guidance 160 and 161). The relative risks of fracture for each treatment for clinical vertebral, hip and wrist fractures were estimated from the manufacturer's direct comparison for each treatment against placebo if data were available. If evidence was not available for a comparator, the following explicit assumptions were made:

  • For interventions that lacked data on the relative risk of clinical vertebral fracture this was assumed to be equivalent to that obtained from morphometric relative risk data.
  • the relative risk for interventions where data for wrist and hip fractures were not available was assumed to be 1.00
  • since no efficacy evidence was identified for intravenous ibandronate compared with placebo, efficacy was assumed to be equivalent to that of oral ibandronate
  • the relative risk for other fractures was assumed to be equivalent to 1.00 for all treatments, because 'other fracture' was not defined consistently across studies.

3.14 The model accounted for observed increases in the risk of mortality after fracture by applying relative risks for mortality obtained from a review of the literature. An increased risk was modelled for the first year and subsequent years after hip fracture or vertebral fracture. For other types of fracture, women were modelled to be at increased risk of mortality for 1 year only. The relative risks of mortality after all types of fracture were adjusted downwards to account for the observation that a substantial proportion of mortality after fracture can be explained by comorbidity. It was assumed that 30% of all mortality after all types of fracture is causally related, which is consistent with similar assumptions in NICE technology appraisal guidance 160 and 161.

3.15 The manufacturer's model also took into account persistence and compliance. Persistence is defined as the duration of time from initiation to discontinuation of therapy, and compliance is defined as the act of conforming to the recommendations made by the provider with respect to timing, dosage and frequency of medication taking. Persistence and compliance were assumed to be 100% for the 5-year treatment period for all modelled treatments. Sensitivity analysis was carried out for oral therapies only.

3.16 Women completed the EQ-5D questionnaire in the FREEDOM study, but the number of fracture events with associated EQ-5D scores recorded was low and the trial design precluded assessment of health status immediately after fracture events. Thus, evidence from the manufacturer's systematic review of the literature on health-related quality of life in osteoporosis was considered to be more meaningful and was applied in the economic analysis. The disutilities associated with fracture were obtained from a systematic review of the literature and applied to population norms in the form of utility multipliers. Utility loss associated with hip and vertebral fractures was modelled in a two-stage process, with a larger decrease in the first year after fracture and an ongoing but less severe utility loss in subsequent years. Utility multipliers for the first and subsequent years after hip fracture were obtained from a meta-analysis of studies using the EQ-5D responses. Utility loss associated with clinically diagnosed vertebral fracture was estimated separately for women managed in hospital and in primary care. The disutilities for women in hospital were derived from the EQ-5D scores of a cohort that were predominantly in hospital. The disutilities for women who were not in hospital were obtained from cohorts with prevalent morphometric fractures. Utility multipliers associated with wrist fracture were also obtained from the literature and applied in the model for 1 year after the event. Because of an absence of evidence, the same multiplier and the same approach were also used to model utility loss associated with other types of fractures. Finally, utility losses associated with selected adverse events were also included in the model.

3.17 Treatment costs and quality-of-life losses associated with wrist fracture or other types of fracture were modelled to last 1 year. Clinically diagnosed vertebral fractures and hip fractures were modelled to incur ongoing costs and loss of quality of life.

3.18 Resource use in the model was as follows. Costs of drug treatment were estimated using the British National Formulary (Edition 58), with assumptions about the costs of administration and monitoring for the comparators. Fracture costs were estimated using hospital episode statistics for England and Wales in conjunction with the Department of Health Healthcare Resource Group tariff; assumptions about the proportion of women treated in hospital, with and without surgery, for the different fracture types were informed by a combination of expert opinion, review of the literature and analysis of routine data. Costs associated with severe adverse events (such as gastrointestinal adverse events associated with oral therapies and cellulitis associated with denosumab) were included. Other types of adverse events associated with denosumab and its comparators were not included.

3.19 The results of the manufacturer's base-case analysis (pairwise comparisons) for the primary comparators showed that, for primary prevention, the incremental cost-effectiveness ratios (ICERs) for denosumab were £29,223 per QALY gained compared with no treatment and £9289 per QALY gained compared with raloxifene, and denosumab dominated strontium ranelate (that is, denosumab was less costly and more effective). For secondary prevention, the ICERs for denosumab were £12,381 per QALY gained compared with no treatment, £2046 per QALY gained compared with raloxifene, and denosumab dominated strontium ranelate. ICERs compared with no treatment for primary prevention were £74,239 per QALY gained for raloxifene and £102,592 per QALY gained for strontium ranelate. ICERs compared with no treatment for secondary prevention were £24,524 per QALY gained for raloxifene and £37,123 per QALY for strontium ranelate.

3.20 The results of the manufacturer's base-case analysis (pairwise comparisons) for the secondary comparators showed that denosumab was the lowest-cost treatment. For primary prevention, the ICERs for the other treatments compared with denosumab were £70,900 per QALY gained for zoledronate, £772,424 per QALY gained for teriparatide, and denosumab dominated ibandronate. For secondary prevention, the ICERs for the other treatments compared with denosumab were £29,029 per QALY gained for zoledronate, £451,269 per QALY gained for teriparatide, and denosumab dominated ibandronate.

3.21 The manufacturer presented a subgroup analysis to demonstrate how the cost effectiveness of denosumab varied when using different treatment cut-offs (that is, all women with a T-score 'at or below' ?2.5, ?3, ?3.5 SD and so on). The manufacturer provided further subgroup analyses for women with and without prior fracture by age and T-score. The results of the manufacturer's subgroup analyses showed that the cost effectiveness of denosumab improved as age increases and as T-score decreases, and with the presence of a prior fragility fracture. For primary prevention, in the circumstances where none of the treatments that have been appraised by NICE are recommended and where oral bisphosphonates are unsuitable, the ICER for denosumab compared with no treatment varied between £19,313 and £71,319 per QALY gained. In the circumstances where strontium ranelate is recommended for primary prevention, denosumab dominated strontium ranelate (that is, denosumab was more effective and less costly). For secondary prevention, in the circumstances where no treatment is currently recommended in the NHS, the ICER for denosumab compared with no treatment varied between £12,289 and £22,957 per QALY gained. In the circumstances where strontium ranelate is recommended for secondary prevention, denosumab dominated strontium ranelate, and in the circumstances where raloxifene is recommended for secondary prevention, denosumab dominated raloxifene or had an ICER of £2046 per QALY gained.

3.22 The manufacturer also provided a subgroup analysis using the FRAX algorithm showing how cost effectiveness varied depending on T score and the presence or absence of independent clinical risk factors for fracture. The results demonstrated that the presence of independent clinical risk factors for fracture, particularly rheumatoid arthritis, also improved the cost effectiveness of denosumab compared with the primary comparators.

