Introduction
Among the osteoporotic fractures, hip fracture in particular imposes not only a clinical burden on patients by aggravating their QOL and health outcomes but also a significant socioeconomic burden of medical expenses for the treatment as well as a nursing care. Survival rates reported for patients who have experienced a hip fracture—81, 49, and 26% for 1, 5, and 10 years, respectively—are lower than rates for the general population [
1]. Also, a health-related QOL score (utility value) of patients in the year following a hip fracture was reduced by 11.5% compared to the baseline [
2]. According to a national medical expenditure survey by the Japanese Ministry of Health, Labor and Welfare, bone density and bone structure as well as fracture-related expenditure in the population aged 65 and over were estimated to be 891.5 billion JPY in 2012 and 943.6 billion JPY in 2013 [
3].
As anti-osteoporosis drugs have become widely used, the incidence rate of hip fracture has declined in the USA and Europe; however, it is still on the rise in Japan. A national survey of hip fractures estimated new fractures at 148,100 (male, 31,300; female, 116,800) in 2007 and 175,700 (male, 37,600; female, 138,100) in 2012, an increase of about 27,600 in 5 years [
4,
5]. As the Japanese population ages, the mounting burden caused by the increased incidence of osteoporotic fractures is of grave concern.
Drug therapy is considered to be an effective measure against the burden incurred by osteoporotic fractures, and a wide variety of options are available today. Zoledronic acid is a bisphosphonate that showed preventive efficacy on osteoporotic fractures in HORIZON-PFT (Pivotal Fracture Trial), a large population-based randomized trial conducted overseas [
6]. One of the major issues with osteoporosis is the low rate of patients receiving treatment. According to the in-country report, the prescription rate for osteoporotic drugs in patients who experienced a hip fracture was 18.7%, while those who had no treatment was 53.3%, suggesting that the number of patients receiving treatment is insufficient [
7]. A yearly intravenous injection of zoledronic acid is expected to facilitate long-term treatment for patients and avoid the adverse effects caused by oral bisphosphonates that require daily, weekly, or monthly dosing.
Although the drug therapy for osteoporosis definitely reduces the risk of fracture and is anticipated to reduce the total treatment cost for osteoporotic fracture, there is the possibility of an increase in the total cost of medication. Recently, the cost-effectiveness of various drug therapies for osteoporosis has been studied in advanced countries, and the results are having an effect on decision-making in clinical practice as well as on healthcare policies. A health economic evaluation of zoledronic acid conducted in Finland, Norway, and Holland by Akehurst and colleagues reported that zoledronic acid is cost-effective compared with basic treatment (placebo, calcium, and vitamin D) or other existing bisphosphonates [
8].
In Japan, cost-effectiveness of alendronate therapy in osteopenic women has been examined. The results indicated that osteoporosis treatment should be considered only for a high-risk population on the basis of age, bone mineral density (BMD), and number of clinical risk factors [
9]. However, to date, no health economic evaluation of the drug therapy including zoledronic acid for postmenopausal women with osteoporosis and with a history of fracture has been reported in Japan. In addition, there are epidemiological characteristics of a lower incidence rate of hip fracture [
10,
11] and a higher incidence of vertebral fracture [
12,
13] in Japanese compared to Western people. The Japanese healthcare system also differs from that of Europe and USA including the drug prices, treatment fees, and socially acceptable thresholds of the incremental cost-effectiveness ratio (ICER). For these reasons, direct application of the results of studies in Western countries to the Japanese population is problematic. The objective of this study was to estimate the cost-effectiveness of zoledronic acid in Japanese women with osteoporosis who have experienced a previous vertebral fracture from the perspective of the Japanese healthcare system.
Discussion
In this study, we estimated the cost-effectiveness of zoledronic acid therapy for Japanese women with osteoporosis and a history of vertebral fracture using state-transition model. Our results demonstrate that zoledronic acid therapy for patients aged 65 and over with a T-score of −2.0 is likely to be dominated by alendronate therapy with quite small difference in QALYs. Furthermore, we found that zoledronic acid is less effective and more costly for those patients who have one of the risk factors―current smoking, high alcohol intake, and a family history of hip fracture compared to alendronate. The perspective of our study is novel in terms of examining the cost-effectiveness of zoledronic acid using various combinations of age, BMD, and number of clinical risk factors compared with alendronate. To estimate incidence rates of osteoporotic fracture in Japanese women, the use of a large cohort-based fracture risk assessment tool, such as FRAX developed by WHO, is preferable. However, in building the model, we did not use FRAX because the algorithm and parameter estimates are not available to the public. In the present study, we developed original prediction equations for the incidence rate of fracture based on the epidemiological data published in Japan. Our model considered the risk of not only hip fracture and clinical vertebral fracture but also of other osteoporotic fractures such as proximal humerus and distal radius fractures. The validity of our prediction equation was verified by comparison of the predicted 10-year osteoporotic fracture probabilities in our model with those derived from FRAX [
9,
41]. The 10-year index case fracture probabilities in our model were confirmed to be almost identical to those from FRAX; thus, we consider this model to assess the cost-effectiveness of osteoporosis therapy in Japanese women to be appropriate.
