Cost-effectiveness of denosumab versus zoledronic acid for preventing skeletal-related events in the Czech Republic

Figures & data

Table 1. Inputs into the cost-effectiveness model: base case.

	Prostate cancer	Breast cancer	Other solid tumors
SRE rate (per 4-week cycle)
Zoledronic acid	0.207	0.138	0.205
Denosumab (derived)	0.170	0.106	0.174
Denosumab treatment effect^13–15
Rate ratio first and subsequent   SRE (95% CI)	0.82 (0.71–0.95)	0.77 (0.66–0.89)	0.85 (0.72–1.00)
SRE type distribution (pooled across both treatment groups)^13–15
Pathologic fracture	0.268	0.582	0.314
Radiation to bone	0.661	0.354	0.575
Surgery to bone	0.015	0.047	0.062
Spinal cord compression	0.056	0.017	0.050
Discontinuation rates per year (excluding death)^30^,^48
Denosumab	0.409	0.284	0.619
Zoledronic acid	0.476	0.288	0.628
Baseline utility QALY decrements^31	0.680	0.660	0.580
SRE QALY decrements^31
Pathologic fracture	0.080
Radiation to bone	0.110
Surgery to bone	0.150
Spinal cord compression	0.535
Composite SRE QALY decrement^31	0.1262	0.1017	0.1242
Serious AE QALY decrements^49
Osteonecrosis of the jaw	0.009	0.008	0.010
Hypocalcemia	0.006	0.006	0.008
Renal toxicity	0.012	0.012	0.015
AE distribution: denosumab
Osteonecrosis of the jaw	0.294
Acute phase reaction	0.011
Hypocalcemia	0.232
Renal toxicity	0.463
AE distribution: zoledronic acid
Osteonecrosis of the jaw	0.213
Acute phase reaction	0.098
Hypocalcemia	0.103
Renal toxicity	0.586
AE rate (per 4-week cycle)
Denosumab	0.0044
Zoledronic acid	0.0044
SC vs IV QALY decrement (per cycle)
SC (denosumab)	0.0012
IV (zoledronic acid)	0.0021
Unit costs (CZK)^17–19
Drugs
Denosumab per 120 mg administration	6,711.62
Zoledronic acid per 4 mg administration	1,749.08
Patient management
Physician office visits	332.88
Laboratory tests (serum creatinine)	73.63
Administration
Denosumab	186.20
Zoledronic acid	409.17
SREs
Pathologic fracture	145,888.87
Radiation to bone	36,183.93
Surgery to bone	183,531.49
Spinal cord compression	50,858.33
AEs
Osteonecrosis of the jaw	12,409.95
Acute phase reaction	2,749.94
Hypocalcemia	2,238.04
Renal toxicity	104,737.22
Discount rates^32
Annual cost	0.030
Annual efficacy	0.030

AE: adverse event; CI: confidence interval; CZK: Czech Republic Koruna; IV: intravenous; QALY: quality-adjusted life-year; SC: subcutaneous; SRE: skeletal-related event.

Table 2. Base case analysis: costs, outcomes, and cost-effectiveness of denosumab vs zoledronic acid in patients with prostate cancer, breast cancer, or other solid tumors.

	Prostate cancer		Breast cancer		Other solid tumors
	Denosumab	Zoledronic acid	Denosumab	Zoledronic acid	Denosumab	Zoledronic acid
Costs (CZK)
Drug	105,500.72	25,696.10	162,572.42	42,054.30	68,251.73	17,668.02
Administration	2,926.90	6,011.13	4,510.24	9,837.83	1,893.50	4,133.11
Patient management	5,232.64	5,972.10	8,063.28	9,773.96	3,385.16	4,106.27
SREs	423,002.61	464,527.50	734,018.05	808,457.99	403,397.17	424,797.47
AEs	3,635.94	4,157.61	5,602.84	6,804.36	2,352.20	2,858.67
Total costs (CZK)	540,298.81	506,364.45	914,766.83	876,928.43	479,279.77	453,563.54
Outcomes
QALYs	0.6648	0.5761	1.5499	1.4573	0.3217	0.2794
SREs	6.602	7.230	7.603	8.334	5.437	5.709
Cost-effectiveness (denosumab vs zoledronic acid)
Cost difference (CZK)	33,934.36		37,838.40		25,716.23
QALY difference	0.0887		0.0926		0.0423
SREs avoided	0.628		0.731		0.272
ICER (denosumab vs zoledronic acid) (CZK)
Per QALY gained	382,673.25		408,450.20		608,132.66
Per SRE avoided	54,007.04		51,765.40		94,425.78

AE: adverse event; CZK: Czech Republic Koruna; ICER: incremental cost-effectiveness ratio; QALY: quality-adjusted life-year; SRE: skeletal-related event.

