Individual Antidepressants and the Risk of Fractures in Older Adults: A New User Active Comparator Study

Figures & data

Table 1 Characteristics of Cases of Hip and Pelvis Fracture and of Other Fractures and Matched Controls

Demographics	Hip and Pelvis Fracture					Other Fractures
	Cases (N= 39,853)		Controls (N= 3,979,510)		aOR^a (95% CI^b)	Cases (N= 31,577)		Controls (N= 3,153,900)		aOR (95% CI)
	N	%	N	%		N	%	N	%
Sex
Women	31,789	79.8	3,175,471	79.8	–	26,528	84.0	2,650,493	84.0	–
Men	8064	20.2	804,039	20.2	–	5049	16.0	503,407	16.0	–
Age (years)
65–74	8213	20.6	821,147	20.6	–	10,130	32.1	1,012,959	32.1	–
75–84	18,296	45.9	1,829,613	46.0	–	13,562	42.9	1,355,996	43.0	–
≥85	13,344	33.5	1,328,750	33.4	–	7885	25.0	784,945	24. 9	–
Co-morbidities
Depression^c	21,057	52.8	1,918,013	48.2	1.21 (1.18–1.23)	16,539	52.4	1,534,934	48.7	1.16 (1.14–1.19)
Dementia^c	12,891	32.3	780,268	19.6	2.12 (2.07–2.17)	7405	23.5	513,432	16.3	1.67 (1.62–1.72)
Anxiety disorders^c	4481	11.2	459,921	11.6	0.97 (0.94–1.00)	72	0.2	8097	0.3	0.97 (0.94–1.00)
Bipolar disorders^c	374	0.9	25,965	0.7	1.44 (1.30–1.60)	350	1.1	23,718	0.8	1.34 (1.19–1.50)
Schizophrenia^c	490	1.2	28,576	0.7	1.72 (1.57–1.88)	1650	5.2	126,852	4.0	1.48 (1.33–1.65)
Obsessive compulsive disorders^c	114	0.3	9433	0.2	1.21 (1.00–1.45)	3905	12.4	396,079	12.6	0.89 (0.70–1.12)
Parkinson’s disease and movement disorders^c	16,386	41.1	1,347,913	33.9	1.37 (1.35–1.40)	11,241	35.6	1,009,029	32.0	1.18 (1.15–1.21)
Delirium^c	923	2.3	38,395	1.0	2.45 (2.29–2.62)	3018	9.6	292,845	9.3	2.11 (1.93–2.31)
Pain^d	37,011	92.9	3,698,908	92.9	0.99 (0.95–1.03)	2694	8.5	198,481	6.3	1.00 (0.95–1.04)
Myocardial infarction^d	4698	11.8	415,653	10.4	1.15 (1.11–1.19)	3018	9.6	292,845	9.3	1.03 (0.99–1.07)
Other coronary heart disease^d	19,550	49.1	1,914,710	48.1	1.04 (1.02–1.06)	14,074	44.6	1,433,384	45.4	0.96 (0.94–0.99)
Atrial fibrillation^d	9219	23.1	772,549	19.4	1.26 (1.23–1.29)	5815	18.4	555,384	17.6	1.06 (1.03–1.09)
Other arrhythmias and conduction disorders^d	18,362	46.1	1,835,765	46.1	1.00 (0.98–1.02)	13,765	43.6	1,414,554	44.9	0.95 (0.93–0.97)
Valvular disorders and endocarditis^d	10,326	25.9	997,520	25.1	1.05 (1.02–1.07)	7465	23.6	759,229	24.1	0.98 (0.95–1.00)
Pericardial disorders^d	464	1.2	39,543	1.0	1.18 (1.07–1.29)	322	1.0	32,259	1.0	1.00 (0.89–1.11)
Myocarditis^d	210	0.5	20,490	0.5	1.02 (0.89–1.17)	181	0.6	16,684	0.5	1.09 (0.94–1.26)
Peripheral vascular disease^d	14,890	37.4	1,373,202	34.5	1.14 (1.11–1.16)	10,681	33.8	1,027,333	32.6	1.06 (1.03–1.08)
Hypertension^d	34,617	86.9	3,475,107	87.3	0.96 (0.93–0.99)	26,960	85.4	2,713,574	86.0	0.95 (0.92–0.98)
