Osteoporosis - primary prevention: Appraisal consultation document
NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE
Appraisal Consultation Document
Alendronate, etidronate, risedronate, raloxifene and strontium ranelate for the primary prevention of osteoporotic fragility fractures in postmenopausal women
The Department of Health and the National Assembly for Wales have asked the National Institute for Health and Clinical Excellence (NICE or the Institute) to conduct an appraisal of alendronate, etidronate, risedronate, raloxifene and strontium ranelate for the primary prevention of osteoporotic fragility fractures in postmenopausal women and provide guidance on their use to the NHS in England and Wales. The Appraisal Committee has had its first meeting to consider both the evidence submitted and the views put forward by the representatives nominated for this appraisal by professional organisations and patient/carer and service user organisations. The Committee has developed preliminary recommendations on the use of alendronate, etidronate, risedronate, raloxifene and strontium ranelate for the primary prevention of osteoporotic fragility fractures in postmenopausal women.
This document has been prepared for consultation with the formal consultees. It summarises the evidence and views that have been considered and sets out the preliminary recommendations developed by the Committee. The Institute is now inviting comments from the formal consultees in the appraisal process (the consultees for this appraisal are listed on the NICE website, www.nice.org.uk).
Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in section 1 are preliminary and may change after consultation.
The process the Institute will follow after the consultation period is summarised below. For further details, see the Guide to the Technology Appraisal Process (this document is available on the Institute’s website, www.nice.org.uk).
The key dates for this appraisal are:
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.
Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in Section 1 are preliminary and may change after consultation.
|1||Appraisal Committee's preliminary recommendations|
This guidance covers the use of a lendronate, etidronate, risedronate, raloxifene and strontium ranelate for the primary prevention of osteoporotic fragility fractures in postmenopausal women who have osteoporosis, but who have not sustained a clinically apparent osteoporotic fracture.
This guidance covers the treatment of postmenopausal women who have normal levels of calcium and vitamin D. Unless clinicians are confident that women who receive osteoporosis treatment have an adequate calcium intake and are vitamin D replete, calcium and/or vitamin D supplementation should be considered.
This guidance does not cover women who are on long-term systemic corticosteroid therapy.
T-score relates to the measurement of bone mineral density (BMD) using dual energy X-ray absorptiometry (DXA) scanning at the neck of the femur (‘femoral neck’). The T-score is expressed as the number of standard deviations [SDs] from the BMD in an average 25-year-old woman.
|1.1||Alendronate is recommended for the primary prevention of osteoporotic fragility fractures in women aged 75 years or older, who are identified as having one or more clinical risk factors (see section 1.6) and confirmed as having a T-score of -2.5 SD or below. When the decision has been made to initiate treatment with alendronate, it should be prescribed on the basis of the lowest acquisition cost|
|1.2||Etidronate is recommended as an alternative treatment option under the circumstances specified in section 1.1.|
Risedronate is recommended as an alternative treatment option in women aged 75 years or older who are identified as having one or more clinical risk factors (see section 1.6) and confirmed as having a T-score of -3 SD or below and:
Strontiu Strontium ranelate is recommended as an alternative treatment option for women aged 75 years or older who are identified as having one or more clinical risk factors (see section 1.6) and confirmed as having T-score of -4 SD or below and:
|1.5||Raloxifene is not recommended as a treatment option for the primary prevention of osteoporotic fractures.|
