Table 2.

Results of cost-effectiveness analyses of drugs for osteoporosis

References	Population (base case)	Comparators	Year of costing valuation	Sensitivity analysis	Results
Active drug(s) vs no treatment/calcium + vitamin D
Golmohamdi et al. [12]	Postmenopausal women with osteoporosis	Zoledronic acid vs placebo	2013	No	One percent increase of BMD on femoral neck, hip trochanter, total hip, and lumbar spine requires further cost of US$386, US$264, US$388, and US$347, respectively. Zoledronic acid is a cheaper and better approach and can be considered as a dominant approach
Kwon et al. [32]	Postmenopausal women aged 55, 60, or 65 years with BMD T-scores from − 2.0 to − 2.4 at the femoral neck, and without previous osteoporotic fractures	Calcium/ vitamin D vs (raloxifene + calcium/ vitamin D) or (risedronate + calcium/vitamin D)	2014	One-way	In comparison with calcium/vitamin D supplements, drug therapy (raloxifene or risedronate + calcium/vitamin D) had an ICER of US$16,472 and US$6741 per QALY gained for treatment started at the age of 55 and 60 years, respectively. Given the WTP threshold (US$25,700), pharmaceutical treatment was cost effective. For older women starting medication at 65 years of age, pharmaceutical intervention was a dominant strategy
Ito et al. [36]	Women aged 85 years with BMD T-score ≤ − 2.0 at the spine, hip, or radius who resided in nursing homes	(Zoledronic acid + calcium/vitamin D) vs usual care (calcium/vitamin D)	2017	One-way probabilistic	In comparison with usual care, zoledronic acid had an ICER of US$207,400 per QALY gained. Given the WTP threshold (US$100,000), zoledronic acid was not cost effective
Mohd-Tahir et al. [17]	Adult patients diagnosed with osteoporosis related to glucocorticoid drugs use	Oral bisphosphonates (alendronate, risedronate or ibandronate) vs calcium/vitamin D	2014	No	Overall, in comparison with calcium/vitamin D, the use of bisphosphonates could not be considered cost effective for treatment of all patients with GIO. Bisphosphonates were considered cost effective if started in patients more than 60 years old. However, bisphosphonates were not cost effective in patients with GIOP secondary osteoporosis. The ICERs of bisphosphonates in patients with previous fracture or with rheumatoid arthritis were estimated at MYR 108,603 and MYR 25,699 per QALY gained, respectively. Given the WTP threshold (MYR 26,317), bisphosphonates were cost effective in patients with rheumatoid arthritis
Cui et al. [34]	Postmenopausal osteoporotic women	Zoledronic acid vs no treatment	2019	One-way	In comparison with no treatment, zoledronic acid had ICERs of US$26,637, US$22,129, US$20,338, US$19,285, US$18,181, US$16,680, US$15,047, and US$14,447 per QALY at FRAX threshold 0.02, 0.06, 0.07,0.08, 0.09, 0.1, 0.5, and 1, respectively. Zoledronic acid was cost effective when the 10-year probability of major osteoporotic fracture based on FRAX was above 7%
Taheri et al. [33]	Women aged 70 years, BMD T-score − 2.5 with previous fracture or BMD T-score -3.0 without prior fracture	Teriparatide vs no treatment	2018	One-way probabilistic	In comparison with no treatment, teriparatide was indicated to be more costly and associated with fewer fractures, more life-years, and more QALYs, with an ICER of IRR 254,750,619 per QALY gained. It could be considered as a cost-effective treatment in severe PMO at the WHO recommended threshold
Active drug(s) versus active drug(s)
Parthan et al. [21]	Men aged 75 years and older with osteoporosis	Denosumab vs (generic alendronate, strontium ranelate, zoledronic acid, generic risedronate, ibandronate, and teriparatide)	2012	One-way probabilistic	Total lifetime costs for denosumab, generic alendronate, strontium ranelate, zoledronic acid, generic risedronate, ibandronate, and teriparatide were €31,004, €33,731, €34,788, €34,796, €34,826, €35,983, and €37,461, respectively. Total QALYs were 5.23, 5.15, 5.15, 5.17, 5.13, 5.12, and 5.22, respectively In comparison with other treatments, denosumab had the lowest costs and highest QALYs. Denosumab dominated all comparators
