Ann Allergy Asthma Immunol 112 (2014) 426e431
Contents lists available at ScienceDirect
Are asthmatic patients prone to bone loss? Jae-Woo Jung, MD, PhD *, y; Hye-Ryun Kang, MD, PhD *, z; Ju-Young Kim, MD *, z; So-Hee Lee, MD *, z, x; Sun Sin Kim, MD, PhD *, z, x; and Sang Heon Cho, MD, PhD *, z, x * Institute
of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea z Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea x Seoul National University Hospital, Healthcare System Gangnam Center, Seoul, Korea y
A R T I C L E
I N F O
Article history: Received for publication October 18, 2013. Received in revised form February 12, 2014. Accepted for publication February 20, 2014.
A B S T R A C T
Background: Recent studies suggest an association between allergic diseases, including asthma, and lower vitamin D level, a well-known risk factor of osteoporosis. However, it is not yet clearly known whether patients with asthma are prone to bone loss. Objective: To evaluate whether the occurrence of airway hyperresponsiveness (AHR) or asthma is related to significant changes in bone mineral density (BMD). Methods: We retrospectively enrolled 7,034 patients who had undergone a health checkup program, including BMD tests and methacholine bronchial challenge tests, at the Seoul National University Hospital, Healthcare System Gangnam Center, from November 1, 2004 to April 30, 2011. Asthma was ascertained by self-reported medical diagnosis by a physician. Patients with a history of systemic corticosteroid medication use were excluded from the study. Results: Among a total of 7,034 patients, 216 (3.1%) had a positive AHR test result, and 217 (3.1%) had a history of asthma. Lumbar spine and femur BMD of patients with AHR were significantly lower than those without AHR (0.53 1.50 vs 0.03 1.49, 0.47 0.97 vs 0.22 0.99, respectively; P < .001 for both). After being adjusted for age, sex, body mass index, smoking status, postmenopausal state, and previous history of hormone replacement therapy, the proportion of patients with osteopenia or osteoporosis was much higher in the AHR-positive group than in the AHR-negative group (odds ratio, 1.715; 95% confidence interval, 1.252-2.349) and in the ever-asthma group than in the never-asthma group (odds ratio, 1.526; 95% confidence interval, 1.120-2.079). Conclusion: In the current study, AHR and asthma were related to clinically meaningful BMD decrease, although the causal relationship is unclear. Ó 2014 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Introduction Allergic diseases and osteoporosis are common in the general population worldwide. More than 20% of the general population has allergic diseases, including allergic rhinitis and asthma.1 Prevalence of osteoporosis is as high as 13.1% for men and 24.3% for women in Korean adults aged 40 to 79 years.2 Therefore, osteoporosis results in major personal and societal costs because of its high morbidity and mortality related to low-trauma fractures in elderly people.3 However, little attention has been paid to the association between allergic diseases and bone loss in the past. Most of the Reprints: Sang Heon Cho, MD, PhD, Seoul National University Hospital 101 Deahakro Jongno-Gu Seoul 110-744 Korea; E-mail: [email protected]. Jae-Woo Jung and Hye-Ryun Kang have contributed equally as first authors. Disclosures: Authors have nothing to disclose. Funding: This study was supported by grant HI10C2020 from the Korea Healthcare Technology R&D Project, Ministry for Health and Welfare, Republic of Korea.
previous studies on bone mineral density (BMD) or osteoporosis in asthma were mainly focused on the adverse effects of prolonged corticosteroid treatment.4 Systemic corticosteroid use, a known risk factor of osteoporosis, increases the risk of fractures in asthma patients in a dose- and duration-dependant manner.4e6 Several studies have reported a dose-related association between use of an inhaled corticosteroid (ICS) and decline in BMD.7,8 In recent decades, many studies have been performed on the association between allergic disease and vitamin Ddan important factor in bone mineralization. The serum vitamin D levels of patients with asthma or airway hyperresponsiveness (AHR) are relatively lower compared with those of healthy controls, and lower levels of vitamin D were found to be related to increased asthma severity and more frequent exacerbations.9,10 Considering that life-long persistence of asthma developed in adulthood and the major role of vitamin D in bone mineralization, asthma morbidity itself can be a potential risk factor for bone loss. However, there are no definite data revealing the status of BMD in
1081-1206/14/$36.00 - see front matter Ó 2014 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.anai.2014.02.013
J.-W. Jung et al. / Ann Allergy Asthma Immunol 112 (2014) 426e431
patients with asthma. We performed a large-scale, cross-sectional study on patients who underwent an annual heath checkup and investigated the association between asthma or AHR and BMD.
