Title: Bisphosphonates for the Primary and Secondary Prevention of Osteoporotic Fractures: A Cost Utility Analysis Date: 22 January 2008 Context and policy issues: Osteoporosis is defined as a systemic skeletal disease characterized by low bone mass and micro-architectural deterioration of bone tissue, leading to increased bone fragility, and a consequent increase in fracture risk. 1 The most common clinical manifestations in women who have osteoporosis are fractures of the hip, vertebrae or wrist. The major source of morbidity from osteoporosis arises from hip fractures. 2 Prevention of such osteoporotic fractures is a key public health issue in Canada. 2 Indeed, the incidence of osteoporosis is expected to increase significantly as the Canadian population ages (i.e. 25% of the population will be over 65 years of age by the year 2041). The condition affects both women and men, albeit to different degrees, and the management of these patients is associated with important medical, social and financial implications. 2 It is reported that in women who sustain a hip fracture, 5 will become dependent on others for their daily activities, one-third of women will be discharged to nursing homes and in older women, excess mortality in the first year may be as high as. 2,3 It follows that the financial burden is significant. Many of the consequences of osteoporosis are potentially preventable through use of a number of non-pharmacological and pharmacological interventions. 2 The most commonly prescribed pharmacological therapies for osteoporosis are bisphosphonates and calcium supplementation. Three different bisphosphonates are licensed for the treatment of osteoporosis in Canada: etidronate, alendronate and risedronate. 4 Typical daily dose for alendronate and risedronate are 10 mg and 5 mg respectively. However recent more convenient dosings of both therapies are available: alendronate 70 mg once weekly and risedronate 35 mg once weekly. Etidronate is taken cyclically; in that a 400 mg tablet is taken every day for two weeks (14 days) followed by two-and-a-half months (76 days) of calcium supplements (500 mg). The calcium supplements are included in the prescription package. This cycle is repeated four times annually. This regimen is specifically recommended for etidronate in order to prevent a complication called osteomalacia which leads to bone softening. 2 Disclaimer: The Health Technology Inquiry Service (HTIS) is an information service for those involved in planning and providing health care in Canada. HTIS responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources and a summary of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. HTIS responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material. It may be copied and used for non-commercial purposes, provided that attribution is given to CADTH. Links: This report may contain links to other information on available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners own terms and conditions.
Since their entry into the Canadian market, utilization of bisphosphonates has significantly increased over the past five years with sales exceeding $300 million in 2004. 5 Thus, given the substantive use and cost of these agents, the need to assess the clinical and cost-effectiveness of this drug class in order to aid decision makers in determining if there is good value in funding these drugs for the primary and secondary prevention of osteoporotic fractures was recognized and two CADTH reports were commissioned and published in 2006. 5,6 The first report consisted of a detailed systematic review of the evidence on the effect of bisphosphonates on osteoporotic fractures. 5 The second report consisted of a comprehensive economic analysis comparing teriparatide, etidronate, alendronate and risedronate. 6 The latter report led to the firm conclusion that teriparatide was not a cost effective treatment and that the cost-effectiveness of bisphosphonates was dependent on the age and fracture history of the patient. Since the publication of these reports further information have become available. The original report only dealt with the daily formulations of risedronate and alendronate 7,8,9 whilst the once weekly formulations are cheaper and as effective. Alendronate is now available in a generic format which is substantially less expensive than the branded format. 