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Dietary and lifestyle factors have important contributions to skeletal health. Fruit- and vegetable-specific antioxidants, such as vitamin C, might help in preventing osteoporosis because vitamin C may decrease oxidative stress and subsequent bone-resorption. Vitamin C is an essential cofactor for collagen formation (an important component of bone matrix) and potentiates vitamin E activity in cells by regenerating α-tocopherol from its oxidized derivative. In this chapter, we highlight findings from previous studies on vitamin C intake and bone measures to underscore our current understanding and emphasize the importance of vitamin C on skeletal health. Taken together, previous studies showed a positive association between dietary vitamin C and bone mineral density. Very few examined serum vitamin C status, vitamin C supplementation or bone loss. The reported associations were complex due to multiple interactions with smoking, calcium and vitamin E intakes and current estrogen use in women. One longitudinal study reported that higher vitamin C intake may be protective against bone loss in men with low calcium or vitamin E intake. There is an urgent need to replicate these findings in larger cohorts with data on bone loss over time. Studies have also suggested that vitamin C intake may be protective against hip fracture as well as other fractures, especially among current smokers and estrogen using women. Larger prospective cohort studies are required to further clarify these interactions. Lastly, good-quality randomized controlled trials are needed to confirm these epidemiological findings to ascertain optimal intakes for osteoporosis prevention.
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87
© Springer International Publishing Switzerland 2016
C.M. Weaver et al. (eds.), Nutritional Infl uences on Bone Health,
DOI 10.1007/978-3-319-32417-3_8
Vitamin C and Bone Health
Shivani Sahni , Douglas P. Kiel ,
and Marian T. Hannan
Abstract
Dietary and lifestyle factors have important contributions to skeletal
health. Fruit- and vegetable-specifi c antioxidants, such as vitamin C,
might help in preventing osteoporosis because vitamin C may decrease
oxidative stress and subsequent bone-resorption. Vitamin C is an essential
cofactor for collagen formation (an important component of bone matrix)
and potentiates vitamin E activity in cells by regenerating α-tocopherol
from its oxidized derivative.
In this chapter, we highlight fi ndings from previous studies on vitamin
C intake and bone measures to underscore our current understanding and
emphasize the importance of vitamin C on skeletal health. Taken together,
previous studies showed a positive association between dietary vitamin C
and bone mineral density. Very few examined serum vitamin C status,
vitamin C supplementation or bone loss. The reported associations were
complex due to multiple interactions with smoking, calcium and vitamin
E intakes and current estrogen use in women. One longitudinal study
reported that higher vitamin C intake may be protective against bone loss
in men with low calcium or vitamin E intake. There is an urgent need to
replicate these fi ndings in larger cohorts with data on bone loss over time.
Studies have also suggested that vitamin C intake may be protective
against hip fracture as well as other fractures, especially among current
smokers and estrogen using women. Larger prospective cohort studies are
required to further clarify these interactions. Lastly, good-quality random-
ized controlled trials are needed to confi rm these epidemiological fi ndings
to ascertain optimal intakes for osteoporosis prevention.
S. Sahni , PhD (*) M. T. Hannan , DSci, MPH
D. P. Kiel , MD, MPH
Institute for Aging Research, Hebrew SeniorLife ,
Beth Israel Deaconess Medical Center,
Harvard Medical School , Boston , MA 02131 , USA
e-mail: ShivaniSahni@hsl.harvard.edu;
Hannan@hsl.harvard.edu; kiel@hsl.harvard.edu
8
88
Keywords
Vitamin C Osteoporosis Fractures Older adults Antioxidant Dietary
intake
Introduction
Worldwide, osteoporosis causes more than 8.9
million fractures annually, resulting in an osteo-
porotic fracture every 3 s [
1 ]. Fifty one percent
of these fractures occurred in Europe and the
Americas, while most of the remainder occurred
in the Western Pacifi c region and Southeast Asia
[
1 ]. By 2050, the worldwide incidence of hip
fracture is projected to increase by 310 % in
men and 240 % in women [ 2 ]. Therefore, osteo-
porosis and related fractures in older adults take
a huge personal and economic toll with an
annual cost of nearly $22 billion to the US
healthcare system [
2 ] and €37 billion to the
European Union [ 3 ].
