Energique Nutrition Articles & Resources

(Rev can prat rech dietet 2002; 63:192-197)

INTRODUCTION

With medical advances and more optimal cystic fibrosis (CF) care, the average life expectancy of CF patients has increased into the third decade (1,2). Along with increased longevity, however, CF-related complications such as diabetes, liver disease, infertility, and osteoporosis have been recognized (3).

The World Health Organization consensus has defined low bone mass, or osteopenia, as bone mineral density (BMD) values between 1 and standard deviations (SD) below the mean for young healthy adults. Low bone mass increases the risk of fractures (4-6). Studies have shown a high prevalence of low BMD in the CF population (3,7-18); 50-60% of CF patients studied were found to be osteopenic or osteoporotic (13,19,20), while in the general population, osteoporosis is common only among older adults (21,22). Risk factors reportedly associated with CF-related low BMD include malnutrition secondary to pancreatic insufficiency, malabsorption, increased nutrient requirements and inadequate intake (7,10,11,18,23); disease severity (7-11,17,18,20); hypogonadism (7,10,11); reduced physical activities, especially weight-bearing exercise (8,11-17); chronic respiratory acidosis (10); low body weight (3,8,9,11,17); genotype (12); and glucocorticoid therapy (11,17,20). Findings, however, have been controversial (3,9,11,16-18), with a low body mass index (BMI) being the most consistent predictor of low BMD (3,8,9,11,17).

Maintaining and normalizing BMD may minimize or prevent osteoporosis. Identifying the underlying causes and correlates for low BMD is important, so that more effective preventive treatment can be facilitated. We therefore examined existing patient data from routine management. Our goals were to a. describe the prevalence of low BMD in a large heterogeneous CF population, b. describe the association between increasing age and decreasing BMD, c. examine the association between BMD and BMI, and d. examine the association between BMD and previous systemic corticosteroid use of more than one month's duration.

METHODS

Patient selection

The University of Alberta Hospital in Edmonton, Alberta, is the centre for Northern Alberta CF patients. All patients in the pediatric and adult CF clinics were diagnosed with CF through documentation of elevated sweat chloride concentration and/or genotype. During their regular clinic visits, they were seen by the CF team, which included a dietitian.

This study cohort comprised all patients aged five years or older who had a BMD study. Younger children were excluded because there is a lack of reference data from dual-energy X-ray absorptiometry (DEXA) manufacturers for subjects under age five. A total of 113 subjects (65 out of 73 children over age five from the pediatric clinic and 48 out of 70 adults from the adult clinic) were included in the study. Our protocol for managing low BMD requires BMD studies using DEXA for all pediatric and adult patients once every two years, and yearly studies for adult patients with a previously low BMD. Our study sample was a random selection based on the timing of the scheduled BMD (within the six-month study period), and regardless of physical state. This study population should therefore be representative of the total CF population at our hospital, which has a catchment of the whole northern Alberta region.

Using different stages of bone cell activities, hormonal changes, and calcium homeostasis in healthy people's bones, we categorized our subjects into five age groups: five to eight years (young childhood), when bone formation is greater than bone resorption; nine to 12 years (pre-puberty), before growth hormone and sex steroids start to increase; 13 to 19 years (puberty), when the sex steroids with a positive effect on BMD increase and peak calcium accretion rates occur in bones; 20 to 34 years (young adulthood), when peak bone mass is reached and a positive calcium balance is maintained; and over age 35 (adulthood), when bone resorption is greater than bone formation (6,22,24-28).

Anthropometric measurements

Standing height in centimetres and weight in kilograms were measured for all subjects while they were wearing light clothing but no shoes. A wall-mounted stadiometer and a Health-O-Meter weight scale, respectively, were used. These data were taken concurrently with BMD measurements. The BMI was calculated as weight in kg/height in m? The BMI percentiles were determined using National Center for Health Statistics data (29).

Bone densitometry

As part of routine care in our CF clinics, BMDs of the lumbar spine (L2 to L4) were evaluated by DEXA (DPXIQ by Lunar Corp. for pediatric patients and QDR 4500A and 4500C by Hologic Corp. for adults). Normative data for DEXA values are institution-- and device-specific. Reference data for gender- and age-matched groups were standardized (30) and provided by Lunar (for pediatric patients) and Hologic (for adults). The BMD values represented 95% confidence intervals and were expressed in g/cm! The BMD Z-score, adjusted for age and sex, was assigned accordingly.

