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Densitometric Threshold and Vertebral Fractures in Heart Transplant Patients

Dalle Carbonare, Luca1,6; Zanatta, Mirko1; Braga, Vania2; Sella, Stefania3; Vilei, Maria Teresa3; Feltrin, Giuseppe4; Gambino, Antonio4; Pepe, Ilenia5; Rossini, Maurizio2; Adami, Silvano2; Giannini, Sandro3

doi: 10.1097/TP.0b013e31821cdeef
Clinical and Translational Research
Free

Background. Bone disease is one of the major complications of solid organ transplantation, causes considerable morbidity, and most patients are treated with immunosuppressant drugs after graft. The majority of studies reported rapid bone loss and an increased incidence of fractures after transplantation. The aim of our study was to evaluate osteoporosis and fracture prevalence, bone metabolism, and the effect of immunosuppressant agents on bone after heart transplantation.

Methods. We planned a cross-sectional study in 180 heart transplant patients recruited from 3 different centers with a less than 10 years from graft. Each patient underwent a densitometric scan, and in 157 of them, an x-ray of the spine was performed to evaluate fractures. Biochemical assessment of bone metabolism was made at the time of the visit. Physical activity, diet, and calcium intake were evaluated using a specific questionnaire.

Results. Vertebral fractures were diagnosed in 40% of subjects, but densitometric osteoporosis was observed only in 13% of spine and in 25% of hip scans. Interestingly, increasing T-score threshold up to −1.5 standard deviation, the prevalence of fractured patient improved significantly, reaching 60% in both genders. Bone content was inversely correlated with glucocorticoids, while a positive correlation was found with cyclosporine A. Almost all subjects had vitamin D deficiency.

Conclusions. Standard densitometric criteria are unreliable to identify bone fragility after transplantation, and a different threshold (−1.5 standard deviation) should be considered. Transplanted patients should be adequately supplemented with vitamin D, and the effects of immunosuppressant agents on bone need further investigation.

1Department of Medicine, Clinic of Internal Medicine, Section D, University of Verona, Verona, Italy.

2Department of Medicine, Section of Rheumatology, University of Verona, Verona, Italy.

3Department of Medical and Surgical Sciences, 1st Clinic of Internal Medicine, University of Padova, Padova, Italy.

4Department of Cardiac Thoracic and Vascular Sciences, Section of Cardiovascular Surgery, University of Padova, Padova, Italy.

5Department of Clinical Medicine and Emerging Diseases, University of Palermo, Palermo, Italy.

The authors declare no conflict of interest.

6Address correspondence to: Luca Dalle Carbonare, M.D., Ph.D., Department of Medicine, Clinic of Internal Medicine, Section D, University of Verona, Piazzale Scuro 37134 Verona, Italy.

E-mail: luca.dallecarbonare@univr.it

L.D.C. participated in research design, writing of the manuscript, and data analysis; M.Z. participated in writing of the manuscript and data analysis; V.B., S.S., A.G., and G.F. participated in performance of the research; M.T.V. contributed analytic tools; M.R. and S.A. participated in research design; and S.G. participated in performance of the research and research design.

Received 17 January 2011. Revision requested 25 February 2011.

Accepted 28 March 2011.

Solid organ transplantation is considered an established therapy for end-stage organ failure, and the number of transplantations increased during past decades. Advances in medical care determined an important improvement in survival, but new challenges have been arisen.

Bone disease causes considerable morbidity both in pretransplantation and posttransplantation period (1, 2). The pathogenesis is multiple (3), and most patients are treated with immunosuppressant drugs (glucocorticoids [GCS] and cyclosporine A [CYA]) after solid organ transplantation. GCS determine osteoblast and osteocyte apoptosis (4), reduce bone formation and increase bone resorption (5, 6), and reduce intestinal calcium absorption and increase hypercalciuria (7). They block gonadotropin and adrenocorticotropic hormone release with low gonadal and adrenal secretion of estrogen and androgen (7).

The role of CYA is controversial (8); it determines a high turnover osteoporosis in rat model (6), reduces testosterone (9, 10), and affects bone through its immunosuppressant effect (11).