Recent ndings from the population-based
Cohort of Swedish Men (COSM) and Swedish
Mammography Cohort (SMC) showed a dose-
response association between fruit and vegetable
intake and hip fracture such that an intake below
the recommended fi ve servings/day conferred
higher rates of hip fracture [
4 ]. Previous studies
had also shown that higher fruit and vegetable
intake has positive effects on bone mineral status
[ 510 ]. Among other nutrients, fruits and vegeta-
bles are rich in vitamin C, a powerful water solu-
ble antioxidant that is thought to prevent bone
resorption due to its anti-oxidative properties as
well as its role in collagen formation. While sev-
eral studies have confi rmed the association
between vitamin C intake or status with bone
mineral density (BMD) and fractures, the results
have not been entirely consistent. This may be
due to a complex association that involves inter-
action of vitamin C with smoking [
1113 ], post-
menopausal estrogen use/hormonal therapy [ 11 ,
14 , 15 ], calcium intake [ 12 , 15 , 16 ] and vitamin E
intake [
13 , 17 ]. In this chapter, we highlight fi nd-
ings from previous studies on this topic to
underscore our current understanding and empha-
size the potential importance of vitamin C on
skeletal health.
Vitamin C Effects on the Skeleton
Vitamin C may affect bone health via several
mechanisms. First , collagen is the most abundant
component of the extracellular bone matrix [
18 ].
In adults, type I collagen represents about 90 %
of the total protein matrix [ 18 ]. Vitamin C is an
essential cofactor required for hydroxylation of
proline and lysine into hydroxyproline and
hydroxylysine respectively [
19 ]. This post-
translational modifi cation of pro-collagen is cru-
cial for the formation of mature collagen molecules
and their assembly into fi brils [
18 ]. Defects in
this process, as seen in the disease scurvy, lead to
the formation of unstable non-hydroxylated pro-
collagen chains, which are degraded within the
cell at normal body temperature. Without the
structural support of collagen, blood vessels, ten-
dons, and skin become fragile. This may also
lead to weakening of bones and subsequent frac-
tures. Previous animal studies have demonstrated
that experimentally induced defi ciency of vita-
min C leads to impaired bone mass, cartilage and
connective tissue [
20 , 21 ]. Second , Oxidative
stress may increase bone resorption through acti-
vation of nuclear factor-kB protein, which is a
crucial mediator of tumor necrosis factor-a and
osteoclastogenetic activity [
2226 ]. Vitamin C, a
strong antioxidant aids in decreasing this oxida-
tive stress [ 27 ] and therefore may play a role in
preventing bone resorption. Third , vitamin E is
another strong antioxidant that has been linked
with bone health [ 28 , 29 ]. Vitamin C potentiates
vitamin E activity in cells by regenerating
α-tocopherol from its oxidized derivative [
30 ].
S. Sahni et al.
89
Vitamin C and Bone Density
Evidence from Cross-Section
and Case–Control Studies
Several cross-sectional and case-control studies
have examined the association of vitamin C
intake with dual-energy X-ray absorptiometry
(DXA)-derived BMD at multiple bone sites.
Most of these studies were focused on either total
or dietary vitamin C intake. Most of the studies
except one [
14 ] showed positive associations
between vitamin C and one or more BMD sites.
Very few examined serum vitamin C status or
vitamin C supplementation. However, the results
of these studies are complicated by multiple
interactions observed between vitamin C intake/
status and other nutritional [
13 , 15 , 16 ] and non-
nutritional [ 11 , 1315 ] factors (Table 8.1 ).
