Hip Fracture Risk in Antiepileptic Drug Initiators and Non-Initiators with Alzheimer’s Disease

Figures & data

Figure 1 Flow chart describing the study population.

Table 1 Characteristics of Incident Users of AEDs and Matched Non-Users with AD and Standardized Mean Differences

	Users (N=5522)		Non-Users (N=11,044)		Standardized Mean Difference (%)
	N	%	N	%	Unweighted	After IPTW
Age (years)^a
<64	431	7.8	1392	12.6	15.9	1.8
65–74	1360	24.6	3663	33.2
75–84	2909	52.7	5005	45.3
85+	822	14.9	984	8.9
Median (25;75 percentile)	81.1 (75.8; 85.5)		81.0 (75.6; 85.2)		–	–
Sex
Men	1941	35.2	3882	35.2	0.0	0.5
Women	3581	64.9	7162	64.9		–
Time since AD diagnosis (days)^a
<315 days	1373	24.9	2572	23.3	3.7	1.1
315 to <803	1382	25.0	2727	24.7	0.8	0.8
803 to <1465	1385	25.1	2759	25.0	0.2	0.4
1465 and above	1382	25.0	2986	27.0	4.6	2.3
Median (25;75 percentile)	803 (315;1465)		850 (344; 1533)
Duration of follow-up (days)
Median (25;75 percentile)	810.5 (293; 1504)		973 (442; 1617)
Health condition at baseline
Psychiatric and neurological
Epilepsy	542	9.8	304	2.8	27.4	0.4
Depression	463	8.4	645	5.8	10.0	0.4
Schizophrenia	157	2.8	284	2.6	1.7	0.6
Hip fracture-related
Vision disturbances^b	2104	38.1	3181	28.8	19.2	0.3
Osteoporosis^c	1036	18.8	1479	13.4	14.1	0.5
Any fracture	797	14.4	1241	11.2	9.2	0.1
Head trauma	439	8.0	687	6.2	6.0	1.0
Rheumatoid arthritis^d	266	4.8	496	4.5	1.5	0.3
Alcohol abuse	186	3.4	332	3.0	1.4	1.1
Other conditions
Cardiovascular diseases^e	3595	65.1	6179	56.0	18.2	0.2
Diabetes^d	1296	23.5	2298	20.8	6.5	0.3
Stroke	847	15.3	1143	10.4	14.6	0.8
Asthma^d	622	11.3	1055	10.0	5.6	<0.1
History of any cancer	488	8.8	1110	10.1	4.1	<0.1
Chronic renal disease	85	1.5	86	0.8	7.1	0.4
Chronic liver disease	27	0.5	82	0.7	2.9	0.9
Drugs at baseline
CNS drugs
Benzodiazepines and related drugs	2338	42.3	2859	25.9	33.1	0.5
Antidepressants	2307	41.8	3289	29.8	23.6	0.6
Memantine	2257	40.9	3970	36.0	6.2	0.3
Antipsychotics	1963	35.6	2698	24.4	21.0	1.1
Opioids	1265	22.9	1007	9.1	36.5	0.5
Antiparkinsonians	297	5.4	510	4.6	3.4	0.1
Other drugs
Cardiovascular drugs^f	4535	82.1	8379	75.9	15.1	0.3
PPIs	1811	32.8	2299	20.8	26.7	<0.1
NSAIDs	1224	22.2	1597	14.5	19.2	0.1
Corticosteroids, systemic	485	8.8	633	5.7	11.3	0.6
Estrogens	481	8.7	760	6.9	6.5	0.2
Drugs for urinary incontinence	313	5.7	551	5.0	3.7	<0.1
Socioeconomic status
Highest	2798	50.7	4241	38.4	5.8	0.6
Middle	980	17.8	2187	19.8	0.2	0.1
Lowest	942	17.1	2606	23.6	3.0	0.2
Unknown	802	14.5	2010	18.2	3.8	1.1

Notes: ^aMatching variables. ^bIncludes hospital diagnosis of cataract, macular degeneration, and glaucoma. ^cComposite of discharge diagnosis (code M80 and M81) and dispensation data (bisphosphonates M05BA and M05BB, bone morphogenetic proteins M05BC, other drugs affecting bone structure and mineralization M05BX (eg, strontium ranelate, denosumab)). ^dComposite variables based on both hospitalization and special reimbursement data. ^eIt includes hypertension, heart failure, peripheral arterial disease, atrial fibrillation, coronary heart disease. ^fIt includes cardiac glycosides (C01AA), antiarrhythmics (C01B), organic nitrates (C01DA), diuretics (C03), beta blocking agents (C07), calcium channel blockers (C08), agents acting on the renin-angiotensin system (C09), lipid modifying agents (C10A, C10BA), antithrombotic agents (B01A).

Abbreviations: AD, Alzheimer’s disease; AED, antiepileptic drug; CNS, central nervous system; HF, hip fracture; IPTW, inverse probability of treatment; NSAID, nonsteroidal anti-inflammatory drugs; PPI, proton pump inhibitors.

