Full text of DOI:10.1359/jbmr.2001.16.1.182

JOURNAL OF BONE AND MINERAL RESEARCH
Volume 16, Number 1, 2001
© 2001 American Society for Bone and Mineral Research
Atherogenic High-Fat Diet Reduces Bone Mineralization
in Mice
FARHAD PARHAMI,1 YIN TINTUT,1 WESLEY G. BEAMER,2 NIMA GHARAVI,1
WILLIAM GOODMAN,3 and LINDA L. DEMER1,4
ABSTRACT
The epidemiological correlation between osteoporosis and cardiovascular disease is independent of age, but
the basis for this correlation is unknown. We previously found that atherogenic oxidized lipids inhibit
osteoblastic differentiation in vitro and ex vivo, suggesting that an atherogenic diet may contribute to both
diseases. In this study, effects of an atherogenic high-fat diet versus control chow diet on bone were tested in
two strains of mice with genetically different susceptibility to atherosclerosis and lipid oxidation. After 4
months and 7 months on the diets, mineral content and density were measured in excised femurs and lumbar
vertebrae using peripheral quantitative computed tomographic (pQCT) scanning. In addition, expression of
osteocalcin in marrow isolated from the mice after 4 months on the diets was examined. After 7 months,
femoral mineral content in C57BL/6 atherosclerosis-susceptible mice on the high-fat diet was 43% lower
(0.73 ؎ 0.09 mg vs. 1.28 ؎ 0.42 mg; p ؍ 0.008), and mineral density was 15% lower compared with mice on
the chow diet. Smaller deficits were observed after 4 months. Vertebral mineral content also was lower in the
fat-fed C57BL/6 mice. These changes in the atherosclerosis-resistant, C3H/HeJ mice were smaller and mostly
not significant. Osteocalcin expression was reduced in the marrow of high fat-fed C57BL/6 mice. These
findings suggest that an atherogenic diet inhibits bone formation by blocking differentiation of osteoblast
progenitor cells. (J Bone Miner Res 2001;16:182–188)
Key words: osteoporosis, oxidized lipids, bone, atherosclerosis, high-fat diet
We previously found that minimally oxidized low-density
lipoprotein (MM-LDL), and other bioactive oxidized lipids
that promote atherogenesis and are increased in atheroscle-
rotic lesions,(14–19) also inhibit osteoblastic differentiation
of bone- and marrow-derived preosteoblasts in vitro.(20,21)
Preosteoblasts harvested from the marrow of mice fed a
high-fat, atherogenic diet showed significantly less osteo-
blastic differentiation.(21) Others have shown a paucity of
INTRODUCTION
PIDEMIOLOGICAL EVIDENCE links osteoporosis with car-
diovascular disease, independently of age.(1,2) Osteopo-
rosis and the subsequent 1 million fractures in the United
States each year(3) results from a combination of increased
bone resorption and decreased bone formation. Low
bone mineral density (BMD) is associated closely with
E
cardiovascular disease mortality,(4–6) cardiovascular cells committed to the bone lineage in osteoporotic bone
calcification,(7–9) atherosclerosis,(10,11) and high lipid marrow and with aging.(22,23) These links between lipids,
levels.(10–13) Such correlations raise the possibility of a vascular disease, and bone suggest the novel hypothesis that
common underlying factor or mechanism.
oxidized lipids are the biological link.
1Division of Cardiology, University of California, Los Angeles School of Medicine, Los Angeles, California, USA.
2The Jackson Laboratory, Bar Harbor, Maine, USA.
3Division of Nephrology, University of California, Los Angeles School of Medicine, Los Angeles, California, USA.
4Departments of Medicine and Physiology, University of California, Los Angeles School of Medicine, Los Angeles, California, USA.
182

ATHEROGENIC DIET REDUCES BONE MINERAL
183
In this study, effects of a high-fat atherogenic diet versus density. Estimates of measurement precision of mineral and
control chow diet on bone mineral content (BMC) and volume of femurs and vertebrae were obtained from the
BMD were tested in two strains of mice with genetically middiaphyseal shaft of a B6C3H-F1 femur and from the
different susceptibility to oxidized lipids and atherogenesis. midbody scans of a B6C3H-F1 L5 vertebra. Six replicate
In 1985, Paigen et al. showed differences in the suscepti- measurements for each bone yielded average values of 1.6,
bility of two inbred strains of mice to development of 2.1, and 2.8% for femoral density, mineral, and volume,
hyperlipidemia and atherosclerotic lesions when fed an respectively, and 3.2, 5.9, and 4.7% for L5 vertebral density,
atherogenic diet(24,25); C3H/HeJ were identified as a resis- mineral, and volume, respectively.
tant strain and C57BL/6 as a sensitive strain. Several years
Femurs were scanned full length at 2-mm intervals with a
later, Liao et al. reported the induction of inflammatory resolution of 0.100 mm/voxel, yielding eight 1-mm-thick
genes by an atherogenic diet in the C57BL/6 but not in the cross-sections representing eight axial levels of the femur.
