The Department of Health and the National Assembly for Wales have asked the National Institute for Clinical Excellence (NICE or the Institute) to conduct an appraisal of bisphosphonates (alendronate, risedronate, etidronate), selective oestrogen receptor modulators (raloxifene) and parathyroid hormone (teriparatide) for the prevention and treatment of osteoporosis and prevention of osteoporotic fractures in postmenopausal women, and to 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, risedronate and etidronate.

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: 23rd January 2004
Second Appraisal Committee meeting: 12th February 2004

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.

Bisphosphonates (alendronate, etidronate and risedronate) are recommended as treatment options for the prevention of osteoporotic fractures in postmenopausal women aged 65 years and older who have experienced a fragility fracture ¹ without need for dual energy X-ray absorptiometry (DEXA) scanning.

¹ For fragility fracture definition, see Section 2.7

Bisphosphonates are recommended as treatment options for postmenopausal women younger than 65 years of age with a fragility fracture if they have either of the following:

• T-score² below -3.2 SD established by a DEXA scan
• T-score below -2.5 SD and either a history of maternal hip fracture or long-term use of systemic corticosteroids.

² For T-score definition, see Section 2.3 and 2.4

Teriparatide is only recommended as an option for the treatment of osteoporosis in postmenopausal women aged 70 years and older who have multiple fragility fractures, if they have had an inadequate clinical response to bisphosphonates and a very high fracture risk, defined as one of the following:

• T-score below -4.0 SD, established by a DEXA scan
• T-score below -3.2 SD and either a history of maternal hip fracture or long-term use of systemic corticosteroid

Osteoporosis is defined as 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.

Bone formation exceeds bone resorption in youth, but by the third decade of life there is a gradual loss of bone mass. Therefore, primary osteoporosis is usually an age-related disease. It can affect both sexes, but women are at greater risk because bone loss is accelerated, to varying degrees, after the menopause because of loss of oestrogen production.

The World Health Organization's classification of osteoporosis has been widely adopted and is based on the measurement of bone mineral density (BMD), with reference to the number of standard deviations (SD) from the BMD in an average 25-year-old woman (T-score):

• normal: T-score of -1 SD or more
• osteopenia: T-score between -1 and -2.5 SD
• osteoporosis: T-score below -2.5 SD
• established/severe osteoporosis: T-score below -2.5 SD, with one or more associated fractures.
  

BMD T-scores can vary by site and method of measurement. A reference standard has therefore been adopted of measurement at the femoral neck using DEXA.

It is estimated that there are 2.1 million women with osteoporosis (that is, BMD T-score below -2.5 SD) in England and Wales. Prevalence increases markedly with age after menopause and approximately 50% of women aged 80 years and older are estimated to have the condition.

Risk factors for osteoporosis include smoking, low body mass index, early menopause, family history of osteoporosis, long-term systemic corticosteroid use and conditions affecting bone metabolism. It is most common in white women.

Fragility fracture is the clinically apparent and relevant (adverse) outcome in osteoporosis. Fragility fractures are fractures that result from low-level trauma, which means mechanical forces that would not ordinarily cause fracture. The World Health Organization has quantified this as forces equivalent to a fall from a standing height or less. In the absence of fragility fracture, the condition is asymptomatic and often remains undiagnosed.

Fragility fractures occur most commonly in the vertebrae, hips and wrists, and are associated with substantial disability, pain and reduced quality of life. It is estimated that there are 180,000 osteoporosis-related symptomatic fractures annually in England and Wales. Of these, 70,000 are hip, 25,000 are vertebral, and 41,000 are wrist fractures. As with osteoporosis, the incidence of osteoporosis-related fractures rises with age in postmenopausal women. In 2000, it was estimated that the total cost of treating osteoporosis-related fractures in postmenopausal women was between £1.5 and £1.8 billion. This is expected to increase to £2.1 billion by 2010.

In women older than 50 years of age, the lifetime risk of vertebral fracture is estimated to be about one in three, and approximately one in six for hip fracture. Postmenopausal women with an initial fracture are at much greater risk of subsequent fractures.

