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* From the Divisions of Endocrinology (Drs. Tschopp and Schmidt) and Pulmonary Medicine (Drs. Speich, Russi, and Boehler), and Department of Biostatistics (Dr. Seifert), University Hospital, CH-8091 Zurich, Switzerland.
Correspondence to: Annette Boehler, MD, FCCP, Division of Pulmonary Medicine, and Lung Transplant Program C HOER 19, University Hospital, CH-8091 Zurich, Switzerland; e-mail: capybara{at}compuserve.com
Abstract
Introduction: Osteoporosis is a common condition in patients with end-stage lung disease, but little attention has been given to bone disease in patients with primary pulmonary hypertension (PPH). The purposes of this study were as follows: (1) to determine the prevalence of osteoporosis in patients with severe PPH before lung transplantation, (2) to investigate whether generally accepted risk factors for osteoporosis would play a role in this special group of patients, and (3) to determine whether there is an association between functional parameters and pretransplantion bone mass.
Design: A retrospective analysis of 18 consecutive patients with PPH accepted for lung transplantation at the University Hospital of Zurich.
Measurements and results: Decreased bone mineral density (BMD) [T score <– 1.0] was found in 11 of 18 patients (61%) at the femoral neck (FN) and 13 of 18 patients (72%) at the lumbar spine (LS). We did not find a significant difference of BMD in a gender- or age-specific manner. Body mass index (BMI) correlated significantly with BMD and T score at the FN and WT. Pulmonary vascular resistance (PVR) was notably linked with BMD at the FN. We found a positive association between walking distance in the 12-min walking test and BMD at the FN and WT.
Conclusions: Low bone density is a very frequent condition in patients with severe PPH. In contrast to the general population, in our study group neither age nor female gender were significantly associated with lower bone mass. Body weight and BMI were highly coupled with BMD. Among the functional parameters, walking distance and PVR were correlated to BMD at the FN. Considering that patients with PPH may have an improved life expectancy in the future, the early diagnosis, prevention, and treatment of osteoporosis should receive high priority.
Key Words: bone mineral density • lung transplantation • osteoporosis • primary pulmonary hypertension
Osteoporosis is a common condition in patients with end-stage respiratory disease. Bone loss and subsequent fractures have been recognized as important pretransplant and posttransplant problems.123456 Although it has been found that patients with any kind of pulmonary disease can be affected, most studies concerning osteoporosis concentrated on the classical risk groups of patients: patients with cystic fibrosis (CF) or COPD. Little attention has been given to bone disease in patients with other underlying diseases such as primary pulmonary hypertension (PPH).1478910 PPH is a rare disease characterized by obliteration of the pulmonary arteries and an extreme and sustained elevation of pulmonary vascular resistance (PVR). Despite recent advances in drug therapy, the prognosis of PPH remains poor.111213 Pulmonary hypertension belongs to the group of diseases for which lung transplantation confers a significant survival benefit.14 We investigated systematically a group of 18 patients with end-stage PPH referred to us for evaluation and accepted for lung transplantation.
The purposes of this study were as follows: (1) to determine the prevalence of osteoporosis in patients with severe PPH before lung transplantation, (2) to investigate whether generally accepted risk factors for osteoporosis (eg, age, gender, and low body mass index [BMI]) would play a role in this special group of patients, and (3) to determine whether there is an association between functional parameters (eg, 12-min walking test) and pretransplant bone mass.
Materials and Methods
Study Population
Among the patients evaluated between November 1992 and November 2000 at the University Hospital of Zurich, 18 patients with severe PPH (unexplained by any secondary cause) were identified and accepted for lung transplantation.15 The Ethics Committee of the University Hospital of Zurich approved the retrospective study. Diagnostic right-heart catheterization was performed in all patients. A 12-min walk test was routinely performed in the course of evaluation, and an osteoporosis workup (including bone mineral density [BMD] measurement) was completed. The study population consisted of 10 women and 8 men with an average age (± SD) of 36.4 ± 10.3 years (median, 37.5 years; range, 20 to 55 years) [Table 1
]. At evaluation, patients were treated with the following medications that may potentially influence BMD and laboratory parameters of bone metabolism: 76% with vitamin K antagonists, 67% with diuretics, and 17% with iloprost. None of the patients received hormone replacement therapy, endothelin receptor antagonist, or supplemental calcium, and only one patient received vitamin D.