C3H/HeJ strain,(26) and Navab et al.(27) and Shih et al.(28) Vertebrae were scanned full length at 0.7-mm intervals with
found differences in the antioxidant defense systems be- the same resolution, yielding three to four 1-mm-thick
tween the susceptible and resistant mouse strains. In the cross-sections. The center-most scan (based on image mor-
present study, we have compared the susceptibility and phology) or the mean of two scans sharing the center
resistance of these two strains of mice to the effects of position was selected for data analyses.
high-fat diet-induced hyperlipidemia on bone. We report
that in the atherosclerosis-susceptible C57BL/6 mice, BMC
Marrow isolation
and BMD were significantly lowered by the high-fat diet
After 4 months on the diets, mouse marrow cells were
versus chow diet. These changes were smaller in the
isolated from both femurs from 2 animals in each group as
atherosclerosis-resistant C3H/HeJ mice. In addition, mar-
previously described.(21,29,30) Marrow from both femurs was
row cells from the high-fat–fed C57BL/6 mice showed
pooled for each animal and RNA was isolated and analyzed
reduced osteocalcin expression.
separately by reverse-transcriptase polymerase chain reac-
Altogether these results suggest that oxidized lipids ad-
tion (RT-PCR). RNA was isolated as previously described
versely affect bone by inhibiting osteoblastic differentia-
using the RNA isolation kit from Stratagene (La Jolla, CA,
tion. If applicable to humans, these studies may result in
new therapeutic approaches to osteoporosis.
USA).(28)
RT-PCR
MATERIALS AND METHODS
RNA in 3-␮g quantities was reverse-transcribed, and PCR
was performed using primers as described previously.(31) Ther-
mal cycling was carried out for 21 cycles (glyceraldehyde-3-
phosphate dehydrogenase [GAPDH]) or 34 cycles (osteocal-
cin) at 60°C annealing temperature for both GAPDH and
osteocalcin. Amplified fragments were isolated on a 6% poly-
acrylamide gel (29:1 acrylamide to bis-acrylamide), and the
autoradiographs were scanned with an AGFA ARCUS II scan-
ner and semiquantitated with NIH Image software, version
1.59, public domain program (National Institutes of Health,
Bethesda, MD, USA).
Mice and diets
At 1 month of age, male C57BL/6 (atherosclerosis-
susceptible strain) and C3H/HeJ (atherosclerosis-resistant
strain) mice (The Jackson Laboratory, Bar Harbor, ME, USA)
were placed on either a control chow diet (National Institutes
of Health [NIH]-31 Mouse/Rat Diet 7013 containing 6% fat)
or a high-fat (atherogenic) diet (Teklad TD90221; Harlan Tek-
lad, Madison, WI, USA; including 1.25% cholesterol, 15.8%
fat, and 0.5% cholate). This atherogenic diet has been found to
cause significant hypercholesterolemia in C57BL/6 mice.(24,25)
Femurs and lumbar vertebrae were harvested from 8 animals
after 4 months and 14 animals after 7 months. The bones were
cleared of soft tissue and fixed in 95% ethanol.
Lipoprotein preparation and oxidation
Human LDL was isolated by density-gradient centrifuga-
tion of serum and stored in phosphate-buffered 0.15 M NaCl
containing 0.01% EDTA. MM-LDL was prepared by iron
oxidation of human LDL as previously described.(20) Min-
imal oxidation of LDL resulted in a 2- to 3-fold increase in
conjugated dienes and 2–3 nmol of thiobarbituric acid re-
active substances per milligram of cholesterol after dialysis.
The concentrations of lipoproteins used in this study are
reported in micrograms of protein. The pre- and postoxida-
tion lipopolysaccharide levels in these lipoprotein prepara-
tions were Ͻ30 pg/ml.
