• National Institute for Health and Clinical Excellence (NICE). Alendronate, etidronate, risedronate, raloxifene, strontium ranelate and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women. London (UK): National Institute for Health and Clinical Excellence (NICE); 2008 Oct. 67 p. (Technology appraisal guidance; no. 161).

This is the current release of the guideline.

This guideline updates a previous version: National Institute for Clinical Excellence (NICE). Bisphosphonates (alendronate, etidronate, risedronate), selective oestrogen receptor modulators (raloxifene) and parathyroid hormone (teriparatide) for the secondary prevention of osteoporotic fragility fractures in postmenopausal women. London (UK): National Institute for Clinical Excellence (NICE); 2005 Jan. 51 p. (Technology appraisal; no. 87).

• Osteoporosis
• Osteoporotic fragility fractures

Assessment of Therapeutic Effectiveness
Management
Prevention
Treatment

Endocrinology
Family Practice
Geriatrics
Internal Medicine
Preventive Medicine

Advanced Practice Nurses
Physician Assistants
Physicians

To evaluate the clinical effectiveness and cost effectiveness of alendronate, etidronate, risedronate, raloxifene, strontium ranelate, and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women

Postmenopausal women with osteoporosis who have normal calcium levels and/or vitamin D levels and who have already sustained at least one fracture as a result of the disease

Note: This guidance does not cover the following:

• Use of alendronate, etidronate, risedronate, raloxifene, strontium ranelate or teriparatide for the secondary prevention of osteoporotic fragility fractures in women with normal bone mineral density (BMD) or osteopenia
• Use of the above mentioned drugs for the secondary prevention of osteoporotic fragility fractures in women who are on long-term systemic corticosteroid treatment

1. Alendronate
2. Alternative treatment options:
   • Risedronate
   • Etidronate
   • Strontium ranelate
   • Raloxifene
   • Teriparatide

• Clinical effectiveness
  • Survival
  • Vertebral or nonvertebral fracture
  • Quality of life
  • Associated effects (both adverse and beneficial)
  • Continuance and compliance
• Cost effectiveness

Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases

Note from the National Guideline Clearinghouse (NGC): The National Institute for Health and Clinical Excellence (NICE) commissioned an independent academic centre to perform a systematic literature review on the technology considered in this appraisal and prepare an assessment report. The assessment report for this technology appraisal was prepared by The University of Sheffield, School of Health and Related Research [ScHARR]. (See the "Availability of Companion Documents" field.)

Clinical Effectiveness

Alendronate, Etidronate, Risedronate, and Raloxifene

Search Strategy

Because of the range of interventions and comparators under review, the literature search aimed to identify all literature relating to the prevention and treatment of osteoporosis. The main searches were conducted in May and July 2002, and updated in September and October 2002. The utilities searches were performed in October and November 2002.

Sources Searched

Fourteen electronic bibliographic databases were searched, covering biomedical, science, social science, health economic, and grey literature. A list of the databases searched is provided in Appendix 2 of the Assessment Report #1 (see "Availability of Companion Documents" field).

In addition, the reference lists of relevant articles and sponsor submissions were handsearched, and various health services research-related resources were consulted via the Internet. These resources included health economics and health technology assessment (HTA) organisations, guideline-producing agencies, registers of generic research and trials, and specialist sites. These additional sources are listed in Appendix 3 of the Assessment Report #1 (see "Availability of Companion Documents" field).

Search Terms

A combination of free-text and thesaurus terms was used. General "population" search terms (e.g., osteoporosis, bone, density, diseases, fracture, etc) were used in order to identify all potentially relevant studies. "Intervention" terms were not used in the main searches since it was felt that these might restrict the results and cause possibly relevant articles to be missed. Utilities searches were performed for breast cancer and for osteoporosis fractures as part of the economic evaluation section of the report. Copies of the Medline search strategies are included in Appendix 4 of the Assessment Report #1 (see "Availability of Companion Documents" field). Search strategies for the other databases are available on request.

