Role of exercise and nutrition status on bone mineral density in cystic fibrosis

Journal of Cystic Fibrosis 2 (2003) 163–170

Role of exercise and nutrition status on bone mineral density in cystic fibrosis夞 Despina D. Frangoliasa,b, Peter D. Pare´ a,b, David L. Kendler, A.G.F. Davidsona,d, Lawrence Wonga,d, Janet Rabouda, Pearce G. Wilcoxa,b,c,* a

University of British Columbia, Vancouver, BC, Canada McDonald Research Laboratories and iCAPTURE Centre, University of British Columbia, St. Paul’s Hospital, 1081 Burrard Street, Room 292, Vancouver, BC, Canada V6Z 1Y6 c Providence Health Care, Vancouver, BC, Canada d Biochemical Diseases, B.C. Children’s Hospital, Canada

b

Received 12 December 2002; accepted 11 June 2003

Abstract Background: Exercise has been shown to maintain or increase bone mineral density (BMD) in non-CF populations. Objectives: The purpose of our study was to elucidate the relationship between exercise, body composition and dietary intake with BMD in an adult CF population with heterogeneous disease severity. Design: We measured spinal (L1-4) and femoral (femoral neck) BMD by dual energy X-ray absorptiometry (DEXA) in 68 CF adults (24 female, 44 male) with a mean age 30.8(1.7) and 27.4(1.3) (range 18–55) years. We used the average BMD Z score for spine and femoral neck for analyses. Differences in disease severity, exercise capacity, physical activity level, dietary intake, body composition, body mass index (BMI), glucocorticoid use were correlated with BMD scores. Exercise capacity was defined as the maximal amount of oxygen consumed by muscles during maximal exercise (VO2max ). Vertebral and non-vertebral fracture rate were also recorded. Results: Fifty-seven patients were identified with low BMD (Z score-y1). Multiple linear regression identified exercise capacity and BMI as significant predictors of BMD. Later diagnosis of CF was also associated with low adult BMD. Conclusions: Low BMD is common in adult CF patients. Exercise capacity and BMI are predictors of low BMD. 䊚 2003 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Keywords: Bone mineral density; Cystic fibrosis; Exercise; Body composition; Nutrition

1. Introduction Cystic fibrosis (CF) is an autosomal recessive multisystem disease with pulmonary and gastrointestinal manifestations. With therapeutic advances, CF patients are living beyond their adolescent years well into adulthood. Long-term complications from the disease are now more frequently seen in association with their increased longevity. These disorders include low bone mineral density and increased fracture risk. In normal adults, peak bone mass is achieved around age 30 years. Genetic factors 夞 Sources of support: This study was funded by a grant from the B.C. Lung Association. D.D. Frangolias is a recipient of a Canadian CF Foundation Ph.D. studentship and a Michael Smith Health Research Award. *Corresponding author.

probably account for 70% of an individual’s peak bone mass with the remainder due to diet, exercise, disease and environmental factors w1x. Specific parameters contributing to peak bone mass are dietary calcium, other dietary factors (vitamin D, caloric intake), weight, activity and sex hormone exposure as indicated by reproductive and menstrual history in women w2x. As with the respiratory manifestations of CF, the pancreatic and GI tract manifestations of the disease are related to the failure of epithelial ion transport. As a consequence, enzymes required for digestion of protein and fat will be lost, resulting in malabsorption of protein, fat, fat-soluble vitamins and calcium. Pancreatic enzyme supplementation improves, but does not always normalize absorption. Malnutrition may result in poor somatic growth as well as skeletal growth, delayed puberty and

1569-1993/03/$30.00 䊚 2003 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. doi:10.1016/S1569-1993Ž03.00087-0