10,11,12 Updated Cochrane reviews on bisphosphonates will be available in January 2008. From a policy perspective, certain Canadian jurisdictions provide reimbursement for all bisphosphonates (open benefit) whilst others are not providing coverage for alendronate and/or risedronate without first treatment with etidronate. Some publicly-funded programs also have a high proportion of Aboriginal population. There is a need to assess the cost-effectiveness of all bisphosphonates, and their associated dosage forms, in this particular population in order to guide policy decisions. Such an assessment will be based on a reanalysis using the same model used in the previous CADTH report. Research questions: 1. For an Aboriginal woman with osteoporosis and a specific age and fracture history, which bisphophonate can be considered cost effective? This research question can be framed as follows: Populations: Women with osteoporosis aged 50 or over with or without previous fracture. Analysis will be conducted for a 50, 55, 60, 65, 70, 75 and 80 year old woman with and without previous fracture. As the analysis conducted in the previously published CADTH report was for the general Canadian population, this analysis will consider whether specific adjustments to the economic model are required for the Aboriginal population. Interventions: All bisphosphonates currently available for treatment of osteoporosis: alendronate, etidronate and risedronate. These include both the once daily and once weekly dosage forms for alendronate and risedronate as well as generic drug products for alendronate. Comparisons: All bisphosphonates will be compared with themselves and with no therapy. Outcomes: Comparisons will be based on incremental costs, incremental quality adjusted life years (QALYs) and the incremental cost per QALY gained. Bisphosphonates for the Primary and Secondary Prevention of Osteoporotic Fractures 2
Methods: Original Model This analysis uses the same decision analytic model for osteoporosis adopted in the original report. 6 A fuller description of the model design and the parameters used to populate the model is contained in the original report. Briefly, the model reflects the natural history of women with osteoporosis incorporating the sequelae associated with osteoporosis (e.g. fracture) and also the transition of women both in terms of the development of osteoporosis, history of fracture and residential status (Figure 1). The model uses the most recently available data relevant to the Canadian population. Given the chronic nature of osteoporosis the model is a Markov model with a one year cycle length and a lifetime horizon. The probability of a woman experiencing a hip, wrist or vertebral fracture is assumed to be dependent on three factors; age, osteoporotic status and previous history of osteoporotic fractures. 13,14,15 Both hip and vertebral fractures are associated with excess mortality and hip fractures are also associated with increased admission to long term care facilities (LTC). 13,16,17 In addition, the probability of hip fracture and the probability of mortality post hip fracture increases if a women resides in LTC facilities. 18 The model is populated with relevant transition probabilities and estimates of the costs and utilities associated with each health state (Table 1). Input parameters estimated through sample information rather than population estimates are represented by a probability density function based on their expected value and the associated uncertainty. The probability density functions represent the likelihood of alternative population estimates for the parameters of interest. Both drug prices and input values obtained from population rather than sample data are assumed fixed. The model is developed within a Microsoft Excel 2000 spreadsheet incorporating the Crystal Ball software enhancement to facilitate Monte Carlo simulation (MCS). 19 The MCS involves obtaining several outcome estimates by re-running the model employing different values for each data input randomly selected from that variables probability density function. 20 Changes to the Original Model Changes to the original model were considered due to the following: The costs of bisphosphonates should reflect currently available prices, including prices of once weekly dosage forms for alendronate and risedronate as well as prices of generic products for alendronate. The costs associated with fracture and long term care need to be updated to 2007 costs The risk of fracture for osteoporotic women could be different for the specific population of Aboriginal women The relative risks of fracture may have changed considerably within the updated Cochrane reviews. Each of these is now considered in turn. Bisphosphonates for the Primary and Secondary Prevention of Osteoporotic Fractures 3
