Low bone mineral density and chronic obstructive pulmonary disease – A missed correlation

Introduction

Chronic obstructive pulmonary disease (COPD) is a common, preventable and treatable disease that is characterized by symptoms of persistent and progressive shortness of breath, chronic cough, weakness, fatigue, etc., leading to reduction in their activities of daily living. Significant co-existing diseases would have an impact on both morbidity and mortality1 in these patients. COPD is now recognised as a systemic disease complicated with various coexisting conditions including cardiovascular abnormalities, cancer of lung, wasting of muscles, reduction in bone mineral density, Diabetes mellitus, Metabolic syndrome and neuropsychiatric manifestations including anxiety or depression.1, 2 Management of the related coexisting diseases in COPD patients is clinically very important to reduce the aftereffects of the associated conditions on COPD disease itself. Osteoporosis is a systemic bony disorder which is characterised by the reduction in bone mass along with or without microarchitectural degradation of bone tissue leading to reduction in bone strength and increased risk of fractures.3 The gold standard method to diagnose Osteoporosis is Dual-Energy X ray Absorptiometry (DXA). Osteoporosis occurrence in COPD patients is often neglected owing to the decreased knowledge about it. Osteoporosis is associated with reduced body mass index, reduced fat free mass, and increased fragility of bones. Low bone mineral density with increased fracture risk is commonly observed in COPD patients when observed in the long run. An association between use of higher doses of inhaled corticosteroids and the chances of fractures are observed. Use of high dose Oral or intravenous corticosteroids significantly increases the risk of acquiring Osteoporosis. Known risk factor for osteoporosis in the healthy and diseased population are female sex, old age, reduced body mass index, underweight, chronic corticosteroid therapy, hyperthyroidism and primary hyperparathyroidism. In COPD, the occurrence of osteoporosis is assumed to be two-to-five fold higher than the healthy adults without airflow obstruction.4 Reduction in bone mineral density (BMD) has higher occurrence in patients with COPD.5 The treatment of osteoporosis is done according to the usual guidelines even in COPD patients. When fractures occur as a consequence of reduction in their bone mineral density in these patients, their activities of daily living are further restricted which leads to muscle deconditioning and further worsening of the disease. Thus, an early diagnosis should aim at the preventive and therapeutic aspects which could avoid or reduce the consequences of osteoporosis in those patients. The present study was undertaken to measure the occurrence of low bone mineral density leading to osteoporosis or osteopenia development in COPD patients attending a tertiary care hospital, and to propose the various risk factors which can contribute to the occurrence of osteoporosis and osteopenia in them.

Materials and Methods

The study was done in the department of T.B. and Respiratory diseases in Sir Sunderlal Hospital, Institute of Medical Sciences, Banaras Hindu University during the period of September 2019 to July 2021.One hundred patients of COPD attending the outpatient clinic or hospitalized in our ward who confirmed the spirometry GOLD diagnostic criteria (FEV₁/FVC < 0.70) and who gave informed consent has been selected for the study. Study subjects were subjected to thorough clinical history, spirometry evaluation to grade the airflow obstruction severity, mMRC grading, COPD assessment test (CAT), Six-minute walk test (6MWT), serum calcium levels, serum vitamin 1,25-dihydrocholecalciferol (D3) levels, DXA scan of Lumbar spine to assess Bone Mineral Density (BMD), Body Mass Index (BMI), CRP Levels, chest X-Ray, X-Ray of the thoracic and lumbar vertebra and of Pelvis to rule out pathological fractures.

Osteoporosis in COPD

Etiopathogenesis of COPD involves the lungs and various other systems, such as skeletal muscle wasting, diabetes mellitus, neuropsychiatric conditions like anxiety, depression or pyschosis, heart disorders, metabolic syndrome and anemia. COPD is characterized by persistent levels of systemic inflammation due to presence of circulating cytokines, chemokines and leucocytes.6 The inflammation grade increases during exacerbations with increase in cytokines and leucocytes leading to further worsening in lung function and various systemic outcomes. Lee et al7 proposed the mechanism of increased reactive oxygen species causing intracellular oxidative stress in severe and very severe COPD subjects. Sedentary behaviour due to worsening of shortness of breath can lead to the occurrence of skeletal muscle weakness and fatigue in COPD patients. They are associated with poorer outcomes as they lead to further deterioration in functional as well as lung status of the patient. COPD patients on the longer run can develop reduction in their bone mineral density predisposing them to development of osteoporosis and sarcopenia. They are well documented in various studies done by the researchers. A strong connotation exists between COPD and Osteoporosis because of common risk factors such as increasing age, underweight (low BMI < 18.5 kg/m2), increased pack years of smoking, persistent inflammatory status, oral or intravenous glucocorticoid use, and reduced physical activity. Large variances have been found in the physical activity levels of COPD patients. Katajisto et al., observed high levels of reduced physical activity and increased awareness of shortness of breath in COPD patients. Reduction in physical activity is an important risk factor for the development of osteoporosis and previous studies have suggested that graded exercises such as those in pulmonary rehabilitation can prevent bone loss. The reduced physical activity in COPD patients is because of various contributory sources like sedentary lifestyles, higher degrees of airflow obstruction, higher mMRC grading, muscle deconditioning with worsened function usually of leg muscles, and use of long-term oxygen therapy. These patients may acknowledge increased shortness of breath during exertional activities, which can lead to a vicious cycle of physical inactivity, muscle deconditioning, and further increased shortness of breath on exertion. This vicious cycle results in reduction of bone mineral density and predisposes them to bony structural deformities and increased risk of fractures. Hence in an ideal set up, all patients with COPD should be screened for osteoporosis using BMD measurements made by DXA scan for the early diagnosis, so that treatment of osteoporosis can be started at the earliest. This will help in improving the quality of life in those patients and thus reducing the disability, morbidity and mortality associated with this condition.