Search Restrictions

No language, date or study-type restrictions were applied to the searches. However, the Biosciences Information Service (BIOSIS) search was performed as title only, and the Citation Indexes searches were limited with brief clinical trials, systematic reviews, guidelines, and economics filters, and to title only, in order to keep the number of hits to a sensible level. A randomized controlled trial (RCT) filter, an economics and quality of life evaluations filter, and a systematic reviews filter were used in the main searches performed in Medline and Embase to assist the identification of articles of these types (see Appendix 5 of the Assessment Report #1 [see "Availability of Companion Documents" field]). After the searches were completed, because of the large number of references retrieved, only the articles identified using these specific filters, the articles from the databases that were not searched with filters (such as BIOSIS), and the papers found through handsearching etc, were reviewed.

Inclusion and Exclusion Criteria

Inclusion Criteria

• Participants: Women with primary osteoporosis who were at least 6 months postmenopausal
• Interventions:
  • Bisphosphonates (alendronate, etidronate, and risedronate)
  • Selective oestrogen receptor modulators (SERMs) (raloxifene)
  • Teriparatide (recombinant human parathyroid hormone [1-34])
• Comparators:
  • Vitamin D
  • Calcitriol (a vitamin 1 alpha-hydroxylated derivative)
  • Pharmacological doses of calcium
  • Oestrogens (opposed and unopposed)
  • Exercise
  • Placebo
  • No treatment
• Outcome measures: Vertebral or nonvertebral fracture, associated effects, quality of life related to the study intervention, continuance and compliance
• Study design: Randomised controlled trials. Trials were accepted as RCTs if the allocation of subjects to treatment groups was described by the authors as either randomised or double-blind.

A discussion of outcome measures is presented in section 3.1.2.1. of the Assessment Report #1 (see "Availability of Companion Documents" field.)

Exclusion Criteria

Studies were excluded if they included participants with secondary osteoporosis (e.g., related to therapy with corticosteroids), or drew their participants exclusively from patients with specific diseases known to affect fracture rates (e.g., Parkinson's disease).

Only published studies (including those only available in abstract form) were included. As unpublished studies are more likely than published studies to demonstrate small or absent treatment effects, it is recognised that this approach is likely to overestimate the true effects of treatment. However, it was not possible in the time available to seek out unpublished studies.

It had originally been intended to include all relevant studies, whatever the language of publication. However, for practical reasons, it was in fact possible only to include those published in English, French, German, Italian or Spanish. This led to the exclusion of one possibly relevant study published only in Japanese.

Sifting

In principle, the references identified by the literature searches were sifted in two stages, being screened for relevance first by title and then by abstract. However, as it was not possible to identify all relevant studies with fracture outcomes from titles alone, the title sifting stage was used essentially to reject studies which were clearly irrelevant. Following this, the abstracts of all studies which used the relevant interventions in the relevant populations were screened (for studies which did not provide abstracts, the full studies were screened). Twenty-eight studies which had been identified by the literature searches were not identified as relevant at the abstract sifting stage, but were identified from other reviews as reporting fracture outcomes. The reason for this was that, as fracture was only a secondary outcome measure in many studies, it was therefore not reported in the abstract.

Refer to Section 3.1 of the Assessment Report #1 (see the "Availability of Companion Documents" field) for more information.

Strontium Ranelate

Search Strategy

Initial clinical effectiveness searches were conducted in September 2004, and updated in March 2005. The utilities searches were performed in October and November 2002.

Sources Searched

Fourteen electronic bibliographic databases were included in the clinical effectiveness searches; these are listed in Appendix 1 of the Assessment report #2 (see the "Availability of Companion Documents" field). In addition, the reference lists of relevant articles and sponsor submissions were hand searched.