After treatment for hip fracture many women are unable to walk independently and perform other activities of daily living, and so are unable to continue to live independently. Hip fractures are also associated with increased mortality. In the 12 months after hip fracture, estimates of the relative mortality risk vary from two to more than ten, depending on age. However, it is unclear to what extent this can be independently attributed to fracture.

Vertebral fractures are associated with loss of height and curvature of the spine. They result in pain, breathing difficulties and gastrointestinal (GI) problems, and difficulties with activities of daily living. Many vertebral fractures (50-70%) may not come to clinical attention. Vertebral fractures are also associated with increased mortality. Estimates of the age-standardised relative mortality risk in the 12 months after vertebral fracture range from two to nine.

The Royal College of Physicians' guidelines on the treatment of osteoporosis and the National Service Framework for Older People recommend a selective case-finding approach, the use of BMD measurement, and drug treatment focused on women with fractures or multiple risk factors.

A number of interventions are used to prevent and treat osteoporosis. Lifestyle modifications include regular weight-bearing exercise, smoking avoidance, and moderation of alcohol intake. In older patients, fall prevention measures, such as home modifications, and hip protectors may also be considered. Drug therapies and supplements include hormone replacement therapy (HRT), bisphosphonates, selective oestrogen receptor modulators (SERMs), parathyroid hormone, calcitonin, calcium, vitamin D, and calcitriol. It is estimated that in the UK 10-20% of women with osteoporosis receive drug treatment for the condition. The choice of interventions is influenced by factors such as BMD, stage of disease progression, nature and site of fracture, patient age, underlying co-morbidities and side effects.

Acute management of osteoporotic fractures may include pain relief, physiotherapy and appropriate orthopaedic management. Surgery is required for most hip fractures, but for vertebral fractures surgery is generally reserved for cases involving neurological deficit or spinal instability.

Bisphosphonates: alendronate, etidronate, risedronate

Bisphosphonates are inhibitors of bone resorption and increase BMD by altering both osteoclast activation and function. Three bisphosphonates are currently licensed in the UK for the management of osteoporosis: alendronate, etidronate and risedronate. It is estimated that approximately 275,000 women in England and Wales are prescribed bisphosphonates, representing around 57% of all prescriptions for osteoporosis.

Alendronate (Fosamax, Merck Sharp & Dohme) is an oral bisphosphonate licensed in the UK at a dose of 5 mg/day for the prevention of postmenopausal osteoporosis and at a dose of 10 mg/day for its treatment. A once-weekly preparation (70 mg) is also licensed for the treatment of postmenopausal osteoporosis. Prices are £25.43 for 28 5-mg tablets, £23.12 for 28 10-mg tablets and £23.12 for four 70-mg tablets (excluding VAT; British National Formulary [BNF] 46th edition). This equates to between £0.83 and £0.91 per day of treatment. Costs may vary in different settings because of negotiated procurement discounts.

The Appraisal Committee (see Appendix A) considered evidence from a number of sources (see Appendix B).

The Assessment Report reviewed data from 39 published randomised controlled trials (RCTs) in postmenopausal women where fracture or quality of life was a primary end point and where the five drugs of interest were compared with the relevant comparators detailed in the scope.

The majority of studies used placebo or no treatment as a control. However, most studies ensured that women in all arms had normal calcium levels or adequate supplementation and some studies also required additional dietary supplementation of vitamin D.

Sixteen RCTs of alendronate in postmenopausal women were reviewed: 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 severe osteoporosis. Overall, 15 studies compared alendronate with placebo or with no treatment; two used active comparators. The quality of many of the studies was poor, although the largest studies - the two arms of the Fracture Intervention Trial (FIT) - were of high quality. All the studies were of women with adequate levels of calcium or receiving calcium supplementation. The studies of women with osteopenia, osteoporosis and severe osteoporosis included participants from a broad age range, with mean ages between 61 and 71 years. In the two studies of women with low or normal BMD, the mean age was around 52 years.

Wide variations in levels of continuance with alendronate therapy were reported, ranging from 100% in a small 18-month study, to 89% after 12 months in the FIT study, and 50% after 6 years in the EPIC study. Clinical adverse events (particularly GI) were the most common reason for withdrawal. However, adherence appeared to be high in those continuing with medication.

