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TitleOsteoporosis in Older Persons: Pathophysiology and Therapeutic Approach
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Page 2

Osteoporosis in Older Persons

Page 100

7. Genetics of Osteoporosis in Older Age 85

resemblance was lower among older subjects
(47). We observed a heterogeneity of linkage on
6p21.2 and 21qter, where fi ndings from the total
sample (44) were not supported by any subsam-
ple. Also, age subsample-specifi c linkage peaks
were found, on 9q22–9q31 (in “younger” sub-
sample) and 17p13.3 (in “older”), which were not
refl ected by the total sample results. Similarly, the
loci identifi ed after stratifi cation by gender dif-
fered among men and women (48). Our study was
the fi rst genome scan in humans that provided
evidence for difference in the linked chromo-
somal regions between younger and older sub-
jects, men and women.

Other studies, such as the FAMilial Osteoporo-
sis Study (FAMOS) (49) and Amish osteoporosis
study (50), stratifi ed their families at 50 years old.
Ralston et al. (49) based their choice of an age
cutoff of 50 years on the fact that this was the
median age of their study sample and is also close
to the average age of menopause in women. The
large sample size of the FAMOS study (3691 indi-
viduals from 715 families) allowed the investiga-
tors to conduct age- and gender-specifi c analyses
simultaneously. Thus, in each gender, they were
able to distinguish quantitative trait loci (QTL) for
peak bone mass (in individuals younger than 50
years) from those that infl uence bone mass in
older people. The linkage peaks were age- and
sex-specifi c; thus, no overlap was found between
chromosomal loci for BMD in older men and
older women (49). Similarly, in analyses of age-
specifi c subgroups, Streeten et al. (50) in the
Amish study found suggestive evidence for linkage
for those younger than 50 years of age on chro-
mosomes 11q22 and 14q23 (LODs = 2.11 and 2.16,
respectively) and for those older than 50 years of
age on 3p25.2 (LOD = 2.32); again, no overlap was
found between chromosomal loci for BMD in
older and younger family members.

Genetic Contribution to Change
in BMD

As mentioned, the BMD phenotype in elderly
persons is perceived as a mix of bone mass
acquired at peak (in young adults) and ensuing
loss, caused by either menopause, senescence, or

both (reviewed in Yang et al. [51]). There is also
evidence of a heritable component for age-related
bone loss, although less well studied than cross-
sectional BMD. It has been proposed that the
genes regulating peak bone mass might differ
from those regulating bone loss (52), and that
genetic factors contributing to change in BMD are
those responsible for the bone remodeling ability
(53). As originally suggested back in 1993, at a
median follow-up of approximately 3 years, BMD
change of both hip and spine was heritable in
twins aged 24–75 years (54). A number of ensuing
studies have attempted to dissect the genetic basis
for the rate of bone loss, with various levels of
success, in humans (55–58) and mice (53).

Yang et al. (51) warn that caution should be
exercised while interpreting results of these
studies, particularly in light of the presumption
that the rate of bone loss can be treated as a phe-
notype independent of BMD. By re-analyzing the
data from a 9.5-years longitudinal study (59),
Yang and colleagues (51) found that approxi-
mately 67% of post-menopausal BMD variation is
attributable to the pre-menopausal BMD (“peak
BMD”), and approximately 29% to the bone loss
rate. The contribution of the rate of bone loss to
low BMD is thus fairly small, but not negligible.
The estimated pre- and post-menopausal bone
loss rates are generally approximately 0.3–1.5%
per year, varying at different skeletal sites; even
during the peri-menopausal period when “rapid”
bone loss occurs, the annual rate of bone loss is
between 0.6–2% (reviewed by Yang et al. [51]).
Bone loss is a relatively slow process, but once
triggered, it tends to steadily progress with age.
Hannan et al. found an average 4-year BMD loss
ranging from 3.4–4.8% in women and 0.2–3.6% in
men at all skeletal sites (4). The mean rate of BMD
change from baseline to follow-up (∼2 years) was
1.2% and 1.1% for women and men, respectively,
in the Rotterdam study (30). Recently, Khosla
et al. (60) used high-resolution 3D pQCT imaging
at the wrist to describe age-related patterns of
bone change in a cross-sectional study design.
Relative to young women (age 20–49 years), whose
cortical volumetric BMD decreased with age,
young men actually had an apparent increase in
vBMD. Both men and women had decreased
vBMD with advanced age in the 50–90 years age
group (−22% in women and −18% in men). Thus,

Page 101

86 D. Karasik and D.P. Kiel

despite signifi cantly higher bone loss in women
than men (p = 0.01) after age 50, Khosla et al. (60)
could not specifi cally show an effect of menopause
on the BMD change (alternatively, this fi nding can
be interpreted as an effect of andropause [61] in
men!). Cross-sectional studies such as these (4,60)
are not totally free from secular trend and survival
bias. Notable is a fi nding of Parsons et al. (62)
that the major predictors of bone loss in post-
menopausal women were menopausal status,
hormone replacement therapy (HRT) use, and
BMI, but not the genetic polymorphisms associ-
ated with BMD.

