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 Appraisal Committee will meet again to consider the original evidence and this Appraisal Consultation Document in the light of the views of the formal consultees.
At that meeting, the Committee will also consider comments made on the document by people who are not formal consultees in the appraisal process.
After considering feedback from the consultation process, the Committee will prepare the Final Appraisal Determination (FAD) and submit it to the Institute.
Subject to any appeal by consultees, the FAD may be used as the basis for the Institute's guidance on the use of the appraised technology in the NHS in England and Wales.

The key dates for this appraisal are:
Closing date for comments: 20 October 2006

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.
1.3	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: who are unable to comply with the special instructions for the administration of alendronate or who are intolerant of alendronate (as defined in section 1.8).
1.4	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: for whom bisphosphonates are contraindicated (see Summaries of Product Characteristics) or who are unable to comply with the special instructions for the administration of bisphosphonates or who are intolerant of bisphosphonates (as defined in section 1.8).
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.
2.3	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: normal: T-score of -1 SD or above osteopenia: T-score of between -1 and -2.5 SD osteoporosis: T-score of -2.5 SD or below established/severe osteoporosis: T-score of -2.5 SD or below with one or more associated fractures.
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.
2.5	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 England and Wales. Of these, 70,000 are hip fractures, 25,000 are clinical vertebral fractures, and 41,000 are wrist fractures.
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.

