Horizon Scanning Technology Briefing National Horizon Scanning Centre Zoledronic Acid (Aclasta) once yearly treatment for postmenopausal osteoporosis December 2006 This technology summary is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes.
Zoledronic Acid (Aclasta) once yearly treatment for postmenopausal osteoporosis Target group Treatment of women with post-menopausal osteoporosis. Background Bisphosphonates are inhibitors of osteoclast-mediated bone resorption. There are several bisphosphonates currently available for the treatment of post-menopausal osteoporosis, with a range of dosing frequencies. Alendronic acid (Fosamax - Merck, Sharp and Dohme) and risedronate sodium (Actonel - Procter and Gamble) are available as oral daily or once weekly preparations. Disodium etidronate (Didronel - Procter and Gamble) is an oral cyclical treatment (given for 14 out of 90 days). Ibandronic acid (Bonviva - Roche) is a once monthly oral, or a three monthly intravenous injection. Zoledronic acid is the first annual bisphosphonate treatment in late-stage development. Technology description Zoledronic acid (Aclasta) is a new bisphosphonate for osteoporosis that is administered as a single once yearly 5mg 15 minute intravenous infusion. It is intended as a substitute for other bisphosphonates. Zoledronic acid is currently available as an intravenous infusion (Aclasta 5mg) for Paget s disease of the bone, and for prevention of skeletal related events in advanced malignancies (Zometra 4mg). Innovation and/or advantages If zoledronic acid once yearly is equivalent to current bisphosphonate preparations, and has an improved side-effect profile compared with alendronic acid (regarding osteonecrosis of the jaw), then it may contribute to improved patient concordance due to the convenience of an annual preparation. Developer Novartis Pharmaceuticals. Place of use Home care e.g. home dialysis Secondary care e.g. general, non-specialist hospital General public e.g. over the counter Community or residential care e.g. district nurses, physio Tertiary care e.g. highly specialist services or hospital Other: Primary care e.g. used by GPs or practice nurses Emergency care e.g. paramedic services, trauma care NHS or Government priority area: Cancer Cardiovascular disease Children Diabetes Chronic conditions Mental health Older people Public health Renal disease Women s health None identified Other: Relevant guidance NICE appraisal. Bisphosphonates (alendronate, etidronate, risedronate), selective oestrogen receptor modulators (raloxifine) and parathyroid hormone (teriparatide) for Dec 2006 2
the secondary prevention of osteoporotic fragility fractures in postmenopausal women, 2005 1. SIGN guidance. Osteoporosis: A national clinical guideline, 2003 2. National Service Framework for Older People, 2001 3. Royal College of Physicians. Osteoporosis: clinical guidelines for prevention and treatment, 1999 4. Update of pharmacological interventions and an algorithm for management, 2001. NICE guideline (in development). Osteoporosis: assessment of fracture risk and the prevention of osteoporotic fractures in individuals at high risk. Date of issue to be announced. NICE appraisals (in development): Osteoporosis secondary prevention including strontium ranelate. Expected date of issue March 2007. Clinical need and burden of disease It is estimated that between 1.2 and 2 million women have osteoporosis (i.e. have a T- score below 2.5 SD a ) in England and Wales 1. Prevalence increases markedly with age after the menopause, and approximately 30% of women in England and Wales aged 80 years and older are estimated to have osteoporosis. The annual incidence of symptomatic osteoporotic fractures (including recurrent fractures) is approximately 180,000 1. Osteoporotic fractures occur most commonly in the vertebrae, hip and wrist and are associated with substantial disability, pain and reduced quality of life. In 2000, it was estimated that the total cost of treating osteoporotic fractures in postmenopausal women was between 1.5 and 1.8 billion 1. It is uncertain how many patients will wish to change from an oral to the intravenous route of administration, but the company state that approximately 66% of postmenopausal women with osteoporosis and osteopenia taking oral alendronate would prefer an annual infusion to a weekly formulation 5. Existing comparators and treatments Advice on preventing osteoporosis given to the general population includes undertaking regular exercise, reduction of smoking and supplementing the diet with calcium and vitamin D. Current management strategies in high risk groups and those with a previous fracture