Search Terms

The clinical effectiveness search strategy utilised terms specific to strontium ranelate. A copy of the Medline search strategy is included in Appendix 2 of the Assessment Report #2 (see the "Availability of Companion Documents" field). Search strategies for the other databases are available on request.

Search Restrictions

No language, date or study-type restrictions were applied to the clinical effectiveness searches.

Inclusion and Exclusion Criteria

Inclusion Criteria

• Participants: Postmenopausal women with osteoporosis, with or without previous fracture
• Intervention: Strontium ranelate
• Comparators:
  • The bisphosphonate alendronate
• Outcome measures:
  • Survival
  • Incident vertebral fracture
  • Incident nonvertebral fracture
  • Adverse effects
  • Continuance
  • Compliance
  • Cost
  • Health-related quality of life
• Study design:
  • Randomised controlled trials
  • Economic evaluations

Exclusion Criteria

• Studies in which patients were not vitamin D replete and/or had insufficient calcium intake
• Studies considered methodologically unsound in terms of either study design or method used to assess fractures, or which did not report results in the necessary detail

Sifting

The references identified by the literature searches were sifted in three stages, being screened for relevance first by title and then by abstract. Those papers which seemed from their abstracts to be relevant were then read in full. Studies for which abstracts were not available were also read in full.

A discussion of outcome measures is presented in section 3.1.2.1 of the Assessment Report #2 (see "Availability of Companion Documents" field.)

Economic Analysis

Identifying the Studies

The review has drawn on papers identified from a series of systematic searches undertaken for a Health Technology Assessment (HTA) review of treatment for osteoporosis. These include searches of papers reporting economic evaluation of the prevention and treatment of osteoporosis, and those reporting on quality of life associated with the main fracture states, breast cancer and coronary heart disease. Studies were identified through searches of electronic databases, hand searching, citation searching, reference list checking and those known to researchers involved in the HTA review (Appendix 8 of the Assessment Report #1 [see "Availability of Companion Documents" field]).

Clinical Effectiveness

Alendronate, Etidronate, Risedronate, Raloxifene, and Teriparatide

A total of 90 individual randomized controlled trials (RCTs) met the review inclusion criteria; these are listed in Appendix 8 of the Assessment Report #1 (see the "Availability of Companion Documents" field).

Strontium Ranelate

A total of 24 articles related to three trials met the review inclusion criteria. (Refer to Appendix 4 of the Assessment Report #2 [see the "Availability of Companion Documents" field]).

Cost Effectiveness

The manufacturers and the Assessment Group provided cost-utility models.

Expert Consensus

Not applicable

Meta-Analysis of Randomized Controlled Trials
Review of Published Meta-Analyses
Systematic Review with Evidence Tables

Note from the National Guideline Clearinghouse (NGC): The National Institute for Health and Clinical Excellence (NICE) commissioned an independent academic centre to perform a systematic literature review on the technology considered in this appraisal and prepare an assessment report. The assessment report for this technology appraisal was prepared by The University of Sheffield, School of Health and Related Research [ScHARR]. (See the "Availability of Companion Documents" field.)

Clinical Effectiveness

Data Extraction Strategy

Data were extracted by one reviewer, using customised data extraction forms. Where available, data relating to the following outcomes were extracted:

• Survival
• Incident vertebral fractures
• Incident nonvertebral fractures
• Incident hip fractures
• Incident wrist fractures
• Incident humeral fractures
• Adverse effects
• Continuance and compliance

Quality Assessment Strategy

The methodological quality of all trials which met the inclusion criteria was assessed using the tool developed by Gillespie et al.* This tool was selected because it was intended specifically for the assessment of randomised or quasi-randomised trials of interventions designed to prevent fractures associated with osteoporosis.

