Normal Annual Increase of Bone Mineral Density During Two Years in Patients With Cystic Fibrosis
* Departments of Pediatrics, West Swedish CF Center, Göteborg, Sweden
Department of Geriatrics, Göteborg University, Göteborg, Sweden
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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Objectives. To determine prospectively for 2 years the change in bone mineral density (BMD) in patients with cystic fibrosis (CF) and to correlate clinical data and routine biochemical parameters of bone metabolism and infection with BMD.
Methods. Fifty-four patients with CF, aged 6 to 33 years, were included. BMD was measured using dual-energy x-ray absorptiometry in lumbar spine (LS) and femoral neck (FN). Anthropometric data and biochemical markers of bone metabolism and infection were measured. The number of intravenous antibiotic courses per year (ivAC) and pulmonary function were assessed.
Results. The patients had normal anthropometric data and normal growth, but 36% and 33% of the patients had BMD z score <–1 standard deviation in LS and in FN, respectively. Nevertheless, BMD increased at a normal rate during the 2 years and was correlated to weight and lung function. Intact parathyroid hormone was positively correlated with the increase of BMD in both LS and FN during childhood. Blood sedimentation rate, serum concentration of immunoglobulin G, and ivAC were negatively correlated with BMD in FN. Patients with 2 more severe CF transmembrane conductance regulator mutations had significantly lower BMD in FN than other genetic combinations.
Conclusion. The study suggests that low BMD in CF is multifactorial and depends on infection and nutritional parameters. Differences in BMD of LS and FN suggested higher susceptibility to infection in FN at all ages. Longitudinal studies starting early before bacterial colonization would be valuable to determine the relative role of infection in the development of BMD in CF.
Key Words: genotype • infection • parathyroid hormone • retinol • vitamin D
Abbreviations: CF, cystic fibrosis • BMI, body mass index • BMD, bone mineral density • DXA, dual energy x-ray absorptiometry • ALP, alkaline phosphatases • 25(OH)D, 25-hydroxyvitamin D • 1,25(OH)2D, 1,25-dihydroxyvitamin D • iPTH, intact parathyroid hormone • IgG, immunoglobulin G • SR, sedimentation rate • ivAC, intravenous antibiotic course • LS, lumbar spine • FN, femoral neck • FVC, forced volume capacity • FEV1.0, forced expiratory volume in 1 second
Disturbed bone metabolism and mineralization in patients with cystic fibrosis (CF) has been recognized for several years and may have potentially greater impact when the improved general therapy has reduced morbidity and mortality.1,2 Osteopenia is common in patients with CF and considered to be associated with poor general status, especially in older patients with low body mass index (BMI).3–5 Pancreatic insufficiency may lead to impaired absorption of fat, calcium, and vitamin D and to low body weight. The chronic inflammation in these patients might also be correlated with osteopenia.6,7 Many CF patients also have a delayed puberty.6 The use of corticosteroids, mandatory after lung transplantation, is another identified risk factor.5,8
Most patients of all ages at the West Swedish CF Center have normal anthropometric data, normal growth, and well-preserved lung function, expressed as z scores, ie, the SD scores.9 Still many of the patients have decreased bone mineral density (BMD).10 Bone remodeling has been found to be disturbed with an indication of increased bone resorption without compensatory increase in bone formation.11,12 To elucidate whether this disturbance is progressive, we performed a 2-year prospective study and compared BMD, measured with dual-energy x-ray absorptiometry (DXA), with routine biochemical bone markers and infectious parameters.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Fifty-four patients who had CF (25 male/29 female), were aged 6 to 33 years (median: 17 years), and regularly attended the West Swedish CF Center in Göteborg were included consecutively in the study except for pregnant patients or patients who had received a transplant. They were investigated in stable conditions at their yearly check-up (Table 1). The CF diagnosis was verified by pathologic sweat test (Cl >60 mmol/L). Nineteen of the patients were older than 20 years at the start of the study. The age of 20 is regarded as the legal adult age in Sweden. All patients had pulmonary symptoms and were encouraged to be physically active as a part of the physiotherapeutic regimen.13 All had oral mucus dissolving therapy (bromhexine) and inhalation of broncholytics (salbutamol and saline or N-acetylcysteine).