related to osteoporosis, include: bisphosphonates selective oestrogen receptor modulators (e.g. raloxifene (Evista) - Lilly) as an alternative treatment option where bisphosphonates are contraindicated teriparatide (Forsteo Lilly) for patients who cannot take or have an unsatisfactory response to bisphosphonates. strontium ranelate (Protelos Servier) is currently under review at NICE Efficacy and safety Within the phase III trial programme (Health Outcomes and Reduced Incidence with Zoledronic acid ONce yearly HORIZON), there are four double-blind, randomised placebocontrolled trials ongoing: a Osteoporosis is defined as a T score of below 2.5 standard deviations (SD) from the bone mass density in an average 25 year old woman Dec 2006 3
Postmenopausal Fracture Trial Recurrent Fracture Trial men and women Prevention of Osteoporosis postmenopausal women Osteoporosis in Men National Horizon Scanning Centre Trial name or code HORIZON - Postmenopausal fracture trial 6 Extension of HORIZON - Postmenopausal fracture trial 7 HORIZON - Recurrent fracture trial after recent hip fracture in men and women 8 Sponsor Novartis Pharmaceuticals Novartis Pharmaceuticals Novartis Pharmaceuticals Status Abstract Ongoing Ongoing. Enrollment complete. Location Multinational Multinational Multinational Design Participants in trial placebo-controlled. Patients received 5mg zoledronic acid infusion once yearly or placebo. Patients also received calcium and vitamin D. n=7,736 postmenopausal women. It is not clear if the women had a previous fracture or just low bone mass. Extension of HORIZON. Patients on placebo in main trial will be switched to zoledronic acid. Patients also receive calcium and vitamin D. n=2,480 postmenopausal women. It is not clear if the women had a previous fracture or just low bone mass. Follow-up 3 years 3 years (6 years from start 2 years of randomised trial) Reporting Not known 2009 Unknown date Primary outcome Incidence of new vertebral fractures and hip fractures. Change in femoral neck bone mass density (BMD) Secondary outcomes Key results Major adverse effects Risk reduction in clinical spine fractures and non-spine fractures. Risk reduction in new spine fractures 70% compared to placebo (p<0.0001); risk reduction in hip fractures 41% (p=0.0024); and 25% for nonvertebral fractures (p=0.0002) b. Comparable to placebo, particularly in kidney and jaw osteonecrosis. b Information provided by company. at year 6 relative to year 3 Change in biochemical markers of bone turnover. Change in spine and distal radius BMD at year 4.5 and 6; change in femoral neck, total hip and trochanter BMD. New vertebral fractures and incidence of clinical fracture. double-blind, placebo controlled. 5mg zoledronic acid iv yearly vs placebo. Patients also received calcium and vitamin D n=2,128, 1,618 (76%) female. 83% of women were over 55 years. Time to first fracture after surgical repair of hip fracture. Change in total hip and femoral neck BMD Dec 2006 4
The most common adverse events included fever, musclepain, flu-like symptoms, headache and bone pain. These mainly occurred in first 3 days and decreased with subsequent treatments. Atrial fibrillation occurred in 1.3% compared to 0.5% in the placebo group. National Horizon Scanning Centre Trial name or code Zoledronic acid versus alendronate 9 Switching trial from alendronate to zoledronic acid 10 Switching trial from teriparatide to zoledronic acid 11 Sponsor Novartis Pharmaceuticals Novartis Pharmaceuticals Novartis Pharmaceuticals Status - Ongoing Abstract Ongoing Location Germany Multicentre USA Design Participants in trial open-label, active control. n=600 post-menopausal women with osteopenia and osteoporosis. double-blind, doubleplacebo. Single infusion of 5mg zoledronic acid vs continuation therapy with oral alendronate 70mg weekly. Patients must have been taking alendronate for at least 1 year prior to randomisation. n=225 postmenopausal women with osteopenia and osteoporosis. Follow-up 1 year 1 year 1 year Reporting Not known Not known Not known date Primary outcome Change in bone metabolism marker. Change in lumbar spine BMD from baseline to one Secondary outcomes Key results Major adverse events Change in biochemical markers of bone turnover; quality of life. year. Change in biochemical markers of bone turnover. BMD values in patients randomised to zoledronic acid similar to those patients who continued treatment with alendronate. Adverse events were similar to those observed in HORIZON trial. Phase II, non-randomised, open-label uncontrolled. n=35 post-menopausal women. Patients must have been taking teriparatide for at least 1 year prior to trial. Change in lumber spine BMD. Change in hip bone density; lumbar spine density; change in biochemical markers of bone turnover. Dec 2006 5