3.23 The manufacturer conducted a range of deterministic and probabilistic sensitivity analyses. The results of the deterministic sensitivity analyses showed that alterations to most key parameters had limited impact on comparisons of denosumab with raloxifene, strontium ranelate and no treatment. The impact on comparisons with intravenous ibandronate, zoledronate and teriparatide were most sensitive to changes in assumptions about the cost of denosumab administration. Following a request from the ERG, the manufacturer provided an analysis in which the cost of administering denosumab was increased, to assess cost effectiveness if it were delivered in secondary care. Under this scenario, the ICER for denosumab compared with no treatment rose to £36,185 per QALY gained in women with no prior fragility fracture, and to £15,720 per QALY gained in women with a prior fragility fracture. This change led to zoledronate dominating denosumab in women with and without a prior fragility fracture. After a further request from the ERG, the manufacturer carried out a sensitivity analysis in which denosumab treatment was assumed to be started in secondary care and thereafter delivered in general practice which showed that the additional cost associated with initiating treatment with denosumab in a secondary care setting had a marginal impact on the cost-effectiveness of denosumab compared with both primary and secondary comparators. The ERG also requested that the manufacturer provided further analysis to assess assuming equal efficacy of denosumab and zoledronate for the prevention of wrist fractures. This analysis showed that the ICER for denosumab appeared to be moderately sensitive to assumptions about the relative efficacy of the two drugs for the prevention of wrist fractures.

3.24 The results of the manufacturer's probabilistic sensitivity analysis showed that denosumab had an approximately 50% probability of being considered cost effective at a willingness-to-pay threshold of £30,000 per QALY gained compared with the primary comparators (strontium ranelate, raloxifene and no treatment) in the base-case population of women aged 70 years with a T-score at or below ?2.5 SD and no prior fracture. The probability in women with a prior fragility fracture was 90%. Against the secondary comparators (ibandronate, zoledronate and teriparatide), denosumab had a 60% probability of being considered cost effective at a willingness-to-pay threshold of £30,000 per QALY gained in the base-case population of women aged 70 years without a prior fracture. The probability in women with a prior fracture was 70%.

3.25 The ERG considered that the evidence of clinical effectiveness presented in the manufacturer's submission was derived from a large high-quality trial of adequate duration. The ERG stated that it did not consider the evidence presented in the manufacturer's submission on the effects of drugs on BMD to be relevant because fracture data were available for all drugs. The ERG also noted that the data for morphometric vertebral fractures were not relevant, and these data were not used in the modelling.

3.26 The ERG noted that the results for the direct comparison of strontium ranelate with placebo (RR for hip fracture of 0.89 and RR for non-vertebral fracture of 0.88) were similar to the meta-analysis provided in NICE technology appraisal 160 (RR for hip fracture of 0.85 and RR for all non-vertebral fractures of 0.84), which provided some confidence in the results. The ERG expressed concerns about the relevant comparator for denosumab and the methodology of the meta-regression to determine whether mean age and BMD were associated with different effects of treatments.

3.27 The ERG noted that the manufacturer provided multiple comparisons of cost effectiveness using a high-quality validated model that took into account a wide range of costs, such as short-term drug costs and long-term nursing home costs, and that the analysis met the NICE reference case. The ERG considered that the appendices to the manufacturer's submission also provided very detailed accounts of underlying model assumptions and sensitivity analyses.

3.28 The ERG identified several problems with the manufacturer's economic model, specifically:

  • the choice of comparator
  • cost assumptions for denosumab
  • the validity of assumptions used for modelling utilities, costs, persistence and compliance
  • variations in cost effectiveness in subgroups of the cohort modelled
  • omission of underlying fracture risk estimates from the probabilistic sensitivity analysis
  • treatment setting and administration of denosumab.

3.29 First, the ERG believed that zoledronate is a key comparator. The manufacturer's submission did not consider zoledronate or intravenous ibandronate to be primary comparators for denosumab because they are used by only 0.7% and 0.6% of currently treated women respectively (according to Intercontinental Marketing Services data), and neither comparator had been appraised by NICE. However, the ERG stated that both ibandronate and zoledronate are licensed and used routinely in UK secondary care clinical practice for treating osteoporosis in postmenopausal women. The ERG noted that, IV ibandronate and zoledronate were similar in effectiveness but that IV ibandronate was given more frequently compared with zoledronate, and therefore given both its effectiveness and the same method of intravenous administration, zoledronate, in the ERGs view was a key comparator.

3.30 The second issue raised by the ERG was that the relative cost effectiveness of denosumab compared with zoledronate depended upon assumptions made about administration costs. The manufacturer assumed that denosumab would be given twice a year in general practice at the average cost of two standard visits to a GP, whereas zoledronate was assumed to be given once a year in hospital clinics (with some monitoring incorporated into the visit). The ERG believed that this approach had the effect of making denosumab much less costly than zoledronate. Therefore the ERG believed that, given the similar effectiveness of denosumab and zoledronate, the cost-effectiveness comparison depended largely on the relative costs used in the model. The ERG carried out additional exploratory analyses which assumed that denosumab was given in secondary care and demonstrated that for primary prevention the ICER for denosumab compared with no treatment was £40,627 per QALY gained. For primary prevention, the ICER for denosumab compared with raloxifene was £25,743 per QALY gained and for denosumab compared with strontium ranelate was £15,866 per QALY gained. For secondary prevention, the ICER for denosumab compared with no treatment was £17,851 per QALY gained, the ICER for denosumab compared with raloxifene was £12,171 per QALY gained, and the ICER for denosumab compared with strontium ranelate was £6606 per QALY gained.

3.31 The ERG identified that a simplifying assumption was used for transitions in the model. Women experiencing a vertebral fracture could no longer experience a wrist fracture or other type of fracture (apart from a clinical vertebral fracture or hip fracture). After a hip fracture women could no longer experience any type of fracture other than a hip fracture. The ERG believed that this assumption was unrealistic because experience of a hip fracture or clinical vertebral fracture would put women at higher risk of further fracture. However, the effect of these assumptions on the cost-effectiveness estimates was unclear.

3.32 The ERG noted that in the manufacturer's base-case analysis, the assumption that fracture risk would return linearly to baseline levels over the course of 1 year after stopping treatment was a conservative assumption that would favour oral therapies. Persistence and compliance were assumed to be 100% for all treatments in the base-case analysis, which was also a conservative assumption. The ERG noted that after initial administration of denosumab, both compliance and persistence would be 100% for 6 months. However, in the long term, persistence with denosumab therapy may be less than 100%. The manufacturer carried out sensitivity analyses that examined variations in persistence for oral therapies, but variation in persistence with denosumab was not examined.

