Osteoporosis and Fractures After
Solid Organ
Transplantation: A Nationwide
Population-Based
Cohort Study
Tung-Min Yu, MD; Cheng-Li Lin, MS; Shih-Ni Chang, MS;
Fung-Chang Sung, PhD, MPH; Shih-Ting Huang, MD; and
Chia-Hung Kao, MD
S
olid organ transplantation (SOT) is the only lifesaving treatment for patientswith major organ failure, including heart,
lung, and liver, and it is considered the treatment of choice for end-stage kidney failure.
Because of the progress made in surgical techniques, perioperative care, and immunosuppressive
regimens, long-term outcomes of SOT
are better than ever before. Despite improvements in patient and graft survival in SOT, an
increasing number of complications after transplantation have become a major concern in
caring for recipients of SOT that may have been caused by either the recipient’s diseases or treatment with immunosuppressant agents. Compared with lethal complications, such as cancer, cardiovascular diseases, and infection, and some metabolic disorders, such as diabetic mellitus, after transplantation, the importance of metabolic bone diseases seems to be ignored
in patients after SOT.
It is reasonable to anticipate that recipients of SOT are at high risk for bone disorders owing to several unfavorable situations. First, in these candidates with chronic, catastrophic illnesses before transplantation, multiple comorbidities such as the underlying disease itself, poor nutrition, immobility, cachexia, and unhealthy lifestyle
factors (heavy tobacco and alcohol
consumption) eventually result in metabolic bone disorders.1 For example, in patients with
hepatic osteodystrophy, multiple factors have been considered as contributing to reduced bone formation, including excessive alcohol consumption,2 decreased insulinlike growth
factor 1 levels,3 and hyperbilirubinemia.4 Substantial
bone absorption caused by hypogonadism is a frequent fnding in patients with liver cirrhosis.5 Renal osteodystrophy prevails in
most patients with chronic renal disease who unavoidably acquired excessive derangement of bone mineralization in a uremic state. Studies have reported an approximately 4.4-fold risk of hip fracture and a risk of vertebral fracture as
high as 21% in patients with end-stage renal disease
compared with the general population.6-8 Recipients of SOT inevitably take
immunosuppressive
medications, such as glucocorticoids
(GCs) and calcineurin inhibitors, for the rest of their lives. Glucocorticoids have been demonstrated to play a dominant role in bone loss and
to profoundly affect bone absorption in patients after organ transplantation.9,10 The mechanisms
are complex, including decreasing osteoblast
replication and differentiation, wasting renal calcium, attenuating intestinal absorption of calcium,
and hypogonadism.11 The deleterious
span are considered to be crucial in contributing to bone disorders after transplantation. Consequently, these unfavorable conditions synergistically
compel the transplant cohort to be at high risk for bone fracture. Although every SOT has different underlying bone diseases depending
on disease progress and the individual immunosuppressant drug regimen, it is generally believed
that the occurrence of bone disorders after organ transplantation is similar irrespective of organ type.12
The impact of osteoporosis in the general population has been clearly addressed and is characterized by low bone mass and vulnerability to bone fractures, leading to excessmortality of 10% to 20% and up to 25% of the general population requiring long-term nursing home care; nevertheless, a large gap still exists in clinical practice.13,14 To date, data regarding
the risk of bone diseases after SOT are limited owing to either small group sizes or restrictions regarding individual SOT or lack of long-term follow-up. The aim of this study was to compare the risk of osteoporosis and fracture
among different types of SOT in a nationwide population-based cohort over a long-term period and to look for potential risk factors associated with patients receiving SOT. PARTICIPANTS AND METHODS
Data Sources
Data analyzed in this study were retrieved from the Taiwan National Health Insurance Research Database (NHIRD), which is managed by the Taiwan National Health Research Institute. In 1995, Taiwan commenced its state-run National Health Insurance program, which registers all medical claims and provides affordable health care for all residents. The National Health
Insurance program covers more than 99% of the population and has contracted with 97% of the hospitals in Taiwan.
