Adverse Alterations in Bone Metabolism Are Associated with Lung Infection in Adults with Cystic Fibrosis

Abstract

Low bone density, fractures, and kyphosis complicate the lives of adults with cystic fibrosis (CF), and inflammatory cytokines (interleukin [IL]-1beta, IL-6, and tumor necrosis factor [TNF]-alpha) that may alter bone metabolism have been previously found to be increased in the lungs and serum of CF patients. The objective of this prospective study was to determine the impact of lung infection on bone physiology in 17 adult CF patients. Serum osteocalcin, a marker of bone formation; urine N-telopeptides of type I collagen and free deoxypyridinoline, both of which are markers of bone breakdown; serum cytokines (TNF-alpha, IL-1beta, and IL-6); and general inflammatory markers (serum C-reactive protein [CRP] and chondrex) were measured at the beginning and end of treatment for an acute exacerbation of lung infection and again 3 wk later. After treatment with conventional antibiotics, decreases in N-telopeptides (147.3 +/- 77.5 [mean +/- SEM] versus 95.5 +/- 57.3 bone collagen equivalents (BCE)/mmol creatinine, p = 0.0014), deoxypyridinoline (8.42 +/- 2.8 versus 6.8 +/- 3.0 mmol/mmol creatinine, p = 0.08), IL-1beta (1.43 +/- 1.13 versus 0.65 +/- 0.63 pg/ml, p = 0.03), IL-6 (9.5 +/- 6.5 versus 4.7 +/- 3.2 pg/ml, p = 0. 012), CRP (43.1 +/- 29.3 versus 23.4 +/- 25.3 mg/ml, p = 0.04), and chondrex (151.7 +/- 111.7 versus 101.4 +/- 67.3 ng/ml, p = 0.014), and increases in osteocalcin levels (14.5 +/- 5.4 versus 22.5 +/- 8. 7 ng/ml, p = 0.010) were observed. Three weeks later, the changes in N-telopeptides and osteocalcin persisted. These data indicate that pulmonary infection, through the elaboration of inflammatory cytokines, may be linked to increased bone resorption and diminished bone formation. These results provide insights into the impact of systemic inflammation on bone health, and suggest novel mechanisms for bone disease in CF.

Relationship between insulin-like growth factor I, dehydroepiandrosterone sulfate and proresorptive cytokines and bone density in cystic fibrosis

“…Methodologic differences used in the measurement of cytokines could have also contributed to the differing results, including either the assay type or its sensitivity and whether serum or saliva were analyzed. The significant inverse correlation between IL1-β and bone mass adds to accumulating evidence suggesting a role for cytokines in the mediation of bone loss in these patients [37,46]. The unique role of IL-1β with regard to skeletal health is unclear and deserves further study.…”

“…Also noteworthy is the fact that cytokine measurements in the current study were obtained at a time of relative health. A previous study that examined the relationship between serum cytokines and bone turnover markers was carried out at the time of an acute infection, a clinical setting that would enhance cytokine secretion [37]. Methodologic differences used in the measurement of cytokines could have also contributed to the differing results, including either the assay type or its sensitivity and whether serum or saliva were analyzed.…”

“…In studies using both rodent [35] and human in vitro [36] models, DHEA supplementation led to decreased IL-6 concentrations, suggesting antiresorptive properties. One study showed increased IL-6, IL-1β, and TNF-α concentrations during acute lung infections in patients with CF that were associated with increased bone resorption and decreased bone formation markers [37].…”

Failure of High-Dose Ergocalciferol to Correct Vitamin D Deficiency in Adults with Cystic Fibrosis

“…One of these issues is bone health, because studies using dual-energy x-ray absorptiometry measurements of bone density have determined that, despite their young age, approximately 20 to 25% of adults with CF have osteoporosis and another 40% have osteopenia (3)(4)(5). The etiology of this bone disease is multifactorial, with contributors including fat malabsorption (resulting in vitamin D malabsorption and abnormal calcium metabolism) (6)(7)(8), glucocorticoid therapy (9, 10), poor nutritional status (11), inadequate gonadal hormones (10,12), and elevated circulating cytokines (13). Recognition of this increased risk of osteoporosis in CF has led to greater efforts to optimize vitamin D status and calcium absorption (4,14).…”

Lactose malabsorption is a risk factor for decreased bone mineral density in pancreatic insufficient cystic fibrosis patients

“…8 Additionally, chronic pulmonary inflammation due to an increase in serum cytokine levels may stimulate increased bone resorption and decreased bone formation. 10 Optimal nutrition, vital for reaching and maintaining proper bone mass, remains a key-challenge in patients with CF. Most of them require a high-energy diet, and those with exocrine pancreatic insufficiency should also receive pancreatic enzyme replacement therapy.…”