3.33 The ERG noted that the manufacturer's quality-of-life review methodology and the primary studies included in the review suggested that suitable utility multipliers had been applied in the model. However, many of the multipliers were derived from observational time-series studies without independent control groups and therefore did not control for all potential confounding factors. The ERG noted that costs and utility losses associated with wrist fractures and other types of fracture were assumed to last for 1 year, whereas hip fractures and clinical vertebral fractures were modelled to incur ongoing costs and utility losses. The ERG also noted that utility loss relative to population norms remained at a constant rate in the second and subsequent years after hip fracture or vertebral fracture, and so this assumption may have slightly overestimated utility loss associated with hip and vertebral fracture if the observed trend towards improved quality of life in the second year after fracture continued in subsequent years.

3.34 The ERG noted that the manufacturer's ICERs varied substantially within subgroups within the cohorts, and that the appropriate comparator also varied by subgroup according to existing NICE guidance. Furthermore, neither raloxifene or strontium ranelate compared favourably with no treatment (ICERs of £74,239 and £102,592 per QALY gained respectively for 70-year-old women with no prior fragility fracture and a T-score of -2.5 SD, and £24,524 and £37,123 per QALY gained respectively for women with a prior fragility fracture), which is consistent with the modelling carried out for NICE technology appraisal guidance 160 and 161. The ERG expressed the view that demonstrating cost effectiveness against these comparators does not allow the conclusion that denosumab is cost effective. The ERG also believed that for the comparison between denosumab and zoledronate there was uncertainty about the costs of administering these two drugs and their relative efficacy for the prevention of wrist fracture. Based on the assumptions in the manufacturer's base-case analysis, a comparison of denosumab with oral bisphosphonates carried out by the ERG suggested that denosumab may be a cost effective option for women who cannot take alendronate (ICERs of £21,189 per QALY gained compared with risedronate and £8680 per QALY gained compared with oral ibandronate in the lower-risk cohort - that is, 70-year-old women with no prior fragility fracture and a T score of -2.5 SD). Therefore, for women who cannot take oral alendronate, denosumab might be considered cost effective compared with risedronate and/or oral ibandronate.

3.35 The manufacturer conducted a range of deterministic and probabilistic sensitivity analyses. The ERG noted that an important omission from the probabilistic sensitivity analysis was the underlying estimates of fracture risk. The manufacturer stated that data limitation meant that distributions could not be estimated for these parameters. The ERG believed that this would have the effect of overestimating the probability of denosumab being considered cost effective at different payment thresholds. It also noted that deterministic sensitivity analysis showed that the cost-effectiveness estimates were sensitive to underlying fracture risk.

3.36 The ERG had concerns about the treatment setting and administration of denosumab in the model. The subcutaneous injection of denosumab is simple and could be carried out by a general practitioner, a practice nurse or the woman herself. However, the ERG believed that denosumab would probably not be started in general practice because it is a new biological agent that has effects on other body systems (including the immune system), and the occurrence of long-term adverse events cannot be ruled out. The ERG stated that it would expect at least one outpatient visit to be needed and, in many cases, continued hospital follow-up would be necessary. Therefore, if follow-up was partly or mainly in general practice, the ERG believed that it was unlikely that administration of denosumab would be provided in primary care as part of general medical services, but would be regarded as an enhanced service for which an additional payment would be negotiated (the size of which is currently unknown, but may be greater than the manufacturer's assumption of the average cost of two visits to a GP per patient). Therefore the marginal costs per patient of administering denosumab in primary care may be greater than the average cost of two general practice visits per year as presented in the manufacturer's model.

3.37 The ERG noted that although denosumab could be self-administered by the woman, the average age of women taking medication for the prevention of fracture in the General Practice Research Database dataset was 71.4 years, and many would be older than that. Such women might not be able to give themselves a subcutaneous injection because of poor eyesight, poor manual dexterity or cognition problems. The oldest age groups also have the highest proportion of women treated with bisphosphonates, and it is for these groups that the manufacturer expects denosumab to be an alternative treatment. Furthermore, training women to self-administer denosumab might not be regarded as worthwhile since they would have to visit a general practice to obtain the pre-filled pen injection device, and after 6 months some may have forgotten how to administer it (which is unlikely to occur with drugs given daily, such as teriparatide). The ERG also expressed the view that an equality issue exists for women who have had a stroke in the past and who are at increased risk of falls and fracture, together with bone loss because of reduced mobility. Such women might have difficulty swallowing or standing to take oral bisphosphonates, and therefore intravenous or subcutaneous drugs may be more suitable.

3.38 Full details of all the evidence are in the manufacturer's submission and the ERG report, which are available from www.nice.org.uk/guidance/TAXXX

Consideration of the evidence

4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of denosumab, having considered evidence on the nature of osteoporotic fractures and the value placed on the benefits of denosumab by postmenopausal women with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

4.2 The Committee discussed the clinical need of postmenopausal women for the prevention of osteoporotic fragility fractures. It heard from the clinical specialists that the main aim of primary prevention is the opportunistic identification of postmenopausal women who are at risk of osteoporotic fragility fractures, and the aim of secondary prevention is to provide the most effective treatment for women who have already had an osteoporotic fragility fracture and are at risk of further fractures.

4.3 The Committee heard from the clinical specialists that current UK clinical practice is to start treatment with oral bisphosphonates, but that these are not suitable for all women (reasons for unsuitability are that the woman is unable to comply with the special instructions for the administration of bisphosphonates, or has a contraindication to or is intolerant of bisphosphonates). The Committee also heard from the clinical specialists that women for whom oral bisphosphonates are unsuitable receive either no treatment or strontium ranelate for primary prevention (as set out in NICE technology appraisal guidance 160), or strontium ranelate or raloxifene for secondary prevention (as set out in NICE technology appraisal guidance 161). The clinical specialists stated that the management of osteoporosis usually takes place in primary care (both strontium ranelate and raloxifene are given in primary care). Women who have severe osteoporosis may receive more potent agents such as zoledronate or intravenous ibandronate and there is limited capacity for treatment in secondary care because of the need for day-case facilities for these intravenous treatments. The patient experts stated that some women who cannot take or cannot tolerate oral bisphosphonates have a preference for strontium ranelate or raloxifene as they do not like the intravenous infusion used for zoledronate treatment, whereas others prefer the convenience of a 12-monthly injection over taking tablets daily. The Committee accepted that the great majority of treatment for the primary and secondary prevention of osteoporotic fragility fractures is provided in primary care. It also accepted that women for whom oral therapies are unsuitable or who have severe osteoporosis may receive more potent agents such as zoledronate or intravenous ibandronate in secondary care. The Committee concluded that the relevant comparator for the primary prevention of osteoporotic fragility fractures is strontium ranelate, and the relevant comparators for the secondary prevention of osteoporotic fragility fractures are strontium ranelate and raloxifene, as both the administration and supervision of these agents are organised in primary care. It also noted that zoledronate is sometimes used in secondary care for the prevention of fractures, and that teriparatide is also used for secondary prevention when women are unable to take other therapies, therefore these are also potential comparators.