Estimated cost and cost impact A single annual 15 minute infusion of zoledronic acid will cost 283.74 per year. There will be additional costs associated with intravenous administration. It is not clear if patients will be managed in a primary care/community setting, or if secondary care services will be required. Current bisphosphonate alternatives cost: Drug Route Dose Annual cost c Alendronate (nonproprietary) oral 70mg once weekly 173 Risedronate sodium oral 35mg once weekly 264 Disodium oral 90 day cycles: one 400mg Didronel x 14 days, 84 etidronate followed by one Calcit tablet daily for 76 days Ibandronic acid oral 150mg once a month 257 iv 15-30 seconds, 3 mg every 3 months 320 Potential or intended impact speculative Patients Reduced morbidity Quicker or more accurate diagnosis Reduced mortality or increased survival Earlier identification of disease Improved quality of life for patients and/or carers Other: Services Increased use e.g. length of stay, Service reorganisation required out-patient visits Decreased use e.g. shorter length of stay, reduced Other: referrals Staff or training required Costs Increased unit cost compared to alternative Increased costs: more patients coming for treatment New costs: - IV administration Savings: Other: Increased costs: capital investment needed References 1 National Institute for Health and Clinical Excellence. Bisphosphonates (alendronate, etidronate, risedronate), selective oestrogen receptor modulators (raloxifine) and parathyroid hormone (teriparatide) for the secondary prevention of osteoporotic fragility fractures in postmenopausal women. Technology Appraisal Guidance No.87, January 2005. London: 2 Scottish Intercollegiate Guidelines Network. Osteoporosis: A national clinical guideline. Edinburgh 2003. 3 Department of Health. National Service Framework for Older People. (March 2001) 4 Guideline Development Group of the Royal College of Physicians. Osteoporosis. Clinical guidelines for prevention and treatment. London: RCP, March 1999 (updated January 2001). 5 Novartis press release: Aclasta (Zoledronic acid 5mg solution for infusion) Fact sheet. March 2006. Available online at http://164.109.68.9/download/news/aclasta_fact_sheet_10_03_06.pdf. Accessed 11/12/2006. Refers to Lindsay R, et al. A single zoledronic acid 5mg infusion is preferred over weekly 70 mg oral alendronate in a clinical trial of postmenopausal women with osteoporosis/osteopenia. Presented at Sixth European Congress on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ECCEO), March 2006, Vienna, Austria. c BNF 52, September 2006. Dec 2006 6
6 Black DM et al. Effect of once-yearly infusion of Zoledronic acid 5mg on spine and hip fracture reduction in postmenopausal women with osteoporosis: The HORIZON pivotal fracture trial. Presented at 28 th Annual meeting of the American Society for Bone and Mineral Research. September 15-19 2006. Philadelphia. 7 ClinicalTrials.gov. Double blind extension of HORIZON pivotal fracture trial (zoledronic acid in the treatment of postmenopausal osteoporosis). Available online at http://clinicaltrials.gov/ct/show/nct00145327?order=1. Accessed 11/12/2006. 8 Lyles KW, Colon-Emeric CS, Pieper CF et al. The Horizon recurrent clinical fracture after recent hip fracture trial (RFT): study cohort description. Presented at 28 th Annual meeting of the American Society for Bone and Mineral Research. September 15-19 2006. Philadelphia. 9 ClinicalTrials.gov. Safety/efficacy of zoledronic acid and alendronate on bone metabolism in postmenopausal women with osteoporosis. Available online at http://clinicaltrials.gov/ct/show/nct00404820?order=1. Accessed 11/12/2006. 10 McClung M et al. Single infusion of zoledronic acid 5mg provides sustained benefits in BMD and biomarkers at 12 months in postmenopausal women with low bone mineral density and prior alendronate therapy. Presenrted at 28 th Annual meeting of the American Society for Bone and Mineral Research. September 15-19 2006. Philadelphia. 11 ClinicalTrials.gov. IV Zoledronic acid after Forteo in postmenopausal women. Available online at http://clinicaltrials.gov/ct/show/nct00361595?order=1. Accessed 11/12/2006. The National Horizon Scanning Centre is funded by the Research and Development Division of the Department of Health, England The National Horizon Scanning Centre, Department of Public Health and Epidemiology University of Birmingham, Edgbaston, Birmingham, B15 2TT, England Tel: +44 (0)121 414 7831 Fax +44 (0)121 414 2269 www.pcpoh.bham.ac.uk/publichealth/horizon Dec 2006 7