This study was conducted to assess the occurrence of fractures in solid-organ transplant recipients.
Within the past 3 decades, organ transplantation has become an established therapy for end-stage diseases of the kidney, liver, and lung. Survival after solid-organ transplantation has improved markedly mainly because of the addition of calcineurin inhibitors, cyclosporine A (CsA), and tacrolimus, to posttransplantation immunosuppressive regimens. With improved survival has come a greater appreciation of complications such as osteoporosis and fractures that negatively influence patients’ quality of life. The pathogenesis of transplantation osteoporosis is complex and incompletely understood. It is probably related to a combination of noxious effects to the skeleton that occur both before and after organ transplantation. Cardiac, kidney, lung, and liver failure each have unique pathophysiologies that influence bone and mineral metabolism before transplantation. Additional factors such as aging, nutritional deficiencies, immobility, diabetes mellitus, tobacco, and alcohol may affect the skeletons of these transplant recipients before and after transplantation. In the posttransplant period, patients are then subjected to a drug regimen that usually includes high doses of glucocorticoids, the most common cause of secondary osteoporosis. Glucocorticoids are prescribed in combination with other immunosuppressive agents, such as calcineurin inhibitors (cyclosporine A or tacrolimus), rapamycin, mycophenylate mofetil, and azathioprine. Of these agents, both cyclosporine A and tacrolimus are thought to have specific adverse effects upon skeletal integrity. It is thought that the independent and interconnected skeletal effects of glucocorticoids and calcineurin inhibitors lead to a form of bone disease characterized by rapid bone loss and high rates of fractures [
While most transplant centers have used triple therapy consisting of a calcineurin-inhibitor (CNI), an antimetabolite, and steroids as induction and maintenance regimens, steroid sparing regimens have been developed due to the concern in the transplant community about the importance of steroid-related morbidity [
The Kovler Transplant Center at Northwestern University is located at Northwestern Memorial Hospital. An extensive clinical database is maintained at Northwestern Memorial Hospital. The status of all patients in the database is maintained as part of the regular posttransplantation care at the respective hospitals. The Institutional Review Board approved this study and all participants provided informed consent.
18 years of age and older recipients of solid-organ transplants between January 1, 2001 and December 31, 2007, survivals for at least 2 years after transplant. Use of glucocorticoids limited to the initial 6 months of immuno-suppressive regimen.
prolonged glucocorticoid therapy, inability to provide informed consent, fractures of digits or toes, and skull fractures. The cohort for this study includes 351 patients who received pancreas, kidney-pancreas, and liver transplants and survived. Adequate fracture information was obtained in 175 subjects. There were 92 liver, 47 kidney-pancreas, 19 kidney-liver, and 17 pancreas transplants preformed and evaluable during the study interval. Kidney-only transplants and cardiac transplants were excluded due to prolonged glucocorticoid use.
Information in symptomatic incident fractures was obtained retrospectively in the organ transplant cohort. All patients were contacted by telephone (88%) or at the clinic visit (12%) and queried about fracture occurrence since the transplant. All fractures identified were verified by review of the medical record for formal radiographic reports or other relevant documentation. Asymptomatic fractures not located in the thoracic spine/rib cage (visualized on chest X-ray) may have been missed because routine thoracic and lumbar spine films were not obtained for spinal morphometry. Fractures of the face and digits were excluded from analysis.
Descriptive statistics such as mean ± SD (standard deviation) were used to summarize patient characteristics for continuous variables whereas frequency and percentage were used for categorical variables. Incidence rate per person-year of fracture was calculated, using the observed fracture frequency in this study cohort as the numerator, and a product of the individuals at risk and the time units as the denominator. The time units were defined as the years since the transplant till whatever happened first during the followup, fracture date, or the interview date. All interviews were conducted between July 1, 2007 and December 31, 2009. Overall person-year fracture incidence rate was computed, as well the age- and gender-specific person-year fracture incidence rate. Age was also stratified as <18, 18–24, 25–44, 45–64, and 65–69, according to 1994 NHIS grouping. Organ-, age-, and gender-specific numbers and rates, and person-years of observation were calculated. Weighted age- and gender-specific fracture rates from 1994 NHIS (National Health Interview Survey) were applied to the number of person-years of observation for each organ-specific age and gender category of transplant patients to calculate an expected number of fractures. The ratio (expressed as an estimated relative risk) of observed and expected number of fractures was used to compare fracture of transplant patients to that of the national sample of the 1994 NHIS.