|1.6||For the purpose of this guidance, clinical risk factors to be considered for case finding for the primary prevention of osteoporotic fractures are: parental history of hip fracture; low body mass index (defined as less than 22 kg/m2); alcohol intake of more than 3 units per day; and medical conditions associated with low bone mineral density.|
|1.7||For the purpose of this guidance, intolerance of bisphosphonates is defined as persistent upper gastrointestinal disturbance that is sufficiently severe to warrant discontinuation of treatment with a bisphosphonate and that occurs even though the instructions for administration have been followed correctly.|
|2||Clinical need and practice|
|2.1||Osteoporosis is a progressive, systemic skeletal disorder characterised by low bone mass and micro-architectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture.|
|2.2||Bone formation exceeds bone resorption in youth, but by the third decade of life there is a gradual loss of bone mass. Osteoporosis is therefore usually an age-related disease. It can affect both sexes, but women are at greater risk because bone loss is accelerated, to a variable degree, after the menopause because of a decrease in oestrogen production.|
Diagnosis of osteoporosis is based on the measurement of BMD, with reference to the number of standard deviations (T-score) from the BMD in an average 25-year-old woman:
|2.4||T-score measurements vary by site and method. It has been recommended that BMD should be measured at the femoral neck using DXA to estimate fracture risk.|
It has frequently been quoted that over 2 million women have osteoporosis (that is, have a T-score of -2.5 or below) in England and Wales. However, recent epidemiological data based on a UK sample indicate that this figure may be closer to 1.1 million. Osteoporosis is most common in older white women. Prevalence of osteoporosis increases markedly with age after the menopause, from approximately 2% at 50 years of age rising to over 25% at 80 years.
|2.6||Fragility fracture is the clinically apparent and relevant outcome in osteoporosis (referred to as ‘fracture’ or ‘osteoporotic fracture’ in the following). In the absence of fracture the condition is asymptomatic and often remains undiagnosed. Osteoporotic fractures occur most commonly in the vertebrae, hip and wrist, and are associated with substantial disability, pain and reduced quality of life.|
|2.7||In women aged over 50 years, the lifetime risk of a vertebral fracture is estimated to be one in three, and one in five for hip fracture. Postmenopausal women with an initial fracture are at substantially greater risk of subsequent fractures. For instance, a woman with a vertebral fracture has an increased relative risk (RR) of 4.4 for a further vertebral fracture, 2.3 for a hip fracture, and 1.4 for a wrist fracture.|
|2.8||It is estimated that annually there are 180,000 osteoporosis-related symptomatic fractures in
|2.9||After a hip fracture, a high proportion of women are permanently unable to walk independently or perform other activities of daily living and, consequently, many are unable to live independently. Hip fractures are also associated with increased mortality; estimates of the relative mortality risk vary from 2 to greater than 10 in the 12 months following hip fracture. However, it is unclear to what the extent this can be attributed to fracture alone as opposed to pre-existing comorbidity.|
|2.10||Vertebral fractures are associated with loss of height and curvature of the spine and result in pain, breathing difficulties, gastrointestinal problems and difficulties performing activities of daily living. It is thought that the majority of vertebral fractures (50–70%) do not come to clinical attention. Vertebral fractures are also associated with increased mortality; UK-specific data indicate a 4.4-fold increase in mortality due to vertebral fractures. However, as with hip fractures, it is unclear to what extent this may be due to comorbidities.|
|2.11||In addition to increasing age and low BMD, other clinical factors have been associated with an increased fracture risk, such as prior fracture, parental history of hip fracture; low body mass index (in the absence of knowledge about BMD and defined as less than 22 kg/m2); alcohol intake of more than 3 units per day; long-term systemic use of corticosteroids; and medical conditions associated with low BMD. These include rheumatoid arthritis, coeliac disease, chronic inflammatory bowel disease, ankylosing spondylitis, hyperthyroidism, hypogonadism, hypopituitarism, anorexia nervosa, organ transplant, chronic obstructive pulmonary disease, type 1 diabetes, untreated premature menopause and conditions associated with prolonged immobility. A full review of risk factors associated with osteoporotic fracture has been carried out for the development of the NICE Clinical Guideline ‘Osteoporosis: assessment of fracture risk and the prevention of osteoporotic fractures in individuals at high risk’|