Systemic corticosteroid use

Information on current and past exposure to systemic corticosteroids was obtained from a review of medical records. All patients using systemic corticosteroids for a cumulative total of at least one month were considered "steroid users," regardless of the steroid type, the dosage, or whether use was intermittent.

Statistical analysis

Patient data were plotted chronologically according to BMD Z-score, and showed that the study population was normally distributed. A student's t-test with an alpha p-value of was used to test for differences between BMD Z-score and age, BMD Z-score and gender, BMD Z-score and BMI percentile, and BMD Z-score and steroid use. Multivariable linear regression was used to determine independent predictors of the BMD Z-score.

RESULTS

There were four main findings. First, the data showed a high prevalence of low BMD in our patient population (Figure 1). Of the 113 tested subjects, 46 (%) had a BMD Z-score of less than -1. Because 79% of the total population was studied, we can only infer that this percentage (%) is representative of the total population if the tested subjects are a true representation of the total population at our clinics. The five- to eight-year age group (young children) was the only age group with a mean BMD Z-score of zero (Figure 2).

Second, the data showed that low BMD became more prevalent with increasing age. The 20- to 34-year age group had the highest prevalence of low BMD. However, there were significant differences in BMD Z-scores when the five- to eight-year age group was compared with all other age groups. The p-values for comparing the five- to eight-year age group with the nine- to 12-year, 13- to 19-year, 20- to 34-year, and over 35-year age groups were , , , and , respectively.

Third, we found that patients with a low BMI percentile also had low BMD Z-scores (Figure 3). All but one patient in the nine- to 12-year and 13- to 19-year age groups with a BMD Z-score less than also had a BMI below the fifth percentile. This relationship did not exist in the older age groups. For the total population, there is a statistical difference in BMI percentile for patients with a BMD Z-score less than -1 when they are compared with those with a BMD Z-score greater than-1 (p=).

Finally, of the 32 patients who used oral corticosteroids by our definition, 63% (20 of 32) had a BMD Z-score less than -1. This finding was most pronounced in the 13- to 19-year (88%, or seven of eight patients) and 20- to 34-year (73%, or eight of 11 patients) age groups. This finding contrasts sharply to BMD Z-scores in steroid "non-users," only 35% (28 of 81) of whom had a BMD Z-score less than --1 (Figure 4). For a steroid user, the odds ratio for a BMD Z-score less than --1 was (p=) in comparison with a non-user. This association remained significant after adjustment for age, gender, and BMI percentile (p = , , and x 10-; respectively). Multivariable linear regression analysis showed that not using steroids increased the BMD Z-score by .

DISCUSSION

Our study confirmed that low BMD is a significant concern in CF patients. This finding is consistent with those of other Canadian and North American studies. Several clinical factors have been found to be related to deficits in bone mineral in CF (3,7-13,15,17), and many of these risk factors are likely interrelated.

In our study, children between the ages of five and eight years did not exhibit signs of low BMD. Low BMD began to appear in prepubertal subjects. These findings are similar to those of Baroncelli et al. (16) and Bhudbikanok et al. (17). In CF patients, BMD has been found to decrease at the rate of one SD per six to eight years (8).

Calcium content, absorption, and accretion influence BMC. Martin et al. (31) measured BMC and estimated calcium accretion in healthy children. They found the rate of bone mass retention peaked at age years in males and age 13 years in females, about one year after their peak linear growth. A similar trend was found in a Dutch study (32). Bone acquisition is more closely correlated with pubertal stage than with chronological age, and pubertal delay is common in CF. Because ours is an observational study, pubertal staging was not performed. Patients with CF have been found to experience a one- to three-year delay in puberty (33-36). This delay would normally translate into peak bone mineral accretion in the 14- to 18-year age range and peak bone mass in the mid-20s. However, we found an increased prevalence of low BMD in adolescence and young adulthood. These subjects seemed not to attain as high a peak BMD as their healthy counterparts. Bone mineral density is also affected by bone mineralization during growth and bone loss in later life. A longitudinal study (17) on bone acquisition showed that younger subjects gain less bone mineral than expected. Other studies (16, 37-39) showed reduced bone formation and accelerated bone loss in CF patients. The inability to maximize peak bone mass has significant implications for osteopenia and osteoporosis in adulthood, when bone resorption exceeds bone formation.

