Lymphangioleiomyomatosis

Estrogen deficiency and pulmonary diseases are associated with bone mineral density (BMD) loss. Lymphangioleiomyomatosis (LAM), a disorder affecting women that is characterized by cystic lung lesions, is frequently treated with antiestrogen therapy, i.e., progesterone and/or oophorectomy. Therefore, we evaluated BMD yearly in 211 LAM patients to determine the prevalence of BMD abnormalities, whether antiestrogen therapy decreased BMD, and if treatment with bisphosphonates prevented bone loss. Abnormal BMD was found in 70% of the patients and correlated with severity of lung disease and age. Greater severity of lung disease, menopause, and oophorectomy were associated with greater decline in BMD. After adjusting for differences in initial lung function and BMD, we found similar rates of BMD decline in progesterone-treated (n = 122) and untreated patients (n = 89). After similar adjustments, we found that bisphosphonate-treated patients (n = 98) had lower rates of decline in lumbar spine BMD (-0.004 ± 0.003 vs. -0.015 ± 0.003 gm/cm^sup 2^, p = 0.036) and T-scores (-0.050 ± 0.041 vs. 0.191 ± 0.041, p

Keywords: bisphosphonates; bone mineral density; interstitial lung disease; lung function; progesterone

Lymphangioleiomyomatosis (LAM), a disease affecting primarily women, is characterized by cystic lung lesions, recurrent pneumothorax, chylous effusions, lymphatic abnormalities, and abdominal tumors, i.e., angiomyolipomas and lymphangioleiomyomas (1-4). LAM occurs sporadically in patients with no evidence of genetic disease and in about one-third of women with tuberous sclerosis complex (5-7). Generally, the pulmonary manifestations dominate the clinical features of LAM. The severity of lung disease, as measured by oxygen requirements, roentgenographic abnormalities, and exercise tolerance, correlates with the severity of the lung function abnormalities (8, 9). These abnormalities, characterized by airflow obstruction and decreased diffusion capacity of the lung for carbon monoxide (DL^sub CO^), may cause respiratory failure, requiring oxygen therapy, and may result in lung transplantation or death. The rate of progression of disease, however, is variable, and some patients have a chronic course lasting more than 20 years (8, 9).

There is evidence suggesting that LAM may be influenced by hormonal factors. Indeed, not only does LAM affect primarily women (1-4), but the disease appears to progress during pregnancy (10, 11) or after the administration of estrogens (12-14). In addition, there is evidence for the colocalization of estrogen and progesterone receptors in LAM cells (15-18). Consequently, hormonal manipulations that reduce the production of estrogens, such as treatment with progesterone and/or oophorectomy, have been employed in the treatment of LAM. Because estrogen deficiency is a recognized cause of osteoporosis (19), we hypothesized that antiestrogen therapy in the presence of lung disease could adversely affect bone mineral density (BMD) in patients with LAM. To test this hypothesis, we measured BMD yearly in a large group of women with LAM followed for more than 3 years. The aims of our study were threefold: (1) to determine the prevalence and factors associated with BMD abnormalities; (2) to determine whether treatment with progesterone is associated with an accelerated loss of bone; and (3) to determine whether treatment with bisphosphonates is associated with lower rates of decline in bone density.

Some of the results of this study have been previously reported in the form of an abstract (20).