Table 2 Characteristics of Incident Users of Newer and Older AEDs with AD and Mean Standardized Differences

	Users^a				Standardized Mean Difference (%)
	Newer AEDs (N=2945)		Older AEDs (N=2577)
	N	%	N	%	Unweighted	After IPTW
Age (years)
<64	132	4.5	299	11.6	26.4	5.4
65–74	625	21.2	735	28.5	26.4	5.4
75–84	1678	57.0	1231	47.8	26.4	5.4
85+	510	17.3	312	12.1	26.4	5.4
Median (25;75 percentile)
Sex
Men	915	31.1	1026	39.8	18.4	2.5
Women	2030	68.9	1551	60.2
Time since AD diagnosis (days)
<315 days	840	28.5	533	20.7	18.3	0.3
315 to <803	828	28.1	554	21.5	15.4	0.2
803 to <1465	716	24.3	669	26.0	3.8	0.7
1465 and above	561	19.1	821	31.9	29.7	1.2
Median (25;75 percentile)	656 (265; 1269)		995 (402; 1697)
Duration of follow-up (days)
Median (25;75 percentile)	982.00 (437.00; 1660.00)		578.00 (198.00; 1221.00)
AED at start treatment (ATC)
Pregabalin (N03AX16)	2349	79.8	–		–	–
Gabapentin (N03AX12)	300	10.2	–		–	–
Oxcarbazepine (N03AF02)	255	8.7	–		–	–
Lamotrigine (N03AX09)	31	1.1	–		–	–
Topiramate (N03AX11)	9	0.3	–		–	–
Valproic acid (N03AG01)	–		1742	67.6	–	–
Carbamazepine (N03AF01)	–		334	13.1	–	–
Clonazepam (N03AE01)	–		263	10.2	–	–
Phenytoin (N03AB02)	–		119	4.6	–	–
Levetiracetam (N03AX14)	–		79	3.1	–	–
Primidone (N03AA03)	–		4	0.2	–	–
Multiple AEDs	1	<0.1	36	1.4	–	–
Health condition at baseline
Psychiatric and neurological
Depression	265	9.0	199	7.7	4.6	0.6
Epilepsy	98	3.3	425	16.5	45.2	11.3
Schizophrenia	63	2.1	94	3.7	9.0	0.1
Hip fracture-related
Vision disturbances^b	1289	43.8	804	31.2	26.2	2.4
Osteoporosis^c	683	23.2	346	13.4	25.5	3.6
Any fracture	466	15.8	326	12.7	9.1	0.3
Head trauma	209	7.1	223	8.7	5.8	2.1
Rheumatoid arthritis^d	178	6.0	88	3.4	12.4	3.4
Alcohol abuse	78	2.7	104	4.0	7.7	0.7
Other conditions
Cardiovascular diseases^e	1993	67.7	1591	61.7	12.4	1.1
Diabetes^d	790	26.8	507	19.7	17.0	1.2
Stroke	411	14.0	431	16.7	7.7	1.1
Asthma^d	393	13.3	229	8.9	14.2	1.3
Any cancer	271	9.2	217	8.4	2.8	< 0.1
Chronic renal disease	52	1.8	33	1.3	4.0	1.8
Chronic liver disease	16	0.5	12	0.5	1.1	0.5
Drugs at baseline
CNS drugs
Benzodiazepines and related drugs	1265	43.0	1036	40.2	5.6	0.7
Antidepressants	1238	42.0	1040	40.4	3.4	3.2
Memantine	984	33.4	1202	46.6	27.3	0.8
Opioids	946	32.1	295	11.5	51.7	1.9
Antipsychotics	708	24.0	1197	46.5	48.3	3.2
Antiparkinsonians	178	6.0	118	4.6	6.5	1.7
Other drugs
Cardiovascular drugs^f	2512	85.3	2019	78.4	18.1	2.8
PPIs	1157	39.3	644	25.0	31.0	3.6
NSAIDs	854	29.0	358	13.9	37.4	4.2
Corticosteroids, systemic	327	11.1	153	6.0	18.6	3.
Estrogens	315	10.7	163	6.3	15.7	2.6
Drugs for urinary frequency and incontinence	215	7.3	104	4.0	14.2	3.3
Socioeconomic status
Highest	597	20.3	666	25.8	13.3	0.5
Middle	256	8.7	232	9.0	1.1	1.7
Lowest	1833	62.2	1481	57.5	9.7	0.1
Unknown	259	8.8	198	7.7	4.0	1.1

Notes: ^a27 persons had both a newer and an older AED and were classified as users of older AED (since they used at least one older AED). ^bIncludes hospital diagnosis of cataract, macular degeneration, and glaucoma. ^cComposite of discharge diagnosis (code M80 and M81) and dispensation data (bisphosphonates M05BA and M05BB, bone morphogenetic proteins M05BC, other drugs affecting bone structure and mineralization M05BX (eg, strontium ranelate, denosumab)). ^dComposite variables based on both hospitalization and special reimbursement data. ^eIt includes hypertension, heart failure, peripheral arterial disease, atrial fibrillation, coronary heart disease. ^fIt includes cardiac glycosides (C01AA), antiarrhythmics (C01B), organic nitrates (C01DA), diuretics (C03), beta blocking agents (C07), calcium channel blockers (C08), agents acting on the renin-angiotensin system (C09), lipid modifying agents (C10A, C10BA), antithrombotic agents (B01A).