Venice et al. [10]	Postmenopausal women aged 45–79 years with low BMD in the lumbar spine and/or right hip, a Karnofsky index of 90–100	Alendronate vs zoledronic acid	2010	No	Compared with oral alendronate, zoledronic acid provided an annual savings of 15% of the direct costs for 1 year. Zoledronic acid infusion is also linked to a higher increase in BMD and compliance
Waure et al. [26]	Postmenopausal women aged 65 years with a BMD T-score < − 4 SD	Denosumab vs (risedronate, generic and branded alendronate, ibandronate, and strontium ranelate)	2009	Probabilistic	The ICERs for denosumab, in comparison with risedronate, generic alendronate, branded alendronate, ibandronate, and strontium ranelate were estimated at €10,302, €18,047, €17,133, €2158, and €69 per QALY gained, respectively. Given the WTP threshold (€30,000), denosumab is cost effective
Darbà et al. [25]	Postmenopausal women age 65 years with BMD T-score ≤ 2.5 or less	Denosumab vs (alendronate, ibandronate, risedronate, strontium ranelate, and no treatment)	2013	Probabilistic, multivariate, univariate	The ICER for denosumab compared with no treatment, alendronate, risedronate, and ibandronate were estimated at €6823, €16,294, €4895, and €2205 per QALY gained, respectively. Given the WTP threshold (€20,000), denosumab is cost effective. Denosumab is a dominant treatment option in comparison with strontium ranelate
Miraci et al. [11]	Menopausal or postmenopausal women aged 50 years with T-score − 1 to -6, diagnosed for the first time	Ibandronate vs alendronate	NR	No	The cost/efficacy ratio (1% change of BMD) was 13.434 units for ibandronate and 31.677 units for alendronate type A1. Ibandronate is more effective and cost effective than alendronate in the treatment of osteoporosis
Silverman et al. [22]	Men with a mean age of 78 years with BMD T-score of − 2.12 and a vertebral fracture prevalence of 23%	Denosumab vs (generic alendronate, risedronate, ibandronate, teriparatide, and zoledronic acid)	2013	One-way probabilistic	Compared with generic alendronate, denosumab had an ICER of US $16,888 per QALY gained. Given the WTP threshold (US $100,000), denosumab is cost effective. Compared with risedronate, ibandronate, teriparatide, and zoledronic acid, denosumab is a dominant option
Chen et al. [31]	Postmenopausal women aged 65 years with BMD T-score ≤ -2.5 at the femoral neck and without previous fractures (initial population)	Raloxifene vs conventional treatment (calcitonin or alendronate or calcium/vitamin D)	2015	One-way probabilistic	Compared with conventional treatment, treatment with raloxifene had an ICER of US$36,891 per QALY gained. Given the WTP threshold of US$20,000), raloxifene was not cost effective
Karnon et al. [14]	Women with a mean age of 72 years (range 60–90 years) with a mean BMD T-score at the femoral neck of − 2.15, and with 24% of women having experienced a previous fracture	Patented denosumab vs generic alendronate	2012	Deterministic probabilistic	Compared with alendronate, denosumab had an ICER of AUD$246,749 per QALY gained. Given the WTP threshold (AUD$100,000), denosumab is not cost effective
Azar et al. [13]	Postmenopausal women aged over 60 years with BMD T-score ≤ 2.5 and with at least a previous spine, wrist, or hip fracture caused by osteoporosis	Risedronate vs (alendronate and teriparatide)	2014	One-way	Compared with risedronate, alendronate and teriparatide had ICERs of US$-2178 and US$483,783 per QALY gained. Given the WTP threshold (US$14,010), alendronate is the dominant and cost-effective treatment option. The treatment strategy of teriparatide is more expensive than risedronate and alendronate and is associated with very little increase in QALYs