Calculations performed prior to approximation of data to 2 decimal places.

Table 3. Scenario analyses: effect of varying discount rate, time horizon, SRE rate, discontinuation of treatment, and asymptomatic SREs on the cost-effectiveness of denosumab vs zoledronic acid.

	Prostate cancer		Breast cancer		Other solid tumors
	Denosumab	Zoledronic acid	Denosumab	Zoledronic acid	Denosumab	Zoledronic acid
Scenario: 0% discount for costs and health benefits
Total costs (CZK)	574,248.60	539,394.84	1,004,703.47	964,989.83	514,909.97	488,623.25
Total QALYs	0.6973	0.6053	1.6837	1.5862	0.3364	0.2931
Total SREs	6.602	7.230	7.603	8.334	5.437	5.709
Cost difference (CZK)	34,853.75		39,713.64		26,286.71
QALY difference	0.0920		0.0974		0.0433
SREs avoided	0.628		0.731		0.272
ICER (denosumab vs zoledronic acid) (CZK)
Per QALY gained	379,038.69		407,598.89		607,466.82
Per SRE avoided	55,470.28		54,330.85		96,520.52
Scenario: 5% discount for costs and health benefits
Total costs (CZK)	520,303.69	486,941.71	863,709.24	826,999.89	459,048.00	433,687.86
Total QALYs	0.6454	0.5587	1.4733	1.3836	0.3131	0.2714
Total SREs	6.602	7.230	7.603	8.334	5.437	5.709
Cost difference (CZK)	33,361.98		36,709.35		25,360.13
QALY difference	0.0867		0.0898		0.0417
SREs avoided	0.628		0.731		0.272
ICER (denosumab vs zoledronic acid) (CZK)
Per QALY gained	384,938.84		408,965.51		608,544.42
Per SRE avoided	53,096.09		50,220.79		93,118.26
Scenario: 39 cycles
Total costs (CZK)	418,203.49	385,521.97	548,592.43	516,746.20	354,212.92	329,185.46
Total QALYs	0.5641	0.4830	1.0216	0.9448	0.2791	0.2381
Total SREs	4.656	5.220	3.870	4.463	3.605	3.867
Cost difference (CZK)	32,681.52		31,846.23		25,027.46
QALY difference	0.0811		0.0768		0.0410
SREs avoided	0.564		0.593		0.263
ICER (CZK) (denosumab vs zoledronic acid)
Per QALY gained	403,024.34		414,579.60		610,965.59
Per SRE avoided	57,945.06		53,721.48		95,306.21
Scenario: SRE rates from Hatoum et al.^29
Total costs (CZK)	428,865.43	384,629.07	714,670.40	657,010.13	373,531.09	342,433.85
Total QALYs	0.8697	0.7999	1.7398	1.6660	0.4850	0.4510
Total SREs	4.865	5.337	5.532	6.069	4.013	4.217
Cost difference (CZK)	44,236.36		57,660.27		31,097.24
QALY difference	0.0697		0.0738		0.0340
SREs avoided	0.473		0.536		0.204
ICER (denosumab vs zoledronic acid) (CZK)
Per QALY gained	634,337.47		781,022.42		915,212.31
Per SRE avoided	93,619.31		107,508.84		152,535.89
Scenario: SRE rates from the SEER database^36
Total costs (CZK)	488,411.03	449,383.00	667,678.17	604,781.45	346,384.27	313,617.91
Total QALYs	0.4824	0.3758	1.2307	1.1057	0.2846	0.2403
Total SREs	6.602	7.230	7.603	8.334	5.437	5.709
Cost difference (CZK)	39,028.02		62,896.73		32,766.36
QALY difference	0.1066		0.1250		0.0443
SREs avoided	0.628		0.731		0.272
ICER (denosumab vs zoledronic acid) (CZK)
Per QALY gained	366,171.98		503,130.23		740,381.22
Per SRE avoided	62,113.69		86,046.82		120,312.71
Scenario: no treatment discontinuations
Total costs (CZK)	507,610.54	437,852.03	817,791.05	745,685.67	435,274.20	380,113.71
Total QALYs	0.8779	0.7433	1.7632	1.5940	0.5060	0.4185
Total SREs	4.622	5.536	4.930	6.305	3.663	4.246
Cost difference (CZK)	69,758.52		72,105.38		55,160.49
QALY difference	0.1345		0.1692		0.0874
SREs avoided	0.914		1.374		0.583
ICER (denosumab vs zoledronic acid) (CZK)
Per QALY gained	518,525.37		426,058.88		630,944.46
Per SRE avoided	76,328.02		52,474.23		94,639.10
Scenario: asymptomatic vertebral fractures
Total costs (CZK)	407,763.91	360,819.00	670,385.72	607,763.58	377,981.88	346,891.78
Total QALYs	0.7375	0.6560	1.6835	1.6044	0.3773	0.3380
Total SREs	6.602	7.230	7.603	8.334	5.437	5.709
Cost difference (CZK)	46,944.91		62,622.14		31,090.10
QALY difference	0.0815		0.0791		0.0393
SREs avoided	0.628		0.731		0.272
ICER (denosumab vs zoledronic acid) (CZK)
Per QALY gained	575,738.45		791,755.52		790,414.81
Per SRE avoided	74,713.53		85,671.17		114,157.76