3	The technology
	Bisphosphonates: alendronate, etidronate, risedronate
3.1	Bisphosphonates are inhibitors of bone resorption and increase BMD by altering osteoclast activation and function. Alendronate, etidronate and risedronate are licensed in the UK for the management of osteoporosis.
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 UK at a daily dose of 10 mg for the treatment of osteoporosis in postmenopausal women to prevent fractures. Weekly alendronate (70 mg) is available generically (Teva Pharmaceutical Industries Ltd) with a price of £13.27 for four 70 mg tablets (excluding VAT, NHS Drug Tariff, 31 August 2006). At this price the drug cost for a year with the once-weekly treatment is £172.98. Branded Alendronate (Merck Sharp & Dohme Ltd) is priced at £22.80 (for four 70 mg tablets) and £23.12 (for 28 10 mg tablets) (excluding VAT, British national formulary Volume 51 [BNF 51]). At these prices, the drug costs for a year are £301.39 with the daily (10-mg) tablets and £297.21 for the once-weekly (70-mg) tablets. Costs may vary in different settings because of negotiated procurement discounts.
3.3	Etidronate (Procter & Gamble Pharmaceuticals UK Ltd) is an oral bisphosphonate licensed in the UK for the treatment of osteoporosis. The drug is administered in 90-day cycles, with each cycle consisting of etidronate (400 mg daily) for 14 days followed by calcium carbonate (1.25 g daily) for the remaining 76 days. The price per 90-day pack is £22.29 (excluding VAT; BNF51), which equates to £90.50 per annum. Costs may vary in different settings because of negotiated procurement discounts.
3.4	Risedronate (Procter & Gamble Pharmaceuticals UK Ltd) is an oral bisphosphonate licensed in the UK at a dose of 5 mg/day or 35 mg/week for the treatment of postmenopausal osteoporosis, to reduce the risk of vertebral fractures, and for the treatment of established postmenopausal osteoporosis, to reduce the risk of hip fractures. Prices are £19.10 for 28 5 mg tablets and also £20.30 for four 35 mg tablets (excluding VAT; BNF 51), which equates to £248.98 per annum for the daily treatment or £264.63 per annum for the once weekly treatment. Costs may vary in different settings because of negotiated procurement discounts.
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
3.7	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.
3.8	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.
3.9	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
3.10	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.
3.11	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.
3.12	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	Clinical effectiveness
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.
4.1.5	Alendronate
4.1.5.1	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.
4.1.5.2	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).
4.1.5.3	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.
4.1.5.4	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).
4.1.5.5	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.
4.1.5.6	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.
4.1.5.7	Prescription event monitoring studies in patients prescribed alendronate (n = 11,916) by general practitioners in England demonstrated a high incidence of dyspepsia, particularly in the first month of treatment. Consultations for dyspepsia ranged from 32.2 per 1000 patient months in the first month of treatment to 10.9 per 1000 patient months in months 2 to 6. 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.
4.1.5.8	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
4.1.6	Etidronate
	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 UK (that is, a 90-day cycle comprising 400 mg etidronate for 14 days, followed by calcium carbonate 1.25 g for the remaining 76 days). None of the studies reported health-related quality of life outcomes.
4.1.6.2	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.
4.1.6.3	An observational study in a general practice setting in the UK reported on fracture rates in people with a diagnosis of osteoporosis who were receiving etidronate compared with those who were not taking a bisphosphonate. People taking etidronate had an RR of non-vertebral fracture of 0.80 (95% CI, 0.70 to 0.92). The RR of hip fracture was 0.66 (95% CI, 0.51 to 0.85) and that of wrist fracture, 0.81 (95% CI, 0.58 to 1.14).
4.1.6.4	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.
4.1.6.5	The systematic review carried out by the NICE decision support Unit (DSU 2006) identified a cohort study conducted in the UK, which indicated that etidronate may be associated with a much lower rate of upper gastrointestinal adverse effects than alendronate or risedronate.
4.1.7	Risedronate
	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.
4.1.7.2	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).
4.1.7.3	Overall and gastrointestinal adverse events were similar in the risedronate and placebo groups in all of the studies.
4.1.7.4	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
4.1.8.1	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).
4.1.9	Raloxifene
4.1.9.1	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 (UK licensed dose for treatment of postmenopausal osteoporosis) and 120 mg/day. Neither reported on health-related quality of life. The mean age in the studies was 67-68 years. The MORE study was extended to further assess fracture, breast cancer, and cardiovascular and uterine safety outcomes. A third study examined the additive effect of raloxifene, compared with placebo, in women with a femoral neck T-score of -2 SD or lower, with or without prior fracture, who were also receiving fluoride, calcium and vitamin D. Because of the use of fluoride as a co-intervention, these results were not included in the Assessment Group's meta-analysis.
4.1.9.2	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).
4.1.9.3	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.
4.1.9.4	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).
4.1.10	Strontium ranelate
4.1.10.1	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.
4.1.10.2	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).
4.1.10.3	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.
4.1.10.4	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
	Bisphosphonates
4.1.11.1	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).
4.1.11.2	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 UK evidence, and few international data, for longer-term persistence with bisphosphonates.
	Raloxifene
4.1.11.3	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.
	Strontium ranelate
4.1.11.4	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	Cost effectiveness
4.2	Manufacturer's models
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.
4.2.5	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 patients aged over 74 and slightly more favourable efficacy data for wrist and proximal humerus fracture. Higher hip-fracture costs were used in the manufacturer's model.
	The Assessment Group model
4.2.6	Following the consultation on their preliminary recommendations, the Appraisal Committee asked for further analysis to be carried out to clarify several areas of uncertainty, notably the cost effectiveness of bisphosphonates when efficacy data for alendronate and risedronate are pooled and when the costs and disutility of adverse events are included. A number of sensitivity analyses were undertaken to explore the effect of alternative assumptions. A systematic review of adverse effects and persistence with therapy was undertaken to inform these further analyses. Further revision of the economic assessment incorporated recent price changes for alendronate.
4.2.7	The Assessment Group provided a cost-utility model with two components: first it calculated absolute fracture risk from the epidemiological literature summarised in a WHO draft report, then it applied RR reductions for fracture taken from the meta-analysis described in section 4.1.8). A single estimate of efficacy was used for alendronate and risedronate based on pooled data for these two drugs. The price of alendronate decreased substantially before the Appraisal Committee meeting to develop the ACD in September 2006, and therefore the most recent analyses were based on this reduced price. Following advice from the osteoporosis Guideline Development Group, it was assumed that RRs remain constant across all ages, T-scores and fracture status.
4.2.8	All osteoporotic fractures were included in the modelling. The RR for hip fracture was assumed to apply also to pelvis and other femoral fractures. The RR for non-vertebral fracture was assumed to apply to proximal humerus, rib, sternum, scapula, tibia, fibula and wrist fracture. Where confidence intervals for RRs spanned unity, it was assumed that there was no effect of treatment. For strontium ranelate, however, non-significant RRs for hip fracture were used in order to acknowledge a statistically significant effect reported in a subgroup of older women. The model used UK-specific epidemiological data on femoral neck BMD.
4.2.9	The model assumed an initial utility in the year of fracture and a higher utility in subsequent years. The time horizon was 10 years, consisting of 5 years treatment with sustained efficacy plus 5 years linear decline to no effect. In the base-case vertebral fracture utility was assumed to be lower than hip fracture utility. The percentage of women that are assumed to move from community living to a nursing home following a hip fracture increased with increasing age. An age-dependent gradient of hip fracture risk was used. An association between vertebral or proximal humerus fracture and increased mortality in osteoporotic patients was included. No follow-up BMD scans were included in the model: this reflects current clinical practice in the UK.