In summary, there is evidence that, compared with placebo, alendronate is effective in protecting against vertebral, non-vertebral, hip and wrist fractures in women with osteoporosis and severe osteoporosis. The available evidence did not show alendronate to be more or less effective than other active treatments in preventing fractures.

Etidronate

Eleven 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; and five in women with severe osteoporosis. Four of these included active comparators, and seven compared etidronate with placebo or with no treatment (although in six of these subjects in all arms received calcium, either alone or with vitamin D). The quality of the studies was variable and many did not use the exact treatment regimen currently licensed in the UK (that is, 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 quality of life outcomes. The studies in women with osteopenia, osteoporosis and severe osteoporosis included participants with a wide age range, with mean ages between 62 and 65 years. In the studies of women with low-to-normal BMD the mean ages were between 53 and 59 years.

For vertebral fractures in women with severe osteoporosis, a pooled analysis of two studies using a 20% reduction in vertebral height as the fracture definition and cyclical etidronate at a dose of 400 mg/day, found an RR of 0.43 (95% CI 0.20 to 0.91) compared with untreated controls, in favour of those treated with etidronate.

There was no robust evidence that etidronate prevents vertebral fractures in women with osteopenia and osteoporosis. Although a pooled analysis of three studies combining women with osteopenia, osteoporosis and severe osteoporosis found a significantly lower RR of vertebral fractures in the treatment group (RR 0.40; 95% CI 0.20 to 0.83), the only study to include all three groups of women did not achieve a statistically significant result (RR 0.14; 95% CI 0.01 to 2.68).

For the prevention of non-vertebral fractures, there was no statistically significant evidence from RCTs that etidronate is effective. An analysis of pooled data from four studies found an RR of 1.04 compared with controls in women with severe osteoporosis (95% CI 0.64 to 1.69). Only one of these studies provided separate information on hip fractures and this found no statistically significant effects of etidronate (RR 0.50; 95% CI 0.05 to 5.34). However, these studies were not powered to detect differences in non-vertebral fractures.

For low or normal BMD in postmenopausal women, the available evidence from three RCTs did not demonstrate that etidronate prevents fractures.

Higher rates of upper-GI 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 upper-GI adverse effects than the other bisphosphonates

Continuance with therapy in the studies varied from 93% of the patients receiving etidronate at 2 years to 61% at 3 years. Two studies that assessed adherence by pill count reported that all subjects took at least 80% of etidronate or placebo over the study period.

In summary, the available evidence showed that, compared with placebo, etidronate is effective in preventing vertebral fractures in postmenopausal women with severe osteoporosis. The available evidence did not show etidronate to be more or less effective than other active treatments in preventing fractures.

Risedronate

Seven RCTs 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 severe osteoporosis. All compared risedronate with placebo (although all subjects in the six studies of osteopenic or osteoporotic women or women with specific risk factors for hip fracture received calcium) and none reported on quality of life. Only one of the studies met all of the quality criteria. The studies included women from a broad age range and, in the main studies considered, the mean ages were between 64 and 83 years.

A pooled analysis of two studies in women with severe osteoporosis, using the licensed UK dose (5 mg/day) and a 15% reduction in vertebral height as the vertebral fracture definition, found an RR of vertebral fracture of 0.63 (95% CI 0.51 to 0.78) compared with placebo, and an RR of non-vertebral fracture of 0.67 (95% CI 0.50 to 0.90).

In women with osteoporosis or osteopenia, risedronate has not been demonstrated to reduce the risk of vertebral fractures. However, the study of women with osteoporosis or specific risk factors for hip fracture found that 70-79-year-old women with osteoporosis who received risedronate had an RR of non-vertebral fracture of 0.80 (95% CI 0.70 to 1.00).

A weekly dose of 35 mg has been demonstrated to be as safe and effective, in relation to BMD and vertebral fracture outcomes, as a daily 5-mg dose.

Overall- and upper-GI adverse events were comparable in the risedronate and placebo groups in all of the studies.