CZK: Czech Republic Koruna; ICER: incremental cost-effectiveness ratio; QALY: quality-adjusted life-year; SEER: Surveillance, Epidemiology, and End Results Program; SRE: skeletal-related event.

Figure 1. Tornado diagram for (a) prostate cancer, (b) breast cancer, and (c) other solid tumors. CZK: Czech Republic Koruna; ICER: incremental cost-effectiveness ratio; IV: intravenous; ONJ: osteonecrosis of the jaw; QALY: quality-adjusted life-year; SC: subcutaneous; SRE: skeletal-related event.

Figure 2. Cost-effectiveness acceptability curves for (a) prostate cancer, (b) breast cancer, and (c) other solid tumors. CZK: Czech Republic Koruna; QALY: quality-adjusted life-year.

Table A1. Prostate cancer probabilistic inputs.

Category	Parameter	Type of distribution	Mean value	Standard error
Patient management costs	Physician office visits	Gamma	332.88 CZK	53.26 CZK
	Lab tests (serum creatinine)	Gamma	73.63 CZK	11.78 CZK
Administration costs	Denosumab	Gamma	186.20 CZK	29.79 CZK
	Zoledronic acid	Gamma	409.17 CZK	65.47 CZK
SRE costs	Pathologic fracture	Gamma	145,888.87 CZK	23,342.22 CZK
	Radiation to bone	Gamma	36,183.93 CZK	5,789.43 CZK
	Surgery to bone	Gamma	183,531.49 CZK	29,365.04 CZK
	Spinal cord compression	Gamma	50,858.33 CZK	8,137.33 CZK
AE costs	ONJ	Gamma	12,409.95 CZK	1,985.59 CZK
	Acute phase reaction	Gamma	2,749.94 CZK	439.99 CZK
	Hypocalcemia	Gamma	2,238.04 CZK	358.09 CZK
	Renal toxicity	Gamma	104,737.22 CZK	16,757.95 CZK
Mortality rate	Mu (intercept)	Normal	6.582	0.043
	Sigma (scale)	Normal	0.924	0.0505
	Delta (shape)	Normal	0.624	0.1119
Discontinuation (not including death)	Denosumab	Gamma	0.031	0.005
	Discontinuation	Gamma	0.036	0.006
SRE rate and treatment effects	Treatment effect (rate ratio) of first and subsequent SRE of denosumab vs zoledronic acid, by study	Log-normal	0.820	0.0587
	Relative SRE rate off therapy	Log-normal	1.750	0.2963
	Relative SRE rate using real-world adjustment	Log-normal	2.84	0.4347
	Crude SRE rate (per person-year): zoledronic acid	Gamma	0.947	0.031
SRE distribution (pooled SREs)	Pathologic fracture	Dirichlet	462	21.494
	Radiation to bone	Dirichlet	1,139	33.749
	Surgery to bone	Dirichlet	26	5.099
	Spinal cord compression	Dirichlet	96	9.798
AE rates: denosumab	ONJ	Gamma	0.017	0.002
	Acute phase reaction	Gamma	0.001	0.000
	Hypocalcemia	Gamma	0.013	0.002
	Renal toxicity	Gamma	0.026	0.003
AE rates: zoledronic acid	ONJ	Gamma	0.012	0.002
	Acute phase reaction	Gamma	0.006	0.001
	Hypocalcemia	Gamma	0.006	0.001
	Renal toxicity	Gamma	0.033	0.003
IV vs SC QALY decrement per cycle	SC: denosumab	Normal	0.0012	0.0004
	IV: zoledronic acid	Normal	0.0021	0.0006
AE QALY decrement	ONJ	Normal	0.009	0.007
	Acute phase reaction	Normal	0.000	0.000
	Hypocalcemia	Normal	0.006	0.002
	Renal toxicity	Normal	0.012	0.002
SRE QALY decrement	Pathologic fracture	Normal	0.080	0.240
	Radiation to bone	Normal	0.110	0.300
	Surgery to bone	Normal	0.150	0.360
	Spinal cord compression	Normal	0.535	0.650

