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
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, pulmonary
function (DLCO and FEV1), VO2max, 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<0.05.
Since 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 zero. 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 bisphosphonates and progesterone, initial DLCO or FEV1, rate of
decline in DLCO and FEV1, and time under observation. All data are presented as
mean ± SEM (standard error of the mean). All reported p-values are two-sided.
Two hundred and eleven patients are the subject of the current report. Forty of the
211 patients had tuberous sclerosis complex (TSC), 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 prior to enrollment into our study.
However, based on the history of LAM-related symptoms (e. g., pneumothorax, chylous
effusions, hemopthysis, breathlessness, angiomyolipoma-related hemorrhage), it was
estimated that, at the time of the first visit, the mean duration of LAM had been 6.8±0.4
years. One hundred and eight patients were pre-menopausal and 103 were post-
menopausal, of which 43 had undergone oophorectomy. The average number of visits
per patient was 3.7±0.1 (range=2 to 8). The mean follow-up in years was 3.2±0.1
(range=0.8 to 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 transplanted patients did not have BMD studies. Sixty-three patients had
undergone only one BMD test prior to 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 74 patients with BMD measurements
who were excluded because they had only one BMD test, of which 11, underwent lung
transplantation prior to 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 body mass index and femoral BMD were also
significantly lower. Lung function, i.e., FEV1 and DLCO were 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 bone mineral density, lung function, and maximal oxygen uptake
Tables 1 and 2 show initial BMD, pulmonary function, and VO2maxdata for the 211
patients who are the subject of this report. The overall initial frequency of osteoporosis
and osteopenia by WHO 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<0.010). VO2 max was not
significantly correlated with bone density.
Multivariate analysis confirmed that DLCO and body mass index (femoral bone only)
were positively correlated with bone density, whereas age was a negative predictor of
Predictors of decline in BMD
Higher initial DLCO and longer follow-up time were significantly correlated with lower
rates of decline in bone density (p<0.05). Higher initial BMD (p=<0.001), menopause
(p=0.003), and oophorectomy (p=0.027) were all associated with a greater loss of bone
at the lumbar spine and anterior radius. At the femoral area the only significant
predictor of accelerated bone loss was a higher initial BMD (p<0.001). Treatment with
progesterone was associated with a lower rate of decline in anterior radius BMD
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<0.01). A lower DLCO (p=0.012) was a significant predictor of a greater rate of
decline in bone density at the femoral area. Menopause was associated with a greater
rate of decline in bone density at the anterior radius (p<0.01).
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 (43.1±0.8 years) of the 211 patients were treated with
progesterone and 89 (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 which 30 (25%) had undergone oophorectomy.
Forty-four (49%) of the 89 untreated patients had also reached menopause, of which
13 (15%) had oophorectomy. A significant greater percentage of progesterone-treated
patients received treatment with bisphosphonates (57 vs.31%, p<0.05). Table 3 shows
initial BMD and lung function and yearly changes in these variables for both patient’s
groups. Progesterone-treated patients had lower initial bone density and lung function
than untreated patients. However, there was no significant difference between the two
groups in the rate of change of BMD and T-scores in the lumbar spine and femur (see
Table 3). Progesterone therapy was associated with a small improvement in anterior
radial bone T-scores (see Table 3).
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<0.05) than in the untreated group.
Further, a significant greater percentage of bisphosphonate-treated patients received
treatment with progesterone (69 vs.46%, p<0.05). Also, patients who were treated with
bisphosphonates were significantly older than untreated patients (45.9±0.9 vs. 42.3±0.8
years, p<0.05). Table 4 shows initial BMD and lung function and yearly changes in
these variables for both patient’s groups. Patients who were treated with
bisphosphonates had more severe pulmonary LAM, and lower initial BMD than
untreated patients. However the lumbar spine rates of decline in BMD and T-scores
are lower in patients treated with bisphosphonates than in untreated patients. There is
also a trend for a lower rate of decline in BMD and T-scores in the proximal femur
(p=0.069). No significant difference in BMD changes was observed in the anterior
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<0.001) at the lumbar spine (see Figure 1).