4.4 The Committee was aware that the licensed indication for denosumab is for the treatment of osteoporosis in postmenopausal women at increased risk of fractures. The Committee noted that the manufacturer's decision problem focused on postmenopausal women diagnosed with osteoporosis for whom oral bisphosphonates are unsuitable. The manufacturer stated that denosumab was not expected to compete with oral bisphosphonates in clinical practice, given the wide availability of generic bisphosphonates in the UK and the need to make efficient use of NHS resources. The Committee also noted that manufacturer did provide an analysis of denosumab compared with oral bisphosphonates for completeness. It accepted that is was reasonable to base its considerations on women for whom oral bisphosphonates are unsuitable and the subsequent discussion focussed on this population only.

4.5 The Committee heard from the clinical specialists that denosumab is a monoclonal antibody that reduces osteoclast activity and hence reduces bone breakdown, that it is the first drug of its class, and that its biological mechanism of action results in targeted therapy with fewer adverse events than other treatments. The Committee considered that a treatment that is administered by subcutaneous injection once every 6 months, such as denosumab, offers an advantage because it may improve adherence with therapy, particularly for women who have problems swallowing or standing to take oral bisphosphonates. The Committee also accepted evidence from the patient experts that many women stop taking oral bisphosphonates because of the adverse events experienced, and often do not go back to their GP. Therefore a 6-monthly subcutaneous injection of denosumab would provide women with an opportunity to have a conversation with the healthcare professional, and this support may improve compliance and persistence with treatment.

Clinical effectiveness

4.6 The Committee considered that the clinical-effectiveness evidence presented in the manufacturer's submission was derived from a large, high-quality trial of adequate duration (FREEDOM) that studied treatment with denosumab compared with placebo. The Committee noted that, as the FREEDOM study did not provide a head-to-head comparison of denosumab against all relevant comparators, the manufacturer carried out a random-effects meta-analysis to obtain direct estimates for each treatment compared with placebo.

4.7 The Committee noted that the FREEDOM trial showed that the 36-month incidence of new radiographically diagnosed vertebral fractures was 2.3% (86 of 3702 women) in the denosumab group and 7.2% (264 of 3691 women) in the placebo group (HR 0.32; 95% CI 0.26 to 0.41; statistically significant 68% reduction in relative risk p < 0.001). The Committee also noted that denosumab significantly reduced the risk of non-vertebral fracture (HR 0.80; 95% CI 0.67 to 0.95; relative reduction of 20%) and of hip fracture (HR 0.60, 95% CI 0.37 to 0.97; relative reduction of 40%). The Committee concluded that the evidence from the FREEDOM trial demonstrated that denosumab was effective in reducing the risk of fracture in postmenopausal women compared with placebo.

4.8 The Committee discussed the meta-analysis that was undertaken by the manufacturer to obtain direct estimates for each treatment compared with placebo. The Committee concluded that the methods used in the meta-analysis were sufficiently robust for use in the economic analysis.

4.9 The Committee discussed the adverse events experienced by postmenopausal women receiving denosumab for the prevention of osteoporotic fragility fractures. The Committee noted that in the FREEDOM trial treatment with denosumab was associated with fewer adverse events than placebo. The patient experts stated that the main concern that women have about treatment for osteoporosis is the duration for which therapies are taken and whether they will experience adverse events over a long period of time. The Committee heard that there may be a risk of infection associated with denosumab treatment, however it accepted evidence from the clinical specialists that this risk was low and that if substantial evidence became available, it may be necessary to assess women with severe infections before considering the use of denosumab. The Committee noted that studies of denosumab for other indications have shown that treatment may be associated with osteonecrosis of the jaw, but it was satisfied with the clinical specialists' views that there was no evidence of this from the clinical studies of denosumab in women with osteoporosis. The clinical specialists confirmed that 14,000 women have received denosumab and that it has been shown to be well tolerated. The Committee concluded that the available clinical evidence on the adverse effects associated with denosumab indicated that it was a well tolerated treatment for the prevention of osteoporotic fragility fractures in postmenopausal women.

Cost effectiveness

4.10 The Committee considered the manufacturer's economic model, and the critique and exploratory sensitivity analyses performed by the ERG. It noted that the manufacturer used a Markov economic model to evaluate the cost effectiveness of denosumab compared with a range of comparators, and that the clinical data were derived from the manufacturer's direct comparison of each comparator with placebo in their random-effects meta-analysis. The Committee considered that the methods used in the analysis were robust. However, the Committee was mindful of the ERG's concerns about a number of aspects of the economic model, such as the long-term effects of fractures on mortality, the setting where denosumab is likely to be given, and the associated administration and monitoring costs modelled.

4.11 The Committee considered the long-term effects of fractures on mortality and the need for nursing home care. It noted that the manufacturer assumed that 30% of the observed mortality for all fracture types is causally related to osteoporotic fracture, and this estimate was varied to 100% in sensitivity analyses. The Committee was aware that the manufacturer's model also assumed that women were at an increased risk of entry into nursing home care following hip fracture and that the lowest cost for private residential care had been applied. The Committee noted that some women may already be in a nursing home, and some may also be self-funding their nursing home care. The Committee concluded that the long-term effects of fractures on mortality and nursing home care may have an impact on the cost-effectiveness estimates for denosumab.

4.12 The Committee discussed the incorporation of health-related quality-of-life benefits and utility values in the economic model. The Committee noted that no significant differences were seen in health-related quality of life between the denosumab and placebo arms of the FREEDOM trial. The Committee heard from the ERG that the number of fracture events with associated EQ-5D scores was low and that there was insufficient information for cross-checking. The ERG stated that omission of the FREEDOM trial EQ 5D data from the economic analysis was justified given the quality and depth of the manufacturer's systematic review of health-related quality-of-life data. The Committee was persuaded that the manufacturer's approach to modelling health-related quality of life was acceptable.