AE: adverse event; CZK: Czech Republic Koruna; IV: intravenous; ONJ: osteonecrosis of the jaw; QALY: quality-adjusted life-year; SC: subcutaneous; SRE: skeletal-related event.

Table A2. Breast cancer probabilistic inputs.

Category	Parameter	Type of distribution	Mean	Standard error
Patient management costs	Physician office visits	Gamma	332.88 CZK	53.26 CZK
	Lab tests (serum creatinine)	Gamma	73.63 CZK	11.78 CZK
Administration costs	Denosumab	Gamma	186.20 CZK	29.79 CZK
	Zoledronic acid	Gamma	409.17 CZK	65.47 CZK
SRE costs	Pathologic fracture	Gamma	145,888.87 CZK	23,342.22 CZK
	Radiation to bone	Gamma	36,183.93 CZK	5,789.43 CZK
	Surgery to bone	Gamma	183,531.49 CZK	29,365.04 CZK
	Spinal cord compression	Gamma	50,858.33 CZK	8,137.33 CZK
AE costs	ONJ	Gamma	12,409.95 CZK	1,985.59 CZK
	Acute phase reaction	Gamma	2,749.94 CZK	439.99 CZK
	Hypocalcemia	Gamma	2,238.04 CZK	358.09 CZK
	Renal toxicity	Gamma	104,737.22 CZK	16,757.95 CZK
Mortality rate	mu (intercept)	Normal	7.217	0.0455
	sigma (scale)	Normal	0.858	0.1272
	delta (shape)	Normal	0.850	0.2216
Discontinuation (not including death)	Denosumab	Gamma	0.022	0.004
	Zoledronic acid	Gamma	0.022	0.004
SRE rate and treatment effects	Treatment effect (rate ratio) of first and subsequent SRE of denosumab vs zoledronic acid, by study	Log-normal	0.770	0.0587
	Relative SRE rate off therapy	Log-normal	1.750	0.2963
	Relative SRE rate using real-world adjustment	Log-normal	2.84	0.4347
	Crude SRE rate (per person-year): zoledronic acid	Gamma	0.631	0.022
SRE distribution (pooled SREs)	Pathologic fracture	Dirichlet	880	29.665
	Radiation to bone	Dirichlet	536	23.152
	Surgery to bone	Dirichlet	71	8.426
	Spinal cord compression	Dirichlet	26	5.099
AE rates: denosumab	ONJ	Gamma	0.017	0.002
	Acute phase reaction	Gamma	0.001	0.000
	Hypocalcemia	Gamma	0.013	0.002
	Renal toxicity	Gamma	0.026	0.003
AE rates: zoledronic acid	ONJ	Gamma	0.012	0.002
	Acute phase reaction	Gamma	0.006	0.001
	Hypocalcemia	Gamma	0.006	0.001
	Renal toxicity	Gamma	0.033	0.003
IV vs SC QALY decrement per cycle	SC: denosumab	Normal	0.0012	0.0004
	IV: zoledronic acid	Normal	0.0021	0.0006
AE QALY decrement	ONJ	Normal	0.008	0.008
	Acute phase reaction	Normal	0.000	0.000
	Hypocalcemia	Normal	0.006	0.002
	Renal toxicity	Normal	0.012	0.001
SRE QALY decrement	Pathologic fracture	Normal	0.080	0.240
	Radiation to bone	Normal	0.110	0.300
	Surgery to bone	Normal	0.150	0.360
	Spinal cord compression	Normal	0.535	0.650

AE: adverse event; CZK: Czech Republic Koruna; IV: intravenous; ONJ: osteonecrosis of the jaw; QALY: quality-adjusted life-year; SC: subcutaneous; SRE: skeletal-related event.

Table A3. Other solid tumors probabilistic inputs.