4.2.10	The model included an assumption about the costs and disutility associated with treatment-related side effects for all drugs, based on the findings of prescription event monitoring studies in patients treated with alendronate. For the base case, the model assumed 50% persistence with therapy. In addition to the base case, the Assessment Group undertook a number of sensitivity analyses for alendronate and risedronate using alternative assumptions regarding: persistence with therapy; efficacy of the drugs at reducing the absolute risk of fracture associated with risk factors other than age, previous fracture and low BMD; efficacy of the drugs in women with osteopenia and normal BMD; disutility of vertebral fracture, updated fracture costs; and the disutility and costs of treatment-related side effects. In the case of strontium ranelate, the effect on VTE was not included in the model.
4.2.11	For raloxifene, 4-year follow-up data from the MORE study were used, and it was assumed that women with low BMD have a lower breast cancer risk than women with normal BMD. The cost effectiveness was modelled excluding the breast cancer benefit, the risk of VTE or the effect on cardiovascular events.
4.2.12	A number of clinical risk factors were aggregated and quantified as absolute risk. The model used an unpublished fracture-risk algorithm currently in development under the auspices of the WHO. The clinical risk factors included body mass index, previous fracture, ever use of corticosteroids, parental history of fracture, current smoking, alcohol intake of more than 2 units per day, and rheumatoid arthritis. The study provided prevalence data for the different risk factors, and risk ratios for hip fracture and osteoporotic fracture for each risk factor, including T-score and age. Using these risk ratios absolute risk of fracture can be calculated which integrates all clinical risk factors.
4.2.13	The estimates of cost effectiveness were generated for different levels of absolute risk derived from a large number of combinations of T-scores (in bands 0.5 SD wide), ages and risk factors. For practical reasons relating to the number of potential combinations, single-point RRs of fracture calculated from the log-normal efficacy distributions were used in the model. Results were presented for population groups categorised according to age, T-score and number of clinical risk factors. This represents a simplification of the algorithm for calculating absolute fracture risk by the WHO approach (see 4.2.12). However, because no standard validated absolute risk calculator is currently available in clinical practice, an approach based on the number of risk factors was chosen as a pragmatic approach to define intervention thresholds.
4.2.14	As women without fracture do not usually present to clinicians, the Assessment Group also estimated the impact of costs of identification of women at risk on the cost effectiveness of the drugs. Identification of women at high risk was modelled using a new case-finding approach based on the WHO study results. For this a net-benefit approach was used, whereby the total net benefit for each identification approach and age band was calculated by subtracting the cost of identification (risk assessment and DXA scanning) from the net benefit of treating all women who can be treated cost effectively. Where the total net benefit is positive, the identification and treatment approach is cost effective on a population level. The net-benefit approach requires an assumption about the willingness to pay for an additional quality adjusted life-year (QALY).
4.2.15	A stepped net-benefit approach was used to ascertain, in reverse order, the cost effectiveness of risk assessment, DXA scanning and treatment of women with or without a prior fracture. An ICER of £20,000 per QALY was applied in the net benefit modelling, in accordance with the NICE -Guide to the Methods of Technology Appraisal.
	The Assessment Group model - results for generic alendronate
4.2.16	The Assessment Group calculated ICERs (cost per QALY using generic alendronate compared with no treatment) without identification costs for all age, T-score and clinical risk factor combinations. The cost per QALY, compared with no treatment, became more favourable with increasing age and number of risk factors and decreasing T-score (that is with increasing annual absolute risk of fracture).
4.2.17	The Assessment Group presented the results of the economic analyses in the form of identification and treatment strategies (based on age, T-score and number of clinical risk factors) that were cost effective given an ICER of £20,000 (cost per QALY compared with no treatment).
4.2.18	For the base case, the model suggested the following strategy. (1) Risk assessment of women younger than 70 years would not be supported (that is, it leads to an ICER of more than £20,000 per QALY). (2) Women aged 70-74 would be assessed for clinical risk factors, those with clinical risk factors would receive a DXA scan, and those with a T-score of -2.5 SD or below would receive generic alendronate (cost of strategy per QALY = £11,259). (3) All women aged 75 or above would receive a DXA scan, and those with a T-score of -2.5 SD or below would receive generic alendronate (cost of strategy per QALY = £8774).
4.2.19	The Assessment Group carried out 16 sensitivity analyses using alternative assumptions to the base case. Eight of the sensitivity analyses resulted in identification and treatment strategies that were not substantially different from the base case. These were using assumptions of 75% persistence with therapy, most alternative fracture cost estimates, doubling or halving the assumptions on cost and disutility of side effects or setting them to zero, or including proton pump inhibitor costs rather than H2 receptor antagonist costs for the treatment of upper gastrointestinal symptoms.
4.2.20	One sensitivity analyses resulted in a less restrictive strategy than the base case; this was when different assumptions of efficacy of treatment for women with osteoporosis, osteopenia and normal BMD, as reported in the FIT trial subgroup analysis, were made.
4.2.21	Six sensitivity analyses resulted in strategies that were more restrictive than the base case. These were assuming: (1) 5% persistence on therapy; (2) 50% efficacy of bisphosphonates on clinical risk factors other than BMD and fracture status; (3) 0% efficacy of bisphosphonates on clinical risk factors other than BMD and fracture status; (4) Health Resource Group costs, but excluding home help costs; (5) vertebral fracture disutility assumed to be equal to that of hip fracture and (6) disutility from bisphosphonate-related side effects set to 10 times that of the base case, reflecting a potentially higher disutility and a higher side-effect rate than is captured by primary care attendances. For two sensitivity analyses, and two combinations of sensitivity analyses, the results were as follows.
4.2.21.1	When bisphosphonates were assumed to act on BMD-related fracture risk only the model suggested the following strategy. (1) Risk assessment of women younger than 75 years would not be supported (that is, lead to an ICER of more than £20,000 per QALY) (2) All women aged 75 or above would receive a DXA scan, and those with a T-score of -2.5 SD or below would receive treatment with generic alendronate (cost of strategy per QALY = £13,248).
4.2.21.2	When the effect of alendronate was assumed to act on only BMD-related fracture risk and vertebral fracture utility was assumed to be equal that of hip fracture, the model suggested the following strategy. (1) Risk assessment of women younger than 75 years would not be supported (that is, led to an ICER of more than £20,000 per QALY). (2) All women aged 75 or above would receive a DXA scan, and those with a T-score of -2.5 SD or below would receive treatment with generic alendronate (cost of strategy per QALY = £15,707).
4.2.21.3	When the effect of alendronate was assumed to act on only BMD-related fracture risk, vertebral fracture utility was assumed to be equal that of hip fracture and the disutility of side-effects multiplied by 10, no identification and treatment strategy led to an ICER of £20,000 per QALY or less).
	The Assessment Group model - results for other drugs
4.2.22	Because of the different prices and effectiveness profiles for the other bisphosphonates, raloxifene and strontium ranelate, additional analyses were conducted to explore identification and treatment strategies that could be cost-effective for these interventions when compared to no intervention. All results except those for etidronate showed less favourable cost effectiveness than generic alendronate. These analyses were carried out in two ways: (1) including costs for risk assessment and DXA scanning (identification cost) and (2) assuming second-line use, that is costs for risk assessment or DXA scanning are excluded as BMD is assumed to be known from the first-line management.
4.2.23	For etidronate the base-case modelling suggested the following identification and treatment strategy to have an ICER of £20,000 per QALY or less. Women aged 70-74 would be assessed for clinical risk factors, those with clinical risk factors and all women aged 75 or above would receive a DXA scan, and those with a T-score of -1.5 SD or below would receive treatment. The cost effectiveness of this strategy is was the same for first-line and second-line treatment. If the women had more than one clinical risk factor, the T-score threshold would be more permissive.
4.2.24	For branded alendronate and risedronate, the base-case modelling suggested the following identification and treatment strategy to be £20,000 per QALY or less. Women aged 70-74 would be assessed for clinical risk factors, those with clinical risk factors and all women aged 75 or above would receive a DXA scan, and those with a T-score of -3 SD or below would receive treatment. This was the same for first line and second line treatment. If the women had more than one clinical risk factor, the T-score threshold would be more permissive.
4.2.25	When bisphosphonates were assumed to act on BMD related fracture risk only, the identification and treatment strategy for branded alendronate or risedronate was associated with a cost per QALY greater than £20,000 at all ages.
