BONE MINERAL DENSITY IN LYMPHANGIOLEIOMYOMATOSIS (LAM).
Angelo M. Taveira-DaSilva, M.D., Ph.D.1, Mario P. Stylianou, Ph.D.2, Carolyn J. Hedin,
C.R.N.P.1, Olanda Hathaway C.R.N.P.1 , and Joel Moss, M.D., Ph.D.1
Pulmonary-Critical Care Medicine Branch 1 and Office of Biostatistics Research 2,
National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
Corresponding author: 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; Telephone:
301-496-1117; Fax: 301-496-2363; E-mail: email@example.com.
Subject code: 75.
Running Head: Bone mineral density in LAM.
Word count: 3540.
Supported by NHLBI Intramural Research.
AJRCCM Articles in Press. Published on October 1, 2004 as doi:10.1164/rccm.200406-701OC
Copyright (C) 2004 by the American Thoracic Society.
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 anti-estrogen
therapy, i.e., progesterone and/or oophorectomy. Therefore, we evaluated BMD
yearly in 211 LAM patients to determine the prevalence of BMD abnormalities,
whether anti-estrogen therapy decreased BMD, and if treatment with
bisphosphonates prevented bone loss. Abnormal BMD, found in 70% of the patients,
was 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 2, p=0.036) and T-scores (-0.050±0.041 vs. -0.191± 0.041,
p<0.001), than untreated patients (n=113). We conclude that abnormal BMD was
frequent in LAM. Progesterone therapy was not associated with changes in BMD;
bisphosphonate therapy was associated with lower rates of bone loss. We
recommend systematic evaluation of BMD and early treatment with bisphosphonates
for patients with LAM.
Word count: 199
Key words: Interstitial lung disease; bone mineral density; 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,
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
(TSC) (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 (DLCO), 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 following the administration of estrogens (12-
14). In addition, there is evidence for the co-localization 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. Since estrogen
deficiency is a recognized cause of osteoporosis (19), we hypothesized that anti-
estrogen 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 three years.
The aims of our study were three fold: 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
Some of the results of this study have been previously reported in the form of an
MATERIAL AND METHODS Word count: 716
Study Population. The study population consisted of 305 patients with LAM referred to NIH
since 1995 for participation in a natural history longitudinal study (NHLBI Protocol 95-H-0186)
approved by the Institutional Review Board of the National Heart, Lung, and Blood Institute. 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 intra-abdominal 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 was 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.
Bone Mineral Density 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). Four different
values (anteroposterior and lateral lumbar spine, proximal femur and lower radius) were
obtained. T-score was defined as the number of standard deviation units below peak
bone mass. Z-score was derived from age-matched reference values. BMD was
classified according to World Health Organization (WHO) guidelines (21): normal BMD,
T-score > -1 standard deviation (SD); osteopenia, between -1 SD and -2.5 SD
inclusive; osteoporosis, T-score < -2.5 SD.
Pulmonary Function Tests
Lung volumes, flow rates, and DLCO 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). Maximal oxygen uptake
(VO2 max) was defined as the highest oxygen uptake observed during any 30-second
Table 3-Initial values and subsequent yearly changes in bone mineral density and lung
function in patients treated with and without progesterone*.
Progesterone No Progesterone
BMD ALS 0.971±0.010 (-0.006±0.003) 1.020±0.010† (-0.005±0.003)
LLS 0.713±0.010 (-0.008±0.002) 0.745±0.010† (-0.011±0.004)
Femur 0.838±0.010 (-0.029±0.002) 0.858±0.010† (-0.032±0.005)
Radius 0.618±0.010 (0.015±0.003) 0.684±0.001 (0.0004±0.0039†)
T scores ALS -0.721±0.110 (- 0.0040±0.017) -0.261±0.120† (-0.032±0.025)
LLS -1.347±0.130 (-0.109±0.034) -0.946±0.130† (-0.148±0.052)
Femur -0.936±0.100 (-0.065±0.020) -0.421±0.100† (-0.117±0.041)
Radius -0.224±0.120 (0.030±0.029) 0.125±0.110† (-0.085±0.038†)
FEV1 72±2 % (-2.0±0.4%) 81±3%† (-1.8±0.6%)
DLCO 68±2 % (-3.4±0.3%) 81±3%† (-2.3±0.6%)
* Yearly changes in bone density and lung function are shown within parenthesis.
Lung function is shown as percent-predicted of the normal values. Changes in lung
function are also shown as percent-predicted of the normal values. For abbreviations,
see Tables 1 and 2. † p<0.05
Table 4- Initial values and subsequent yearly changes in bone mineral density and lung
function in patients treated with and without bisphosphonates
Bisphosphonates No Bisphosphonates
BMD ALS 0.930±0.010 (-0.003±0.003) 1.044±0.010† (-0.008±0.002)
LLS 0.673±0.010 (-0.004±0.003) 0.769±0.010† (-0.015±0.003†)
Femur 0.796±0.010 (-0.025±0.002) 0.890±0.010† (-0.035±0.004)
Radius 0.608±0.010 (0.012±0.004) 0.679±0.010† (0.005±0.003)
T scores ALS -1.063±0.110 (0.0032±0.017) -0.072±0.100† (-0.073±0.025†)
LLS -1.853±0.120 (-0.050±0.041) -0.648±0.110† (-0.191±0.041†)
Femur -1.211±0.040 (-0.054±0.031) 0.291±0.090† (-0.117±0.028)
Radius -0.500±0.130 (0.003±0.033) 0.220±0.090† (-0.039±0.034)
FEV1 70±3 % (-1.4±0.3%) 80±2%† (-2.3±0.5%)
DLCO 70±3 % (-3.1±0.3%) 77±2%† (-2.9±0.5%)
* Yearly changes in bone density and lung function are shown within parenthesis. Lung
function is shown as percent-predicted of the normal values. Changes in lung function
are also shown as percent-predicted of the normal values. For abbreviations, see
Tables 1 and 2. † p<0.05