ORIGINAL INVESTIGATION

ORIGINAL INVESTIGATION The Cost-effectiveness of Therapy With Teriparatide and Alendronate in Women With Severe Osteoporosis Hau Liu, MD, MBA, MPH; Kaleb Michaud, MS; Smita Nayak, MD; David B. Karpf, MD; Douglas K. Owens, MS, MD; Alan M. Garber, MD, PhD Background: Teriparatide is a promising new agent for the treatment of osteoporosis. Methods: The objective of this study was to evaluate the cost-effectiveness of teriparatide-based strategies compared with alendronate sodium for the first-line treatment of high-risk osteoporotic women. We developed a microsimulation with a societal perspective. Key data sources include the Study of Osteoporotic Fractures, the Fracture Intervention Trial, and the Fracture Prevention Trial. We evaluated postmenopausal white women with low bone density and prevalent vertebral fracture. The interventions were usual care (UC) (calcium or vitamin D supplementation) compared with 3 strategies: 5 years of alendronate therapy, 2 years of teriparatide therapy, and 2 years of teriparatide therapy followed by 5 years of alendronate therapy (sequential teriparatide/ alendronate). The main outcome measure was cost per quality-adjusted life-year (QALY). Results: For the base-case analysis, the cost of alendronate treatment was $11 600 per QALY compared with UC. The cost of sequential teriparatide/alendronate therapy was $156 500 per QALY compared with alendronate. Teriparatide treatment alone was more expensive and produced a smaller increase in QALYs than alendronate. For sensitivity analysis, teriparatide alone was less costeffective than alendronate even if its efficacy lasted 15 years after treatment cessation. Sequential teriparatide/ alendronate therapy was less cost-effective than alendronate even if fractures were eliminated during the alendronate phase, although its cost-effectiveness was less than $50 000 per QALY if the price of teriparatide decreased 60%, if used in elderly women with T scores of 4.0 or less, or if 6 months of teriparatide therapy had comparable efficacy to 2 years of treatment. Conclusions: Alendronate compares favorably to interventions accepted as cost-effective. Therapy with teriparatide alone is more expensive and produces a smaller increase in QALYs than therapy with alendronate. Sequential teriparatide/alendronate therapy appear expensive but could become more cost-effective with reductions in teriparatide price, with restriction to use in exceptionally high-risk women, or if short courses of treatment have comparable efficacy to that observed in clinical trials. Arch Intern Med. 2006;166:1209-1217 Author Affiliations: Division of Endocrinology and Metabolism (Drs Liu and Karpf) and Center for Primary Care and Outcomes Research (Drs Liu, Nayak, Owens, and Garber and Mr Michaud), Stanford University, Stanford, Calif; and Department of Medicine, VA Palo Alto Health Care System, Palo Alto, Calif (Drs Nayak, Owens, and Garber). RECOMBINANT HUMAN PARAthyroid hormone 1-34 (teriparatide), approved by the Food and Drug Administration in 2002, is the first drug in a promising new class of osteoporosis medications known as anabolic agents. Other therapies for osteoporosis, including the commonly prescribed bisphosphonates, prevent fractures by modestly increasing bone density and reducing bone turnover. 1-10 Daily treatment with teriparatide results in substantially greater increases in bone density and reduces vertebral and nonvertebral fractures by directly stimulating new bone formation. 11 An estimated 600 000 prescriptions were written for teriparatide in 2005, resulting in worldwide sales of more than $350 million, 12 with annual sales projected to approach $750 million by 2007 to 2008. 12,13 While treatment with teriparatide reduces fractures in women with severe osteoporosis (ie, those with low bone mass and preexisting fractures), 11 and a recent cost-effectiveness analysis 14 from Sweden suggested that it may be costeffective compared with no treatment, the efficacy of teriparatide relative to other osteoporosis agents, including the US market leader, alendronate sodium, is uncertain. To our knowledge, no head-to-head trials of the 2 compounds using fracture as a primary end point have been performed because a large sample would be needed to detect differences in efficacy. 15 Teriparatide therapy may prevent fractures comparably to alendronate therapy in women with severe osteoporosis, 11,16 although it is more expensive, is approved for only 2 years of continuous therapy, and requires a daily subcutaneous injection. 1209