The majority of the studies agree that bone loss is rapid after transplantation (2) with a decrease that ranges from 3% to 9% at the spine and 6% to 11% at femoral neck during the first year (1, 12). An increased incidence of fragility fractures that ranges between 14% and 36% has been reported (5, 13).

Our work focused its analysis on heart transplantation. Longitudinal studies show that bone mineral density (BMD) may be reduced by 10% to 20% before the graft (14), whereas bone loss during the first year after surgery achieved 10%, that is considerable when compared with the 1.41% decrease at the spine and 0.35% at the femoral neck in healthy population (1). The prevalence of fragility fractures is estimated between 18% and 50% (15, 16), with the highest incidence (36%) during the first year after the graft (17, 18).

Nevertheless, the real prevalence of transplantation- induced osteoporosis (TIOP) and of fragility fractures is still unclear. Many studies found that the relationship between BMD and fractures is weak because most patients experience a fracture at a relative normal BMD, and in some cases, a low incidence of fractures was observed although bone loss was manifested (17–19). A stronger association between fractures and hip densitometry has been suggested (20), and other relationships have been evaluated, such as with immunosuppressant medications and bone turnover.

Because the pathogenesis of TIOP is multiple, physician approach should be different with respect to “common” postmenopausal osteoporosis (PO), as the experience in GCS-induced osteoporosis (GIOP) has taught (21).

On the basis of these considerations, we studied a population of heart transplanted patients trying to find out new criteria for the stratification of fracture risk. Interestingly, we were able to improve the diagnostic power of our analysis modifying T-score threshold, according to what had been previously proposed in GIOP (21).

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RESULTS

Study Population Parameters

Table 1 describes the anthropometric parameters of the study population. We enrolled 180 patients, aged 53±13.4 years, 156 men (age 53.1±13.8 years) and 24 women (age 54.2±11.0 years). Fifty-nine percent of the population smoked in the past, 11% were still smoking, and 30% never smoked. Among women, 75% were postmenopausal, whereas 25% were premenopausal, and none was taking estrogens therapy at the time of study evaluation.

TABLE 1

TABLE 1

As we can appreciate in Table 1, mean body mass index (BMI) was 25.90±4.81 kg/m2, in particular 60% of men and 30% of women were overweight, whereas 10% of men and 4% of women were underweight. The heart disease leading to transplantation was ischemic in the 30% of cases, dilated cardiomyopathy in 40%, and idiopathic in 25% of patients. Mean duration of heart disease was 6.16 years (0.07–43.05 years), and the time from transplant to visit was 3.91 years (0.07–10.05 years).

Chronic rejection was caused mainly by cardiac allograft vasculopathy, and the incidence was 11.5% after the first year, approximately 30% at 5 years and 55% at 10 years (22). Barthel index at the time of transplant showed that 12% of patients were totally dependent on nurse assistance, 3% needed a high-level nurse assistance, 30% a low level, and 55% were self sufficient. At the time of study evaluation, only one patient needed low-degree nurse assistance. We did not find differences in terms of heart disease, duration of disease, Barthel index, and smoking habit between fractured patients (FX) and unfractured patients (UN-FX) and between patients with osteoporosis and those without.

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Densitometric and Fracture Analysis

Each patient underwent densitometry of the lumbar spine and of the hip. Spine BMD was available in 171 of 180 patients, whereas femoral neck BMD was available in 177 patients (Table 1). Prevalence of osteoporosis and osteopenia is represented in Table 2. Morphometric analysis of the spine was available in 157 subjects. Vertebral fractures were diagnosed in 63 subjects (40.12%; 43.0% of men and 22.7% of women), and the distribution is represented in Figure 1.

TABLE 2

TABLE 2

FIGURE 1.

FIGURE 1.

A small number of osteoporotic nonvertebral fractures was registered (two of the hip, seven of the forearm, and one of the homer). They all occurred in men showing an incidence of 6.4%, and in the 20% of cases, a concomitant vertebral fracture was diagnosed. A significantly higher number of vertebral fractures was present in patients with femoral neck osteoporosis (P=0.01), whereas no difference was found using lumbar spine BMD. The difference remained significant only for men (P=0.02), mainly because of the small number of women and for the few fractures diagnosed in them. We observed a significant correlation between femoral neck T-score and the number vertebral fractures (P=0.03), whereas the significance was not achieved using spine T-score. Furthermore, the prevalence of osteoporotic patients with vertebral fractures was low, 20.63% in patients with spine osteoporosis and 22.22% in those with femoral osteoporosis.

