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Keywords:

  • Bone mineral density;
  • immunosuppression;
  • intestinal failure;
  • multivisceral transplant;
  • osteoporosis;
  • parenteral nutrition (PN);
  • small bowel transplant

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Despite continuous improvement in long-term survival, there is no knowledge about risk of bone health impairment and management strategies before and after intestinal transplantation. Therefore, 147 adults were retrospectively studied via chart review; 70 long-term survivors, 53 candidates and 24 recipients with longitudinal follow-up. Evaluation process included measurement of bone mineral density (BMD) and allied biochemical markers. Both long-term survivors and candidates showed low bone mass with lower (p < 0.05) z-scores at hip, femoral neck and spine. Vitamin D deficiency and secondary hyperparathyroidism were observed in both groups. Prevalence of osteoporosis was 44% among long-term survivors and 36% in candidates with age, BMD, duration of parenteral nutrition, type of immunosuppression and rejection being significant risk factors. Fragility fractures occurred at a higher (p = 0.02) rate among long-term survivors (20%) compared to candidates (6%). The longitudinal study documented acceleration (p = 0.025) of bone loss after transplantation with a decline of 13.4% (femoral neck), 12.7% (hip) and 2.1% (spine). Alendronate reduced (p < 0.05) but did not prevent bone loss. In conclusion, intestinal transplant recipients are at risk of osteoporosis secondary to bone loss before and after transplantation. Accordingly, current management includes comprehensive preventive measures with prompt therapeutic intervention utilizing intravenous bisphosphonates or subcutaneous human PTH 1–34.


Abbreviations: 
BMI

body mass index

BMD

bone mineral density

DXA

dual energy X-ray absorptiometry

eGFR

estimated glomerular filtration rate

HPN

home parenteral nutrition

PTH

parathyroid hormone

SE

standard error

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Intestinal and multivisceral transplantation has evolved over last 20 years to be a life-saving procedure for patients with gut failure and complex abdominal pathology (1,2). The procedure is currently considered as the standard of care for patients who no longer can be maintained on home parenteral nutrition (HPN) (1). With the recent achievement of survival outcome similar to other solid abdominal organs, the quality of life of these unique visceral recipients has become a primary therapeutic end point (2,3).

In contrast to solid organ transplants, we hypothesized that visceral recipients are at a higher risk of metabolic bone disease. Such an assumption stemmed from the previously acknowledged deleterious metabolic effects of HPN, gut failure, primary gastrointestinal diseases and other concomitant systemic disorders (4,5). In addition, the high allointestine immunogenicity and the lack to achieve full nutritional autonomy in all recipients may play a major role in the early and late deterioration of bone health after transplantation (3,6).

This report is the first to address integrity of skeletal health among visceral recipients before and after allotransplantation. The observed initial results of bone loss among our long-term survivors triggered the recent introduction of a thorough bone health assessment as an essential part of the institution pretransplant evaluation protocol. Subsequently, the degree of bone health impairment before and after transplantation was properly addressed with identification of potential risk factors and implementation of a comprehensive management strategy.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Study design

This descriptive study reflects the evolution of bone health management at the Intestinal Rehabilitation and Transplantation Center, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center. The medical records of 147 patients managed between October 2000 and November 2009 were retrospectively reviewed after approval of the Institutional Review Board. Inclusion criteria included availability of at least one bone mineral density (BMD) measurement at our institution and survival of allograft recipients for more than 6 months. Exclusion criteria included individuals who received medications other than alendronate to augment bone mineral metabolism and BMD studies that were performed outside our institution to avoid the skew effect of the wide variability between the different utilized dual energy X-ray absorptiometry (DXA) devices (7). It is imperative to note that the study population represents wide geographic referral pattern with different health insurance policies.