164

D.D. Frangolias et al. / Journal of Cystic Fibrosis 2 (2003) 163–170

skeletal maturation, low body mass, deficiency in fatsoluble vitamins (including vitamin D) and poor calcium absorption. Plasma 25-hydroxyvitamin D (25-OH vitamin D) levels have been commonly reported to be low in CF patients w3–8x despite oral supplementation w6,8,9x. Adequacy of dietary intake to estimated requirements and expenditures in relation to BMD has not been addressed. In most series, pulmonary disease severity is the best predictor of BMD. This factor, however, only moderately predicts BMD w5,6,8,10x. Exercise, an important predictor of BMD in non-CF populations, has in the CF population usually been evaluated by recall questionnaires of activity and has not accurately predicted BMD. Other associations with low BMD in CF patients include homozygosity for the DF508 mutation w4x, delayed puberty w5,7,8,10x, hypogonadism w7,8x, diabetes, corticosteroid use w11,12x and chronic pulmonary infection. As CF patients’ life expectancy continues to improve, it is important to anticipate adverse long-term skeletal effects and to appropriately intervene in patients at risk. Exercise has been shown as an important determinant of BMD in the non-CF population. The benefits of exercise in CF are multifactorial and exercise is also prescribed as a chest physiotherapy modality. This study determines the relationship of exercise capacity and nutritional status and dietary intake on BMD in an adult CF population with heterogeneous severity of pulmonary disease. 2. Methods 2.1. Subjects This study was prospective and cross-sectional. Patients were recruited from the St. Paul’s Hospital Adult Cystic Fibrosis clinic, which serves most of the adult CF patient population for the province. The diagnosis of CF was confirmed by clinical signs and two elevated sweat chloride tests or CFTR genotyping. All consenting CF patients attending the St. Paul’s Hospital Adult CF clinic over a 2-year period were recruited. A total of 67 patients (over 18 years of age) exhibited mild to severe airway obstruction were recruited from a potential of 140 patients attending the clinic. Transplanted patients (lung, heart-lung, liver) were excluded. Patient evaluations were made during periods of clinical stability without hospitalization or home therapy with intravenous antibiotics for pulmonary infection within 1 month of entry. St. Paul’s Hospital and the University of British Columbia ethics committee approved the study and study participants consented to participating by signing the study consent following an explanation of the study.

2.2. Clinical measurements Measurements were taken during stable clinical status (non-pulmonary exacerbation). A pulmonary exacerbation was defined as a pulmonary infection that required intravenous antibiotic intervention. Subjects performed spirometry including forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) according to ATS criteria with instruments adhering to accepted standards w13x. Values were expressed as the percentage of normal values based on age, gender and height. The best-recorded post-bronchodilator measurements were used for the study. Schwachman–Kulczycki (S–K) scores were calculated. Chest and lateral spine radiographs were obtained from patients’ charts, as was information on activity patterns, pulmonary and nutritional status for S–K scoring as described by Schwachman and Kulczycki w14x. Chest radiographs were scored utilizing the Brasfield clinical scoring system w15x. Corticosteroid use was documented both during puberty and at the time of measurement of BMD. Patients were classified as corticosteroids users if usage was for 2 months per year or more. The number of pulmonary infections requiring intravenous antibiotic therapy (i.e. number of pulmonary infections over 12 months and mean days on IV therapy per infectious episode) was gathered via chart review. In this study we defined exercise capacity as the direct measurement of maximal oxygen consumption (VO2max) and specifically as the maximum amount of oxygen consumed by the muscles during a progressive incremental exercise test to maximal effort. VO2max test was performed on a Monark娃 stationary bicycle and followed a continuous progressive incremental regimen w16x. Patients were categorically grouped as exercisers or sedentary based on exercise habits (defined as exercisers if they performed a minimum three 20-min exercise sessions per week. Patients were asked to complete a questionnaire on fracture history. The fracture history questionnaire used by the Canadian Multicenter Osteoporosis Study (CaMOS) was used. Information was collected on fracture history, cause of fractures and trauma level to indicate how the fracture happened (due to severe or minimal trauma or due to other diseases) w17x. Thoracic and lumbar spine radiographs were examined for evidence of thoracic vertebral compression, evaluated semiquantitatively by the Genant method w18x. Anterior, mid and posterior vertebral heights were measured from the anteroposterior chest radiographs and the least value expressed as a percentage of maximum vertebral height. A 20% decrease in vertebral height was indicative of vertebral compression and kyphosis was measured with a surveyor’s flexicurve w19x.

D.D. Frangolias et al. / Journal of Cystic Fibrosis 2 (2003) 163–170

2.3. Laboratory measurements

3. Results

Subjects completed a 3-day dietary recall diary where they were asked to record all foods, beverages and supplements taken for 2 weekdays and one weekend day or non-working day, analyzed using Nutritionist IV (Microsoft Windows 1995, First DATABank division of The Heart Corporation, 1111 Bayhill drive, San Bruno, California 94066, USA). Supplements were incorporated into specific nutrient totals. The 3-day recall used in this study is the one regularly used by the CF dietician for nutritional assessment.

