Bone strength parameters in children and adolescents with cystic fibrosis: examining the muscle-bone unit

Brookes, Denise Susanne Kaesler (2012). Bone strength parameters in children and adolescents with cystic fibrosis: examining the muscle-bone unit PhD Thesis, School of Medicine, The University of Queensland.

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Author Brookes, Denise Susanne Kaesler
Thesis Title Bone strength parameters in children and adolescents with cystic fibrosis: examining the muscle-bone unit
School, Centre or Institute School of Medicine
Institution The University of Queensland
Publication date 2012-05
Thesis type PhD Thesis
Supervisor Peter S. W. Davies
Rebecca J. Hill
Craig Munns
Julie N. Briody
Total pages 364
Total colour pages 31
Total black and white pages 333
Language eng
Subjects 1114 Paediatrics and Reproductive Medicine
1103 Clinical Sciences
1102 Cardiovascular Medicine and Haematology
Formatted abstract

An increased prevalence of low areal bone mineral density (aBMD) is reported in individuals with Cystic Fibrosis (CF), concurrent with their longer life expectancy. Inadequate bone mineral accrual is partly suggested as a cause of the reported low aBMD, which evolves during the child and adolescent growth period. The evidence for the reported low aBMD is equivocal because of the poor understanding of the independent and combined effects of the disease and treatment on bone metabolism, and the size dependent limitations of using dual-energy x-ray absorptiometry (DXA) to assess bone health in this population. Furthermore, the high incidence of short stature potentially causes an overestimation of low aBMD in this population. Alternatively, due to the links between muscle mass and bone development, the collected evidence suggests that DXA assessed lean tissue mass (LTM) and bone mineral content (BMC) relationships could provide a differential diagnosis to the low aBMD for age and sex that is currently reported. Additionally, and importantly, DXA is not a volumetric measure of BMD (vBMD) and shadows potential changes in the bone structural parameters and/or true vBMD that may indirectly affect the muscle-bone relationships and bone strength. It would be appropriate to assess the bone structural parameters, vBMD, and their interactions with muscle mass, in children and adolescents with CF using peripheral quantitative computer tomography (pQCT). This has not been done. The main aims of this thesis are: (1) to use pQCT to provide a comprehensive assessment of bone strength parameters in children and adolescents with CF, and (2) to determine if the reported low aBMD in individuals with CF is more a reflection of altered/compromised structural parameters, in addition to low vBMD, via dysfunctional muscle-bone interaction.


Altogether, 53 individuals with CF (19 males, 34 females) and 53 controls (19 males, 34 females) between the ages of 7.00 and 17.99 years were involved in the cross-sectional comparisons of DXA (Chapter 5) and pQCT (Chapter 6) data. Of these, a sub-group of 10 females with CF and 10 female controls had been involved in previous research. These cohorts were specifically selected for a near 7-year longitudinal study (Chapter 4). The previously assessed data was used for initial measurements, with follow-up data provided by testing in this current thesis. For all subjects, BMC, aBMD and body composition were assessed by DXA. Bone structural parameters, vBMD, muscle cross-sectional area (mCSA) and estimations of bone strength (SSI and BSIc) at the 4% and 66% sites of the radius and tibia were assessed by pQCT. Anthropometric, clinical and historical data were concurrently measured and collected on these testing days. Bone ages were measured via left hand-wrist X-rays and calculated using Tanner-Whitehouse methods. Pubertal stages were determined by each subject's self-report, using the pictorial grading system defined by Tanner for pubic genital development. Total body potassium counting (TBK) was used to assess each participant’s nutritional status. Muscle function was assessed in upper extremities using a hand grip strength dynamometer, and in the lower extremities using vertical jump, with the relevant estimates of muscle power calculated. Vitamin D levels were determined using automated immunoassay. The validated physical activity questionnaire for older children (PAQ-C) was used to assess general physical activity levels of the participants during the school year. Consecutive 3-day food diaries, that included a food frequency questionnaire, were used to evaluate nutritional intake, specifically calcium intake. Historical data were collected via retrospective hospital chart reviews.