427
correlation analysis was used to confirm the association between AHR level and BMD. P < .05 was considered statistically significant. Results
Methods Study Design This was a cross-sectional study performed on patients older than 18 years who had undergone a health checkup program at the Seoul National University Hospital Healthcare System Gangnam Center from November 1, 2004 to April 30, 2011. Electronic medical records of the patients were reviewed. Among 7,078 patients who had undergone both BMD and methacholine bronchial provocation tests, 44 recipients with a history of systematic corticosteroid use were excluded, leaving a total 7,034 recipients for subsequent analysis. The BMD test was included in the routine basic health checkup program, and the methacholine bronchial provocation test was performed optionally in patients who had selected it. The methacholine bronchial provocation test and the BMD test were performed on the same day because all health checkup programs provided in our center are designed to be completed within a half day. We investigated each patient’s age, sex, smoking status, comorbidity (eg, hypertension, diabetes mellitus, asthma, and allergic rhinitis) diagnosed by a physician, body mass index (BMI), white blood cell counts, peripheral eosinophil counts, serum creatinine level, alanine transaminase level, alkaline phosphatase (ALP) level, serum total IgE level, pulmonary function, and presence of atopy. For women, information on menopause and history of hormone replacement therapy (HRT) was also recorded because of their potential to affect BMD. Atopy was defined as positivity to at least one common inhalant allergen in the skin prick test or the multiple allergen simultaneous test (MAST; Hitachi Chemical Diagnostics Inc, Mountain View, California). This study was approved by the institutional review board of Seoul National University Hospital, and informed consent was waived.
Patient Demographics Among a total of 7,034 patients, 2,909 (41.4%) were male, and the mean (SD) age was 55.62 (10.78) years (Table 1). Hypertension, found in 27.4%, was the most common underlying disease, followed by diabetes, asthma, and allergic rhinitis. Skin tests or MASTs were performed in 73.4% of study patients (957 skin tests and 5,147 MASTs), and the atopy rate was 44.1%. In women, 65.6% were postmenopausal, and 15.4% had previous experience with HRT. The mean (SD) FEV1 predicted value of the study patients was 104.96% (14.51%), and the forced vital capacity (FVC) predicted value was 97.38% (12.12%). In the methacholine provocation test, 216 (3.1%) had positive AHR test results (Table 2). Among 217 patients with a history of physician-diagnosed asthma, 40 (18.4%) demonstrated AHR on testing. Of the 6,817 patients without a history of asthma, 176 (2.6%) had positive AHR test results. Mean (SD) lumbar and femur BMD were 0.04 (1.49) and 0.23 (0.99), respectively. A total of 2,110 patients (30.0%) had osteopenia; 290 (4.1%) had osteoporosis. Comparison of Clinical Characteristics According to AHR When the patients were grouped according to AHR, the positive group was older and had a higher current smoking rate compared with the negative group (P < .001 for both; Table 2). Atopy rate was also higher in the AHR-positive group than in the AHR-negative group (56.4% vs 43.8%; P ¼ .007). The mean (SD) FEV1 predicted value (91.83% [13.37%] vs 105.38% [14.35%]; P < .001) and the mean (SD) FEV1/FVC value (71.11% [7.79%] vs 79.49% [6.62%]; P < .001) were significantly lower in the AHR-positive group than in the AHRnegative group. BMI, postmenopausal state, and history of HRT did not differ between the groups. Serum creatinine, calcium, and phosphorus