METHODS

Study Population

The study population consisted of 305 patients with LAM referred to the National Institutes of Health since 1995 for participation in a natural history longitudinal study (NHLBI Protocol 95-H-0186) approved by the Institutional Review Board of the NHLBI. In addition to self-referral or referral through individual physicians, subjects were informed of the study by the LAM Foundation and the Tuberous Sclerosis Alliance. All subjects gave informed consent before enrollment. Sixty-three patients who had only one set of BMD studies and 31 patients who had lung transplantation were excluded. Complete data for analysis were available from 211 patients. The diagnosis of LAM was made by lung or intraabdominal tissue biopsy, or by clinical and roentgenographic data (9). Patients were considered to have reached menopause when menopause had occurred naturally (low estradiol levels and elevated follicle-stimulating hormone levels) or was surgically induced (bilateral oophorectomy). A patient was defined as postmenopausal if hormonal levels as well as history were consistent with a menopausal state for most of the duration of the study. The decision to initiate progesterone therapy and the choice of route of administration were made independently by the patients' physicians and were not part of the NHLBI protocol. The majority of the progesterone-treated patients were on this therapy for the duration of the study. Patients with osteoporosis were advised to take bisphosphonates but the final decision for implementation of this therapy was left up to the patient and her family physician. However, in the majority of the patients, bisphosphonate therapy was started after the first abnormal BMD test and continued thereafter. Hormonal replacement therapy was discontinued after the first visit. Compliance with progesterone or bisphosphonate therapy was monitored by interviewing the patient at the time of each visit.

BMD Measurements

BMD of the lumbar spine (anterior and lateral), proximal right femur, and right radius was assessed by dual energy X-ray absortiometry (Hologic QDR-4000, Bedford, MA). Four different values (anteroposterior and lateral lumbar spine, proximal femur and lower radius) were obtained. T-score was defined as the number of SD units below peak bone mass. Z-score was derived from age-matched reference values. BMD was classified according to World Health Organization guidelines (21): normal BMD, T-score greater than -1 SD; osteopenia, between -1 SD and -2.5 SD inclusive; and osteoporosis, T-score less than -2.5 SD.

Pulmonary Function Tests

Lung volumes, flow rates, and DL^sub CO^ were measured using a computerized system (Master Screen PFT; Erich Jaeger, Wuerzburg, Germany) according to American Thoracic Society standards (22-24).

Cardiopulmonary Exercise Testing

Patients were exercised on a bicycle ergometer or treadmill using a computerized metabolic cart (Vmax 229 Cardiopulmonary Exercise System; Sensormedics, Yorba Linda, CA), using standard incremental protocols (9). VO^sub 2^max was defined as the highest oxygen uptake observed during any 30-second measurement period.

Statistical Methods

To identify factors associated with BMD at the time of initial testing, we ran univariate regression analyses between BMD or T-scores, and age, body mass index (BMI), pulmonary function (DL^sub CO^ and FEV^sub 1^), VO^sub 2^max, menopausal state and oophorectomy. Then, using a stepwise procedure, we ran a multiple regression analysis with BMD or T-scores as the dependent variables and all the independent variables found to be statistically significant at a 0.10 level in the univariate regression analysis. The level of significance for inclusion in the model is set at p

Because our data set contained multiple BMD measurements for the 211 patients, we summarized the information from each subject by using the yearly rate of change (slope) calculated from a linear regression with the raw BMD or T-scores for each of the bone areas as the response variables and the time of each test as the independent variable, considering the first test as Time 0. The effect of bisphosphonate and progesterone treatment on the yearly rate of change in BMD was tested using a two-sided t test. Similar to the baseline analyses, we ran univariate and multivariate regression analyses to identify factors related to the rate of change in BMD. In addition to the explanatory variables considered in the baseline analyses, we included treatment or no treatment with bisphosphonatcs and progesterone, initial DL^sub CO^ or FEV^sub 1^, rate of decline in DL^sub CO^ and FEV^sub 1^, and time under observation. All data are presented as mean ± SEM. All reported p values are two-sided.

RESULTS

Study Population

Two hundred eleven patients are the subject of the current report. Forty of the 211 patients had tuberous sclerosis complex based on established criteria (e.g., presence of skin lesions, cerebral tubers, and a history of seizures). The diagnosis of LAM had been established 2.8 ± 0.2 years before enrollment in our study. However, based on the history of LAM-related symptoms (e.g., pneumothorax, chylous effusions, hemoptysis, breathlessness, or angiomyolipoma-related hemorrhage), it was estimated that, at the lime of the first visit, the mean duration of LAM had been 6.8 ± 0.4 years. One hundred eight patients were premenopausal and 103 were postmenopausal, of whom 43 had undergone oophorectomy. The average number of visits per patient was 3.7 ± 0.1 (range = 2-8). The mean follow-up in years was 3.2 ± 0.1 (range = 0.8-6.8) for a total of 667 patient/years. Ninety-four patients were excluded from the study. Of these, 31 patients underwent lung transplantation. Twelve patients had lung transplantation before their first visit and 19 had it subsequent to the first visit. Eight of the patients who had lung transplantation did not have BMD studies. Sixty-three patients had undergone only one BMD test before the closure of our study.