Sets of information available for the NHIRD include all medical services by each insurant
from 1996 to 2010 and characteristics of the patients, hospitals, and physicians. In this study,we
used the hospitalization claims data of all enrollees (23 million) in Taiwan, which contained information on sex, date of birth, dates of hospital
admission and discharge, diagnoses, surgical procedures, discharge status, and expenditures by
admission. Diagnoseswere coded using the International Classifcation of Disease, Ninth Revision,
Clinical Modifcation (ICD-9-CM). Several Taiwan studies demonstrated the high accuracy and validity of ICD-9 code diagnoses in the NHIRD.15,16
Study Participants
The study participants were identifed in the database between January 1, 1997, and December 31, 2010, as having newly diagnosed SOT, including kidney transplantation (ICD-9-CM code V42.0 or operation code 55.69), liver transplantation (ICD-9-CM code V42.7 or operation codes 50.51-50.59), heart transplantation
(ICD-9-CM code V42.1 or operation code 37.5), and lung transplantation (ICD-9-CM code V42.6 or operation codes 33.50-33.52). The date of the frst hospital admission for transplant was used as the index date.We excluded patients with osteoporosis (ICD-9-CM codes 733.00-733.09) or pathologic fracture (ICD-9-CM codes 733.10-733.19) before the index date. Patients with multiple SOTs or retransplantation were excluded. In Taiwan, the diagnosis of osteoporosis and fracture through ICD-9 codes is derived fromthe evidence strictly based on the clinic data of bone mineral density (BMD) measurement by
dual X-ray absorptiometry (for the hip and spine) and ultrasound densitometry (for the heel). In this study, patients who acquired fractures by trauma or tumor metastasis were also excluded. The diagnosis of pathologic fracture was defned as related fracture when it did not result from trauma or metastasis. Finally, we extracted 9428 transplant recipients to be used as study patients, defned as the SOT cohort.
For each SOT patient, we randomly selected 4 non-SOT patients fromthe same study period and used the same exclusion criteria and frequency matched them with the SOT cohort
for age and sex to form the non-SOT cohort
with 38,140 individuals. Outcome Measurement and Comorbidities We identifed the frst diagnosis of osteoporosis
or pathologic fracture from hospitalization records from 1997 to 2010 as the study end
point. All the study participants were observed from the index date to occurrence of the end point, withdrawal from the database, the end of 2010, or whichever date came frst.
We also incorporated inpatient diagnosis
records to ascertain the baseline comorbidities,
including diabetes (ICD-9-CM code 250), hypertension (ICD-9-CM codes 401-405), and
hyperlipidemia (ICD-9-CM code 272). Statistical Analyses
The distributions of baseline characteristics (sex, age, and comorbidities) were compared between the SOT and non-SOT cohorts by the
c2 test. The incidence rates of osteoporosis and pathologic fracture were calculated in the follow-up period until the end of 2010. Follow-up time (in person-years) was calculated for each participant until osteoporosis or pathologic fracture was diagnosed or until censorship.
assumption. For estimating the cumulative incidence of osteoporosis or pathologic fracture
risk in the SOT and non-SOT cohorts, we performed survival analyses using the
Kaplan-Meier method, with signifcance based on the log-rank test. For the risk of osteoporosis and pathologic fracture in SOT recipients, crude and adjusted hazard ratios (HRs) and 95% CIs
were calculated by using univariable and multivariable Cox proportional hazards regression
models. The confounders, including age, sex, and the comorbidities of hypertension, diabetes, and hyperlipidemia, were adjusted in the multivariable analysis. All the analyses were performed
using a statistical software program
(SAS for Windows, version 9.1; SAS Institute Inc), and the signifcance level was set at P<.05. RESULTS
As a whole, age and sex were comparable in both groups, and approximately 61% of patients were male in the study (Table 1). Patients
in the SOT group were more likely to have hypertension (47.2% vs 4.27%), diabetes (17.0%
vs 2.75%), and hyperlipidemia (8.73% vs 1.61%) than in the control group without SOT. We observed 83 cases of osteoporosis (41 in the non-SOT cohort and 42 in the SOT cohort) and 253,349 person-years, with an incidence density of 1.97 per 10,000 person-years for the non-SOT cohort and 9.19 per 10,000 personyears for the SOT cohort (incidence rate ratio,
4.65; 95% CI, 4.36-4.97) (Table 2). Multivariable Cox proportional hazards regression analysis revealed that the risk of osteoporosis in the SOT cohort was 5.14-fold higher than that in the non-SOT cohort (HR, 5.14; 95% CI, 3.13-8.43). The highest sex- and age-specifc HRs were observed in male patients (HR, 7.09; 95%
CI, 3.09-16.3) and in those 50 years or younger (HR, 7.38; 95% CI, 2.46-22.1). Recipients of SOTwithout comorbidity had a 9.03-fold higher risk of osteoporosis than non-SOT participants (HR, 9.03; 95% CI, 5.29-15.4) (Table 2).
