Introduction

The burden of osteoporosis and its dreaded consequence of fragility fractures is expected to increase worldwide as populations age. It is estimated that the number of individuals at risk for such fractures worldwide is going to increase two-fold from the 158 million it was in 2010 to 319 million in 2040 [1]. Nowhere is this grave projection going to hold more true than in Asia, which is home to 4.5 billion people. The population in Asia aged over 65 years is projected to more than quadruple by 2050, and to further grow by almost six-fold by the year 2100 [2]. It is predicted that by 2050, over half of the world’s hip fractures will occur in Asia [38] and clinical data [39].

To model a real-life scenario with alendronate, we used a similar methodology as that has been used previously that focused on medication persistence. Persistence has been shown to have the most influence on cost-effectiveness [40]. Real-world persistence data with oral bisphosphonates were derived from a recent systematic review suggesting that the mean persistence was 53% at 6 months, 46% at 1 year, 37% at 2 years and 31% at 3 years [41]. For patients who stopped taking their therapy, the treatment cost immediately stopped and the offset (assumed as a period similar to duration on therapy) period started at the same time. For those who discontinued therapy within 6 months, no treatment effect was assumed, since at least 6 months of treatment is necessary to reduce the risk of fractures.

Treatment costs including medication costs, cost of follow-up visits at outpatient clinics, and bone density measurement were obtained from pre-subsidy charges at public healthcare institutions from the Ministry of Health. In accordance with the usual clinical practice in Singapore, it was assumed that there would be 2 clinic visits in the first 1 year followed by 1 visit annually in subsequent years. Each clinic visit costs SGD 200. The cost of one BMD measurement (SGD 180) using axial DXA scanning per year was also included. Gastrointestinal adverse events observed with oral bisphosphonates have been noted to be generally mild and transient in our patients. The cost and quality of life impact of these adverse events would thus only be minor and not affect the results and were therefore not included in the analysis.

Analyses

Under this microsimulation model, a total of 1,000,000 of individual patient simulations were run for each analysis. Total healthcare costs and accumulated QALYs were estimated for each treatment strategy. The incremental cost-effectiveness ratio (ICER) was then calculated for alendronate considering both full and real-world adherence compared with no treatment. ICER was defined as the difference between the active treatment and the comparator treatment in terms of total costs (expressed in SGD2019) divided by the difference between them in terms of QALYs. If the ICER is above a cost-effectiveness threshold (representing the decision makers’ willingness to pay), then the cost is too high for the benefits, and the intervention is not considered as cost-effective at the selected IT.

There is no agreed willingness-to-pay threshold for adopting health technologies in Singapore. While the threshold of one GDP per capita as recommended by the World Health Organization (WHO) is commonly used in publications [42], countries with explicit thresholds have adopted more stringent levels, with the thresholds of £20,000/QALY and £30,000/QALY used by UK’s Health Technology Agency corresponding to 0.70 and 1.04 times of UK’s GDP in 2015. For our base analysis, we used a stringent threshold with SGD 62,500 equivalent to 0.7 of Singapore’s GDP per capita of SGD 89,000 in 2019.

FRAX®-based intervention thresholds

In this current economic study, the cost (SGD) per QALY gained of generic alendronate compared with no treatment at different FRAX®-based age-dependent mean-weighted MOF and HF ITs obtained through the translational approach described earlier [18] was assessed. At each age and at the corresponding FRAX® MOF and HF IT values, the ICER was derived. In addition, we also determined the MOF and HF ITs at which treatment with generic alendronate compared with no treatment became cost-effective using a cost-effectiveness threshold of SGD 62,500.

Sensitivity analysis

Two sensitivity analyses were conducted, one with a less stringent cost-effectiveness threshold (i.e. SGD 89,000 corresponding to 1× GDP) and one assuming reduced monitoring with only one BMD measurement every 2 years instead of annually and only one visit per year.