While the cost-effectiveness of alendronate and other osteoporotic agents has been assessed, 17-24 to our knowledge, the cost-effectiveness of teriparatide-based strategies in the United States has not been evaluated. We evaluated the cost-effectiveness of 3 promising firstline treatment strategies in women with severe osteoporosis: alendronate therapy alone, teriparatide therapy alone, and teriparatide therapy followed by alendronate therapy. Given incomplete clinical data, we performed extensive sensitivity analyses to evaluate the effects of key variables on the cost-effectiveness of these strategies. METHODS We constructed a cost-effectiveness model incorporating morphometric (ie, radiologic) vertebral and clinical vertebral, hip, and wrist fractures to compare usual care (UC) (calcium or vitamin D only) with UC plus 3 treatment strategies: 5 years of alendronate therapy (alendronate alone), 2 years of teriparatide therapy (teriparatide alone), and 2 years of teriparatide therapy followed by 5 years of alendronate therapy (sequential teriparatide/alendronate). The model produced a set of incremental cost-effectiveness ratios for the treatment strategies in units of cost per quality-adjusted life-year (QALY) gained. We designed the model to be consistent with published guidelines 25-28 on osteoporosis modeling. A technical appendix, which provides additional detail regarding our model, can be found online (http://iis-db.stanford.edu/pubs/21034/osteoporosis _CEA-technical_appendix.pdf). OSTEOPOROSIS MODEL As recommended by Vanness et al 28 and Kanis et al, 17 we developed a microsimulation using computer software (TreeAge Pro 2004; TreeAge Software, Williamstown, Mass). Our model consists of 6 key elements: treatment strategy chosen, fracture state, survival during cycle, entrance to nursing home, new fracture occurrence, and adverse events from medication (data available in the previously described technical appendix). Each microsimulation consisted of 200 000 trials. We used a lifetime horizon, societal perspective, and a 3-month cycle. We discounted costs and health utilities by 3%. 29 PATIENT POPULATION The target population for our analysis was postmenopausal white women with severe osteoporosis, defined by low bone mass (base case, femoral neck bone mineral density [BMD] T score of 2.5) and preexisting vertebral fracture. 30,31 We chose this population because the Food and Drug Administration recommends that teriparatide be used in postmenopausal women who are at high risk for fracture. 32 We chose a 70-year-old woman as our base case to mirror the age of participants of the clinical trials used in our analysis. TREATMENT STRATEGIES Our model consisted of UC (calcium or vitamin D supplementation) and 3 active treatment arms (alendronate alone, teriparatide alone, and sequential teriparatide/alendronate, all incremental to UC). We assumed 100% compliance in our base case. The effectiveness of a strategy consisting solely of calcium or vitamin D supplementation is uncertain, 33-36 particularly in the community-dwelling ambulatory population. Consequently, we assumed in the base case that there was no additional fracture reduction benefit with calcium or vitamin D supplementation (relative risk, 1) and varied this in sensitivity analyses. The alendronate-alone strategy consisted of alendronate sodium, 10 mg/d, with a 5-year treatment period. For teriparatide alone, we assumed that teriparatide was used at 20 µg/d subcutaneously for 2 years. For sequential teriparatide/alendronate, we assumed treatment with teriparatide for 2 years at 20 µg/d followed by alendronate therapy for 5 years at 10 mg/d. MORBIDITY AND MORTALITY We based fracture rates for women receiving UC on the Study of Osteoporotic Fractures, 37 a large observational study of elderly US women. We developed logistic regressions to predict future fracture probabilities based on age, femoral neck BMD, and the presence of prior vertebral fracture (data available in the previously described technical appendix). In our base case, we assumed that clinical vertebral fractures accounted for 35% of morphometric vertebral fractures. 38 We derived baseline mortality rates from US age-stratified mortality tables. 39 We assumed increased mortality after hip and vertebral fracture as reported in the Study of Osteoporotic Fractures and other studies (data available in the previously described technical appendix). 