The quality assessment tool included the following items:

• Adequacy of randomisation, and masking of randomisation
• Blinded assessment of outcomes—whether outcome assessors were blind to subjects' treatment allocation
• Withdrawals—whether the outcomes of people who withdrew were described and included in the analysis
• Comparability of groups at baseline
• Confirmation of diagnosis of hip or other appendicular skeleton fracture
• Method of diagnosis of vertebral fracture

Definitions of the various levels of randomisation and concealment of randomization derived from Prendiville et al. 1988** were incorporated in the tool (see Appendix 3 of the Assessment Report #2 [see "Availability of Companion Documents" field]).

It is recognised that the quality assessment tool assesses reporting quality, and not necessarily the true methodological quality of each study. However, where trials were reported in more than one publication, the quality score was calculated on the basis of the combined data from all relevant publications.

The quality assessment of studies included in the review of clinical effectiveness was carried out by one researcher. Blinding of the quality assessors to author, institution or journal was not considered necessary.

*Gillespie W, Avenell A, Henry D, O'Connell D, Robertson J. Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis. The Cochrane Library (Oxford) **2001 Issue 4 (27p) (27 ref 21 bib) Update Software, online of CD-ROM, updated quarterly, 2001; 2001-2ROM.

*Prendville W, Elbourne D, and Chalmers I. The effects of routine oxytocic administration in the management of the third stage of labour: an overview of the evidence from controlled trials. British Journal of Obstetrics & Gynaecology 1988; 95 3-16

Meta-Analysis Strategy

Studies which met the review's entry criteria were eligible for inclusion in the metaanalyses, if this was appropriate (i.e. if the study populations, dose and outcomes were comparable), and provided that they reported fracture incidence in terms of the number of subjects sustaining fractures to enable calculation of the relative risk of subjects in the intervention group developing a new fracture or fractures, compared with subjects in the control group. Studies which reported only the number of fractures, or the proportion of subjects in each group who suffered fractures, could not be included in the meta-analyses unless it was possible to obtain from the authors unpublished information on the actual number of subjects in each group who were known to have either suffered or not suffered fractures.

Meta-analysis was carried out using Review Manager. A random-effects model was used, as this both allows generalisation beyond the sample of patients represented by the studies included in the meta-analysis and provides wider, more conservative confidence intervals than a fixed-effects model. Where possible, relative risks for individual studies have also been calculated in Review Manager using the random effects model. Where this has not been possible, but relative risks have been calculated by the study investigators, these have been reported, and the fact that they are the investigators' calculations has been noted.

Expert Consensus

Considerations

Technology appraisal recommendations are based on a review of clinical and economic evidence.

Technology Appraisal Process

The National Institute for Health and Clinical Excellence (NICE) invites 'consultee' and commentator' organisations to take part in the appraisal process. Consultee organisations include national groups representing patients and carers, the bodies representing health professionals, and the manufacturers of the technology under review. Consultees are invited to submit evidence during the appraisal and to comment on the appraisal documents.

Commentator organisations include manufacturers of the products with which the technology is being compared, the National Health Service (NHS) Quality Improvement Scotland and research groups working in the area. They can comment on the evidence and other documents but are not asked to submit evidence themselves.

NICE then commissions an independent academic centre to review published evidence on the technology and prepare an 'assessment report'. Consultees and commentators are invited to comment on the report. The assessment report and the comments on it are then drawn together in a document called the evaluation report.

An independent Appraisal Committee then considers the evaluation report. It holds a meeting where it hears direct, spoken evidence from nominated clinical experts, patients and carers. The Committee uses all the evidence to make its first recommendations, in a document called the 'appraisal consultation document' (ACD). NICE sends all the consultees and commentators a copy of this document and posts it on the NICE website. Further comments are invited from everyone taking part.

When the Committee meets again it considers any comments submitted on the ACD; then it prepares its final recommendations in a document called the 'final appraisal determination' (FAD). This is submitted to NICE for approval.

Consultees have a chance to appeal against the final recommendations in the FAD. If there are no appeals, the final recommendations become the basis of the guidance that NICE issues.