Costs of Bisphosphonates The current acquisition costs for bisphosphonates were obtained from the Alberta Drug Program Formulary 21 and included a pharmacy dispensing fee of $10.93 per three month period. Costs for alendronate (generic once a week) and risedronate (branded once a week) were now substantially lower than in the original report. Costs of Fractures and Long Term Care The costs of fractures and long term care were increased by an inflation rate of 15.1% based on the increase in costs from 2001 to 2007. 22 It was assumed that the resources used in association with the care of patients with fractures would not have changed substantially in this period. Risk of Fracture in the Aboriginal Population The First Nations Bone Health study found evidence that Canadian Aboriginal women have lower bone mineral density (BMD) than white Canadian women. 23 A similar finding has been reported for Native American women. 24 These differences in BMD have been linked to the twofold increase in fractures found in Canadian Aboriginal women. 25 Numerous studies have explored the reasons for the identified decrease in BMD and increased fracture rates. Studies have suggested that differences between ethnic groups in terms of bone area 23, prevalence of diabetes and other comorbidities 25, prevalence of substance abuse 25, calcium intake 26, body weight 27 and smoking behaviour 28 may be contributing factors. These differences need not imply that the baseline risk of fracture within the decision model has to be adjusted. The model stratifies women by age, BMD and fracture history. The differences between ethnic groups may be explained by different proportions within these stratified groupings rather than differences in fracture risk within these groupings. The one study which explored this was a US study of almost 200 000 postmenopausal women. 27 The study found that after adjusting for BMD, fracture history and other covariates the risk of fracture was lower for Native American women although this finding was not statistically significant. Thus, the limited evidence available suggests that differences in fracture rates between white and aboriginal women may be explained by differences in BMD rather than inherent higher risks within one population. Thus, the original analysis based on the general Canadian population data on fracture risks is assumed to be appropriate for the Aboriginal population, though it should be expected that a higher proportion of elderly women in this population will be osteoporotic. Relative Risks of Fracture The final published version of the updated Cochrane reviews was not available at the time this report was prepared. However, there are no substantive differences in the estimates of relative risks of fracture for each of the bisphosphonates from the original CADTH report. 5 Furthermore, the updated Cochrane reviews do not include an analysis based on the number of fractures and the number of years of therapy as required for the economic analysis nor does it distinguish between types of non vertebral fractures. Thus, given that the data from the upcoming review would not be suitable for inclusion in this analysis, it was assumed that the relative risks used in the original report were suitable. Bisphosphonates for the Primary and Secondary Prevention of Osteoporotic Fractures 4
Analytical framework The model allows the conduct of a cost utility analysis, where outcomes are expressed in terms of QALYs. Analysis is presented in terms of the incremental cost per outcome gained. Analysis is conducted from the perspective of a provincial ministry of health or equivalent. 29 Costs and benefits were discounted at 5% per annum. 