3.1. Patient characteristics

2.4. Bone mineral density and body composition measurements We obtained lumbar spine (L1-4), proximal femur (femoral neck and total hip including trochanter, Ward’s triangle), and total body BMD using the DEXA scanner (Norland Medical Systems Inc., 1998) and the Norland normative data set 392. Bone mass was expressed as bone mineral density (gycm2) and bone mineral content (grams). In order to account for differences in age of our patients, BMD data are expressed as Z scores (S.D. below age, racial and sex matched control subjects, Norland). Average Z score of L1-L4 and femoral neck were used for all analyses. Normal bone density was defined as a BMD above 1 standard deviation (S.D.) below the mean for young healthy adults; osteopenia is 1–2.5 S.D.’s below mean for young adults; osteoporosis is G2.5 S.D.’s below mean for young adults according to World Health Organization criteria. We also obtained total lean muscle mass, total fat mass using DEXA. Studies have shown that use of DEXA for measurement of fat and lean muscle mass is better than skinfold or bioelectrical impedance, but as with these other measurement techniques regional differences in fat distribution in males and females will affect readings w20,21x. 2.5. Statistical analysis Data analysis was performed using SPSS version 7.0 (SPSS Inc., Chicago, IL, USA). Data are reported as mean "S.E. of the mean (S.E.M.). Relationships between covariates are described using Pearson product moment or Spearman coefficient for non-parametric data. We utilized for multiple regression analysis a composite score for L1-L4 lumbar spine BMD and femoral neck BMD as the dependent variable. Age and gender were included in the regression analyses as covariates. Stepwise regression was used to examine the contribution of exercise (VO2max and exercise activity status), BMI, current nutritional status (caloric intake, calcium and vitamin D intake) and pulmonary disease severity (i.e. %FEV1) to low BMD. The number of subjects available for analysis ranged from 46 to 67.

165

Reduced BMD was a common finding in our CF cohort (67 patients who participated in the study, 17 of the 67 patients tested had BMD z-scores of y2 or less). Table 1 summarizes the demographic characteristics of the study population, exercise capacity, clinical measures of disease severity by BMD. To ensure that our study sample was representative of the clinic population, we compared participants and clinic non-participant CF patients on a number of clinical parameters (for age (28.6(1.0) vs. 29.8(1.3) years, Ps0.89; BMI (21.1(0.4) vs. 21.4(0.40) kgym2, Ps0.46), and gender (MyF ratio 44y24 vs. 34y30, Ps0.27) and showed no significant differences. For %predFEV1 there was a statistically significant difference between the study group and clinic non-participants (57.6(3.0) vs. 63.9(3.7)%, Ps0.001), however, the difference is not considered clinically significant. Variables reported in this paper were checked for normality and are normally distributed. 3.2. Exercise and nutritional status Our stepwise regression model including BMI, VO2max, age and gender accounted for 35% of the variance for BMD (BMDsy4.68q0.14=BMIq Ps0.0001, 0.04=VO2maxy0.01=AGE-0.14=SEX; Ns65). Measures of pulmonary disease severity were not significant predictors of BMD when VO2max was entered into the analysis. Exercise capacity is lower in the low BMD groups (Table 1). VO2max and BMD were moderately correlated (rs0.42, Ps0.001), and this value was higher than correlations of BMD with common measures of disease severity (i.e. (%predFEV1 : rs 0.35, Ps0.004; S–K clinical score: rs0.40, Ps0.001 and Brasfield score: rs0.38, Ps0.001). VO2max was moderately associated with these measures of disease severity in CF (i.e. %predFEV1: rs0.45, Ps0.0001; S–K scores: rs0.47, Ps0.0001; and Brasfield score: rs0.43, Ps0.0001). Another variable we investigated was age of CF diagnosis. Although this variable was neither an important predictor of BMD status, nor did we show significant associations with measures of disease severity, VO2max or nutritional status, we found that the patients in our group who were classified as osteoporotic were significantly older and were diagnosed with CF later in life. Although gender was not a significant predictor of BMD, there were more male patients in both the osteopenic and osteoporotic groups. In our study we did not show a significant association between BMD and homozygosity for DF508 mutation (rsy0.13, Ps0.34, Ns52).

D.D. Frangolias et al. / Journal of Cystic Fibrosis 2 (2003) 163–170

166

Table 1 Characteristics of study subjects by BMD classifications P-value

Significant post-hoc differences

37.5 (4.0)

0.01

Normal-Osteoporotic

2.8 (0.8)

11.5 (4.6)

0.003

Normal-Osteoporotic Osteopenic-Osteoporotic

69.5 (7.4)

59.0 (3.5)

35.4 (4.8)

0.006

Normal)Osteoporotic Osteopenic)Osteoporotic

S–K scores

74.1 (5.3)

68.6 (2.1)

48.9 (6.7)

0.001

Normal)Osteoporotic Osteopenic)Osteoporotic

Brasfield scores

18.0 (1.3)

15.2 (0.6)

10.9 (1.6)

0.001

Normal)Osteoporotic Osteopenic)Osteoporotic

Frequency of pulmonary infections over 12 months

1.1 (0.4)

1.8 (0.6)

0.14

Pulmonary exacerbations (IV daysytxt)

17.8 (1.2)

17.3 (1.6)

0.82

Variable

G1: Normal (Z score-y1.0)

G2: Osteopenic (Z score: y1.0 to 2.5)