Who is on the Appraisal Committee?

NICE technology appraisal recommendations are prepared by an independent committee. This includes health professionals working in the NHS and people who are familiar with the issues affecting patients and carers. Although the Appraisal Committee seeks the views of organisations representing health professionals, patients, carers, manufacturers and government, its advice is independent of any vested interests.

Not applicable

External Peer Review

Consultee organizations from the following groups were invited to comment on the draft scope, Assessment Report and the Appraisal Consultation Document (ACD) and were provided with the opportunity to appeal against the Final Appraisal Determination.

• Manufacturer/sponsors
• Professional/specialist and patient/carer groups
• Commentator organisations (without the right of appeal)

In addition, individuals selected from clinical expert and patient advocate nominations from the professional/specialist and patient/carer groups were also invited to comment on the ACD.

None provided

The type of evidence supporting the recommendations is not specifically stated.

Appropriate use of alendronate, etidronate, risedronate, raloxifene, teriparatide, and strontium ranelate for the secondary prevention of osteoporotic fragility fractures in postmenopausal women

• This guidance represents the view of the Institute, which was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. The guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
• Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.

Living with Illness
Staying Healthy

Effectiveness
Patient-centeredness

• National Institute for Health and Clinical Excellence (NICE). Alendronate, etidronate, risedronate, raloxifene, strontium ranelate and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women. London (UK): National Institute for Health and Clinical Excellence (NICE); 2008 Oct. 67 p. (Technology appraisal guidance; no. 161).

Not applicable: The guideline was not adapted from another source.

2005 Jan (revised 2008 Oct)

National Institute for Health and Clinical Excellence (NICE) - National Government Agency [Non-U.S.]

National Institute for Health and Clinical Excellence (NICE)

