Oxygen desaturation during the 6-min walk test as a risk for osteoporosis in non-cystic fibrosis bronchiectasis

Non-cystic fibrosis (non-CF) bronchiectasis is a chronic lung disease characterized by irreversibly dilated and damaged bronchi and bronchioles [1]. It is associated with several important clinical traits, namely, poor mucus clearance, airflow obstruction, and chronic systemic inflammation. With disease progression, there is deterioration of pulmonary function, diminution of exercise capacity, and an increase in mortality [2, 3]. Comorbidities such as gastroesophageal reflux disease, pulmonary hypertension, and osteoporosis frequently occur with non-CF bronchiectasis [3, 4].

Osteoporosis is one of the most common comorbidities of non-CF bronchiectasis [3]. The prevalence of diminished bone density in patients with non-CF bronchiectasis is high with more than 25% of the patients having osteoporosis and approximately 40–80% having osteopenia [5]. Risk factors for osteoporosis include age, gender, nutrition, inflammation, and ethnicity [6]. In other chronic respiratory diseases such as cystic fibrosis, chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea, bone mineral density (BMD) scores have been associated with pulmonary function, hypoxia and systemic inflammation [7‐10]. However, these risk factors associated with osteoporosis have not been completely explored in patients with non-CF bronchiectasis.

The six-minute walk test (6MWT) is a simple test to assess lung function and oxygen saturation during walking, which has been widely used in the clinical follow-up of patients with cardiopulmonary diseases, such as COPD, bronchiectasis, and idiopathic pulmonary fibrosis [11‐14]. Desaturation during 6MWT has been used to predict the risk of dying from bronchiectasis [13]. Hypoxia may affect bone density through hypoxia-inducible factor (HIF) accumulation [15], which stimulates osteoclast activities [16], directly inhibits mesenchymal stem cells osteogenic differentiation [17], and attenuates the parathyroid hormone anabolic actions on bone formation in mature bone [18]. Hypoxia increases bone damage induced by acidosis and inflammation. The episodic hypoxia during daily activities seen in non-CF bronchiectasis may cause recurrent ischemic injury, which induces inflammation and an acidotic microenvironment in bone. In addition, hypoxia plays a role in NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 or Nod-like receptor protein 3) inflammasome activation [19], during bacterial infection with Pseudomonas aeruginosa, thus leading to the release of interleukin (IL)-1β with the induction of pulmonary inflammation [20]. Airway secretions of non-CF bronchiectasis patients with Pseudomonas or other chronic infection contain higher levels of IL-1β [20] which is a powerful proinflammatory cytokine stimulating osteoclastogenesis and increasing in vitro and in vivo bone loss [21]. Because exertional desaturation is a common manifestation after chronic lung destruction in non-CF bronchiectasis [13], we hypothesize that bronchiectasis patients who desaturated during exercise may develop osteoporosis demonstrated by a reduction in bone mineral density. There is scarcity of data concerning the contribution of exertional desaturation to the risk of developing osteoporosis in non-CF bronchiectasis. Therefore, we investigated the associated risk factors for osteoporosis based on the presence or absence of desaturation during 6-min walk test in Asian non-CF bronchiectasis patients.

Among the 66 non-CF bronchiectasis patients, 45(68%) were desaturators and 21(32%) were non-desaturators (Table 1). There was no significant difference in age, gender, or body mass index distribution between the groups. For all included patients, the prevalence of osteoporosis was 70% and that of osteopenia was 23%. The proportion of desaturators with osteoporosis (37/45, 82%) was higher than that of non-desaturators (9/21, 43%, p < 0.01).

The desaturators during 6MWT were characterized by a significantly lower FEV₁, FVC and 6MWD, higher HRCT scores and severe exacerbations compared to non-desaturators (Table 1). The BMD at the levels of femoral neck, lumbar spine and proximal hip in the desaturators were all significantly lower than those of non-desaturators (Table 1).