Studies showed that continuance rates with risedronate varied from 46% to 78% at 2 years and from 51% to 62% at 3 years. One study reported that 86% of the subjects in the 5 mg arm who completed the protocol (62%) took at least 80% of their medication.

In summary, there was evidence that, compared with placebo, risedronate is effective in preventing vertebral, non-vertebral and hip fractures in women with severe osteoporosis. There was also some evidence that it may prevent hip fractures in women with osteoporosis, although this may not be the case in women older than 80 years of age. There is no evidence as to whether risedronate is more or less effective than other active treatments in preventing fractures.

Raloxifene

Two RCTs of raloxifene in postmenopausal women were considered: one in women with osteoporosis, of whom 37% had vertebral fracture at entry, the other in women with severe osteoporosis. Both compared raloxifene with placebo (in both studies, subjects in both arms received calcium and vitamin D). One study - Multiple Outcomes of Raloxifene Evaluation (MORE) - was of high quality, while the second, smaller study was of a lower quality. 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 quality of life. The mean age in the studies was 67-68 years. The MORE study was extended to further assess fracture, breast cancer, cardiovascular and uterine safety outcomes.

For vertebral fracture, defined as 20% reduction in vertebral height, the MORE study found an RR in women with osteoporosis or severe osteoporosis of 0.65 (95% CI 0.53 to 0.79) at 60 mg and 0.54 (95% CI 0.44 to 0.67) at 120 mg in favour of raloxifene compared with placebo. The RR in women with osteoporosis but without fracture was 0.53 (95% CI 0.35 to 0.79) at 60 mg and 0.62 (95% CI 0.43 to 0.91) at 120 mg and, in women with severe osteoporosis, 0.69 (95% CI 0.56 to 0.86) at 60 mg and 0.51 (95% CI 0.40 to 0.65) at 120 mg. The smaller study of women with severe osteoporosis failed to find a statistically significant difference in vertebral fractures using a 15% height reduction definition. A re-analysis, using a definition of 30% reduction or more, found a statistically significant reduction in risk in the 120 mg group only (RR 0.31; 95% CI 0.11 to 0.87).

The manufacturers presented a subgroup analysis of pooled data from the MORE study as evidence that raloxifene is also effective in preventing vertebral fractures in osteopenic women without a baseline vertebral fracture (RR 0.53; 95% CI 0.32 to 0.88). However, this appears to be inconsistent with the entry criteria for the MORE study.

For hip and wrist fractures and grouped non-vertebral fractures, the evidence did not demonstrate that raloxifene has a preventative effect. The MORE study examined pooled non-vertebral fractures and the smaller study measured hip fractures but no statistically significant differences between raloxifene and placebo were found. However, it may be that the ability of the MORE study to detect such differences was undermined by loss of women from the study, particularly in the control group, because of disease progression.

The most serious adverse effect associated with raloxifene is the approximately three-fold increased risk of venous thromboembolism. A significantly higher incidence of hot flushes, arthralgia, dizziness, leg cramps, influenza-like symptoms, endometrial cavity fluid, peripheral oedema and worsening diabetes have also been found with raloxifene than with placebo.

The MORE study suggests that raloxifene may protect against breast cancer, with the RR at 4 years of 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). The impact of raloxifene on cardiovascular disease is unclear, although there is evidence that it lowers fibrinogen and total and LDL cholesterol without increasing HDL cholesterol.

The percentage of women receiving 60 mg raloxifene who completed treatment varied from more than 90% at 1 year down to 78% at 3 years. However, an analysis of women taking raloxifene in a large health maintenance organisation in the USA found that 56% had discontinued treatment after 2 years. Another study found that adherence was significantly higher with raloxifene than with HRT (95% vs 86%, p < 0.01).

In summary, there is evidence that, compared with placebo, raloxifene is effective in preventing vertebral fractures in women with osteoporosis and severe osteoporosis. There is no evidence as to whether raloxifene is more or less effective than other active treatments in preventing vertebral fractures.

