Lung-related risk factors associate with low bone mineral density in individuals with former tobacco exposure not meeting osteoporosis screening criteria

Abstract

Summary

Low bone mineral density (BMD) increases fracture risk, poor life-quality, and death. Low BMD is prevalent in tobacco-exposed individuals with lung disease; however, they are not included in current screening guidelines. In our study, a majority of individuals with former tobacco exposure not meeting current screening criteria had low BMD.

Purpose

Low bone mineral density (BMD) is prevalent in tobacco-exposed individuals with lung disease. Guidelines recommend dual x-ray absorptiometry (DXA) screening for osteoporosis in individuals with current tobacco use, but former tobacco use, chronic obstructive pulmonary disease (COPD), and emphysema are not recommended indications for screening. We hypothesized that tobacco-exposed individuals not meeting current osteoporosis screening guidelines have a high prevalence of low BMD, and that low BMD associates with lung-specific risk factors in this population.

Methods

We measured total hip, femoral neck, and lumbar spine BMD with DXA in a tobacco-exposed cohort of men and women 40 years of age and older with ≥ 10 pack years cigarette use. Osteoporosis screening eligibility was determined by modified Fracture Risk Assessment Tool (FRAX) criteria. We investigated lung-related factors associated with low BMD adjusting for age, sex, and diabetes.

Results

Of 472 individuals with former tobacco exposure, 28% did not meet study-defined osteoporosis screening criteria. Of participants not meeting screening criteria, 55% had low BMD on DXA assessment. The presence of CT-determined emphysema was associated with low BMD (adjusted OR 2.1, 95% CI [1.02, 4.42]) in participants not eligible for osteoporosis screening. Lung function, respiratory symptoms, pack years cigarette use, and inhaled corticosteroid use were not associated with low BMD.

Conclusion

Emphysema on chest CT scan independently associates with low BMD in tobacco-exposed individuals not meeting traditional osteoporosis screening criteria. These findings suggest that osteoporosis screening recommendations should include emphysema as a risk factor for early BMD assessment.

Introduction

Low bone mineral density (BMD) is common in individuals with chronic obstructive pulmonary disease (COPD), even in those at earlier clinical stages of disease [1–4]. Emphysema on chest CT imaging associates with low BMD independent of spirometric airflow obstruction and is predictive of BMD loss and fracture in individuals with current and former tobacco exposure [1, 4, 5]. While the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Report recognizes emphysema as an independent risk factor for osteoporosis, specific recommendations for screening are not provided [6]. In addition, general population osteoporosis screening guidelines do not include a diagnosis of COPD or emphysema with former tobacco use as an indication for early osteoporosis screening in individuals without other major risk factors [7].

Current osteoporosis screening guidelines recommend dual x-ray absorptiometry (DXA) assessment of BMD based on age, sex, and major osteoporosis risk factors [7]. Widely used risk assessment tools, such as the Fracture Risk Assessment Tool (FRAX), consider active tobacco use to be a major risk factor for osteoporosis but do not include a diagnosis of tobacco-related lung disease (i.e., radiographic emphysema or airflow obstruction) or former cigarette use as either a major risk factor for fracture or as an indication for DXA screening [8]. British guidelines use a similar age and risk assessment tool approach which incorporates additional chronic disease risk factors, including diabetes, but omits COPD or other chronic lung diseases [9]. From a global perspective, the World Health Organization recommends using risk assessment tools such as FRAX, though acknowledges that guidelines in different settings may vary depending on local availability of DXA scan [10]. We hypothesize that low BMD is prevalent in individuals with former tobacco exposure lacking major osteoporosis risk factors, and that low BMD is associated with lung-specific risk factors in this patient population.

