Introduction
Osteoporosis leads to fragility fractures and constitutes a major medical and public health concern worldwide. Vertebral fracture is one of the most common fragility fractures and can be symptomatic (i.e., clinical vertebral fracture) or asymptomatic (i.e., morphometric vertebral fracture). Clinical vertebral fracture can lead to significant morbidity and loss of quality of life [
1]. Compared with Caucasians, the Japanese population has been reported to have higher annual incidence rates of clinical vertebral fracture and lower rates of hip fracture [
2,
3]. This makes a strategy to reduce the risk of vertebral fracture important in the Japanese population, especially in those at high risk for vertebral fracture, such as those with a prior history of vertebral fracture [
4].
Teriparatide is a recombinant parathyroid hormone that stimulates bone formation and activates bone remodeling, and was the first anabolic agent to become available for the treatment of osteoporosis. The current Japanese guidelines for the prevention and treatment of osteoporosis conclude that there is high-quality evidence for teriparatide increasing bone mineral density and reducing the risk of vertebral fracture. The guidelines recommend that teriparatide generally should not be used as a first-line drug for the treatment of osteoporosis, but could be considered a treatment of choice for those at high risk for osteoporotic fracture [
5].
Teriparatide’s expense is one of its main disadvantages. Indeed, brand versions of teriparatide (i.e., daily and weekly versions available in Japan) are the most expensive medications for the treatment of osteoporosis in Japan and consisted of 20% of the total costs (i.e., the sums of payments by third-party payers and by patients out-of-pocket) for medications for osteoporosis in Japan in 2017, followed by vitamin D supplementation (35%) and bisphosphonates (32%) [
6]. Biosimilar daily teriparatide has been available in Japan since November 2019, and the initial price of the biosimilar version was set to be 60% of the equivalent brand product [
7]. Biosimilar drugs are biological products that are highly similar to the approved biologic reference products and have no clinically meaningful differences from the reference products [
8].
In our previous study in the US setting, we examined the potential health economic impact of generic or biosimilar (i.e., generic/biosimilar) daily teriparatide availability after the market exclusivity for brand teriparatide expired in August 2019 in the USA. We found that among high-risk older osteoporotic white women, even with generic/biosimilar teriparatide availability, teriparatide followed by alendronate (i.e., sequential teriparatide/alendronate) would not be cost-effective unless the cost of generic/biosimilar teriparatide was heavily discounted with respect to the current brand cost [
9].
To the best of our knowledge, a cost-effectiveness analysis including teriparatide has not yet been conducted in Japan. Generating a specific cost-effectiveness analysis for Japan is important, because results of cost-effectiveness analyses performed for one country may not apply to another country with a different disease epidemiology, healthcare system costs, and willingness-to-pay threshold. With the recent availability of the less expensive biosimilar version of teriparatide in Japan, we therefore aimed to examine the cost-effectiveness of including teriparatide as part of osteoporosis treatment in the Japanese setting.
As a typical scenario for teriparatide’s use, we compared the cost-effectiveness of sequential teriparatide/alendronate, which in this study was defined as daily subcutaneous teriparatide for 2 years followed by weekly oral alendronate for 8 years, compared with weekly oral alendronate monotherapy for 10 years among women with prior clinical or morphometric vertebral fracture in Japan. Worldwide, teriparatide is approved for no more than a 2-year treatment period because of the potential risk of osteosarcoma observed in animal studies [
10]. Bisphosphonates are typically prescribed after the completion of teriparatide to prevent decline in bone mineral density and provide continued fracture prevention [
9]. Although the optimal duration of alendronate has not been determined, those who are at high risk for osteoporotic fractures may benefit from more than 5 years, and up to 10 years of therapy [
5,
11‐
14].