Chronic pulmonary disease^d	19,419	48.7	1,958,446	49.2	0.98 (0.96–1.00)	15,131	47.9	1,541,941	48.9	0.96 (0.94–0.98)
Pulmonary circulation disorders^d	2860	7.2	235,671	5.9	1.23 (1.18–1.28)	1908	6.0	175,665	5.6	1.09 (1.04–1.14)
Rheumatoid arthritis, arthropathies and connective tissue disorders^d	9841	24.7	966,583	24.3	1.02 (1.00–1.05)	7831	24.8	783,674	24.8	1.00 (0.97–1.02)
Liver insufficiency^d	9963	25	958,498	24.1	1.05 (1.03–1.08)	7906	25	784,447	24.9	1.01 (0.98–1.04)
Renal insufficiency^d	9176	23	777,839	19.5	1.24 (1.21–1.27)	5851	18.5	552,253	17.5	1.07 (1.04–1.10)
Cancer^d,e	12,136	30.5	1,152,267	29.0	1.08 (1.05–1.10)	9234	29.2	896,549	28.4	1.04 (1.02–1.07)
Diabetes^d,f	14,750	37	1,409,909	35.4	1.07 (1.05–1.09)	10,941	34.6	1,072,758	34.0	1.03 (1.01–1.05)
Osteoporosis and other diseases of bone density and structure^d	19,393	48.7	1,565,117	39.3	1.52 (1.49–1.55)	14,772	46.8	1,232,731	39.1	1.41 (1.38–1.44)
Syncope and dizziness^d	21,211	53.2	1,945,839	48.9	1.20 (1.17–1.22)	15,417	48.8	1,472,308	46.7	1.09 (1.07–1.12)
Vision disorders^d	32,204	80.8	3,270,698	82.2	0.91 (0.89–0.93)	25,294	80.1	2,558,450	81.1	0.94 (0.91–0.96)
Dyslipidemia^d	24,731	62.1	2,578,665	64.8	0.89 (0.87–0.91)	19,972	63.2	2,065,600	65.5	0.91 (0.89–0.93)
Infectious diseases^g	15,378	38.6	1,481,169	37.2	1.06 (1.04–1.08)	512	1.6	24,548	0.8	0.99 (0.97–1.02)
Hip and pelvis fracture^d	0	-	0	-	–	14,265	45.2	243,315	7.7	11.43 (11.16–11.70)
Other fractures^d	31,025	77.8	862,005	21.7	13.72 (13.40–14.06)	0	-	0	-	–
Traumatic brain injury^d	7717	19.4	544,903	13.7	1.53 (1.49–1.57)	5104	16.2	370,959	11.8	1.46 (1.42–1.51)
Co-medications
Insulin^d	3668	9.2	273,290	6.9	1.38(1.33–1.42)	2526	8.0	204,483	6.5	1.26 (1.21–1.31)
Antidiabetic drugs^d	6713	16.8	617,003	15.5	1.10 (1.08–1.13)	4877	15.4	473,352	15.0	1.04 (1.00–1.07)
Antithrombotic drugs^d	23,938	60.1	2,132,977	53.6	1.31 (1.29–1.34)	16,965	53.7	1,577,306	50.0	1.17 (1.14–1.19)
Cardiac glycosides^d	5895	14.8	527,646	13.3	1.14 (1.11–1.17)	3543	11.2	369,746	11.7	0.95 (0.92–0.98)
Anti-arrhythmic drugs^d	1928	4.8	151,544	3.8	1.29 (1.23–1.35)	1240	3.9	117,680	3.7	1.06 (1.00–1.12)
Other antihypertensive drugs^d	3753	9.4	372,944	9.4	1.01 (0.97–1.04)	2720	8.6	285,925	9.1	0.95 (0.91–0.98)
Diuretics^d	25,160	63.1	2,258,086	56.7	1.33 (1.30–1.36)	17,630	55.8	1,666,077	52.8	1.14 (1.11–1.17)
Vasodilators^d	13,871	34.8	1,391,925	35.0	0.99 (0.97–1.01)	9963	31.6	1,028,486	32.6	0.95 (0.93–0.97)
Beta-adrenergic agonists^d	24,850	62.4	2,456,283	61.7	1.03 (1.01–1.05)	19,091	60.5	1,934,631	61.3	0.96 (0.94–0.99)
Calcium antagonists^d	17,722	44.5	1,779,622	44.7	0.99 (0.97–1.01)	13,333	42.2	1,347,792	42.7	0.98 (0.96–1.00)