Method

Study design and participants

The University of Pittsburgh single-center, COPD Specialized Center of Clinically Oriented Research (SCCOR) tobacco-exposed cohort enrolled males and females 40 years of age and older with current or former cigarette use (≥ 10 pack years) at enrollment (N = 574). Exclusion criteria for the SCCOR cohort included clinical or radiographic evidence of another pulmonary diagnosis (e.g., interstitial lung disease), history of lung cancer, new, suspicious nodule on CT scan, obesity with BMI > 35. The parent study excluded BMI > 35 because of concern for impact on lung function and systemic inflammation. All participants underwent pre- and post-bronchodilator spirometry, chest CT imaging, and shuttle walk testing. National Health and Nutrition Examination Survey spirometry prediction equations were used. Medical history, medication use, exacerbation history, and tobacco burden were self-reported. The St. George’s Respiratory Questionnaire, a validated tool which assesses respiratory symptoms and well-being, was used to quantify disease specific quality of life [11]. Participants underwent DXA measurement of femoral neck, total hip, and lumbar spine BMD. Our current analysis included SCCOR cohort participants with complete DXA measurements (n = 472). Research was conducted under University of Pittsburgh Institutional Review Board approved protocols and written informed consent was obtained for each participant.

Osteopenia was defined as a T score between − 1.0 and − 2.5 at any site (femoral neck, total hip, or lumbar spine), and osteoporosis was defined as a T score ≤  − 2.5 at any site. Osteoporosis screening eligibility was determined by the following criteria, which reflect age and major risk factors included in current guidelines [8, 12]: age ≥ 65 years for women, age ≥ 70 years for men, active smoking, oral glucocorticoid use, and history of rheumatoid arthritis. Alcohol use, a family history of osteoporosis or osteoporotic fracture, and prior fracture history were not available for cohort participants. CT-determined emphysema was assessed by blinded chest radiologist review, using a previously validated six-point semiquantitative scoring system [1], then further categorized into none, trace (1–9%), mild (10–24%), or moderate/severe (≥ 25%). High tobacco burden was defined as a report of greater than 30 pack years based on prior literature [13]. We adjusted our analyses for participant demographics. We also adjusted our analyses for diabetes because of its association with incident hip fracture [5].

Statistical analysis

Analyses were limited to cohort participants not meeting osteoporosis screening eligibility based on either age thresholds or having major FRAX-defined risk factors as described above. We assessed the association of lung-related risk factors, including post-bronchodilator FEV1% predicted, presence of emphysema on chest CT scan, symptom scores assessed by the SGRQ, exacerbation history, tobacco burden, shuttle walk distance (measure of exercise capacity), and inhaled corticosteroid use with low BMD using generalized logistic regression analysis adjusted for age, sex, and self-reported diabetes. Statistical analyses were conducted using the “glm” function in base R (Version 4.3, The R Foundation for Statistical Computing).

Results

Among 570 total participants in the SCCOR cohort, mean age was 65 years [interquartile range (IQR), 61, 70], 53.5% were male, 94.6% were white, 4.7% were African American, 50.2% had obstructive spirometry, and mean FEV1 was 92.6% predicted [IQR, 83.8%, 103%]. Of these total participants, 472 completed DXA measurements and 135 of the 472 (28%) participants with DXA measurements did not meet study criteria for BMD screening and were included in our analysis. Compared to cohort participants not analyzed (n = 435), participants not meeting screening criteria (n = 135) were more likely to be male (63.7% vs 50.5%), were younger (62 [IQR, 59, 64] vs 67 [IQR, 62, 72]), had less obstructive spirometry (37.0% vs 54.1%), had similar FEV1 (90.6% predicted [IQR, 77.2, 100] vs 92.0% predicted [IQR, 82.9, 101) and similar race demographics (96.3% vs 94.7% white).

Notably, more than half of the women and nearly half of the men who did not study meet criteria for BMD screening in fact had low BMD on study DXA (Table 1). Although the analysis only included individuals with former tobacco use, tobacco burden was high with a median tobacco exposure of 42.0 pack years (range, 10.0–184.0). Additionally, 37% exhibited obstructive spirometry patterns (FEV/FVC < 0.70), and the median BMI was 27.4 (range, 18.2–36.3). Diabetes, a known risk factor for fractures, was uncommon, affecting only 9.6% of the group (Tables 1 and 2).

