Osteoporosis and risk of fracture in heart transplant patients

Introduction Significant bone loss occurs after heart transplantation, predominantly in the first year, with increased risk of incident fractures. The goal of this study was to evaluate the prevalence of fragility fractures in a population of heart transplantation patients and to identify the independent risk factors for fractures. Methods This was a prospective monocentric study that included patients with heart transplantation occurring < 10 years who were undergoing heart transplantation monitoring. All patients underwent bone mineral density evaluation by dual-energy X-ray absorptiometry and radiographies to establish the presence of vertebral fractures. Results We included 79 patients (61 men); the mean age was 56.8 ± 10.8 years. The mean time between transplantation and inclusion was 32.3 ± 35.0 months. Incident fractures were diagnosed in 21 (27%) patients after heart transplantation. Vertebral fractures were the most frequent (30 vertebral fractures for 15 patients). Osteoporosis was confirmed in 22 (28%) patients. Mean bone mineral density at the femoral neck and total hip was lower with than without fracture (femoral neck: 0.777 ± 0.125 vs 0.892 ± 0.174 g/cm2, p<0.01; total hip: 0.892 ± 0.165 vs 0.748 ± 0.07 g/cm2, p<0.001), with a significant result on multivariate analysis. The mean time from transplantation to the first fracture was 8.0 ± 7.6 months. Discussion Our study confirmed a high vertebral fracture risk in heart transplant patients, especially during the first year after transplantation.


Introduction
Heart transplantation is an established therapy for end-stage heart failure, and the number of transplantations has increased during the past decades (1).Medical advances have improved the survival of these patients, but new challenges arise, such as osteoporosis and increased risk of fragility fractures.
Bone disease causes morbidity and mortality pre-and post-heart transplantation.The prevalence of osteoporosis at the time of heart transplantation ranges from 7% to 23% (2)(3)(4), with significant bone loss after transplantation (3)(4)(5).The significant bone loss after heart transplantation is predominant in the first year, with a prevalence ranging from 3% to 10% at the spine and 6% to 11% at the femoral neck (3)(4)(5) and 20% increased risk of fracture in the first year (3,6).
Several factors could be linked to osteoporosis in patients with heart transplantation: prolonged immobilization, impaired renal function, lack of exposure to sunlight (vitamin D deficiency), the etiology of the heart disease (excessive alcohol consumption), cardiac insufficiency-related treatments, and immunosuppressive drugs, notably glucocorticoids.However, the prevalence of fragility fractures in patients with heart transplantation and the independent risk factors associated with incident fractures remain unclear (6-8).
Mortality is increased after a fragility fracture.A large study showed increased mortality risk for 5 to 10 years after a low trauma fracture.The age-adjusted standardized mortality during the first 5 years after fracture was estimated at 2.5 to 3.5 for hip fractures and 1.7 to 2.3 for vertebral fractures (9).To our knowledge, no study has evaluated mortality after fracture in heart transplant patients, but the results in a general population suggest a similar result in this specific population.Consequently, improving risk stratification for incident fractures could be of great value in that therapeutic intervention could help reduce the decline of bone loss (10,11).
Therefore, the goal of this study was to evaluate the prevalence of incident fragility fractures after heart transplantation and identify independent risk factors.

Study population
This was a cross-sectional monocentric study that included patients with heart transplantation < 10 years previous who were undergoing heart transplantation monitoring from January 2017 to December 2019.Exclusion criteria were age < 18 years, multiorgan transplantation and dialysis.All patients were evaluated by a senior rheumatologist.The following data were systematically collected: 1) demographic characteristics including sex, age, smoking status, excessive alcohol consumption (>20 g/day for women and >30 g/ day for men), and diabetes; 2) the etiology of heart disease and treatment received after the transplant; 3) previous history of fractures and previous treatments for osteoporosis (calcium, vitamin D and osteoporotic therapies).Dietary calcium intake was evaluated with a specific questionnaire (12).

Bone mineral density evaluation
BMD was measured by dual-energy X-ray absorptiometry (Hologic Inc., Waltham, MA) at the lumbar spine (second to fourth vertebrae and vertebral fractures were excluded for BMD evaluation) and the upper part of the left femur (total femur and femoral neck).The results were given as BMD (g/cm 2 ) and T-scores (standard deviation).Sex-specific T-scores were based on female and male reference curves.The device was controlled by measuring a spine phantom at least three times per week throughout the study.All examinations were performed according to the manufacturer's recommendations.Osteoporosis was defined for patients ≥50 and <50 years as a T-score ≤-2.5 SD and Z-score ≤-2 SD at the lumbar spine (L1-L4), femoral neck or total femur.Osteopenia was defined for patients ≥50 and <50 years old as a T-score ≤-1 SD and Z-score ≤-1 SD at the lumbar spine (L1-L4), femoral neck or total femur (13).

Fracture evaluation
Data on previous fractures (location, date) were collected.All patients underwent radiography with anteroposterior and lateral views of the dorsal and lumbar spine to establish the presence of vertebral fractures.Vertebral fracture diagnosis was confirmed in the presence of a reduction > 20% of the height of the vertebra ( 14).An experienced rheumatologist analyzed the radiographs.

Ethics statement
The Institutional Review Board (No.12-011) of Paris North Hospitals approved this study.Written informed consent was obtained from all participants in agreement with French bioethics laws.