Discussion
Although teriparatide is generally not considered to be a first-line treatment for osteoporosis, from the health economic standpoint teriparatide (including both daily and weekly versions) represented 20% of the total costs of medications used for osteoporosis in Japan in 2017 [
5,
6]. We examined the cost-effectiveness of sequential daily teriparatide/alendronate compared with alendronate monotherapy among community-dwelling older osteoporotic women with prior vertebral fracture in Japan. In our model, without an intervention, the lifetime probabilities of a woman having a hip or vertebral fracture after the starting ages were approximately 35% or 69–72%, respectively, representing a high-risk population for osteoporotic fracture. Sequential teriparatide/alendronate was not cost-effective at any age examined, even with the recent availability of biosimilar teriparatide, at the conventionally accepted willingness-to-pay threshold (i.e., ¥5million, or $47,500/QALY).
In Japan, the Ministry of Health, Labour and Welfare determines and revises drug prices under the universal healthcare insurance system. The price of biosimilar teriparatide was initially set to be 40% discounted relative to the brand version when the biosimilar version became available on the Japanese market in November 2019. In April 2020, the prices of brand and biosimilar teriparatide were decreased by approximately 17% and 3%, respectively, making the price of the biosimilar 30% discounted relative to the brand product [
7]. Sequential teriparatide/alendronate became cost-effective if the costs of biosimilar teriparatide were 85%, 50%, and 15% discounted relative to the current biosimilar price (or approximately 91%, 71%, and 51% discounted compared with the price of the brand version before November 2019) at ages 70, 75, and 80, respectively, at the willingness-to-pay of ¥5million ($47,500). At a willingness-to-pay of ¥10million ($95,000), sequential teriparatide/alendronate became cost-effective with discounts of 65% and 15%, respectively, (i.e., approximately 80% and 51% discounted compared with the price of the brand version before November 2019) at ages 70 and 75, and was cost-effective with no discount at age 80. Based on these results, it seems unlikely that teriparatide will be cost-effective at age 70 for the foreseeable future.
In an earlier analysis, we found that among community-dwelling older osteoporotic women with prior vertebral fracture in the USA, even with generic/biosimilar teriparatide availability, sequential teriparatide/alendronate would not be cost-effective unless the cost of generic or biosimilar teriparatide was heavily discounted with respect to the brand cost (i.e., 75%, 65%, and 70% discount at ages 70, 75, and 80, respectively) [
9]. Parameter inputs differ markedly by setting (Supplemental Table 4), which shows the importance of conducting country-specific cost-effectiveness analyses.
In deterministic sensitivity analyses, we found that varying the efficacy of teriparatide or alendronate would impact the ICERs of sequential teriparatide/alendronate compared with alendronate monotherapy, which is not surprising. In deterministic sensitivity analyses, a relative risk of 0.16 was used for the lowest (i.e., most efficacious) value for efficacy of teriparatide for prevention of clinical vertebral fracture. Of note, this value is very similar to the relative risk of 0.17 reported in a secondary analysis of back pain findings from the global, multi-site Fracture Prevention Trial [
41]. Persistence with teriparatide or alendronate also appears to influence ICERs substantially, consistent with the role of persistence noted in our previous work [
15].
As evidence accumulates regarding the value of sequential therapy for the treatment of osteoporosis, cost-effectiveness analyses evaluating sequential therapy have also been performed [
42]. In addition to our previous study comparing sequential teriparatide/alendronate with alendronate monotherapy [
9], three more cost-effectiveness analyses regarding sequential therapy have been reported, all of which were performed in women in the US setting. Abaloparatide followed by alendronate was dominant (i.e., more effective and less expensive) compared with sequential teriparatide/alendronate and was cost-effective compared with alendronate monotherapy [
23,
43,
44]. In our current study, however, abaloparatide was not included as it was not available in Japan at the time of this analysis.