4.13 The Committee considered the key drivers of cost effectiveness and noted that alterations to most key parameters in the manufacturer's sensitivity analyses had limited impact on comparisons of denosumab with raloxifene, strontium ranelate and no treatment. Comparisons with ibandronate, zoledronate and teriparatide were most sensitive to changes in the assumptions about the cost of administering denosumab. When the manufacturer increased the cost of administering denosumab (by assuming that it would be delivered in secondary care), this increased the ICER for denosumab compared with no treatment from £29,200 to £36,200 per QALY gained for primary prevention, and from £12,400 to £15,700 per QALY gained for secondary prevention. The Committee noted that given the similar cost and efficacy of denosumab and zoledronate, changes to this assumption also resulted in zoledronate dominating denosumab for both primary and secondary prevention. However, the Committee was mindful that, although licensed for treatment of osteoporotic fragility fractures, the cost effectiveness of zoledronate has not been appraised by NICE. The Committee concluded that with the exception of administration costs for denosumab, alterations to most key parameters had limited impact on comparisons between denosumab and the primary and secondary comparators.

4.14 The Committee noted the ERG's view that administration of denosumab may not be provided in primary care. However, the clinical specialists stated that there is no reason why denosumab should only be used in secondary care. The clinical specialists highlighted that because denosumab is a new biological agent they expected that treatment would be started in secondary care, but with follow-up in primary care (except for women with severe osteoporosis, who would be followed up in secondary care in accordance with current UK clinical practice). The Committee discussed whether the administration of denosumab would be part of general medical services or whether it would be regarded as an enhanced service for which an additional payment would be negotiated. The clinical specialists stated that women would not need to go through a screening process before starting treatment with denosumab, and that women receiving denosumab are not likely to be at high risk of side effects and so follow-up in secondary care would not be necessary. The clinical specialists also stated that although denosumab is a biological agent that also has effects on the immune system, it is specifically targeted for regulating bone cells. The clinical specialists therefore felt that the potential safety concerns associated with other biological agents (such as anti-tumour necrosis factors) may not be applicable to denosumab. The clinical specialists stated that because treatment with denosumab would not involve substantial additional activities to standard practice for the management of osteoporosis, it is likely that it would be provided as part of general medical services. The Committee concluded that it is likely that treatment with denosumab will be started in secondary care and subsequently delivered in primary care, but with follow-up of women with severe osteoporosis in secondary care in accordance with current UK clinical practice.

4.15 The Committee accepted that the most likely cost-effectiveness estimates would lie between the manufacturer's base case (using primary care assumptions) and the ERG's additional analyses (using secondary care assumptions), and that the most plausible ICERs were likely to be closer to the manufacturer's base case estimates, given that care would mostly be in the primary setting.

4.16 The Committee noted that for the primary prevention of osteoporotic fragility fractures, denosumab dominated strontium ranelate in the manufacturer's base case, and the ICER was £15,900 per QALY gained for denosumab compared with strontium ranelate in the ERG's additional analyses (assuming denosumab is always given in secondary care). The Committee noted that in NICE technology appraisal guidance 160, strontium ranelate is recommended for postmenopausal women:

  • who are unable to comply with the special instructions for the administration of alendronate and either risedronate or etidronate, or have a contraindication to or are intolerant of alendronate and either risedronate or etidronate and
  • who also have a combination of T-score, age and number of independent clinical risk factors for fracture (parental history of hip fracture, alcohol intake of 4 or more units per day, and rheumatoid arthritis) is as indicated in the following table.
  T-scores (SD) at (or below) which strontium ranelate is recommended when alendronate and either risedronate or etidronate cannot be taken
Age (years) 0 1 2
65-69 -a -4.5 -4.0
70-74 -4.5 -4.0 -3.5
75 or older -4.0 -4.0 -3.0

a Treatment with denosumab is not recommended

The Committee concluded that for the primary prevention of osteoporotic fragility fractures, denosumab was a cost-effective use of NHS resources as a treatment option only for postmenopausal women at increased risk of fractures for whom oral bisphosphonates are unsuitable (as described above), and who have the same level of fracture risk as described in the recommendations of NICE technology appraisal 160 for strontium ranelate.

4.17 The Committee was aware that for women for whom oral bisphosphonates are unsuitable and who do not currently fulfil the criteria for treatment with strontium ranelate, there is no treatment currently recommended by NICE for the primary prevention of osteoporotic fragility fractures. The Committee noted that the ICER for denosumab compared with no treatment was £29,200 per QALY gained in the manufacturer's base-case analysis, and this increased to £40,600 per QALY gained in the ERG's additional analyses. It concluded that the ICER for base case population (women [70 years and over] with osteoporosis [T-score of -2.5 SD or below]) for denosumab compared with no treatment was likely to lie within this range. The Committee explored the results for subgroups of women at higher risk by age and T-score, for whom oral bisphosphonates are unsuitable (as described above) and in circumstances where none of the treatments that have been appraised by NICE are recommended. The ICERs for denosumab compared with no treatment from the manufacturers model varied between £19,300 and £71,300 per QALY gained. The Committee agreed that the most plausible ICERs were likely to be higher, based on the ERGs amended assumptions. Taking into account the uncertainties around the long-term effects of fractures on mortality and nursing home care, and the setting where denosumab is likely to be given, the Committee concluded that denosumab was not a cost-effective use of NHS resources for women for whom oral bisphosphonates are unsuitable and where none of the treatments that have been appraised by NICE are recommended.

4.18 For the secondary prevention of osteoporotic fragility fractures, the Committee noted that the ICER for denosumab compared with no treatment in women for whom oral bisphosphonates are unsuitable was £12,400 per QALY gained in the manufacturer's base-case analysis, which increased to £17,900 per QALY gained in the ERG's additional analyses. Denosumab dominated raloxifene or had an ICER of £2000 per QALY gained in the manufacturer's base-case analysis, which increased to £12,200 per QALY gained in the ERG's additional analyses. The cost effectiveness results for denosumab compared with strontium ranelate ranged from strontium ranelate being dominated by denosumab in the manufacturer's base-case analysis to an ICER of £6600 per QALY gained in the ERG's additional analyses. The Committee also noted the results of the subgroup analysis by age and T-score for women for whom bisphosphonates are unsuitable (as described above) and in circumstances where none of the treatments that have been appraised by NICE are recommended, in which the ICER for denosumab compared with no treatment varied between £12,289 and £22,957 per QALY gained. The Committee concluded that treatment with denosumab was a cost-effective use of NHS resources for the secondary prevention of osteoporotic fragility fractures in women for whom oral bisphosphonates are unsuitable.

4.19 The Committee noted that teriparatide is recommended in NICE technology appraisal guidance 161 as a treatment option for the secondary prevention of osteoporotic fragility fractures in women with severe osteoporosis for whom oral bisphosphonates and strontium ranelate are unsuitable. The Committee noted that in the manufacturer's base case analysis, denosumab was slightly less effective and much less costly than teriparatide. Therefore the Committee concluded that denosumab may provide an alternative treatment option that would be a cost-effective use of NHS resources for women who are eligible for treatment with teriparatide as defined in NICE technology appraisal guidance 161.