40-45 COSTS We based prescription drug prices on average wholesale prices listed in the Drug Topics Red Book 46 and calculated costs for medical services and fractures from Medicare diagnosis related group and Current Procedural Terminology reimbursement rates or other published cost reviews (data available in the previously described technical appendix). 47,48 We based nursing home costs on data from a national nursing home insurance survey. 49 We included annual medical expenditures 50 and indirect medical costs 38 associated with fracture in sensitivity analysis but not the base case because age at death was similar in all treatment arms and indirect medical costs for 70-year-old women are small. All cost figures are presented in 2003 US dollars. 51 UTILITIES AND NURSING HOME VARIABLES We obtained health state utilities from studies 52-56 that applied time trade-off or standard gamble methods, where available; otherwise, we used values obtained from expert opinion 23 or surrogate values (data available in the previously described technical appendix). For the base case, we assumed the same disutility for clinical and morphometric vertebral fractures within the first year after fracture (0.82), 57 although we assumed a greater disutility during the first year of clinical vertebral fracture (0.62) in sensitivity analysis. 57 We used data from multiple sources 49,58-60 to determine rates of nursing home admission, length of stay, discharge rates, and mortality rates for patients with a hip fracture (data available in the previously described technical appendix). ADVERSE EVENTS The model incorporates mild hypercalcemia and osteosarcoma (teriparatide) and esophagitis and esophageal ulceration (alendronate) as possible adverse events from active therapy (data available in the previously described technical appendix). We assumed that patients who experienced osteosarcoma or esophageal ulceration discontinued therapy, while patients who experienced gastrointestinal discomfort or hypercalcemia received treatment for these conditions 61 and continued therapy. We obtained adverse event rates from pub- 1210

Table 1. Key Model Variables Domain Variable Value Cost, $* Alendronate sodium, annual cost 894 46 Teriparatide, annual cost 6720 46 Hip fracture, direct medical costs 17 353 48 Clinical vertebral fracture, direct medical costs 7097 48 Wrist fracture, direct medical costs 3853 48 Nursing home, annual cost 57 700 49 Health state utility Osteoporosis, no fracture Aged 60-64 y 0.829 55 Aged 65-69 y 0.806 55 Aged 70-74 y 0.747 55 Aged 75-79 y 0.731 55 Aged 80-84 y 0.699 55 Aged 85 y 0.676 55 Hip fracture, first year/subsequent year (multiplier) 0.797 56 /0.9 55 Vertebral fracture, first year/subsequent year (multiplier) 0.82 (0.62) 57 /0.931 57 Wrist fracture, first year/subsequent year (multiplier) 0.981 54 /1.0 55 Relative risk of fracture, base case (while taking drug) Alendronate-alone strategy Vertebral fracture 0.53 1 Hip fracture 0.49 1 Wrist fracture 0.52 1 Teriparatide-alone strategy Vertebral fracture 0.35 11 Hip fracture 0.47 11 Wrist fracture 0.47 11 Sequential teriparatide/alendronate strategy Teriparatide Vertebral fracture 0.35 11 Hip fracture 0.47 11 Wrist fracture 0.47 11 Alendronate Vertebral fracture 0.19 Hip fracture 0.23 Wrist fracture 0.24 Discount rate Costs 0.03 QALYs 0.03 Abbreviation: QALYs, quality-adjusted life-years. *Given in 2003 US dollars. Used in sensitivity analysis. Further detail is given in the Utilities and Nursing Home Variables subsection of the Methods section and in the Health State Utilities section in the technical appendix. In our base case for sequential teriparatide/alendronate strategy, we assumed that alendronate would decrease fracture risk in the same proportion as it would in a treatment-naive patient. Further detail is given in the Fracture Risk Reduction: Base Case subsection of the Methods section. lished trials. 1,11 We assumed that no cases of osteosarcoma occurred in the base case. FRACTURE RISK REDUCTION: BASE CASE We reviewed studies 1,10,11,17,62-65 reporting fracture rates in osteoporotic women with prevalent fractures taking alendronate or teriparatide. We calculated relative risks for each treatment strategy, and multiplied these risks by UC fracture rates to determine treatment fracture rates (data available in the previously described technical appendix). We assumed that the reduction in the relative risk of fractures reached published rates on initiation of therapy. 