Bone mineral density and vitamin D levels in patients with group a COPD

Abstract

Introduction

Chronic Obstructive Pulmonary Disease (COPD) is a chronic, inflammatory airway disease associated with osteoporosis. Reduced bone mineral density (BMD) and impaired bone quality were shown to cause increased bone fragility and fractures in COPD patients. The aim of this study was to evaluate vitamin D levels and BMDs in Group A COPD patients.

Methods

This case-control study involved 33 males aged 50 or above diagnosed with Group A COPD and 44 age-matched healthy males. Participants’ serum vitamin D and other indicators were evaluated as well as lumbar and hip BMD of COPD patients.

Results

Vitamin D levels were significantly lower in COPD patients (15.13 ± 6.02 ng/L) than controls (21.89 ± 4.49 ng/L). Two patients had a history of thoracic vertebral fracture. Lumbar (L1–L4) T scores were normal in 16 patients (48.5%) and indicated osteopenia in 15 (45.5%) and osteoporosis in 2 (6%). Hip femur total T scores were normal in 19 patients (57.6%) and indicated osteopenia in 14 (42.4%).

Conclusion

Vitamin D deficiency/insufficiency is prevalent in COPD patients, and BMD decreases in the early period of the disease. Vitamin D and BMD should be evaluated in the early stages to prevent osteoporosis and its complications in COPD patients.

Keywords:

• COPD
• osteoporosis
• vitamin D
• bone mineral density

Introduction

Chronic Obstructive Pulmonary Disease (COPD) is a chronic, inflammatory disease characterized by progressive and irreversible airway restriction. COPD is associated with various systemic comorbidities, including osteoporosis, ischemic heart disease, sarcopenia, and anxiety/depression [1]. The main focus of treatment is to eliminate the symptoms and comorbidities due to pulmonary dysfunction [1].

Osteoporosis is characterized by increased bone fragility and increased the probability of fractures due to low bone mass and deterioration of bone tissue microstructure. Osteoporosis is considered to be one of the major complications leading to increased morbidity and mortality in COPD [2]. In COPD patients, osteoporosis develops in connection with the decreased physical activity and skeletal muscle mass due to dyspnea in lung diseases, systemic inflammation, pharmaceutical treatments (especially corticosteroids), aging, vitamin deficiencies, hypogonadism, smoking, and alcohol consumption [2,3]. COPD is among important causes of secondary osteoporosis. It has been reported that osteopenia was observed in 35–72% and osteoporosis was observed in 22–44% of patients with COPD [3,4].

Vitamin D is a prehormone with secosteroid structure targeting ubiquitous receptors in various tissues [5]. The effects of vitamin D on pulmonary and immune systems as well as the musculoskeletal system have been reported in the patients with COPD [5].

In order to increase the quality of life of the patients with COPD, it is also important to assess bone mineral density (BMD), take preventive measures, and start osteoporosis treatment before fracture formation [6]. The aim of this study was to evaluate vitamin D levels and the BMD in Group A COPD patients based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines.

Materials and methods

Patients

This case-control study included GOLD Group A COPD patients who were followed up and treated at clinic of Chest Diseases of Izmir Dr. Suat Seren Chest Diseases and Thoracic Surgery Training and Research Hospital. They were referred to the outpatient clinic for Physical Medicine and Rehabilitation of İzmir Tepecik Training and Research Hospital. The study was approved by the local Ethics Committee (Approval # 2018/10–3).

The study included a total of 33 patients who were 50 years or older, had been diagnosed with Group A COPD based on Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 guidelines for at least one year [7], were not receiving corticosteroids and bronchodilator therapy as a medical treatment, and who volunteered to participate. The study excluded those who were Group B, C, or D, had respiratory diseases other than COPD, had diseases that would affect bone metabolism (endocrine, renal, metabolic, hepatic, rheumatologic), or used medications that would affect bone metabolism. The control group included 44 volunteers who were 50 years and older, had no respiratory disease, were nonsmokers, and had no disease or took no medication that would affect bone metabolism in the last 12 months (vitamin D, calcium, bisphosphonate).

The work plan

The pulmonologist diagnosed patients with GOLD Group A COPD diagnosis based on clinical examination and laboratory tests (Modified British Medical Research Council Questionnaire for breathlessness – mMRC) Table 1, COPD Assessment Test (CAT).