4.2.26	For raloxifene, when risk assessment and DXA scanning was included, the base case modelling did not result in any identification and treatment strategy to be £20,000 per QALY or less. For second-line use, that is when BMD is assumed to be known, only women age 70 or above with 2 or more clinical risk factors and a T-score of -5 SD (two clinical risk factors) or -4.5 SD (more clinical risk factors), would receive treatment.
4.2.27	For strontium ranelate, when risk assessment and DXA scanning was included, the base case modelling did not result in any identification and treatment strategy to be £20,000 per QALY or less for women under the age of 75. Women age 75 and above would be assessed for clinical risk factors and those with clinical risk factors would receive a DXA scan, and those with a T-score of -3.5 SD would receive treatment. If the women had two or more clinical risk factors, the T-score thresholds would be more permissive. For second line use, that is when BMD is assumed to be known, the base case modelling resulted in the following identification and treatment strategy to be £20,000 per QALY or less: Women aged 70-74 would be assessed for clinical risk factors, those with clinical risk factors and all women aged 75 or above would receive a DXA scan, and those with a T-score of -4 SD or below would receive treatment. If the women had more than one clinical risk factor, the T-score thresholds would be more permissive.
4.3	Consideration of the evidence
4.3.1	The Committee reviewed the data available on the clinical and cost effectiveness of alendronate, etidronate, risedronate, raloxifene and strontium ranelate, having considered evidence on the nature of the condition and the value placed on the benefits of these drugs by people with osteoporosis, those who represent them, and clinical experts. It also considered the consultation comments received in response to its first appraisal consultation document. It remained mindful of the need to ensure that its advice took account of the effective use of NHS resources. The Committee was aware of a previous decision of the National Screening Committee not to recommend screening to prevent osteoporotic fracture because of concerns about the accuracy of BMD assessment for the prediction of fracture and because there was no trial evidence indicating that such screening would reduce the incidence of fractures.
4.3.2	The Committee considered the clinical effectiveness data for all the bisphosphonates (alendronate, etidronate, risedronate), strontium ranelate and raloxifene. It noted that all these drugs have proven efficacy in the reduction of vertebral fragility fractures for women with osteoporosis, but there were differences between the drugs as to the degree of certainty that a reduction in hip fracture resulted from treatment (considered a crucial goal in osteoporosis management). In the case of alendronate and risedronate it was accepted that there was sufficiently robust evidence to suggest a reduction in hip fracture. However, the Committee noted that the available RCTs for etidronate were of insufficient size to show statistically significant reductions in hip fracture, but that observational data leant support to this effect.
4.3.3	The Committee noted that strontium ranelate was effective in preventing vertebral and pooled non-vertebral fractures, and resulted in a non-significant 15% reduction in hip-fracture incidence. The Committee also was also aware of the result of a post-hoc subgroup analysis showing a statistically significant reduction in the incidence of hip fractures in women over the age of 74 who have a T-score of -2.4 or below.
4.3.4	The Committee noted that the evidence for raloxifene did not show any effect on hip fractures but that there is evidence for a beneficial side effect on the incidence of breast cancer.
4.3.5	The Committee noted that, for all the drugs, efficacy in reducing fracture-risk was less well established for osteopenic women (equivalent to a T-score between -2.5 and -1 SD) than for women with osteoporosis. The Committee was also aware that three of the drugs under consideration (weekly alendronate, weekly risedronate and strontium ranelate) have marketing authorisations only for the treatment of osteoporosis, implying a T-score of -2.5 SD or lower. The Committee therefore concluded that it was inappropriate for it to make recommendations about the use of the drugs in osteopenic women and suggested that this issue be explored by the Guideline Development Group in the forthcoming NICE guideline.
4.3.6	The Committee noted that fracture risk is clearly related to age, low BMD and previous fracture. The Committee accepted that most of the risk factors identified by the WHO study (see section 4.2.12) were likely to be associated with an increased fracture risk, which is partially independent of BMD. The exceptions were the risk factors 'current smoking' and'alcohol consumption of less than 4 units per day' because the Committee was not persuaded that the WHO data provided sufficient evidence for these two risk factors in women. The Committee further noted that a full review of other risk factors is being carried out as part of the development of the clinical guideline on osteoporosis.
4.3.7	The Committee noted that there was an absence of evidence to demonstrate that treatment with any of the drugs under consideration would reduce fracture risk that was not associated with low BMD, age or prior facture. The Committee therefore concluded that preventative drug therapy should be targeted to women whose absolute risk of fracture is driven by low BMD and that the recommendations should be made on the basis of BMD in the form of T-scores below which treatment is recommended.
	Cost-effectiveness modelling
4.3.8	As women who have not had a fracture would not normally present to clinicians, the Committee considered it necessary to include the cost involved in the assessment of fracture risk and DXA scanning in the total cost that is included in the cost-effectiveness modelling.
4.3.9	The Committee acknowledged the efforts of the Assessment Group to build on the model used previously, particularly in using the so-far unpublished and complex WHO data to calculate transition probabilities and to model the identification approaches. Apart from the issue that there was not evidence for a treatment effect on fracture risk related to risk factors other than low BMD and age (see 4.3.7), the Committee concluded that the Assessment Group's model was a sound basis for exploring the estimates of cost effectiveness; it used data for a wide age range (age 50-75 years and over), and was updated to use all fracture sites, more recent utility, prevalence and risk-factor data, and an adjusted prevalence of fractures in the average population. Although the Assessment Group's model considered a shorter time period (10 years) than the manufacturers models, the Committee thought that this was appropriate considering the age groups involved and the uncertainties around health effects over a longer period.
4.3.10	The Committee discussed the assumptions underpinning the most recent economic modelling undertaken by the Assessment Group. It noted that some of the uncertainties surrounding the results of the previous modelling had been partially addressed by the inclusion of assumptions relating to the costs and disutility associated with treatment-related side effects and with non-persistence with therapy in a proportion of patients. The Committee also noted the effect of the recent price reductions for alendronate (70 mg weekly dose) on the cost effectiveness of these drugs.
4.3.11	The Committee compared the base-case assumptions with those that were varied in the one-way sensitivity analyses and selected the assumptions that it considered most credible. The Committee noted that the fracture costs used in the base-case analysis were those used in the original assessment report developed in 2002 and considered that these were likely to be outdated. The Committee agreed that costs based on Health Resource Groups, including home help costs, were likely to provide the most accurate reflection of the cost of fractures to the NHS and personal social services.
4.3.12	The Committee considered the utility multiplier for the first year after a vertebral fracture (0.626) used in the base-case analysis and noted that it was considerably worse than that for a hip fracture (0.792). Although the Committee acknowledged that vertebral fracture can lead to greatly reduced quality of life, it considered that it was implausible that this would so greatly outweigh the utility decrement associated with a hip fracture. The Committee therefore considered it reasonable to assume that the disutility in the first year after a vertebral fracture was equivalent to the disutility in the first year after a hip fracture.
4.3.13	Following its conclusion that the drugs under consideration had not been shown to reduce fracture risk that was attributable to risk factors not mediated through BMD, the Committee considered that the sensitivity analysis that was more likely to reflect the true efficacy of the drugs was the one that assumed no efficacy on fractures associated with risk factors other than age and low BMD.
4.3.14	The Committee discussed additional issues relevant to its recommendations. These included the possibility that side effects of the bisphosphonates exceed the model's new base-case assumptions. The Committee noted that the modelling of side effects had been based solely on patients who report their side-effects to their GP. The Committee noted that the sensitivity analysis that assumed side effects to be an order of magnitude higher suggested that no case-finding in primary prevention was cost effective. The Committee also heard that a possible long-term effect of bisphosphonates could be inhibition of the formation of new bone; but that this was not represented in the model.