Methacholine Bronchial Challenge Test Methacholine was inhaled as an aerosol using a nebulizer (DeVilbiss, Carlsbad, California) and Rosenthal-French dosimeter (Laboratory for Applied Immunology, Baltimore, Maryland) in 5 inspiratory capacity breaths.11 The nebulizer used in the study delivered 9 mL of solution per 0.6-second actuation during inhalation. The methacholine concentrations used were 0.0625, 0.25, 1, 4, and 16 mg/mL. The test was stopped when the forced expiratory volume in 1 second (FEV1) decreased 20% or more from the baseline. AHR was defined as the provocative concentration of methacholine that causes a 20% decrease in FEV1 from the baseline (PC20) being 16 mg/mL or lower. BMD Evaluation By using DEXA (LUNAR Prodigy; GE Medical, Chalfont St Giles, United Kingdom), we measured BMD of lumbar spines (L1-L4) and femur. On the basis of the lowest Tscores, we classified the patients into 3 groups according to the criteria of the World Health Organization.12 Normal BMD was defined as a T score of 1.0 SD or greater; osteopenia, between 1.0 and 2.5 SDs; and osteoporosis, 2.5 SDs or less. Statistic Analysis Analysis was performed with SPSS statistical software, version 17.0 (SPSS Inc, Chicago, Illinois). Both c2 and t tests were used for comparisons according to the presence of AHR or allergic disease. We performed linear regression tests and binary logistic regression tests to adjust for other factors that could affect BMD. A Pearson
Table 1 Demographic characteristics of the study population Characteristic
Finding (N ¼ 7,034)
Male, No. (%) Age, mean (SD), y Body mass index, mean (SD) Smoking status, non/ever/current, % Postmenopausal state in females, No. (%) Hormone replacement therapy in females, No. (%) Hypertension, No. (%) Allergic rhinitis, No. (%) Diabetes mellitus, No. (%) Bronchial asthma, No. (%) Atopy, No. (%) Airway hyperresponsiveness, No. (%) Blood WBC counts, mean (SD), /mL Blood eosinophil counts, mean (SD), /mL Serum total IgE, mean (SD), U/mL Alanine transaminase, mean (SD), IU/L Creatinine, mean (SD), mg/dL Alkaline phosphatase, mean (SD), IU/L Calcium, mean (SD), mg/dL Phosphorus, mean (SD), mg/dL FEV1, mean (SD), % predicted FVC, mean (SD), % predicted FEV1/FVC, mean (SD), % Bone mineral density Lumbar spine, mean (SD) Femur, mean (SD) Normal/osteopenia/osteoporosis, %
2,909 (41.4) 55.62 (10.78) 23.94 (2.95) 49.5/29.5/21.0 1,907/2,909 (65.6) 448/2,900 (15.4) 1,920 (27.4) 556 (10.6) 639 (9.1) 217 (3.1) 2,274/5,159 (44.1) 216 (3.1) 5,604.00 (1,597.23) 156.51 (154.01) 215.39 (652.06) 26.71 (20.74) 0.98 (0.22) 61.34 (19.21) 9.24 (0.38) 3.59 (0.56) 104.96 (14.51) 97.38 (12.12) 79.23 (6.81) 0.04 (1.49) 0.23 (0.99) 65.9/30.0/4.1
Abbreviations: FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; WBC, white blood cell.
428
J.-W. Jung et al. / Ann Allergy Asthma Immunol 112 (2014) 426e431
Table 2 Comparison of clinical characteristics according to airway hyperresponsiveness Characteristic
Airway hyperresponsiveness
Patients, No. (%) Male, No. (%) Age, mean (SD), y Body mass index, mean (SD) Smoking status, non/ever/current, % Atopy, No. (%) Postmenopausal state in females, No. (%) Hormone replacement therapy in females, No. (%) Creatinine, mean (SD), mg/dL Alkaline phosphatase, mean (SD), IU/L Calcium, mean (SD), mg/dL Phosphorus, mean (SD), mg/dL FEV1, mean (SD), % predicted FVC, mean (SD), % predicted FEV1/FVC, mean (SD), %
P value
Negative
Positive
6,818 (96.9) 3,990 (58.5) 55.47 (10.76) 23.93 (2.93) 49.9/29.5/20.5 2,208/5,042 (43.8) 1,847/2,828 (65.3) 439/2,820 (15.6) 0.98 (0.22) 61.15 (19.16) 9.24 (0.38) 3.59 (0.55) 105.38 (14.35) 97.51 (12.11) 79.49 (6.62)
216 (3.1) 135 (62.5) 60.47 (10.56) 24.22 (3.29) 35.6/29.4/35.1 66/117 (56.4) 60/81 (74.1) 9/80 (11.3) 0.99 0.20 67.07 (20.03) 9.20 (0.37) 3.61 (0.74) 91.83 (13.37) 93.18 (11.97) 71.11 (7.79)
NS
Contents lists available at ScienceDirect
Are asthmatic patients prone to bone loss? Jae-Woo Jung, MD, PhD *, y; Hye-Ryun Kang, MD, PhD *, z; Ju-Young Kim, MD *, z; So-Hee Lee, MD *, z, x; Sun Sin Kim, MD, PhD *, z, x; and Sang Heon Cho, MD, PhD *, z, x * Institute
of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea z Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea x Seoul National University Hospital, Healthcare System Gangnam Center, Seoul, Korea y
A R T I C L E
I N F O
Article history: Received for publication October 18, 2013. Received in revised form February 12, 2014. Accepted for publication February 20, 2014.