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Laboratory Measurements
Serum calcium, phosphate, creatinine, and alkaline phosphatase levels were determined (Hitachi Autoanalyzer 747; Hitachi; Tokyo, Japan). Intact parathyroid hormone (PTH) was measured by an immunoassay (Allegro Intact PTH IRA; Nichols Institute; San Juan Capistrano, CA). 25-Hydroxyvitamin D and osteocalcin were measured by radioimmunoassay (Incstar Corporation; Stillwater, MN; Nichols Institute). Serum total testosterone was determined by radioimmunoassay using a commercial kit (CIS Bio International; Oris Industries; Gif-Sur-Yvette, France). Urinary deoxypyridinoline was measured by an enzyme-linked immunosorbent assay (Metra Biosystems; Mountain View, CA) and expressed relative to creatinine excretion.
Statistical Analysis
Results are expressed as mean ± SD and as median and range when appropriate. The Mann-Whitney U test was used to compare continuous variables between groups, and Fisher exact test was used to compare nominal variables between groups. Spearman rank correlations were used between continuous variables. Differences were considered statistically significant at p < 0.05.
Results
The mean age in our study population was 36.4 ± 10.3 years (range, 20 to 55 years). Male (n = 8) and female (n = 10) patients had comparable ages (35.1 ± 11.3 years and 37.3 ± 9.9 years, respectively). Functional characteristics of the patients are given in Table 1. During evaluation, cardiac catheterization was performed to establish the diagnosis of PPH. The mean systolic pressure difference between the right ventricle and right atrium was 79.9 ± 18.9 mm Hg. Pulmonary arterial pressure was also assessed noninvasively by Doppler echocardiography.
The mean pretransplant BMD was low at the FN, WT, and LS; similarly, the mean T and Z scores were decreased at all three sites (Table 1). Osteoporosis, a T score < – 2.5, was found in five patients (28%) at the FN, two patients (11%) at the WT, and two patients (11%) at the LS. Osteopenia, a T score between – 1.0 and – 2.5, was found in 6 patients (33%) at the FN, 8 patients (44%) at the WT, and 11 patients (61%) at the LS; and only 3 patients (17%) showed normal T scores at all examined sites.
No association was detected between age and BMD and T scores, respectively. We also did not find a significant difference of BMD between women and men at any sites, but there was a remarkable trend to lower BMD at the FN and WT in female patients and at the LS in male patients (Table 1). Due to the low number of patients, we could not see whether sex hormone deficiency in male (decreased testosterone level) and female (menstrual condition) patients or pretransplant medication were associated with BMD.
The mean body weight was 66.0 ± 14.6 kg, and mean BMI was 22.8 ± 3.6 kg/m2. The best association to BMD was found with body weight and BMI. Body weight and BMI correlated positively and in a significant manner with BMD (Fig 1 ) and T scores (Table 2 ) at the FN and WT, respectively, but not at the LS. Similarly, Z scores at the FN and WT, but not at the LS, correlated significantly with body weight and BMI (Table 2).
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A 12-min walking test was performed to estimate the capacity for physical performance and mobility. The mean walking distance was 460 ± 242 m (median, 450 m; range, 90 to 960 m). There was a trend toward lower walking distance in female patients compared to male patients (354 ± 183 m and 592 ± 251 m, respectively; p = 0.09). We found a significant association between the walking distance and BMD (T score) at the FN and WT. The walking distance was also significantly associated with Z score at the FN (p = 0.02) and nearly significant at the WT (p = 0.06). There was no association between walking distance and BMD (T score and Z score) at the LS. Data for the FN and LS are shown in Figure 2 . We did not detect an association between the walking distance and laboratory parameters of bone formation and resorption.