4.3.15	The Committee agreed to make recommendations based on the results of a sensitivity analysis that adopted the following assumptions: the interventions were assumed not to be effective at reducing the risk of fracture attributable to risk factors other than age and low BMD; the disutility multiplier in the first year after a vertebral fracture assumed to be equal to that of hip fracture; and Health Resource Group costs (including home help costs) were used for fracture costs.
	Bisphosphonates- alendronate
4.3.16	The Committee noted the relative cost-effectiveness results for the bisphosphonates. The new price for generic alendronate resulted in generic alendronate being estimated as more cost-effective than risedronate or branded alendronate. This was not the case when generic alendronate was compared with etidronate. However the Committee had concluded that the evidence base for etidronate was less robust than for the second generation bisphosphonates, particularly for hip and other non-vertebral fractures, and had noted that clinical experts and a number of consultees and commentators had indicated that etidronate was generally considered to be less clinically useful than alendronate or risedronate. The Committee therefore concluded that alendronate should be considered as the first-line treatment option, and that it should be prescribed on the basis of the lowest acquisition cost
4.3.17	The Committee considered the results of its preferred sensitivity analysis (see section 4.3.15) and observed that for generic alendronate, identification and treatment strategies were not cost effective in women aged under 75. The Committee noted that the results of the model indicated that all women aged 75 and older with a T-score of -2.5 SD or lower could be identified and treated cost effectively. However, the Committee considered that this strategy needed added caution given that the adoption of such a strategy would result in many women (that is, all women aged over 75 visiting their GP for any reason) being referred for DXA scanning and that many of these women may be ostensibly well and asymptomatic and not at high risk of fracture. The Committee therefore agreed to exercise caution in formulating its recommendations, and to recommend DXA scanning only in women with at least one clinical risk factor, other than age, suggesting a low BMD.
4.3.18	The Committee considered both the costs and the other benefits the NHS would have to forego in paying for additional QALYs gained through primary prevention of osteoporotic fractures. It acknowledged that the population were essentially asymptomatic but at measurable risk of future fracture. It balanced this against the impact associated with initiating potentially lifelong treatment in a large, asymptomatic population. On balance, it did not consider there to be compelling additional considerations associated with the primary prevention of osteoporotic fractures that would lead it to adopt a less cautious approach.
4.3.19	Having reviewed the evidence on risk factors and the views of the clinical experts, the Committee agreed that the appropriate clinical risk factors to be considered for case finding for the primary prevention should be: parental history of hip fracture; low body mass index (defined as less than 22 kg/m 2); alcohol intake of more than 3 units per day; and medical conditions associated with low BMD (as listed in section 2.11).
	Bisphosphonates - etidronate and risedronate
4.3.20	In view of its concerns surrounding the evidence base for etidronate, and taking into account the views of clinical experts and consultees, the Committee decided that etidronate should not be recommended in preference to generic alendronate, but that on the basis of its cost effectiveness it should be available as an alternative treatment option for women using the same criteria.
4.3.21	The Committee noted that risedronate was less cost effective than generic alendronate and etidronate because of the difference in acquisition cost. Consequently, the Committee concluded that risedronate should not be recommended as a first-line treatment and that it should only be recommended in women who are unable to comply with the special instructions for the administration of alendronate or who are intolerant of alendronate.The Committee observed that the identification costs associated with finding women who could be cost-effectively treated with risedronate would be negligible because women eligible to receive it would have already undergone risk assessment and had a DXA scan in order to qualify for first-line treatment with alendronate. The Committee therefore decided that treatment with risedronate should be available in women aged 75 years or older with a clinical risk factor and a T-score of -3 SD or less who could not comply with the instructions for treatment with, or were intolerant of alendronate.
	Strontium ranelate
4.3.22	The Committee considered the clinical evidence for strontium ranelate from RCTs and heard statements from experts. It noted that strontium ranelate was effective in preventing vertebral and pooled non-vertebral fractures, and resulted in a not statistically significant 15% reduction in hip-fracture incidence. The Committee also noted the result of a post-hoc subgroup analysis showing a statistically significant reduction in the incidence of hip fractures in women over the age of 74 and with low BMD. The Committee agreed that, on balance, the RR for hip fracture used in the modelling could be accepted but it did not accept an even more favourable estimate of efficacy in preventing hip fracture from the post-hoc subgroup analysis.
4.3.23	On the basis of the incremental analysis carried out the 2005 Assessment Report, the Committee agreed that strontium ranelate was likely to be dominated by bisphosphonates. Therefore, the Committee concluded that strontium ranelate should be an alternative treatment option for women for whom bisphosphates are contraindicated, or who are unable to comply with the special recommendations for use of bisphosphonates, or who cannot take them because of intolerance. The identification costs associated with finding women who could be cost-effectively treated with strontium ranelate would be negligible because women eligible to receive it would have already undergone risk assessment and had a DXA scan in order to qualify for first-line treatment with generic alendronate. The Committee therefore agreed that strontium ranelate should be recommended in women aged 75 years and older with at least one clinical risk factor and a T-score of -4 SD or below who could not take bisphosphonates, because bisphosphonates were contraindicated, or the women could not comply with the instructions for treatment with, or were intolerant of bisphosphonates. The Committee agreed that intolerance to 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.
	Raloxifene
4.3.24	The Committee considered the evidence from the main RCT showing that raloxifene is effective in preventing vertebral fractures. The clinical experts acknowledged that there is no evidence that raloxifene is effective in preventing non-vertebral fractures.
4.3.25	The Committee discussed the reported benefits of raloxifene on breast cancer risk, and heard from the experts that the possibility of preventing vertebral fractures and breast cancer simultaneously could be attractive particularly to younger post-menopausal women. The Committee also heard from the experts that evidence on the effect of raloxifene in reducing cardiovascular risk is not considered to be robust and, furthermore, there is some concern over the increased risk of VTE (see 4.1.9.3).
4.3.26	The Committee noted that a higher proportion of the overall benefit associated with raloxifene was attributable to its effect on the prevention of breast cancer than to its effect on the prevention of osteoporotic fractures. The Committee agreed that, in principle, the side effects of using a technology should be considered, but there were a number of reasons why the Committee considered that the breast cancer benefit should not be the sole factor in deciding whether raloxifene is a cost effective option for the treatment of osteoporosis. From the evidence presented, raloxifene was not as effective as bisphosphonates for treating osteoporosis. Raloxifene's effect on the prevention of breast cancer has not been assessed by the regulatory authorities. Full assessment of raloxifene's effect on the prevention of breast cancer and its cost effectiveness in this indication would require consideration of how it compares with other drugs that potentially could be used for breast cancer prevention.
4.3.27	The Committee observed that the cost effectiveness of raloxifene, in terms of fracture prevention, was very unfavourable relative to the bisphosphonates and strontium ranelate. The benefits of raloxifene's breast cancer effect were in any case noted to be most valuable in younger women rather than those for whom primary prevention of osteoporotic fractures could be considered cost-effective. On balance, the Committee concluded that raloxifene should not be recommended as a treatment option for the primary prevention of osteoporotic fragility fractures in postmenopausal women.
	Calcium and vitamin D prerequisites for treatment
4.3.28	The Committee discussed the effect of calcium and vitamin D on the clinical effectiveness of the drugs considered. In the studies that formed the basis of this appraisal, all participants were said to have adequate calcium and vitamin D levels. The Committee appreciated that the general population, particularly the elderly population, cannot be assumed to have adequate dietary intake of calcium and vitamin D. It was also considered important to note that adequate levels of calcium and vitamin D are needed to ensure optimum effects of the treatments for osteoporosis. The Committee concluded that calcium and/or vitamin D supplementation should be provided unless clinicians are confident that women who receive osteoporosis treatment have an adequate calcium intake and are vitamin D replete. The Committee suggested that the forthcoming clinical guideline could specify how such assessment should be made and what supplementation should be prescribed.