ACE inhibitors^d	25,394	63.7	2,440,606	61.3	1.11 (1.09–1.13)	18,762	59.4	1,855,914	58.8	1.02 (1.00–1.05)
Angiotensin II antagonists^d	10,763	27.0	1,194,188	30.0	0.86 (0.84–0.88)	8708	27.6	946,872	30.0	0.89 (0.87–0.91)
Lipid-lowering drugs^d	16,536	41.5	1,678,964	42.2	0.97 (0.95–0.99)	12,884	40.8	1,331,916	42.2	0.94 (0.92–0.96)
Hormone therapy^d	10,467	26.3	1,155,009	29.0	0.85 (0.83–0.87)	9763	30.9	1,063,627	33.7	0.86 (0.84–0.89)
Drugs for the treatment of bone diseases^d	8345	20.9	601,777	15.1	1.51 (1.47–1.55)	14,772	46.8	1,232,731	39.1	1.41 (1.38–1.44)
Glucocorticoids^d	15,141	38.0	1,446,436	36.3	1.07 (1.05–1.10)	11,702	37.1	1,169,528	37.1	1.00 (0.98–1.02)
Anti-Parkinson drugs^d	6548	16.4	495,063	12.4	1.39 (1.35–1.43)	4477	14.2	379,303	12.0	1.21 (1.17–1.25)
Respiratory drugs^d	11,836	29.7	1,184,752	29.8	1.00 (0.98–1.02)	9185	29.1	943,351	29.9	0.96 (0.94–0.99)
Non-steroidal anti-inflammatory drugs^d	33,448	83.9	3,333,556	83.8	1.01 (0.99–1.04)	26,560	84.1	2,647,158	83.9	1.01 (0.98–1.05)
Antipsychotics^g	14,169	35.6	1,032,325	25.9	1.60 (1.57–1.64)	9370	29.7	763,695	24.2	1.33 (1.30–1.37)
Antiepileptic drugs^g	4432	11.1	327,887	8.2	1.40 (1.35–1.44)	3262	10.3	254,939	8.1	1.31 (1.27–1.36)
Anxiolytics^g	5351	13.4	428,011	10.8	1.29 (1.25–1.33)	3671	11.6	324,785	10.3	1.15 (1.11–1.19)
Hypnotics and sedatives^g	4999	12.5	379,701	9.5	1.36 (1.32–1.40)	3448	10.9	286,248	9.1	1.23 (1.19–1.27)
Muscle relaxants^g	1449	3.6	118,460	3.0	1.23 (1.17–1.30)	980	3.1	100,498	3.2	0.97 (0.91–1.04)
Indicators of lifestyle habits
Alcohol abuse	2144	5.4	115,741	2.9	1.92 (1.83–2.00)	1520	4.8	93,433	3.0	1.67 (1.58–1.76)
Illicit drug abuse	1515	3.8	116,821	2.9	1.31 (1.24–1.38)	1197	3.8	92,681	2.9	1.30 (1.23–1.38)
Obesity	7670	19.2	883,250	22.2	0.83 (0.81–0.85)	6871	21.8	742,756	23.6	0.90 (0.88–0.93)
Smoking	2318	5.8	139,544	3.5	1.72 (1.65–1.79)	1650	5.2	126,852	4.0	1.32 (1.26–1.39)
Indicators of health status, frailty and use of health care
Charlson Comorbidity Index >2^d,h	27,563	69.2	2,493,742	62.7	1.35 (1.32–1.38)	19,786	62.7	1,881,284	59.6	1.14 (1.11–1.17)
Hospitalized time >5%^c,h	10,458	26.2	506,059	12.7	2.53 (2.47–2.59)	5992	19.0	372,883	11.8	1.78 (1.73–1.83)
Number of medications^h,i
1–4	12,372	31.0	1,649,310	41.4	0.63 (0.62–0.64)	12,136	38.4	1,367,912	43.4	0.81 (0.79–0.83)
5–8	20,300	50.9	1,814,090	45.6	1.24 (1.22–1.27)	14,846	47.0	1,379,623	43.7	1.14 (1.12–1.17)
≥10	6344	15.9	38,2808	9.6	1.79 (1.75–1.84)	3667	11.6	286,402	9.1	1.32 (1.28–1.37)
Nursing home residence^c,h	3397	8.5	17,2028	4.3	2.15 (2.07–2.23)	1725	5.5	109,779	3.5	1.64 (1.56–1.73)