29 Analysis is presented for the following women 50 year old osteoporotic women with no previous fracture 55 year old osteoporotic women with no previous fracture 60 year old osteoporotic women with no previous fracture 65 year old osteoporotic women with no previous fracture 70 year old osteoporotic women with no previous fracture 75 year old osteoporotic women with no previous fracture 80 year old osteoporotic women with no previous fracture 50 year old osteoporotic women with previous fracture 55 year old osteoporotic women with previous fracture 60 year old osteoporotic women with previous fracture 65 year old osteoporotic women with previous fracture 70 year old osteoporotic women with previous fracture 75 year old osteoporotic women with previous fracture 80 year old osteoporotic women with previous fracture In the original report a wide degree of sensitivity analysis was conducted to assess the robustness of the study s results to changing assumptions within the model. These had little effect on the estimates of incremental cost and outcome and a repeat of these analyses was not considered necessary for this report. An additional sensitivity analysis was conducted relating to the potential cost of a generic formulation for risedronate. For this analysis, it was assumed that the generic cost of risedronate would have the same degree of relative price reduction as found with the generic formulation of alendronate. Estimates of cost and QALYs for each therapy were obtained through MCS analysis. 20 As the relationship between input parameters and outcomes can be non linear, the expected values of outcomes obtained from a MCS analysis can differ from that of the deterministic analysis. 30 Probability distributions were specified for relevant parameters and different estimates of outcomes such as costs, time with response and QALYs were obtained by re-running the model employing values for each data input randomly selected from that variables probability distribution. In this study, 3 000 replications were conducted; i.e. a set of 3 000 outcome estimates were obtained. Cost effectiveness acceptability curves (CEACs) are supplied for six patient scenarios (65, 70 and 75 year old women with and without previous fracture). 31 Sensitivity analysis is conducted with the CEACs reproduced assuming the availability of generic risedronate. Within a CEAC, the probability that a particular treatment therapy is the optimal therapy is depicted for each potential value of λ (the threshold value for a QALY). Bisphosphonates for the Primary and Secondary Prevention of Osteoporotic Fractures 5
Summary of findings: For all patient scenarios alendronate is shown to be both less costly and equally or more effective than risedronate (Tables 2 and 3). In all patient scenarios etidronate is shown to be more costly and no more effective than no therapy (Tables 2 and 3). Thus, for all patient scenarios, the most cost effective treatment options are either no therapy or alendronate with the optimum being dependent on the willingness of a decision maker to pay for a QALY gained. If a decision maker was willing to pay $50 000 per QALY gained, alendronate would be the most cost effective option for women aged over 65 with a previous fracture and osteoporotic women aged 70 and over without a previous fracture. For all other women, none of the bisphosphonates can be considered cost effective. However, if a decision maker was willing to pay up to $100 000 per QALY gained, alendronate would be the most cost effective option for all osteoporotic women aged over 65. When compared to no therapy, risedronate is not as cost effective as alendronate (Table 4). Indeed, the available data suggests that alendronate is more effective and more cost effective than risedronate. However, an important limitation of these findings is that they are based on indirect comparisons as there is no data comparing the two therapies in terms of their effects on site specific fracture. The only comparative trial of once weekly alendronate and risedronate did find that patients on alendronate were more likely to maintain or gain BMD than those on risedronate. 