Summary of Appraisal Committee's key conclusions

TAXXX

(STA)

Appraisal Title: Denosumab for the prevention of osteoporotic fractures in postmenopausal women ACD section
Key conclusions

Denosumab is recommended as a treatment option for the primary prevention of osteoporotic fragility fractures only in postmenopausal women at increased risk of fractures:

  • who are unable to comply with the special instructions for the administration of oral bisphosphonates, are intolerant of oral bisphosphonates or for whom treatment with oral bisphosphonates is contraindicated and
  • who also have a combination of T-score 2, age and number of independent clinical risk factors for fracture (see section 1.3) is as indicated in the following table.
  T-scores (SD) at (or below) which denosumab is recommended when oral bisphosphonates are unsuitable
Age (years) 0 1 2
65-69 -a -4.5 -4.0
70-74 -4.5 -4.0 -3.5
75 or older -4.0 -4.0 -3.0

a Treatment with denosumab is not recommended

Denosumab is recommended as a treatment option for the secondary prevention of osteoporotic fragility fractures only in postmenopausal women at increased risk of fractures:

  • who are unable to comply with the special instructions for the administration of oral bisphosphonates, are intolerant of oral bisphosphonates or for whom treatment with oral bisphosphonates is contraindicated

For the purposes of this guidance, independent clinical risk factors for fracture are parental history of hip fracture, alcohol intake of 4 or more units per day, and rheumatoid arthritis.


The Committee accepted that there was good quality evidence to support the clinical effectiveness of denosumab compared with placebo and that denosumab would be a clinically effective alternative to existing treatment options for the prevention of osteoporotic fragility fractures in postmenopausal women.


The Committee concluded that denosumab was a cost effective use of NHS resources only in postmenopausal women at increased risk of fractures for whom oral bisphosphonates are unsuitable, and who have the same level of fracture risk as described in the recommendations of NICE technology appraisal 160 for strontium ranelate.

The Committee concluded that treatment with denosumab was a cost-effective use of NHS resources for the secondary prevention of osteoporotic fragility fractures in postmenopausal women at increased risk of fractures for whom oral bisphosphonates are unsuitable.


1.1
Current practice
Clinical need of patients
including the availability of alternative treatments

The main aim of primary prevention is the opportunistic identification of postmenopausal women who are at risk of osteoporotic fragility fractures, and the aim of secondary prevention is to provide the most effective treatment for women who have already had an osteoporotic fragility fracture and are at risk of further fractures.


The Committee accepted that current UK clinical practice is to start treatment with oral bisphosphonates, but that these are not suitable for all women (reasons for unsuitability are that the woman is unable to comply with the special instructions for the administration of bisphosphonates, or has a contraindication to or is intolerant of bisphosphonates). Women for whom oral bisphosphonates are unsuitable receive either no treatment or strontium ranelate for primary prevention (as set out in NICE technology appraisal guidance 160), or strontium ranelate or raloxifene for secondary prevention (as set out in NICE technology appraisal guidance 161). Treatment usually takes place in primary care (both strontium ranelate and raloxifene are given in primary care). Women who have severe osteoporosis may receive more potent agents such as zoledronate or intravenous ibandronate.


The Committee also noted that zoledronate is sometimes used in secondary care for the prevention of fractures, and that teriparatide is also used for secondary prevention when women are unable to take other therapies.

4.2

4.3

4.3

The technology

Proposed benefits of the technology

How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits

The Committee considered that a treatment that is administered by subcutaneous injection once every 6 months, such as denosumab, offers an advantage because it may improve adherence with therapy, particularly for women who have problems swallowing or standing to take oral bisphosphonates.

The Committee noted that denosumab is a monoclonal antibody that reduces osteoclast activity and hence reduces bone breakdown. It also heard from the clinical specialists that it is the first drug of its class, and that its biological mechanism of action results in targeted therapy with fewer adverse events than other treatments.

4.5
What is the position of the treatment in the pathway of care for the condition The Committee noted that the manufacturer's decision problem focused on postmenopausal women diagnosed with osteoporosis for whom oral bisphosphonates are unsuitable, and that the manufacturer stated that denosumab was not expected to compete with oral bisphosphonates in clinical practice, given the wide availability of generic bisphosphonates in the UK. The Committee also noted that manufacturer did provide an analysis of denosumab compared with oral bisphosphonates for completeness. It accepted that is was reasonable to base its considerations on women for whom oral bisphosphonates are unsuitable and the subsequent discussion focussed on this population only. 4.4
Adverse effects The Committee heard that there may be a risk of infection associated with denosumab treatment, however it accepted evidence from the clinical specialists that this risk was low and that if substantial evidence became available, it may be necessary to assess women with severe infections before considering the use of denosumab.
The Committee concluded that the available clinical evidence on the adverse effects associated with denosumab indicated that it was a well tolerated treatment for the prevention of osteoporotic fragility fractures in postmenopausal women.
4.9
Evidence for clinical effectiveness
Availability, nature and quality of evidence The Committee considered that the clinical effectiveness evidence presented in the manufacturer's submission was derived from a large, high-quality trial of adequate duration (FREEDOM). As the FREEDOM study did not provide a head-to-head comparison of denosumab against all relevant comparators, the manufacturer carried out a random-effects meta-analysis to obtain direct estimates for each treatment compared with placebo. 4.6
Relevance to general clinical practice in the NHS The Committee accepted that denosumab is not expected to compete with oral bisphosphonates in clinical practice, given the wide availability of generic bisphosphonates in the UK as stated by the manufacturer. 4.4
Uncertainties generated by the evidence

There was no head-to-head clinical trial evidence comparing denosumab with active relevant comparators (the comparator in the FREEDOM trial was placebo). The manufacturer carried out a random-effects meta-analysis to obtain direct estimates for each treatment compared with placebo. The Committee accepted the methods used in the meta-analysis as sufficiently robust for use in the economic analysis.

The Committee heard that there may be a risk of infection associated with denosumab treatment, however it accepted evidence from the clinical specialists that this risk was low and that if substantial evidence became available, it may be necessary to assess women with severe infections before considering the use of denosumab.

4.6 & 4.8

4.9

Are there any clinically relevant subgroups for which there is evidence of differential effectiveness Subgroups by T-score, age and clinical risk factors were explored in the economic model and considered by the Appraisal Committee - see below. 4.17 & 4.18
Estimate of the size of the clinical effectiveness including strength of supporting evidence

The Committee concluded that the evidence from the FREEDOM trial demonstrated that denosumab was effective in reducing the risk of fracture in postmenopausal women compared with placebo.
The Committee discussed the meta-analysis that was undertaken by the manufacturer to obtain direct estimates for each treatment compared with placebo. The Committee concluded that the methods used in the meta-analysis were sufficiently robust for use in the economic analysis.