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Only 1 patient was treated with oral steroids for the last 2 years. She also inhaled steroids, as did 4 other patients, 1 intermittently and the other 3 for an average of 2 to 4 years. Four patients were pancreatic sufficient. These patients were not in better nutritional status than the others. All patients were routinely prescribed extra vitamin D (500–1000 IU/day), vitamin A (5000 IU), and vitamin E (100–400 mg). Ten patients had a mild CF-associated liver disease as revealed by increased serum transaminases above reference values (+2 SD) and verified by biopsies only showing steatosis or mild fibrosis. Four children had a verified nonsymptomatic cirrhosis, and 1 child had clinical liver disease with portal hypertension. All 15 patients were treated with ursodeoxycholic acid. Four patients had insulin-dependent CF-related diabetes.
Thirty-three (61%) patients were chronically colonized with Pseudomonas aeruginosa. They had repeatedly positive growth of the bacterium in sputum for 
6 months and increased serum titers against pseudomonal exotoxin A.14
Thirty-three patients were homozygous and 17 were compound heterozygous for dF508. The allele characteristic of the Northern countries, 394delTT, was found in 6 patients, 2 in homozygous and 4 in heterozygous form (394delTT/dF508). E60X was present in 4 patients and 621 + 1G-T in 3, all in combination with dF508. Another 8 mutations were identified, but none of these were present in >1% of the alleles.15 Two percent of the alleles were unidentified. The study was approved by the Ethical Committee of Göteborg University, and informed consent was obtained from patients and parents.
Clinical and Biochemical Data
Height, weight, and BMI were related to Swedish standards with z scores.16,17 Spirometry was performed with Jaeger spirometer, and the results were related to the Swedish population.18,19 Working capacity was determined with bicycle ergometer to a pulse frequency of 120/min and compared with reference values from the literature.20,21
Blood samples were drawn after an overnight fasting, and serum was used for determination of calcium, phosphate, alkaline phosphatases (ALP), 25-hydroxyvitamin D (25[OH]D), 1,25-dihydroxyvitamin D (1,25[OH]2D), retinol (vitamin A), and intact parathyroid hormone (iPTH) according to routine. Infection parameters as immunoglobulin G (IgG), blood sedimentation rate (SR), and white blood cell count were measured with routine methods, and reference values were obtained from the laboratory. The number of intravenous antibiotic courses per year (ivAC) was registered.
BMD Measurements
DXA was measured at the first to fourth lumbar spine (LS) and at the femoral neck (FN), performed with a Hologic QDR-2000 (pencil-beam mode). The coefficient of variation with spine phantom measurements in the Hologic 2000 during the period 1996–2000 was 0.48%. Reference values were obtained from the manufacturer and expressed in age- and gender-matched z scores. Reference values for FN for children 9 to 19 years were obtained from the literature.22 In a longitudinal based cohort of 234 16-year-old healthy individuals in Göteborg followed annually to 21 years, a very good agreement was obtained to the manufacturer's values, deviating 0% to 2% in the female subjects and –4% to 2% in the male subjects (D Mellström, unpublished observation).23 In parallel to osteopenia and osteoporosis, which are defined by t scores, decreased BMD was defined in the text as BMD z score <–1 SD and osteoporosis <–2.5 SD for any site.
Statistical Analysis
Statistical analyses were performed with t test, 1-sample t test, and paired t test at normal distribution of data, otherwise with nonparametric tests as Mann-Whitney U test and Wilcoxon paired sign rank test. Univariant correlation was made with Spearman rank correlation. Partial correlation coefficients were calculated (A. Odén, PhD). Mantel test was used for testing the correlation between FN z score and age with elimination of the influence of gender. Mean (SD) was used if not otherwise indicated. Statistical significant difference was set at P < .05.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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BMD
Forty-one percent and 35% of the patients had decreased BMD z score of LS at baseline and follow-up, respectively, and 33% of the patients had decreased BMD z score of FN at both investigations. Three boys slightly decreased their BMD in LS (range: 0.04 to –0.01 g/cm2), and 7 children in FN (range: –0.05 to –0.006 g/cm2; Figs 1 and 2). The mean annual change in BMD for adults was normal, ie, not different from 0 (Table 2). Most children had a good annual accretion of BMD (Table 2, Fig 3). Despite this positive development, the z scores were reduced in the LS and FN in both children and adults (Table 3), without significant differences after 2 years. A z score of BMD <–2.5 SD was seen in only 4 patients.