Notes: ^aModel adjusted for all listed covariates. ^b95% confidence interval. ^cAssessed within 365 days before index date and at index date. ^dAssessed any time before the index date. ^eExcept for malignant neoplasm of the skin. ^fIncludes both type 1 and type 2 diabetes. ^gAssessed within 181 days before and at index date. ^hCut-offs were defined as follows: for Charlson Comorbidity Index the first tertile among controls, for a number of medications prior studies, for hospitalized time the first decile among controls. ⁱMedication of different therapeutic classes.

Abbreviations: aOR, adjusted odds ratio; 95% CI, 95% confidence interval; ACE, angiotensin-converting enzyme.

Table 2 Odds Ratio (OR), with 95 Confidence Interval (95% CI), of Hip–Pelvis Fracture and Other Non-Vertebral Fractures in Users of Individual Antidepressants (AD) Compared with Current Users of Mirtazapine and with Remote Users of Any AD. Main Analysis (DDDs + 150%)

	Hip–Pelvis Fractures				Other Non-Vertebral Fractures
	Cases	Controls	Matched OR^a (95% CI)	Adjusted OR^b (95% CI)	Cases	Controls	Matched OR^a (95% CI)	Adjusted OR^b (95% CI)
Current users	(N=39,853)	(N= 3,979,510)			(N= 31,577)	(N= 3,153,900)
TCA
Doxepin	640 (1.6)	64,954 (1.6)	0.71 (0.63–0.80)	0.87 (0.77–0.98)	468 (1.5)	49,843 (1.6)	0.80 (0.70–0.93)	0.91 (0.78–1.05)
Amitriptyline	2231 (5.6)	168,378 (4.2)	1.10 (1.04–1.16)	1.28 (1.21–1.35)	1592 (5.0)	129,821 (4.1)	1.14 (1.07–1.22)	1.18 (1.11–1.26)
Opipramol	914 (2.3)	124,842 (3.1)	0.60 (0.56–0.65)	0.88 (0.82–0.95)	774 (2.5)	100,276 (3.2)	0.72 (0.66–0.78)	0.94 (0.87–1.02)
Trimipramine
Trimipramine	449 (1.1)	48,263 (1.2)	0.77 (0.69–0.85)	1.00 (0.91–1.11)	381 (1.2)	37,116 (1.2)	0.95 (0.85–1.06)	1.16 (1.03–1.29)
SSRI
Sertraline	866 (2.2)	55,329 (1.4)	1.28 (1.19–1.38)	1.27 (0.17–1.37)	566 (1.8)	40,991 (1.3)	1.28 (1.17–1.40)	1.33 (1.21–1.46)
Citalopram	6082 (15.3)	371,599 (9.3)	1.35 (1.30–1.41)	1.33 (1.27–1.39)	4274 (3.5)	263,557 (8.4)	1.51 (1.44–1.59)	1.50 (1.42–1.58)
Paroxetine	260 (0.7)	20,035 (0.5)	1.05 (0.92–1.19)	1.20 (1.05–1.36)	244 (0.8)	16,935 (0.5)	1.32 (1.16–1.51)	1.49 (1.30–1.71)
Fluoxetine	232 (0.6)	17,115 (0.4)	1.11 (0.97–1.27)	1.27 (1.11–1.46)	190 (0.6)	13,724 (0.4)	1.28 (1.10–1.48)	1.45 (1.24–1.68)
Escitalopram	465 (1.2)	28,908 (0.7)	1.34 (1.21–1.47)	1.30 (1.17–1.43)	326 (1.0)	21,690 (0.7)	1.40 (1.25–1.58)	1.40 (1.24–1.58)
SSNRI
Duloxetine	548 (1.4)	32,334 (0.8)	1.37 (1.25–1.50)	1.32 (1.21–1.45)	444 (1.4)	26,150 (0.8)	1.56 (1.41–1.73)	1.54 (1.39–1.71)
Venlafaxine	581 (1.5)	36,245 (0.9)	1.29 (1.18–1.40)	1.29 (1.18–1.41)	454 (1.4)	29,787 (0.9)	1.39 (1.26–1.54)	1.41 (1.27–1.56)
NASSA
Mirtazapine^c	3362 (8.4)	283,463 (7.1)	(Reference)	(Reference)	2094 (6.6)	200,487 (6.4)	(Reference)	(Reference)