|2.12||Under the auspices of the World Health Organization (WHO), an algorithm is currently being developed that quantifies the absolute risk of osteoporotic fracture on the basis of risk factors.|
|Bisphosphonates: alendronate, etidronate, risedronate|
Bisphosphonates are inhibitors of bone resorption and increase BMD by altering osteoclast activation and function. Alendronate, etidronate and risedronate are licensed in the
|3.2||Alendronate is an oral bisphosphonate licensed as a once-weekly preparation (70 mg) for the treatment of postmenopausal osteoporosis. It is also licensed in the
|3.3||Etidronate (Procter & Gamble Pharmaceuticals UK Ltd) is an oral bisphosphonate licensed in the
|3.4||Risedronate (Procter & Gamble Pharmaceuticals UK Ltd) is an oral bisphosphonate licensed in the
|3.5||Gastrointestinal side effects are common with oral bisphosphonates. In people with oesophageal abnormalities and other factors that delay oesophageal transit or emptying, risedronate should be used cautiously and alendronate is contraindicated. For full details of side effects and contraindications, see the Summaries of Product Characteristics.|
|3.6||Bisphosphonates have relatively complex instructions for administration. Alendronate and risedronate must be taken with 200 ml and 120 ml of water, respectively. Before and immediately after administration patients may not eat or drink, and must remain upright for stipulated time periods. Etidronate should be taken at the midpoint of a 4 hour fast (that is, 2 hours before and 2 hours after food or medication).|
Selective oestrogen receptor modulators (SERMs): raloxifene
SERMs are a class of drugs with selective activity in various organ systems, acting as weak oestrogen receptor agonists in some systems and as oestrogen antagonists in others. The aim of treatment with SERMs is to maximise the beneficial effects of oestrogen on bone and to minimise the adverse effects on the breast and endometrium.
Raloxifene(Eli Lilly and Company Ltd) is the only SERM licensed for the treatment of osteoporosis in postmenopausal women. The recommended dose is 60 mg/day. The prices of 28- and 84-tablet packs are £19.86 and £59.59, respectively (excluding VAT; BNF 51), which equates to £258.89 per annum. Costs may vary in different settings because of negotiated procurement discounts.
Raloxifene is contraindicated in people with a history of venous thromboembolism (VTE), hepatic impairment, cholestasis, severe renal impairment, undiagnosed uterine bleeding, and endometrial cancer. Raloxifene should not be co‑administered with systemic oestrogens and, in patients with breast cancer, it should not be used for osteoporosis treatment and prevention until treatment of the breast cancer, including adjuvant therapy, has been completed. Raloxifene is associated with an increased risk of venous thromboembolic events, particularly during the first 4 months of treatment, which is similar to the reported risk associated with hormone replacement therapy. For full details of side effects and contraindications, see the Summary of Product Characteristics.
Strontium ranelate (Servier Laboratories Ltd) is composed of two atoms of stable strontium (an element with properties similar to calcium) and one molecule of ranelic acid. It is thought to have a dual effect on bone metabolism, increasing bone formation and decreasing bone resorption. It is licensed for the treatment of postmenopausal osteoporosis to reduce the risk of vertebral and hip fractures. The recommended dose is one 2 g sachet/day, taken as a suspension in water. The price of a 28-sachet pack is £25.60 (excluding VAT; BNF 51), which equates to £333.71 per annum. Costs may vary in different settings because of negotiated procurement discounts.
The absorption of strontium ranelate is reduced by food, milk and derivative products. It should therefore be administered between meals, ideally at bedtime and preferably at least 2 hours after eating.