The Committee accepted that there was good evidence to support the clinical effectiveness of denosumab compared with placebo and that denosumab it would be a clinically effective alternative to existing treatment options for the prevention of osteoporotic fragility fractures in postmenopausal women.

For details of treatment effect size see relative risks reported in the ACD sections 3.3, 3.6 and 4.7.

4.6

4.8

4.19

Evidence for cost effectiveness
Availability and nature of evidence The Committee noted that the manufacturer used a Markov economic model to evaluate the cost effectiveness of denosumab compared with a range of comparators (split into primary and secondary comparators). The clinical data were derived from the manufacturer's direct comparison of each comparator with placebo from their random-effects meta-analysis. 4.10
Uncertainties around and plausibility of assumptions and inputs in the economic model

The Committee was mindful of the ERG's concerns around a number of aspects of the economic model, such as the long term effects of fractures and nursing home care, the setting where denosumab is likely to be given and the associated administration and monitoring costs modelled.

The Committee concluded that the long term effects of fractures on mortality and nursing home care did not have a substantial impact on the cost effectiveness estimates for denosumab.

The Committee concluded that with the exception of administration costs for denosumab, alterations to most key parameters had limited impact on comparisons between densumab and the primary and secondary comparators.

4.10

4.11

4.13

Incorporation of health-related quality of life benefits and utility values

Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?

The Committee noted that no significant differences were seen in health-related quality of life between the denosumab and placebo arms of FREEDOM.

The ERG stated that omission of the EQ-5D data from FREEDOM was justified given the quality and depth of the manufacturer's systematic review of health-related quality of life data. The Committee was persuaded that the manufacturer's approach to modelling health-related quality of life was acceptable.

4.12
Are there specific groups of people for whom the technology is particularly cost-effective?

The Committee noted that for the primary prevention of osteoporotic fragility fractures, denosumab dominated strontium ranelate in the manufacturer's base case, and the ICER was £15,900 per QALY gained for denosumab compared with strontium ranelate in the ERG's additional analyses (assuming denosumab is always given in secondary care). The Committee noted that in NICE technology appraisal guidance 160, strontium ranelate is recommended for postmenopausal women:

  • who are unable to comply with the special instructions for the administration of alendronate and either risedronate or etidronate, or have a contraindication to or are intolerant of alendronate and either risedronate or etidronate and
  • who also have a combination of T-score, age and number of independent clinical risk factors for fracture (parental history of hip fracture, alcohol intake of 4 or more units per day, and rheumatoid arthritis) is as indicated in the following table.

The Committee concluded that for the primary prevention of osteoporotic fragility fractures, denosumab was a cost-effective use of NHS resources as a treatment option only for postmenopausal women at increased risk of fractures for whom oral bisphosphonates are unsuitable (as described above), and who have the same level of fracture risk as described in the recommendations of NICE technology appraisal 160 for strontium ranelate.

For the secondary prevention of osteoporotic fragility fractures, the Committee also noted the results of the subgroup analysis by age and T-score, for women for whom bisphosphonates are unsuitable (as described above) and in circumstances where none of the treatments that have been appraised by NICE are recommended, in which the ICER for denosumab compared with no treatment varied between £12,289 and £22,957 per QALY gained. The Committee concluded that treatment with denosumab was considered to be a cost-effective use of NHS resources for the secondary prevention of osteoporotic fragility fractures in women for whom oral bisphosphonates are unsuitable.

4.16

4.18

What are the key drivers of cost effectiveness? The Committee concluded that with the exception of administration costs for denosumab, alterations to most key parameters had limited impact on comparisons between denosumab and the primary and secondary comparators. 4.13
Most likely cost-effectiveness estimate (given as an ICER)

The Committee accepted that the most likely cost-effectiveness estimates would lie between the manufacturer's base case (using primary care assumptions) and the ERG's additional analyses (using secondary care assumptions), and that the most plausible ICERs were likely to be closer to the manufacturer's base case estimates, given that care would mostly be in the primary setting.

The Committee noted that for the primary prevention of osteoporotic fragility fractures, denosumab dominated strontium ranelate in the manufacturer's base case, and the ICER was £15,900 per QALY gained for denosumab compared with strontium ranelate in the ERG's additional analyses (assuming denosumab is always given in secondary care). The Committee concluded that for the primary prevention of osteoporotic fragility fractures, denosumab was a cost-effective use of NHS resources as a treatment option only for postmenopausal women at increased risk of fractures for whom oral bisphosphonates are unsuitable (as described above), and who have the same level of fracture risk as described in the recommendations of NICE technology appraisal 160 for strontium ranelate.

The Committee was aware that for women for whom oral bisphosphonates are unsuitable and who do not currently fulfil the criteria for treatment with strontium ranelate, there is no treatment currently recommended by NICE for the primary prevention of osteoporotic fragility fractures. The Committee noted that the ICER for denosumab compared with no treatment was £29,200 per QALY gained in the manufacturer's base-case analysis, and this increased to £40,600 per QALY gained in the ERG's additional analyses. It concluded that the ICER for base case population (women [70 years and over] with osteoporosis [T-score of ?2.5 SD or below]) for denosumab compared with no treatment was likely to lie within this range.

For the secondary prevention of osteoporotic fragility fractures, the Committee noted that the ICER for denosumab compared with no treatment in women for whom oral bisphosphonates are unsuitable was £12,400 per QALY gained in the manufacturer's base-case analysis, which increased to £17,900 per QALY gained in the ERG's additional analyses. Denosumab dominated raloxifene or had an ICER of £2000 per QALY gained (age 70, T-score -2.5) in the manufacturer's base-case analysis, which increased to £12,200 per QALY gained in the ERG's additional analyses. The ICER for denosumab compared with strontium ranelate ranged from strontium ranelate being dominated by denosumab in the manufacturer's base-case analysis to £6600 per QALY gained in the ERG's additional analyses. The Committee concluded that treatment with denosumab was considered to be a cost-effective use of NHS resources for the secondary prevention of osteoporotic fragility fractures in women for whom oral bisphosphonates are unsuitable.

The Committee noted that in the manufacturer's base case analysis, denosumab was slightly less effective and much less costly than teriparatide. Therefore the Committee concluded that denosumab may provide an alternative treatment option that would be a

cost-effective use of NHS resources for women who are eligible for treatment with teriparatide as defined in NICE technology appraisal guidance 161.

4.15

4.16

4.17

4.18

4.19

Additional factors taken into account
Patient Access Schemes
(PPRS)
Not applicable. No patient access scheme was submitted.  
End of life considerations Not applicable to this disease area.  
Equalities considerations, SVJ Not applicable. The Committee noted that no equalities issues were raised during the scoping workshop or during the appraisal.  

