Background and introduction
Calcium and mineral metabolism is one of the
fundamental biological processes underlying eukaryote cell function and vertebrate physiology. Changes in calcium metabolism have been noted in patients with CF for over 30 years, both in cell biology and whole body aspects. Bone mineral density (BMD) is the most widely reported, and among the most easily measured, aspects of calcium metabolism. There are subtle gender differences in calcium metabolism, body composition and bioenergetics (apportionment of energy supplies), attributed to the burden of reproductive function in women, probably mediated by differences in the hormonal milieu. Survival in CF has improved in the past 3 decades, but females have shorter life expectancy than males, and this gender difference in mortality has persisted, notwithstanding increases in survival rate. The aim of this work was to test the hypothesis that female disadvantage is related to enhanced calcium conservation in females compared with males, even in those with severe disease. To enhance
generalisability of the conclusions, this subject is approached from both an epidemiological and case study perspective.
Two meta-analyses of BMD in CF were undertaken, the first to determine whether BMD is reduced overall in CF patients, and the second to examine gender differences. A cross sectional study of 150 CF and 150 control subjects aged 5 - 5 6 years was undertaken, to test the hypothesis that calcium metabolism is abnormal in CF. Survival in Queensland CF patients born from 1979 - 1981 attending the Royal Children's Hospital was analysed, in order to confirm the existence of the 'gender gap' in the local population. Definition of disease severity in CF is difficult, because of phenotype heterogeneity (even on a similar genetic background), confounding of lung function with age, and the survivor effect, whereby adults with CF represent a highly
selected survivor population. Several statistical models for quantification of disease severity were developed and compared, the best model selected, and applied to subjects in the case study, for comparison of calcium metabolism according to disease severity.
The meta-analyses confirmed that BMD was lower than the normal population in CF subjects, and that BMD was lower in males than in females with CF. From the case study, biochemical alterations in calcium metabolism were present in CF subjects of all ages, including low 1,25 dihydroxy vitamin D, magnesium, vitamin A, and increased variation in PTH both above and below the normal range. Adolescents and adults with CF had low BMD. In adolescents, low BMD was attributable mainly to males, and associated with growth failure. In adolescents there were also gender differences in vitamin D, with CF females
having lower 25 hydroxy vitamin D and lacking the normal peri-pubertal spike in 1,25 dihydroxy vitamin D. Adults with CF of both genders had low BMD. The vitamin A study showed that low serum vitamin A in the CF group was associated with inflammatory status as reflected by CRP. The survival analysis confirmed that females with CF had about twice the risk of death of males (odds ratio 1.96, CI 1.12 to 3.44). Of the models for disease severity, a Bayesian model, which corrected for non-ignorable drop-out (loss of subjects due to death, related to disease severity), was selected over several logistic regression models. The study of gender dimorphism in calcium metabolism and its relationship with disease severity showed that females with severe disease had preserved bone density, compared with males. Males with severe disease had poorer nutritional status, lower BMD and growth failure, but improved survival, compared with females.
There were significant associations between calcium metabolism, gender and disease severity in CF. Evolutionary pressure appears to have selected human females to be more resistant to malnutrition and starvation than males because of reproductive fitness. We hypothesise that the gender gap in CF is a manifestation of this trait. Growth failure and low BMD in males may represent a protective adaptation to malnutrition and increased energy expenditure, an adaptation which is less available to females, whose biological and hormonal milieu promotes growth and storage of fat and mineral stores for reproductive fitness.
These observations suggests that future research focus on improved strategies for nutritional therapy, particularly from the peri-pubertal years, with a view to supporting the increased energy demands of puberty and adulthood, and also on gender
differences in bioenergetics and body composition in CF.