Results

The cost (SGD) per QALY gained of alendronate compared with no treatment at different age-dependent MOF intervention thresholds in Singapore is shown in Table 2. Alendronate was shown to be cost-effective (i.e. ICER < SGD62,500 per QALY gained) at MOF IT from the age of 65 years, at both full adherence and real-world adherence levels. The cost (SGD) per QALY gained of alendronate compared with no treatment at different age-dependent hip fracture intervention thresholds in Singapore is shown in Table 2. Alendronate was cost-effective at HF IT from the ages of 60 and 65 years, assuming full adherence and real-world adherence levels, respectively. Intervention with alendronate (in a scenario involving full adherence) was cost-saving at ages 80 years and above.

Table 2 Incremental cost-effectiveness ratio (expressed in costs (SGD) per QALY gained) of alendronate compared with no treatment at different major osteoporotic fracture intervention thresholds (MOF ITs) and hip fracture intervention thresholds (HF ITs) in Singapore
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Assuming real-world adherence for alendronate (Fig. 2), a MOF IT of 14% resulted in a cost per QALY gained below cost-effectiveness threshold of SGD 62,500 at all ages.

Fig. 2
figure 2

Cost per QALY gained of full and real-world adherence with alendronate compared to no treatment in women with a 14% risk of MOF at all ages

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Assuming real-world adherence for alendronate (Fig. 3), a HF IT of 3.5% resulted in a cost per QALY gained below cost-effectiveness threshold of SGD 62,500 at all ages.

Fig. 3
figure 3

Cost per QALLY gained of full and real-world adherence with alendronate compared to no treatment in women with a 3.5% risk of HFP at all ages

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On the sensitivity analysis, it was found that the cost per QALY gained decreased, with lesser frequency of clinic visits and DXA scanning. Under this scenario, alendronate was cost-effective (i.e. ICER < SGD 62,500 per QALY gained) at MOF ITs from the ages of 60 and 65 years, assuming full adherence and real-world adherence levels, respectively (Table 3). For HF IT, alendronate was cost-effective from the age of 60 years in both adherence scenarios. Cost-saving was seen for HF ITs under both full and real-world adherence scenarios from the age of 75 years and for full adherence for MOF ITs from the age of 80 years (Table 3). Under this sensitivity analysis, a MOF IT of 12% and a HF IT of 3% lead to cost-effectiveness results for generic alendronate for the entire age range.

Table 3 Sensitivity analysis (lower monitoring costs) on the incremental cost-effectiveness ratio (expressed in costs (SGD) per QALY gained) of alendronate compared with no treatment at different major osteoporotic fracture (MOF) and hip fracture (HF) intervention thresholds (ITs) in Singapore
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Assuming a threshold of SGD 89,000 per QALY gained (i.e. 1× GDP), age-dependant MOF and HIP ITs were cost-effective from the age of 60 to 65 years, respectively, with both full and real-world adherence. Using this cost-effectiveness threshold, generic alendronate was cost-effective with at a MOF IT of 13% and a Hip fracture IT of 3% for the entire age range.

Discussion

Our study shows that interventions aimed at reducing fracture risk in osteoporotic patients can be implemented in a cost-effective manner in Singaporean women at high risk of fracture, at FRAX® MOF and HF ITs of 14% and 3.5% respectively; i.e. treating with generic alendronate can be considered as cost-effective in Singapore when the 10-year probability of a MOF equals or exceeds 14% or when the similar probability of a HF exceeds 3.5% and above. On the other hand, using the translational approach, it appears that prescription of generic alendronate for Singaporean women is cost-effective at age-dependent ITs from the age of 65 years for both MOF and HF assuming real-world adherence and from 65 years for MOF and 60 years for HF assuming full adherence.