5	Implementation
5.1	The Healthcare Commission assesses the performance of NHS organisations in meeting core and developmental standards set by the Department of Health in 'Standards for better health' issued in July 2004. The Secretary of State has directed that the NHS provides funding and resources for medicines and treatments that have been recommended by NICE technology appraisals normally within 3 months from the date that NICE publishes the guidance. Core standard C5 states that healthcare organisations should ensure they conform to NICE technology appraisals.
5.2	'Healthcare Standards for Wales' was issued by the Welsh Assembly Government in May 2005 and provides a framework both for self-assessment by healthcare organisations and for external review and investigation by Healthcare Inspectorate Wales. Standard 12a requires healthcare organisations to ensure that patients and service users are provided with effective treatment and care that conforms to NICE technology appraisal guidance. The Assembly Minister for Health and Social Services issued a Direction in October 2003 which requires Local Health Boards and NHS Trusts to make funding available to enable the implementation of NICE technology appraisal guidance, normally within 3 months.
5.3	NICE has developed tools to help organisations implement this guidance (listed below). These are available on our website (www.nice.org.uk/TAXXX). [Note: tools will be available when the final guidance is issued] The NICE Costing Unit is currently developing this section. A costing template and report will be available at the time of publication of the final guidance.

6	Proposed recommendations for further research
6.1	The Committee recommends that head-to-head studies should be conducted to enable direct comparisons of efficacy to be made between the different drugs for osteoporosis, the Committee recommends that head-to-head studies should be conducted.
6.2	Given the emergence of evidence from one bisphosphonate that the benefits of the drug may continue for several years beyond treatment cessation, the Committee recommends that research should be carried out to define the optimal duration of treatment with individual bisphosphonates.
6.3	The Committee recommends research into the long-term effects of bisphosphonates on bone quality, given the inhibitory effects of these drugs on bone resorption.
6.4	There is some evidence that strontium ranelate may interfere with the results of DXA scanning as it has a higher molecular weight than calcium. It may also affect the measurement of calcium levels in the blood or urine calcium levels. This could have implications in the clinical care setting and further research is recommended.
6.5	The Committee notes that there is an ongoing study to investigate the clinical and cost effectiveness of identifying women at high risk in the prevention of osteoporotic fracture.