Patient population

Subjects were divided into three cohorts according to time and number of eligible BMD studies with the aim to address (1) degree of bone health impairment among long-term survivors, (2) status of bone health in patients referred for transplant and (3) effect of transplantation with and without alendronate treatment. Accordingly, group I consisted of 70 recipients without pretransplant DXA who were followed for 9–234 months [mean (SE): 71 ± 44] and received a single study at variable times due to clinical, biochemical and/or radiologic evidence suggestive of impaired bone health. Group II was a cohort of 53 visceral transplant candidates who underwent pretransplant bone health assessment signaling the initiation of our current standardized protocol. Of these, 33 (62%) were transplanted with no postoperative BMD studies due to allograft enterectomy, patient death, recent transplantation and insurance constraints. The remaining 20 (38%) patients were deemed to be unsuitable candidates (n = 16) or awaiting transplant (n = 4). Group III was a cohort of 24 patients who had at least two DXA studies at our institution with baseline evaluation before transplantation in 16 and early after surgery in the remaining 8 with a mean of 3.5 ± 0.3 months (range: 2.4–5.5). The second evaluation for the 24 recipients was done at variable times after alloengraftment with achievement of clinical nutritional autonomy in all but two. In addition to standard calcium and vitamin D supplementation, 7 (29%) of group III patients received 70 mg of alendronate per week. All patients in group I, II and III were followed as of March 1, 2010.

The clinical features of groups I and II are summarized in Table 1. The underlying pathology was primarily nonmalignant intestinal and visceral vascular disorders in both groups with hypercoagulability, commonly associated with myeloproliferative disorders and JAK-2 mutation, being the leading cause of vascular thrombosis (3,8).

Table 1.  Clinical features, bone mineral density and bone turnover biomarkers in 70 visceral transplant survivors and 53 potential candidates
 Recipients (N = 70)Candidates (N = 53)
  1. Data are numbers or mean ± Standard Errors (SE) with percentage or range values between parentheses.

  2. Multivisceral graft = stomach, duodenum, pancreas, intestine and liver.

  3. 1HPN duration prior to transplant.

  4. 2Data were available on 46 patients; 3From time of transplant to date of DXA.

  5. *p < 0.05 comparing the two groups; **p = 0.139 comparing the two groups; ***p < 0.05 compared to zero or age-matched peers of the general population.

Age at DXA (year)44 ± 11 (25–65)46 ± 2 (26–69)
Gender ratio (female: male)46:2434:19
Body mass index (BMI, kg/m2)24 ± 0.6 (14–40)24 + 0.8 (13–40)
Home parenteral nutrition (HPN)
  Number of patients (%)66 (94)31 (58)
  Duration (month)42 ± 8132 ± 7
Underlying pathology
  Primary intestinal disease (%)19 (27)19 (36)
  Visceral vascular thrombosis (%)22 (31)24 (45)
  Other disorders (%)29 (42)10 (19)
Type of visceral graft
  Intestine32 (46%)Not Applicable
  Liver-intestine & multivisceral38 (54%) 
Total hip z-score*−1.53 ± 0.13 (−4.30 to 1.60) ***−1.04 ± 0.20 (−4.10 to 2.80) ***
Femoral neck z-score*−1.42 ± 0.13 (−4.30 to 1.10) ***−0.98 ± 0.17 (−3.60 to 1.90) ***
Spine z-score−1.21 ± 0.17 (−4.70 to 1.70) ***−0.71 ± 0.23 (−5.20 to 5.20) ***
Bone health classification**
 - Normal (%)7 (10.0)12 (22.6)
 - Low bone mass (%)32 (45.7)22 (41.5)
 - Osteoporosis (%)32 (44.3)19 (35.9)
Fragility fracture (%)14 (20)3 (6)
Total serum calcium level (mg/dL)8.9 ± 0.1 (7.1–10.7)8.9 ± 0.1 (7.3–10.8)
Total 25-OH vitamin D
 - Serum level (ng/dL)19 ± 2 (4–68)19 ± 2 (4–45)
 - Deficiency (<20 ng/dL) (%)41 (64.1)29 (61.7)
Parathyroid hormone (PTH)
 - Serum level (pg/mL)99 ± 14 (3–587)72 ± 11 (11–496)
 - Hyperparathyroidism (>65 pg/mL) (%)27 (59)226 (50)
Follow-up (month)334 ± 5Not applicable