Quantitative computed tomographic scanning
Peripheral quantitative computed tomographic (pQCT)
scans were performed on individual bones (left femur, L4
vertebrae) from each mouse. Scanning was done with a
STRATEC XCT 960M unit (Norland Medical Instruments,
Ft. Atkinson, WI, USA) specifically configured for small
bone specimens. Mineral thresholds were set at 1.30 for
low-density bone and 2.00 for high-density bone. These
thresholds excluded mouse fat, water, muscle, and tendon
from true bone. Daily calibration was performed with a
manufacturer-supplied phantom (hydroxyapatite in Lucite)
of defined density. Calibration with a set of known hydroxy-
Statistical analysis
Differences in BMC and BMD were assessed using Stu-
apatite standards (0.05–1000.0 mg/mm3) yielded a correla- dent’s two-tailed t-test, allowing for unequal variances and
tion of 0.998 with XCT 960M estimation of volumetric unequal sample sizes where appropriate.

184
PARHAMI ET AL.
TABLE 1. QCT BONE PARAMETERS FOR FEMURS FROM C57BL/6 MICE AFTER 7 MONTHS ON A
CONTROL CHOW OR HIGH-FAT DIET
Chow versus
high fat
Chow versus
high fat
Mineral content (mg)
Mineral density (mg/mm3)
Slice
Chow
High fat
p
Chow
High fat
p
1
2
3
4
5
6
7
8
2.29 Ϯ 0.82
1.05 Ϯ 0.21
1.02 Ϯ 0.08
0.99 Ϯ 0.07
1.19 Ϯ 0.14
1.26 Ϯ 0.12
1.32 Ϯ 0.16
1.13 Ϯ 0.43
1.28 Ϯ 0.42
0.74 Ϯ 0.19
0.53 Ϯ 0.20
0.77 Ϯ 0.10
0.72 Ϯ 0.06
0.78 Ϯ 0.07
0.86 Ϯ 0.10
0.75 Ϯ 0.19
0.71 Ϯ 0.31
0.73 Ϯ 0.09
0.002
0.001
0.502 Ϯ 0.05
0.365 Ϯ 0.05
0.447 Ϯ 0.05
0.440 Ϯ 0.02
0.520 Ϯ 0.04
0.573 Ϯ 0.04
0.515 Ϯ 0.05
0.538 Ϯ 0.03
0.488 Ϯ 0.07
0.441 Ϯ 0.04
0.355 Ϯ 0.05
0.400 Ϯ 0.06
0.391 Ϯ 0.02
0.410 Ϯ 0.03
0.465 Ϯ 0.05
0.416 Ϯ 0.04
0.476 Ϯ 0.05
0.419 Ϯ 0.04
0.01
0.70
0.02
0.05
0.01
Ͻ0.0001
0.1
0.01
0.0001
0.0003
Ͻ0.0001
Ͻ0.0001
0.0008
0.001
Mean Ϯ SD
0.008
0.03
Scans were performed at 8 longitudinal axis positions (slices) for each femur with 1 being most proximal and 8 most distal. Values
of BMC and BMD are expressed as mean Ϯ SD over all animals in each diet group.
TABLE 2. QCT BONE PARAMETERS FOR FEMURS FROM C3H/HeJ MICE AFTER 7 MONTHS ON A
CONTROL CHOW OR HIGH-FAT DIET
Chow versus
high fat
Chow versus
high fat
Mineral content (mg)
Mineral density (mg/mm3)
Slice
Chow
High fat
p
Chow
High fat
p
1
2
3
4
5
6
7
8
2.73 Ϯ 0.79
1.60 Ϯ 0.24
1.72 Ϯ 0.16
1.88 Ϯ 0.24
2.01 Ϯ 0.18
2.28 Ϯ 0.27
2.01 Ϯ 0.41
1.47 Ϯ 0.40
1.96 Ϯ 0.40
2.00 Ϯ 0.84
1.26 Ϯ 0.15
1.40 Ϯ 0.13
1.66 Ϯ 0.16
1.73 Ϯ 0.16
2.06 Ϯ 0.14
1.95 Ϯ 0.15
1.55 Ϯ 0.21
1.70 Ϯ 0.29
0.12
0.01
0.002
0.07
0.009
0.09
0.75
0.67
0.59
0.596 Ϯ 0.06
0.510 Ϯ 0.06
0.800 Ϯ 0.03
0.883 Ϯ 0.07
0.853 Ϯ 0.03
0.922 Ϯ 0.06
0.694 Ϯ 0.11
0.612 Ϯ 0.07
0.734 Ϯ 0.15
0.542 Ϯ 0.06
0.426 Ϯ 0.06
0.720 Ϯ 0.05
0.909 Ϯ 0.03
0.846 Ϯ 0.02
0.911 Ϯ 0.02
0.807 Ϯ 0.09
0.562 Ϯ 0.04
0.715 Ϯ 0.19
0.11
0.016
0.005
0.39
0.63
0.68
0.05
0.15
0.26
Mean Ϯ SD
Scans were performed at 8 longitudinal axis positions (slices) for each femur with 1 being most proximal and 8 most distal. Values
of BMC and BMD are expressed as mean Ϯ SD over all animals in each diet group.