The MOF fixed IT of 14% in women over the age of 50, obtained from the cost-effectiveness approach in our study, was approximately the same as was seen in Switzerland [17] of 13.8%. Our IT for HF of 3.5% was lower than the 7% noted in a study from Taiwan [43] and slightly higher than the 3% denoted as cost-effective in the USA [15]. The reasons for these differences could include the variations in the risk of osteoporotic fractures between countries, the methodology used for epidemiological studies on fractures and for cost-effectiveness analyses and in WTP which varies with the GDP in different countries.

The National Institute for Health and Care Excellence (NICE) of UK’s updated multiple technology appraisal (MTA) on bisphosphonate use in osteoporosis concluded that generic oral bisphosphonates were cost-effective for people with even a 1% major osteoporotic fracture risk [37]. The recommendations made in this appraisal have been criticized for their clinical inappropriateness [44] and contradict that found in our study, in which cost-effectiveness was seen only at much higher intervention thresholds. This is not surprising given that the total costs of treatment including costs of clinic visits and DXA scanning are much higher in Singapore than in the UK.

Branded alendronate was used for the cost-effectiveness analysis study in Switzerland [17] unlike in ours where the cost-effectiveness of generic alendronate was explored. However, age-dependent intervention thresholds were cost-effective only at older ages in both countries with the threshold being cost-effective from the age of 60 in Swiss women and from the age of 65 in Singapore. This is likely because the total costs of treatment are likely similar in our countries with the cost of BMD monitoring and clinic visits being very high in Singapore. This likely outweighs the financial benefit of generic alendronate.

In the sensitivity analysis in our study, when less frequent clinic visits and DXA scanning were factored in, the MOF and HF ITs decreased, but only slightly to 12% and 3%. A less stringent cost-effectiveness threshold of SGD 89,000 (the GDP per capita of Singapore) also lowered the cost-effective MOF and HF ITs slightly to 13% and 3%, respectively.

Our findings pertain to the use of only generic alendronate. Generic alendronate was chosen for our study as it is the most frequently prescribed anti-osteoporosis agent in Singapore currently. It is possible that more effective, albeit costlier agents may prevent more fractures in higher risk people. This might result in more cost-savings and a net increase in QALYs than what was seen with the current scenario with generic alendronate. Other antiosteoporosis medications, such as branded alendronate, risedronate, raloxifene, zoledronic acid (given as an annual intravenous infusion), teriparatide (given as a daily subcutaneous injection) and denosumab (administered as a subcutaneous injection once in 6 months), are also available in Singapore. Though direct head-to-head comparisons are lacking, there exists some data to suggest that agents such as Zoledronic acid and Denosumab may be more efficacious at reducing fracture risk than alendronate [37]. From a purely economic perspective, the cost-effectiveness of each treatment would differ, and each medication would have a different cost-effective threshold to intervene with at. However, to deprive a patient of a certain medication unless she attains the threshold that is needed for her to be on that medication would be ethically wrong, and deriving and implementing intervention thresholds for every single medication is impractical. It is to avoid this problem and because treatments with other medications were found to be cost-effective at their country's currently acceptable WTP thresholds that the National Osteoporosis Guideline Group in the UK has also recommended utilizing the same intervention thresholds for these other medications as is used for generic alendronate despite the formers' higher costs [19, 45].

Access to DXA is relatively easy in Singapore with 16.9 DXA machines available per 1 million population [46], and thresholds to identify who to send for bone densitometry using the Osteoporosis Self-Assessment tool for Asians (OSTA) and/or FRAX® have recently been suggested for Singapore [47]. The recently published Singapore Osteoporosis Guidance for primary care, recommends pharmacological intervention in patients with a BMD T-score at any axial site of ≤ − 2.5 and/or a history of a fragility fracture [48]. FRAX®-based ITs can be considered as an addition to these already accepted intervention thresholds. If cost-effectiveness is the sole desired outcome, then fixed MOF and HF ITs of 14 and 3.5% should be recommended in all Singaporean women aged 50 and above. When these ITs were applied on a cohort of 1056 post-menopausal community dwelling Singaporean women recruited for an assessment threshold study [47], it was seen that 17% of women above the age of 50 would qualify for treatment. An alternative approach that would be still cost-effective would be to recommend age-dependent thresholds in women 65 years and above, and in those below the age of 65 years, MOF and HF ITs of 14% and 3.5%, respectively. With this latter strategy, approximately 27% of women 65 years and older and 6% of women below the age of 65 years would be eligible for treatment. This approach could also potentially avoid unnecessary treatment of younger individuals who are likely to be at lower fracture risk while directing treatment to older individuals who are at higher risk.