Group III showed an equal distribution of gender with a mean age of 47 ± 2 years (range: 26–59). The underlying pathology was intestinal in 5 (21%), vascular in 13 (54%) and other benign disorders in remaining 6 (25%) patients. Pretransplant HPN duration was 24 ± 11 months (range: 2–252) with development of liver failure in 13 (54%). Body mass index (BMI) at baseline evaluation was 24 ± 1 kg/m2 (range: 13–40). With a posttransplant mean follow-up of 41 ± 3 months, eight (33%) allografts were lost due to chronic rejection (n = 3) and opportunistic infections (n = 5). Of these, two were removed 106 and 252 days prior to the second study point. The remaining six allografts were lost 170 to 600 days after completion of the study.

Management

All patients with residual native small bowel and recipients with functioning allograft were encouraged to increase their total calcium intake to over 1200 mg a day and vitamin D to 800–1000 IU daily. HPN formula, including intravenous mineral and multivitamin supplements, was also adjusted according to the biochemical and nutritional profile of the intestinal failure patients. With transplantation, enteric feeding and oral intake were initiated within first two postoperative weeks with discontinuation of intravenous nutrition in most recipients within 2–3 weeks after surgery. All recipients had diverting ileostomy for 6 to 12 months after transplantation.

With full details described elsewhere, immunosuppression was tacrolimus-based in all recipients (3). In group I recipients, cyclophosphamide or daclizumab was added as induction therapy to the immunosuppression protocol in 13 (19%) and 43 (61%) were pretreated (preconditioned) with rATG or alemtuzumab as an antilymphocyte depleting agent. None of group III patients received induction therapy and 19 (79%) were enrolled in the preconditioning protocol. Methylprednisolone boluses were used for induction and treatment of rejection with a mean (g/patient) of 6 ± 0.4 and 5 ± 0.6, respectively. With 16 (23%) of group I and 2 (8%) of group III recipients being completely off glucocorticoids at time of posttransplant BMD studies, the daily maintenance prednisone dose (mg) was 11 ± 1 and 14 ± 2, respectively. OKT3 and rATG or alemtuzumab were used to treat steroid-resistant rejection in 81% of group I and 58% of group III.

In addition to immunosuppressive drug therapy, most intestinal recipients received long-term proton pump inhibitors, ursodeoxycholic acid and other medications include antidiarrheal, antihypertensive and antimicrobial agents. Patients with hypercoagulable disorders were anticoagulated for life with low-molecular weight heparin before and early after transplantation. After recovery of the intestinal allograft absorptive functions, heparin treatment was replaced with oral warfarin. Full details of pre- and postoperative management is described elsewhere (3,6,9–11).

BMD measurement

Assessment of BMD (g/cm2) of the posterior-anterior (PA), lumbar spine (L1-L4) and hip (femoral neck and total hip) was performed by Hologic Discovery® DXA (Hologic, Inc., Bedford, MA, USA). The BMD was expressed as a standard deviation score (Z-score). All BMD assessments were performed by a certified technician at the Osteoporosis Prevention and Treatment Center, Montefiore University Hospital, Pittsburgh, PA. Precision errors of scans in patients with low bone mass were 1.2% for the total hip, 1.9% for the femoral neck and 1.5% for the PA spine (12).