In C3H/HeJ mice, which are resistant to the atherogenic
effects of a high-fat diet and lipid oxidation products,(24,25)
the high-fat diet had less effect on bone mineralization.
After 4 months on the diet, C3H/HeJ mice showed no
significant difference in femoral BMC at any of the eight
levels examined (data not shown); BMD was significantly
lower at one of eight scanned sites (p ϭ 0.01).
After 7 months on the diet, the fat-fed C3H/HeJ mice had
significantly (p Յ 0.01) lower BMC compared with chow-
fed mice at only three of eight levels (Table 2). However,
the overall mean difference for all eight levels did not reach
statistical significance (p ϭ 0.59). There also was no sig-
nificant effect of the high-fat diet on femoral mineral den-
sity (p ϭ 0.26; Table 2).
RESULTS
Femoral BMC and BMD
After 4 months, femoral BMD was significantly lower in
fat-fed C57BL/6 mice at three of the eight levels scanned (p Ͻ
0.04; from 0.488 Ϯ 0.038 mg/mm3 to 0.423 Ϯ 0.043 mg/
mm3). All three levels were in the middiaphyseal region where
variance caused by anatomic complexity is minimized. BMC
was not significantly different between the two groups.
After 7 months, femoral BMC was significantly lower in
fat-fed C57BL/6 mice compared with control chow-fed
mice at all eight levels scanned. Mean mineral content was
lowered 43% (from 1.28 Ϯ 0.42 mg to 0.73 Ϯ 0.09 mg; p Յ
0.002; Table 1) on the high-fat diet. Changes in mineral
content were most significant (p Յ 0.0003) at the four
middiaphyseal levels (scans 3–6). Femoral mineral density
was also significantly lower in fat-fed C57BL/6 mice com-
pared with chow-fed mice at six of eight levels, with a
Lumbar vertebral mineral content and mineral density
At 4 months, there was no significant difference between
14.5% mean difference (from 0.488 Ϯ 0.066 mg/mm3 to chow and high-fat diet groups in either vertebral mineral
0.419 Ϯ 0.035 mg/mm3; p ϭ 0.03; Table 1).
content or density in either mouse strains. However, at 7

ATHEROGENIC DIET REDUCES BONE MINERAL
185
TABLE 3. QCT BONE PARAMETERS FOR L4 VERTEBRAE FROM C57BL/6 AND C3H/HeJ MICE AFTER 7 MONTHS
ON A CONTROL CHOW OR HIGH-FAT DIET
Total bone
Mineral density (mg/mm3)
Chow High fat
Cortical bone
Mineral content (mg)
Mineral density (mg/mm3)
Chow High fat Chow High fat
C57BL/6
Mineral content (mg)
Chow High fat
1.20 Ϯ 0.10 0.77 Ϯ 0.10 0.229 Ϯ 0.02 0.212 Ϯ 0.03 0.317 Ϯ 0.08 0.088 Ϯ 0.05 0.455 Ϯ 0.01 0.445 Ϯ 0.01
Ͻ0.001 0.30 Ͻ0.001 0.09
p
C3H/HeJ
1.41 Ϯ 0.35 1.31 Ϯ 0.14 0.248 Ϯ 0.03 0.217 Ϯ 0.01 0.624 Ϯ 0.25 0.445 Ϯ 0.13 0.481 Ϯ 0.02 0.474 Ϯ 0.01
0.49 0.03 0.12 0.48
p
Values are for the central slice or slices for each of the L4 vertebrae and are expressed as mean Ϯ SD over all animals in each diet
group.
months, vertebral mineral content was significantly lower in
the C57BL/6 fat-fed mice (Table 3). Total mineral content
of the central section or sections was lower by a mean of
35% (from 1.2 Ϯ 0.1 mg to 0.77 Ϯ 0.1 mg; p Ͻ 0.001),
primarily because of changes in high-density cortical bone
(i.e., a 72% decrease). Total mineral density decreased 7%
on the high-fat diet, but this change was not statistically
significant. In C3H/HeJ mice, a 7% decrease in total mineral
content was found, as well as a 29% decrease in cortical
mineral content. These changes did not reach statistical
significance. Total mineral density of vertebrae from C3H/
HeJ mice decreased 12.5% on the high-fat diet (from
0.248 Ϯ 0.03 to 0.217 Ϯ 0.01 mg/mm3; p ϭ 0.03).