Strontium ranelate is not recommended in patients with severe renal impairment and should be used with caution in patients at increased risk of VTE. Treatment with strontium ranelate should be discontinued during treatment with oral tetracycline or quinolone antibiotics. For full details of side effects, drug interactions and contraindications, see the Summary of Product Characteristics.
|4||Evidence and interpretation|
|The Appraisal Committee considered evidence from a number of sources (see Appendix B).|
|4.1.1||The Assessment Report reviewed data from published randomised controlled trials (RCTs) in postmenopausal women where fracture or health-related quality of life was an endpoint and where one of the five drugs of interest was compared with a relevant comparator including: no treatment, placebo, or one of the other included interventions. The majority of studies used placebo or no treatment as a control. Most studies ensured that women in all trial arms had normal calcium levels or adequate supplementation, and some studies used additional dietary supplementation with vitamin D.|
|4.1.2||For this appraisal, reductions in RRs associated with treatment were pooled regardless of the baseline BMD and fracture status of the participants in the studies. It was also assumed that these reductions in RR remain constant at all ages, although little evidence was available for the effectiveness of the drugs in women aged 80 years and older.|
|4.1.3||For vertebral fractures, some studies used clinical (that is, symptomatic) fractures as their endpoint while others used fractures that were identified radiographically. Vertebral fractures identified radiographically, which are termed ‘radiographic fractures’ or ‘morphometric fractures’, include both symptomatic and asymptomatic fractures. There are different definitions of a vertebral radiographic fracture, but those definitions that require a 20% reduction in vertebral height are generally recognised as producing more reliable results than those that require a 15% reduction.|
|4.1.4||For non-vertebral fracture types, individual data on hip, leg, pelvis, wrist, hand, foot, rib and humerus were sometimes provided, while some studies only presented data for all non-vertebral fractures grouped together.|
|126.96.36.199||Sixteen RCTs of alendronate in postmenopausal women were included in the Assessment Report: two studies in women with low or normal BMD; one in women with osteopenia; eight in women with osteopenia or osteoporosis; four in women with osteoporosis; and one in women with established osteoporosis. Overall, 15 studies compared alendronate with placebo or with no treatment; and two used active comparators. All the studies were conducted in women who had adequate levels of calcium from dietary intake or were receiving calcium supplementation.|
|188.8.131.52||Two studies, one comparing alendronate with oestrogen or oestrogen/alendronate combined and the other comparing alendronate with teriparatide (licensed only for secondary and not primary prevention), found no statistically significant differences in clinically apparent fractures of any type in women with osteoporosis. However, back pain was reported less frequently by women in the teriparatide group compared with women in the alendronate group (6% versus 19%, p = 0.012).|
|184.108.40.206||In addition to the 16 RCTs, a 2-year study demonstrated the equivalence of weekly and daily doses of alendronate, in terms of clinical fracture incidence and gastrointestinal adverse events. However, this study was not included in the analysis, as it did not have the specified comparators.|
The meta-analysis for alendronate relative to placebo, carried out by the Assessment Group, resulted in an RR of vertebral fracture of 0.56 (95% confidence interval [CI] 0.46 to 0.68, 4 RCTs, n = 7039); an RR of hip fracture of 0.62 (95% CI, 0.40 to 0.98, 3 RCTs, n = 7455), an RR of wrist fracture of 0.67 (95% CI, 0.34 to 1.31, 4 RCTs, n = 7931) and an RR for other non-vertebral fractures of 0.81 (95% CI, 0.68 to 0.97; 6 RCTs, n = 9973).
|220.127.116.11||A post-hoc analysis data from the largest study on alendronate, the FIT RCT (non vertebral fracture population) suggested that alendronate may be less effective at reducing fractures in women with T-scores greater than -2.5 SD. These results for T-scores greater than -2.5 SD were not statistically significant.|
|18.104.22.168||Gastrointestinal adverse events including nausea, dyspepsia, mild oesophagitis/gastritis and abdominal pain were reported in at least one third of the participants in studies of alendronate. However, only one study found the increased frequency of these symptoms to be statistically significant relative to placebo. This is consistent with post-marketing studies indicating that around one-third of alendronate users experience gastrointestinal adverse events. In order to avoid oesophagitis, the Summary of Product Characteristics now recommends that alendronate should be taken, upon rising for the day, with a full glass of water. It is possible that these instructions were not followed in all of the studies, particularly the earlier ones.|
Prescription event monitoring studies in patients prescribed alendronate (n = 11,916) by general practitioners in
These studies lacked a comparator to allow assessment of the extent to which these rates of upper gastrointestinal events may be above a baseline for those not taking bisphosphonates.