Table 2 also shows the pathologic fracture
incidence densities in the SOT and non-SOT cohorts and the HRs of pathologic fracture in the
SOT cohort. Overall, the incidence of pathologic fracture was higher in the SOT cohort (12.7 per 10,000 person-years) than that in the non-SOT cohort (2.65 per 10,000 person-years), with an incidence rate ratio of 4.79 (95% CI, 4.49-5.11) and an HR of 5.76 (95% CI, 3.80-8.74). In addition, the highest sex- and age-specifc HRs were also observed in male patients (HR, 8.94; 95% CI, 4.49-16.3) and in those aged 50 years or younger (HR, 6.29; 95% CI, 1.72-23.0). The incidences and HRs of osteoporosis
and pathologic fracture were calculated according to different types of SOT (Table 3). The
incidence of osteoporosis was highest in the lung transplant cohort (HR, 191.4; 95% CI,
41.6-881.4) vs participants without SOT, followed by heart transplant (HR, 8.40; 95% CI,
3.71-19.0), liver transplant (HR, 4.40; 95% CI, 1.97-9.82), and kidney transplant (HR, 3.40; 95% CI, 1.78-6.48). The incidence of pathologic fracture was highest in the lung transplant cohort (HR, 326.6; 95% CI, 92.2-1156.9), followed by liver transplant (HR, 9.68; 95% CI, 5.78-16.2), kidney transplant
(HR, 3.42; 95% CI, 1.89-6.17), and heart transplant (HR, 3.46; 95% CI, 1.31, 9.12).
The cumulative incidences of osteoporosis and pathologic fracture in the SOT and non-SOT cohorts are shown in the Figure. The
were signifcantly higher for patients in the SOT cohort than for individuals without SOT (log-rank P<.001 for both).
Table 4 shows the risks of osteoporosis and fracture at different sites in univariable and multivariable Cox proportional hazards regression models. Recipients of SOT were found to
have the highest risk of osteoporosis not related to senile or idiopathic osteoporosis, which
reached statistical signifcance (HR, 5.39; 95% CI, 3.26-8.90). In addition, compared with the non-SOT cohort, the SOT cohort was shown
to have the highest risk of fracture of neck of femur (lower limbs) (HR, 24.3; 95%, 4.71-125.0).
DISCUSSION
Osteoporosis and related bone fractures have drawn much attention in the general population; nevertheless, their severity has been underestimated in recipients of SOT. In this cohort study,
we reported signifcantly higher incidence rates of osteoporosis and related fractures in patients after SOT compared with those in the general
population. To our knowledge, this is the frst study to compare the risk of osteoporosis and
related fractures in different SOTs on a nationwide scale during a long follow-up. These results
straightforwardly indicated that patients after
SOT are highly susceptible tometabolic bone disorders, and multiple factors are believed to result
in the dilemma of bone loss, including preexisting
primary underlying diseases and various immunosuppressant agents.
Several studies have suggested that overt absorption of bone within the frst 1 to 2 years after
transplant is attenuated gradually if the GC level is tapered and that the long-term effect of metabolic bone disorders seems to be modest beyond the frst 2 years.17-19 However, the present
data show a substantial increase in incidence rates of metabolic bone diseases in the
cohort after SOT throughout follow-up. Hence, these data suggest that the increase in the risk of osteoporosis and fracture extends over a much longer period after organ transplantation. Although most data suggest that fracture
risk attenuates in the later period after transplant, Vautour et al20 were the frst to fnd
that fracture risk continued to increase during 10-year follow-up in 86 recipients of kidney transplant.20 In the present study, we estimated
the overall fracture risk in recipients of different SOTs over a long duration and disclosed a consistent fnding with the previous study. The traditional risk factors contributing to
osteoporosis in the general population are female sex, old age, and comorbidities such as diabetic mellitus.13 In contrast, a subgroup analysis of
the SOT and non-SOT cohorts showed that a
signifcantly higher risk of osteoporosis and fracture was noted in male recipients of SOT at a
younger age. In addition, when patients were stratifed as the subgroups with and without
comorbidities, including diabeticmellitus, hypertension, and hyperlipidemia, an increase in the
risk of bone diseases was noted in SOT patients without any comorbidity, which reached statistical signifcance. Taken together, the multiple
layer analysis identifed a higher risk of bone diseases in younger male patients after excluding
associated comorbidities contributing to osteoporosis. These fndings suggest that compared with
the occurrence of osteoporosis in the general population, immunosuppressant agents might play a
potential role in bone changes after SOT, and the long-term impact of immunosuppressant drugs on bone diseases is more apparent after eliminating
other confounding factors of metabolic bone disorders.
Immunosuppressant agents impose protean effects on bone metabolism. Glucocorticoids
have been well documented to aggravate osteoporosis,
21 but data regarding the effect of calcineurin
inhibitors, mycophenolate mofetil, and
sirolimus on osteoporosis have been conficting.