The cost-effectiveness of zoledronic acid varies from country to country. A study in Finland reported that zoledronic acid dominated alendronate in 50- to 80-year-old patients who have a history of fracture and a T-score of −2.5 [
8]. In a Norwegian study, zoledronic acid has also been shown to be dominant (more effective and less costly) compared to alendronate in patients aged 70 and 80 years; in patients aged 50 and 60 years, the ICER of zoledronic acid compared with alendronate was NOK 76,188 and NOK 83,954 per QALY gained, respectively [
8]. In Holland, the ICER of zoledronic acid compared with alendronate ranged from 36,927 EUR per QALY in patients aged 60 years to 48,383 EUR per QALY in patients aged 80 years [
8]. However, the results of our base case analyses showed that zoledronic acid was dominated by alendronate. Several factors are suggested for this gap including the differences in the fracture risk of baseline, discount rate of cost and health benefits, fracture treatment costs, and drug costs. One of the possible reasons for the gap is a setting of efficacy on the RR for hip fracture. To date, there have been no head-to-head clinical trials with these drugs, and therefore, no evidence for direct comparison for fracture risk decline has been established. Hence, we indirectly evaluated the cost-effectiveness of zoledronic acid therapy compared to oral alendronate therapy using the evidence from network meta-analysis. The results of our base case analyses showed that zoledronic acid was slightly less effective and costly than alendronate (incremental QALY, −0.004 to −0.000; incremental cost, 366 to 493 USD). Zoledronic acid was more effective in preventing major osteoporotic fractures (RR = 0.935–0.944) but less effective in preventing hip fracture (RR = 1.000–1.059) compared to alendronate. Deterministic sensitivity analyses of our model indicated that parameters associated with hip fracture had a relatively strong effect on the cost-effectiveness of osteoporotic treatments. Based on the published network meta-analysis, the RR of hip fracture compared to basic treatment was estimated to be 0.50 in the zoledronic acid arm and 0.45 in the alendronate arm. Therefore, we consider the main explanation for our results to be the settings related to hip fracture. The results from the study in Finland, Norway, and Holland indicated that zoledronic acid was a cost-effective or cost-saving option compared with alendronate, which were considerably different from our results [
8]. We consider these gaps to be mainly derived from the difference in the setting of the RR for hip fracture compared to basic treatment. They estimated the RR for hip fracture by zoledronic acid to be 0.59 from the HORIZON-PFT and the RR by alendronate to be 0.62 from the economic evaluation reported by NICE, assuming that the treatment effect observed in clinical trials was independent of patient’s baseline risk factors. Although various studies have used data of the restraining effects on fractures derived from different sources for model analysis, we believe that caution is necessary when handling such data. For an assessment of cost-effectiveness comparing a variety of treatments, a more appropriate indirect comparison such as network meta-analysis is required. In our study, we estimated the comparative effectiveness among multiple osteoporotic treatments by using a recently published network meta-analysis, which we considered to be the best source of available data [
28]. However, network meta-analyses generally require advanced technical skills and thorough understanding. The results vary depending on the trials included in a syntactic analysis as well as the timing of the trials. Therefore, caution needs be taken when using these analyses.
The results of the deterministic sensitivity analysis on patients with a T-score of −2.5 indicated that a parameter such as the efficacy of zoledronic acid has a relatively strong impact on the base case result. If the RR of hip fracture with zoledronic acid was equal to 0.34 (lower limit of 95% CI), the ICER of zoledronic acid compared to alendronate was 5890 USD per QALY gained. In other words, judgment of the cost-effectiveness of zoledronic acid compared to alendronate may vary if the restraining effect of zoledronic acid on hip fracture is higher. Our analysis thus suggests that zoledronic acid treatment might be cost-effective compared to alendronate for a selected population, that is, one in which the treatment has a high therapeutic effect. A subgroup analysis of HORIZON-PET by Eastell et al. indicated that zoledronic acid has preventive effects on vertebral fracture in relatively young women with a normal creatinine clearance with BMI ≥25 kg/m
2 [
42]. However, they found that background factors had no statistical significance on the hip fracture preventive effects [
42]. Therefore, using the results of our analysis requires an understanding that the cost-effectiveness of zoledronic acid is sensitive to the degree of the restraining effect on hip fracture. Our simulation was based on the annual drug cost of zoledronic acid which has only recently been approved in Japan. If the annual drug cost of zoledronic acid is 30% lower than the set value of 39,485 JPY (329 USD), the ICER of alendronate compared to zoledronic acid was 159,760 USD per QALY gained. In this case, zoledronic acid becomes a cost-effective option compared to alendronate applying a WTP of 50,000 USD per QALY gained.