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) and FN (
) in 54 patients with CF in relation to age.
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Clinical Data
Anthropometric Data
The average weight and height were normal and the z scores did not change during the 2 years (Table 1). Only 1 patient had a z score for weight and height <–2 SD. Adult patients had a lower z score for height compared with children (P
.05) but still not significantly different from normals. The mean BMI for the adults was normal; 1 adult only had a BMI <16.17,24 Over the 2 years, the z scores for height and weight increased significantly in adults (P = .02, respectively) and for BMI in both children and adults (P = .0001 for each).
Biochemical Analysis
All biochemical values had means and medians within the normal range; average concentrations were as follows: calcium, 2.3 mmol/L (0.1; reference values: 2.2–2.6); phosphate, 1.5 nmol/L (0.2; reference values: 0.8–1.4); iPTH, 43.8 ng/L (21.7; reference values: 10–65); vitamin A, 1.6 nmol/L (0.4; reference values: 0.95–3.31); 1,25(OH)2D, 32.4 pg/mL (14.8; reference values: 15–55); and 25(OH)D, 25.3 ng/mL (9.8; reference values: 10–65). ALP had serum concentrations within reference values in relation to age: children, 12.3 µkat/L (4.1; reference values: 4–18); adults, 4.7 µkat/L (1.6; reference values: <5). No significant difference related to seasons was found in the serum concentration of vitamin D, but to exclude any possible influence of seasonal variation, all investigations at 2 years interval were made at the same time of the year in the individual patient. Three (6%) patients had vitamin D deficiency (below reference values). Another 13 (26%) patients had levels <20 ng/mL, considered insufficient,12 and an additional 20 patients had values <30 ng/mL (Fig 4). Six (11%) patients had increased iPTH (Fig 4). The mean values of the infection parameters were normal (Table 4).
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Pulmonary Function
The mean forced volume capacity (FVC) and forced expiratory volume in 1 second (FEV1.0) were reduced in the adults but not in the children (Table 4). Three patients had severe lung disease (FEV1.0 <40% of predicted) at baseline, which persisted low in 2. All of them were chronically colonized with P aeruginosa. The working capacity was normal (mean 3 W/kg [0.8] body weight) for both children and adults during the observation period.
Relation to Clinical Parameters
There was a difference in several individuals between relative BMD of LS and FN. This was also illustrated in relation to clinical parameters (Table 5). Chronic pseudomonas colonization or pancreatic insufficiency did not correlate to z scores of LS or FN. Patients with diabetes or liver disease did not show extreme values. LS z score did not correlate to genotype. FN z score was significantly lower in the adults who were homozygous for 
F508 and those who carried 394delTT compared with the other patients who were heterozygous for F508 (P = .02 for each). Also, BMD FN was significantly lower in all patients who were homozygous for F508 (P < .05).
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The LS and FN BMD and the z scores in children were correlated to z score for weight and BMI (Table 5). The 3 boys with decreasing BMD of LS had low z scores for height and weight initially. The FN z score decreased significantly with age (P = .01), when the influence of gender was eliminated.
The LS BMD was inversely correlated to serum phosphate in the children. No correlation was found to calcium, 25(OH)D, 1,25(OH)2D, vitamin A, or ALP. In adults, the correlation to iPTH showed a negative trend as expected, but in the children, there was a significant positive correlation to the increment in BMD. BMD and BMD z score in FN were negatively correlated to infection parameters. LS BMD z score showed an inverse association to ivAC and SR, but this significance completely disappeared when the 3 boys without increasing BMD were excluded (Table 5). When patients were grouped according to normal or pathologic IgG, the latter group showed a significantly negative correlation to the increments of BMD in FN and LS. Similar but nonsignificant difference was found for SR (Fig 5). FN BMD and the z score showed significant correlations to SR (Table 5).
