Case report on possible causes of severe osteoporosis: diffuse panbronchiolitis

Osteoporosis (OP) is a condition characterized by systemic degenerative bone disease, with key features including: destruction of bone microstructure, increased bone fragility, and reduced bone mass, ultimately leading to an increased risk of fractures [1]. Due to the increased fragility of bones in osteoporosis, almost any bone can fracture. These fractures are closely associated with higher healthcare costs, physical disability, impaired quality of life, and increased mortality [2]. Therefore, early detection and preventive treatment of potential risk factors are of utmost importance. Researchers have evaluated the prevalence of osteoporosis in patients with bronchiectasis and chronic obstructive pulmonary disease (COPD) [3, 4] , observing that increased systemic inflammation, as determined by markers such as C-reactive protein, IL-6, or TNF-α, is associated with reduced bone mass and disease progression in patients with bronchiectasis and COPD, significantly increasing the risk of osteoporosis (low BMD) [5]. However, no studies have yet investigated whether diffuse panbronchiolitis (DPB) can induce and exacerbate postmenopausal osteoporosis. Diffuse panbronchiolitis (DPB) is a chronic airway infection with diffuse bilateral micronodular lung lesions, primarily affecting East Asian populations [6]. It is a chronic, potentially life-threatening lower respiratory tract disease characterized by chronic infiltration of inflammatory cells. Compared to other chronic lung diseases, patients with DPB have high concentrations of neutrophils, lymphocytes, and inflammatory cytokines in their bronchoalveolar lavage fluid [7].

A 72-year-old female patient experienced a height reduction of 10 cm over 10 years and presented to our outpatient clinic in early November 2023 with severe back pain after an unstable standing twist. She had a history of coughing and sputum production for over 30 years, menopause at 49, and no other medical history. The patient's back pain and bilateral rib pain gradually worsened over a week, becoming more pronounced during activity and coughing, and alleviating with rest. Physical examination revealed: height 158 cm, weight 52 kg, visible spinal deformity, reduced chest-abdominal wall distance, and a bow-shaped kyphosis on spinal examination. Lung auscultation revealed moist rales. MRI indicated: 1. Fresh compression fractures of T9-11, with bone marrow edema changes in the T9 lamina; 2. Compression fractures of L1, 2, 4 (old); 3. Disc protrusion at L3/4, L4/5, and Schmorl's nodes formation at L1-4; 4. Osteoporosis of the thoracolumbar spine; thoracolumbar degenerative changes; subcutaneous fasciitis of the back as shown in Fig. 1. Dual-energy X-ray absorptiometry indicated: L1-4 bone density 0.560 g/cm², T-score -4.4, Z-score -1.5, representing severe osteoporosis. To determine the cause of the patient's osteoporosis, serum levels of calcium, phosphorus, and parathyroid hormone (PTH) were checked: calcium, 1.85 mmol/L; phosphorus, 0.83 mmol/L; PTH, 81.20 pg/mL, all within normal ranges. Additionally, tests showed white blood cells, 5.22*10^9/L; red blood cells, 3.88*10^12/L; hemoglobin, 111 g/L; C-reactive protein, 3.33 mg/L; 25-hydroxyvitamin D, 16.30 ng/mL; thyroid-stimulating hormone (TSH), 1.2729 μIU/mL; urea, 4.47 mmol/L; creatinine, 41.2 μmol/L; aspartate aminotransferase, 20 U/L; alanine aminotransferase, 17 U/L; all immune series negative, ruling out hyperparathyroidism, hyperthyroidism, liver dysfunction, kidney dysfunction, and immune series diseases. Given her 30-year history of coughing and sputum production, a chest scan was completed, and paranasal sinus scan indicated: left maxillary sinusitis, slight deviation of the nasal septum, possible chronic bilateral otitis media; multiple small nodules in both lungs, slightly enlarged mediastinal lymph nodes; osteoporosis, uneven bone density of the manubrium, fracture of the left second anterior rib, sternal fracture, compression fractures of T6, L9, L10. She had a 30-year history of persistent coughing and sputum production, with paranasal sinus CT indicating chronic sinusitis, chest CT showing diffuse small nodular shadows as in Fig. 2, lung auscultation with moist rales, diagnosed as diffuse panbronchiolitis (DPB). After ruling out secondary factors and common pathogenic factors, it was suspected that her severe osteoporosis might be closely related to diffuse panbronchiolitis, and whether DPB could induce or exacerbate osteoporosis. Based on this hypothesis, the patient was treated with anti-osteoporosis and anti-inflammatory medications. Currently, her pain has alleviated, and she can perform daily activities, but she remains under continuous treatment.