32 However, without detailed data on fracture rates it is not possible to conclude with certainty that alendronate would be more effective in primary or secondary prevention of fractures. Of interest, the relative cost-effectiveness of risedronate would be much improved should a generic formulation of risedronate become available. However, the incremental cost per QALY for risedronate would still be much higher than for alendronate and therefore for all threshold values for a QALY, risedronate could be considered cost effective compared to no therapy for only a small proportion of osteoporotic women. There is a great deal of uncertainty over these results as shown by the CEACs (Figure 2). The older the women the greater the probability that alendronate will be the most cost effective treatment option. For all patient scenarios the probability that either no therapy or etidronate is most cost effective is non negligible. However, the probability that risedronate would be the most cost effective is less than 5% for all scenarios for all values of a QALY between $0 and $100 000. This finding did not change when considering a potential generic price of risedronate (Figure 3). Conclusions and implications for decision or policy making: This analysis concludes that the optimum therapy will vary by a woman s age and fracture history and by the decision maker s willingness to pay for a QALY gained. Alendronate would be considered the most cost effective option in osteoporotic women over 65 with a previous fracture and in those 70 and over without a previous fracture given a willingness to pay of $50 000 per QALY. For all other women, none of the bisphosphonates can be considered cost effective, based on a willingness to pay of $50 000. For a willingness to pay of $100 000 alendronate would be considered the most cost effective option for all osteoporotic women aged over 65. These conclusions apply to both the general Canadian population as well as to the Aboriginal population of women with osteoporosis and take into consideration the availability of once weekly dosage forms for alendronate and risedronate as well as generic alendronate products. Bisphosphonates for the Primary and Secondary Prevention of Osteoporotic Fractures 6
Prepared by: Doug Coyle; Department of Epidemiology and Community Medicine, University of Ottawa. Kathryn Coyle; Coyle Consultancy Kelly Farrah, MLIS, Information Specialist, HTIS Health Technology Inquiry Service Email: htis@cadth.ca Tel: 1-866-898-8439 Bisphosphonates for the Primary and Secondary Prevention of Osteoporotic Fractures 7
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14. Marshall D, Johnell O, Wedel H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ 1996;312:1254-9. 15. Klotzbuecher CM, Ross PD, Landsman PB et al. Patients with prior fractures have an increased risk of future fractures: A summary of the literature and statistical synthesis. J Bone Min Res 2000;15:721-39. 16. Kado DM, Browner WS, Palermo L et al. Vertebral fractures and mortality in older women: a prospective study. Study of Osteoporotic Fractures Research Group. Arch Intern Med 1999;159:1215-20. 17. Cree M, Soskolne CL, Belseck E et al. Mortality and institutionalization following hip fracture. J Am Geriatr Soc 2000;48:283-288. 18. Papadimitropoulos E. An economic evaluation of calcium and vitamin D versus hormone replacement therapy, for the prevention of hip fractures in Canadian postmenopausal women [dissertation]. Toronto: University of Toronto; 1999. 19. Crystal Ball [version 5.1]. Denver (CO): Decisioneering; 2000. 20. Doubilet P, Begg CB, Weinstein MC et al. Probabilistic sensitivity analysis using Monte Carlo simulation: a practical approach. Med Decis Making 1985;5:157-177. 21. Drug benefit list. Edmonton: Alberta Health & Wellness. Available: https://www.ab.bluecross.ca/dbl/publications.html (accessed 2008 Jan 10). 22. Inflation calculator. Ottawa: Bank of Canada; 2006. Available: http://www.bankofcanada.ca/en/rates/inflation_calc.html (accessed 2008 Jan 10). 23. Leslie WD, Metge CJ, Weiler HA et al. Bone density and bone area in Canadian Aboriginal women: the First Nations Bone Health Study. Osteoporos Int 2006;17:1755-62. 24. Perry HM, III, Bernard M, Horowitz M et al. The effect of aging on bone mineral metabolism and bone mass in Native American women. J Am Geriatr Soc 1998;46:1418-22. 25. Leslie WD, Derksen S, Prior HJ et al. The interaction of ethnicity and chronic disease as risk factors for osteoporotic fractures: a comparison in Canadian Aboriginals and non- Aboriginals. Osteoporos Int 2006;17:1358-68. 26. Pothiwala P, Evans EM, Chapman-Novakofski KM. Ethnic variation in risk for osteoporosis among women: a review of biological and behavioral factors. J Womens Health (Larchmt) 2006;15:709-19. 27. Barrett-Connor E, Siris ES, Wehren LE, Miller PD, Abbott TA, Berger ML, et al. Osteoporosis and fracture risk in women of different ethnic groups. J Bone Miner Res 2005;20:185-94. 28. Filner JJ, Krohn KD, Lapidus JA, Becker TM. Risk factors for osteoporosis in Alaska Native women: a cross-sectional survey. Alaska Med 2002;44(1):8-13, 21. Bisphosphonates for the Primary and Secondary Prevention of Osteoporotic Fractures 9