Biochemical assessment

The serum levels of parathyroid hormone (PTH), vitamin D metabolites and total calcium were measured in all patients at the time DXA scan was performed. Intact PTH (1–84) was measured with a chemiluminescence assay (Bayer Centaur PTH Immunoassays, Bayer, Tarrytown, NY, USA) with a normal range of 10–65 pg/mL. The 25-hydroxy-vitamin D [25(OH) D] was measured by Radio Immune Assay (RIA Immunodiagnostic Systems, Boldon Business Park, UK). With a normal range of 25–100 ng/mL, a level <20 ng/mL was indicative of vitamin D deficiency.

Statistical analysis

SAS® version 9.2 (SAS Institute, Inc., Cary, NC, USA) was used for all statistical analysis. For the classification of osteoporosis using the World Health Organization criteria (13,14), only participants age 25 or older who had already reached peak bone mass were included (15–17).

All continuous variables were presented as mean ± standard errors and categorical data as proportion. One-sample t-test was used to compare z-scores of allograft recipients and pretransplant candidates to the fixed value of zero representing average of their age-matched peers in the reference population. Categorical and continuous variables were compared between and within cohorts using chi-square, McNemar and independent sample t-tests.

Subcohort analysis was conducted among the 24 group III patients to study the effect of transplantation in the 16 recipients with pre and posttransplant bone health evaluation and therapeutic efficacy of alendronate in the seven treated patients. Paired and independent sample t- as well as chi-square tests were used to examine and compare changes in the continuous and categorical variables, respectively.

Risk analysis was conducted in group I utilizing logistic regression models. In group II, the association between measures of bone density and potential risk factors were examined using Pearson product-moment correlation coefficient (r). No multivariate risk analysis was performed for the 24 group III patients because of small sample size. Variables of interest included age, gender, BMI, vitamin D level, type of immunosuppression, glucocorticoid therapy, rejection episodes, serum creatinine and estimated glomerular filtration rate (eGFR) and renal insufficiency.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Descriptive analysis

Transplant recipients (group I); Between times of transplant and date of DXA, with a mean follow-up of 34 ± 5 months, BMD was impaired with higher reduction at the hip and femoral neck compared to the lumbar spine. The three z-scores were significantly (p < 0.05) below that of age-matched peers (Table 1). The liver-contained allograft recipients showed lower (p = 0.4–0.6) z-scores compared to those who received intestine only (Figure 1). Serum 25-OH vitamin D was deficient in 41 (64%) patients with secondary hyperparathyroidism in 27 (59%) out of 46 patients with available PTH serum levels. With 44% incidence of osteoporosis, bone health was impaired in 90% of recipients (Table 1). Fragility fractures developed in 14 (20%) patients with avascular necrosis in three; two hip and one right medial malleolus. The fracture sites were hip (n = 4), spine (n = 4) and upper (n = 4) or lower extremities (n =2).

image

Figure 1. z-Scores of the 70 transplant recipients at hip, femoral neck and spine. The bone loss was significant (p < 0.05) at the three skeletal sites in comparison to zero or age-matched peers of the general population. The z-scores were lower among the liver-intestine and multivisceral recipients compared to those who received intestine-only allografts (p = 0.4–0.6).

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At the time of bone health evaluation, serum creatinine ranged from 0.6 to 4.2 mg/dL with a mean of 1.4 ± 0.07. The eGFR was 14 to 124 mL/min with a mean of 60 ± 3. None of the patients required dialysis at the time of BMD studies.

Candidates (group II); As shown in Table 1, BMD was reduced at hip, femoral neck and spine with z-scores significantly (p < 0.05) lower than age-matched peers in the reference database. Similar to group I, the reduction was higher at hip and femoral neck compared to lumbar spine. With 62% of patients deficient in 25-OH vitamin D serum levels, secondary hyperparathyroidism developed in 26 (50%) (Table 1). Prevalence of osteoporosis was 36% with 77% overall incidence of impaired bone health. Fragility fractures were documented in 3 (6%) patients (2 hip and 1 spine) with no single example of avascular necrosis.