In many studies, low BMI has been reported as a consistent predictor for low BMD (3, 8, 9, 11, 15), and it was also evident in ours. Young patients with a BMI below the fifth percentile had a mean BMD Z-score of . In our pediatric and adolescent population, BMI percentiles can be used to identify those at risk for low BMD. These findings suggest that aggressive nutritional support should begin when BMI is at the 25th percentile, and should be provided for all patients with a BMI at or below the 15th percentile. The caloric cost of the illness significantly increases CF patients' basal requirements. Gibbens et al. (10) also found that low BMD in CF patients correlated with poor nutritional status. Because low weight may reflect nutritional deficits, close monitoring of nutritional status is essential.

Most studies have shown that the use of systemic corticosteroids is correlated with osteopenia and osteoporosis (11, 13, 20, 40-42). The effect of corticosteroids on skeletal health likely varies with pubertal stage, steroid type, dose, and duration of use, and may reflect disease severity, which may be an independent risk factor for low BMD. Collecting cumulative data on steroid use was beyond the scope of this study. However, even after adjusting for potential confounding factors, we did find a significant positive association between low BMD and systemic steroid use of at least one month's duration. This finding is both statistically significant and clinically important, because this group of patients is prone to steroid exposure. Future studies on the effects of oral steroid use on BMD should include a more detailed patient profile, and information on disease severity, type of steroid, dose, and length of therapy.

Study strengths include a large heterogeneous CF population (113 subjects), which comprised pediatric and adult patients in the same geographic region. The setting provided an opportunity to examine the distribution of BMD at various stages of life.

However, the study has several limitations. The data are cross-sectional and from one centre, and we used BMD for comparison. Bone mineral density measurement provides projectional (g/cm^sup 2^) density values and depends on bone size, and the measurement is influenced by bone dimensions. Because a BMD measurement may underestimate bone density in smaller subjects with impaired growth such as those with CF, it therefore may not be an accurate indicator of abnormality. The expression of volumetric BMD or bone mineral apparent density (BMAD) has been reported to provide a more reasonable comparison of bone mineral properties in subjects of different heights, and to minimize the effect of bone size (3,4,43). Future studies should include BMAD calculations.

Different DEXA machines were employed because of the difference in pediatric and adult clinic set-ups. The BMD Z-scores were calculated using normative data from the DEXA manufacturers. There may be some variations in the different DEXA software programs. In vivo and in vitro assessments of a number of different phantoms indicate that BMD values obtained from Lunar instruments are 12-24% higher than those from Hologic machines. Notwithstanding these differences, BMD values obtained in these systems have been shown to be highly correlated (r > ) (44).

Despite the study limitations, it demonstrates that low BMD is common in CF. Children and adolescents with a low BMI or patients who have previously used systemic steroids are particularly at risk. Early intervention should therefore be directed at improving body weight and avoiding or minimizing the use of systemic corticosteroids. Efforts should also be made to achieve or maintain normal bone mineralization, starting in childhood, and to maximize calcium accretion in adolescence. A longitudinal study including other variables such as inadequate calcium, vitamin D, and energy intakes; reduced weight-bearing exercise; disease severity; delayed puberty, and/or genotype will provide further insight into the prevention and/or correction of osteopenia and osteoporosis. With CF patients' increased life expectancy, efforts should be made to identify and prevent or correct its related complications to improve quality of life.

RELEVANCE TO PRACTICE

Energy imbalance in CF is common because of poor oral intake and increased energy expenditure secondary to pancreatic insufficiency and increased pulmonary expenditure. Energy requirements are further increased during disease exacerbation. Adequate nutrition is essential to ensure optimal energy intake for weight gain, and adequate calcium and vitamin D intake (15, 45, 46) to maximize bone health. Nutritional status should be closely monitored; monitoring should include serial measurements and comparisons of anthropometric and biochemical data (including serum vitamin D levels). Food records should also be analyzed for assessment and to optimize counselling. Nutritional supplements or enteral nutrition may be necessary. Appropriate enzyme therapy and weight-bearing exercise should also be addressed and their importance reinforced with patients, and routine BMD studies should be performed.

This study serves as an example of practice-based research in which easily accessible data were used and risk factors were identified for nutritional intervention. By communicating with our patients and families about their BMD and study findings, and involving them in goal setting, we have found increased awareness and willingness to adhere to treatment, including nutritional management. Serum vitamin D levels have been monitored and reviewed with patients to reinforce the importance of vitamin supplementation. A second set of BMD studies is in progress, and will be evaluated for comparison.

Acknowledgement

The authors thank Dr. Sumit Majumdar for his expertise and assistance in statistical analysis, and for his valuable suggestions during the preparation of this manuscript.