A Chi-square or Fisher’s exact test was used to assess the association between categorical variables (i.e., gender) and the occurrence of fracture. A two-sample
The specific patient characteristics stratified by type of organ transplant are shown in Table
Characteristics of organ transplant recipients and patients with fractures.
Patient features | Kidney/liver | Kidney/pancreas | Liver | Pancreas |
---|---|---|---|---|
Number of patients | 19 | 47 | 92 | 17 |
Gender (% female) | 52.6 | 46.8 | 35 | 58.8 |
Age at transplant in years (mean ± SD) | ||||
Number with fractures | 4 | 15 | 22 | 7 |
Men | 1/9 | 7/25 | 16/60 | 1/7 |
All women | 3/10 | 8/22 | 6/32 | 6/10 |
30% | 32% | 19% | 60% | |
Postmenopausal women** | 2/10 | 5/22 | 5/22 | 0/1 |
20% | 23% | 23% | 0% |
Type of fracture by type of solid-organ transplant.
Patient characteristics were stratified by type of organ transplant (Table
Fifteen of 47 kidney-pancreas (32%) recipients had their initial symptomatic fracture during the 207.1 person-years of observation for a crude fracture rate of 0.068 per year of observation. The mean age at the time of initial fracture was 48.3 ± 9.3 years, (median: 50; range: 32–63), and the mean number of months from transplant to initial fracture was 51.0 ± 23.2 months (median: 59; range: 5–80). The most common site of fracture in this group was the foot, and occurred equally in males and females 28.0% versus 31.8%, respectively. Five axial (rib and spine) fractures occurred compared with 7 limb fractures in this group as compared to 15 limb fractures. Two of the 3 patients who reported multiple fractures were women.
Twenty-two (24%) of 92 liver transplant recipients had fractures during the 383.3 person-years of observation, for a crude fracture rate of 0.065 per year of observation. The mean age at the time of initial symptomatic fracture was 54.4 ± 12.2 years (median: 57; range: 25–71), and the mean number of months from transplant 36.0 ± 28.9 months (median: 30; range: 3–86). Nine axial (vertebral and hip) fractures occurred compared with 18 limb fractures. Four patients receiving liver transplants sustained multiple fractures.
Seven (41%) of the 17 pancreas transplant recipients had fractures during the 66.5 person-years of observation for a crude fracture rate of 0.090 per year of observation. The mean age at the time of initial symptomatic fracture was 40.6 ± 6.5 years (median: 42; range: 31–50), and the mean number of months from transplant to initial fracture was 41.7 ± 22.1 months (median: 42; range; 26–57). All 3 fractures in this group were limb fractures (1 wrist and 2 foot (metatarsal)), and none sustained multiple fractures.
Age- and gender-specific fracture incidence rates representative of the US civilian, noninstitutionalized population from the 1994 NHIS are shown in Tables
Age- and gender-specific fracture incidence rates in
Women | Men | ||||||||
Age in years | Person-years at risk | Observed number of fractures | Expected number of fracture | Estimated relative risk | Person-years at risk | Observed number of fractures | Expected number of fractures | Estimated relative risk | |
<18 | 0 | 0 | — | — | 0 | 0 | — | — | |
18–24 | 2.8 | 1 | — | — | 0 | 0 | — | — | |
25–44 | 106.1 | 6 | 0.33 | 18.2 | 127.0 | 9 | 0.83 | 10.9 | |
45–64 | 155.1 | 16 | 0.47 | 34.4 | 280.3 | 12 | 0.81 | 14.8 | |
65–69 | 14.1 | 0 | 0.06 | 0 | 31.1 | 3 | 0.09 | 0 |
Age and gender specific fracture incidence rates in the US population. National Center for Health Statistics, National Health Interview Survey (NHIS) 1994.