A B S T R A C T
Background: Recent studies suggest an association between allergic diseases, including asthma, and lower vitamin D level, a well-known risk factor of osteoporosis. However, it is not yet clearly known whether patients with asthma are prone to bone loss. Objective: To evaluate whether the occurrence of airway hyperresponsiveness (AHR) or asthma is related to significant changes in bone mineral density (BMD). Methods: We retrospectively enrolled 7,034 patients who had undergone a health checkup program, including BMD tests and methacholine bronchial challenge tests, at the Seoul National University Hospital, Healthcare System Gangnam Center, from November 1, 2004 to April 30, 2011. Asthma was ascertained by self-reported medical diagnosis by a physician. Patients with a history of systemic corticosteroid medication use were excluded from the study. Results: Among a total of 7,034 patients, 216 (3.1%) had a positive AHR test result, and 217 (3.1%) had a history of asthma. Lumbar spine and femur BMD of patients with AHR were significantly lower than those without AHR (0.53 1.50 vs 0.03 1.49, 0.47 0.97 vs 0.22 0.99, respectively; P < .001 for both). After being adjusted for age, sex, body mass index, smoking status, postmenopausal state, and previous history of hormone replacement therapy, the proportion of patients with osteopenia or osteoporosis was much higher in the AHR-positive group than in the AHR-negative group (odds ratio, 1.715; 95% confidence interval, 1.252-2.349) and in the ever-asthma group than in the never-asthma group (odds ratio, 1.526; 95% confidence interval, 1.120-2.079). Conclusion: In the current study, AHR and asthma were related to clinically meaningful BMD decrease, although the causal relationship is unclear. Ó 2014 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Introduction Allergic diseases and osteoporosis are common in the general population worldwide. More than 20% of the general population has allergic diseases, including allergic rhinitis and asthma.1 Prevalence of osteoporosis is as high as 13.1% for men and 24.3% for women in Korean adults aged 40 to 79 years.2 Therefore, osteoporosis results in major personal and societal costs because of its high morbidity and mortality related to low-trauma fractures in elderly people.3 However, little attention has been paid to the association between allergic diseases and bone loss in the past. Most of the Reprints: Sang Heon Cho, MD, PhD, Seoul National University Hospital 101 Deahakro Jongno-Gu Seoul 110-744 Korea; E-mail: [email protected]. Jae-Woo Jung and Hye-Ryun Kang have contributed equally as first authors. Disclosures: Authors have nothing to disclose. Funding: This study was supported by grant HI10C2020 from the Korea Healthcare Technology R&D Project, Ministry for Health and Welfare, Republic of Korea.
previous studies on bone mineral density (BMD) or osteoporosis in asthma were mainly focused on the adverse effects of prolonged corticosteroid treatment.4 Systemic corticosteroid use, a known risk factor of osteoporosis, increases the risk of fractures in asthma patients in a dose- and duration-dependant manner.4e6 Several studies have reported a dose-related association between use of an inhaled corticosteroid (ICS) and decline in BMD.7,8 In recent decades, many studies have been performed on the association between allergic disease and vitamin Ddan important factor in bone mineralization. The serum vitamin D levels of patients with asthma or airway hyperresponsiveness (AHR) are relatively lower compared with those of healthy controls, and lower levels of vitamin D were found to be related to increased asthma severity and more frequent exacerbations.9,10 Considering that life-long persistence of asthma developed in adulthood and the major role of vitamin D in bone mineralization, asthma morbidity itself can be a potential risk factor for bone loss. However, there are no definite data revealing the status of BMD in
1081-1206/14/$36.00 - see front matter Ó 2014 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.anai.2014.02.013
J.-W. Jung et al. / Ann Allergy Asthma Immunol 112 (2014) 426e431
patients with asthma. We performed a large-scale, cross-sectional study on patients who underwent an annual heath checkup and investigated the association between asthma or AHR and BMD.