Sample size

11

48

Gender (maleyfemale)

6y5

32y16

6y3

Age at time of testing (years)

27.0 (1.6)

30.6 (1.1)

1.4 (0.9)

%PredFEV1 (%)

Age at time of CF diagnosis (years)

G3: Osteoporotic (Z scoreG2.5) 9

0.85 (0.2)

16.1 (1.4)

3.3. Dietary status

3.4. Kyphosis and cumulative vertebral fractures

Eighty seven percent of study patients were pancreatic insufficient (2, 6 and 1 in the normal, osteopenic and osteoporotic groups, respectively, were pancreatic sufficient) and were on enzyme supplementation. Table 2 shows BMI, body composition measures and calculated caloric intake by BMD status.

There were no significant associations between BMD, exercise or nutritional status parameters and vertebral fractures or kyphosis (results not shown). Kyphosis, vertebral fractures of T8-T12, and %predFEV1 were predictors of low BMD, but this association could only explain 11% (Ps0.005) and 8% (Ps0.01), respective-

Table 2 Exercise capacity and nutritional characteristics of study subjects by BMD classifications Variable

G1: Normal (Z score-y1.0)

G2: Osteopenic (Z score: y1.0 to 2.5)

G3: Osteoporotic (Z score)2.5)

P-value

Significant post-hoc differences

VO2max (ml.kgy1.miny1)

32.4 (3.0)

30.5 (1.2)

22.6 (3.3)

0.03

Normal)osteoporotic Osteopenic)osteoporotic

% of predicted VO2max (%)

78.5 (5.8)

73.7 (2.7)

57.3 (7.8)

0.04

Pancreatic sufficiency (sufficientyinsufficient)

2y9

6y41

1y8

0.87q

BMI

23.4 (1.4)

21.1 (0.4)

19.2 (0.7)

0.01

Normal)osteoporotic

13946.4 (883.9)

12399.7 (2164.4)

0.01

Normal)osteopenic Normal)osteoporotic

0.41

*

Fat mass (g)

21307.7 (4055.9)

Lean mass (g)

44826.1 (2619.6)*

44155.6 (1213.0)

40367.2 (2387.4)

Total sample available for analysis

11

48

9

*

Data available for 9, 35 and 7 of the subjects in the normal, osteopenic and osteoporotic groups.

D.D. Frangolias et al. / Journal of Cystic Fibrosis 2 (2003) 163–170

ly, of the variability for low BMD by the variables kyphosis and vertebral fracture (results not shown). 3.5. Prevalence of non-vertebral fractures We did not observe an increased fracture risk in our osteoporotic group. We did observe a greater incidence of refracture in the osteopenic group. Fracture and refracture incidences were more common in those subjects who lead a more active lifestyle (regular participation in sports). Two out of the three normals and 11 out of the 12 osteopenic subjects who experienced fractures classified themselves as active (moderately active to heavy labor). These individuals also engaged in regular sports, which likely increased their risk of fracture (results not shown). 3.6. Steroid use We documented steroid use at puberty and current use via chart review. Patients classified as taking corticosteroids were taking inhaled preparations (Beclovent娃, Beclofort娃, Flovent娃, Pulmacort娃) for the study duration. There were no significant differences in uses of inhaled corticosteroids during adulthood by BMD grouping (Normal 5 out of 10, Osteopenic 17 out of 48, Osteoporosis 5 out of 9; x2s1.6, Ps0.4). Only three patients were on short-term oral corticosteroids at puberty (1 and 2 characterized as normal and osteopenic at adulthood, respectively). 4. Discussion Exercise capacity and nutritional status are predictive of BMD in CF patients. Exercise capacity and BMI were the best predictors and explained a moderate portion of the variance for hip and spine BMD. The prevalence of low BMD in our current sample was high, only 15% of our sample had normal BMD for their age and gender. Thirteen and 72% of our sample were classified as osteoporotic (i.e. Z scoreG2.5) and osteopenic (i.e. Z score: y1.0 to 2.5), respectively. Twentyfive percent of our sample had BMD Z scores of y2.0 or less, which according to Cummings and colleagues suggests a threefold increased risk of fracture compared to individuals of the same age and gender with normal BMD w22x. Haworth et al. and Bhudhikanok and associates showed higher prevalence of BMD Z scores of y2 or less (43% and 53%, respectively) in their cohorts of younger CF patients but similar pulmonary disease severity w4,8x. This value was higher in the study by Donovan and associates on CF patients with end-stage pulmonary disease (73.3%) w6x. VO2max was an important predictor of BMD status, better than measures of pulmonary disease severity. VO2max is a measure of the maximal amount of oxygen