29. Canadian Agency for Drugs and Technologies in Health. Guidelines for the economic evaluation of health technologies: Canada. 3rd ed. Ottawa: The Agency; 2006. 30. Fenwick E, Claxton K, Sculpher M. Representing uncertainty: the role of costeffectiveness acceptability curves. Health Econ 2001;10:779-87. 31. Thompson KM, Graham JD. Going beyond the single number: using probabilistic risk assessment to improve risk management. Human and Ecological Risk Assessment 1996;2:1008-34. 32. Bonnick S, Saag KG, Kiel DP et al. Comparison of weekly treatment of postmenopausal osteoporosis with alendronate versus risedronate over two years. J Clin Endocrinol Metab. 2006;91:2631-7. 33. Statistics Canada. Life tables, Canada and provinces, 1990-92. 84-537 Occasional. Ottawa: Statistics Canada; 1995. 34. Hu R, Mustard CA, Burns C. Epidemiology of incident spinal fracture in a complete population. Spine 1996;21:492-9. 35. Coyle D, Cranney A, Lee KM et al. Cost effectiveness of nasal calcitonin in postmenopausal women: use of Cochrane Collaboration methods for meta-analysis within economic evaluation. PharmacoEconomics 2001;19:565-75. 36. Tenenhouse A, Joseph L, Kreiger N et al. Estimation of the prevalence of low bone density in Canadian women and men using a population-specific DXa reference standard: The Canadian Multicentre Osteoporosis Study (CaMos). Osteoporos Int 2000;10:897-904. 37. Statistics Canada. National population health survey. Ottawa: Statistics Canada; 1995. 38. Wiktorowicz ME, Goeree R, Papaioannou A et al. Economic implications of hip fracture: health service use, institutional care and cost in Canada. Osteoporos Int 2001;12:271-8. 39. Goeree R, O Brien B, Pettitt D et al. An assessment of the burden of illness due to osteoporosis in Canada. Journal SOGC 1996;Supplement;15-22. 40. Ontario guide to case costing (version 2). Toronto: Ontario Case Costing Initiative; 2000. 41. Ontario Ministry of Health and Long-term Care. Ontario Health Insurance (OHIP) schedule of benefit and fees. Toronto: The Ministry; 2001. 42. Cranney A, Coyle D, Pham BA et al. The psychometric properties of patient preferences in osteoporosis. J Rheum 2001;28:132-7. Bisphosphonates for the Primary and Secondary Prevention of Osteoporotic Fractures 10
Appendices: Figure 1: Design of Decision Model a. Fractures No fracture No fracture Hip fracture Hip fracture Hip fracture 2 nd year Hip fracture 2 nd year Wrist fracture Wrist fracture Vertebral fracture Vertebral fracture b. Osteoporotic status Non osteoporotic Non osteoporotic Osteoporotic no fracture history Osteoporotic fracture history Osteoporotic no fracture history Osteoporotic fracture history c. Residential status Community dwelling Living in long term care Community dwelling Living in long term care Bisphosphonates for the Primary and Secondary Prevention of Osteoporotic Fractures 11
Table 1: Parameter Estimates Parameter Annual probability of death : all cause 33 Probability of mortality post hip fracture: community 18 Probability of mortality post hip fracture: long term care 18 Annual probability of hip fracture: community 13 Annual probability of hip fracture: long term care 18 Annual probability of vertebral fracture 34 50-59 60-69 70-79 >80 Annual probability of wrist fracture 35 50-59 60-69 70-79 >80 Proportion of vertebral fractures requiring 60-69 hospitalization 34 70-79 >80 Proportion of women residing in LTC 18 65-69 70-74 75-79 80-84 >85 Proportion of women who are osteoporotic 36 50-59 60-69 70-79 >80 Utility value for no current fracture 37 65-69 70-74 75-79 80-84 >85 Probability of admission to LTC post hip fracture 17 65-74 75-84 >85 Estimate Age specific 0.010*e 0.084*age 0.055*e 0.072*age 0.0578*e 0.096*age 73.99*e 0.049*age 0.000543 0.000899 0.001920 0.004383 0.000814 0.003152 0.004021 0.004380 0.30 0.38 0.45 0.68% 1.57% 4.19% 10.71% 29.93% 0.06 0.182 0.27 0.421 0.86 0.83 0.79 0.70 0.55 0.056 0.166 0.298 Bisphosphonates for the Primary and Secondary Prevention of Osteoporotic Fractures 12