Mori et al. [18]	Postmenopausal osteoporotic women without previous hip or vertebral fractures at various ages of therapy initiation (65, 70, 75, and 80 years)	Alendronate vs denosumab vs no treatment	2016	One-way probabilistic	For patients aged 75 and 80 years, denosumab was cost saving from any of the three perspectives, in comparison with alendronate For patients aged 65 and 70 years, denosumab had an ICER of US$25,700 and US$5000 per QALY gained, from a societal perspective, and did not exceed a WTP threshold (US$50,000). Therefore, denosumab was a cost-effective option
Mori et al. [19]	Community-dwelling non-Hispanic white women at different starting ages (65, 70, 75, and 80 years) and without previous hip, vertebral, or wrist fractures	Oral bisphosphonate vs no treatment, combined strategy (bisphosphonate + falls prevention exercise) and (falls prevention exercise only)	2014	One-way probabilistic	Compared with an oral bisphosphonate alone, the combined strategy had ICERs of US$202,020, US$118,460, US$46,870, and US$17,640 per QALY for patients aged 65, 70, 75, and 80 years, respectively. Given the WTP threshold (US $100,000), the combined strategy for patients ages 75 and 80 years was cost effective. The combined strategy provided better health at lower cost than the falls prevention exercise alone at ages 70, 75, and 80 years
Moriwaki et al. [30]	Women of 70 years with BMD T-score of − 2.5 and a previous vertebral fracture	Alendronate + basic treatment (placebo + calcium + vitamin D) vs basic treatment; (zoledronic acid + basic treatment) vs (alendronate + basic treatment)	2016	Deterministic probabilistic	For patients 70 years of age, zoledronic acid was dominated by alendronate. However, the incremental QALY is quite small in extent. Considering the advantage of annual zoledronic acid treatment in compliance and persistence, zoledronic acid may be a cost-effective treatment option compared to alendronate
O'Hanlon et al. [35]	Women of 70 years with BMD T-scores < − 2.5 and a previous vertebral fracture	Alternative bone-forming agent profiles vs the teriparatide reference case; alternative bone-forming agent profiles vs (sequential teriparatide + denosumab)	2016	No	In comparison with teriparatide, alternative bone-forming agent profiles produced a net monetary benefit of US$17,000,000 per 10,000 treated patients during the 1.5 years and US$80,000,000 over a lifetime horizon that included 3.5 years of maintenance treatment with denosumab
Yoshizawa et al. [29]	Women aged 75 years with BMD T-score − 2.87 and with a previous vertebral body fracture	Denosumab vs alendronate; alendronate vs no treatment	2016	Deterministic probabilistic	Compared with alendronate, denosumab had an ICER of US$40,241 per QALY gained. Assuming a WTP threshold (US$50,000), denosumab was cost effective
Chokchalermwong et al. [23]	Postmenopausal women aged ≥ 50 years with osteoporosis and without previous fractures	(Oral bisphosphonates, raloxifene, strontium ranelate, and denosumab) vs no treatment	2015	One-way probabilistic	In comparison with no treatment, none of the alternative drugs were cost effective at baseline case. For women from the age of 65 years, with a BMD T-score ≤ -2.5, oral bisphosphonates were the only drugs cost effective (the ICER was THB130,049), followed by denosumab and raloxifene, respectively. Strontium ranelate was dominated by no treatment
Coyle et al. [24]	Women aged 70–74 years with osteoporosis and without previous fractures who are able to tolerate oral bisphosphonates	Alendronate vs etidronate vs risedronate vs zoledronic acid vs denosumab vs no treatment	2017	Probabilistic	For patients who can tolerate oral bisphosphonates, in comparison with no treatment, alendronate, risedronate, zoledronic acid, and denosumab had ICERs of CAN$3751, CAN$85,557, CAN$83,503, and CAN$238,523 per QALY gained, respectively. Given the WTP threshold (CAN$50,000), alendronate was the only cost-effective drug. In comparison with alendronate, risedronate and etidronate were dominated, and zoledronic acid and denosumab were associated with a high ICER. For patients who are unable to tolerate oral bisphosphonates, dependent on age and fracture history, compared with no treatment, the ICER for zoledronic acid had a range from CAN$17,770 to CAN$94,365 per QALY. Denosumab was dominated by zoledronate or had an ICER greater than CAN$3.0 million