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Differences in bone metabolism of FN and LS were suggested in the comparison between patients who improved or deteriorated in BMD during the 2 years. In LS, significant differences were found between these groups regarding z score for height (P < .001) but less prominent correlations to infectious parameters as IgG (P < .05) and SR (P < .01). Corresponding comparison in FN showed correlation to z score for height (P < .01) and strong relation to IgG, SR, and number of ivAC (P < .001 for each).
BMD and BMD z scores of LS and FN correlated to lung function (Table 5). Similar correlations were found in adults for FN. Working capacity correlated mainly to BMD and BMD z score in FN.
The variable with the strongest correlation with LS z score among the anthropometric variables was weight (z score) and among the spirometric ones was FVC. There was a significant correlation between LS and weight when the influence of the spirometric variables FVC and FEV1.0 was eliminated. There was also a significant correlation between LS and FVC when the anthropometric variable weight was eliminated (Table 6). Thus, both anthropometric and spirometric variables independently were of importance for LS. Furthermore, the lung function and SR independently correlated to FN z score. The partial correlation coefficient between phosphate and LS when height and BMI were eliminated was –0.46, suggesting that also calcium-phosphorus homeostasis was of importance.
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The variable with the strongest correlation with FN among the anthropometric variables was weight (z score) and among the spirometric ones was FEV1.0. There was no significant correlation between FN and weight when the influence of FEV1.0 was eliminated (Table 6). However, there was a significant correlation between FN and FEV1.0 when the influence of weight was eliminated.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Despite normal growth and normal anthropometric status of the CF patients, low BMD z scores in LS and FN were seen in 36% and 33%, respectively, of the CF patients during a 2-year period. Very low levels as in osteoporosis were rare. The yearly gain in BMD of the LS as well as of the FN was similar to that in healthy Swedish children who were 13 to 16 years of age and had high physical activity, ie, close to 0.055 g/cm2 and 0.04 g/cm2, respectively.25,26 In the Swedish reference material, the annual growth was for LS 7.9% and 6.8% for boys and girls, respectively, and for FN 5.9% and 3.6%. Because our group of children represents a larger group (mean: 12 years) including ages with lower bone growth rate, an annual increase of 5.8% and 3.4% for LS and FN, respectively, is reasonably close to the normal percentage accretion for a larger group of children. A support for this assumption was found when the BMD growth rate of the CF patients (n = 8) aged 13 to 16 years was analyzed separately. Three girls had a mean increment of 0.11g/cm2 in LS and 0.06 g/cm2 in FN. The corresponding figures in 5 boys were 0.05 g/cm2 and 0.04 g/cm2, respectively. The annual increases in BMD were for these subgroups 13% and 8% for girls and 6.5% and 5% for boys in LS and FN, respectively. We therefore consider that the figures suggest a normal gain in BMD in our CF patients (Table 2). BMD z score was unchanged in the LS of the female children, and although not statistically declining in the boys, the trend was negative, suggesting that young men gained less bone mineral than expected for age, probably reflecting a later puberty.6 A decrease in absolute BMD in LS was seen only in 3 boys (Fig 1). The female adults with CF generally had lower z scores in both LS and FN than the men, probably reflecting low levels of estrogen.27
Decreased BMD has been reported to be a frequent complication of CF at all ages and mainly related to poor nutrition and impaired lung function.1,3,8,28 Some authors report normal BMD, but the normality was seen only in relation to children stunted to the same degree as the CF patients but not compared with age- and gender-matched control subjects.29,30 In the adults with CF, no significant decline in BMD was found in FN and LS. Our results thus are different from those recently published in a 1-year prospective study, in which the annual decline was more prominent in the FN.2 In children, we even had normal bone growth opposite to previous longitudinal reports.1,2 The normal anthropometric data in our patients and that we generally do not use corticosteroids might explain the difference to other studies.
