MEDICAL/SCIENTIFIC TOPIC

Bone Disease in Cystic Fibrosis
Robert M. Aris, M.D.

Bone disease first described as a part of the CF syndrome in 1979, has recently emerged as a common complication in CF. The origin of bone disease is complex. However, some studies observed that 50-75% adults with CF (AWCF) have low bone density. Decreased quantity and quality of bone mineral can lead to increased fracture rates and kyphosis or spinal curvature. Kyphosis, which usually occurs over the age of 50 in the normal healthy population, often occurs earlier in people with CF (PWCF). Prevention, early recognition, and treatment are the most effective strategies for sustaining bone health in PWCF.


DESCRIPTION OF BONE DISEASE IN CF

Correlation of Low Bone Density and Osteoporosis

More than 50 reports have observed low bone density and increased fractures in PWCF. Bone mineral density is the best predictor of fracture risk. Osteopenia or low bone mineral density (BMD) is commonplace in both post-pubertal children and adults with CF. Adults have more risk factors and therefore tend to be more affected by BMD (see figure 1). According to the National Osteoporosis Foundation definition, 20-34% of AWCF have osteoporosis (fragile bones). However, the prevalence of osteopenia or low BMD is as high as 85% in some adult studies of CF patients.

“Several studies demonstrated that PWCF who have higher lung function scores and better nutritional status also have stronger bones”

However, BMD data should be interpreted with care because many factors must be taken into account such as petite body size and small bone structure. The prevalence of bone disease increases with severity of lung disease and malnutrition. Younger and healthier individuals may have normal BMD. Several studies demonstrated that PWCF who have higher lung function scores and better nutritional status also have stronger bones. CF patients with severe pulmonary disease (FEV1 <30%) requiring transplant center referral, often have bone disease with evidence of kyphosis and previous fractures in the long bones, vertebrae, and ribs.

Bone Disease in CF

Bone density studies provide a myriad of information.

• Bone density studies conducted over several years in children and adolescents, suggest that CF bone disease begins near or during the pubertal growth spurt when CF individuals often fall behind their healthy counterparts. Studies suggest an imbalance in bone turnover, which causes the rate of bone breakdown, to exceed the rate of bone formation. Moreover, studies over many years observed an increased bone loss in AWCF.

• Studies indicate that certain chemical imbalances present in all PWCF, even those without bone disease can affect bone density. This imbalance in adults is worse during flare ups of lung disease. However, these abnormalities tend to resolve when lung infection is treated.

• Calcium absorption in the intestine may be lower in AWCF and bone calcium deposition is lower in CF children. Thus, reduction in the rate of bone calcium deposition in the bones may contribute to reduced bone mass.

• More than 20 reports found vitamin D insufficiency common in PWCF. The cause of vitamin D insufficiency in CF has not been adequately studied but likely factors include reduced sunlight exposure and reduced body fat.

• Individuals with CF may become inactive due to reduced lung function and prolonged treatments. Most CF studies found an association between total activity or hours of weight-bearing activity and the rate of BMD. Interestingly, the rate was similar to the general population but the outcome is the same. Low activity negatively affects BMD.

• Low BMD also occurs among the ~10% of PWCF with pancreatic sufficiency (and normal digestion) indicating a role for chronic infection or other factors in causing poor bone health.

• An estimated 20-50% of individuals with CF are treated with glucocorticoids (aka steroids) to improve pulmonary function. Many, but not all, studies have found steroid therapy to be a risk factor for low bone mass in CF. The association between steroid use and BMD is confounded by disease severity since sicker patients are generally selected for steroid therapy. Chronic glucocorticoid therapy in children impairs linear growth, delays puberty and may compromise the peak bone mass attained by early adulthood.

• Immunosuppression, always experienced after lung transplantation, may further decrease pre-existing low BMD in PWCF. Lung transplant patients have declines of 1-5% in spine and thigh bone density during the first 6-12 months after transplant. Most importantly, lung transplant patients have very high rates of fractures, ranging from 37%-42% presumably related to high bone turnover, reduced bone quality, or increased physical activity superimposed on pre-existing low BMD. For this reason, individuals with CF, with very low BMD, and a history of prior fractures may be considered high risk and be excluded from transplantation on this basis.

• Since malnutrition, corticosteroid use, physical inactivity and disease severity often overlap; it is difficult to identify the independent contribution of each of these factors on BMD.