We chose to evaluate cost-effectiveness from the combined public healthcare and long-term care payer’s perspective as a primary analysis, and from the public healthcare payer’s perspective as a sub-analysis, the latter being considered standard per Japanese guidelines [
18]. The rationale behind this decision is that osteoporotic fracture leads to not only increased medical but increased long-term care expenditures, and we believed that in an older population, the economic burden on society caused by medical conditions/diseases is better evaluated by the sum of medical and long-term care expenditures, rather than medical expenditures alone [
26,
45]. In this study, the ICERs of two perspectives turned out to be similar and the conclusions remained the same, even though long-term care represents approximately two-thirds of all costs.
We note several limitations. First, although the annual incidence rate of clinical vertebral fractures and the cost of long-term care after clinical vertebral fractures were key parameters, we estimated these values indirectly because of the lack of reliable data. Second, as the target population was those who had prior vertebral fracture, we modeled an increased risk of fracture associated with prior vertebral fracture. Bone mineral density (BMD) is also known to be a critical risk factor for fracture. However, we did not consider various BMD thresholds in our study, as the existing literature does not allow us to differentiate the increased risk associated with prior fracture from that associated with lower BMD (since the two are correlated). In a deterministic sensitivity analysis, we varied the annual incidence rates of hip and clinical vertebral fracture simultaneously from 50 to 150% of the base case to examine how these changes would affect the ICERs. By doing so, we have indirectly examined how changes in BMD thresholds would affect the ICERs
. Third, we only included hip and clinical vertebral fractures and did not include other types of osteoporotic fractures, such as distal forearm or proximal humerus fractures. We believe, however, that including these other fracture types would have little influence on the overall results. Epidemiologic data from a Japanese city showed that hip and clinical vertebral fractures accounted for approximately 77% (ages 70–74), 84% (ages 75–79), 85% (ages 80–84), and 88% (ages 85 and older) of the four types of fractures (i.e., hip, clinical vertebral, distal forearm, and proximal humerus). In addition, among these four types of fractures, hip fractures are associated with the greatest medical and long-term care costs, reduced health-related quality of life in the first and subsequent years after the fracture, and excess mortality; while vertebral fractures are associated with medical and long-term care costs and reduced health-related quality of life in the first and subsequent years. In contrast, distal forearm and proximal humerus fractures are typically only associated with medical cost and reduced health-related quality of life in the first year after the fracture. Therefore, hip and clinical vertebral fractures are likely to be the key clinical events that need to be explicitly modeled. Fourth, to keep the model parsimonious, we did not include adverse events (e.g., hypercalcemia with teriparatide) [
10,
34]. However, serious adverse events caused by teriparatide are considered to be rare and therefore were unlikely to impact the results of cost-effectiveness analyses [
9]. Fifth, alendronate was prescribed after the completion of teriparatide in our analysis. However, another medication such as denosumab can be prescribed afterward instead of alendronate, which was beyond the scope of our analysis [
9]. Finally, our results may be best applied to postmenopausal women in Japan, and may not generalize to women of other races/ethnicities or in other countries, or men.
Despite these limitations, our study has notable strengths. First, to our knowledge, this is the first economic evaluation to examine the cost-effectiveness of a teriparatide-based treatment strategy in Japan. Second, we incorporated the cost of biosimilar teriparatide that became recently (i.e., November 2019) available in Japan and then examined how further discounts of the costs of biosimilar teriparatide would affect cost-effectiveness. As in our previous study in the US setting, we identified that one of the main drivers of sequential teriparatide/alendronate not being cost-effective was the cost of teriparatide. Third, we incorporated medication persistence and adherence into the model and extensively examined how the changes in these parameters affect the ICERs in deterministic sensitivity analyses, as persistence and adherence rates have been known to be essential parameters in cost-effectiveness analyses regarding osteoporosis [
9,
15].
In conclusion, among community-dwelling older osteoporotic women with prior vertebral fracture in Japan, sequential teriparatide/alendronate is not cost-effective compared with alendronate monotherapy at the ages examined, even with the availability of biosimilar teriparatide.
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