The prospective 7 year data (Chapter 4) found, over time, the bone mineral accrual (BMC) rates remained lower in the well-nourished females with CF compared to the female controls. These patterns of bone mineral accrual were significantly related to height and LTM, with a large proportion of the variance in BMC accounted for by LTM. The females with CF showed atypical linear growth and increases in LTM, and had significantly less BMC per kilogram of LTM, irrespective of age, compared to the female controls. After adjusting both parameters for height, BMC was appropriate for the amount of LTM prior to puberty, but remained significantly less for the amount of LTM at puberty, in the females with CF.

In the cross-sectional comparison of the DXA data (Chapter 5), as a group, the well-nourished individuals with CF showed adequate mean LTM for height (relative LTM), as did the controls. Reductions in BMC were primarily due to the shorter stature in the pre-pubertal individuals with CF compared to the pre-pubertal controls, and a normal muscle-bone interaction is suggested. An inadequate adaption of BMC to the amount of LTM was significantly shown in the pubertal females with CF, to suggest a potential primary bone defect. While a normal muscle-bone interaction was statistically shown in the pubertal males with CF, trends suggest similar interactions to that of the pubertal females with CF. The subject numbers in the male pubertal cohort may have been responsible for the lack of statistical significance found.

In the cross-sectional comparisons of the pQCT data (Chapter 6), the pre-pubertal individuals with CF showed bone structural parameters and bone strength indices that were not different to the controls, at both the 4% and 66% sites of the tibia and radius. Higher vBMDs were shown in the pre-pubertal individuals with CF compared to the pre-pubertal controls. The pubertal individuals with CF had slightly higher vBMDs than in the pre-pubertal individuals with CF, but compared to pubertal controls, appeared with relative reductions, particularly of the cortical and trabecular vBMD. With age, individuals with CF showed greater reductions in the structural parameters; progressively smaller bone and mCSA with less BMC. This was significantly shown in the adolescent females with CF, in addition to a thinner bone cortex and smaller medullary cavity, at the tibia. These results appeared only as trends in the pubertal males with CF compared to the male controls.

Bone strength was lower in the individuals with CF, independent of age, at the tibia and radius, and became progressively lower with age at the tibia only, compared to the controls. Although the variances accounted for in bone strength by mCSA were always less in the individuals with CF, at the tibia more so than the radius, mCSA was the strongest independent predictor of bone strength. A smaller mCSA predicted lowered bone strength at both limbs in the individuals with CF compared to the controls, even when adjusted for size (relative mCSA). Moreover, the individuals with CF developed a significantly smaller relative mCSA with age, only at the tibia, not at the radius.


Individuals with CF present with an inadequate development of BMC for their lower amount of LTM, around the time of puberty, even when adjusted for size, to suggest a dysfunctional muscle-bone relationship. This was significantly presented in the pubertal females with CF. The vBMD in the appendicular skeleton in individuals with CF appears to remain at a similar level with age, with relative variations mainly due to changes in the bone size and BMC. Muscle CSA was a significant independent predictor of bone strength, such that a smaller mCSA with progressing age was predictive of lowered bone strength in the participants with CF compared to the controls, particularly at the tibia. The altered bone structural parameters, and their implications for bone strength in these children and adolescents with CF, are potentially due to a reduced bone strain, secondary to reduced muscle force. In children and adolescents with CF, recommended strategies to be incorporated into routine care for future long-term management of CF-related bone disease are to:

     1) evaluate densitometric data for height and muscle mass;
     2) use volumetric densitometry, where possible; and
     3) optimise bone structural parameters via an increased muscle-bone interaction.
Keyword pQCT
Bone structure
Bone strength
Muscle-bone unit
Paediatric growth
Cystic Fibrosis (CF)

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Created: Fri, 11 Jan 2013, 14:05:15 EST by Denise Brookes on behalf of Scholarly Communication and Digitisation Service