CLINICAL MANIFESTATIONS OF BONE DISEASE IN CF

“Despite the frequent chest pain reported by patients, vertebral body fractures often go unrecognized on chest x-rays since the interpretations usually concentrate on the lungs”

Several cross-sectional studies (which provide a “snapshot” of the frequency and characteristics of a disease in a population at a particular point in time), have observed a higher incidence of fractures in individuals with CF. Fracture rates are normal in CF children, who generally have better bone density. Fractures can affect both the long bones, vertebrae, ribs and sternum and fracture rates as high as 12-41% have been reported in adolescent or adult CF groups. Despite the frequent chest pain reported by patients, vertebral body fractures often go unrecognized on chest x-rays since the interpretations usually concentrate on the lungs. In addition, kyphosis has been reported in many CF studies and possibly contributes to diminished stature in 75% of PWCF. In addition to causing pain and debilitation, rib and vertebral fractures produce chest wall deformities that reduce lung function such as total lung capacity and forced vital capacity which might inhibit effective cough, hinder airway clearance, and, ultimately, accelerate the course of CF.


SCREENING AND TREATMENTS FOR OPTIMAL BONE HEALTH IN CF

Vitamin D Supplementation

The jury is still out on the best dosing strategy for vitamin D to achieve optimum serum levels in PWCF and more research is required. A synopsis of available literature on Vitamin D supplements from CF Clinical Practice Guidelines in westernized countries indicates that recommended adult doses are often inadequate to achieve optimum serum levels.

Calcium and Vitamin K Supplementation

To date, there have been no randomized controlled trials of these supplements in CF. In the absence of data specific to CF, calcium and vitamin K supplementation should follow the Dietary Reference Intakes for the general population.. Comprehensive assessments can be performed by nutritionists affiliated with most CF Centers.

Hormone Replacement Therapy (HRT)

One research study prescribing testosterone supplementation [200mg (694mmol) by intra-muscular injection every 3 weeks] to adolescent young males demonstrated improvements in linear growth rate and sexual maturation after 12 months of supplementation. Trials of estrogen replacement for females with CF and delayed puberty or premature menopause have not been conducted. The complicated nature of CF bone disease and the risk/benefit ratio for HRT make sit important to individualize therapy.

Antiresorptive Agents

Bisphosphonate, the most commonly used antiresorptive drug (drugs which reduce bone breakdown and prevent fractures), has been tested in several research studies in adults with CF. Clinical Trials of these drugs in children with CF have not been conducted to date. Several potential safety issues with oral bisphosphonates are worth mentioning. The incidence of erosive “pill” esophagitis may be higher since individuals with CF have a high incidence of gastro-esophageal reflux. Reducing the dose to once weekly or once monthly oral bisphosphonate may improve compliance. Here is an overview of conducted studies.

• Pamidronate (30 mg IV every 3 months) was the first bisphosphonate used in AWCF because it circumvented the potential problems related to oral malabsorption. While significant gains in lumbar spine and total hip BMD occurred after 6 months, significant adverse events (severe bone pain, fever, and phlebitis in almost 3/4 of the patients) occurred with pamidronate. Prednisone therapy had a protective effect for these adverse events. Thus, a 3-5 day course of prednisone may be useful before pamidronate infusions.

• Two randomised controlled trials are underway in CF patients with the newer intravenous bisphosphonate, zoledronic acid. Unpublished comments suggest that it is effective but , like pamidronate, it is associated with bone pain. In one trial of CF lung transplant recipients, pamidronate also resulted in robust improvements in BMD without adverse events.

• Alendronate (10 mg/day orally) has also shown promise for treating bone disease in CF in a very well designed clinical trial of alendronate. The patients treated with alendronate gained in spine and femur bone density. Other alendronate trials are underway in PWCF.

• To date, no study has been performed with risedronate.


CONCLUSIONS

Bone disease is largely a result of the markedly increased longevity experienced by individuals with CF over the last few decades. With better recognition and more attention paid to this problem, low bone density can be treated before spinal curvature and fragility fractures occur so that individuals with CF can continue to expect gains in both quality and quantity of life.

Acknowledgements

I thank the many CF patients that participated in clinical trials that allowed research to move forward in this area. I also thank Sue Brown, MD, Gayle Lester, PhD and David Ontjes, MD for their ongoing support over the last decade.


Robert Aris is an Associate Professor of Medicine at the University of North Carolina at Chapel Hill (USA). He has a longstanding interest in CF bone complications, and has authored or co-authored 20 research and review articles or book chapters and has chaired several symposia at national meetings on this topic. He is also interested in lung transplantation especially as it pertains to individuals with CF. He has authored more than 30 research articles and book chapters in clinical aspects of transplant medicine and the basic immunology of rejection and chaired numerous symposia at national meetings on related topics. He may be contacted at: aris@med.unc.edu

 

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