167

consumed by the muscles and is a direct measurement of exercise capacity. The reason why VO2max may be a better predictor of BMD is that this parameter is also affected by lean muscle mass or BMI as well as pulmonary function. A positive relationship has been shown between BMD and exercise in healthy normal children w23x and young adults w24x, with exercise playing a role in further increasing BMD before the onset of puberty w25x. Gains in BMD achieved through physical activity have also been shown to be shortlived; with gains lost with cessation of the activity, and this has been shown both in athletic populations w26,27x and in intervention studies aiming to augment BMD w27,28x. To our knowledge this is the only CF study investigating BMD, which has directly measured exercise status; previous CF studies have used recall diary questionnaires to quantitate activity level, which has not been shown as a significant predictor of BMD w3,5,8x, but in some studies they showed higher fitness to be associated with higher BMD in univariate analyses w3,4,11x. Measurement of exercise capacity from patient recall is indirect and can be inaccurate and less sensitive than direct measurement of exercise capacity. Level of pulmonary disease will also affect the intensity of exercise and the mode of exercise in this cohort, therefore, a direct measurement of exercise capacity allows for a more objective measurement of exercise status. With increasing pulmonary disease severity, a CF patient may adopt a lower exercise training intensity to minimize oxygen desaturation and the sensation of breathlessness. This switch in exercise mode and intensity inferring lower impact may also translate to a lower benefit for bone health. Activity recall questionnaires may not be as sensitive to identifying this change in mode, intensity and duration of exercise sessions. Even so, non-aerobic forms of exercise such as strength training which have been shown to be beneficial in BMD augmentation or maintenance would not necessarily be associated with high VO2max. Therefore, some form of activity questionnaire in concert with a VO2max test would be optimum. Prescription of regular weight bearing exercise and possibly strength training to maintain BMD would seem to be indicated and of benefit in this population and should be further studied. Previous studies have identified measures of disease severity such as %predFEV1 and S–K clinical scores or other related clinical scores to be moderately associated with BMD w3–5,8,29–31x. The lack of significant correlations between disease severity and BMD in other studies w6,7,32x is likely related to the homogeneity of their study subjects (i.e. characterized predominantly by severe pulmonary disease or low BMD). BMD studies on children have generally shown declining trends in BMD with increasing age and pulmonary disease severity w31x, even within the first 18 years w31x. It is clearly difficult to distinguish between progressive decline in

168

D.D. Frangolias et al. / Journal of Cystic Fibrosis 2 (2003) 163–170

pulmonary and overall clinical status in CF patients and aging as they are integrally-related. In our analyses disease severity measures (i.e. %predFEV1 , S–K and Brasfield) were not included in the final model, but univariate analyses did show significantly lower values in patients with low BMD. This is not surprising as we showed exercise capacity to be moderately associated with these measures. A higher correlation was shown between VO2max and the disease severity parameter, S– K scores, which includes a measure of activity and BMI in its construct. There are a number of possible mechanisms which have been set forth to explain how severity of pulmonary disease could affect BMD. One is a reduced capacity for exercise with increased severity of pulmonary disease. Loss of appetite may also occur with increasing symptoms of disease progression. Changes in disease management with increased use of corticosteroids with the progressive increase in pulmonary disease may adversely affect BMD w9x. Another is chronic inflammation and infection and resulting increased production of inflammatory cytokines may also interfere with bone growth and bone mineral accretion w33,34x as well as contribute to weight loss and muscle wasting w33,35x. Lifestyle or other events, which may have occurred during childhood preventing CF children from achieving peak bone mass during the critical pubertal years is another possibility for low BMD in adulthood. In our study cohort, CF patients classified as osteoporotic were diagnosed as having CF later in life. Pancreatic insufficiency was common in our study group. Both these factors have implications for attainment of peak bone mass. Later diagnosis could mean that pancreatic abnormalities may have been overlooked and underlying nutritional deficiencies neglected during the interim, consequently affecting (slowing or permanently stunting) growth during puberty and jeopardizing attainment of peak bone mass. Losses in BMD may have started in childhood in this group or alternatively BMD losses may be greater compared to patients diagnosed within the first few years of life in relative terms because their attained peak bone mass is lower. Even in those diagnosed in childhood, severe pulmonary disease is usually linked with poor physical growth and poor nutritional status and while significant declines in BMD are not always shown at this stage w36x; these clinical parameters invariably contribute to the low BMD in adulthood w5,11,37,38x. Current macro- and micronutrient dietary intake was not predictive of BMD, as has been shown previously w3,7x. Low 25-OHD levels indicative of vitamin D deficiency have been shown in the literature even with adequate caloric intake and vitamin D supplementation w3–8,11x. This latter phenomenon may also be related to inadequate exposure to sunlight w39x. Another possibility is that pancreatic disease was not adequately