Statistical analysis
All data are expressed as mean ± SD and were compared by Mann Whitney test.Categorical data are described with number (%; percentages were calculated excluding missing data) and were compared by chi-square test or Fisher exact test, as appropriate.Univariate analysis (p<0.15) was performed to select potential explanatory variables that were then tested in the multivariable model (stepwise method).Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated.P < 0.05 was considered statistically significant.

Biochemical variables
Biochemical variables are described in Table 1.At the time of the visit, 58 (77%) patients had vitamin D deficiency and 44% (n=34) had increased level of parathyroid hormone.Patients with and without fracture and with and without osteoporosis did not differ in 25 hydroxy-vitamin D level, percentage of vitamin D deficiency, or secondary hyperparathyroidism (p>0.05).Bone turnover was assessed with ßCTX, osteocalcin and B-ALP levels.Bone turnover did not differ between patients with and without fracture or those with and without osteoporosis.Only 9.7% of patients had an increased ßCTX level.

Therapies
All patients received 2 or 3 immunosuppressant therapies.Overall, 90% (n=71) received calcineurin inhibitors and 86% (n=77) mycophenolate mofetil.Patients with and without fracture and with and without osteoporosis did not differ in immunosuppressant therapies.Dietary daily calcium intake was lower than recommended levels in 58% (n=35) of patients, with no difference between groups (with and without fracture or with and without osteoporosis).

Discussion
In this study, the prevalence of fractures was 27% in patients with heart transplantation since 2.6 years.We found a significant association between fractures and femoral neck and total hip BMD.
The prevalence of fractures in this work is similar to that observed in other studies.Leidig-Bruckner et al. found 21% of 105 patients with at least one vertebral fracture in the first year after heart transplantation and 27% at 2 years after (6).Another study reported 40% of fractures in 180 patients with heart transplantation less than 10 years' previous (8).In our population, the mean time from transplantation to the first fracture was 8 months; this result confirmed a high risk during the first year after the transplantation.Previous studies showed a decrease in BMD during the first year post-transplantation (3)(4)(5)(6).This observation could be explained by a high dose of corticosteroids to avoid acute graft rejection.Glucocorticoids reduce bone formation (16), induce apoptosis of osteoblasts and osteocytes (17), increase bone resorption and reduce intestinal calcium absorption (18).We did not find an association between prednisone dose and risk of fractures probably because of lack of data of cumulative corticosteroids dose.In our study, only 28% of patients were osteoporotic, and for patients with fracture, 43% had a T-score <-2.5 SD at at least one site.We found no association between spine BMD and risk of fracture, even though vertebral fractures were the most frequent in our population.BMD is an important factor for evaluating the risk of fracture but is insufficient to identify all patients at risk.Osteocyte apoptosis decreases bone quality, which results in early increased risk of fracture even before BMD decreases.The indirect effects of glucocorticoids could also be involved in the risk of fracture: reduced muscle mass leading to increased risk of falls (19).We confirmed vitamin D deficiency in 57% of our patients, and 44% had secondary hyperparathyroidism.The vitamin D deficiency in heart transplant patients could be explained by heart disease, lack of exposure to sunlight and hepatic dysfunction.In candidates for heart transplantation, 17% had 25 hydroxy-vitamin D level < 9 ng/ ml, with a significant association with bone turnover markers (20).The implication of vitamin D in bone metabolism and the high prevalence of severe deficiency in this population confirm that all transplantation patients and candidates should receive adequate supplementation.The objective is to maintain 25 hydroxy-vitamin D level > 75 nmol/l (30 ng/ml) (21).
We did not find a significant association between immunosuppressive therapies and fracture or osteoporotic state.The role of calcineurin inhibitors is controversial, with opposite results on bone turnover in rats treated with calcineurin inhibitors (22,23).Carbonare et al. showed an association between femoral-neck T-score and daily cyclosporine dosage and suggested the protective effect of calcineurin inhibitors.In our work, the daily dosage of calcineurin inhibitors is unknown, and 90% of patients received calcineurin inhibitors, which could explain the lack of a significant difference (8).Vertebral fractures are the most frequent localization of fractures in heart transplant patients.In our study, 15 patients had vertebral fractures, and for half of them the fractures were unknown and diagnosed on systematic radiography.This result remains that vertebral fracture could be asymptomatic.The International Society of Heart and Lung Transplantation proposed spine radiography for all adult heart transplant candidates (21).In case of acute dorsal or lumbar pain even without trauma in heart transplant patients or candidates, spine radiography (or CT if necessary) must be performed.
Our study has some limitations: the study was monocentric with a relative small number of patients.BMD was not assessed before heart transplantation, so the longitudinal evaluation of BMD after transplantation could not be evaluated.Data on cumulative glucocorticoids or calcineurin inhibitors use were not available.Nevertheless, the strength of our study was the systematic evaluation of BMD and radiography for all patients in a real-life study.
In summary, our study confirmed high vertebral fracture risk in heart transplant patients, especially during the first year after transplantation.The prevalence of vitamin D insufficiency and deficiency was high in this population.This study confirmed that more attention to bone fragility is necessary to reduce the fracture risk.

FIGURE 1 Flowchart
FIGURE 1Flowchart of patients in the study.

TABLE 1
Main characteristics of the overall study population and patients with and without fracture after heart transplantation.

TABLE 2
Main characteristics of patients with and without osteoporosos after heart transplantation.