Risk factors for fractures following liver transplantation: a population-based cohort study

Figures & data

Table 1. Classification of all first fracture sites post-transplant.

Fracture site	n (%)
Vertebra	73 (16.9 %)
Femur	58 (13.5%)
Upper extremity (humerus, radius and ulna)	107 (24.8%)
Wrist and hand	32 (7.4%)
Clavicle/scapula/sternum/rib	63 (14.6%)
Lower extremity (tibia, fibula, patella, ankle, foot)	91 (21.1%)
Pelvis and others	7 (1.6%)

Table 2. Comparison of demographics and comorbidities between the liver recipients with and without a post‐transplant fracture.

	Total	Fracture	Without fracture
	n = 4821	n = 419	n = 4402
Female recipient	1253 (26.0%)	161 (38.4%)	1092 (24.8%)
Age at transplant	52.7 ± 9.3	53.4 ± 9.2	52.6 ± 9.3
Age at transplant ≥ 65 years	356 (7.4%)	41 (9.8%)	315 (7.2%)
Overseas transplantation	593 (12.3%)	51 (12.2%)	542 (12.3%)
Fracture in 1 year prior to transplant	118 (2.4%)	33 (7.9%)	85 (1.9%)
Chronic liver or biliary disease prior to transplantation
Acute and subacute necrosis of liver	555 (11.5%)	38 (9.1%)	517 (11.7%)
Alcohol-related cirrhosis	1671 (34.7%)	156 (37.2%)	1515 (34.4%)
Primary biliary cholangitis	365 (7.6%)	48 (11.5%)	317 (7.2%)
Chronic non-alcoholic fatty liver disease	29 (0.6%)	NA	NA
Hepatitis B	3115 (64.6%)	241(57.5%)	2874 (65.3%)
Hepatitis C	1588 (32.9%)	171 (40.8%)	1417 (32.2%)
Wilson’s disease	37 (0.8%)	3 (0.7%)	34 (0.8%)
Biliary atresia	25 (0.5%)	0 (0.0%)	25 (0.6%)
Malignancy	2870 (59.5%)	243 (58.0%)	2627 (59.7%)
Comorbidity
Osteoporosis	34 (0.7%)	11 (2.6%)	23 (0.5%)
Hyperthyroidism	17 (0.4%)	0 (0.0%)	17 (0.4%)
Hypertension	889 (18.4%)	87 (20.8%)	802 (18.2%)
Diabetes mellitus	1241 (25.7%)	120 (28.6%)	1121 (25.5%)
Systemic lupus erythematous	19 (0.4%)	4 (1.0%)	15 (0.3%)
Hyperlipidemia	158 (3.3%)	16 (3.8%)	142 (3.2%)
Coronary artery disease	156 (3.2%)	20 (4.8%)	136 (3.1%)
Cerebrovascular disease	108 (2.2%)	19 (4.5%)	89 (2.0%)
Chronic obstructive pulmonary disease	139 (2.9%)	22 (5.3%)	117 (2.7%)
Malnutrition	8 (0.2%)	0 (0.0%)	8 (0.2%)
Rheumatoid arthritis	22 (0.5%)	NA	NA
Hypogonadism and postmenopausal disorder	20 (0.4%)	3 (0.7%)	17 (0.4%)
Alcoholism	1102 (22.9%)	112 (26.7%)	990 (22.5%)
Mean dosage of glucocorticoids
0–1.61 mg/day	1205 (25.0%)	90 (21.5%)	1115 (25.3%)
>1.61-3.78 mg/day	1205 (25.0%)	90 (21.5%)	1115 (25.3%)
>3.78-9.18 mg/day	1206 (25.0%)	144 (34.4%)	1062 (24.1%)
>9.18 mg/day	1205 (25.0%)	95 (22.7%)	1110 (25.2%)
Bone-protective medications
Bisphosphonate therapy	102 (2.1%)	13 (3.1%)	89 (2.0%)
Calcium	336 (7.0%)	35 (8.4%)	301 (6.8%)
Vitamin D	70 (1.5%)	5 (1.2%)	65 (1.5%)
Calcium and vitamin D	36 (0.7%)	5 (1.2%)	31 (0.7%)
Immunosuppressive medications
Tacrolimus	4599 (95.4%)	391 (93.3%)	4208 (95.6%)
Cyclosporine	384 (8.0%)	52 (12.4%)	332 (7.5%)
Mycophenolate mofetil/mycophenolic acid	4064 (84.3%)	372 (88.8%)	3692 (83.9%)
Sirolimus/everolimus	1389 (28.8%)	74 (17.7%)	1315 (29.9%)

NA: not available.