Changes in BMD may obviously depend on
errors in bone density measurement, technology
changes from old to new densitometric devices,
as well as changes in anthropometric measures of
the patient (such as advanced kyphosis and weight
loss). The baseline and follow-up scan compara-
bility needs to be rigorously assessed before using
such data for genetic analyses; further adjustment
needs to be done for change in weight and BMI,
as well as for the type of device used at each mea-
surement occasion, in order to avoid or control
measurement errors.

Candidate Genes for Fractures and
Bone Mass in Aging

There are indications that genotype-phenotype
associations with regard to osteoporosis and BMD
in older-age individuals differ from those in
younger ages. There are several examples, focus-
ing on the most widely studied biological candi-
date genes for osteoporosis.

Interleukin (IL)-6 Gene
Promoter Polymorphisms

Estrogen defi ciency is involved in bone loss via
the direct action of estrogen on bone cells, as
well as mediation of cytokines in bone marrow.
The decline in estrogen production after meno-
pause leads to increased production of pro-
infl ammatory cytokines, such as IL-6, which are
normally suppressed by estrogen (63). Increased
levels of IL-6, in turn, promote the differentia-
tion of osteoclast precursor cells into mature

osteoclasts, which increase resorption within the
bones (64).

Several studies have identifi ed the IL-6 gene
locus (7p21) to be linked to BMD in post-meno-
pausal women (65,66) and in families of oste-
oporotic probands (67,68), whereas no linkage
was found in young, healthy sister pairs (69).
These observations suggest that IL-6 genetic
variation might specifi cally contribute to the pop-
ulation variance in bone mass primarily in older
women (64,70). Dinucleotide repeat polymor-
phisms at the IL-6 locus have been associated with
or linked to BMD in post-menopausal, but not
pre-menopausal, women (64,70).

In order to elucidate the contribution of the
IL-6 gene to BMD in women, we studied an inter-
action between IL-6 promoter polymorphisms
and factors known to affect bone turnover, namely
years since menopause, estrogen status, dietary
calcium and vitamin D intake, physical activity,
smoking, and alcohol in the Offspring Cohort of
the Framingham Heart Study (71). We found that
BMD was signifi cantly lower in women with geno-
type −174 GG compared to CC, and intermediate
with GC, who were more than 15 years past meno-
pause, estrogen-defi cient, or who had insuffi cient
calcium intake (<940 mg/day). No associations
were observed in pre-menopausal women. (Of
note, in the Belfast Elderly Longitudinal Ageing
Study, a reduction in frequency of GG homozy-
gotes was associated with higher serum levels of
IL-6 in the oldest [octo/nonagenarian] age group
[72]). In women with both estrogen-defi ciency
and poor calcium intake, BMD differences at
the hip between IL-6 −174 CC and GG were as
high as 16.8% (71). Results of this study may be
interpreted not only as an age-specifi c, but also
syndrome-specifi c genetic infl uence. Thus, a phe-
notype in women more than 15 years post-meno-
pause may be an indication of the “senile” rather
than “menopausal” osteoporosis.

Most recently, the IL-6 −174 G allele was
confi rmed to also be associated with lower bone
ultrasound properties and an increased risk of
fracture (OR 1.5, 95% CI 1.1–2.0) in a large cohort
of 964 post-menopausal women aged 75 years
(73). Together, these data indicate that the infl u-
ence of IL-6 gene variants on bone mass may
depend on gender, age, estrogen status, and
dietary calcium.

Page 200

Index 185

Peak bone mass, 21. See also Bone
mineral density

genetic v. environmental factors,
21, 72

Pelvis fractures, 72
Peroxisome proliferator-activated

receptor gamma (PPAR� ),
22–23

Pharmaceutical treatment. See
Medications; Medications
for osteoporosis

Pharmacoeconomics, medications
for senile osteoporosis, 156

Phenotype, 3–5, 14
endo-, 82–83, 89
premature aging, 3–5, 60–62,

65–66
Plates, low-profi le, 166, 176–178
PMMA. See

Polymethylmethacrylate
Polymethylmethacrylate (PMMA),

164–165, 176–177
Polymorphisms, 87–88, 90
Polypharmacy, medications for

senile osteoporosis,
156–157

Population doublings (PD), 19
PPAR� . See Peroxisome

proliferator-activated
receptor gamma

Prevent Recurrence of
Osteoporotic Fractures
(PROOF), 76

Psychoactive medications, 128–129
PTH. See Parathyroid hormone
PTH-related peptide, 5–6

Q
Qualitative trait locus (QTL), 60,

85

R
Radius fractures, 72, 176–177
Raloxifene, 76
Reactive oxygen species (ROS), 20,