17,38 For the alendronate-alone strategy, we assumed a relative risk of 0.53/0.49/0.52 for vertebral/hip/wrist fractures while receiving therapy (Table 1). 1 We assumed that fracture risk returned to UC rates in a linear fashion over 5 years after cessation of alendronate therapy. 26 For the teriparatide-alone strategy, we assumed a relative risk of 0.35/0.47/0.47 for vertebral/hip/wrist fractures during therapy (Table 1). 11 We applied the overall nonvertebral fracture relative risk from the teriparatide Fracture Prevention Trial (FPT) 11 to determine hip and wrist fracture rates. We assumed that the fracture relative risks from the FPT (18 months of treatment) remained constant during the 2 years of teriparatide treatment. On cessation of teriparatide treatment, we assumed fracture risk returned to UC rates in a linear fashion over 5 years. We assumed that before initiating alendronate therapy, fracture relative risk in the sequential teriparatide/alendronate strategy was the same as that of teriparatide alone. When alendronate treatment was started, we assumed that fracture risk decreased in the same proportion as it would in a treatmentnaive patient. For example, we assumed a relative risk of vertebral fracture of 0.53 for alendronate 1 and of 0.35 for teriparatide compared with UC. 11 We assumed that subsequent alendronate therapy would, therefore, result in a relative risk of vertebral fracture of 0.19 (ie, 0.53 0.35) (Table 1). We assumed that fracture risk returned to UC rates in a linear fashion over 5 years after cessation of alendronate therapy. 26 SENSITIVITY ANALYSIS We performed sensitivity analyses to evaluate the effects of key variables on cost-effectiveness. We varied the duration of effi- 1211

Effectiveness, QALY BEffectiveness, QALY AEffectiveness, QALY Alendronate Alone Usual Care Sequential Teriparatide/Alendronate Teriparatide Alone Alendronate Alone Usual Care Sequential Teriparatide/Alendronate Teriparatide Alone 7.1 7.0 $11 600/QALY $156 500/QALY $172 300/QALY 7.1 7.0 25% 40% 50% 75% $6720 $11 400/QALY $40 200/QALY 25% 40% 50% 75% $6720 6.9 10000 15 000 20000 25000 Cost, $ 6.9 10000 15000 20000 25000 Cost, $ Figure 1. Incremental cost-effectiveness ratio, base case. Alendronate sodium alone costs $11 600 per quality-adjusted life-year (QALY) compared with usual care, and sequential teriparatide/alendronate (2 years of teriparatide therapy followed by 5 years of alendronate therapy) costs $156 500 per QALY compared with alendronate alone. Teriparatide alone is not a rational choice because it is more expensive and produces a smaller increase in QALYs than alendronate alone. However, in those for whom alendronate use is not feasible, teriparatide alone costs $172 300 per QALY compared with usual care. 7.1 7.0 $41 600/QALY 0.5 y 0.5 y 1.0 y 1.0 y 1.5 y 1.5 y 2.0 y 2.0 y cacy after cessation of teriparatide. We calculated the results for 2 polar assumptions about the efficacy of alendronate therapy following teriparatide. In one, we assumed that alendronate only maintained the antifracture benefits accrued while receiving teriparatide therapy; and in the other, we assumed that it completely eliminated fractures. We also varied the cost of alendronate and teriparatide, the BMD, age, teriparatide treatment length, compliance, and other variables to evaluate their effect on cost-effectiveness. RESULTS BASE CASE Treatment with alendronate alone costs $11 600 per QALY compared with UC, and sequential teriparatide/alendronate costs $156 500 per QALY relative to alendronate alone (Figure 1). Teriparatide alone is not a rational choice, because it is more expensive and produces a smaller increase in QALYs compared with alendronate alone; however, in those in whom alendronate use is not feasible, teriparatide alone costs $172 300 per QALY relative to UC. SENSITIVITY ANALYSIS Teriparatide Efficacy After Treatment Cessation Even if teriparatide could exert an antifracture effect for 15 years after treatment cessation, teriparatide alone remains less cost-effective than alendronate alone ($346 900/ QALY compared with alendronate alone). Fracture Efficacy of Alendronate Following Teriparatide 6.9 10000 15000 20000 25000 Cost, $ Figure 2. Key sensitivity analyses for price modification of teriparatide (A) and teriparatide treatment length (B). In A, the price of teriparatide was varied from 25% to 100% of its base price ($6720/y). At 40% of the base price ($2688/y), sequential teriparatide/alendronate