Parameter Relative risk of fracture for reduction in BMD equivalent to one standard deviation of the young adult mean 14 1.5 Estimate Relative increase in risk of fracture for osteoporotic women with previous fracture 15 1.32 Relative risk of mortality post vertebral fractures 16 1.16 Attributability of long term care post fracture to fracture 9 0.5 Cost of hip fracture 38 Women living in the community 50-64 65-74 75-84 >85 Women moving to LTC 50-64 65-74 75-84 >85 Women who remain living in LTC 50-64 65-74 75-84 >85 $16 238 $25 469 $32 005 $31 429 $40 799 $50 030 $56 565 $55 990 $8 841 $18 073 $24 608 $24 032 Women who die following fracture $17 841 Cost of wrist fracture 39,40,41 $317 Cost of vertebral fracture 39,40,41 ambulatory hospitalized $147 $5 348 Annual cost of long term care 6 $26 472 Utility values 42 hip fracture wrist fracture vertebral fracture Annual cost of drug therapy 21 alendronate (generic) etidronate risedronate (brand) 0.536 0.976 0.674 $334 $211 $567 Bisphosphonates for the Primary and Secondary Prevention of Osteoporotic Fractures 13
Parameter Estimate Continuation rates with therapy 6 0.57 Coefficient for benefit beyond therapy curtailment (0= linear decline) 6 0 Relative reduction in hip fractures 5,6 alendronate 0.47 etidronate 1.14 risedronate 0.74 Relative reduction in wrist fractures 5,6 alendronate 0.50 etidronate 0.80 risedronate 0.65 Relative reduction in vertebral fractures 5,6 alendronate 0.49 etidronate 0.45 risedronate 0.59 Details of the probability distributions used for parameter estimates can be obtained from the original report. 6 Bisphosphonates for the Primary and Secondary Prevention of Osteoporotic Fractures 14
Table 2: Costs, QALYs and ICERs for Patients with Previous Fracture Lifetime Costs Lifetime QALYs Incremental Cost per QALY versus no Therapy Interpretation Age 50 Alendronate $3 600 13.218 $474 600 Cost effective if value of a QALY greater than $474 600 Risedronate $4 000 13.217 $1 630 100 Dominated by Alendronate Etidronate $3 300 13.216 Dominated Dominated by no therapy No Therapy $2 900 13.216 N/A Cost effective if value of a QALY less than $474 600 Age 55 Alendronate $4 600 12.192 $291 200 Cost effective if value of a QALY greater than $291 200 Risedronate $5 100 12.191 $1 037 100 Dominated by Alendronate Etidronate $4 400 12.189 Dominated Dominated by no therapy No Therapy $4 000 12.190 N/A Cost effective if value of a QALY less than $291 200 Age 60 Alendronate $5 700 10.951 $159 500 Cost effective if value of a QALY greater than $159 500 Risedronate $6 200 10.949 $597 200 Dominated by Alendronate Etidronate $5 500 10.946 Dominated Dominated by no therapy No Therapy $5 100 10.947 N/A Cost effective if value of a QALY less than $159 500 Age 65 Alendronate $6 900 9.496 $66 600 Cost effective if value of a QALY greater than $66 600 Risedronate $7 400 9.493 $330 400 Dominated by Alendronate Etidronate $7 000 9.487 Dominated Dominated by no therapy No Therapy $6 500 9.490 N/A Cost effective if value of a QALY less than $66 600 Age 70 Alendronate $7 800 7.817 $25 800 Cost effective if value of a QALY greater than $25 800 Risedronate $8 400 7.812 $189 300 Dominated by Alendronate Etidronate $8 100 7.803 Dominated Dominated by no therapy No Therapy $7 500 7.807 N/A Cost effective if value of a QALY less than $25 800 Age 75 Alendronate $8 600 6.056 Dominant No therapy is dominated by Alendronate Risedronate $9 500 6.047 $88 300 Dominated by Alendronate Etidronate $9 600 6.033 Dominated Dominated by no therapy No Therapy $8 800 6.040 N/A No therapy is dominated by Alendronate Age 80 Alendronate $8 500 4.304 Dominant No therapy is dominated by Alendronate Risedronate $9 500 4.292 $44 800 Dominated by Alendronate Etidronate $10 000 4.272 Dominated Dominated by no therapy No Therapy $9 000 4.282 N/A No therapy is dominated by Alendronate Bisphosphonates for the Primary and Secondary Prevention of Osteoporotic Fractures 15
Table 3: Costs, QALYs and ICERs for Patients with No Previous Fracture Lifetime Costs Lifetime QALYs Incremental Cost per QALY versus no Therapy Interpretation Age 50 Alendronate $3 000 13.231 $603 200 Cost effective if value of a QALY greater than $603 200 Risedronate $3 400 13.231 $2 038 300 Dominated by Alendronate Etidronate $2 700 13.230 Dominated Dominated by no therapy No Therapy $2 400 13.230 N/A Cost effective if value of a QALY less than $603 200 Age 55 Alendronate $3 900 12.209 $369 100 Cost effective if value of a QALY greater than $369 100 Risedronate $4 300 12.208 $1 289 500 Dominated by Alendronate Etidronate $3 600 12.207 Dominated Dominated by no therapy