427
correlation analysis was used to confirm the association between AHR level and BMD. P < .05 was considered statistically significant. Results
Methods Study Design This was a cross-sectional study performed on patients older than 18 years who had undergone a health checkup program at the Seoul National University Hospital Healthcare System Gangnam Center from November 1, 2004 to April 30, 2011. Electronic medical records of the patients were reviewed. Among 7,078 patients who had undergone both BMD and methacholine bronchial provocation tests, 44 recipients with a history of systematic corticosteroid use were excluded, leaving a total 7,034 recipients for subsequent analysis. The BMD test was included in the routine basic health checkup program, and the methacholine bronchial provocation test was performed optionally in patients who had selected it. The methacholine bronchial provocation test and the BMD test were performed on the same day because all health checkup programs provided in our center are designed to be completed within a half day. We investigated each patient’s age, sex, smoking status, comorbidity (eg, hypertension, diabetes mellitus, asthma, and allergic rhinitis) diagnosed by a physician, body mass index (BMI), white blood cell counts, peripheral eosinophil counts, serum creatinine level, alanine transaminase level, alkaline phosphatase (ALP) level, serum total IgE level, pulmonary function, and presence of atopy. For women, information on menopause and history of hormone replacement therapy (HRT) was also recorded because of their potential to affect BMD. Atopy was defined as positivity to at least one common inhalant allergen in the skin prick test or the multiple allergen simultaneous test (MAST; Hitachi Chemical Diagnostics Inc, Mountain View, California). This study was approved by the institutional review board of Seoul National University Hospital, and informed consent was waived.
Patient Demographics Among a total of 7,034 patients, 2,909 (41.4%) were male, and the mean (SD) age was 55.62 (10.78) years (Table 1). Hypertension, found in 27.4%, was the most common underlying disease, followed by diabetes, asthma, and allergic rhinitis. Skin tests or MASTs were performed in 73.4% of study patients (957 skin tests and 5,147 MASTs), and the atopy rate was 44.1%. In women, 65.6% were postmenopausal, and 15.4% had previous experience with HRT. The mean (SD) FEV1 predicted value of the study patients was 104.96% (14.51%), and the forced vital capacity (FVC) predicted value was 97.38% (12.12%). In the methacholine provocation test, 216 (3.1%) had positive AHR test results (Table 2). Among 217 patients with a history of physician-diagnosed asthma, 40 (18.4%) demonstrated AHR on testing. Of the 6,817 patients without a history of asthma, 176 (2.6%) had positive AHR test results. Mean (SD) lumbar and femur BMD were 0.04 (1.49) and 0.23 (0.99), respectively. A total of 2,110 patients (30.0%) had osteopenia; 290 (4.1%) had osteoporosis. Comparison of Clinical Characteristics According to AHR When the patients were grouped according to AHR, the positive group was older and had a higher current smoking rate compared with the negative group (P < .001 for both; Table 2). Atopy rate was also higher in the AHR-positive group than in the AHR-negative group (56.4% vs 43.8%; P ¼ .007). The mean (SD) FEV1 predicted value (91.83% [13.37%] vs 105.38% [14.35%]; P < .001) and the mean (SD) FEV1/FVC value (71.11% [7.79%] vs 79.49% [6.62%]; P < .001) were significantly lower in the AHR-positive group than in the AHRnegative group. BMI, postmenopausal state, and history of HRT did not differ between the groups. Serum creatinine, calcium, and phosphorus