sodium (2 years of teriparatide therapy followed by 5 years of alendronate therapy) costs $40 200 per quality-adjusted life-year (QALY) compared with alendronate alone. At 25% of the base price ($1680/y), sequential teriparatide/alendronate is more cost-effective than alendronate alone, and costs $11 400 per QALY compared with usual care. Teriparatide alone is more expensive and produces less QALYs than alendronate alone in all scenarios. In B, the length of teriparatide treatment was varied from the base-case assumption of 2.0 years to 0.5, 1.0, and 1.5 years. If 6 months of teriparatide therapy could attain the fracture relative risks reported in the Fracture Prevention Trial, 11 and other fracture risk assumptions of the base case are maintained, sequential teriparatide/alendronate would cost $41 600 per QALY compared with alendronate alone. Teriparatide alone is more expensive and produces fewer QALYs than alendronate alone in all scenarios. Base-case results are presented in black; and results of sensitivity analyses, in gray. The Sensitivity Analysis subsection in the Methods section provides further details. Sequential teriparatide/alendronate remains less costeffective than alendronate alone even if fractures are eliminated during the alendronate treatment phase of sequential teriparatide/alendronate therapy ($91 400/QALY compared with alendronate alone). If alendronate therapy could only maintain the fracture benefits gained while receiving teriparatide treatment, the cost of sequential teriparatide/alendronate would be $389 200 per QALY compared with alendronate alone. Teriparatide and Alendronate Cost At 40% ($2688/y) of the base cost of teriparatide therapy, sequential teriparatide/alendronate costs $40 200 per QALY compared with alendronate alone (Figure 2A). At 25% ($1680/y) of the base cost of teriparatide therapy, the cost of sequential teriparatide/alendronate ($11 400/ QALY) would be better than that of alendronate alone. 1212

BCost-effectiveness Ratio, $/QALY ACost-effectiveness Ratio, $/QALY Alendronate alone is cost saving at half its base-case price ($447/y) (data not shown). Teriparatide Treatment Length Assuming 6 months of teriparatide therapy could attain the fracture relative risks reported in the FPT, sequential teriparatide/alendronate costs $41 600 per QALY compared with alendronate alone (Figure 2B). 60 000 40 000 20 000 FN T Score of 2.5 FN T Score of 3.0 FN T Score of 3.5 FN T Score of 4.0 BMD and Age The cost-effectiveness of alendronate alone and sequential teriparatide/alendronate generally improves with increasing age and decreasing femoral neck BMD (Figure 3A and B, respectively), except when sequential teriparatide/ alendronate is used in very elderly women. The costeffectiveness of sequential teriparatide/alendronate worsened from the age of 70 to 80 years (Figure 3B), likely because of the high cost of teriparatide and the limited residual lifespan in which to obtain benefit. Additional Sensitivity Analyses 0 300000 250000 200000 150000 100000 50000 50 60 70 80 Age, y The relationship between the cost-effectiveness of treatment strategies does not change appreciably with modification in the discount rate, adverse event rates, costs, health state utility values, baseline fracture rates, compliance rates, or other key variables (Table 2). COMMENT tk;2 Although teriparatide is a promising new agent for the treatment of osteoporosis, we find that teriparatidebased strategies are consistently less cost-effective than alendronate, primarily because of the high cost of teriparatide. Specifically, using teriparatide alone is not a costeffective first-line strategy in women with severe osteoporosis; it is more expensive and produces a smaller increase in QALYs than alendronate alone. While the cost-effectiveness ratio of sequential teriparatide/ alendronate is consistently higher than that of alendronate alone, the ratio would decrease to less than $50 000 per QALY if the price of teriparatide was reduced 60%, if used in women with an exceptionally low BMD (femoral neck T score, 4.0), or if shorter courses of teriparatide (6 months) could provide the same fracture reduction efficacy as those reported in longer clinical trials. 