No Therapy $3 200 12.208 N/A Cost effective if value of a QALY less than $369 100 Age 60 Alendronate $4 800 10.973 $198 100 Cost effective if value of a QALY greater than $198 100 Risedronate $5 200 10.971 $715 000 Dominated by Alendronate Etidronate $4 500 10.968 Dominated Dominated by no therapy No Therapy $4 200 10.969 N/A Cost effective if value of a QALY less than $198 100 Age 65 Alendronate $5 700 9.522 $91 400 Cost effective if value of a QALY greater than $91 400 Risedronate $6 200 9.520 $408 300 Dominated by Alendronate Etidronate $5 700 9.515 Dominated Dominated by no therapy No Therapy $5 200 9.517 N/A Cost effective if value of a QALY less than $91 400 Age 70 Alendronate $6 400 7.847 $40 700 Cost effective if value of a QALY greater than $41 000 Risedronate $7 000 7.842 $237 100 Dominated by Alendronate Etidronate $6 600 7.835 Dominated Dominated by no therapy No Therapy $6 100 7.838 N/A Cost effective if value of a QALY less than $41 000 Age 75 Alendronate $7 000 6.088 Dominant No therapy is dominated by Alendronate Risedronate $7 800 6.081 $120 800 Dominated by Alendronate Etidronate $7 800 6.070 Dominated Dominated by no therapy No Therapy $7 100 6.076 N/A No therapy is dominated by Alendronate Age 80 Alendronate $6 900 4.337 Dominant No therapy is dominated by Alendronate Risedronate $7 800 4.328 $66 400 Dominated by Alendronate Etidronate $8 000 4.311 Dominated Dominated by no therapy No Therapy $7 200 4.320 N/A No therapy is dominated by Alendronate Bisphosphonates for the Primary and Secondary Prevention of Osteoporotic Fractures 16
Table 4: Incremental Cost per QALY for Risedronate and Alendronate versus No Therapy Incremental Cost per QALY versus No Therapy Alendronate Branded Risedronate Potential Generic Risedronate Previous Fracture Age 50 $474 600 $1 630 100 $1 003 700 Age 55 $291 200 $1 037 100 $635 400 Age 60 $159 500 $597 200 $361 600 Age 65 $66 600 $330 400 $189 000 Age 70 $25 800 $189 300 $101 900 Age 75 Dominant $88 300 $33 800 Age 80 Dominant $44 900 $8 100 No Previous Fracture Age 50 $603 200 $2 038 300 $1 257 100 Age 55 $369 100 $1 289 500 $791 800 Age 60 $198 100 $715 100 $434 100 Age 65 $91 400 $408 300 $237 400 Age 70 $40 700 $237 100 $131 400 Age 75 Dominant $120 800 $54 300 Age 80 Dominant $66 400 $21 700 Bisphosphonates for the Primary and Secondary Prevention of Osteoporotic Fractures 17
Figure 2: Cost Effectiveness Acceptability Curves 75 Year Old Woman with Previous Fracture 10 9 8 7 6 5 4 Alendronate Branded Risedronate Etidronate No therapy 70 Year Old Women with Previous Fracture 10 9 8 7 6 5 4 Alendronate Branded Risedronate Etidronate No therapy Bisphosphonates for the Primary and Secondary Prevention of Osteoporotic Fractures 18
65 Year Old Women with Previous Fracture 10 9 8 7 6 5 4 Alendronate Branded Risedronate Etidronate No therapy 75 Year Old Women with No Previous Fracture 10 9 8 7 6 5 4 Alendronate Branded Risedronate Etidronate No therapy Bisphosphonates for the Primary and Secondary Prevention of Osteoporotic Fractures 19
70 Year Old Women with No Previous Fracture 10 9 8 7 6 5 4 Alendronate Branded Risedronate Etidronate No therapy 65 Year Old Women with No Previous Fracture 10 9 8 7 6 5 4 Alendronate Branded Risedronate Etidronate No therapy Bisphosphonates for the Primary and Secondary Prevention of Osteoporotic Fractures 20
Figure 3: Cost Effectiveness Acceptability Curves Assuming Availability of Generic Risedronate 75 Year Old Women with Previous Fracture 10 9 8 7 6 5 4 Alendronate Potential Generic Risedronate Etidronate No therapy 70 Year Old Women with Previous Fracture 10 9 8 7 6 5 4 Alendronate Potential Generic Risedronate Etidronate No therapy Bisphosphonates for the Primary and Secondary Prevention of Osteoporotic Fractures 21
65 Year Old Women with Previous Fracture 10 9 8 7 6 5 4 Alendronate Potential Generic Risedronate Etidronate No therapy 75 Year Old Women with No Previous Fracture 10 9 8 7 6 5 4 Alendronate Potential Generic Risedronate Etidronate No therapy Bisphosphonates for the Primary and Secondary Prevention of Osteoporotic Fractures 22
70 Year Old Women with No Previous Fracture 10 9 8 7 6 5 4 Alendronate Potential Generic Risedronate Etidronate No therapy 65 Year Old Women with No Previous Fracture 10 9 8 7 6 5 4 Alendronate Potential Generic Risedronate Etidronate No therapy Bisphosphonates for the Primary and Secondary Prevention of Osteoporotic Fractures 23