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In a recent issue of Thorax Haworth and coworkers reported that low bone mineral density—that is, osteoporosis—commonly occurred in patients with cystic fibrosis.1 These results supported previous reports of osteopenia in patients with cystic fibrosis.2-4 However, the mechanism of bone loss in these patients has not been elucidated.
Although the pathogenesis of osteoporosis is probably multifactorial in patients with cystic fibrosis, the increased production of cytokines—primarily tumour necrosis factor α (TNF-α)—may play a critical role in adult patients.3 Among the important factors implicated in the pathogenesis of bone loss are circulating cytokines such as TNF-α, interleukin (IL)-1, and IL-6. TNF-α is a potent inhibitor of bone collagen synthesis and stimulator of osteoclastic bone resorption, the net effect of which is to cause bone loss.5 Experimental animal studies have also shown that the neutralising antibody to TNF-α slowed the bone elongation rate and bone marrow hyperplasia, and decreased trabecular bone volume.6 It has been reported that the production of TNF-α by lung macrophages is increased in patients with cystic fibrosis.7 8 The increased production of TNF-α is also implicated in the pathogenesis of weight loss and cachexia in various diseases. Because body weight is associated with bone mineral content in normal subjects and those with cystic fibrosis, the weight loss or cachexia associated with increased production of TNF-α may also be involved in the pathogenesis of bone mineral deficit in these patients. Taken together, the increased production of cytokines, particularly TNF-α, may be a contributing risk factor for bone loss in patients with cystic fibrosis. It is therefore reasonable to assume that anti-inflammatory treatment with proinflammatory cytokines may prevent the development of osteoporosis.
The putative mechanism of bone loss is partly explained by the recent study in which treatment with an oral corticosteroid reduced both pamidronate induced bone pain and the level of TNF-α in patients with cystic fibrosis.4 The measurement of serum levels of cytokines including TNF-α may therefore provide a means of identifying cystic fibrosis patients who are at risk of rapid bone loss.
authors' reply We thank Shinji Teramoto for his continued interest in our work and note his current (and previous) comments about the possible role of proinflammatory cytokines in the development of low bone mineral density in patients with cystic fibrosis.l As stated in our discussion, tumour necrosis factor α, interleukin 1, and interleukin 6 may influence osteoclast activity in patients with cystic fibrosis.1-2 In fact, the significant negative relationship between the mean bone mineral density Z score and the C reactive protein concentration in our study provides the first evidence of an association between chronic pulmonary infection/inflammation and low bone mineral density in the cystic fibrosis population.1-2
Cystic fibrosis patients with low bone mineral density do not necessarily have osteoporosis. It is important to emphasise that the precise histomorphometric characteristics of cystic fibrosis bone have not been comprehensively described. In our study 38% of patients were vitamin D insufficient, which may predispose them to osteoporosis, but 7% of patients had 25-hydroxyvitamin D levels associated with osteomalacia.1-2 Thus, some patients could have both osteoporosis and osteomalacia. Furthermore, a recent report suggested that the bone disease of cystic fibrosis was complex and possibly unique.1-3
We have previously reported that bone pain is common in patients with cystic fibrosis after intravenous pamidronate and that it might be prevented by the concomitant use of oral corticosteroids.1-4 1-5 It is important to clarify that this was a retrospective observation and has not been evaluated prospectively.
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