Table 1 shows baseline characteristics, including initial BMD and lung function, for the 211 patients who are the subject of our study, and the 74 patients with BMD measurements who were excluded because they had only one BMD test, of whom 11 underwent lung transplantation before having a second BMD test.

As shown in Table 1, the percentage of patients who had reached menopause or were treated with progesterone and bisphosphonates was significantly lower in the 74 excluded patients. Further, their BMI and femoral BMD were also significantly lower. Lung function, i.e., FEV^sub 1^ and DL^sub CO^, was more severely impaired in the patients who were excluded from the analyses because this group included 11 patients with very severe disease who thereafter underwent lung transplantation.

Initial BMD, Lung Function, and Maximal Oxygen Uptake

Tables 1 and 2 show initial BMD, pulmonary function, and V^sub O2^ data for the 211 patients who are the subject of this report. The overall initial frequency of osteoporosis and osteopenia by World Health Organization criteria at any of the four sites was 23% (n = 49) and 47% (n = 100), respectively. At the lumbar spine, osteopenia and osteoporosis were found, respectively, in 38% and 18% of the patients. At the proximal femur, the corresponding figures were 40% and 4%, respectively. At the anterior radius, osteopenia was observed in 18% of the patients. One patient had osteoporosis at this site. The overall frequency of osteoporosis and osteopenia in the 74 excluded patients at any of the four sites was 12% (n = 9) and 42% (n = 31), respectively.

Predictors of Initial BMD

Single regression analysis showed that bone density was positively correlated with lung function and negatively correlated with age. BMI was also a significant positive predictor of BMD but only at the femoral bone site (p

Multivariate analysis confirmed that DL^sub CO^ and BMI (femoral bone only) were positively correlated with bone density, whereas age was a negative predictor of bone density.

Predictors of Decline in BMD

Higher initial DL^sub CO^ and longer follow-up time were significantly correlated with lower rates of decline in bone density (p

A weighted multivariate analysis of the slopes of BMD and T-scores showed that menopause was associated with a greater rate of bone loss at the lumbar spine (p

Four of the 211 patients suffered fractures throughout the span of the study.

Effect of Treatment with Progesterone on BMD

One hundred and twenty-two (mean age 43.1 ± 0.8 years) of the 211 patients were treated with progesterone and 89 (mean age 45.0 ± 0.9 years) received no hormonal therapy. The average monthly dose of progesterone in the treated group was 588 ± 40 mg, and the mean duration of therapy was 62 ± 4 months. Fifty-nine of the progesterone-treated patients (48%) had reached menopause, of whom 30 (25%) had undergone oophorectomy. Forty-four (49%) of the 89 untreated patients had also reached menopause, of whom 13 (15%) had oophorectomy. A significant greater percentage of progesterone-treated patients received treatment with bisphosphonates (57 vs. 31%, p

Effect of Treatment with Biphosphonates on BMD

Ninety-eight of the 211 patients were treated with bisphosphonates and 113 received no therapy. A significantly greater percentage of patients had reached menopause in the bisphosphonate-treated group (60 vs. 39%, p

A weighted multivariate analysis of the slopes of BMD and T-scores showed that treatment with bisphosphonates was associated with a lower rate of decline in both BMD (p = 0.036) and T-scores (p

To determine whether the beneficial effect of treatment with bisphosphonates in preventing loss of bone in the lumbar spine was present in premenopausal patients, we also analyzed the data for the premenopausal subgroup only. Thirty-nine premenopausal patients were treated with bisphosphonates and 69 did not receive treatment. The conclusions remain the same in terms of the BMD variables. Furthermore, age and lung function variables are similar in both groups, which make the conclusions even stronger. We, therefore, believe that our conclusions are valid for the whole population of LAM patients and not just for the postmenopausal group.