Interaction with Smoking
In the Framingham Osteoporosis study, the asso-
ciation of vitamin C (total, supplemental, and
dietary) intake with BMD at the hip [femoral neck,
trochanter], spine, and radial shaft was examined
in 334 men and 540 women (mean age = 75 years)
[
13 ]. Mean BMD was estimated, for men and
women, by tertile/category of energy adjusted
vitamin C intake. Negative associations were
reported between total and supplemental vitamin
C intake and trochanter-BMD among current male
smokers (P-trend = 0.01). Among male nonsmok-
ers, total vitamin C intake was positively associ-
ated with femoral neck BMD (P-trend = 0.04). No
signifi cant associations were reported among
women. Smoking is an established risk factor of
osteoporosis as outlined in our recent review [
31 ].
Interaction with Smoking
and Estrogen Use
Simon and Hudes analyzed data collected from
13,080 adults (aged 20–90 years) enrolled in the
Third National Health and Nutrition Examination
Survey (NHANES III) during 1988–1994.
Because they identifi ed three-way interactions
among smoking, history of estrogen use, and
dietary and serum ascorbic acid in post-
menopausal women, they analyzed these rela-
tions stratifi ed by smoking and estrogen use.
Dietary ascorbic acid intake was independently
associated with BMD among pre- menopausal
women ( P = 0.002). Among men, serum ascorbic
acid was associated in a nonlinear fashion with
BMD ( P < 0.05). Among post- menopausal
women without a history of smoking or estrogen
use, serum ascorbic acid was unexpectedly asso-
ciated with lower BMD ( P = 0.01). However,
among post-menopausal women with a history of
smoking and estrogen use, a standard deviation
increase in serum ascorbic acid was associated
with a 49 % decrease in fracture prevalence
( P = 0.001) [
11 ]. Estrogen-use increases the turn-
over of ascorbic acid [ 32 ] and is associated with
lowered ascorbic acid levels in animals and
humans [
3335 ]. Studies have also demonstrated
that smoking decreases the absorption and
increases the turnover of ascorbic acid, thereby
lowering blood ascorbic acid levels [
36 ].
Therefore, interaction of vitamin C with smoking
and estrogen use is expected. However, results of
these interactions have been inconsistent.
Interaction with Calcium Intake
Using the data from Postmenopausal Estrogen/
Progestin Interventions (PEPI) Trial, Hall and
Greendale examined the association of food
frequency questionnaire (FFQ) based dietary
vitamin C with BMD at the femoral neck, total
hip and lumbar spine in women aged 45–64
years. They reported that with each 100 mg
increment in dietary vitamin C intake, there
was a 0.017 g/cm
2 increment in BMD at the
femoral neck ( P = 0.002) and total hip
( P = 0.005). Association with lumbar spine
BMD was not statistically signifi cant ( P = 0.08).
This study further reported an effect modifi ca-
tion by calcium intake. Upon stratifi cation by
calcium intake (>500 mg/day and 500 mg/
8 Vitamin C and Bone Health
90
Table 8.1 Studies of BMD according to vitamin C intake or status in men and women
Study Sample, age (years) Vitamin C Measurement/Site Principal nding
New SA et al.
(1997) [
41 ]
994 healthy pre- menopausal
women aged 45–49 years
FFQ based total vitamin C BMD lumbar spine, femoral
neck (FN), femoral trochanter,
and femoral Wards
Non-linear association observed. Participants
in 3rd quartile of total vitamin C intake had
higher lumbar spine BMD (P < 0.002) and
femoral neck BMD (P < 0.01) compared to
those in the lowest quartile
Hall and Greendale,
(1998) [
16 ]
775 women aged 45–64 years
from the Postmenopausal
Estrogen/Progestin Interventions
(PEPI) Trial
FFQ based dietary vitamin C BMD femoral neck, total hip
and lumbar spine
Each 100 mg increment in dietary vitamin C
intake, was associated with a 0.017 g/cm
2
increment in BMD (P = 0.002 femoral neck;
P = 0.005 total hip). Association with lumbar
spine BMD was not statistically signifi cant
(P = 0.08).