Table 1. mMRC: Modified Medical Research Council Dyspnea Scale.

mMRC 0: Dyspnea only with strenuous exercise

mMRC 1: Dyspnea when hurrying or walking up slight hill

mMRC 2: Walks slower than people of the same age because of dyspnea or has to stop for breath when walking at own pace

mMRC 3: Stops for breath after walking 100yards(91 m) or after a few minutes

mMRC 4: To dyspneic to leave house or breathless when dressing

GOLD Staging [7]:

• Group A: Exacerbation history ≤ 1 (not leading to hospital admission), mMRC ≤ 1, CAT < 10

• Group B: Exacerbation history ≤ 1 (not leading to hospital admission), mMRC ≥ 2, CAT ≥ 10

• Group C: Exacerbation history ≥ 1 (leading to hospital admission), mMRC ≤ 1, CAT < 10

• Group D: Exacerbation history ≥ 1 (leading to hospital admission), mMRC ≥ 2, CAT ≥ 10

COPD Assesment Test (CAT)

This is a patient-completed questionnaire assessing all aspects of the impact of COPD (cough, sputum, breathlessness, chest tightness, confidence, activity, sleep and energy levels) There are 8 questions on a 1 to 5 point scale [7].

Group A patients were not receiving medical treatment.

The physical therapy and rehabilitation specialist recorded the demographic characteristics (age, occupation, duration of COPD, smoking, body mass index (BMI), history of fracture) of the patients during face-to-face interviews or form patient files.

Pack-year history of smoking is the number of packs of cigarettes smoked per day multiplied by the number of years the person has smoked and indicates the amount of smoking; >20 is considered high.

The presence of the fracture was questioned; if present, its location was recorded (hip, dorsal, lumbar, radius, or other regions).

Serum vitamin D, calcium, phosphorus, and parathormone levels were measured in the patient and control groups. Bone mineral density (BMD) was assessed in the patient group. The BMD was not studied in the control group since there was no indication for doing so.

Biochemical markers

Serum calcium, phosphorus, parathormone were determined by standard methods. Vitamin D level was measured as serum 25(OH)-Vitamin D with COBAS 411 (Roche Diagnostics) using electrochemiluminescent immunoassay (ECLIA) method [8]. Vitamin D levels were stratified as a deficiency (<20 ng/L), insufficiency (21–29 ng/L), and adequate (≥30 ng/L) [8].

BMD measurement

Bone mineral density was measured using dual-energy X-ray absorptiometry (DEXA) with Hologic QDR-1000 densitometer (Waltham, MA, USA). The DEXA method is considered to be the gold standard for BMD measurement. Lumbar spine (lumbar L1–L4) and hip (femur total) T scores were used [9]. The T score defines the difference between the measured BMD and the average BMD of a standard young adult population in terms of standard deviation (SD) and refers to peak bone mass. According to World Health Organization criteria, a T score of ≥ −2.5 SD indicates osteoporosis, a T score between −1 and −2.5 SD indicates osteopenia, a T score of< −1 indicates normal BMD. Osteoporosis can be diagnosed by T score values alone in postmenopausal women and men ≥ 50 years old according to regarded guidelines. The use of Z score is recommended for the diagnosis of osteoporosis in premenopausal osteoporosis and men <50 years old [9].

Statistical methods

The data were analyzed with SPSS v21 program (SPSS Inc., Chicago, IL, USA). In descriptive statistics, number and percentage distribution were used for categorical data; mean ± SD were used for numerical data. Normal distribution of the numerical data was analyzed with the Kolmogorov–Smirnov test. Mann–Whitney U test was used to compare the vitamin D levels in the patient and control groups; the Wilcoxon test was used to compare lumbar T scores and femur T scores in COPD patients. The level of statistical significance was set at 95% confidence interval (CI); p < .05 was considered statistically significant.

Results

The study included 33 male patients and 44 healthy male controls. The mean age was 55.64 ± 6.65 years in the patient group and 57.45 ± 5.30 years in the control group; groups were similar in terms of age distribution (p > .05). Demographic and clinical characteristics of the patient group were given in Table 2.

Table 2. Demographic and clinical characteristics of COPD patients.

Characteristic	n	%	Mean ± SD
Age			55.64 ± 6.65
Gender (male/female)	33/0	100/0
Smoking (pack-year)			35 ± 12.5
Occupation
Worker	18	56
Public Servant	5	14
Retired	8	25
Self-employed	2	5
COPD duration (year)			1.2 ± 0.6
BMI (kg/m^2)			28.71 ± 5.36
Normal	10	30.3
Overweight	9	27.3
Obese	14	42.4
FEV1 (%)			81.4 ± 1.5
FEV1 (mL)			2659 ± 377
FVC (%)			103 ± 6.2
FVC (mL)			3960 ± 588
History of fracture
Yes	2	5
No	31	95

COPD: chronic obstructive pulmonary disease; BMI: body mass index; FVC: forced vital capacity; FEV1: forced vital capacity in the first second.

The mean serum vitamin D levels were 15.13 ± 6.02 ng/L in the patient group and 21.89 ± 4.49 ng/L in the control group. The patient group had significantly lower vitamin D levels than controls (p = .015). The patient and control groups stratified based on vitamin D levels were given in Table 3.