References

1. Corey MF, McLaughlin FJ, Williams M, et al. A comparison of survival, growth, and pulmonary function in patients with cystic fibrosis in Boston and Toronto. J Clin Epidemiol 1988;41:583-91.

2. Huang NN, Schidlow DV, Szatrowski TH, et al. Clinical features, survival rate, and prognostic factors in young adults with cystic fibrosis. Am J Med 1987;82:871-9.

3. Bachrach LK, Loutit CW, Moss RB. Osteopenia in adults with cystic fibrosis. Am J Med 1994;96:27-34.

4. Lambert J. Osteoporosis: a new challenge in cystic fibrosis. Pharmacotherapy 2000,20(1):34-51.

5. Heany RP. Bone mass, nutrition and other lifestyle factors, Nutr Rev 1996; 54(4):S3-S10.

6. Compstan JE, Rosen CJ. Osteoporosis. 2nd ed. Albuquerque NM: Health Press; 1999:10.

7. Stamp TCB, Geddes GM. Osteoperosis and cystic fibrosis. Thorax 1993;48:585-6.

8. Henderson RC, Madsen CD. Bone density in children and adolescents with cystic fibrosis. J Pediatr 1996;128(1):28-34.

9. Grey AB, Ames RW, Matthews RD, et al. Bone mineral density and body composition in adult patients with cystic fibrosis. Thorax 1993;48:589-93. 10. Gibbens DT, Gilsanz V, Boechat MI, et al. Osteoporosis in cystic fibrosis. J Pediatr 1988;113(2):295-300.

11. Bhudhikanok GS, Lim J, Marcus R, et al. Correlates of osteopenia in patients with cystic fibrosis. Pediatrics 1996;97(1):103-11.

12. Merkel PA, Herlyn K, Lapey A, et al. Osteoporosis in adults with cystic fibrosis. Pediatr Pulmonol 1999;519:294.

13. Hansen S, Freitag AP, Hennessey R, et al. The prevalence and risk factors of osteoporosis in a Canadian adult cystic fibrosis centre population. Pediatr Pulmonol 1999;519:298.

14. Henderson RC, Specter BB. Kyphosis and fractures in children and young adults with cystic fibrosis. J Pediatr 1994;125(2):208-12.

15. Donovan DS, Papadopoulos A, Staron R, et al. Bone mass and vitamin D deficiency in adults with advanced cystic fibrosis lung disease.

Am J Respir Crit Care Med 1998;157:1892-9.

16. Baroncelli GI, de Luca F, Magazzu G, et al. Bone demineralization in cystic fibrosis: evidence of imbalance between bone formation and degradation. Pediatr Res 1997;41 (3):397-403.

17. Bhudhikanok GS, Wang M-C, Marcus R, et al. Bone acquisition and loss in children and adults with cystic fibrosis: a longitudinal study. J Pediatr 1998;133(1):18-27.

18. Henderson RC, Madsen CF. Bone mineral content and body composition in children and young adults with cystic fibrosis. Pediatr Pulmonol 1999;27:80-4.

19. Brenchmann C, Papaioammou A, Freitag A, et al. Annual changes in bone mineral density (BMD) and the use of oral and inhaled corticosteroids in patients with cystic fibrosis. [abstract]. XIII International Cystic Fibrosis Congress, Stockholm Sweden, June 4-8, 2000.

20. Conway SP, Morton AM, Oldroyd B, et al. Osteoporosis and osteopenia in adults and adolescents with cystic fibrosis: prevalence and associated factors. Thorax 2000;55:798-804.

21. Ross PD. Epidemiology of osteoporosis. In: Genant HK, Guglielmi G, Jergas M, eds. Bone densitometry and osteoporosis. New York: Springer-Verlag; 1998:21-42.

22. Looker AC, Orwoll ES, Johnston C, et al. Prevalence of low femoral bone density in older . adults from NHANES III. J Bone Miner Res 1997;12(11):1761-8.

23. Lark RK, Lester GE, Ontjis DA, et al. Diminished and erratic absorption of ergocalciferol in adult cystic fibrosis patients. Am J Clin Nutr 2001;73(3):602-6.

24. Adams JS. Genetics of osteoporosis. In: Adams JS, Lukert BP, eds. Osteoporosis: genetics, prevention and treatment. Norwell MA: Kluwer Academic Publishers, 1999:25-32.