Effect of Lung Transplantation on BMD

In 11 of the 31 patients who had lung transplantation, BMD was evaluated before transplantation and at the first posttransplantation visit. As shown in Figure 2, anterior and lateral lumbar spine T-scores declined from -0.515 ± 0.404 to -1.089 ± 0.418 (p = 0.010) and from -0.869 ± 0.587 to -2.134 ± 0.434 (p = 0.011), respectively. Femoral neck T-scores declined from -0.970 ± 0.400 to -1.220 ± 0.284 but the difference was not significant (p = 0.305). Anterior radius T-scores declined from +0.780 ± 0.395 to +0.475 ± 0.396 (p = 0.046).

DISCUSSION

Our study shows that BMD is decreased in the majority of patients with LAM, with less than one-third of the 211 patients having normal BMD. This high frequency of abnormal BMD was not related to weight loss because BMI was increased in our patients (26.9 ± 0.5 kg/m^sup 2^, range 17-53). The major factors associated with abnormal BMD appeared to be estrogen deficiency, caused by natural or surgically induced menopause, and the severity of lung disease, evidenced by a decline in DL^sub CO^ and FEV^sub 1^. Treatment with progesterone was not associated with an adverse effect on BMD. Treatment with bisphosphonates, however, was associated with a beneficial effect on lumbar spine BMD in both pre- and postmenopausal patients. Finally, lung transplantation was associated with increased loss of bone.

The prevalence of bone mineral loss in our patients was higher than that reported in women of similar age. Between the ages of 30 and 49, the proportion of white women with osteoporosis at any bone site is low (25). Above the age of fifty the frequency of osteoporosis and osteopenia increases rapidly, reaching 20% and 50%, respectively (26, 27). However, 75% of our patients were under the age of fifty, so age alone does not account for the high prevalence of abnormal BMD observed in our cohort. Furthermore, low BMD (T-score

Our patients differ considerably from those with CF or chronic obstructive pulmonary disease. Low BMI was not a factor, and there was no evidence of chronic recurrent pulmonary infections. Calcium/phosphate and vitamin D levels were, in general, within normal limits, and the majority of the patients were taking mineral and vitamin supplements, including calcium and vitamin D. Only six patients gave a history of sporadic use of oral corticosteroids, and less than one-third of the patients reported using inhaled steroids. Nevertheless, inhaled corticosteroids could possibly be an additional factor in causing bone loss in our patients. Although data on this subject are conflicting, it is believed that the duration of therapy and the dosage level are the primary factors determining whether bone loss is associated with the use of inhaled steroids (41). In our patient population, however, high-dose inhaled corticosteroids were not employed and the duration of therapy was on average less than 3 years.

The unique features of our cohort were an early onset of menopause induced by oophorectomy and treatment with progesterone. Hypoestrogenic states are major determinants of bone mass and risk of fractures in women (19, 41), whereas hormonal replacement therapy improves BMD and reduces the risk of fractures in postmenopausal women (42). Because of the potential adverse effects of estrogens on LAM (12-14), none of our postmenopausal patients received hormonal replacement therapy and all premenopausal patients discontinued the use of oral contraceptives once the diagnosis of LAM was established. However, 122 patients received progesterone therapy, and progesterone has been reported to cause bone loss in premenopausal women (43, 44). Young women who received contraceptive doses of medroxyprogesterone, especially those under the age of 20 who subsequently used it for over 15 years, experienced increased BMD loss (45); duration of therapy was correlated with bone loss (46). Use of contraceptive doses of progesterone (150 mg every 3 months) for periods ranging from 1-3 years was also associated with bone mineral loss (47-49), although the effect was largely reversible (49). Others have found no significant adverse effect of progesterone on BMD in premenopausal women (50-53). It is possible that the effects of progesterone are confined to younger patients or adolescents, in whom peak bone mass has not been achieved, who take the drug for many years (54, 55).