Probabilistic sensitivity analysis showed that the probability of zoledronic acid of being cost-effective in patients with a T-score of −2.0, −2.5, and −3.0 was 7.5, 9.7, and 12.9% compared with alendronate treatment and basic treatment alone when using the WTP of 50,000 USD per QALY, respectively. The probability that alendronate becomes the most cost-effective option ranged from 87.1 to 91.2% in those patients. In terms of medical economics, our results suggest that for this patient group, the use of alendronate is recommended.
The main limitation of our analysis is the assumptions about compliance and persistence of the treatment. In the base case analysis of this study, we assumed that there was no difference in the compliance and persistence between zoledronic acid and alendronate. However, one of the major issues with osteoporosis is poor adherence and persistence with drug therapies in clinical practice, which may affect the cost-effectiveness in real world. Although the real-life compliance and persistence data of zoledronic acid is not yet available in Japan, it has been reported that 65.5% of the patients received a second infusion of zoledronic acid after 1 year, while 44.8% of patients remained on the weekly oral alendronate treatment in Germany [
40]. Therefore, we performed scenario analysis considering treatment persistence by using this data. The scenario analysis showed that zoledronic acid might be a cost-effective treatment option compared to weekly oral alendronate (ICER, 10,749 USD to 47,435 USD per QALY gained). Furthermore, we estimated the ICER of zoledronic acid with different combinations of the proportion of patients who could continue drug therapy for over a year in zoledronic acid arm and alendronate arm. As a result, we found that zoledronic acid might be cost-effective compared to alendronate if zoledronic acid was expected to improve the proportion of patients who continued treatment for over a year by 10% compared to alendronate with a few exceptions. Recently, Kishimoto and Maehara reported that the 1 year medication possession ratio (MPR), which was used as an indicator of compliance, was 70.6% for weekly oral bisphosphonates in Japan [
43]. If we assumed the proportion of patients who continued therapy for over a year in alendronate arm was equal to 70% based on the previous report, the cost-effective threshold for the proportion of treatment persistence for over a year in zoledronic acid arm was estimated to be about 80% or more. The data obtained from this study will possibly facilitate decision-making to determine medical practice. However, comparable data with zoledronic acid or other bisphosphonates on compliance and persistence are insufficient at present. The advantage of an annual injection of zoledronic acid in compliance and persistence in Japanese setting should be challenges for the future studies.
Another limitation is that we estimated the efficacy of zoledronic acid treatment based on the network meta-analysis using a randomized clinical trial that was conducted in countries other than Japan. A subgroup analysis of HORIZON-PET indicated that background factors such as race (Caucasian, Asian, or other) and geographical region (Europe, Asia, or the Americas) had no statistically significant effect on the preventive effects of the treatment on osteoporotic fractures [
42]. Therefore, we concluded that, to some extent, extrapolating the preventive effect of zoledronic acid from the population of HORIZON-PET to Japanese women would be acceptable. The sensitivity analysis showed that the uncertainty about the efficacy of zoledronic acid on the RR for hip fracture had a relatively large impact on the ICER of preventive zoledronic acid therapy, and therefore, the efficacy of zoledronic acid in postmenopausal Japanese women with osteoporosis should be determined to confirm the validity of our results. Although the average age of patients in HORIZON-PET was 73, we assumed the average age of a patient to be 70 and ranged from 65 to 75 in the base case analysis. The subgroup analysis showed that for the preventive effects on vertebral fracture, there was a statistically significant difference between the treatment and the age of patients [
42]. Therefore, the RR of vertebral fracture by zoledronic acid should vary depending on the age of the patient. However, our sensitivity analysis showed that the impact of the RR for vertebral fracture from zoledronic acid on the ICER was relatively small. Therefore, we used a fixed value for the point estimate of the RR for vertebral fracture from zoledronic acid.
Finally, it is important to note that the cost-effectiveness of zoledronic acid treatment for Japanese osteoporosis patients varies depending on the social acceptability of the ICER threshold. The WTP threshold of 50,000 USD per QALY in the USA and 20,000–30,000 GBP per QALY in the UK is commonly acceptable [
44,
45]. However, as noted above, it varies from country to country, and there is no international consensus. In Japan, a study by Ohkusa and Sugawara has proposed a WTP threshold of 6,350,000–6,700,000 JPY (52,917–55,833 USD) per QALY gained [
46]. Although still controversial, the population for which drug treatment is cost-effective may vary depending on Japanese societal WTP for an additional QALY.