Teriparatide

Three RCTs of teriparatide in postmenopausal women were considered: one study compared teriparatide with alendronate in women with osteoporosis, and two were placebo-controlled (although subjects also received vitamin D and calcium or nutritional advice to ensure adequate calcium intakes). The largest trial was conducted in women with severe osteoporosis, and the second in women with severe osteoporosis or osteoporosis who had been receiving HRT for at least 2 years. The RCT that compared teriparatide (at twice the licensed dose) with alendronate was methodologically poor, with potential for bias in randomisation and blinding. The placebo-controlled studies were higher quality, although in the larger study randomisation may have been open to bias. The mean age in this study was 70 years. No relevant studies of quality of life were found.

For vertebral fractures (using a 20% reduction in vertebral height as the fracture definition) and grouped non-vertebral fractures in women with severe osteoporosis, the main placebo-controlled RCT found an RR of 0.35 (95% CI 0.22 to 0.55) and 0.65 (95% CI 0.43 to 0.98) respectively, in favour of teriparatide. When considered separately, the study did not demonstrate that teriparatide prevents hip and wrist fractures in women with severe osteoporosis (RR for hip fractures 0.5; 95% CI 0.09 to 2.73, RR for wrist fractures 0.54; 95% CI 0.22 to 1.35).

Data from a follow-up observational study cited in the manufacturer's submission (published in abstract form or available as unpublished manuscript only) suggests that 18 months after the end of treatment with teriparatide there was a 41% reduction in vertebral fracture risk compared with placebo (p = 0.004). Further data from the same study 31 months after end of treatment with teriparatide suggested that proportionally fewer women who had received teriparatide reported non-vertebral fractures than those who had received placebo (13.3% in the placebo group; 8.5% in the 20 micrograms/day teriparatide group; 7.3% in the 40 micrograms/day teriparatide group; p = 0.03 for both treatment groups versus placebo). No information was given on vertebral fractures for the 31-month follow up.

The study comparing 40 micrograms/day teriparatide (twice the licensed dose) with 10 mg/day alendronate found an RR of non-vertebral fracture in women with osteoporosis of 0.30 (95% CI 0.09 to 1.05). The study did not provide data on vertebral fractures. Back pain was reported less frequently in the teriparatide group (6% vs 19%, p = 0.012).

Nausea and headaches occurred more frequently with teriparatide in the main placebo-controlled trial and a large proportion of women taking teriparatide were reported to suffer mild discomfort at the injection site, although the smaller placebo-controlled RCT reported no reports of nausea. In addition, a systematic review of parathyroid hormone reported that treatment in a small proportion of women was associated with hypercalcaemia.

The main placebo-controlled RCT reported that adherence to injections varied from 79% to 83% and that there were no statistically significant differences between the teriparatide and placebo groups. The smaller placebo-controlled trial found that, after 3 years, 78% of women receiving teriparatide completed treatment, compared with 100% on placebo.

In summary there is evidence that, compared with placebo, teriparatide reduces vertebral and non-vertebral fractures in women with severe osteoporosis.

Cost effectiveness

The Assessment Group provided a cost-utility model based on a modified, individualised Markov approach. The patient population modelled consisted of three different subgroups of women with osteoporosis aged 50, 60, 65, 70 or 80 years as follows:

• women with a fragility fracture and a doubled risk of further osteoporotic fracture because of a lower T-score (-3.2 SD) or other risk factors
• women with a fragility fracture and a T-score of -2.5 SD
• women without a fragility fracture, and with a T-score of -2.5 SD (that is, at the threshold of osteoporosis; only carried out for ages 70 and 80)

The prevalence of fractures in the average population was adjusted so that women with osteoporosis were excluded, and an age-dependent rate for entry into a nursing home after hip fracture was used. The Assessment Group model simulated patients either until they died or for up to 10 years (5 years of treatment plus 5 years linear fall time (that is, decline of effect to zero), apart for teriparatide, where the fall time was 1 year). The comparator for the analyses was no treatment, but assuming an adequate intake of calcium and vitamin D.

Alendronate

Generally, the cost per quality-adjusted life-year gained (CQG) improved with increasing patient age. Using the Assessment Group's model for women with a fragility fractur