Methacholine Bronchial Challenge Test Methacholine was inhaled as an aerosol using a nebulizer (DeVilbiss, Carlsbad, California) and Rosenthal-French dosimeter (Laboratory for Applied Immunology, Baltimore, Maryland) in 5 inspiratory capacity breaths.11 The nebulizer used in the study delivered 9 mL of solution per 0.6-second actuation during inhalation. The methacholine concentrations used were 0.0625, 0.25, 1, 4, and 16 mg/mL. The test was stopped when the forced expiratory volume in 1 second (FEV1) decreased 20% or more from the baseline. AHR was defined as the provocative concentration of methacholine that causes a 20% decrease in FEV1 from the baseline (PC20) being 16 mg/mL or lower. BMD Evaluation By using DEXA (LUNAR Prodigy; GE Medical, Chalfont St Giles, United Kingdom), we measured BMD of lumbar spines (L1-L4) and femur. On the basis of the lowest Tscores, we classified the patients into 3 groups according to the criteria of the World Health Organization.12 Normal BMD was defined as a T score of 1.0 SD or greater; osteopenia, between 1.0 and 2.5 SDs; and osteoporosis, 2.5 SDs or less. Statistic Analysis Analysis was performed with SPSS statistical software, version 17.0 (SPSS Inc, Chicago, Illinois). Both c2 and t tests were used for comparisons according to the presence of AHR or allergic disease. We performed linear regression tests and binary logistic regression tests to adjust for other factors that could affect BMD. A Pearson
Table 1 Demographic characteristics of the study population Characteristic
Finding (N ¼ 7,034)
Male, No. (%) Age, mean (SD), y Body mass index, mean (SD) Smoking status, non/ever/current, % Postmenopausal state in females, No. (%) Hormone replacement therapy in females, No. (%) Hypertension, No. (%) Allergic rhinitis, No. (%) Diabetes mellitus, No. (%) Bronchial asthma, No. (%) Atopy, No. (%) Airway hyperresponsiveness, No. (%) Blood WBC counts, mean (SD), /mL Blood eosinophil counts, mean (SD), /mL Serum total IgE, mean (SD), U/mL Alanine transaminase, mean (SD), IU/L Creatinine, mean (SD), mg/dL Alkaline phosphatase, mean (SD), IU/L Calcium, mean (SD), mg/dL Phosphorus, mean (SD), mg/dL FEV1, mean (SD), % predicted FVC, mean (SD), % predicted FEV1/FVC, mean (SD), % Bone mineral density Lumbar spine, mean (SD) Femur, mean (SD) Normal/osteopenia/osteoporosis, %
2,909 (41.4) 55.62 (10.78) 23.94 (2.95) 49.5/29.5/21.0 1,907/2,909 (65.6) 448/2,900 (15.4) 1,920 (27.4) 556 (10.6) 639 (9.1) 217 (3.1) 2,274/5,159 (44.1) 216 (3.1) 5,604.00 (1,597.23) 156.51 (154.01) 215.39 (652.06) 26.71 (20.74) 0.98 (0.22) 61.34 (19.21) 9.24 (0.38) 3.59 (0.56) 104.96 (14.51) 97.38 (12.12) 79.23 (6.81) 0.04 (1.49) 0.23 (0.99) 65.9/30.0/4.1
Abbreviations: FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; WBC, white blood cell.
428
J.-W. Jung et al. / Ann Allergy Asthma Immunol 112 (2014) 426e431
Table 2 Comparison of clinical characteristics according to airway hyperresponsiveness Characteristic
Airway hyperresponsiveness
Patients, No. (%) Male, No. (%) Age, mean (SD), y Body mass index, mean (SD) Smoking status, non/ever/current, % Atopy, No. (%) Postmenopausal state in females, No. (%) Hormone replacement therapy in females, No. (%) Creatinine, mean (SD), mg/dL Alkaline phosphatase, mean (SD), IU/L Calcium, mean (SD), mg/dL Phosphorus, mean (SD), mg/dL FEV1, mean (SD), % predicted FVC, mean (SD), % predicted FEV1/FVC, mean (SD), %
P value
Negative
Positive
6,818 (96.9) 3,990 (58.5) 55.47 (10.76) 23.93 (2.93) 49.9/29.5/20.5 2,208/5,042 (43.8) 1,847/2,828 (65.3) 439/2,820 (15.6) 0.98 (0.22) 61.15 (19.16) 9.24 (0.38) 3.59 (0.55) 105.38 (14.35) 97.51 (12.11) 79.49 (6.62)
216 (3.1) 135 (62.5) 60.47 (10.56) 24.22 (3.29) 35.6/29.4/35.1 66/117 (56.4) 60/81 (74.1) 9/80 (11.3) 0.99 0.20 67.07 (20.03) 9.20 (0.37) 3.61 (0.74) 91.83 (13.37) 93.18 (11.97) 71.11 (7.79)
NS