Table 1

Risk factors for osteoporosis in COPD8

1.	General/Common
	Older age
	Low BMI
	Reduced physical activity
2.	Disease-specific
	Systemic inflammation
	Pulmonary dysfunction
	Glucocorticoid use
	Vitamin D insufficiency/deficiency

Figure 1

COPD related factors for OP & functional consequences9

Results

A total of 100 cases of COPD confirmed by spirometry and satisfying the GOLD criteria were included in the final analysis. The spirometry criteria for airflow limitation is a post-bronchodilator fixed ratio of FEV₁/FVC < 0.70. Patients are classified into various stages of COPD based on the following degrees of severity of airflow obstruction.

Figure 2

GOLD grading of severity of airflow obstruction10

The World Health Organization (WHO) defines osteoporosis as a bone density that falls 2.5 standard deviations (SD) below the mean for young healthy adults of the same age, sex and race, also referred to as a T-score of -2.5.

Figure 3

WHO definition of osteoporosis and osteopenia3

The patients in the age group of 65-75 were found to be with increased number of COPD cases.

BMI (kg/m²) grading has been based on WHO Asian- BMI classification where patients with BMI < 18.5 is classified as underweight, BMI of 18.5 to 22.9 is classified as normal, BMI of 23 to 24.9 is classified as overweight, BMI of 25 to 29.9 is classified as Obese-I, and BMI of >30 is classified as obese-II.

The patients were divided into those having osteoporosis, osteopenia and normal Bone Mineral Density (BMD) based on WHO definition of T-score.

Discussion

The COPD patients had higher number of osteoporosis than the general population. In the present study, prevalence of osteoporosis was observed to be 52% and that of osteopenia to be 22%. Various research studies done in the world confirmed prevalence of osteoporosis to be 9-69% in COPD affected person versus 0-13% in healthy people.11 Among a variety of studies on osteoporosis in COPD patients, Graat Verboom et al5 and TORCH trial were the important ones. They discovered occurrence of osteoporosis to be 21% and 65% and that of osteopenia 41% and 65% respectively. A recent Indian research12 done among 37 patients of COPD showed occurrence of osteoporosis and osteopenia to be 21.6% and 27% respectively in those patients. We have used DXA scan for the diagnosis and detection of osteoporosis, which is regarded as a gold standard tool and the subjects were categorised based on T-score according to the World Health Organization (WHO) definition of osteoporosis. The variances in distribution of osteoporosis has been due to differences in the study people characteristics, various age groups, co-morbidities, previous history of rheumatic disorders and other factors.

In a meta-analysis done by Graat Verboom et al.,5 involving 13 studies with a total of 775 COPD patients, there were more male patients (67%) and the prevalence of osteoporosis varied from 9 to 69% and the prevalence of osteopenia varied from 27 to 67%. Various studies showed the higher number of osteoporosis cases in the female population. In our study, there were more male patients compared to female patients. Anyhow, the prevalence of osteoporosis was higher among female patients with a prevalence of 64.9%. Osteopenia was higher among the male patients with a prevalence of 22.2%.

Advancing age is an independent risk factor for development of osteoporosis in the general population.3 COPD patients in the higher age group division has been found to have a higher number of osteoporosis cases in various studies. The patients of osteoporosis were more in the 65-75 age group in the present study. The prevalence of osteoporosis in the age groups 45-55, 55-65, 65-75, 75-85, >85 was 7.7%, 25%, 40.4%, 13.4%, 13.4% respectively in the present study. The risk of osteoporosis increased in the older age groups. It has been consistent with Graat-Verboom et al.,5 and Hattiholi and Gaude et al.,9