Appraisal Committee

Committee Members: Professor Keith Abrams (2006–2008), Professor of Medical Statistics, University of Leicester; Ms Julie Acred (2004–2005), Chief Executive, Derby Hospitals NHS Foundation Trust; Dr Ray Armstrong (2008), Consultant Rheumatologist, Southampton General Hospital; Dr Jeff Aronson (2006–2008), Reader in Clinical Pharmacology, University Department of Primary Health Care, University of Oxford; Dr Darren Ashcroft (2004–2008), Senior Clinical Lecturer, School of Pharmacy and Pharmaceutical Sciences, University of Manchester; Professor David Barnett (2004–2008), Professor of Clinical Pharmacology, University of Leicester; Dr Peter Barry (2004–2008), Consultant in Paediatric Intensive Care, Leicester Royal Infirmary; Professor Stirling Bryan (2006–2008), Head, Department of Health Economics, University of Birmingham; Mr Brian Buckley (2004–2006), Vice Chairman, InContact; Professor John Cairns (2006–2008), Public Health and Policy, London School of Hygiene and Tropical Medicine; Professor David Chadwick (2005–2006), Professor of Neurology, Walton Centre for Neurology and Neurosurgery; Dr Peter I Clark (2004–2006), Honorary Chairman, Association of Cancer Physicians; Ms Donna Covey (2004–2005), Chief Executive, Asthma UK; Dr Mike Davies (2004–2008), Consultant Physician, University Department of Medicine and Metabolism, Manchester Royal Infirmary; Mr Richard Devereaux-Phillips (2004–2006), Public Affairs Manager, Medtronic Ltd; Professor Jack Dowie (2004–2008), Health Economist, London School of Hygiene and Tropical Medicine; Professor Trisha Greenhalgh (2004–2005), Professor of Primary Health Care, University College London; Lynn Field (2006–2008), Nurse Director, Pan Birmingham Cancer Network; Professor Gary A Ford (2004–2005), Professor of Pharmacology of Old Age/Consultant Physician, Royal Victoria Infirmary, Newcastle upon Tyne; Professor Christopher Fowler (2006–2008), Professor of Surgical Education, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London; Dr Fergus Gleeson (2004–2008), Consultant Radiologist, Churchill Hospital, Oxford; Ms Sally Gooch (2004–2008), Independent Nursing and Healthcare Consultant; Mrs Barbara Greggains (2006–2008), Lay member; Mr Sanjay Gupta (2005–2008), Former Service Manager in Stroke, Gastroenterology, Diabetes and Endocrinology, Basildon and Thurrock University Hospitals Foundation NHS Trust; Ms Linda Hands (2004–2005), Consultant Vascular Surgeon, John Radcliffe Hospital, Oxford; Professor Philip Home (2005–2006), Professor of Diabetes Medicine, University of Newcastle upon Tyne; Dr Peter Jackson (2005–2006), Clinical Pharmacologist, University of Sheffield; Professor Peter Jones (2004–2006), Professor of Statistics and Dean Faculty of Natural Science, Keele University; Professor Robert Kerwin (2004–2005), Professor of Psychiatry and Clinical Pharmacology, Institute of Psychiatry, London; Dr Mike Laker (2005–2007), Medical Director, Newcastle Hospitals NHS Trust; Ms Joy Leavesley (2004), Senior Clinical Governance Manager, Whittington Hospital; Dr Ruth Lesirge (2004), Lay member; Ms Rachel Lewis (2004–2006), Nurse Adviser to the Department of Health; Mr Terence Lewis (2006–2008), Lay member; Dr George Levvy (2005–2006), Lay member; Professor Gary McVeigh (2006–2008), Professor of Cardiovascular Medicine, Queens University, Belfast; Professor Jonathan Michaels (2004–2006), Professor of Vascular Surgery, University of Sheffield; Dr Ruairidh Milne (2004–2008), Senior Lecturer in Health Technology Assessment, National Coordinating Centre for Health Technology, University of Southampton; Dr Neil Milner (2004–2008), General Practitioner, Tramways Medical Centre, Sheffield; Dr Rubin Minhas (2004–2008), General Practitioner, CHD Clinical Lead, Medway PCT; Dr John Pounsford (2006–2008), Consultant Physician, Frenchay Hospital, Bristol; Dr Rosalind Ramsay (2006–2008), Consultant Psychiatrist, Adult Mental Health Services, Maudsley Hospital, London; Dr Christa Roberts (2006–2008), UK Country Manager, Abbott Vascular; Dr Stephen Saltissi (2006–2008), Consultant Cardiologist, Royal Liverpool University Hospital; Mr Miles Scott (2004–2006), Chief Executive, Bradford Teaching Hospitals NHS Foundation Trust; Dr Lindsay Smith (2005–2008), General Practitioner, East Somerset Research Consortium; Mr Roderick Smith (2006–2008), Finance Director, West Kent PCT; Mr Cliff Snelling (2006–2008), Lay member; Mr Malcolm Stamp (2004), Chief Executive, Addenbrookes NHS Trust; Professor Ken Stein (2004–2008), Professor of Public Health, Peninsula College of Medicine and Dentistry, University of Exeter; Professor Andrew Stevens (Chair) (2004–2008), Professor of Public Health, University of Birmingham; Dr Rod Taylor (2006–2008), Associate Professor in Health Services Research, Peninsula Medical School, Universities of Exeter and Plymouth

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.

This is the current release of the guideline.

This guideline updates a previous version: National Institute for Clinical Excellence (NICE). Bisphosphonates (alendronate, etidronate, risedronate), selective oestrogen receptor modulators (raloxifene) and parathyroid hormone (teriparatide) for the secondary prevention of osteoporotic fragility fractures in postmenopausal women. London (UK): National Institute for Clinical Excellence (NICE); 2005 Jan. 51 p. (Technology appraisal; no. 87).

This NGC summary is based on the original guideline, which is subject to the guideline developer's copyright restrictions.