managed, which has been previously documented in this population w40x, but may also be related to increased catabolism in patients who have more severe disease. These values only give us a snapshot of current dietary intake and nutritional status and do not provide us, however, with a picture of the patient’s nutritional intake during the pivotal skeletal growth years. However, our results suggest that we should monitor dietary and supplement intake in those CF patients with apparent normal BMD as a preventative measure to ensure optimal BMI and continuing normal BMD in their future. Increased bone turnover has been shown in prepubertal, pubertal and young CF adults (even though these patients’ caloric intake was 150% of recommended and were on vitamin D and calcium supplementation) w29x and in CF patients with low BMD w4x. Homozygosity for the DF508 mutation has been shown to be associated with higher levels of some bone turnover markers (i.e. BS-APase and urinary deoxypyridinoline crosslinks) compared to heterozygotes for the DF508 mutation. As more severe disease is usually associated with a DF508 genotype both from a pulmonary and pancreatic (i.e. pancreatic insufficiency) perspective this is not surprising. In this case, dietary inadequacy, chronic higher levels of inflammatory cytokines as well as inactivity would be associated phenotypes. Heer and associates showed increases in bone formation and decreases in bone resorption markers in anorexia nervosa patients following an 11-week dietary plan to increase BMI from 14.2 to 17.1 kgym w41x. Adequate dietary intake to maintain BMI within the normal range may have added importance in maintaining BMD. Only a few studies have investigated the association between kyphosis, fracture frequency and low BMD but results as in our study have been inconclusive, likely due to small sample size and the cross-sectional nature of these studies. Fracture studies suggest an association between low bone mass and incident fractures w6,42x, especially in CF patients on long-term prednisone w7,8x. Non-vertebral fractures were common in our study cohort and while it would seem that fractures were more common in those with BMD Z score -y2.5, this may simply be due to our small group of patients with BMD Z score Gy2.5. This paradox may be explained, however, as study patients with BMD Z score-y2.5 had higher VO2max and less severe pulmonary disease, which would suggest a more active lifestyle and thus increased opportunity for injury and fracture. Patients with BMD Z score Gy2.5, however, were characterized with lower VO2max and more severe pulmonary disease and consequently were more likely to be sedentary and thus less likely to be in a fracture-causing setting. This view is supported by others w3,7,8,11,29x. Contrary to previous findings w3,5,32x, we showed no associations between vertebral fractures or degree of kyphosis and low spinal

D.D. Frangolias et al. / Journal of Cystic Fibrosis 2 (2003) 163–170

BMD. CF patients in the latter two studies were characterized as having more severe pulmonary disease w5,32x, which has been associated with increased prevalence of kyphosis and more pronounced vertebral wedging w43x. Long-term corticosteroid use is likely to affect BMD in CF and has been documented in other populations such as asthma and chronic obstructive lung disease (COPD) w44,45x including CF w3,8,11,12x. Others including our own study have not found an association between corticosteroid use and low BMD w7,29,46x. Use was minimal in our cohort, however, and was limited to short-term use of inhaled forms. In conclusion, VO2max and BMI are important predictors of BMD in adult CF patients. Osteoporosis is also a known common complication of organ transplantation and it is, therefore, important to assist CF patients to maintain normal BMD values so as to reduce pre and post-transplant fracture risk. As maintenance of BMD is a life-long process, it is important to make certain that CF patients receive adequate caloric and nutrient intake during the critical growth years in order to achieve peak bone mass as well as adopt a life-long exercise regime. Adequate pancreatic enzyme supplementation in pancreatic insufficient patients is also imperative to ensure maximal absorption of vitamin D and other nutrients and, therefore, the prevention of malnutrition. Early diagnosis of CF will also guarantee that malabsorption problems are aggressively addressed during childhood. Regular aerobic weight bearing exercise would have multifactorial benefits in this population. Longitudinal studies investigating BMD, diet, exercise, growth and attainment of peak bone mass, chronic corticosteroid use, the role of inflammatory cytokines in bone loss will definitively determine the impact of childhood practices and the chronic inflammatory nature of CF on adult BMD. Acknowledgments We would like to thank Ms Ruth Foster for performing the DEXA scans and Mrs Treena MacDonald for help with laboratory techniques. We also would like to acknowledge and thank all the patients who volunteered their time to participate in the study. References w1x Tanner JM. Foetus into man: physical growth from conception to maturity. Cambridge, Massachusetts: Havard University Press, 1990. w2x Aloia JF. The gain and loss of bone in the human life cycle. Adv Nutr Res 1994;9:1 –33. w3x Conway SP, Morton AM, Oldroyd B, Truscott JG, White H, Smith AH, et al. Osteoporosis and osteopenia in adults and adolescents with cystic fibrosis: prevalence and associated factors. Thorax 2000;55(9):798 –804.