Because FX were significantly older than UN-FX, we performed a logistic regression analysis. Our model included age, BMI, lumbar spine and femoral neck BMD, bone turnover, and daily and cumulative dosage of immunosuppressant treatments. Femoral neck BMD remained significantly lower in FX with respect to UN-FX (P=0.02 for T-score and 0.04 for BMD).

In consideration of the low number of vertebral fractures identified using −2.5 standard deviation (SD) T-score, we tried to test a different T-score threshold. We used femoral neck BMD because it showed a more significant relationship with fractures. We selected a T-score of −1.5 SD, because it was the mean of femoral neck T-score in our population and because it represents the threshold proposed for GIOP (21).

Fifty-three percent of subjects had a T-score lower than −1.5 (OP1; 44.06% of men and 66.6% of women). OP1 had a higher number of vertebral fractures with respect to those with a T-score more than −1.5 SD (OP0), and the significance was achieved in men (P=0.05) but not in women, according to what we have observed with −2.5 SD threshold. More interestingly, the prevalence of fractures greatly increased: it reached 60% in both genders.

In a subanalysis performed selecting patients with less than 5 years from transplantation, prevalence of fractures was even higher in OP1 than in OP0 (P=0.03, P=0.02 in men). Positive and negative predictive values for fracture risk were 0.5 and 0.63 for −1.5 SD, T-score threshold, 0.6 and 0.63 for −2.5 T-score, respectively.

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Biochemistry

Table 3 shows the most relevant biochemical parameters measured. Almost all subjects recruited had a vitamin D (VitD) deficiency (92%; 92.3% of men and 83.3% of women); a mild deficiency was diagnosed in 55.5% of patients (58.3% of men and 37.5% of women) and a severe one in 35.5% of cases (32.9% of men and 45.8% of women).

TABLE 3

TABLE 3

Parathyroid hormone (PTH) level was increased in 6.1% of cases (5.1% of men and 12.5% of women); it was negatively correlated with VitD levels (r=−0.22, P=0.01), whereas it was not significantly different in patients with fractures or lower BMD. Only 12.2% of patients showed an increased bone turnover (11.5% of men and 16.6% of women). An increased bone resorption was observed in 30.5% of patients (29.4% of men and 37.5% of women), whereas bone formation was increased in 21.6% of cases (21.8% of men and 20.8% of women).

Bone turnover was not different between FX and UN-FX, whereas an inverse significant correlation was observed with spine densitometry (P=0.004 for S-C-terminal collagen peptide [CTX], r=−0.22; P=0.01 for bone-specific alkaline phosphatase [B-ALP], r=−0.18). Finally, we did not find any significant difference in sexual hormones values, mainly for their important age variability that impair a reliable analysis in our study population.

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Pharmacologic Treatment

We did not find any difference in concomitant pharmacologic treatments. None received any medication that was able to interfere with bone metabolism and were supplemented with calcium/VitD. Dietary daily calcium intake was 887.5±506.2 mg. All patients received a combined immunosuppressant therapy with GCS, CYA, and azathioprine. Mean daily intake of GCS was 15.3±25.3 mg (3.28–265.5 mg daily), and in the 40% of patients, cumulative dosage exceed 10 g. Mean daily intake of CYA was 280.7±264.5 mg/day, whereas cumulative intake was 381.66 ±302.26 g. Cumulative dosage of azathioprine was 37.68±51.32 g.

We did not find any significant difference in immunosuppressant dosages neither between patients with T-score less than −2.5 SD and normal population nor between FX and UN-FX. Instead, OP1 patients received a significantly higher daily dosage of GCS than OP0 patients (P=0.02). A significant inverse correlation was also observed between mean daily GCS and BMD both at lumbar spine and at femoral neck (P=0.001, r=−0.24, both for lumbar spine and femoral neck T-score; Fig. 2A).

FIGURE 2.

FIGURE 2.