Table 1.

Characteristics of participants not meeting osteoporosis screening criteria. Of note, no participants using oral steroids are included, as oral steroids are a major risk factor for osteoporosis. FEV1 forced expiratory volume in the first second, FVC forced vital capacity, low BMI =  < 18.5 kg/m²

	Total not meeting screening criteria (N = 135)	Normal BMD (N = 61)	Low BMD (N = 74)
Sex
Male	86 (63.7%)	44 (72.1%)	42 (56.8%)
Age median [IQR]	62.0 [59.0, 64.0]	62.0 [56.0, 69.0]	61.0 [40.0, 69.0]
FEV 1/FVC < 70	50 (37.0%)	18 (29.5%)	32 (43.2%)
FEV1% predicted median [IQR]	90.6 [77.2, 100]	90.9 [26.2,129]	90.4 [22.6, 123]
FEV1% predicted
< 30%	2 (1.5%)	1 (1.6%)	1 (1.4%)
30–49%	8 (5.9%)	3 (4.9%)	5 (6.8%)
50–79%	28 (20.7%)	9 (14.8%)	19 (25.7%)
≥ 80%	97 (71.9%)	48 (78.7%)	49 (66.2%)
CT emphysema (yes)	66 (48.9%)	24 (39.3%)	42 (56.8%)
Ever exacerbations (yes)	20 (14.8%)	9 (14.8%)	11 (14.9%)
BMI median [IQR]	29.3 [26.6, 31.8]	30.9 [28.7, 33.2]	28.0 [25.1, 30.9]
Low BMI	0 (0%)	0 (0%)	0 (0%)
Inhaled corticosteroids	39 (11.6%)	5 (8.2%)	12 (16.2%)
Diabetes	13 (9.6%)	9 (14.8%)	4 (5.4%)
Pack years median [IQR]	42.0 [30.0, 60.0]	43.0 [30.0, 60.0]	40.0 [30.0, 60.0]

Table 2.

Lung-related risk factors and low BMD in participants not meeting current screening criteria. *Adjusted for age, sex, diabetes. **Adjusted for age, sex. SGRQ, St. George’s Respiratory Questionnaire; shuttle walk, shuttle walk in 10 m scale

	Unadjusted OR	95% CI	Demographic adjusted OR**	95% CI	Adjusted OR*	95% CI*
Lung-related measurements
CT emphysema **	2.02	1.02, 4.07	2.12	1.03, 4.43	2.10	1.02, 4.42
FEV1/FVC < 70%	1.82	0.90,3.78	2.03	0.96, 4.42	2.07	0.97, 4.56
FEV1% predicted	0.36	0.06, 1.98	0.36	0.06, 1.99	0.33	0.06, 1.66
Shuttle walk	1.00	0.98, 1.03	1.00	0.97, 1.03	1.00	0.97, 1.03
Lung symptom scores
Total SGRQ	1.00	0.98, 1.02	1.00	0.98, 1.02	1.00	0.98, 1.02
History of exacerbations	1.01	0.39, 2.68	0.84	0.30, 2.39	0.86	0.30, 2.48
Lung-related history
Greater than 30 pack years	1.35	0.62, 2.93	1.06	0.52, 2.20	1.08	0.52, 2.24
ICS use (yes/no)	0.46	0.14, 1.33	0.46	0.13, 1.40	0.47	0.13, 1.46

Among participants who did not meet osteoporosis screening criteria, emphysema detected on chest CT was significantly associated with low BMD, adjusting for age, sex, and diabetes status. In contrast, other lung related measures, including FEV1/FVC ratio, FEV1 percentage predicted, and history of acute exacerbations of COPD, were not associated with low BMD. High tobacco exposure (greater than 30 pack years) and inhaled corticosteroid (ICS) use were also not linked to lower bone density in this group.