169

w4x Haworth CS, Selby PL, Webb AK, Dodd ME, Musson H, Mc LNR, et al. Low bone mineral density in adults with cystic fibrosis. Thorax 1999;54(11):961 –7. w5x Grey AB, Ames RW, Matthews RD, Reid IR. Bone mineral density and body composition in adult patients with cystic fibrosis. Thorax 1993;48(6):589 –93. w6x Donovan DS Jr, Papadopoulos A, Staron RB, Addesso V, Schulman L, McGregor C, et al. Bone mass and vitamin D deficiency in adults with advanced cystic fibrosis lung disease. Am J Respir Crit Care Med 1998;157(6 Pt 1):1892 –9. w7x Bachrach LK, Loutit CW, Moss RB. Osteopenia in adults with cystic fibrosis. Am J Med 1994;96(1):27 –34. w8x Bhudhikanok GS, Lim J, Marcus R, Harkins A, Moss RB, Bachrach LK. Correlates of osteopenia in patients with cystic fibrosis. Pediatrics 1996;97(1):103 –11. w9x Haworth CS, Freemont AJ, Webb AK, Dodd ME, Selby PL, Mawer EB, et al. Hip fracture and bone histomorphometry in a young adult with cystic fibrosis. Eur Respir J 1999;14(2):478 –9. w10x Gibbens DT, Gilsanz V, Boechat MI, Dufer D, Carlson ME, Wang CI. Osteoporosis in cystic fibrosis. J Pediatr 1988;113(2):295 –300. w11x Bhudhikanok GS, Wang MC, Marcus R, Harkins A, Moss RB, Bachrach LK. Bone acquisition and loss in children and adults with cystic fibrosis: a longitudinal study. J Pediatr 1998;133(1):18 –27. w12x Flohr FLA, App EM, Matthys H, Reincke M. Bone mineral density and quantitative ultrasound in adults with cystic fibrosis. Eur J Endocrinol 2002;146(4):531 –6. w13x Anonymous. Standardization of Spirometry, 1994 update. American Thoracic Society. Am J Respir Crit Care Med, 1995; 152(3):1107–1136. w14x Shwachman H, Kulczycki L. Long-term study of one hundred five patients with cystic fibrosis. Am J Dis Child 1958;96:6 – 15. w15x Brasfield D, Hicks G, Soong S, Tiller RE. The chest roentgenogram in cystic fibrosis: a new scoring system. Pediatrics 1979;63(1):24 –9. w16x Frangolias DD, Wilcox PG. Predictability of oxygen desaturation during sleep in patients with cystic fibrosis: clinical, spirometric and exercise parameters. Chest 2001;119(2):434 – 41. w17x Adachi JD, Loannidis G, Berger C, Joseph L, Papaioannou A, Pickard L, et al. The influence of osteoporotic fractures on health-related quality of life in community-dwelling men and women across Canada. Osteoporos Int 2001;12(11):903 –8. w18x Genant HK, Faulkner K, Gluer C-C. Measurement of bone mineral density: current status. Am J Med 1991;91(Suppl. 5B):49S–53S. w19x Milne JS, Lauder IJ. The relationship of kyphosis to the shape of vertebral bodies. Ann Hum Biol 1976;3(2):173 –9. w20x Steiner MC, Barton RL, Singh SJ, Morgan MDL. Bedside methods vs. dual energy X-ray absorptiometry for body composition measurement in COPD. Eur Respir J 2002;19:626 – 31. w21x Bachrach LK. Dual energy X-ray absorptiometry (DEXA) measurements of bone density and body composition: promise and pitfalls. J Pediatr Endocrinol Metab 2000;13(Suppl. 2):983 –8. w22x Cummings SR, Black DM, Nevitt MC, Browner W, Cauley J, Ensrud K, et al. Bone density at various sites for prediction of hip fractures. The Study of Osteoporotic Fractures Research Group. Lancet 1993;341(8837):72 –5. w23x Kroger H, Kotaniemi A, Vainio P, Alhava E. Bone densitometry of the spine and femur in children by dual-energy X-ray absorptiometry. Bone Miner 1992;17(1):75 –85.