Whether to employ a completely FRAX®-based intervention threshold approach or to consider them as an addition to existing intervention strategies in Singapore is a matter that should be gravely discussed at a healthcare policy decision-making level before implementation.

It should also be kept in mind that ITs based on cost-effectiveness analysis should not be the sole modality employed for decision-making in osteoporosis care. They should be used in conjunction with other clinical parameters to afford the best and most appropriate individualized care for patients.

Our study has some limitations. Some data such as mortality rates after hip and vertebral fractures, utility data for osteoporosis and osteoporotic fractures and data on persistence with oral bisphosphonate therapy were lacking in Singapore, and therefore, they had to be obtained from studies done elsewhere as described earlier. Another potential limitation of the study is that we did not adjust mortality according to baseline fracture probability and different combinations of risk factors of FRAX®. The risk factor combinations that yield the same fracture probability may yield different mortality effects.

Generic alendronate may be associated with poorer adherence [49] than the branded formulation. However, this is unlikely to be an issue with our study since we adopted a very cautious approach by estimating that only 53%, 46%, 37%, and 31% of patients would be persistent to the medication at 6 months, 1 year, 2 years, and 3 years, respectively [40], and by including this real-world adherence in our modelling strategy. While not including relatively common side effects of bisphosphonate therapy in our analysis might be considered as a limitation, it has to be noted that most economic evaluations of oral bisphosphonates have not included side effects, considering they are transient and do not affect quality of life and costs substantially. A few studies such as the NICE appraisal [37] have incorporated gastrointestinal disorders associated with oral bisphosphonates in cost-effective analysis by including additional general practitioner (GP) consultations and the use of a proton pump inhibitor and this was found to be connected with additional costs and a utility loss of 1 month. However, the inclusion of side effects has been shown to only have a very modest effect on cost-effectiveness using the lifetime horizon [50].

Our study has several advantages. It is the first such study from the only advanced economy in Southeast Asia [51]. We explored the cost-effectiveness of both age-dependent FRAX® ITs that have been previously obtained using a translational approach as well as derived fixed ITs that are cost-effective at all age ranges between 50 and 80 years. Our study considered real-world adherence with oral bisphosphonate therapy while determining the cost-effectiveness of ITs. Data on fracture incidences and osteoporosis and fracture care costs were obtained from the Singapore Ministry of Health’s comprehensive databases. This ensured that the data used was nationally representative, credible and accurate. Ours is also the first such study on cost-effectiveness of osteoporosis care that had the close input of the Ministry of Health of a country. Such a collaboration between healthcare providers and policymakers enables the co-creation of solutions for problems in osteoporosis management. Having done the analysis using FRAX®-based fracture probabilities which is a very granular approach to estimate fracture risk incorporating several risk factors provides a more realistic reflection of everyday clinical practice.

Conclusion

Treatment of women with the most frequently prescribed anti-osteoporosis agent in Singapore, namely, generic alendronate, is cost-effective at age-dependant FRAX® intervention thresholds at 65 years and older. Furthermore, identifying women at any age above 50 years with a 10-year risk of MOF or HF of 14% or 3.5%, respectively, would lead to efficient use of healthcare resources. Cost-effective access to therapy for elderly patients at high fracture probability based on FRAX® could contribute to reduce the growing burden of osteoporotic fractures in Singapore.