11 Two studies 14,66 on the cost-effectiveness of teriparatide as a single agent compared with no active treatment reported conflicting results. Stevenson et al 66 performed an economic evaluation of osteoporosis medications for the United Kingdom s National Health Service. By using cost and fracture data from the British health care system, they found teriparatide alone costs 134 700 per QALY ($240 800/QALY 67 ) compared with no treatment for a 70-year-old woman with previous fracture and a BMD T score of 2.5. In contrast, Lundkvist et al, 14 in an industry-sponsored analysis, estimated the costeffectiveness of teriparatide alone in a 69-year-old Swedish woman with previous fracture and a femoral neck BMD 0 50 60 70 80 Age, y Figure 3. Effect of bone mineral density and age at initiation of therapy on cost-effectiveness for alendronate sodium alone (A) and sequential teriparatide/alendronate (2 years of teriparatide therapy followed by 5 years of alendronate therapy) (B). The incremental cost-effectiveness ratio of alendronate alone was compared with usual care, and the incremental cost-effectiveness ratio of sequential teriparatide/alendronate was compared with alendronate alone. Teriparatide alone is not shown because it is more expensive and produces fewer quality-adjusted life-years (QALYs) than alendronate alone in all scenarios. (The figures have different scales.) In A, at a femoral neck (FN) T-score of 3.5 or 4.0, alendronate alone is cost saving at the ages of 60, 70, and 80 years. At a femoral neck T score of 3.0, alendronate alone is cost saving at the ages of 70 and 80 years. In B, the cost-effectiveness of sequential teriparatide/alendronate worsens from the age of 70 to the age of 80 years, likely owing to the high cost of teriparatide and the limited residual lifespan in which to obtain benefit from therapy. T score of 3.0 to range from 20 000 to 64 000 per QALY ($24 000-$77 000/QALY 67 ) compared with calcium and vitamin D supplementation alone. However, their analysis hinges on Swedish epidemiologic data for fracture and mortality risk in the years immediately following fracture, findings that remain to be validated in other populations. More important, Lundkvist et al evaluate only teriparatide treatment vs no active treatment, and they do not compare the cost-effectiveness of teriparatide against other viable osteoporosis treatments (such as bisphosphonates), thus improving the apparent cost-effectiveness of teriparatide. Selection of appropriate comparison interventions is critical in cost-effectiveness analysis, 29 particularly if the evaluated intervention is more costly and intensive than existing therapies. We believe our results, which compare teriparatide with the most commonly prescribed osteoporosis agent in the US market and UC, to be more relevant to clinical practice. The effect of teriparatide on fracture risk following cessation of therapy is unclear. In the follow-up observational study 68 of the FPT, participants treated with teriparatide who did not take subsequent osteoporosis medication 1213

Table 2. Additional Sensitivity Analyses: Incremental Cost-effectiveness Ratios for Treatment Strategies* Sequential Teriparatide/ Area Scenario Alendronate-Alone, $/QALY Alendronate, $/QALY Base case NA 11 600 156 500 Adverse events Alendronate poorly tolerated: 30% esophagitis and 5% esophageal ulceration 15 000 165 600 Teriparatide well tolerated: 0% hypercalcemia and 0% osteosarcoma Teriparatide: osteosarcoma at 100 baseline rates 11 600 193 800 Clinical vertebral fracture, 20% 12 900 158 400 % of morphometric vertebral fractures 50% 10 200 154 500 Costs Include annual medical expenditures 20 100 164 700 Include indirect medical costs 11 200 156 100 Median fracture costs used 48 14 700 160 400 Fracture costs 30% higher 8700 153 000 Fracture costs 30% lower 14 500 159 900 Discount rate 5% 15 100 195 100 7% 19 000 239 300 Fracture rates (change from usual care rates) All fractures 30% higher (RR, 1.3) 2300 115 800 All fractures 30% lower (RR, 0.7) 26 700 240 800 Vertebral fractures 30% higher 12 000 141 400 Health state utilities Clinical vertebral fracture utility 0.62 during first year after fracture 57 10 800 142 300 Age-adjusted health utilities 30% higher 8900 120 400 Age-adjusted health utilities 30% lower 16 500 223 500 Fracture health utility multipliers 30% higher 14 200 202 900 Fracture health utility multipliers 30% lower 11 300 159 200 Intervention compliance Alendronate, 80%; and teriparatide, 80% 12 600 164 200 Alendronate, 50%; and teriparatide, 50% 13 100 169 500 Mortality 14% of post hip fracture mortality due to hip fracture 45 11 200 160 200 Teriparatide Vertebral fractures eliminated while receiving teriparatide therapy 11 600 143 600 