The nadir of exertional SpO₂ during the 6MWT was significantly negatively correlated with HRCT score (r = − 0.538, p < 0.01), suggesting an association between the extent of lung destruction and oxygen desaturation (Fig. 1). BMD was correlated positively with the lowest SpO₂ during the 6MWT (r = 0.426, p < 0.01) (Fig. 2a) and DSP (r = 0.479, p < 0.01) (Fig. 2b), but negatively with the fall of saturation (ΔSpO₂) (r = − 0.462, P < 0.01) (Fig. 3a) and severe exacerbations (r = − 0.451, p < 0.01) (Fig. 3b). No significant correlation was noted between BMD and HRCT score.

In univariate analysis, BMI, desaturation during 6MWT, 6MWD, the lowest SpO₂ during 6MWT, FEV₁, severe exacerbation and short-term systemic corticosteroid loading were significantly associated with BMD at the level of femoral neck (Table 2), while age, gender and HRCT score were not. The full model of the multivariate analysis was present in Table 3, and the model R² was 0.50. And then stepwise multivariate regression analysis (Table 3) was used to evaluate the relative contribution of each variable to predict the change in BMD and, as a result, age, BMI, being a desaturator, and severe exacerbation were the selected independent factors for BMD (with R² of 0.48) finally due to colinear issue between the variables. In addition, short-term systemic corticosteroid loading was added to the model, but it was not found to be an independent factor because it correlated with severe exacerbation (Table 3).

To the best of our knowledge, this is the first study to investigate the severity and risk factors for osteoporosis in Asian non-CF bronchiectasis patients. Of our patients with non-CF bronchiectasis, 68% exhibited exertional desaturation during the 6MWT and osteoporosis was evident in 82% desaturators and 43% non-desaturators. The lowest SpO₂ during 6MWT and DSP were both positively correlated with BMD. In multivariate analysis, desaturation during the 6MWT was the factor most closely related to osteoporosis in patients with non-CF bronchiectasis. Other risk factors included old age, low BMI, and severe exacerbation. Thus, desaturation during 6MWT was highly associated with osteoporosis in patients with non-CF bronchiectasis.

Osteoporosis ranks amongst the top five comorbidities associated with non-CF bronchiectasis and 15.9% of a multicenter European non-CF bronchiectasis cohort (986 patients) had osteoporosis [3], while in a much smaller cohort of 20 of bronchiectasis patients, 25% had osteoporosis [4]. Our results, while supporting the findings of the previous studies [3, 4], further revealed that Asian populations with non-CF bronchiectasis appear to have more severe osteoporosis (70%) than non-Asian populations. Ethnic differences may also be involved, although the true incidence of Asian non-CF bronchiectasis-associated osteoporosis is unclear.

The detailed mechanism involved in the development of osteoporosis in patients with non-CF bronchiectasis is still unknown. In the multivariate analysis, the major factors affecting BMD were old age, desaturation during 6MWT, low BMI, and the number of severe exacerbation events. The possible pathogenesis of osteoporosis is multifactorial, and old age and low BMI have been known to contribute to low BMD [6]. The surprising link of the study is that we found a high degree of association between exertional desaturation and osteoporosis, which may provide new insight into the underlying pathogenesis of this disease. Hypoxia is an important pathophysiological change in non-CF bronchiectasis due to lung structural damage and airflow obstruction, and these patients are likely to experience desaturation during exercise. In this study, HRCT scores were correlated with the lowest SpO₂ during the 6MWT. Notably, most of these patients had sufficient SpO₂ at rest but developed severe desaturation during walking, which could constitute an intermittent hypoxia model. Intermittent hypoxia is associated with bone resorption and abnormal bone metabolism in patients with obstructive sleep apnea [9]. Osteogenic–angiogenic coupling is regulated by the HIF-1α transcription factor [17], which accumulates in response to hypoxia [15]. Thus, HIF-1α directly promotes osteoclast activities [16], directly inhibits osteoblast differentiation [17], and blocks anabolic actions of parathyroid hormone on bone formation in mature mouse [18]. HIF-1α induces the production of vascular endothelial growth factor (VEGF). VEGF stimulates osteogenic differentiation and the subsequent proliferation and survival of osteoblasts [17], and also stimulates hematopoietic stem cell differentiation into osteoclasts and increases bone resorption in humans [27]. Hypoxia affects bone metabolism and microarchitecture [28] and induces osteoporosis change by blocking the growth and differentiation of osteoblasts and strongly stimulates the formation of osteoclast [29, 30]. HIF-1α and VEGF both promote the activities of osteoclasts but have opposing effect on osteoblasts under different conditions, such as hypoxia. Taken together, hypoxia may affect bone cell function and can be considered as a risk factor for the development of osteoporosis [30], especially in non-CF bronchiectasis patients with desaturation during walking or exercise.