There is a certain correlation between severity of COPD disease and risk of osteoporosis both in terms of T-score as well as bone mineral density. In the present study, majority of patients who had osteoporosis had stage III and stage IV COPD Disease. In a study by Jorgensen et al.,13 it was observed that there was increased incidence of reduction in bone mineral density in severe stages of COPD disease. Another study by de Vries, et al.,14 observed that the risk of fractures associated with osteoporosis increased in patients with COPD. It was also detected that patients with more severe airflow obstruction in COPD had higher risk of osteoporosis and bone fractures. Gratt Verboom et al.,5 observed that the prevalence of osteoporosis increased with the severity of airflow obstruction in COPD. In another study by Vries et al.,14 it was observed that prevalence of osteoporosis was higher in the severe and very severe stages of COPD disease as compared to mild and moderate stages. Our study has prevalence of 51.92% and 44.23% in GOLD stage III and stage IV respectively. The mean FEV₁% osteoporosis and osteopenia in our study group were 58.35±11.01 and 65.55±14.18 respectively.

Use of inhaled or systemic corticosteroids for the symptom relief and during exacerbations in the COPD disease has also been evaluated as an independent risk factor for the development of osteoporosis. The dose of steroids used during exacerbation of COPD disease is much higher which in the long run can predispose to the higher incidence of reduced bone mineral density. The exacerbations make the patients prone to their bed-ridden status. The rising prevalence of glucocorticoid induced bone loss is so common that the National Osteoporosis Foundation15 formulated the guidelines and recommended that every patient’s receiving chronic corticosteroid treatment for more than 1 month with 7.5 mg/day of prednisone or its equivalents should undergo screening for osteoporosis. In the present study, most of the patient with COPD were prescribed steroids during exacerbations and steroid use increased with the higher number of exacerbations and hospitalizations. All the patients were characterized as those not on any steroids, those who used only inhaled steroids, those who used < 1,000 mg of steroids (Cumulative dose; equivalent of prednisolone). Osteoporosis was observed to be high in those using >1000mg (cumulative dose, prednisolone) and the association was statistically significant (p<0.001). COPD patients on higher doses of glucocorticoid therapy exhibit a rapid decline of their bone mineral density within the first 6 months.16

Smoking has been found to be an independent risk factor for the development of osteoporosis in men as well as women. Incalzi et al,17 reported that lumbar spine BMD was 12% lower in smokers who have smoked 20 pack years compared to non-smokers. Both vertebral fractures and hip fractures are increased in smokers. The present study has prevalence of osteoporosis around 53.7% in smokers. Prevalence of osteoporosis was observed to be more in those with history of smoking more than 10 pack years.

It was observed that patients with low body weight and low Body Mass Index (BMI) had higher prevalence of osteoporosis9 (55.6%) as compared to overweight patients. It was observed that obese individuals had some protective effect against development of osteoporosis. The present study also had increased number of osteoporosis patients belonging to the underweight group and those with normal BMI.

The present study shows higher prevalence of osteoporosis (68 .6%) among patients who had 2 or more moderate to severe exacerbations or one leading to a hospital admission and is statistically significant.

It has been observed that patients with CAT scores more than10 has associated with higher prevalence of osteoporosis (70.6%) and is statistically significant with a p value of <0.001.

The mean BMD (gm/cm²) observed in our study group with osteoporosis and osteopenia were 0.74±0.10 and 1.12±0.27 and is statistically significant (p<0.001). It has been observed that reduced BMD is associated with increased risk of osteoporosis in COPD subjects.5

It has been observed that vitamin D3 levels has been significantly reduced in COPD patients and has been an independent risk factor development of osteoporosis.9 Our study had increased number of osteoporosis cases in those with vitamin D deficiency.

Conclusion

In conclusion, it was observed that reduction in bone mineral density and development of osteoporosis in COPD patients is multifactorial. The clinical implication of these individual risk factors varies in different studies. It is evident from the present study that the patients with moderate-to-severe stages of COPD who have advanced nature of the disease which predisposes them to osteoporosis, by virtue of being elderly or chronically disabled, and having chronic systemic inflammation. COPD in recent years has been recognized as an inflammatory condition of the lung and has been recognized for its systemic inflammation and the presence of extrapulmonary manifestations. Patients with COPD are often treated with oral or parenteral glucocorticoids, during exacerbations. Such oral or parenteral glucocorticoid therapy along with various other risk factors clearly increases the risk for the development of osteoporosis in these patients.

Hence, in an ideal set up, all patients with COPD should be screened for osteoporosis using BMD measurements made by DXA scan, which is considered as the gold standard tool for the early diagnosis and so proper therapy for this condition can be started at the earliest to prevent further disability. This aids in discovering osteoporosis at an early stage and helps in the treatment of it and also prevents further decline in patient day-to-day activities, bedridden status and fall in FEV₁. This will help in improving the quality of life in these patients and thus improving the morbidity and mortality of this condition.

Source of Funding

None.

Conflict of Interest

The authors declare no conflict of interest.