170

D.D. Frangolias et al. / Journal of Cystic Fibrosis 2 (2003) 163–170

w24x Cooper C, Cawley M, Bhalla A, Egger P, Ring F, Morton L, et al. Childhood growth, physical activity and peak bone mass in women. J Bone Miner Res 1995;10(6):940 –7. w25x Slemenda CW, Reister TK, Hui SL, Miller JZ, Christian JC, Johnston CC Jr. Influences on skeletal mineralization in children and adolescents: evidence for varying effects of sexual maturation and physical activity. J Pediatr 1994;125(2):201 – 7. w26x Michel BA, Lane NE, Bjorkengren A, Bloch DA, Fries JF. Impact of running on lumbar bone density: a 5-year longitudinal study. J Rheumatol 1992;19(11):1759 –63. w27x Dalsky GP, Stocke KS, Ehsani AA, Slatopolsky E, Lee WC, Birge SJ Jr. Weight-bearing exercise training and lumbar bone mineral content in postmenopausal women. Ann Intern Med 1988;108(6):824 –8. w28x Hatori M, Hasegawa A, Adachi H, Shinozaki A, Hayashi R, Okano H, et al. The effects of walking at the anaerobic threshold level on vertebral bone loss in postmenopausal women. Calcif Tissue Int 1993;52(6):411 –4. w29x Baroncelli GI, De Luca F, Magazzu G, Arrigo T, Sferlazzas C, Catena C, et al. Bone demineralization in cystic fibrosis: evidence of imbalance between bone formation and degradation. Pediatr Res 1997;41(3):397 –403. w30x Henderson RC, Madsen CD. Bone mineral content and body composition in children and young adults with cystic fibrosis. Pediatr Pulmonol 1999;27(2):80 –4. w31x Laursen EM, Molgaard C, Michaelsen KF, Koch C, Muller J. Bone mineral status in 134 patients with cystic fibrosis. Arch Dis Childhood 1999;81(3):235 –40. w32x Aris RM, Renner JB, Winders AD, Buell HE, Riggs DB, Lester GE, et al. Increased rate of fractures and severe kyphosis: sequelae of living into adulthood with cystic fibrosis. Ann Intern Med 1998;128(3):186 –93. w33x Ionescu AA, Nixon LS, Evans WD, Stone MD, Lewis-Jenkins V, Chatham K, et al. Bone density, body composition and inflammatory status in cystic fibrosis. Am J Respir Crit Care Med 2000;162(3 Pt 1):789 –94. w34x Manolagas SC, Jilka RL. Bone marrow, cytokines and bone remodeling. Emerging insights into the pathophysiology of osteoporosis. N Engl J Med 1995;332(5):305 –11.

w35x Heeckeren van AM, Tscheikuna J, Walenga RW, Konstan MW, Davis PB, Erokwu B, et al. Effect of pseudomonas infection on weight loss, lung mechanics and cytokines in mice. Am J Respir Crit Care Med 2000;161(1):271 –9. w36x Sood M, Hambleton G, Super M, Fraser WD, Adams JE, Mughal MZ. Bone status in cystic fibrosis. Arch Dis Child 2001;84(6):516 –20. w37x Hardin DS, Arumugam R, Seilheimer DK, LeBlanc A, Ellis KJ. Normal bone mineral density in cystic fibrosis. Arch Dis Child 2001;84(4):363 –8. w38x Haworth CS, Selby PL, Webb AK, Adams JE. Osteoporosis in adults with cystic fibrosis. J R Soc Med 1998;91(Suppl. 34):14 –8. w39x Reiter EO, Brugman SM, Pike JW, Pitt M, Dokoh S, Haussler MR, et al. Vitamin D metabolites in adolescents and young adults with cystic fibrosis: effects of sun and season. J Pediatr 1985;106(1):21 –6. w40x Feranchak AP, Sontag MK, Wagener JS, Hammond KB, Accurso FJ, Sokol RJ. Prospective, long-term study of fatsoluble vitamin status in children with cystic fibrosis identified by newborn screen. J Pediatr 1999;135(5):601 –10. w41x Heer MMC, Grzella I, Drummer C, Herpertz-Dahlmann B. Changes in bone turnover in patients with anorexia nervosa during eleven weeks of inpatient dietary treatment. Clin Chem May 2002;48(5):754 –60. w42x Aris RM, Neuringer IP, Weiner MA, Egan TM, Ontjes D. Severe osteoporosis before and after lung transplantation. Chest 1996;109(5):1176 –83 (see comments). w43x Ross J, Gamble J, Schultz A, Lewiston N. Back pain and spinal deformity in cystic fibrosis. Am J Dis Child 1987;141(12):1313 –6. w44x Adinoff AD, Hollister JR. Steroid-induced fractures and bone loss in patients with asthma. N Engl J Med 1983;309(5):265 – 8. w45x Packe GE, Douglas JG, McDonald AF, Robins SP, Reid DM. Bone density in asthmatic patients taking high dose inhaled beclomethasone dipropionate and intermittent systemic corticosteroids. Thorax 1992;47(6):414 –7. w46x Tschopp OBA, Speich R, Weder W, Seifert B, Russi EW, Schmi C. Osteoporosis before lung transplantation: association with low body mass index, but not underlying disease. Am J Transplant 2002;2(2):167 –72.