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To our knowledge, this is the first study on pretransplant osteoporosis concentrating on patients with advanced PPH. In other studies, these patients were usually included in very heterogeneous groups with other underlying diseases, eg, pulmonary fibrosis. Our study shows that low BMD and osteoporosis are frequent in patients with end-stage PPH awaiting lung transplantation. Overall, a T score <– 1.0 was present in nearly 60% of the patients.
Higher age, female gender, sex hormone deficiency, and low body weight are accepted risk factors for osteoporosis in the general population. In contrast, in our study population, neither higher age nor female gender were clearly associated with lower bone mass. However, in agreement with an earlier study of Aris and colleagues,1 we detected a strong association of BMD with body weight and BMI. Similarly, in the general population, a protective influence of high body weight on BMD has been found in the Framingham study.17 A more recent study18 suggested that weight loss is associated with loss of BMD. In patients with CF referred for lung transplantation, BMI is a predictor of survival, but it is unknown whether there is a similar association in patients with pulmonary hypertension.19
Whereas malnutrition and low peak bone mass in CF patients and glucocorticoid therapy in COPD patients are well-established risk factors for osteoporosis, the reasons for low BMD in patients with PPH are unclear, and the pathogenetic mechanisms (besides low BMI) leading to decreased bone mass remain unknown. BMD values of patients with pulmonary hypertension tend to be higher than those of patients with CF or with COPD but lower than those of patients awaiting heart transplantation.920
Apart from severe cardiopulmonary disease, which limits physical activity and thereby constitutes an increased risk for osteoporosis, genetic factors could also play a role, ie, an inherited background that could predispose individuals to both lung vascular and bone disease. Germ-line mutations in the bone morphogenetic protein receptor 2 (BMPR-2) have been described in familial and sporadic forms of PPH.2122232425 Although transforming growth factor-ß and bone morphogenetic proteins play an important role in bone, it is clear that the main phenotype of impaired BMPR-2 signaling is pulmonary vessel disease. Genetically modified mice with heterozygous mutations in the BMPR-2 gene have an increased mean pulmonary arterial pressure and vascular resistance as well as greater thickness of pulmonary arteries.26 It should be considered, however, that the genetic background predisposing to PPH is rather complex and heterogeneous, eg, variants or mutations in the gene-encoding serotonin transporters have also been linked to pulmonary hypertension; altered availability of or responsiveness to serotonin, prostacyclin, endothelin, angiotensin II, and others may also play a role in the pathobiology of severe pulmonary hypertension.27282930 Thus far, we have not examined whether our patients are affected by BMPR-2 mutations or not. It remains unclear why these patients have an increased susceptibility for low BMD and osteoporosis. Intriguingly, there is even an association between PVR (one of the main characteristics of PPH) and BMD.
The 6-min walk test is widely used in the evaluation of patients with PPH to assess the efficacy of drug treatment such as epoprostenol or bosentan.31 This functional test has been shown to be related to peak exercise oxygen uptake and to survival rate.11121329 Since we had used the 12-min walking test for years as a global test of cardiopulmonary capacity in patients evaluated for lung transplantation, and since physical activity has been shown to be important in the prevention of osteoporosis, we investigated whether the 12-min walk test correlated with BMD.3233 We found a significant correlation between the 12-min walking distance and BMD and T scores at the FN and WT. Remarkably, we found this association within a small subgroup of patients but not in a larger study including a higher number of more heterogeneous patients.10 The walking test at the time of evaluation may in part reflect physical activity and performance over the last few months and therefore be related to BMD at the FN and WT more clearly than to BMD at the LS. The impact of reduced physical activity on BMD might often be overridden by other risk factors. Possibly, loss of body weight is a more stable indicator for loss of muscle mass than the walking distance and FEV1 at evaluation for lung transplantation.