On the contrary, our results showed a direct and significant correlation between mean daily CYA and femoral neck BMD (P=0.001, r=0.26 for neck BMD and P=0.002, r=0.25 for neck T-score; Fig. 2B). Analyzing the population with a time from transplantation less than 5 years, daily GCS persisted significantly higher in FX (P<0.001) and CYA remained significantly higher in UN-FX (P=0.03).

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DISCUSSION

Our study presents one of the largest population of heart transplanted patients, in which we focused our attention on bone fragility. The incidence of TIOP is still unclear (17–19), and the real prevalence of fractures varies from 18% to 50% (15–18). We reported a prevalence of 40% that is in agreement to that observed in the majority of studies.

Although transplanted recipients are at high risk of fractures, in our work, a minority of them were osteoporotic, and just 20% of FX had a T-score less than −2.5 SD. BMD is an important determinant of bone fragility, but it is inadequate to identify all subjects at risk. Specific algorithms have been developed to improve diagnostic criteria in PO (17), and an higher densitometric threshold was proposed for the diagnosis of GIOP (−1.5 SD) (21).

In our study population, we were not able to discriminate among FX and UN-FX, and according with the experience in GIOP (21), we modified T-score threshold to −1.5 SD. As expected, the percentage of patients with fractures increased (up to 60%), but the numbers of vertebral fractures remained significantly higher in those with a T score less than −1.5 SD.

Positive and negative predictive values of the new threshold were similar to those obtained with a T-score of −2.5 SD, but the number of fractures that they referred to is significantly higher, confirming the consistency of our hypothesis. The relationship between fractures and BMD was stronger using femoral densitometry, as observed by others (3, 20). Radiologic artifacts (osteoarthritis, aortic calcifications, vertebral fractures, and scoliosis) could impair BMD assessment of the spine. A metabolic explanation is also possible: secondary and tertiary hyperparathyroidism is a frequent complication of end-stage organ disease, and PTH is known to affect rapidly both trabecular and cortical bone. As a consequence, femoral neck better represents the whole bone mineral content (5).

In our population, we observed a severe deficiency of VitD, suggesting that osteomalacia could play an important role in TIOP. Even if we might expect such an important deficiency in kidney and liver organ diseases, it is important to stress that this is a more diffuse problem (23, 24). Many activities of VitD have been revealed on immunologic system, glucose metabolism, cardiovascular risk, and neoplastic transformation (28), and because they are strictly related with transplantation, it is necessary to guarantee an adequate supplementation to exploit both skeletal and extraskeletal effects. As a matter of fact, according to the high incidence of VitD deficiency and the absence of important contraindications associated with the use of VitD precursors (cholecalciferol and ergocalciferol), we suggest to prescribe VitD supplementation even if the laboratory dosage is not available: at least 800 to 1000 U daily (28, 29).

We observed an increase of bone turnover and an inverse correlation between S-CTX and BMD. Bone remodeling markers can be used to evaluate bone disease activity and to check for treatment efficacy in transplanted recipients (30, 31), because they are effectively inhibited by antiresorptive agents that have been tested successfully in TIOP (30, 33, 34).

Finally, we described a significant inverse correlation between mean daily dosage of GCS and BMD. This observation confirms the importance of densitometry in TIOP but supports the need to change diagnostic criteria, because a minority of patients would be treated if a T-score less than −2.5 SD was chosen as a decision threshold.

Furthermore, we observed a positive correlation between CYA bone formation markers and BMD. Many works supposed that CYA first stimulates both osteoblasts and osteoclasts, counteracting the negative effect of GCS (8). On the contrary, long time treatment seems deleterious inducing a high bone turnover osteoporosis (8). This finding suggests a different action of CYA with respect to other immunosuppressant (35).

The limitation of our study is the retrospective analysis of the data and then lack of longitudinal monitoring of BMD. However, we think that it is clinically relevant, because the number of transplanted patients will increase continuously together with bone complications, and our results might help to change current medical approach for the diagnosis and treatment of TIOP.

In conclusion, TIOP is a complex model; standard densitometric criteria are unreliable to identify patients at risk of fracture, and a different densitometric threshold (T-score ≤−1.5 SD) should be considered. From a metabolic point of view, VitD deficiency is widespread, and all transplanted patients should be adequately supplemented. Finally, the effect of immunosuppressant agents on bone must be further evaluated because CYA increases bone formation markers and might counteract, at least in part, the negative effects of GCS.