Discussion

Over half of the women and nearly half of the men not meeting study-defined screening criteria for osteoporosis in our tobacco-exposed cohort had low bone mineral density (BMD) on DXA scan, revealing potential gaps in current screening guidelines. Low BMD was prevalent despite the relatively mild nature of the underlying lung disease in this group, with only 37% meeting spirometric criteria for COPD and only 14% reporting a history of acute exacerbations of COPD. Emphysema on chest CT imaging, prevalent in 49% of our cohort, was a key independent risk factor for low BMD, even in individuals who would not qualify for early osteoporosis screening based on the current criteria of age, sex, and the presence of major risk factors. These findings underscore the importance of re-evaluating osteoporosis screening guidelines to include emphysema in tobacco-exposed individuals as a criterion for earlier BMD assessment.

The independent association between CT emphysema and low BMD in individuals with tobacco exposure has been strongly established in the literature [1, 2, 4]. Visual and quantitative measures of emphysema on CT scans have been associated with lower BMD in various studies [1, 2]. Furthermore, severity and patterns of emphysema are strong predictors of low BMD in smokers with and without COPD [14]. Elevated markers of bone resorption and emphysema have been found to associate with accelerated BMD decline in tobacco-exposed individuals [15, 16]. Notably, CT-determined emphysema is associated with incident hip fracture independent of current tobacco exposure and oral corticosteroid use [1, 2, 5]. The GOLD committee report highlights osteoporosis as an important comorbidity in COPD leading to worse outcomes, and recognizes emphysema as an independent risk factor for low BMD [6]. However, recommendations fall short of providing specific guidance for osteoporosis screening in patients with COPD and emphysema.

This study and others would suggest that early DXA screening should be considered in individuals with radiographic emphysema. As such, future research efforts are needed to study implementation of early BMD assessment in patients with emphysema, and the impact of early screening on clinically meaningful outcomes including fracture, quality of life, and mortality. Opportunistic screening for emphysema and low BMD in patients undergoing low-dose chest CT scans for lung cancer screening should also be explored as a population health approach and means to guide further targeted osteoporosis assessment (i.e., DXA) in this high-risk population.

Our analysis has several limitations. Our parent study excluded those with BMI > 35, to exclude effects of obesity mediated inflammation on lung function, which limits the generalizability of our findings to individuals who are obese. Both personal and family history of fracture are major risk factors for BMD screening. However, data regarding prior personal history or family history of fracture were not collected as part of the parent cohort study. Using a conservative estimate of 20% of men and 20% of women in our analysis having either a personal or family history of fracture and assuming that all individuals with a personal or family fracture history fell within the low BMD group, we would still see that 45% of the women and 29% of the men remaining have low DXA BMD, which is clinically significant. Other lung-related risk factors, including severity of spirometric airflow obstruction, exacerbation history, and inhaled corticosteroid (ICS) use, were not associated with low BMD in our study population. The low prevalence of exacerbations in our cohort may explain the lack of association between exacerbation history and BMD, despite previous studies suggesting a connection between exacerbations and increased fracture risk [5]. On the cellular level, respiratory exacerbations have been associated with low BMD via inflammatory mediators linked to bone and fat metabolism [15], which may be less active in our study population which included individuals with former tobacco exposure, some without emphysema or obstructive lung disease. We were also likely underpowered to detect this relationship given the low number of reported exacerbations overall, highlighting a limitation in our analysis.

Conclusion

Expanding osteoporosis screening guidelines to include emphysema as a major risk factor could play a crucial role in preventing fractures and improving quality of life in tobacco-exposed populations. Guidelines for both care of individuals with COPD and general osteoporosis screening should consider incorporating DXA assessment early in this high-risk population.

Funding

Open access funding provided by the Carolinas Consortium. Grants from National Institutes of Health/ National Heart, Lung and Blood Institute: R01HL128289, R01HL128289-01, P50 HL084948.

Declarations

Conflicts of interest

None.