Age in Years | Women | Men |
---|---|---|
<18 | 5.9 | 10.7 |
18–24 | 1.8 | 10.3 |
25–44 | 3.1 | 6.5 |
45–64 | 3.0 | 2.9 |
65–69 | 4.6 | 2.8 |
Age- and gender-specific fracture incidence rates in
Women | Men | ||||||||
Age in years | Person-years at risk | Observed number of fractures | Expected number of fractures | Estimated relative risk | Person-years at risk | Observed number of fractures | Expected number of fractures | Estimated relative risk | |
<18 | 0 | 0 | — | — | 0 | 0 | — | — | |
18–24 | 0 | 0 | — | — | 0 | 0 | — | — | |
25–44 | 7.0 | 0 | 0.02 | 0 | 5.5 | 0 | 0.04 | 0 | |
45–64 | 30.1 | 2 | 0.09 | 22.1 | 28.8 | 2 | 0.08 | 12.0 | |
65–69 | 5.3 | 0 | 0.02 | 0 | 0 | 0 | — | — |
Age- and gender-specific fracture incidence rates in
Women | Men | ||||||||
Age in years | Person-years at risk | Observed number of fractures | Expected number of fractures | Estimated relative risk | Person-years at risk | Observed number of fractures | Expected number of fractures | Estimated relative risk | |
<18 | 0 | 0 | — | — | 0 | 0 | — | — | |
18–24 | 0 | 0 | — | — | 0 | 0 | — | — | |
25–44 | 44.5 | 2 | 0.14 | 7.2 | 62.3 | 4 | 0.40 | 9.9 | |
45–64 | 43.8 | 6 | 0.13 | 45.7 | 52.4 | 4 | 0.15 | 26.2 | |
65–69 | 0 | 0 | — | — | 0 | 0 | — | — |
Age- and gender-specific fracture incidence rates in
Women | Men | ||||||||
Age in years | Person-years at risk | Observed number of fractures | Expected number of fractures | Estimated relative risk | Person-years at risk | Observed number of fractures | Expected number of fractures | Estimated relative risk | |
<18 | 0 | 0 | — | — | 0 | 0 | — | — | |
18–24 | 2.8 | 1 | 0.005 | 201.5 | 0 | 0 | — | — | |
25–44 | 33.2 | 1 | 0.10 | 9.7 | 33.3 | 4 | 0.22 | 18.5 | |
45–64 | 75.3 | 7 | 0.23 | 31.0 | 189.2 | 6 | 0.55 | 16.4 | |
65–69 | 8.8 | 0 | 0.04 | 0 | 31.1 | 3 | 0.09 | 34.5 |
Age- and gender-specific fracture incidence rates in
Women | Men | ||||||||
Age in years | Person-years at risk | Observed number of fractures | Expected number of fractures | Estimated relative risk | Person-years at risk | Observed number of fractures | Expected number of fracture | Estimated relative risk | |
<18 | 0 | 0 | — | — | 0 | 0 | — | — | |
18–24 | 0 | 0 | — | — | 0 | 0 | — | — | |
25–44 | 25.0 | 4 | 0.08 | 51.7 | 25.8 | 2 | 0.17 | 6 | |
45–64 | 5.9 | 1 | 0.02 | 56.5 | 9.9 | 0 | 0.03 | 0 | |
65–69 | 0 | 0 | — | — | 0 | 0 | — | — |
The male liver transplant recipients aged 45–64 years at the Kovler Transplant Center cohort had 100 person-years of observation. The estimated relative risk of fracture was nearly seventeen-times higher in male liver transplant recipients ages 45–64 years compared with the general male population of those age groups.
For those 175 transplant recipients who provided valid fracture data (yes or no), the median followup was 4.46 years (range: 0–7.93 years), 75% nonfracture time was 5.04 years (95% confidence interval: 4.08–5.37 years). Figure
Proportion of fracture among all patients over time.
This study is the first to quantify the magnitude of excess fractures occurring in solid-organ transplant recipients (liver) on glucocorticoid-sparing immuno-suppressive regimens. An elevated fracture risk (17-fold increased risk of fractures) was identified, in fact, the fracture incidence was similar to our prior studies of transplant recipients on conventional antirejection regimens [
Post transplantation osteoporosis is a complex and multifactorial disease with preexisting bone loss associated with end-stage organ failure, immobility, aging, high-dose glucocorticoid use, and immune suppressant therapy having been implicated. End-stage kidney or liver disease, and congestive heart failure are associated with low bone mineral density, fractures, and abnormalities of mineral metabolism [
Additionally, we identified that calcium supplementation and vitamin D was common in transplant recipients, but failed to reduce fracture risk. Bisphosphonate therapy however, was identified as being associated with a reduction in fracture risk. These preliminary findings suggest important treatment options in transplant candidates with suitable kidney function such as CKD stage 2-3 (GFR > 35 cc/min/ 1.73 m2).