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Currently known risk factors for osteoporosis and related fractures include aging, female gender, early menopause, prolonged inactivity, and long-term use of corticosteroids. Factors that may increase the risk of osteoporosis in postmenopausal women include low calcium intake, smoking, hip fractures, use of long half-life psychotropic drugs, and heavy alcohol consumption [8]. However, no one has yet discovered that diffuse panbronchiolitis (DPB) may induce and exacerbate postmenopausal osteoporosis. Diffuse panbronchiolitis (DPB) is an idiopathic inflammatory disease characterized by chronic inflammation, primarily confined to the respiratory bronchioles and adjacent centrilobular areas, with characteristic interstitial accumulation of foamy histiocytes, neutrophils, and lymphocytes. Neutrophils and T lymphocytes, especially CD8 + T cells, and cytokines interleukin-8 and macrophage inflammatory protein-1, are believed to play a key role in the occurrence of DPB [9]. The local and systemic inflammation in DPB patients can worsen, and this systemic inflammation may be related to osteoporosis and its incidence [10]. At the same time, changes in immune cells can promote the development of postmenopausal osteoporosis. Although neutrophils play an important role in bone homeostasis, their excessive activation under estrogen-deficient conditions promotes osteoclast apoptosis by releasing reactive oxygen species and increasing osteoclastogenesis through RANKL signaling, leading to bone mass reduction. In estrogen-deficient conditions, with the increase of pro-inflammatory cytokines, changes in fracture healing may occur, potentially leading to healing disorders [10]. CD8 + T cells also play an important role in the pathogenesis of osteoarthritis (OA), with a subset of CD8 + T cells known as Foxp3CD8 Tregs, which can inhibit osteoclast formation and activity by secreting various anti-osteoclast factors. Foxp3CD8 Tregs not only regulate osteoclast survival but also affect osteoclast maturation by inhibiting the formation of osteoclast actin rings, forming a bidirectional regulatory loop [11]. However, this bidirectional regulatory mechanism does not require the presence of various pro-inflammatory cytokines. In DPB patients, the CD4/CD8 T lymphocyte ratio is increased, and interleukin-8 is elevated [12], which may cause the bidirectional regulatory loop to lose balance, and any dysregulation may lead to increased bone loss reported in osteoporosis. Diffuse panbronchiolitis (DPB) is characterized by chronic airway infection with diffuse bilateral micronodular lung lesions [6]. Studies have shown that chronic airway infection is accompanied by a significant increase in the local concentration of several cytokines, including TNF-α, IL-1β, IFN-γ, IL-2, IL-4, and IL-5 [13]. IL-1β, IL-6, and TNF-α are products of stromal cells and monocytes, which can increase the production of RANKL and OPG. The main result of these three cytokines is a net increase in RANKL activity, leading to bone loss. Additionally, the increase in RANKL and OPG can also upregulate the expression of IL-6 and TNF-α [14], which may enhance systemic inflammation in DBP patients. Systemic inflammation may increase the serum levels of inflammatory cytokines, disrupting the balance of the OPG/RANK/RANKL system and leading to a dominant trend of RANKL. This trend may result in bone loss and reduced bone mass/osteoporosis in DBP patients.This case illustrates the necessity of osteoporosis risk screening for DPB patients, using dual-energy X-ray absorptiometry to measure bone density. Any patient at risk should be actively prevented, with early anti-inflammatory treatment to control inflammation and improve prognosis [13]. Nutritional interventions should be implemented, including adequate protein intake, moderate salt, various vegetables and fruits, calcium-rich diet, calcium + vitamin D supplementation, and appropriate exercise. If bone density reduction has already occurred, active pharmacological intervention should be undertaken, such as using anti-resorptive drugs or hormone replacement therapy [15]. Preventing postmenopausal osteoporosis is an important area of contemporary research, and early identification and active treatment can effectively slow the progression of osteoporosis, while identifying high-risk patients is also one of the important measures.