Compared to group I, candidates had a lower serum creatinine at time of evaluation with a mean of 1.1 ± 0.1 mg/dL (range: 0.5–3). The eGRF was also better with a mean of 81 ± 5 mL/min (range: 19–154). Two patients were hemodialysis dependent due to end-stage renal failure.

Longitudinal study patients (group III); Changes in the individual BMD (g/cm2) values for the 16 patients with pre- and posttransplant evaluation are illustrated in Figure 2. As shown in panel A, total hip BMD was reduced in most patients (n = 13, 81%) with similar trends at the femoral neck (panel B). However, the lumbar spine experienced less BMD reduction with more examples of stabilization or improvement (panel C). With a total mean time of 17 ± 2 months (3.3 ± 0.7 before transplant and 14 ± 2 after transplant), the overall decline in BMD was 13.4% for femoral neck, 12.7% for hip and 2.1% for lumbar spine.

image

Figure 2. The individual changes in the absolute bone mineral density (BMD) among the 16 recipients who were evaluated before and after transplantation. The reduction in the BMD was more observed at the hip (A) and femoral neck (B) compared to the lumbar spine (C).

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With similar vitamin D and PTH levels, z-scores at hip and femoral neck were significantly reduced after transplantation with values lower than that of age-matched peers (Table 2). There was no significant difference in lumbar spine z-score. Risk of osteoporosis was increased (p = 0.025) after transplantation with a new onset in five of the six osteoporotic recipients. None of the 16 recipients developed new fractures or avascular necrosis with a single example before transplantation.

Table 2.  Bone mineral density, and biomarkers of the 16 intestinal recipients who were studied before and after transplantation
 Before transplantAfter transplant
  1. Data are mean ± Standard Error (SE) with range values between parentheses.

  2. *p < 0.05 comparing baseline to follow-up data; **p < 0.05 for comparison with reference population.

  3. 1Missing data in three patients.

  4. 2From date of DXA to transplant.

  5. 3From date of transplant to DXA.

Total hip z-score*−0.30 ± 0.23 (−1.60 to 2.20)−1.38 ± 0.32 (−3.80 to 2.40) **
Femoral neck z-score*−0.21 ± 0.23 (−1.10 to 2.80)−1.28 ± 0.34 (−3.20 to 4.40)**
Spine z-score−0.16 ± 0.37 (−2.90 to 3.60)−0.52 ± 0.50 (−3.20 to 4.40)  
Bone health classification
 - Normal6 (38%)1 (6%)
 - Low bone mass9 (56%)9 (56%)
 - Osteoporosis1 (6%)6 (38%)
Total serum calcium level (mg/dL)9 ± 0.3 (7–10)9 ± 0.2 (8–10)
Total 25-OH vitamin D1
 - Serum level (ng/dL)16 ± 2 (7–22)15 ± 1 (10–40)
 - Deficiency (<20 ng/dL)10 (77%)11 (85%)
Parathyroid hormone (PTH)1
 - Serum level (pg/mL)74 ± 12 (18–153)61 ± 9 (31–139)
 - Hyperparathyroidism (>65 pg/mL)5 (36%)3 (23%)
Osteoporotic fracture (%)1 (4)0 (0)
Avascular necrosis (%)1 (4)0 (0)
Follow-up (month)3.3 ± 0.7214.0 ± 2.03

The pretransplant serum creatinine was 1.1 ± 0.1 mg/dL (range: 0.6–2.6) with eGFR of 83 ± 11 mL/min (range: 25–168). The posttransplant serum creatinine was higher (1.5 ± 0.2 mg/dL) with lower (72 ± 12 mL/min) eGFR. The difference was not statistically significant with p values of 0.097 and 0.2698, respectively.

Alendronate treatment. As expected, the seven patients who received alendronate treatment had initial z-scores significantly (p < 0.05) lower than the 17 patients who were only treated with calcium-vitamin D supplemental therapy (Table 3). All of the alendronate-treated patients were female and 71% of the supplemented group were male with no significant differences in baseline calcium, PTH and vitamin D levels (Table 3).