Our data on four self-reported symptomatic fractures in 19 liver-kidney transplant recipients represents both genders. Symptomatic axial fractures were less frequently reported than limb fractures. There is a paucity of studies assessing the incidence of fractures in these transplant recipients. All four fractures occurred in patients with pretransplant chronic hepatitis, none of these patients had diabetes mellitus. We reported on 15 fractures occurring in 47 kidney-pancreas recipients, all of whom had diabetes mellitus and end-stage kidney disease. In the kidney pancreas transplant recipients followed for a mean time of 6.3 years we noted more limb than axial fractures. Our findings confirm the high incidence of fractures of 20–45% in prior studies [
We described 22 symptomatic fractures in 92 liver transplant recipients, this cohort was followed for a mean of 6 years, the crude fracture rate was 0.063 per year. These data are comparable to the frequency of postliver-transplant fractures reported in other studies ranging from 20–40% [
We also reported on seven fractures in 17 pancreas transplants with diabetes and followed for a mean of 4 years. The most common site affected was the foot. Patients who received kidney pancreas and pancreas transplants were diabetic and 10 years younger than other solid-organ transplant recipients. In all cases, fractures were limb fractures.
Calcineurin inhibitors have allowed for improved survival and reductions in glucocorticoid therapy in transplantation. However, the calcineurin inhibitors, cyclosporine (CsA), and tacrolimus (FK506) have also been implicated in posttransplant bone disease. These drugs stimulate loss of bone mass independent of glucocorticoid therapy, with high-turnover bone metabolism noted in rat models [
There are several limitations with this analysis as comparisons between the fracture rates in the transplant cohort and the NHIS data should be interpreted with caution. First, the NHIS data includes self-reported fractures that were not verified. We used a more stringent case finding procedure in the transplant cohort as we verified the patient’s self-report of fracture. Thus, our observed number of fractures is more conservative than the NHIS data. Second, the number of person-years of observation in some of our strata are small, especially for kidney pancreas and kidney-liver recipients. Thus, the expected number of fractures are small, resulting in relative risk estimates that are unstable and liable to inflation from a very small number of events. Thus, we did not use test of significance for these results. Fractures rates for patients included only the initial posttransplant fracture while some patients experienced more than one fracture. Therefore, the number of fracture events in the transplant cohort represent the lowest estimate of the problem. In the strata with at least 100 person-years, we determined that fractures in transplant patients were increased nearly seventeen-fold compared with expected numbers from national data. The frequency of fractures in this transplant cohort clearly represent the lower boundary of the problem because routine surveillance for asymptomatic vertebral fractures was not performed. Nevertheless, using our conservative estimate from the occurrence of symptomatic fractures, these data demonstrate the magnitude of this excess risk.
There is limited information in medical records about potential risk factors for increased fracture rate observed in this study. Previous studies of those risk factors reveal inconsistent findings. For kidney transplant patients, risk factors associated with fracture included low BMD, prior parathyroidectomy, higher glucocorticoid use, and longer interval between transplant and fracture [
Patients with kidney/pancreas and pancreas transplantation appear to be at higher risk of fracture. Diabetics are predisposed to low bone turnover bone disease, neuropathy, and osteopenia. Factors uniquely associated with osteopenia in diabetics include chronic hypocalcemia, insulin deficiency, hypomagnesemia, relative hypoparathyroidism, negative protein balance, immobility, hypogonadism, and metabolic acidosis [
In liver transplant recipients, initial BMD, interval change in BMD, menopause, primary biliary cirrhosis, long-term glucocorticoid use, calcineurin inhibitors, underlying pretransplant disease severity, multiple fractures, and pretransplant fracture have been identified as risk factors for fractures [
This study is the first to quantify the magnitude of excess fractures occurring in solid-organ transplant recipients on glucocorticoid-sparing immuno-suppressive regimens. Liver transplant recipients have a 17-fold increased risk of fractures as compared to age- and gender-matched controls. Additional research must be conducted to clarify pathogenesis of bone loss and fractures and the development of suitable preventive strategies.
Cyclosporine
Tacrolimus
Mycophenolate mofetil
Calcineurin inhibitor
National Health Interview Survey.
A. Desai, J. Tsai, H. Du, G. R. Edwards, A. D. Bunta, A. Hahr, M. Abecassis, and S. Sprague declare no conflict of interests.
Funding was provided by the Alliance for Bone Health. The authors retained full independence in study design and analysis. B. J. Edwards works as a consultant at Eli Lilly, Amgen, Warner Chilcott.