Fracture reduction Relative risk of hip and wrist fractures for teriparatide increased to 1.0 11 600 Dominated efficacy Relative risk of hip and wrist fractures for teriparatide decreased to 0.33 11 600 119 600 Decreased antifracture benefit achieved with sequential therapy 11 600 219 200 Therapy variables Alendronate for 5 y, decrease to usual care fracture rates over 10 y 3100 136 100 Alendronate for 10 y, decrease to usual care fracture rates over 5 y 16 600 155 500 Alendronate and teriparatide with decrease to usual care fracture rates over 1 y after therapy cessation 22 300 181 600 Abbreviations: NA, data not applicable; QALY, quality-adjusted life-year; RR, relative risk. *Base-case variables assumed unless otherwise specified; additional details about assumptions and methods are in a technical appendix, available from the authors. Alendronate was administered as alendronate sodium. Incremental cost-effectiveness ratio for alendronate alone compared with usual care. Incremental cost-effectiveness ratio for sequential teriparatide/alendronate compared with alendronate alone. Utility value set to 1 if adjusted utility value exceeds 1. The RR for hip and wrist fracture for teriparatide decreased to 0.33 from the base-case assumption of 0.47 (30% improvement). The RR for fracture equals 0.26/0.35/0.35 for vertebral/hip/wrist fractures during the alendronate phase of therapy (compared with a base-case RR of 0.19/0.26/0.26 for vertebral/hip/wrist fractures). Further details are given in the Sensitivity Analysis subsection of the Methods section and in the Sensitivity Analyses section in the technical appendix. lost one third of their vertebral BMD gains within 18 months. Although teriparatide therapy s fracture effect after its cessation is unknown, it has minimal effect on the costeffectiveness of the teriparatide-alone strategy. Even if we assumed that the effect of teriparatide lasted 15 years after cessation of therapy with it, teriparatide alone is dominated by the other treatment strategies. Recent studies suggest that antiresorptive therapy following cessation of teriparatide therapy increases BMD and possibly reduces fractures. Rittmaster et al 69 showed that vertebral BMD gains nearly doubled in osteoporotic women after 1 year of alendronate therapy following 12-month treatment with recombinant human parathyroid hormone (1-84). Similar increases in vertebral BMD after bisphosphonate use following the use of teriparatide or other forms of parathyroid hormone have been found in other populations. 68,70,71 These studies suggest that a potent antiresorptive agent following teriparatide treatment withdrawal will likely maintain or increase BMD gains and may result in fewer fractures. While the precise fracture reduction relative risk for teriparatide therapy followed by alendronate is unknown, our results suggest that sequential teriparatide/alendronate would not be more cost-effective than alendronate even if it could eliminate hip, wrist, and vertebral fractures during the alendronate phase of therapy. Our results are sensitive to the costs of alendronate and teriparatide therapy. A 50% reduction in the price of alendronate would make it cost saving, a price decrease that might occur after alendronate s scheduled loss of patent protection in 2008. 72 At 25% of the base price of teriparatide, the cost-effectiveness of sequential teripa- 1214

ratide/alendronate would be better than that of alendronate alone. Other formulations of parathyroid hormone, including intranasal (1-34) and subcutaneous (1-84) versions are under evaluation. 73-75 The pricing of these agents could significantly alter the cost-effectiveness of parathyroid hormone based regimens. Consistent with prior studies, 17,38 our results show that the cost-effectiveness of treatment generally improves with decreasing BMD and increasing age. While the Food and Drug Administration has recommended that teriparatide be used in postmenopausal women who are at high risk for fracture, 32 it has not explicitly defined what is meant by high risk. Sequential teriparatide/alendronate may cost less than $50 000 per QALY in elderly postmenopausal women with prior vertebral fractures and a femoral neck BMD T score of 4.0 or less. The cost-effectiveness of sequential teriparatide/ alendronate may improve substantially if shorter courses of teriparatide reduce fracture at the same rate as observed in the FPT. 11 A recent study 76 demonstrated that cyclic teriparatide therapy