Abbreviations: AD, Alzheimer’s disease; AED, antiepileptic drug; ATC, anatomical therapeutic chemical; CNS, central nervous system; HF, hip fracture; IPTW, inverse probability of treatment; NSAID, nonsteroidal anti-inflammatory drugs; PPI, proton pump inhibitors.

Table 3 Age- and Sex-Adjusted Incidence Rate (IR) and Hazard Ratio (HR), with 95% Confidence Interval (95% CI), of Hip Fracture (HF) According to Use of AED

	Incident HF (N= 1028)		Age- and Sex- Adjusted IR/100 Person-Years (95% CI)	Matched HR^a (95% CI)		Propensity Score Adjusted HR (95% CI)		IPTW HR^b (95% CI)		Stabilized IPTW HR^c (95% CI)
	N	%
Non-users	673	65.5	1.8 (1.6; 1.9)	Reference		Reference		Reference		Reference
Users	355	34.5	2.0 (1.8; 2.2)	1.24	(1.07; 1.44)	1.10	(0.93; 1.29)	1.17	(1.05; 1.30)	1.16	(1.00; 1.36)
Duration of use^d, e - any AED (weeks)
Short (<14)
Non-users	57	8.5	0.1 (0.1; 0.2)	Reference		Reference		Reference		Reference
Users	112	31.6	0.6 (0.5; 0.7)	4.30	(3.13; 5.92)	3.98	(2.84; 5.57)	3.64	(2.90; 4.58)	3.62	(2.65; 4.93)
Medium (14 to <64)
Non-users	161	23.9	0.4 (0.3; 0.5)	Reference		Reference		Reference		Reference
Users	114	32.1	0.9 (0.7; 1.1)	2.23	(1.76; 2.84)	1.71	(1.32; 2.21)	1.74	(1.48; 2.05)	1.74	(1.36; 2.22)
Long (≥64)
Non-users	455	67.6	1.2 (1.1; 1.4)	Reference		Reference		Reference		Reference
Users	129	36.3	1.7 (1.4; 2.0)	1.47	(1.21; 1.78)	1.25	(1.01; 1.54)	1.23	(1.08; 1.40)	1.24	(1.01; 1.51)
Type of AED
Older	88	57.9	2.6 (2.1; 3.3)	1.52	(1.10; 2.10)	1.10	(0.77; 1.57)	1.46	(1.03; 2.08)	1.37	(1.00; 1.88)
Newer	64	42.1	1.4 (1.1; 1.9)	Reference		Reference		Reference		Reference
Duration of use^d, f (weeks)
Short (<14)
Older	27	17.8	0.2 (0,4; 1.0)	1.88	(1.00; 3.54)	1.51	(0.74; 3.05)	1.27	(0.83; 1.95)	1.27	(0.69; 2.33)
Newer	15	9.9	0.1 (0.1; 0.4)	Reference		Reference		Reference		Reference
Medium (14 to <64)
Older	31	20.4	0.9 (0.6; 1.3)	1.60	(0.92; 2.78)	1.71	(0.92; 3.18)	2.00	(1.33; 3.01)	2.00	(1.12; 3.56)
Newer	21	13.8	0.4 (0.3; 0.7)	Reference		Reference		Reference		Reference
Long (≥64)
Older	30	19.7	1.2 (0.9; 1.8)	1.26	(0.75; 2.10)	1.20	(0.69; 2.10)	1.06	(0.75; 1.49)	1.06	(0.65; 1.72)
Newer	28	18.4	0.9 (0.6; 1.3)	Reference		Reference		Reference		Reference

Notes: ^aAdjusted for age, sex, and time since AD diagnosis (days) by matching. ^bWeighted with inverse probability of treatment weights (IPTW). ^cWeighted with stabilized inverse probability of treatment weights (IPTW). ^dCut-offs based on tertile distribution of duration of AED use: 1st tertile 13.9 weeks, 2nd tertile 63.7 weeks. ^eReference category for each duration of any AED use group is the non-users with same follow-up duration. ^fReference category for each duration of older AED use group is the users of newer AEDs with same duration of use.

Figure 2 Hazard ratio (HR) weighted for inverse probability of AED treatment, with 95% confidence interval, of hip fracture comparing incident users and non-users by age class. The following HR point estimates are in bold: 1.83; 1.34; 1.07; 1.06.

Data Availability Statement

The data used to conduct the research are available from the corresponding author but restrictions by the register maintainers and Finnish legislation apply to the availability of these data. Therefore, the data are not publicly available without permissions of the register maintainers.