No correlation was found between BMD and serum concentrations of calcidiol, calcitriol, or calcium. A slight disturbance in the calcium-phosphorus homeostasis was suggested by the significant inverse relation of LS BMD to the serum concentration of phosphate. The high serum P values were not attributable to renal impairment (data not shown). It is interesting that increased iPTH in the children was correlated to better increase of LS BMD, suggesting that iPTH might have an anabolic effect on bone mineralization in the LS during childhood.31 Conversely, it might be an expression of impaired calcium balance as a result of high growth rate, because very high calcium intake is necessary for normal bone development.32 In the FN of the adult CF patients, high iPTH indicated a lower BMD z score, as could be expected, but the difference was not significant (Fig 6).
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The serum levels of vitamin D were mainly within the normal range (Fig 4). Only 6% of our patients had low serum 25(OH)D levels (<10 ng/mL) compared with approximately one third of the patients in some recent studies.12,33 However, 61% had serum values <30 ng/mL, which is the level recommended by Holick34 as lowest values in CF patients. The slightly higher mean value of 25(OH)D in children compared with adults might reflect that most children had fat-soluble vitamin supplementation in water dispersion but the adults had tablets. Others have also noted mild secondary hyperparathyroidism in CF.12,33,35 It would be of interest to investigate whether iPTH and BMD would be normalized by a supply of very high doses of vitamin D to the patients.
Serum concentrations of vitamin A were not increased in our patients despite regular supplementation. We have previously shown that vitamin A was not stored excessively in the liver when serum concentrations were normal,36 indicating that despite a high intake, the body pool was probably not increased. In recent studies, high dietary intake of retinol in adults seemed to be associated with osteoporosis.37–39 No relation was found between the serum levels of vitamin A and BMD in our series of patients.
No relation was found between deterioration rate of lung function or of bacterial colonization and changes in BMD, but a significant negative correlation was found in adults to the number of ivAC (P < .01), suggesting that the bacterial load and degree of inflammation might contribute to the low BMD. This correlation was not restricted to patients with chronic pseudomonas colonization. The influence of infection was illustrated further by increased routine inflammatory markers, such as SR and IgG, being associated with lower gain in BMD in both LS and FN. Inflammatory cytokines, such as interleukin-1ß, interleukin-6, and tumor necrosis factor-
, are increased in serum and sputum of CF patients during exacerbations, and these cytokines are related to increased bone resorption.6,7,40 Although SR and IgG were only slightly increased in our patients, the levels of cytokines in CF patients in stable condition might be increased.37
A difference in bone metabolism of LS and FN was suggested further by the comparison of patients who improved or not in BMD during the 2 years. The data support that LS seemed to be more influenced by body growth (hormonal factors?) and FN seemed to be more susceptible to infection. Similar differences between LS and FN have been observed in inflammatory bowel disease.41
We also found an association between more severe cystic fibrosis transmembrane conductance regulator mutations and the FN z score, which is in line with the results of the infection parameters. In a previous study, an association was found between bone resorption markers and homozygosity for dF508.33
In conclusion, significant negative correlations between infection, number of ivAC, and routine inflammatory markers and the changes in BMD during a 2-year period support the view that inflammation is an important factor in the decreased BMD of the CF patients. That influence may start early in life because the growth rate of BMD was not different from normal,25 which would be expected because most patients had normal anthropometric data.
The secondary hyperparathyroidism suggested an additional impact of latent calcium or vitamin D deficiencies.34,42 The results suggest differences in the impact of inflammation on LS and FN and illustrate the complexity of the bone mass homeostasis in CF, indicating a need for longitudinal prospective studies from early childhood into adult life.
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ACKNOWLEDGMENTS |
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This study was supported by grants from the Swedish Medical Research Council (4995), Swedish Association of Cystic Fibrosis, Gunnar and Märta Begendahls Foundation, and the Faculty of Medicine.
We are grateful to Anders Odén, PhD, for statistical advice.
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FOOTNOTES |
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Received for publication Feb 13, 2003; Accepted Jul 13, 2003.
Reprint requests to (E.G.) Department of Pediatrics, West Swedish CF Center, Queen Silvia Children's Hospital, 416 85 Göteborg, Sweden. E-mail: eva.gronowitz{at}vgregion.se
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