7	Related guidance
7.1	The Institute has issued guidance on technologies for the secondary prevention of osteoporotic fragility fractures in postmenopausal women. National Institute for Clinical Excellence (2005) Bisphosphonates (alendronate, etidronate, risedronate), selective oestrogen receptor modulators (raloxifene) and parathryroid hormone (teriparatide) for the secondary prevention of osteoporotic fragility fractures in postmenopausal women, NICE Technology Appraisal Guidance No. 87, London: National Institute for Clinical Excellence.
7.2	NICE plans to publish the guideline 'Osteoporosis: assessment of fracture risk and the prevention of osteoporotic fractures in individuals at high risk' (publication date TBA).
7.3	NICE plans to publish the guidance 'Alendronate, etidronate, risedronate, raloxifene, strontium ranelate and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women' (publication date TBA).

8	Proposed date for review of guidance
8.1	The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators.
8.2	It is proposed that the guidance on this technology is considered for review in March 2009.

Andrew Stevens

Chair, Appraisal Committee

September 2006

Appendix A. Appraisal Committee members

NOTE The Appraisal Committee is a standing advisory committee of the Institute. Its 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. The Appraisal Committee meets regularly and membership is split into three branches, with the chair, and a number of other members attending meetings of both branches. Each branch considers its own list of technologies and ongoing topics are not moved between the branches.

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

Professor David Barnett

Professor of Clinical Pharmacology, University of Leicester

Dr Peter Barry

Consultant in Paediatric Intensive Care, Leicester Royal Infirmary

Mr Brian Buckley

Vice Chairman, InContact

Professor John Cairns

Public Health and Policy, London School of Hygiene and Tropical Medicine

Professor David Chadwick

Professor of Neurology, Walton Centre for Neurology and Neurosurgery

Dr Peter I Clark

Honorary Chairman, Association of Cancer Physicians

Ms Donna Covey

Chief Executive, Asthma UK

Dr Mike Davies

Consultant Physician, University Department of Medicine & Metabolism, Manchester Royal Infirmary

Mr Richard Devereaux-Phillips

Public Affairs Manager, Medtronic Ltd

Professor Jack Dowie

Health Economist, London School of Hygiene and Tropical Medicine

Professor Gary A. Ford

Professor of Pharmacology of Old Age/Consultant Physician, Royal Victoria Infirmary, Newcastle upon Tyne

Dr Fergus Gleeson

Consultant Radiologist, The Churchill Hospital, Oxford

Ms Sally Gooch

Former Director of Nursing & Workforce Development, Mid Essex Hospital Services NHS Trust

Mr Sanjay Gupta

Stroke Services Manager, Basildon and Thurrock University Hospitals NHS Trust

Ms Linda Hands

Consultant Vascular Surgeon, John Radcliffe Hospital, Oxford

Professor Philip Home

Professor of Diabetes Medicine, University of Newcastle upon Tyne

Dr Peter Jackson

Clinical Pharmacologist, University of Sheffield

Professor Peter Jones

Professor of Statistics & Dean Faculty of Natural Sciences, Keele University

Dr Mike Laker

Medical Director, Newcastle Hospitals NHS Trust

Dr George Levvy

Lay Member

Professor Robert Kerwin

Professor of Psychiatry and Clinical Pharmacology, Institute of Psychiatry, London

Ms Rachel Lewis

Nurse Advisor to the Department of Health

Mr Terence Lewis

Mental Health Consultant, National Institute for Mental Health in England

Professor Jonathan Michaels

Professor of Vascular Surgery, University of Sheffield

Dr Neil Milner

General Medical Practitioner, Sheffield

Dr Ruairidh Milne

Senior Lecturer in Health Technology Assessment, National Coordinating Centre for Health Technology

Dr Rubin Minhas

General Practitioner, Primary Care Cardiovascular Society

Dr Rosalind Ramsay

Consultant Psychiatrist, Adult Mental Health Services, Maudsley Hospital

Mr Miles Scott

Chief Executive, Bradford Teaching Hospitals NHS Foundation Trust

Dr Lindsay Smith

General Practitioner, East Somerset Research Consortium

Mr Roderick Smith

Finance Director, Arun and Worthing PCT

Dr Ken Stein

Senior Lecturer, Peninsula Technology Assessment Group (PenTAG), University of Exeter

Professor Andrew Stevens (Chair)

Professor of Public Health, University of Birmingham

The following individuals, representing the National Collaborating Centre responsible for developing the Institute's clinical guideline related to this topic, attended the meeting to observe and to contribute as advisors to the Committee.