Effect modifi cation by calcium intake,
signifi cant associations were seen with higher
calcium intake (>500 mg/day) but not with
lower calcium intake
Simon and Hudes
(2001) [
11 ]
3204 pre-menopausal women,
2906 post- menopausal women
and 5739 men from the Third
National Health and Nutrition
Examination Survey (NHANES
III)
Dietary vitamin C from 24-h
recall and serum ascorbic
acid
BMD hip Three-way interactions among smoking,
history of estrogen use, and dietary and serum
ascorbic acid were identifi ed. Dietary
ascorbic acid intake was associated with
BMD among premenopausal women
(P = 0.002). Among men, serum ascorbic acid
was associated in a nonlinear fashion with
BMD (P < 0.05). Among post- menopausal
women without a history of smoking or
estrogen use, serum ascorbic acid was
unexpectedly associated with lower BMD
(P = 0.01)
S. Sahni et al.
91
Morton et al.
(2001) [
15 ]
994 post-menopausal women Vitamin C supplement use BMD ultradistal and midshaft
radius, hip, and lumbar spine
Vitamin C users had higher BMD at the
femoral neck (P < 0.02) and total hip
(P < 0.06). Women taking both estrogen and
vitamin C had higher BMD levels at all sites.
Among current estrogen users, those also
taking vitamin C had higher BMD levels with
marginal signifi cance achieved at the
ultradistal radius (P < 0.07), femoral neck
(P < 0.07), and total hip (P < 0.09). Women
who took vitamin C plus calcium and estrogen
had the highest BMD at the femoral neck (P
<0.001), total hip (P = 0.05), ultradistal radius
(P = 0.02)
Wolf et al.
(2005) [
14 ]
11,068 women aged 50–79 years
from Women’s Health Initiative
Dietary and total vitamin C
intake from FFQ
BMD whole body, L2–L4 spine,
total hip, femoral neck,
trochanter, total hip BMD t
score
No signifi cant associations with diet or total
vitamin C intake (P range = 0.08–0.33).
Effect modifi cation by use of hormone
therapy. Current hormone therapy associated
with higher BMD at multiple bone sites in
women with high total vitamin C intake (P
range = 0.03–0.05)
Sahni et al.
(2008) [
13 ]
334 men and 540 women (mean
age 75 years) from the
Framingham Osteoporosis Study
Total, dietary and
supplemental vitamin C
intake from FFQ
BMD femoral neck, trochanter,
spine, and radial shaft
Interaction by sex and smoking. Total and
supplemental vitamin C intakes were
negatively associated with trochanter-BMD
among current male smokers (P-trend = 0.01).
Among male nonsmokers, total vitamin C
intake was positively associated with femoral
neck BMD (P-trend = 0.04)
8 Vitamin C and Bone Health
92
day), women with higher calcium intake had an
increment of 0.0190 g/cm
2 in femoral neck
BMD ( P = 0.002), 0.0172 g/cm
2 in total hip
BMD (P = 0.01) and 0.0199 g/cm
2 in lumbar
spine BMD (P = 0.02) per 100 mg vitamin
C. No relation between BMD and vitamin C
was evident in the lower calcium stratum for
any of the bone sites examined. Vitamin C aids
in the absorption of calcium, therefore, interac-
tive effects of these two nutrients upon BMD
have been reported with cross-sectional studies
reporting a benefi cial role of higher vitamin C
intake with higher calcium intakes.
Interaction with Calcium Intake
and Estrogen Use
In the Rancho Bernardo study, Morton et al.
evaluated the independent relation of daily vita-
min C supplement use with BMD in a popula-
tion-based sample of 994 post-menopausal
women. Daily vitamin C supplement intake
ranged from 100 to 5000 mg; the mean daily
dose was 745 mg and average duration of use
was 12.4 years. Vitamin C users had BMD lev-
els ~3 % higher at the mid- shaft radius, femoral
neck, and total hip ( P < 0.05) after adjustment
for confounders and covariates. In the fully
adjusted model, signifi cant differences remained
at the femoral neck ( P < 0.02) and marginal sig-
nifi cance was observed at the total hip ( P < 0.06).
