Table of Contents:
Antenatal Bartter syndrome, also known as hyperprostaglandin E syndrome (HPS group) is one of the
congenital hypokalaemic salt-losing tubulopathies. A disorder in the ascending segment of the loop of
Henle results in hypokalaemia, hypercalciuria, metabolic alkalosis and to excessive renal and
systemic prostaglandin E2 synthesis (Seyberth et al. 1985; Seyberth et al. 1987). Besides
polyhydramnios, a severe increase in risk of premature birth, growth retardation and osteopenia also
occur (Seidel et al. 1995; Shoemaker et al. 1993; Proesmans 1997). Bone metabolism in antenatal
Bartter syndrome is influenced by different factors, which can lead to reduced bone density. This
includes hypercalciuria, increased prostaglandin E synthesis, as well as an increased parathyroid
hormone-induced osteolysis, and the occurrence of a particular basic fibroblast growth factor (b-FGF)
complex that promotes bone resorption. The consequences of prematurity also result in increased
The aim of the study was to investigate growth retardation and osteopenia more closely, based on the
bone density and bone geometry of patients of pre-school age with antenatal Bartter syndrome.
Practices established for measuring bone density in adulthood (DXA, QCT) make use of densitydependent
attenuation by x-rays. However, certain requirements and characteristics must be taken
into account when selecting the osteodensitometry method for childhood. Digital radiogrammetry
(DXR), the technique selected, combines a number of advantages (no renewed exposure to x-rays, no
influence by the variable soft tissue mantle) for osteodensitometry in childhood (Kotzki et al. 1994;
Genant et al. 1996; Bottcher et al. 2005). Interpreting bone density measurements and determining
the bone geometry in children is a complex procedure. Changes as a result of children’s development
and growth must be taken into consideration and the results must be corrected accordingly.
Consequently, the pairs to be compared in this study were primarily formed according to bone age to
prevent errors as a result of anthropometric effects. The control groups were made up of former
premature babies (FG group) on the one hand, and paired healthy children (norm group) on the other.
A comparison of the anthropometric data showed growth retardation in both the HPS and FG groups,
as opposed to the norm collective. The patients with antenatal Bartter syndrome and the former
premature babies were significantly smaller and lighter than the norm collective. On average, a height
of 113.91 cm was found in the HPS group, and 114.22 cm in the FG group, compared to 127.86 cm in
the norm group (p<0.001). A comparison of the body weight showed that the HPS group with 20.29 kg
and the FG group with 19.22 kg was significantly different to the norm collective with 30.14 kg
(p<0.001). Growth retardation was also shown by means of significant differences in bone age when
comparing children of the same age.
In order to investigate osteopenia in the patient collective, the bone density was determined and
compared with statistical twins from the premature baby group. Patients with antenatal Bartter
syndrome showed a distinctly low bone density (0.361 g/cm2) compared to the FG group (0.405 g/cm2)
(p=0.003). Significant changes in bone structure were also found when examining the bone geometry.
The metacarpals of the HPS group were considerably thinner and also had thinner cortical bone
compared to the FG group (p<0.05). A comparison of the former premature babies and the norm
collective did not show a significant difference in the bone density and bone geometry. Besides the bone density and the bone geometry, innovative parameters such as the porosity (cortical
microarchitecture) are determined by means of DXR. Here, the former premature babies showed a
highly significant greater porosity when compared to the norm (p=0.001). Similarly, when comparing
the HPS group with the FG group, an increased porosity was determined in children with antenatal
Bartter syndrome, although a significance level was not reached. Compared to the norm collective, a
significant increase (p=0.01) was again determined.
The precise pathogenesis of osteopenia is not known. In antenatal Bartter syndrome, as is also the
case in this patient collective, increased calcium elimination (Shoemaker et al. 1993; Proesmans
1997) can be seen. Besides metabolic factors, such as increased production of cytokines as local
mediators for bone resorption (Pacifici et al. 1990; Manolagas 2000), and dietetic factors, such as
increased protein absorption (Pietschmann et al. 1992), genetic factors (Prié et al. 2002) were also
shown as part of pathogenesis of osteopenia in hypercalciuria. A proven basic fibroblast growth factor
complex could play a key role in bone metabolism in antenatal Bartter syndrome. This complex leads
to increased bone resorption (Shoemaker et al. 1998; Williams et al. 1999). Seybarth et al. (Seybarth
et al 1985; Leonhardt et al. 1992) assumed that this increased bone resorption is mediated by the
PGE2 increase. However, prostaglandins stimulate both bone resorption and bone structure via
different receptors (Li et al. 2007; Hartke, Lundy 2001). In antenatal Bartter syndrome the EP4
receptor plays a dominant role (Nüsing et al. 2005). Studies in which the EP4 receptor was examined
more closely showed a catabolic effect (Li et al. 2005; Suzawa et al. 2000). Should the anabolic effect
of the prostaglandin E2 nonetheless be predominant, treatment using indomethacin as a prostaglandin
synthesis inhibitor could impact negatively on bone density. The parathyroid hormone, as inductor of
osteolysis, could represent an additional reason for demineralisation. Hyperparathyroidism leads to
endosteal resorption of cortical bone and increased porosity (Richardson et al. 1986; Parfitt 2003).
In order to estimate the risk of fractures, additional parameters, besides reduced bone density, play a
key role; these factors include cortical thickness and porosity (Bouxsein et al. 2004; Wenzler 2003;
Skaggs et al 2001; Rauch et al. 2001). The fact that measurement of the cortical thickness may even
be superior to measurement of the bone density when estimating the risk of fractures was shown in
studies concluded on treatment using bisphosphonates (Hyldstrup et al. 2001).
In this thesis it was thus established that an increased risk of fractures may exist in antenatal Bartter
syndrome due to reduced bone density, increased porosity and reduced cortical thickness. When
comparing the former premature babies with the norm collective, significant bone changes were also
determined, based on the increased porosity.