Table 3.  Baseline clinical features, bone mineral density and biomarkers of the 24 longitudinally studied recipients substratified according to the treatment regimen
 Bisphosphonate treatment
Yes (n = 7)No (n = 17)
  1. Data are numbers or mean ± Standard Error (SE) with percentage or range values between parentheses.

  2. *p < 0.05 comparing recipients who were treated with alendronate versus those who received calcium-vitamin D supplementation; **p < 0.05 for comparison with reference population.

  3. 1Missing data in two patients.

  4. 2Between baseline and last assessment.

Age (year)45 ± 3 (27–53)47 ± 3 (26–59)
Gender ratio (female:male)*7:05:12
Body mass index (BMI, kg/m2)21 ± 2 (16–26)26 ± 2 (13–40)
Total serum calcium level (mg/dL)9.1 ± 0.3 (8.1–10.5)8.9 ± 0.2 (7.5–9.8)
Total 25-OH vitamin D1
 - Serum level (ng/dL)14 ± 2 (6.0–22)15 ± 2 (4–26)
 - Deficiency (<20 ng/dL)6 (86%)12 (80%)
Parathyroid hormone (PTH)1
 - Serum level (pg/mL)72 ± 27 (8–228)69 ± 10 (18–166)
 - Hyperparathyroidism (<65 pg/mL)2 (29%)6 (40%)
Total hip Z-score*−1.56 ± 0.35 (−0.50 to 1.30) **−0.34 ± 0.23 (−1.90 to 2.20)
Femoral neck Z-score*−1.40 ± 0.28 (−2.40 to -0.40) **−0.32 ± 0.27 (−3.00 to 2.80)
Spine Z-score*−1.53 ± 0.44 (−3.00 to -0.20) **−0.25 ± 0.41 (−3.90 to 3.60)
Follow-up (day)2515 ± 63 (369–762)  531 ± 53 (121–975) 

With calcium and vitamin D supplementation alone, there was a significant (p < 0.05) decline in the baseline BMD at both femoral neck (17.3 ± 3.5%) and total hip (16.5 ± 3.4%). With similar mean time intervals between baseline and last DXA, the reduction at both sites was significantly (p < 0.05) less with alendronate treatment as shown in Figure 3. The amount by which alendronate prevented bone loss was 0.028 ± 0.032 g/cm2 and 0.028 ± 0.029 g/cm2, respectively. There were no significant changes in BMD at lumbar spine in the two subcohorts (Figure 3).

image

Figure 3. Changes in bone mineral density (BMD) following visceral transplantation among patients who were treated with alendronate (open bars) and those who received calcium and vitamin D supplementation only (solid bars).*p < 0.01 difference from baseline; p < 0.05 no treatment versus alendronate.

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Group comparison

With similar age, gender and BMI, the mean duration of pretransplant HPN was longer in group I compared to group II. Pretransplant liver failure that required simultaneous hepatic replacement occurred in 54% of group II with a lower (28%) incidence among the candidate patients (Table 1). The leading causes of intestinal failure were similar between the 2 groups (Table 1).

With no significant (p > 0.05) difference in the levels of calcium, vitamin D and PTH, the z-scores of both the transplant recipients and candidate patients were significantly lower than that of age-matched peers of the general population (Table 1). However, the transplant recipients experienced a higher (44%) incidence of osteoporosis compared to the candidate patients (36%) with no significant (p = 0.1386) difference in the overall bone health classification. The hip z-score was also lower (p < 0.05) in the recipients compared to the candidates with a similar trend at femoral neck (Table 1). Nonetheless, the transplant recipients experienced a higher (p = 0.0225) incidence of fragility fractures at hip, spine and femoral neck.