62
Receptor activator of NF� B ligand

(RANKL), 9–10, 73–74, 78,
79. See also Resorption

Receptor-regulated Smads, 6–7
Receptors for advanced glycation

end products (RAGES), 20,
27

Repeat fractures, 105–106

Resistin, 23
Resorption, 3–5, 10–13, 21, 73–74,

78, 79
Risedronate, 77, 142–143, 159
ROS. See Reactive oxygen species
Runx2, 4

S
Salmon calcitonin, 76. See also

Calcitonin
SAM. See Senescence-accelerated

mice
Screws, 164–165, 171, 176
Seasons, fractures v., 103–104
Selective estrogen receptor

modulators (SERMs), 76,
144, 159–160

Senescence. See also Aging
-accelerated mice, 60
cellular, 20
genetic contribution to BMD

change during, 85–86
Senescence-accelerated mice

(SAM), 60
Senile osteoporosis, 71–79. See also

Aging
bone healing challenges,

166–168
biological solutions, 166–168
electrical stimulation, 168

fi xation challenges, 163–165
postmenopausal osteoporosis v.,

26, 71, 77
Prevent Recurrence of

Osteoporotic Fractures, 76
secondary, 155
treatment

distal radius fracture, 72,
176–177

hip fracture, 98–99, 100, 104,
105, 132–133, 165–166,
169–172

odontoid fracture, 166,
175–176

thoracic and lumbar fracture,
172–175

tibial plateau fracture,
177–178

Treatment of Peripheral
Osteoporosis, 145

vertebral fractures, 72, 99, 100,
102–103, 140–145, 166

young/healthy bone v.,
168–169

SERMs. See Selective estrogen
receptor modulators

Sex steroids, 47–55. See also
Estrogen; Testosterone

aging and bone mineral density,
48–49

gender-specifi c mortality v. hip
fracture, 105, 166

men, 49–51, 53–55
ovariectomy, 59, 166
women, 51–53

Single-nucleotide polymorphisms
(SNPs), 88–89

Smads, 6–7
Smoking cessation, 158
SNPs. See Single-nucleotide

polymorphisms
Soft collar, 176
SOTI. See Spinal Osteoporosis

Therapeutic Intervention
Spinal Osteoporosis Therapeutic

Intervention (SOTI), 145
Stem cells

bone marrow, 19–20, 22,
89–90

hematopoietic, 13–14
mesenchymal, 21–22
tissue repair capacity of, 1,

13–14
Stromal cells, 13–14, 21

lineage of, 2–3
marrow, 19–20, 22, 89–90

Strontium ranelate, 79, 145–146,
160

Sub-trochanteric fractures, 72,
171–172

Sunlight exposure, 34–35, 158. See
also Geographic location

fracture risk v., 104

T
Tartrate-resistant acid phosphatase

(TRAP), 12
Telopeptides, 12
Teriparatide, 78–79, 144, 160
Testosterone

bone mineral density impact of,
48–49

skeleton maintenance and,
47–55

aging infl uencing, 48
methodologic issues,

47–48
in women, 51–53

Page 201

186 Index

TGF. See Transforming growth
factor

Thyroid hormone (T3), 8
TNF. See Tumor necrosis factor
TNFR (Tumor Necrosis Factor

Receptor) super family,
9–10

Transforming growth factor (TGF),
6, 27

TRAP. See Tartrate-resistant acid
phosphatase

Treatment of Peripheral
Osteoporosis (TROPOS),
145

Tri-malleolar ankle fractures, 72,
101, 104

Trochanteric fractures, 72, 171–172
TROPOS. See Treatment of

Peripheral Osteoporosis
Tumor necrosis factor (TNF), 27

U
Ulna fractures, 72
Urinary calcium excretion, 10

V
Vascular endothelial growth factor

(VEGF), 20
VDR. See Vitamin D receptor
VEGF. See Vascular endothelial

growth factor
Venous thrombosis, 79
Vertebral fractures, 72, 99, 100,

102–103, 140–145, 166. See
also Senile osteoporosis

Vertebroplasty, 166, 172–174
Visual interventions,

127–128
Vitamin D, 6, 139–142. See also

Vitamin D receptor
defi ciency, 25–26, 34–38
hypovitaminosis D osteopathy,

36
metabolism of, 35
muscle function, 118–122,

158–159
osteoporosis v., 74–75
physiological role of, 34
preventing falls, 118–122

supplementation, 6, 25–26,
34–38, 41, 74–75, 87–88,
118–122, 139–142

markers of, 38
in nursing homes, 155, 158–159

Vitamin D receptor (VDR), 87–88,
122

W
WAT. See White adipose tissue
Westin-Bainton cells. See Stromal

cells
WHI. See Women’s Health

Initiative
White adipose tissue (WAT), 24.

See also Adipocytes;
Adipogenesis

Wnt signaling molecules, 5, 8, 23,
25

Women’s Health Initiative (WHI),
76

Z
Zoledronic acid, 78, 159

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