22,23 It is generally believed that calcineurin
inhibitors, such as cyclosporine and tacrolimus, may have a deleterious effect on bone loss in in vitro and in vitro studies.24,25 As seen in the
study results, to a certain degree, it may refect the metabolic effect of immunosuppressant
agents accumulating on bone changes over a
long duration after tapering GCs to the minimumdosage as soon as possible in the posttransplant
period, and recipients ordinarily recover
with better health conditions after organ transplantation. In patients receiving SOT, we suggest
that the immunosuppressant agents that they commonly use for the rest of their lives may
play a detrimental role, contributing to bone diseases after SOT, and the exact mechanisms need
to be explored further in future studies. Bone disorders can develop before all types of organ transplantation; however, they have been reported to be pronounced in patients with chronic lung diseases,26,27 and a variety
of factors could be involved, including heavy long-term tobacco smoking, hypoxia, malnutrition, limited physical activity, and long-term
administration of corticosteroids for underlying lung diseases.28 Dolgos et al28 measured BMD
in patients awaiting transplantation for different sites of end-stage organ failure, including lung, liver, heart, and kidney. They found the highest prevalence of osteoporosis in patients with endstage
lung diseases, followed by liver, kidney,
and heart.28 In the present study, we compared
the risk of osteoporosis and fracture among different types of SOT using Cox proportional hazards regression models. Comparison of the different SOT types showed that the highest risk of osteoporosis and fracture was in patients undergoing lung transplantation, followed by heart, liver, and kidney transplantation. It is well-known that renal osteodystrophy prevails in most potential kidney recipients, especially those who have experienced chronic kidney failure and dialysis for a long period. It has been estimated that an approximately 4-fold increase in the risk of fracture exists in kidney transplant patients29,30 compared
with that in the general population, which was consistent with the 3.92-fold increased risk in the present cohort. We primarily hypothesized that serious bone disease after transplantation would be found in patients undergoing kidney transplantation because it could occur earlier at the stage of chronic kidney failure. However, a comparison showed that a higher fracture risk was noted in the major organs, such as lung and liver, compared with kidney transplantation. This may be explained by the fact that
the more complicated underlying diseases
before transplantation seem to affect bone disease more after transplantation. Actually, some
evidence suggests that physician awareness of renal osteodystrophy and greater experience regarding transplantation may help alleviate bone disease after kidney transplantation.28
Further evidence of intervention regarding metabolic bone diseases in SOT is needed in the
near future.Although contemporarymedications, including bisphosphonate, vitamin D analogues,
and calcitoninmay attenuate bone loss in patients receiving SOT, the effcacy to reduce bone fracture in SOT has been demonstrated to be equivocal.
31 It was considered that the change in
BMD in recipients of SOT was not consistent with the occurrence of fracture.32 In addition to
the recommendation to prevent osteoporosis, such as the broad measure of BMD at an earlier stage,20 we suggest that it is essential to carefully
evaluate the associated fracture risks and metabolic factors in patients receiving SOT. Although
most caregivers may try to minimize exposure to immunosuppressive agents, a greater concern regarding the occurrence of acute rejection and
graft loss in SOT recipients may impede the motivation for practice.33 Nevertheless, clinicians
should remember that the detrimental effect of immunosuppressant agents on bone disease persists, and they should remain cautious when caring
for such recipients.
The results of this study indicate that patients receiving SOT are highly susceptible to
osteoporosis and fracture not only during the frst 1 to 2 years after transplantation but also for a much longer period. Preexisting underlying diseases and treatment with immunosuppressant agents aggravate such bone disorders
sequentially in patients receiving SOT. The strengths of this study include its use
of population-based data that are highly representative of the general population.However, certain
limitations to these fndings should be further clarifed. First, the NHIRD does not contain detailed information regarding socioeconomic status and family history of systemic diseases, all of which may be risk factors for osteoporosis or pathologic fracture. Second, the evidence derived from a retrospective cohort study is generally
lower in statistical quality than that fromrandomized trials because ofpotential biases related to adjustments for confounding variables. In addition,
because study participants were enrolled using only ICD-9 codes, the number of patients with osteoporosis would be underestimated. Despite the meticulous study design and control measures for confounding factors, bias resulting
from unknown confounders may have affected these results. Third, all data in the NHIRD are anonymous. Thus, relevant clinical variables, such as blood pressure, imaging results, pathology fndings, and serum laboratory data, were unavailable regarding the study patient cases.
However, data regarding the diagnoses of SOT,
osteoporosis, and pathologic fracture were nonetheless reliable.
CONCLUSION
To our knowledge, this is the frst nationwide study to investigate the neglected complications regarding recipients of SOT. A signifcantly
higher risk of osteoporosis and bone
fracture prevails in patients after SOT during
long-term follow-up. Preexisting underlying diseases and treatment with immunosuppressant
agents are important factors in the development of bone diseases in SOT.