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, not just the
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 post-transplantation 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±
Our study shows that bone mineral density is decreased in the majority of patients
with LAM, with less than one third of 211 patients having normal BMD. This high
frequency of abnormal BMD was not related to weight loss, because body mass index
was increased in our patients (26.9±0.5 Kg/m 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 DLCO and FEV1. 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, seventy-five percent 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 bone mineral density (T-score <-1.0) is present in only about
15% of premenopausal women (28), whereas in our study we found that 55% of 108
premenopausal patients had either osteopenia or osteoporosis. This is consistent with
reports showing that osteoporosis and osteopenia are frequent in patients with chronic
lung diseases, such as cystic fibrosis (CF) and chronic obstructive pulmonary disease
(COPD). Conway et al (29) reported osteopenia or osteoporosis in 66 % of 114
patients with CF and demonstrated a correlation between BMD, and both disease
severity, and use of corticosteroids. However, CF is a disease that begins early in life
and is accompanied by low body weight and recurrent pulmonary infections. Low BMD
and increased bone loss in CF is, indeed, associated with loss of muscle mass in the
presence of a chronic inflammatory, catabolic state (30) and, consequently, is a
sensitive indicator of health status (31). BMD is also reduced in adults with other
pulmonary diseases and is correlated with loss of lung function, exercise capacity, and
body mass index (32-35). In COPD, lung function is an independent predictor of BMD
(36,37), but other factors such as smoking, vitamin D deficiency, sedentary life and use
of corticosteroids may also contribute to low BMD (38-40).
Our patients differ considerably from those with CF or COPD. Low body mass index
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 three 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 three months) for periods ranging from one to three 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 five years, intramuscularly or orally, on BMD, 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 . Further, 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 following 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 post-
oophorectomy 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 can not 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), can not 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 which 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).
We thank Drs. Martha Vaughan and Vincent Manganiello for their helpful discussions and
critical review of the manuscript. We thank Xiaoling Chen for her assistance in compilation and
analysis of the data. We 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
our clinical research protocols.
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Figure 1. Yearly changes in T-scores at four bone sites in patients treated with
bisphosphonates (white bars) and untreated patients (black bars). There is a
significantly lower rate of decline in T-scores in the lumbar spine of bisphosphonate-
treated patients. ALS: anterior lumbar spine; LLS: lateral lumbar spine. * p<0.05.
Figure 2. T-scores at four bone sites in 11 LAM patients before (white bars) and after
(black bars) lung transplantation. There is a significant decline in lumbar spine and
radius T-scores. ALS: anterior lumbar spine; LLS: lateral lumbar spine.
Table 1. Baseline characteristics of patients included in the longitudinal analyses as
compared to those excluded.
Number 211 74
Age 43.9±0.6 (19-74) 43.2±1.0 (21-77)
BMI 26.9±0.5 25.3±0.6 †
Menopause (%) 4935 †
Bisphosphonates (%) 4711 †
Oophorectomy (%) 2120
Progesterone (%) 58 41 †
BMD (ALS) 0.993±0.010 1.031±0.094
T-score (ALS) -0.526±0.087 -0.281±0.162
Z-score (ALS) -0.043±0.85 0.201±0.166
BMD (LLS) 0.728±0.008 0.752 ±0.015
T-score (LLS) -1.175±0.096 -0.864±0.179
Z-score (LLS) -0.144±0.091 0.177±0.168
BMD (Femur) 0.847±0.009 0.805±0.016 †
T-score (Femur) -0.722±0.076 -0.683±0.138
Z-score (Femur) -0.361±0.073 -0.241±0.133
BMD (Radius) 0.654±0.007 0.685±0.001 †
T-score (Radius) -0.038±0.085 0.026±0.133
Z-score (Radius) 0.511±0.085 0.574±0.126
FEV1 75±2 % 65±4 % †
DLCO 73±2 % 65±3 % †
* Abbreviations used: BMD, bone mineral density in gm/cm 2 ; ALS, anterior lumbar
spine; LLS, lateral lumbar spine; FEV1, forced expiratory volume in the first second;
DLCO, diffusion capacity for carbon monoxide. Lung function is shown as percent-
predicted of the normal values. † p<0.05
Table 2. Pulmonary function and maximal oxygen uptake in 211 patients with LAM*
TLC 4.78±0.06 (91.9±1.0 %)
FRC 2.63±0.04 (93.4±1.6 %)
RV 1.69±0.03 (98.8 ±2.1%)
RV/TLC 35.2±0.5 %
FVC 3.09±0.04 (88.3±1.1%)
FEV1 2.02±0.04 (75.0±1.6 %)
FEV1/FVC 64.9±1.1 %
DLCO 15.4±0.3 (73.4±1.7 %)
VO2 max 1,290±60 (75.1±3.2 %)
* Abbreviations used are: TLC, total lung capacity (liters); FRC, functional residual
capacity (liters); RV, residual volume (liters); RV/TLC, ratio between RV and TLC
(percent); FVC, forced vital capacity (liters); FEV1, forced expiratory volume in the first
second (liters); FEV1 /FVC, ratio of FEV1 to FVC (%); DLCO, diffusion capacity for
carbon monoxide (ml/min/mmHg); VO2 max , maximal oxygen uptake (ml/min).
Percent- predicted values are shown within brackets.
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