Category	Parameter	Type of distribution	Mean	Standard error
Patient management costs	Physician office visits	Gamma	332.88 CZK	53.26 CZK
	Lab tests (serum creatinine)	Gamma	73.63 CZK	11.78 CZK
Administration costs	Denosumab	Gamma	186.20 CZK	29.79 CZK
	Zoledronic acid	Gamma	409.17 CZK	65.47 CZK
SRE costs	Pathologic fracture	Gamma	145,888.87 CZK	23,342.22 CZK
	Radiation to bone	Gamma	36,183.93 CZK	5,789.43 CZK
	Surgery to bone	Gamma	183,531.49 CZK	29,365.04 CZK
	Spinal cord compression	Gamma	50,858.33 CZK	8,137.33 CZK
AE costs	ONJ	Gamma	12,409.95 CZK	1,985.59 CZK
	Acute phase reaction cost	Gamma	2,749.94 CZK	439.99 CZK
	Hypocalcemia	Gamma	2,238.04 CZK	358.09 CZK
	Renal toxicity	Gamma	104,737.22 CZK	16,757.95 CZK
Mortality rate	mu (intercept)	Normal	5.851	0.058
	sigma (scale)	Normal	1.214	0.0431
	delta (shape)	Normal	0.134	0.1028
Discontinuation (not including death)	Denosumab	Gamma	0.047	0.015
	Zoledronic acid	Gamma	0.047	0.017
SRE rate and treatment effects	Treatment effect (rate ratio) of first and subsequent SRE of denosumab vs zoledronic acid, by study	Log-normal	0.850	0.0714
	Relative SRE rate off therapy	Log-normal	1.750	0.2963
	Relative SRE rate using real-world adjustment	Log-normal	2.84	0.4347
	Crude SRE rate (per person-year): zoledronic acid	Gamma	0.936	0.040
SRE distribution (pooled SREs)	Pathologic fracture	Dirichlet	315	17.748
	Radiation to bone	Dirichlet	577	24.021
	Surgery to bone	Dirichlet	62	7.874
	Spinal cord compression	Dirichlet	50	7.071
AE rates: denosumab	ONJ	Gamma	0.017	0.002
	Acute phase reaction	Gamma	0.001	0.000
	Hypocalcemia	Gamma	0.013	0.002
	Renal toxicity	Gamma	0.026	0.003
AE rates: zoledronic acid	ONJ	Gamma	0.012	0.002
	Acute phase reaction	Gamma	0.006	0.001
	Hypocalcemia	Gamma	0.006	0.001
	Renal toxicity	Gamma	0.033	0.003
IV vs SC QALY decrement per cycle	SC: denosumab	Normal	0.0012	0.0004
	IV: zoledronic acid	Normal	0.0021	0.0006
AE QALY decrement	ONJ	Normal	0.010	0.007
	Acute phase reaction	Normal	0.000	0.000
	Hypocalcemia	Normal	0.008	0.003
	Renal toxicity	Normal	0.015	0.002
SRE QALY decrement	Pathologic fracture	Normal	0.080	0.240
	Radiation to bone	Normal	0.110	0.300
	Surgery to bone	Normal	0.150	0.360
	Spinal cord compression	Normal	0.535	0.650

AE: adverse event; CZK: Czech Republic Koruna; IV: intravenous; ONJ: osteonecrosis of the jaw; QALY: quality-adjusted life-year; SC: subcutaneous; SRE: skeletal-related event.

Stopeck A, Rader M, Henry D, et al. Cost-effectiveness of denosumab vs zoledronic acid for prevention of skeletal-related events in patients with solid tumors and bone metastases in the United States. J Med Econ 2012;15:712-23

 PubMedGoogle Scholar

Amgen. Data on file (Clinical study reports 20050103, 20050136 and 20050244)

 Google Scholar

Matza LS, Chung K, Van Brunt K, et al. Health state utilities for skeletal-related events secondary to bone metastases. Eur J Health Econ 2014;15:7-18

 PubMed Web of Science ®Google Scholar

Amgen. Data on file

 Google Scholar

Skoupá J, Annemans L, Hájek P. Health economic data requirements and availability in the European Union: results of a survey among 10 European countries. Value Health 2014;4:53-7

 Google Scholar

Hatoum HT, Lin SJ, Smith MR, et al. Zoledronic acid and skeletal complications in patients with solid tumors and bone metastases: analysis of a national medical claims database. Cancer 2008;113:1438-45

 PubMed Web of Science ®Google Scholar

National Cancer Institute. Surveillance, Epidemiology and End Results (SEER) program. SEER*Stat Database: incidence. http://seer.cancer.gov/seerstat. Accessed April 5, 2016

 Google Scholar