Hiligsmann et al. [27]	Postmenopausal women aged 60–80 years with BMD T-score ≤ -2.5 and/or prevalent vertebral fractures	Gastro-resistant risedronate vs (generic risedronate, alendronate and no treatment)	2017	One-way probabilistic	The ICER for GR risedronate, compared with alendronate, generic risedronate and no treatment, ranged from €2037 to €21,875 per QALY gained. Given the WTP threshold (€60,000), GR risedronate was cost effective In women aged 75 years and older, GR risedronate was even shown to be dominant
Li et al. [15]	Women aged over 60 years with BMD T-score ≤ 2.5 in the lumbar spine or femoral neck and without previous fractures	(Alendronate, zoledronic acid, raloxifene and teriparatide) vs calcium/vitamin D; (alendronate, raloxifene and teriparatide) vs zoledronic acid	2018	Univariate probabilistic	Compared with calcium/vitamin D, zoledronic acid had an ICER of US$7864 per QALY gained. Given the WTP threshold (US$28,624), zoledronic acid was cost-effective. The ICER of teriparatide versus zoledronic acid was US$470,797 per QALY gained, which exceeded the threshold. Alendronate and raloxifene were dominated by zoledronic acid
Sequential therapies
Hiligsmann et al. [28]	Women aged 50–80 years with a BMD T-score ≤ -3.5 and without fracture history or with a BMD T-score − 2.5 to − 3.5 and a history of at least one osteoporotic fracture	(Sequential abaloparatide + alendronate) vs (sequential teriparatide + alendronate) and no treatment	2017	One-way probabilistic	In comparison with sequential TPTD/ALN therapy, sequential ABL/ALN therapy was dominant in all simulated populations. Compared with no treatment, in women with BMD T-score ≤ 3.5 (age over 70 years), the sequential ABL/ALN therapy was cost saving; and in women with a BMD T-score -2.5 to -3.5 and history of one osteoporotic fracture, the ICER was estimated at US$125,493, US$91,394, US$81,865, US$51,906, US$38,763, US$31,390, and US$28,086 for patients aged 50 years, 55 years, 60 years, 65 years, 70 years, 75 years, and 80 years, respectively. Given the WTP threshold (US$100,000), sequential ABL/ALN therapy was cost effective for patients aged over 55 years
Le et al. [16]	Postmenopausal women aged 68.8 years with osteoporosis	(Sequential abaloparatide + alendronate) vs (sequential teriparatide + alendronate) and (placebo + alendronate)	2017	One-way probabilistic	Compared with TPTD/ALN over a 10-year time horizon, ABL/ALN was dominant. In comparison with PBO/ALN, ABL/ALN had an ICER of US$333,266 per QALY gained. In high-risk women, ABL/ALN was also cost effective in comparison with TPTD/ALN, and had an ICER of US$188,891 per QALY gained relative to PBO/ALN
Mori et al. [20]	Community-dwelling white osteoporotic women aged 65, 70, 75, and 80 years with previous vertebral fracture	(Sequential teriparatide + alendronate) vs alendronate alone	2018	One-way probabilistic	Compared with alendronate alone from the societal perspective, sequential teriparatide/alendronate had an ICER of US$434,400, US$330,000, US$280,100, and US$290,800 per QALY for women aged 65, 70, 75, and 80 years, respectively. From a healthcare perspective, the ICERs were US$441,700, US$336,700, US$288,200, and US$299,100 per QALY, respectively, Given the WTP threshold (US$150,000), sequential teriparatide/alendronate was not cost effective unless the costs of generic/biosimilar teriparatide were heavily discounted with respect to the current brand cost

ABL abaloparatide, ALN alendronate, AUD Australian Dollar, BMD bone mineral density, GIOP glucocorticoid-induced osteoporosis, GR gastro-resistant, ICER incremental cost-effectiveness ratio, IRR Iranian Rial, NR not reported, PBO placebo, PMO postmenopausal osteoporosis, PTH parathyroid hormone, QALY quality-adjusted life-year, MYR Malaysian Ringgit, THB Thai Baht, TPTD teriparatide, WTP willingness to pay, WHO World Health Organization