25. Notelovitz M. Osteoporosis: prevention, diagnosis and management. 1" ed. Caddo OK: Professional Communications Inc, 1994:23-37.

26. Katzman DK, Backrach LK, Carter DR, et al. Clinical and anthropometic correlates of bone mineral acquisition in healthy adolescent girls. J Clin Endocrinol Metab 1991;73:1332-9.

27. Standing Committee on the Scientific Evaluation of DRI, Food

and Nutrition Board, Institute of Medicine. Dietary reference intake for calcium, phosphorus, magnesium, vitamin D and fluoride. Washington, DC: National Academy Press, 1997.

28. Haworth CS, Selby PL, Webb HK, et al. Osteoporosis in adults with cystic fibrosis. J Royal Soc Med 1998;91 (Suppl 34):14-8.

29. Najjarand MF, Rowland M. Anthropometric reference data and prevalence of overweight, United States, 1976-1980. Washington, DC: US Government Printing Office, US Department of Health and Human Services Publication (PHS) 87-1688, Vital and Health Statistics 1987; series 11, no 38:17-22.

30. Genant HK. Universal standardization for dual X-ray absorptiometry: patient and phantom cross-calibration results. J Bone Miner Res 1995;10:997-8.

31. Martin AD, Bailey DA, McKay HA, et al. Bone mineral and calcium accretion during puberty. Am J Clin Nutr 1997;66:611-5.

32. Boot AM, de Ridder MAJ, Pols HAP, et al. Bone mineral density in children and adolescents: relation to puberty, calcium intake, and physical activity. J Clin Endocrinol Metab 1997;82(1):57-62.

33. Johannesson M, Gottlieb C, Hjelte L. Delayed puberty in girls with cystic fibrosis despite good clinical status. Pediatrics 1997;99(1):29-34. 34. Jurema MW, Vlahos N, Wallach EE. Reproductive health and cystic fibrosis. Postgrad Obstet Gynecol 2001;21(2):1-4.

35. Landon C, Rosenfeld RG. Short stature and pubertal delay in male adolescents with cystic fibrosis. Am J Dis Child 1984;138:388-91.

36. Reiter EO, Stem RC, Root AW. The reproductive endocrine system in cystic fibrosis. Am J Dis Child 1981;135:422-6.

37. Haworth CS, Selby PL, Mawer EB, et al. Reduced bone accretion and accelerated bone loss in cystic fibrosis adults. Pediatr Pulmonol 1999;519:295.

38. Aris RM, Ontjes DA, Lark RK, et al. Increased bone resorption in adults with cystic fibrosis. Pediatr Pulmonol 1999;519:296.

39. Ionescu AA, Nixon LS, Buss D, et al. Urinary excretion of pseudouridine is increased in adults with cystic fibrosis (CF) and correlates with bone resorption markers. Pediatr Pulmonol 1999;$19:296.

40. Canalis E. Mechanisms of glucocorticoid action in bone: implications to glucocorticoid-induced osteoporosis. J Clin Endocrinol Metab 1996;81(10):3441-7.

41. American College of Rheumatology Task Force on Osteoporosis Guidelines. Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Rheum 1996;39(11): 1791-801.

42. Lubert BP, Raisz LG. Glucocorticoid-induced osteoporosis: pathogenesis and management. Ann Intern Med 1990;112:352-64.

43. Carter DR, Bouxsein ML, Marcus R New approaches for interpreting projected bone densitometry data. J Bone Miner Res 1992;7(2):137-45. 44. Kohrt WM. Dual-energy X-ray absorptiometry: research issues

and equipment in emerging technologies for nutrition research. Washington, DC: National Academy Press, 1997:151-67.

45. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine. Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D, and fluoride. Washington, DC: National Academy Press, 1999.

46. Vieth R Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr 1999;69(5):842-56.

JENNY FOK, BHEc, RD, Pediatric and Adult Cystic Fibrosis Clinics, University of Alberta Hospital, Edmonton, AB;

NEIL E. BROWN, MD, FRCP(C), Adult Cystic Fibrosis Clinic, University of Alberta Hospital, Edmonton, AB;

PETER ZUBERBUHLER MD, FRCP(C), Pediatric Cystic Fibrosis Clinic, University of Alberta Hospital, Edmonton, AB;

JOAN TABAK, RN, Pediatric and Adult Cystic Fibrosis Clinics, University of Alberta Hospital, Edmonton, AB;

MEI TOM, BSc, RD, Adult Cystic Fibrosis Clinic, University of Alberta Hospital, Edmonton, AB