Risk analysis

Age, BMI, type of immunosuppression and number of rejection episodes were significant osteoporotic risk factors among long-term visceral allograft survivors (group I) with p values of 0.0412, 0.0187, 0.0156 and 0.0219, respectively. Each year of age increased the risk by 5% and each unit of BMI decreased the risk by 13%. Recipient pretreatment with rATG or alemtuzumab reduced the risk by 87% and each rejection episode increased the risk by 43%. Gender, vitamin D level, severity of rejection, maintenance glucocorticoids, creatinine and eGFR were not significant risk factors with p values of 0.851, 0.418, 0.384, 0.597, 0.159 and 0.392, respectively.

In group II, duration of HPN was a significant risk factor. Figure 4 illustrates a negative correlation between the z-scores measured at the three skeletal sites and duration of HPN with p-values of 0.003 (hip), 0.002 (femoral neck) and 0.04 (spine). BMI showed significant (p < 0.05) but weak (r = 0.2–0.5) correlation with the three different z-scores. There was no association between vitamin D levels and z-scores.

image

Figure 4. The correlation between the duration of home parenteral nutrition (HPN) and z-scores at the hip (A), femoral neck (B) and lumbar spine (C). Note the significant negative linear regression in the three panels particularly in panels A and B.

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

With increased number of long-term survivors, quality of life has become one of the primary therapeutic end points after intestinal transplantation (2,3,18). In contrast to solid organs, visceral recipients are at a relatively high risk of impaired bone health due to the primary disease gravity and the challenges inherited with the multidimensional aspects of the procedure (19–24). In principle, chronic impairment of gut homeostasis, compounded with long-term HPN therapy, chronic malnutrition and development of hepatic insufficiency is detrimental to bone metabolism prior to transplant. Further deterioration in bone health is also expected after transplantation because of technical complexity of the procedure and high immunogenicity of the visceral allograft (19).

This multicohort descriptive analysis unveiled a 36% incidence of osteoporosis among potential candidates for visceral transplantation similar to what has been reported among cell and solid organ recipients (20–25). Gut failure disrupts calcium homeostasis and electrolyte imbalance along with lower BMI as documented in this study. Of the pathogenic mechanisms are low levels of adipokine leptin with altered osteoblastic activity and disruption of the biomechanical osteogenic milieu with imposed limited physical activities (26). Similar to other published studies, the reported herein deleterious effect of HPN is related to a common constant state of bone demineralization with biochemical impairment of bone metabolism (5,27–29). These preexisting nutritional deficiencies may continue to impair bone health early after transplantation as a paradoxical ‘catch-up’ phenomenon. With development of liver cirrhosis, other factors may come to play such as hypogonadism, mineral overload, hyperbilirubinemia and low levels of insulin-like growth factor I with increased serum oncofetal fibronectin (30–35). The coexistence of a hypercoagulable state due to a myeloproliferative disorder with JAK2 mutation may also contribute to the pathogenesis of impaired bone health as demonstrated here among our long-term visceral allograft survivors with simultaneous hepatic replacement (8,30,36).

Similar to other abdominal and thoracic organs, visceral transplantation increased the risk of osteoporosis (20,37–39). Age, BMI, type of immunosuppression and number of rejection episodes were identified as significant risk factors. Without recipient pretreatment, intense alloimmune response is expected with T-cell activation and massive cytokine release that undoubtedly dysregulates the recipient immune system with disruption of the autoregulatory feedback mechanisms of bone turnover. Of particular interest, is the overexpression of both Tumor Necrosis Factor alpha and the Receptor Activator of the Nuclear Factor-Kappa B (RANK)/RANK-Ligand–osteoprotegerin axis that lead to pathogenic augmentation of the osteoclastogenic differentiation process and subsequent bone resorption (40,41). In addition to being a surrogate marker for glucocorticoid therapy, repeated rejection episodes is anticipated to induce a state of chronic allograft dysfunction with impaired gut absorption.

