what-when-how
In Depth Tutorials and Information
A patient with moderately severe OI had a homozy-
gous abnormality carboxylpropeptide (C-propeptide)-
coding region of the pro-alpha2(I) collagen gene and
made only alpha 1 trimers. His parents were third cous-
ins and were heterozygotes for the same gene defect.
The parents were asymptomatic, but did have low
BMD in their thirties. Thus, the parents' diagnosis was
either low BMD or osteoporosis with a collagen type I
mutation.
Type I collagen was pursued as a candidate gene
for osteoporosis, because type I collagen is the most
abundant protein in the body - its structural impor-
tance for bone, the OI phenotype and the above rare
mutations causing more mild disease similar to osteo-
porosis. Polymorphisms of the type I collagen genes
have been identified and the transcription factor Sp1
site in intron 1
32
has been shown to be associated with
low BMD,
33
increased fractures
32,34
and a size determi-
nant in different studies. Furthermore, in a cross-sec-
tional study of women aged 45-64 and 98% Caucasian
done in England, the “s” allele was associated with
reduced BMD at the spine, increased spinal fractures
and increased urinary pyridinolone secretion.
35
More
recently, Tran et al. showed that the COL1A1 Sp1 site
polymorphism predicted fracture risk in postmeno-
pausal Australian Caucasian women.
36
Several studies
in different populations demonstrated no association
of the polymorphism with fractures or BMD. A recent
meta-analysis reviewing 32 studies with 24,511 patients
and 7864 fractures suggested a modest impact on BMD
and a 1.3% increase in hip and vertebral fractures.
37
The
above data suggest that the impact of genetic muta-
tions in type I collagen causing osteoporosis is likely
a rare event and the polymorphism has a small effect.
However, it is possible that multiple genes and the
environment may influence the quantity of type I col-
lagen in the bone. Osterix mutation was already men-
tioned as a rare cause of OI associated with decreased
type I collagen. There are two gene studies that when
combined yielded evidence that osterix is associated
with lumbar spine and femoral neck BMD in adults.
38,39
Timpson et al.
40
studied children and also found a
relationship between a single nucleotide polymorphism
(SNP) in the osterix region that correlated with childhood
total body BMD and height. Interestingly, Zhao found an
association between the osterix locus and obesity in girls.
41
Premenopausal women with low BMD with or with-
out fractures are challenging consultations. The dif-
ferential diagnosis includes OI, but that rarely is the
correct diagnosis. In our experience women have reg-
ular menses, are petite, the sclera is usually white but
may be blue, flexibility is frequently increased and the
apposition of the first to third inger surrounding the
wrist overlaps by a digit. They may have thin and vel-
vety skin. The laboratory tests are unremarkable.
Investigators at both Columbia and Creighton uni-
versities have published several papers describing
premenopausal women with low BMD plus or minus
fractures. Bone microarchitecture was measured by
high-resolution peripheral quantitative computed
tomography (HPQCT) and showed that all trabecu-
lar measures were decreased at the radius and tibia
and cortical thickness was decreased at the tibia.
42
Microarchitectural deterioration was equal in both
those with and without fractures. A bone biopsy study
from a subgroup demonstrated decreased cancellous
osteoid width and endocortical and intracortical wall
width. The authors suggested an osteoblast defect in
bone matrix formation per completed osteon.
43
A similar study using HPQCT was performed in type
I OI patients with 26 women and 13 men with an average
age of 53. Compared to the control group, the OI group
had lower trabecular measures at both the radius and
tibia and the cortical bone area was lower at the tibia.
44
Meunier's group performed bone histology on iliac crest
samples in adults and children with OI. The adults had
thin cortices, decreased trabecular bone volume, low thick-
ness of osteoid seams and decreased calcification rate. The
latter two findings were interpreted as showing that the
osteoblasts' bone matrix production was decreased.
45
Premenopausal women with low bone mineral den-
sity appear to be a heterogeneous group with micro-
architectural changes that are less severe than those
of AOI. Genetic defects of type I collagen are unlikely
in this premenopausal group, but multiple genes that
influence the quantity of type I collagen and its quality
are likely candidates. The various genes responsible for
both collagenous and noncollagenous proteins in the
matrix are likely to influence the phenotype. Ehlers-
Danlos disease and Marfan's disease are clinical exam-
ples of this concept. Are there genes important for the
bone matrix associated with osteoporosis?
There are multiple genome-wide association stud-
ies (GWAS) that were designed to identify osteoporosis
genes. Xiong showed that TGFBR3 (transforming growth
factor beta receptor 3) is associated with spine BMD.
46
TGF-beta is an important regulator of the matrix. Another
recent GWAS study suggested that an SNP near the LTBP3
(latent transforming growth factor beta binding protein 3)
site was associated with BMD and found supporting evi-
dence for the association with TGFBR3 and BMD.
47
In summary, AOI can be thought of as the more
severe end of the osteoporosis spectrum and the bone
matrix is crucial to understanding both diseases.
MARFAN'S SYNDROME
Marfan's syndrome (MFS) is another connective
tissue disease that is not generally considered in the