Professor Juliet Compston

Professor of Bone Medicine University of Cambridge School of Clinical Medicine and Addenbrooke's NHS Trust

Dr Peter Selby

Consultant Physician, Central Manchester and Manchester Children's University Hospitals NHS Trust

NICE Project Team

Each appraisal of a technology is assigned to a Health Technology Analyst and a Technology Appraisal Project Manager within the Institute.

Kate Burslem, Ruaraidh Hill

Technical Leads

Elisabeth George

Technical Adviser

Emily Marschke

Project Manager

Appendix B. Sources of evidence considered by the Committee for the appraisal of alendronate, etidronate, risedronate, raloxifene and strontium ranelate for the primary prevention of osteoporotic fractures in postmenopausal women
A	The assessment reports for this appraisal were prepared by The University of Sheffield, School of Health and Related Research (ScHARR). Stevenson M (2006). [Analyses of cost-effectiveness incorporating alendronate price reduction]. Sheffield: School of Health and Related Research (ScHARR). Stevenson M, Lloyd Jones M, Davis S et al (2006) Analyses of the cost-effectiveness of pooled alendronate and risedronate, compared with strontium ranelate, raloxifene, etidronate and teriparatide . Sheffield: School of Health and Related Research (ScHARR). Lloyd Jones M and Wilkinson A (2006) Adverse effects and persistence with therapy in patients taking oral alendronate, etidronate or risedronate: systematic reviews . Sheffield: School of Health and Related Research (ScHARR). . Stevenson M, Davis S, Lloyd Jones M and Beverley C (2005). Strontium ranelate for the prevention of osteoporotic fragility fractures in postmenopausal women. Sheffield: School of Health and Related Research (ScHARR). . Stevenson M, Davis S (2005). Addendum to the Assessment Report: The clinical effectiveness and cost effectiveness of technologies for the primary prevention of osteoporotic fragility fractures in postmenopausal women. Sheffield: School of Health and Related Research (ScHARR). Stevenson M, Davis S (2005). Addendum to the Assessment Report: Analyses of the cost-effectiveness of pooled alendronate and risedronate, compared with strontium ranelate, raloxifene, etidronate and teriparatide Sheffield: School of Health and Related Research (ScHARR).

B.	The following organisations accepted the invitation to participate in this appraisal. They were invited to make submissions and comment on the draft scope and assessment report. They are also invited to comment on the Appraisal Consultation Document and consultee organisations are provided with the opportunity to appeal against the Final Appraisal Determination. I Manufacturers/sponsors: Alliance for Better Bone Health Eli Lilly & Company Ltd Merck Sharp & Dohme Ltd Proctor & Gamble Pharmaceuticals Servier Ltd TEVA II Professional/specialist and patient/carer groups: Arthritis and Musculoskeletal Alliance Bone and Tooth Society British Geriatrics Society British Menopause Society British Orthopaedic Association British Society for Rheumatology Department of Health Institute for Ageing and Health National Osteoporosis Society National Rheumatoid Arthritis Society Primary Care Rheumatology Society RADAR (The Royal Association for Disability and Rehabilitation) Royal College of General Practitioners Royal College of Nursing Royal College of Pathologists Royal College of Physicians Society for Endocrinology Southwark Primary Care Trust The Society and The College of Radiographers Women's Health Women's Health Concern Women's Nutritional Advisory Service III Commentator organisations (without the right of appeal): British National Formulary National Collaborating Centre for Nursing and Supportive Care NHS Quality Improvement Scotland Novartis Pharmaceuticals Ltd Research Institute for the Care of the Elderly Strakan Group Ltd Welsh Assembly Government

C.	The following individuals were selected from clinical expert and patient advocate nominations from the professional/specialist and patient/carer groups. They participated in the Appraisal Committee discussions and provided evidence to inform the Appraisal Committee's deliberations. They gave their expert personal view on technologies for the primary prevention of osteoporotic fractures in postmenopausal women by attending the initial Committee discussion and/or providing written evidence to the Committee. They are invited to comment on the Appraisal Consultation Document: Mrs Jackie Parrington, Deputy Chief Executive, National Osteoporosis Society - Patient Expert nominated by the National Osteoporosis Society Mrs Anthea Franks - Patient Expert nominated by the National Osteoporosis Society Professor Juliet Compston, Professor of Bone Medicine University of Cambridge School of Clinical Medicine and Addenbrooke's NHS Trust - Clinical Expert nominated by the Royal College of Physicians Dr R.M. Francis, Reader in Medicine (Geriatrics) and Honorary Consultant Physician, British Geriatrics Society - Clinical Expert nominated by the British Geriatrics Society and the National Osteoporosis Society Dr Caje Moniz, Consultant and Clinical Director, King's Healthcare NHS Trust -Clinical Expert nominated by the National Osteoporosis Society Dr Peter Selby, Consultant Physician, Central Manchester and Manchester Children's University Hospitals NHS Trust - Clinical Expert nominated by the Society of Endocrinology and the National Osteoporosis Society

This page was last updated: 30 March 2010

Raloxifene for the primary prevention of osteoporotic fragility fractures in postmenopausal women

Osteoporosis - primary prevention: Appraisal consultation document

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