Table 3. Serum vitamin D levels of the patient and control groups.

	COPD		Control
Vitamin D Levels	n	%	n	%
Deficiency (20 ng/L)	29	89	27	61.3
Insufficiency(21–29 ng/L)	3	9	5	11.4
Normal (30 ng/L< )	1	2	12	27.3

Lumbar region average BMD was 1.020 ± 0.224, and hip total average BMD was 0.953 ± 0.190; the difference between them was statistically significant (p = .008). The BMDs of the patient group stratified based on T scores were given in Table 4.

Table 4. The BMDs of the patient group stratified based on T scores.

	n	%
Lumbar (L1–L4) T Score
Normal	16	48.5
Osteopenia	15	45.5
Osteoporosis	2	6.0
Hip Femur Total T Score
Normal	19	57.6
Osteopenia	14	42.4
Osteoporosis	–	–

Discussion

Vitamin D deficiency or insufficiency was found to be very prevalent among early-stage (GOLD Group A) COPD patients (98%), their vitamin D levels were significantly lower than the age-matched controls. Based on BMD, osteopenia in lumbar and hip regions were found in 45.5% and 42.6% of these patients, respectively. Hip total BMD was significantly lower than that of the lumbar region. Changes in bone microstructure occur, thus, osteoporosis is one of the main comorbidities of COPD. Among these changes are the loss of bone mineral density, deterioration of bone quality, decrease in trabecular bone score, and low bone turnover; however, pathophysiology of bone fragility has not been fully understood [10].

COPD is an important cause of secondary osteoporosis, and the risk of osteoporosis was reported to be 1.5–2 times higher in patients with COPD compared to the normal population [11,12]. Regan et al. [13] found COPD in the etiology of osteoporotic hip fractures in 47% of the patients (n = 12.646) and emphasized that hip fractures were common in patients with COPD as well as decreased mobility and increased mortality.

Osteoporotic risk factors in COPD include age, smoking, low BMI, low BMD, decreased physical activity, systemic inflammation, pulmonary dysfunction, glucocorticoid use, and vitamin D deficiency or insufficiency [10–13]. In particular, age and smoking are common risk factors for COPD and osteoporotic fractures [12,13]. Smoking has been shown to decrease BMD proportional to the duration and quantity smoked and to increase the risk of vertebral fracture by 32% in men and by 13% in women. Wards et al. have shown that the effect of smoking on bone health varies with gender, with a dose-dependent effect independent of bone loss and an increased risk of fracture that can be partially reversed with quitting [14]. Smoking is known to have toxic effects on osteoblasts, disrupt osteoblastic differentiation and collagen synthesis in osteoprogenitor cells, and increase oxidative stress, thereby to increase the free radicals that lead to bone resorption, decrease estrogen and bone mineral content, and increase fracture risk [15–17]. Several studies reported that smoking and low BMI contribute significantly to the fracture risk in men with COPD [15–18]. Average pack-year smoking (35 pack-years) was very high in this study. The high rate of smoking may have a negative impact on BMD in patients with early-stage COPD.

The COPD guidelines are focused mostly on the prevention of weight loss to prevent comorbidities. Weight loss is particularly common in advanced COPD patients and is associated with poor prognosis. In general, BMI is a predictor of fracture risk. Cachexia and decreased bone mechanical loading associated with weight loss and low BMI accelerate osteoporosis in COPD [19]. In severe COPD, cachexia is attributed to systemic inflammation, oxidative stress, and increased cytokine levels such as tumor necrosis factor alpha (TNFα). Systemic inflammation and oxidative stress were suggested to cause metabolic abnormalities in the bone. Inflammatory cytokines interleukin-1β (IL-1β), IL-6, and TNFα increase bone resorption by influencing the osteoporosis-related proteins (OPG/RANK/RANKL system) [20]. Our study included early-stage COPD patients, and the average BMI was in the overweight range. Similarly, Verbene et al. found a greater portion of the early-stage COPD patients to have BMIs higher than 25 [21]. They found that osteoporosis and anxiety were less common in this group.

In BMD evaluation, approximately half of the patients without steroid use were found to have osteopenia in the lumbar and hip region; only 6% were found to have osteoporosis. Likewise, Graat-Velboom et al. [22] found the frequency of osteoporosis and osteopenia in 775 COPD patients as 9–69% and 27–67%, respectively. They emphasized that the most important factors were body composition, disease severity, and the use of corticosteroids. They also reported more severe osteoporosis in patients with advanced disease and waiting for a lung transplant. The fact that the patients in our study were in the early stages and did not use steroids might have contributed to a lower rate of osteoporosis.