FIG. 1. Effects of a high-fat diet on osteocalcin expres-
sion in marrow cells. One-month-old C57BL/6 mice were
placed on a high-fat or chow diet for 4 months. The animals
were killed and femoral marrow was isolated from each
mouse and used to isolate total RNA. RT-PCR analysis
showed an expected size band of 360 base pairs (bp).
Expression of GAPDH was used for normalization. Each
lane represents RNA isolated from an individual mouse.
Gene expression in marrow cells
After 4 months on the high-fat or chow diets, the marrow
isolated from 2 C57BL/6 mice on each diet was analyzed
for the expression of three markers of osteoblastic differen-
tiation: alkaline phosphatase, bone sialoprotein, and osteo-
calcin. All three markers were expressed by the marrow
cells. Of the three, only osteocalcin expression was affected
by diet, showing a 35% reduction with the high-fat diet
when normalized to GAPDH values (Fig. 1).
underlying reason for their degree of susceptibility to ath-
erosclerosis. These differences include: (1) the level of
induction of inflammatory genes such as monocyte chemo-
tactic protein-1, colony-stimulating factors, heme oxygen-
ase, and serum amyloid A and activation of nuclear factor
␬B (NF␬B) transcription factor in response to atherogenic
diet(26,27,32) and (2) the ability of high-density lipoprotein
(HDL) to protect against the effects of atherogenic diet,
because of variability in the level of antioxidant enzyme
DISCUSSION
The present study is the first to show that 7-month treat- paraoxonase.(28) The latter difference is important in light of
ment with an atherogenic high-fat diet lowers BMD and the observation that the protective effect of HDL appears to
BMC in vivo in atherosclerosis-susceptible C57BL/6 mice, correlate inversely with atherosclerosis,(33) and a direct cor-
with much smaller effects in the atherosclerosis-resistant relation between HDL levels and BMD in fat-fed mice has
C3H/HeJ mice. The atherogenic diet resulted in a signifi- been shown (T. Drake, University of California, Los Ange-
cantly lower femoral mineral content and femoral mineral les [UCLA], Department of Pathology, personal communi-
density in the C57BL/6 mice. Smaller changes were seen in cation, 1999). It is intriguing to speculate that similar ge-
the C3H/HeJ mice. The differential effects of the athero- netically regulated factors, involved with defense against
genic diet on bones in the two strains of mice are similar to atherogenic oxidized lipids, also determine susceptibility to
the effects of that diet on the development of atherosclero- osteoporosis.
sis. Previous reports showed differences in genetically
Because femoral mineral content was more substantially
determined factors in response to diet-induced hyperlipid- changed by the atherogenic diet than mineral density, the
emia and lipid oxidation in these mouse strains to be the effect may be caused by quantitatively less bone formation

186
PARHAMI ET AL.
and/or shorter bones in the high-fat–fed mice. Although we women,(38) as well as with population studies showing an
did not measure femoral size after 7 months in this study, in association of cholesterol levels with osteoporosis in wo-
a separate study, we found no significant change in the men(13) and, preliminarily, in men.(39) Recent evidence
femoral or tibial length between chow-fed versus high-fat– suggests that 3-hydroxy-3-methylglutaryl coenzyme A
fed C57BL/6 mice after 4 months on the diet ( F. Parhami, (HMG-CoA) reductase inhibitors (statins), lipid-lowering
unpublished observations, 1999). Because our previous in agents commonly used to treat cardiovascular disease, have
vitro and in vivo studies showed inhibition of osteoblastic potent positive effects on bone formation in rodents,(40)
differentiation and bone formation by marrow stromal cells and statin therapy in humans correlates with reduced
isolated from C57BL/6 mice on the high-fat diet versus osteoporosis.(41–45) Although the mechanism is proposed to
chow diet, we speculate that bone formation is inhibited by be a direct stimulation of osteoblasts, an equally likely
the atherogenic diet. More direct future studies will further mechanism is an indirect effect through lipid-lowering,
validate this speculation. It is important to note that the mice given that the dominant site of action of these agents, in
used in the present study were in their growing stage when both humans and rodents,(46) is in the liver where statins are
peak bone mass is achieved. Inhibition of bone formation mostly cleared from circulation.
during growth stage also would have adverse consequences
Evidence suggests that the atherogenic nature of the high-
by reducing peak bone mass. The reducing effects of the fat diet is essential for effects on bone. Wohl et al. previ-
dietary fat on BMC and BMD would translate into a reduc- ously showed a minimal effect on BMC of a noncholesterol,
tion in this important determinant of bone strength.