in patients taking alendronate, resulting in a 50% reduction in teriparatide dose over 2 years, may be as effective as continuous teriparatide therapy in these patients. Given the potential clinical and economic benefits of such strategies, determining the optimal therapy length and dose for teriparatide and other anabolic agents remains an important area for future research. The cost-effectiveness of alendronate alone is consistently less than $30 000 per QALY and is cost saving under certain conditions. These findings are consistent with those of prior published cost-effectiveness evaluations 17,18,20,21,23,24 of alendronate. Our analysis differs from prior models in that others have used shorter time horizons 17,18,20,21 and primarily non-us data sources, 17,18,20,21 and have developed cohort-based Markov models. 18,21 The consistency of our results with prior work strengthens our conclusion that the cost-effectiveness of alendronate for treatment of high-risk osteoporotic women compares favorably with other interventions accepted as cost-effective. Our model has several limitations. First, the results are specific to treatment-naive women and may not be applicable to patients receiving treatment for osteoporosis. However, given that osteoporosis is significantly underdiagnosed and undertreated, 77,78 we believe our results are relevant to many patients. Second, we assumed that teriparatide decreased hip and wrist fractures, although the FPT showed teriparatide to only decrease nonvertebral fractures collectively. Teriparatide-based therapies would be less costeffective if teriparatide does not decrease hip or fracture rates individually. Third, whileweeklyalendronatedosingiscommonly used, our model relies on fracture efficacy data from the Fracture Intervention Trial, 8 which used daily dosing. Given that recent studies 79,80 have suggested that the 2 dosing schemes are equal in efficacy, we believe our results are also applicable to weekly alendronate dosing. Fourth, our model did not evaluate raloxifene hydrochloride, because it seems to be less effective than alendronate in reducing fractures. 5 Given that risedronate sodium and alendronate seem to have comparable antifracture effect 3 and cost, 46 our findings are also likely broadly applicable to risedronate. Fifth, we did not include a quality-of-life decrement for daily subcutaneous injection of teriparatide, although including such a decrement would only strengthen our conclusions. Finally, the results of our model are specific to our model inputs. The Study of Osteoporotic Fractures, the Fracture Intervention Trial, and the FPT enrolled elderly volunteers, who may be different from elderly women in the general population, although the Study of Osteoporotic Fractures and the Fracture Intervention Trial used a population-based recruitment strategy. 81 The cost-effectiveness of alendronate alone for the treatment of high-risk osteoporotic women compares favorably with other interventions accepted as cost-effective. The use of teriparatide alone is more expensive and produces a smaller increase in QALYs than alendronate. Sequential therapy with teriparatide followed by alendronate is expensive; this strategy could become more cost-effective with significant reductions in the price of teriparatide, with restriction to use in exceptionally high-risk women, or if short courses of treatment have comparable efficacy to that observed in clinical trials. Accepted for Publication: February 2, 2006. Correspondence: Hau Liu, MD, MBA, MPH, 117 Encina Commons, Stanford, CA 94305 (hauliu@stanford.edu). Author Contributions: Dr Liu and Mr Michaud had full access to all of the data in this study and take responsibility for the integrity of the data and the accuracy of the data analysis. Financial Disclosure: Dr Karpf has received honoraria for giving educational talks on osteoporosis from Procter & Gamble and Merck & Co, Inc. Funding/Support: This study was supported by National Research Service Award grant HS000028-19 from the Agency for Healthcare Research and Quality (Dr Liu and Mr Michaud); and by the Department of Veterans Affairs (Drs Owens and Garber). Dr Nayak is the recipient of a Department of Veterans Affairs Ambulatory Care Fellowship. Role of the Sponsor: The funding bodies had no role in data extraction and analyses, in the writing of the manuscript, or in the decision to submit the manuscript for publication. 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