No adverse effects on BMD of high doses of medroxyprogesterone taken for approximately 5 years intramuscularly or orally were found in our patients. Instead, we found an improvement in radial bone BMD in progesterone-treated patients. This could be due to the fact that in our population progesterone therapy was initiated at an age well after BMD had reached its peak and the duration of progesterone therapy was not sufficiently long to produce significant effects on bone density. Furthermore, the majority of our patients were taking calcium and vitamin D supplements. Nevertheless, our findings are reassuring to those patients with LAM who choose to be treated with progesterone.

Treatment with bisphosphonates improved lumbar spine BMD but had no statistically significant effect on the other bone areas. A beneficial effect of bisphosphonates on BMD of patients with lung diseases is at best poorly documented, except in the setting of corticosteroid therapy (38, 40) or after lung transplantation (56, 57). One study, done in patients with CF after transplantation, showed that intravenous pamidronate was more effective than calcium and vitamin D in improving bone mineral density (57). Another study, conducted in 45 patients who underwent transplantation (56), showed fewer fractures and preservation of bone mass in patients treated with bisphosphonates, especially when treatment was begun before transplantation. These beneficial effects of bisphosphonates were recently (58) confirmed in a placebo-controlled randomized trial conducted in adult patients with CF.

From our study we conclude that there is a high prevalence of abnormal BMD in LAM. Based on our findings we recommend that patients with LAM, especially postoophorectomy patients, undergo periodic evaluation of BMD. We recommend that all three areas be tested: lumbar spine, femoral neck, and anterior radius. Indeed, the presence of osteoporosis at a bone site cannot be predicted by measurements at another site (21) unless T-score thresholds are modified (59). Those with osteoporosis should be treated with calcium and vitamin D supplements and bisphosphonates. In view of the rapid deterioration in BMD observed in our patients after lung transplantation, early initiation of aggressive therapy in LAM patients with severe lung disease and osteopenia at any bone site is recommended. We propose this aggressive approach because achieving a substantial reduction of osteoporotic fractures, which may adversely affect lung function (40), cannot probably be accomplished by treating only patients with T-scores of -2.5 or less (60). Moreover, patients undergoing eventual lung transplantation will be exposed to medications that lead to further loss of bone. In addition to pharmacologic therapy, weight-bearing exercise and strength training should be encouraged (59) because of the growing evidence that exercise improves bone density (61, 62).

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Angelo M. Taveira-DaSilva, Mario P. Stylianou, Carolyn J. Hedin, Olanda Hathaway, and Joel Moss

Pulmonary-Critical Care Medicine Branch and Office of Biostatistics Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland

(Received in original form June 2, 2004; accepted in final form September 29, 2004)

Supported by National Heart, Lung, and Blood Institute Intramural Research.

Correspondence and reprint requests should be addressed to Angelo M. Taveira-DaSilva, M.D., Ph.D., Pulmonary-Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Building 10, Room 6D05, MSC 1590, Bethesda, MD 20892-1590. E-mail: dasilvaa@nhlbi.nih.gov

Am J Respir Crit Care Med Vol 171. pp 61-67, 2005

Originally Published in Press as DOI: 10.1164/rccm.200406-701OC on October 1, 2004

Internet address: www.atsjournals.org

Conflict of Interest Statement: A.M.T-D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; M.P.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; C.J.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; O.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; J.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Acknowledgment: The authors thank Drs. Martha Vaughan and Vincent Manganiello for their helpful discussions and critical review of the manuscript. They thank Xiaoling Chen for her assistance in compilation and analysis of the data, and they also thank the LAM Foundation and the Tuberous Sclerosis Alliance for their assistance in recruiting patients. This study would not have been possible without the cooperation of patients with LAM, who, in many cases, traveled great distances to participate in the clinical research protocols.

Copyright American Thoracic Society Jan 1, 2005
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