8% fat diet in adult roosters.(47) Because cholesterol feeding
The present results also suggest that increased dietary is necessary to induce atherosclerosis in roosters,(48) this
lipids interfere with osteoblast maturation in vivo, based on finding suggests that a nonatherogenic high-fat diet is not
dietary inhibition of osteocalcin messenger RNA (mRNA) sufficient to induce bone changes.
expression. Although the effect of the high-fat diet on the
Collectively, these observations suggest the adverse ef-
expression of osteocalcin alone is not sufficient to draw fects of lipids on bone. The possibility that lipid oxidation
definitive conclusions about differentiation of osteoblasts, products are the biologically active factors linking a high-fat
this inhibition is consistent with previous ex vivo evidence diet with reduced bone formation is supported by the finding
that exposure to a high-fat diet reduced marrow preosteo- of substantially reduced effects in mice that are resistant to
blastic maturation in culture,(21) as well as in vitro evidence the effects of oxidized lipids and by the anabolic effects of
that lipid and lipoprotein oxidation products inhibit osteo- the antioxidant vitamin E on bone.(49) Because cardiovas-
blast differentiation and function.(20,21) Previous studies us- cular disease is the highest risk cause of death for patients
ing the same atherogenic diet in C57BL/6 mice have shown with osteoporotic fracture(4,5) and low BMD is associated
2- to 3-fold increases in cholesterol levels after 3–4 weeks with mortality independent of fractures,(50) elucidation of
on this diet, as well as a significant drop in the HDL common lipid- and lipid oxidation–mediated mechanisms
levels.(24,25) We therefore speculate that the adverse effects has great importance for identifying new preventive mea-
of the high-fat diet on bone in the C57BL/6 mice are caused sures for both osteoporosis and cardiovascular disease. The
by dyslipidemia and subsequent increases in lipid oxidation. possibility that high lipid levels are a common underlying
The diet-induced hyperlipidemia in circulation further trans- factor in atherosclerosis and bone loss may explain the
lates into increased lipid accumulation in highly vascular epidemiological evidence for correlation between cardio-
tissues and the artery wall because of the diffusion of vascular disease and osteoporosis.
lipoproteins across the vascular endothelium. Once apart
from the protective, antioxidant environment of serum,
these lipoprotein particles are oxidized further into biolog-
ACKNOWLEDGMENTS
ically active forms responsible for inflammatory processes
in atherosclerosis and vascular calcification.(19,20) Because
The authors are grateful to Vien Le and Jeanenne
O’Connor for technical assistance and Alan Han for manu-
script preparation. They also thank Dr. Theodore J. Hahn,
Dr. Judith A. Berliner, and Dr. Robert Marcus for their input
on this manuscript. F. Parhami is a recipient of a Career
Development Award from the Claude D. Pepper Older
American Independence Center at UCLA. This work was
funded in part by NIH grants HL30568, AR43618,
DK52905, DK35423, and RR00865 as well as the Laubisch
Fund.
bone and marrow are both vascularized, circulating lipids
can access both sites of active bone remodeling where
osteoprogenitor cells are present: (1) the subendothelial
space of the osteons and (2) the marrow stroma at the
trabecular surface or endosteum. Lipid accumulation(34) and
monocyte accumulation and plaquing(35) have been ob-
served in the vessels of osteons in osteoporotic and aging
bone. The presence of circulating lipoproteins in the marrow
is expected because marrow is a site for clearance of chy-
lomicrons and chylomicron remnants derived from dietary
fat,(36) and dietary fat has been found to alter the lipid profile
in the marrow.(37) Thus, lipid oxidation products may un-
derlie the paradoxical association of cardiovascular disease
with osteoporosis.
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Address reprint requests to:
Farhad Parhami, Ph.D.
Division of Cardiology
47–123 CHS
Box 951679
University of California, Los Angeles School of Medicine
Los Angeles, CA 90095-1679, USA
Received in original form April 24, 2000; in revised form July 26,
2000; accepted August 24, 2000.