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MATERIALS AND METHODS

Study Population and Questionnaire

We planned a multicenter cross-sectional study. We enrolled 180 patients, aged 53.0±13.4 years (Table 1), in 3 centers of the Northern part of Italy: 40 patients in Padova, 20 in Verona, and 120 in Montescano. All patients were selected from heart transplanted patients who visited the Day Hospital service of each center.

Inclusion criteria were heart transplantation from less than 10 years. Exclusion criteria were an age less than 15 years, multiorgan transplantation, retransplantation, more than 10 years heart transplantation from, and severe worsening of renal function with respect to the time of transplantation (defined as serum creatinine >2.5 mg/dL, dialysis, or kidney transplantation). Clinical history was collected from clinical files available in each Day Hospital service and from each recipient using a printed module.

Questions analyzed anthropometric parameters and lifestyle factors, baseline heart disease and other comorbidities, history of fractures, pharmacologic treatments during at least the 6 months before and after the graft, and pain intensity and its relationship with daily activity. Dietary calcium intake was studied through a specific questionnaire. Performance status was determined according to Barthel index at the time of transplant and at the study evaluation. Written informed consent was obtained from each patient.

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Bone Densitometry and Fracture Evaluation

Each patient underwent densitometry of the lumbar spine and of the hip. Three different devices were available: two Hologic QDR 4500 (Hologic, Waltham, MA) and one Norland XR-26 (Norland, Madison, WI). All scans collected with Norland XR-26 were expressed in Hologic data using a cross calibration analysis. All densitometric scores were then analyzed using Hologic standard curve. World Health Organization criteria for the diagnosis of PO were used (36).

To establish the presence of vertebral fractures, anteroposterior and latero-lateral x-ray of dorsal and lumbar spine were taken. A qualitative analysis was made by a specialized radiology, and subsequently, a semiquantitative evaluation, according to Genant score, was conducted from T4 to L4 (38). Lumbar vertebral fractures were excluded from densitometric analysis. Almost all patients had made an x-ray of the column before the transplantation even if in the majority of them only the dorsal tract was available (lateral projection of a chest x-ray). Nonvertebral fractures were recorded from clinical history, and traumatic fractures were excluded from the statistical analysis.

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Biochemical Analyses

Laboratory analysis was made once at the time of study evaluation. Nevertheless, all patients underwent periodic laboratory assessments since the time of transplantation. Serum for biochemical analysis was obtained in the morning under fasting conditions. Some parameters regarding bone metabolism were tested independently in each center (calcium, phosphorus, ALP, creatinine, and albumin).

Centralized evaluation of PTH, S-CTX, B-ALP, osteocalcin, VitD, luteinizing hormone, follicle-stimulating hormone, testosterone, sex hormone binding globulin, 17-β-estradiol, dehydroepiandrosterone sulfate, oestrone, and androstenedion were performed in Pisa. B-ALP and S-CTX were also expressed after adjustment for age (ZB-ALP and ZCTX; Table 3).

We defined a VitD deficiency as a serum level less than 30 ng/mL, a mild deficiency between 10 and 30 ng/mL, and a severe deficiency when the value was less than 10 ng/mL. An increased bone turnover was classified by increase of both B-ALP and S-CTX, whereas an increment of bone resorption or formation was represented by a single increase of S-CTX or B-ALP, respectively.

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Statistical Analysis

All data are expressed as mean±SD. Differences between groups were tested for significance using Student's t test, whereas the analysis of frequency was performed using chi-square test. Logistic regression was made to verify the role of the main determinants of fracture: age, gender, BMI, lumbar BMD, femoral neck BMD, bone turnover, and daily and cumulative dosage of immunosuppressant treatments.

For the correlation analysis, Spearmen coefficients were calculated when appropriate, and linear regression was represented. Statistical significance was considered for a P less than 0.05. Statistical analyses were performed using SPSS for windows, version 16.0 (SPSS Inc, Chicago, IL).

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Keywords:

Densitometry; Vertebral fracture; Heart transplantation; Immunosuppressant treatment; Vitamin D

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