As discussed, FEV1 and walking distance also tended to be positively correlated with each other in this group of patients. These findings are all the more remarkable since PPH cannot be primarily considered as an obstructive lung disease; reduced FEV1 values are often found in patients with severe PPH and are probably not fully explained by airway obstruction in these patients.34 The findings concerning the relationship between walking distance and BMD (at the FN and WT) are in agreement with the physiologic concept that physical activity is important for bone health. Site-specific muscle contraction forces are considered more relevant for bone mass than loads from body weight; loss of skeletal muscle and reduced physical activity affect BMD because less natural stress on bone impairs maintenance of BMD.35 Loading and locomotion provide the stress on the skeleton, which is required to maintain osteoblastic activity; physical activity may be particularly relevant at the site of the femur. A positive relationship between walking distance and BMD and T score, respectively, at the FN and WT has rarely been documented in a clinical study concerning young adult patients. Possibly, the restriction of our analysis to a relatively homogeneous group of patients with a limited number of severe confounders allowed this observation that may, however, also occur by chance since the patient number is rather low, and the possibility of a statistical error should be considered. In contrast, the positive association between BMI and BMD at the FN and WT is very strong and consistent with published data.110 Our analysis does not allow to distinguish whether fat or muscle mass accounts for the strong association in this specific patient group.
There was no significant association of BMD and biochemical indexes of bone turnover and calcium homeostasis. Despite increased urinary deoxypyridinoline excretion, serum osteocalcin levels were often low, suggesting an impaired coupling of bone resorption and bone formation. With respect to biochemical markers of bone turnover and PTH values, the patients with PPH were closer to heart transplant recipients than to patients awaiting lung transplantation for the more frequent end-stage lung diseases CF and COPD.1020
Our study shares some limitations with earlier studies concentrating on osteoporosis in patients with end-stage respiratory diseases awaiting transplantation, particularly for a relatively rare disease. The annual incidence of PPH is estimated at 1 to 2 per 1,000,000 individuals. The number of our patients is too low for strong statistical power. Additional investigations with a higher number of patients are needed. Comorbidity and pretransplant medication (although not evaluated in detail), however, appeared to be less prevalent than in other patients such as those with CF. Age at onset of relevant symptoms and clinical signs (insidious shortness of breath) most typically develop during the third or fourth decade of life; therefore, most of these patients might be expected to have reached normal peak bone mass (although this could not be formally tested). Moreover, these patients have not been exposed to excessive glucocorticoid therapy. Thus, patients with PPH do not share with other patients (CF and COPD) awaiting lung transplantation some of the well-recognized risk factors for osteoporosis.
In conclusion, osteopenia and osteoporosis are frequent conditions in patients with advanced PPH awaiting transplantation. Body weight and BMI were highly correlated with BMD in patients with end-stage lung disease and in patients with PPH. In the latter, walking distance in the 12-min test was also positively correlated to BMD at the FN and WT but not at the LS. In pulmonary hypertension, the walk test not only reflects exercise capacity and disease severity, it is also associated with mortality/survival and complications such as osteoporosis and therefore of great help in decisions regarding care for this patient group. Considering that patients with PPH may have an improved life expectancy in the future, the impact of osteoporosis on the morbidity and quality of life in these patients is likely to increase. Early diagnosis, prevention, and treatment of osteoporosis should receive high priority.36
Acknowledgements
The authors thank Rahel Naef, lung transplant coordinator, for collecting data.
Footnotes
Abbreviations: BMD = bone mineral density; BMI = body mass index; BMPR-2 = bone morphogenetic protein receptor-2; CF = cystic fibrosis; FN = femoral neck; LS = lumbar spine; PPH = primary pulmonary hypertension; PTH = parathyroid hormone; PVR = pulmonary vascular resistance; VC = vital capacity; WT = Ward triangle
Dr. Boehler holds a Swiss National Science Foundation professorship position.
This work was supported in part by the Swiss National Science Foundation (No. 32–46808.96), and the Zurich Lung League.
Received for publication May 29, 2005. Accepted for publication October 4, 2005.
References
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