The vicious circle of bronchiectasis results from repetitive infection and systemic inflammation [31]. Acute exacerbations reflect the overall severity of inflammation and infection in clinical practice. The frequent attacks result in decreased lung function and increased mortality [32]. In our study, frequent severe exacerbation was also independently associated with osteoporosis. Previous studies have found that systemic inflammatory markers such as C reactive protein and airway cytokines (tumor necrosis factor-α, IL-1, IL-8) are increased in patients with bronchiectasis [32‐34]. IL-1, IL-6 and TNF-α are strong inducers of bone resorption and subjects with highly expression of these cytokines are susceptible to develop osteoporosis [35, 36]. In addition, hypoxia may promote bacterial infection, enhance the activation of hypoxia inducible factors (HIF) and nuclear factor (NF)-κB, and propagate systemic inflammation or increase recurrent exacerbations [37, 38]. Pro-inflammatory cytokines disturb the balance of bone metabolism, and stimulate osteoclast function through the receptor activator of nuclear factor-B (RANK) and its functional ligand (RANKL), such as TRANCE (TNF-related activation-induced cytokines) and macrophage colony stimulating factor (M-CSF) [7]. Thus, the interaction of hypoxia and inflammation may aggravate osteoporosis in non-CF bronchiectasis patients who experience desaturation.

Bronchiectasis patients were treated with oral or parenteral corticosteroids during a hospitalised exacerbation [39]. Oral corticosteroid treatment is known to cause loss of bone density and the cumulative corticosteroid dose can be a major significant predictor for bone loss [40]. We have shown that the cumulative dose of systemic corticosteroids was higher in bronchiectasis patients who desaturated because of frequent exacerbation. In univariate analysis, the loading dose of systemic steroids was also one of risk factor for osteoporosis in non-CF bronchiectasis with desaturation. However, in multivariate analysis, the cumulative dose of systemic corticosteroids which was not an independent risk for osteoporosis in non-CF bronchiectasis was less important than desaturation and acute exacerbation. There is currently no control randomized study supporting the use of oral corticosteroids in non-CF bronchiectasis either for short-term (during an exacerbation) or long-term use [41]. In light of our observations, overuse systemic corticosteroid or cumulative steroid loading during acute exacerbations that may predispose to diminished bone density is warning. Nebulized or oral antibiotics combined with airway clearance instead of oral systemic steroids are mandatory for treatment of bronchiectasis exacerbation [39], thus attenuating the potential aggravation of osteoporosis in non-CF bronchiectasis.

The 6MWT is a convenient clinical evaluation tool and many variables derived from the 6MWT are useful for evaluating prognosis [42]. The current research results indicate that the lowest oxygen saturation value and DSP were correlated with BMD. DSP is a composite measure that reflects both exercise capacity and desaturation. Therefore, DSP could be used to evaluate physical activity, which is an important factor associated with osteoporosis. 6MWT may provide a useful tool to assess the clinical phenotype of non-CF bronchiectasis for clinicians, and identify the risk factors potentially influencing clinical care.

Osteoporosis was a common comorbidity in non-CF bronchiectasis patients, particularly in those who were older, had low BMI, and exhibited frequent severe exacerbation. Desaturation during 6MWT was a strong independent predictive factor for osteoporosis. Future research is warranted to clarify the underlying pathogenesis. The 6MWT may be a useful tool to identify the clinical phenotype of non-CF bronchiectasis and thus raise clinician awareness regarding the disease, thus promoting early intervention, thereby preventing the development of osteoporosis or other comorbidities.