Women taking both estrogen and vitamin C had
signifi cantly higher BMD levels at all sites.
Among current estrogen users, those also taking
vitamin C had higher BMD levels at all sites,
with marginal signifi cance achieved at the ultra-
distal radius ( P < 0.07), femoral neck ( P < 0.07),
and total hip ( P < 0.09). Women who took vita-
min C plus calcium and estrogen had the highest
BMD at the femoral neck ( P = 0.001), total hip
( P = 0.05), ultradistal radius ( P = 0.02), and lum-
bar spine. Vitamin C supplement use appears to
have a benefi cial effect on levels of BMD, espe-
cially among postmenopausal women using
concurrent estrogen therapy and calcium sup-
plements [
15 ].
Evidence from Longitudinal Studies
of Vitamin C and Bone Loss
To our knowledge only two studies have exam-
ined the effect of vitamin C intake on bone loss
(Table 8.2 ). Kaptoge et al. examined the associa-
tion of dietary vitamin C intake (from 7-day food
dietary) with total hip BMD loss over 3 years in
470 men and 474 women (aged 67–79 years)
[
37 ]. No associations were reported in men but in
women, low intake of vitamin C was associated
with faster rate of total hip BMD loss. Women in
the lowest tertile (7–57 mg/day) of vitamin C
intake lost BMD at an average rate of −0.65 %
p.a., which was signifi cantly faster compared to
loss rates in the middle (58–98 mg/day) and
upper (99–363 mg/day) tertiles of intake, which
were −0.31 % p.a. and −0.30 % p.a., respectively
(P = 0.016).
In the Framingham Osteoporosis study,
Sahni et al. examined the association of vitamin
C (total, supplemental and dietary) intake with
BMD loss over 4 years in 213 men and 393
women (mean age was 75 years). In contrast to
the study by Kaptoge et al. [
37 ], results from the
Framingham Osteoporosis Study showed vita-
min C to be protective against bone loss but only
in men not women. In this study, higher total
vitamin C intake was associated with less femo-
ral neck and trochanter-BMD loss in men with
low calcium (all P -trend 0.03) or vitamin E
intakes (all P -trend = 0.03, Fig.
8.1 ). Higher
dietary vitamin C intake tended to be associated
with lower femoral neck-BMD loss
( P -trend = 0.09). These associations were atten-
uated but retained borderline signifi cance
( P -trend <0.1) after adjusting for potassium
intake (a marker of fruit and vegetable intake),
suggesting that vitamin C effects may not be
separated from other protective factors in fruit
and vegetables. No signifi cant associations were
observed among women. In light of the studies
highlighted in this review that examined vitamin
C with BMD and BMD loss, there is a strong
evidence that higher vitamin C intake is associ-
ated with higher BMD. However, the associa-
tions are complex due to several reported
S. Sahni et al.
93
Table 8.2 Studies of change in BMD according to vitamin C intake in men and women
Study Sample, age (years) Vitamin C Measurement/Site Principal nding
Kapotge et al. (2001)
[
37 ]
470 men and 474 women aged
67–79 years from the EPIC-
Norfolk study
Dietary vitamin C from 7-day
food diaries
3-year BMD change in total hip In men, no effect of dietary
vitamin C on total hip bone
loss. In women, low intake of
vitamin C was associated with
greater bone loss. Women in the
lowest tertile (7–57 mg/day) of
vitamin C intake lost BMD at
an average rate of 0.65 %
per annum (p.a.), which was
signifi cantly greater compared
to loss rates in the middle
(58–98 mg/day) and upper
(99–363 mg/day) tertiles of
intake, which were 0.31 % p.a.
and 0.30 % p.a., respectively
(P = 0.016)
Sahni et al. (2008) [
13 ] 213 men and 393 women (mean
age 75 years) from the
Framingham Osteoporosis Study
Total, dietary and supplemental
vitamin C intake from FFQ
4-year BMD change in femoral neck,
trochanter, spine, and radial shaft
Interaction by sex, calcium and
vitamin E intake. Higher total
vitamin C intake was associated
with less femoral neck and
trochanter-BMD loss in men
with low calcium (median
vitamin C intake across
tertiles = 74,139, and 200 mg/
day, all P-trend 0.03) or
vitamin E intakes (all
P-trend = 0.03). Higher dietary
vitamin C intake tended to be
associated with lower femoral
neck-BMD loss (P-trend = 0.09).