Notes: ^aAdjusted for age, sex and length of follow-up by matching. ^bModel adjusted for myocardial infarction, other coronary heart disease, atrial fibrillation, other cardiac arrhythmias and conduction disorders, valvular disorders and endocarditis, pericardial disorders, myocarditis, peripheral vascular disease, hypertension, dementia, chronic pulmonary disease, pulmonary circulation disorders, rheumatic arthritis/collagen vascular disease, liver disease, Parkinson’s disease, other extrapyramidal and movement disorders, depression, diabetes, renal failure, cancer (except malignant neoplasm of skin), obesity, alcohol abuse, drug abuse, osteoporosis and other disorders of bone density and structure, syncope, dizziness and tendency to fall, vision disorders, dyslipidemia, bipolar disorders, schizophrenia, smoking, anxiety disorders, obsessive compulsive disorders, other movement disorders, pain, infectious diseases, delirium, use of insulin, antidiabetic medications, antithrombotic medications, cardiac glycosides, anti-arrhythmic medications, other antihypertensive medications, diuretics, vasodilators, beta-adrenergic agonists, calcium antagonists, ACE inhibitors, angiotensin II antagonists, lipid-lowering medications, hormone therapy, glucocorticoids, anti-Parkinson medications, respiratory medications, non-steroidal anti-inflammatory medications, antipsychotics, antiepileptic medications, anxiolytics, hypnotics and sedatives, muscle relaxants, number of medications (1 to 4; 5 to 8, 9 and more), hospitalized time (≤5%; >5%), Charlson Comorbidity Index (≤2; >2), nursing home residence. ^cReference category.

Abbreviations: TCA, tricyclics; SSRI, selective serotonin reuptake inhibitors; SSNRI, selective serotonin-noradrenaline reuptake inhibitors; NASSA, noradrenergic and specific serotonergic antidepressants.

Figure 1 Odds ratio (OR) with 95% confidence interval (95% CI) of hip–pelvis fracture in current users of antidepressants (ADs) compared with current users of mirtazapine, by depression.

Notes: The model did not converge in the group of age 85 years and above. *Model adjusted for all variables listed in Table 1.
Abbreviations: TCA, tricyclics; SSRI, selective serotonin reuptake inhibitors; SSNRI, selective serotonin-noradrenaline reuptake inhibitors; NASSA, noradrenergic and specific serotonergic antidepressants; NARI, noradrenaline reuptake inhibitors; MAO, monoamine oxidase inhibitors.

Figure 2 Odds ratio (OR) with 95% confidence interval (95% CI) of other non-vertebral fractures in current users of antidepressants (ADs) compared with current users of mirtazapine, by depression.

Notes: The model did not converge in the group of age 85 years and above. *Model adjusted for all variables listed in Table 1.
Abbreviations: TCA, tricyclics; SSRI, selective serotonin reuptake inhibitors; SSNRI, selective serotonin-noradrenaline reuptake inhibitors; NASSA, noradrenergic and specific serotonergic antidepressants; NARI, noradrenaline reuptake inhibitors; MAO, monoamine oxidase inhibitors.