|22.214.171.124||One study reported health-related quality of life outcomes. At 12 months there were statistically significant improvements in the alendronate group but not in the control group in scores for pain, social isolation, energy level and physical ability|
Twelve RCTs of etidronate in postmenopausal women were reviewed: three studies in women with low-to-normal BMD; two in women with osteopenia or osteoporosis; one in women with osteoporosis; one in women with osteoporosis or established osteoporosis, and five in women with established osteoporosis. Four studies included active comparators, and eight compared etidronate with placebo or with no treatment (although in six of these, study participants in all arms received calcium, either alone or with vitamin D). Some studies did not use the exact treatment regimen currently licensed in the
|126.96.36.199||The meta-analysis of RCTs for etidronate relative to placebo, carried out by the Assessment Group resulted in an RR of vertebral fracture of 0.40 (95% CI, 0.20 to 0.83, 3 RCTs, n = 341); an RR of hip fracture of 0.50 (95% CI, 0.05 to 5.34, 2 RCTs, n = 180), and an RR for other non-vertebral fractures of 1.04 (95% CI, 0.64 to 1.69; 4 RCTs, n = 410). There were no data for wrist fracture.|
An observational study in a general practice setting in the
|188.8.131.52||Higher rates of gastrointestinal adverse effects were found in the etidronate groups of four RCTs, although the differences were not always statistically significant. However, non-RCT evidence and testimonies from clinical experts and patient experts suggested that etidronate may be associated with fewer gastrointestinal adverse effects than are other bisphosphonates.|
The systematic review carried out by the NICE decision support Unit (DSU 2006) identified a cohort study conducted in the
|Seven RCTs of risedronate in postmenopausal women were reviewed: one study in women with normal BMD; one in women with osteopenia; one in women with osteopenia or osteoporosis; one in women with osteoporosis or specific risk factors for hip fracture such as a recent fall; and three in women with established osteoporosis. All compared risedronate with placebo (although, with the exception of those in the normal BMD study, all women also received calcium) and none reported on health-related quality of life.|
The meta-analysis for risedronate relative to placebo, carried out by the Assessment Group resulted in an RR of vertebral fracture of 0.61 (95% CI , 0.50 to 0.75, 3 RCTs, n = 2301); an RR of hip fracture of 0.74 (95% CI, 0.59 to 0.93, 3 RCTs, n = 11,770), an RR of wrist fracture of 0.68 (95% CI, 0.43 to 1.08, 2 RCTs, n = 2439) and an RR for other non-vertebral fractures of 0.76 (95% CI, 0.64 to 0.91; 5 RCTs, n = 12,399).
|184.108.40.206||Overall and gastrointestinal adverse events were similar in the risedronate and placebo groups in all of the studies.|
|220.127.116.11||Prescription event monitoring studies in patients (n = 13,643) prescribed risedronate suggested a high incidence of dyspepsia, particularly in the first month of treatment. Consultations for dyspepsia ranged from 26.9 per 1000 patient months in the first month of treatment to 8.1 per 1000 patient months in months 2 through 6.|
|4.1.8||Alendronate and risedronate: meta-analysis|
Pooled analysis of data from alendronate and risedronate studies, carried out by the DSU (2006), resulted in a RR of vertebral fracture of 0.58 (95% CI , 0.51 to 0.67, 7 RCTs, n = 9340); an RR of hip fracture of 0.71 (95% CI , 0.58 to 0.87, 6 RCTs, n = 19,233, an RR of wrist fracture of 0.69 (95% CI , 0.45 to 1.05, 6 RCTs, n = 1037) and an RR for other non-vertebral fractures of 0.78 (95% CI , 0.69 to 0.88, 11 RCTs, n = 22,372).