In contrast to nonvisceral allotransplantation, specific risk factors are inherited with visceral engraftment including the dynamic interaction between the allograft absorptive functions and the bionutritional aspect of bone homeostasis. Of relative importance, is the technical inability to restore continuity of the lymphatic and autonomic nervous system with development of fat malabsorption and gut dysmotility (1,3,19,42,43). In addition, most visceral recipients require life-long anticoagulation therapy and higher levels of maintenance immunosuppression in the milieu of multifactorial chronic renal impairment (3).

One of the interesting findings in this study is the preferential bone loss at the cortical rather than the trabecular site similar to what has been previously published after bone marrow transplantation (44,45). This may reflect a long-standing state of malnutrition with impaired collagen metabolism and chronic immobilization. Equally important, is high serum concentration of fluoride due to high beverage intake commonly seen in short gut syndrome patients and recipients with diversion ileostomy or graft dysfunction.

In addition to standard of care measures including vitamin D-calcium supplements and hormonal replacement, alendronate was used during the study period to treat long-term allograft survivors with impaired bone health. Similar to other organ recipients, oral bisphosphonate treatment improved but failed to effectively prevent bone loss which could be partially attributed to low (less than 1%) drug bioavailability compounded by suboptimal allograft absorptive functions (46–49). Before transplantation, oral therapy is also of very limited therapeutic benefits since most candidates suffer intestinal failure.

With the clinical recognition of significant metabolic bone disease development, all of our patients have been recently subjected to a thorough preoperative evaluation and yearly posttransplant assessment with prompt restorative intervention including preventative measures, preemptive therapy and active treatment. The protocol entails the conventional supplemental measures including optimization of HPN before transplantation and parenteral therapy with yearly bisphosphonate (zoledronic acid) or daily human PTH 1–34 (hPTH1–34) therapy particularly in patients with impaired skeletal integrity and associated bone disease. More frequent follow-up measures with augmentation of antiresorptive drug therapy have also been recently adopted for recipients with recurrent rejection episodes and heavy glucocorticoid treatment. With encouraging results among bone marrow and solid organ transplant recipients, prospective randomized control study is required to examine the therapeutic benefits of prophylactic intravenous bisphosphonate among visceral recipients (50–52). Equally important, is defining the appropriate algorithmic management and long-term efficacy of both the antiresorptive and anabolic agents that are currently available to restore bone health in this unique population.

In addition to the retrospective nature of this study, the report has several limitations that could potentially induce statistical bias: first, a nonstandardized protocol was used to manage nearly half of the study population, particularly long-term visceral allograft survivors, reflecting our learning experience with the historic evolution of the field; second, the heterogenous distribution of the study time points across the three main descriptive cohorts because of the multifaceted complexity of this orphan population; third, the relatively large number of recipients who did not have the opportunity to receive posttransplant DXA studies at our center because of their diversified global geographic distribution and the constraints imposed by most insurance carriers; fourth, the lack of healthy controls with the need to utilize the manufacturer database as a reference population; finally, the heterogenous distribution of age as well as sex among the study patients.

In summary, recipients of visceral allotransplantation are at risk of impaired bone health before and after transplantation. With the unfolded herein risk factors and allied mechanistic pathways, efforts should be aimed at early transplantation, minimization of immunosuppression and utilization of newly developed agents such as the antiosteoclastic human monoclonal antibody ‘Denosumab’ (3,19,53). With continuation of these translational efforts, further improvement in the therapeutic efficacy of visceral transplantation including quality of life is readily achievable.

Acknowledgment

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

The authors would like to thank the staff at the Intestinal Rehabilitation and Transplantation Center for their dedication and great efforts in taking care of these complex patients.

Disclosures: The manuscript was not prepared or funded in any part by a commerical organization, including educational grants. The co-author, Dr. Susan Greenspan, is a consultant for Merck, Amgen and Sanofi-Aventis and a researcher for Lilly and Sanofi-Aventis. The primary, senior, and remaining co-authors have no disclosures.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References