Implementation

5.1 The Secretary of State and the Welsh Assembly Minister for Health and Social Services have issued directions to the NHS on implementing NICE technology appraisal guidance. When a NICE technology appraisal recommends use of a drug or treatment, or other technology, the NHS must provide funding and resources for it within 3 months of the guidance being published. If the Department of Health issues a variation to the 3-month funding direction, details will be available on the NICE website. The NHS is not required to fund treatments that are not recommended by NICE.

5.2 NICE has developed tools to help organisations put this guidance into practice (listed below). These are available on our website (www.nice.org.uk/guidance/TAXXX). [NICE to amend list as needed at time of publication]

  • Slides highlighting key messages for local discussion.
  • Costing report and costing template to estimate the savings and costs associated with implementation.
  • Implementation advice on how to put the guidance into practice and national initiatives that support this locally.
  • A costing statement explaining the resource impact of this guidance.

Audit support for monitoring local practice.

Related NICE guidance

Published

  • Alendronate, etidronate, risedronate, raloxifene and strontium ranelate for the primary prevention of osteoporotic fragility fractures in postmenopausal women (amended). NICE technology appraisal guidance 160 (2008; amended 2010). Available from www.nice.org.uk/guidance/TA160
  • Alendronate, etidronate, risedronate, raloxifene, strontium ranelate and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women (amended). NICE technology appraisal guidance 161 (2008; amended 2010). Available from www.nice.org.uk/guidance/TA161

Under development
NICE is developing the following guidance (details available from www.nice.org.uk):

  • Osteoporosis: assessment of fracture risk and the prevention of osteoporotic fractures in individuals at high risk. NICE clinical guideline (publication date to be confirmed).

Proposed date for review of guidance

7.1 NICE proposes that the guidance on this technology is considered for review by the Guidance Executive in June 2013. NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.

Peter Clark
Chair, Appraisal Committee
June 2010

Appendix A: Appraisal Committee members and NICE project team

A Appraisal Committee members

The Appraisal Committees are standing advisory committees of NICE. Members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. There are four Appraisal Committees, each with a chair and vice chair. Each Appraisal Committee meets once a month, except in December when there are no meetings. Each Committee considers its own list of technologies, and ongoing topics are not moved between Committees.

Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.

The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website.

Dr Darren Ashcroft
Senior Clinical Lecturer, School of Pharmacy and Pharmaceutical Sciences, University of Manchester

Dr Matthew Bradley
Value Demonstration Director, AstraZeneca

Professor Usha Chakravarthy
Professor of Ophthalmology and Vision Sciences, The Queen's University of Belfast

Professor Peter Clark (Chair)
Consultant Medical Oncologist, Clatterbridge Centre for Oncology

Dr Ian Davidson
Lecturer in Rehabilitation, University of Manchester

Professor Simon Dixon
Professor of Health Economics, University of Sheffield

Dr Martin Duerden
Medical Director, Conwy Local Health Board

Dr Alexander Dyker
Consultant Physician, Wolfson Unit of Clinical Pharmacology

Dr Jon Fear
Consultant in Public Health Medicine, Head of Healthcare Effectiveness NHS Leeds

Dr Kevin Hardy
Consultant Physician, St Helens & Knowsley Teaching Hospitals NHS Trust

Professor John Hutton
Professor of Health Economics, University of York

Dr Steven Julious
Senior Lecturer in Medical Statistics, University of Sheffield

Professor Jonathan Michaels (Vice Chair)
Professor of Vascular Surgery, University of Sheffield

Professor Oluwafemi Oyebode
Professor of Psychiatry & Consultant Psychiatrist, The National Centre for Mental Health

Dr Phillip Rutledge
GP and Consultant in Medicines Management, NHS Lothian

Dr Brian Shine
Consultant Chemical Pathologist, John Radcliffe Hospital

Mr Paddy Storrie
Lay member

Dr Cathryn Patricia Thomas
GP and Associate Professor, University of Birmingham

Mr Mike Wallace
Health Economics & Reimbursement Director, Johnson & Johnson Medical Ltd

Dr Lok Yap
Consultant in Acute Medicine & Clinical Pharmacology, Whittington Hospitals NHS Trust


B NICE project team

Each technology appraisal is assigned to a team consisting of one or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.

Fay McCracken
Technical Lead

Helen Knight
Technical Adviser

Kate Moore
Project Manager


Appendix B: Sources of evidence considered by the Committee

The Evidence Review Group (ERG) report for this appraisal was prepared by the Aberdeen Health Technology Assessment Group:
Scotland G, Royle P, Henderson R et al. Evidence review: denosumab for the prevention of osteoporotic fractures in post-menopausal women (March 2010)

The following organisations accepted the invitation to participate in this appraisal as consultees and commentators. They were invited to comment on the draft scope, the ERG report and the appraisal consultation document (ACD). Organisations listed in I were also invited to make written submissions. Organisations listed in II and III had the opportunity to give their expert views. Organisations listed in I, II and III also have the opportunity to appeal against the final appraisal determination.

Manufacturer/sponsor:

  • Amgen

Professional/specialist and patient/carer groups:

  • British Health Professionals in Rheumatology
  • British Society for Rheumatology
  • National Osteoporosis Society
  • Primary Care Rheumatology Society
  • Royal College of Nursing
  • Royal College of Pathologists
  • Royal College of Physicians
  • Royal College of Radiographers
  • Society for Endocrinology

Other consultees:

  • Coventry Teaching PCT
  • Department of Health
  • NHS North Somerset
  • Welsh Assembly Government


Commentator organisations (did not provide written evidence and without the right of appeal):

  • National Institute for Health Research Health Technology Assessment Programme
  • NHS Quality Improvement Scotland
  • Novartis
  • Pfizer
  • Roche
  • Servier


The following individuals were selected from clinical specialist and patient expert nominations from the non-manufacturer/sponsor consultees and commentators. They gave their expert personal view on denosumab for the prevention of osteoporotic fractures in postmenopausal women by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

  • Professor Roger Francis, Professor of Geriatric Medicine, nominated by the National Osteoporosis Society - clinical specialist
  • Professor Jon Tobias, Professor of Rheumatology and Honorary Consultant Rheumatologist, nominated by the British Society for Rheumatology - clinical specialist
  • Niki Gonty, nominated by National Osteoporosis Society - patient expert
  • Angela White, nominated by the National Osteoporosis Society - patient expert


Representatives from the following manufacturer attended Committee Meetings. They contributed only when asked by the Committee chair to clarify specific issues and comment on factual accuracy.

  • Amgen


This page was last updated: 12 July 2010