|18.104.22.168||Three RCTs of raloxifene in postmenopausal women were identified, but only two were included in the Assessment Group’s meta analysis: the largest study (the Multiple Outcomes of Raloxifene Evaluation study – MORE) was in women with osteoporosis, of whom 37% had a vertebral fracture at entry, and a smaller study was in women all of whom had established osteoporosis. Both compared raloxifene with placebo (in both studies, women in both arms received calcium and vitamin D). Both studies examined raloxifene at doses of 60 mg/day (
The meta-analysis for raloxifene relative to placebo, carried out by the Assessment Group resulted in an RR of vertebral fracture of 0.65 (95% CI , 0.53 to 0.79, 1 RCT, n = 4551); an RR of hip fracture of 1.13 (95% CI, 0.66 to 1.96, 2 RCTs, n = 6971), an RR of wrist fracture of 0.89 (95% CI, 0.68 to 1.15,1 RCT, n = 6828) and an RR for other non-vertebral fractures of 0.92 (95% CI, 0.79 to 1.07; 1 RCT, n = 6828).
|22.214.171.124||The most serious adverse effect associated with raloxifene is the approximately three-fold increased risk of VTE. Statistically significantly higher incidences of hot flushes, arthralgia, dizziness, leg cramps, influenza-like symptoms, endometrial cavity fluid, peripheral oedema and worsening diabetes were also found with raloxifene compared with placebo. The impact of raloxifene on cardiovascular disease is unclear, although there is evidence that it lowers fibrinogen and both total and LDL cholesterol without increasing HDL cholesterol.|
|126.96.36.199||The MORE study shows that raloxifene protects against breast cancer, with the RR at 4 years, for all types of breast cancer, reported as 0.38 (95% CI, 0.24 to 0.58) and for invasive breast cancer as 0.28 (95% CI, 0.17 to 0.46).|
|188.8.131.52||Three RCTs of strontium ranelate in postmenopausal women were identified: one study in women with osteoporosis and two in women with osteoporosis or established osteoporosis. All three studies compared strontium ranelate against placebo. All three studies provided calcium and vitamin D supplementation to ensure an adequate intake.|
|184.108.40.206||The Assessment Group reported the results of a published meta-analysis, which resulted in an RR for vertebral fracture of 0.60 (95% CI 0.53 to 0.69, 2 RCTs, n = 6551); and an RR for all non-vertebral fractures (including wrist fracture) of 0.84 (95% CI 0.73 to 0.97, 2 RCTs, n = 6551). Hip fracture efficacy was established in one study: The RR for hip fracture in the whole study population was 0.85 (95% CI 0.61 to 1.19, 1 RCT, n = 4932). A post-hoc subgroup analysis in women over 74 years of age and with a T-score of -2.4 SD resulted in an RR for hip fracture of 0.64 (95% CI 0.41 to 0.98, 1 RCT, n = 1977).|
|220.127.116.11||In general, strontium ranelate was not associated with an increased risk of adverse effects and for the most part adverse effects were mild and transient. Transient nausea, diarrhoea and creatine kinase elevations were the most commonly reported clinical adverse effects. A serious adverse event associated with strontium ranelate therapy was an increased incidence (RR = 1.42) of VTE and pulmonary embolism. This finding is being investigated further with the extension of ongoing studies and by post-marketing surveillance.|
|18.104.22.168||One study published results on health-related quality of life. Strontium ranelate was said to benefit quality of life when compared with placebo, as assessed by the QUALIOST osteoporosis-specific questionnaire and by the general health perception score of the SF-36 general scale.|
|4.1.11||Persistence and compliance|
|22.214.171.124||Data from 14 RCTs indicated that between 81% and 100% of patients persisted with bisphosphonates in the first year of treatment, with lower rates of persistence of between 51% and 89% in the third year of treatment (eight RCTs).|
|126.96.36.199||A prescription event monitoring study of patients (n = 11,916) prescribed alendronate indicated that 24% discontinued therapy within 1 year. In a similar study (n = 11,742) of risedronate 30% of patients appear to have discontinued therapy within 6 months. In another 12 studies reviewed, persistence at 1 year ranged from 16 to 90%. Of note, is the absence of