Low bone mineral density due to osteoporosis is asymptomatic; however, vertebral fractures that appear with the progression of osteoporosis lead to pain in the back and lumbar region, height loss, kyphoscoliosis, reduced rib-pelvis distance, volume reduction in the chest cage, and restrictive type pulmonary dysfunction. Vital capacity and total lung capacity are also reduced. This leads to the aggravation of clinical symptoms of the disease [3,23].

It has been found that osteoporosis-associated kyphosis leads to limitations in the movement of ribs and in the function of inspiratory muscles, which was related to reductions in FEV1 and FVC [3]. Fractures are particularly evident in men with severe COPD who use glucocorticoids [23].

It has been reported that two-thirds of the vertebral fractures in COPD are asymptomatic and that the prevalence of vertebral fractures is 24–79%. Osteoporotic fractures in the vertebral region were most frequently reported in thoracic (T7–8) and thoracolumbar (T12–L1) regions [24]. Frequent coughing, dynamic lung compliance, and changes in respiratory muscle strength were found to affect the fractures in the thoracic region [24,25].

A significant increase in the frequency of hip and vertebral fractures in COPD was reported in Global Longitudinal Study of Osteoporosis Women (GLOW) [26]. Hip fractures were especially common in patients with advanced disease, lengthy hospital stay, steroid treatment, and low BMI [27]. A retrospective study of 87,360 men over the age of 50 years reported a 3 times higher risk of hip fracture in those with chronic lung disease compared to the normal population [28]. In our study, two patients had a history of thoracic vertebral fracture (4.5%) and these patients were osteopenic. Watanabe et al. [29] reported vertebral fractures in 79.4% of 132 COPD patients and found BMDs consistent with osteoporosis in only 38.8% of the patients with fractures. They found that the association between BMD and the fracture rate was lower than expected and suggested that BMD-independent mechanisms, the disease itself in particular, affected skeletal tissue and bone strength in patients with COPD.

In our study, the BMD in the hip region was lower than that in the lumbar region. This may be due to degenerative changes in the lumbar region and regional calcifications related to age; however, Duckers et al. [29] found that the BMD in the hip was lower than the lumbar region in those with mild to moderate COPD. They maintained that the mechanism for the loss of BMD was uncertain and emphasized the need for early identification of potential risk factors.

Vitamin D influences calcium absorption from the intestine, skeletal calcification, and muscle strength. Vitamin D has effects on the pulmonary system as well as on the musculoskeletal system. Therefore, it is of great importance for patients with COPD [30]. Vitamin D affects the pulmonary system through increasing the production of antimicrobial peptides, regulating the inflammatory response, and airway remodeling. It inhibits proinflammatory cytokine production and leads to the suppression of Th1 and Th17 responses that could play a role in the pathogenesis of COPD. Vitamin D deficiency may also contribute to chronic respiratory tract infections and airway colonization, thus optimizing the vitamin D levels in COPD patients may reduce bacterial load and concomitant exacerbations [30–32]. Vitamin D deficiency is a common global problem in all age groups. Vitamin D deficiency and insufficiency results in an increased risk of bone loss and fractures. It is also associated with muscle weakness and falls, which increase the risk of fractures [32]. Similar to our study, vitamin D deficiency has been reported to be quite common in patients with COPD.

Vitamin D is known to be associated with exercise capacity and BMD in COPD patients [33,34]. Vitamin D deficiency was reported to stem from poor sunlight exposure associated with decreased physical activity, poor nutrition, advanced age, smoking, and glucocorticoid use in COPD patients. Vitamin D levels were particularly reduced in the intermediate and advanced stages of the disease [33,35,36]. It has been shown that the vitamin D status was associated with femoral neck BMD in patients with advanced COPD, and vitamin D deficiency increased the risk of osteoporosis 7.5 times [37]. In a study of vitamin D levels in the COPD patients and a control group, Graat-Verboom et al. [38] found vitamin D deficiency in both groups but no difference between the groups. They emphasized that long-term vitamin D supplementation was effective in reducing acute exacerbations in patients with COPD [38–40].

Vitamin D should be administered at the appropriate dose and duration [41].

Conclusion

Vitamin D deficiency/insufficiency is prevalent in early-stage COPD patients who did not use steroids; bone mineral density decreases in the early stage of the disease. Vitamin D and bone mineral density should be evaluated in order to maintain bone health and to prevent osteoporosis, one of the common comorbidities of COPD, and other complications. Evaluations and taking necessary measures in the early stages could reduce fractures or the risk of fractures due to osteoporosis. This risk reduction, in turn, will lead to better prognosis and quality of life in patients with COPD in the longer-term.

Limitations of the study

1. No measurement of bone mineral density in the control group.

2. No measurement of free testosterone for male osteoporosis.

Disclosure statement

No potential conflict of interest was reported by the authors.