Table 3. Analysis of risk factors for post-transplant fractures in the liver transplant recipients.

	Univariable		Multivariable
	HR (95% CI)	p value	HR (95% CI)	p value
Age at transplant ≥ 65 years	1.613 (1.168–2.227)	*0.004	1.566 (1.122–2.186)	*0.008
Female recipient	1.973 (1.620–2.403)	*<0.001	1.648 (1.319–2.057)	*<0.001
Overseas transplantation	0.773 (0.577–1.037)	0.086
Fracture in 1 year prior to transplant	5.284 (3.7000–7.547)	*<0.001	3.664 (2.503–5.364)	*<0.001
Chronic liver or biliary disease prior to transplantation
Acute and subacute necrosis of liver	0.750 (0.537–1.047)	0.091
Alcohol-related cirrhosis	1.259 (1.033–1.536)	*0.023	0.954 (0.691–1.316)	0.773
Primary biliary cholangitis	1.381 (1.022–1.866)	*0.035	1.200 (0.874–1.648)	0.259
Chronic non-alcoholic fatty liver disease	0.989 (0.246–3.968)	0.988
Hepatitis B	0.633 (0.521–0.769)	*<0.001	1.076 (0.867–1.335)	0.505
Hepatitis C	1.634 (1.344–1.986)	*<0.001	1.594 (1.289–1.970)	* <0.001
Wilson’s disease	0.744 (0.239–2.316)	0.609
Biliary atresia	0.049 (0.000–17.340)	0.314
Malignancy	0.969 (0.798–1.177)	0.751
Comorbidity
Osteoporosis	3.049 (1.675–5.551)	*<0.001	1.722 (0.909–3.261)	0.095
Hyperthyroidism	0.049 (0.000–62.887)	0.410
Hypertension	1.371 (1.082–1.736)	*0.009	1.280 (0.998–1.642)	0.052
Diabetes mellitus	1.349 (1.091–1.667)	*0.006	1.140 (0.911–1.426)	0.252
Systemic lupus erythematous	2.900 (1.083–7.765)	*0.034	1.569 (0.576–4.276)	0.379
Hyperlipidemia	0.905 (0.549–1.492)	0.696
Coronary artery disease	1.538 (0.982–2.411)	0.060
Cerebrovascular disease	2.227 (1.405–3.529)	*0.001	1.595 (0.989–2.571)	0.055
Chronic obstructive pulmonary disease	1.489 (0.969–2.289)	0.069
Malnutrition	0.050 (0.000–13389.353)	0.638
Rheumatoid arthritis	1.113 (0.277–4.466)	0.880
Hypogonadism and postmenopausal disorder	1.180 (0.379–3.676)	0.775
Alcoholism	1.387 (1.116–1.723)	*0.003	1.557 (1.087–2.230)	**0.016
Mean dosage of glucocorticoids
0–1.61 mg/day	1	1
>1.61–3.78 mg/day	1.476 (1.098–1.982)	*0.010	1.354 (1.005–1.824)	*0.047
>3.78–9.18 mg/day	4.506 (3.419–5.939)	*<0.001	4.182 (3.155–5.544)	*<0.001
>9.18 mg/day	13.938 (10.064–19.303)	*<0.001	13.334 (9.506–18.703)	*<0.001
Bone-protective medications
Bisphosphonate therapy	1.729 (0.995–3.005)	0.052
Calcium	0.852 (0.602–1.206)	0.366
Vitamin D	0.605 (0.250–1.461)	0.264
Calcium and vitamin D	1.094 (0.452–2.646)	0.842
Immunosuppressive medications
Tacrolimus	0.618 (0.420–0.908)	*0.014	0.617 (0.417–0.913)	*0.016
Cyclosporine	1.322 (0.988–1.770)	0.060
Mycophenolate mofetil/mycophenolic acid	0.987 (0.728–1.337)	0.931
Sirolimus/everolimus	0.592 (0.460–0.762)	*<0.001	0.504 (0.391–0.650)	*<0.001

CI: confidence interval; HR: hazard ratio. *p < 0.05.

Data availability statement

The Taiwan’s NHIRD is an anonymized database. Researchers can apply access to Taiwan’s NHIRD database after ethical approval from the institutional review board. The applicant must be Taiwanese or be affiliated with a Taiwanese research institute. After receiving permission of gaining access to Taiwan’s NHIRD database, the Health and Welfare Data Centre asks qualified investigators to conduct on-site data analysis by using provided computers and software including SAS, Stata, R, and SPSS at one branch of Health and Welfare Data Centre through remote connection to Health and Welfare Data Centre servers. No individual-level data may be taken out from centres. Therefore, data sharing is not applicable to this study due to privacy and ethical concerns.