|188.8.131.52||US-based paid claims data suggested that only 18% of initiating raloxifene therapy continued to take their medication uninterrupted and an investigation of a pharmacy prescription database indicated that only 44% continued therapy by the end of year 2.|
|184.108.40.206||Compliance data were reported for two RCTs of strontium ranelate ranging from 83 to 93% and was similar in the strontium ranelate and placebo arms.|
|4.2.1||For branded alendronate, compared with no treatment, the manufacturer’s model provided an incremental cost-effectiveness ratio (ICER) of £8622 per quality-adjusted life year (QALY) for 70-year-old women with a T-score below -2.5 SD. The manufacturer’s results were more favourable than the original (2003) Assessment Group’s model. This could be because the manufacturer’s model was not adjusted for baseline fracture prevalence, different utilities for vertebral fractures and different efficacy data, different risk groups used, or the longer time horizon used in the manufacturer’s model.|
|4.2.2||For etidronate, compared with no treatment, the manufacturer’s model provided an ICER of £18,634 per QALY for 70-year-old women with a T-score below -2.5 SD. The manufacturer’s model included morphometric vertebral fractures and corticosteroid use as risk factors for further fractures. It is unclear whether the manufacturer’s ICER was for women with or without osteoporotic fragility fracture.|
|4.2.3||For risedronate, compared with no treatment, the manufacturer provided data from two models. The ICER derived from the manufacturer’s own model was £577 per QALY for age 74. In the second model provided by the manufacturer, which was commissioned from an external body, the ICER was more than £35,000 per QALY for all women without fragility fracture and with a T-score of -2.5 SD. However, for those at slightly higher fracture risk, and age 70 and older, the corresponding ICER was £13,500 per QALY or less. The ICER calculated by the manufacturer’s own model is difficult to substantiate from the information given. The ICERs generated by the second model are more consistent with the figures provided by the original (2003) Assessment Group’s model though they do differ somewhat. This may be due to different cost and RR inputs.|
|4.2.4||For raloxifene, compared with no treatment, the manufacturer provided data for different age groups and different risk levels. All of the analyses included the breast cancer benefits. It was not clear how the different risk levels were defined. The ICERs ranged from £12,000 to £22,000 per QALY. The manufacturer’s results were more favourable than the original (2003) Assessment Group’s analysis, even when the Assessment Group included the breast cancer benefit. In the original (2003) Assessment Group’s model, the RR for the breast cancer effect was higher (0.38) than the RR of invasive breast cancer used in the manufacturer’s model (0.28) and the breast cancer risk was adjusted for the association between low BMD and decreased risk of breast cancer. Additionally, the manufacturer’s model was not adjusted for baseline fracture prevalence, and included different utilities for vertebral fractures, different efficacy data, different risk groups, and a longer time horizon.|
For strontium ranelate, compared with no treatment, the manufacturer provided a model developed by an external organisation. The ICER was £45,028 per QALY for 65-year-old women with a T-score of -2.5 SD and £26,686 per QALY for 80-year-old women with a T-score of -2.5 SD. The manufacturer’s results were more favourable than the original (2005) Assessment Group’s results because different modelling assumptions were used. For example, fewer health-state transition possibilities were incorporated. Compared with the Assessment’s Group model, the manufacturer’s model used more favourable hip-fracture efficacy data from a subgroup of pati
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