These associations were
attenuated but retained
borderline signifi cance
(P-trend < 0.1) after adjusting
for potassium intake (a marker
of fruit and vegetable intake)
8 Vitamin C and Bone Health
94
interactions with smoking, calcium and vitamin
E intakes and current estrogen use in women.
Some of these interactions were also replicated
in longitudinal studies of bone loss. While two
prospective cohort studies provided strong evi-
dence for vitamin C intake reducing hip bone
loss, there is still a need to replicate these data in
other larger cohorts. These data may be
suffi cient to support a randomized controlled
trial of vitamin C supplementation. In the study
by Kaptoge et al. [
37 ] and by Sahni et al. [ 13 ],
the bone protective effects of vitamin C intakes
were seen at intake levels that were greater than
the dietary recommended intakes of 75 mg/day
for women and 90 mg/day for men. This
information can be useful in designing future
randomized controlled trials to ascertain opti-
mal intakes of vitamin C for osteoporosis
prevention.
Evidence from Intervention Studies
To date there has been one double-blind random-
ized control trial of vitamin C (along with vita-
min E) and bone density in 30 men and women
[
38 ]. The treatment groups received 400 IU of
vitamin E daily and either 500 or 1000 mg/day of
vitamin C for 12 months. The group with the
highest vitamin C intake had signifi cantly less
hip bone loss compared with the placebo group
but no signifi cant association was seen for lum-
bar spine BMD. Another study by Chuin et al.
was a 6-month randomized controlled of 34
women that examined the effect of vitamin C in
combination with other treatments and bone den-
sity [
39 ]. Vitamin group received ascorbic acid
(1000 mg/day) and a-tocopherol (600 mg/day).
Exercise and placebo group received 60 min of
resistance training three times/week and placebo
(lactose) and exercise and vitamin group received
60 min of resistance training three times/week
and ascorbic acid (1000 mg/day) and a- tocopherol
(600 mg/day). Lumbar spine (LS) BMD
decreased signifi cantly by 1 % in the placebo
group but remained stable in the other three inter-
vention groups. Taken together, evidence from
these two trials investigating vitamin C’s effect
Tertiles of total vitamin c intake (mg/day)a
bTertiles of total vitamin c intake (mg/day)
T1
4-year change in femoral neck BMD (g/cm2)4-year change in femoral neck BMD (g/cm2)
T2
Low calcium
0
–0.01
–0.02
–0.03
–0.04
–0.05
–0.06
–0.07
0.02
0.01
0
–0.01
–0.02
–0.03
–0.04
–0.05
–0.06
–0.07
–0.08
–0.09
–0.1
–0.11
P trend = 0.03
P trend = 0.03
T3 T1 T2
High calcium
T3
T1 T2
Low vitamin E High vitamin E
T3 T1 T2 T3
Fig. 8.1 Adjusted mean 4-year changes in femoral neck
by tertiles of total vitamin C intake among men stratifi ed
by ( a ) total calcium intake and ( b ) total vitamin E intake.
Low calcium group: total calcium intake median intake
(661 mg/day); high calcium group: total calcium
intake > median intake. Low vitamin E group: total vita-
min E intake median intake (7.7 mg TE/day); high vita-
min E group: total vitamin E intake > median intake.
Models were adjusted for age at the baseline (years), BMI
(kg/m
2 ), height at the time of enrollment (m), total energy
intake (MJ/day), baseline physical activity index, alcohol
intake (none/moderate: <26.4 g/day of alcohol; high:
26.4 g/day of alcohol), smoking (never/former/current
smokers), and intake of total vitamin D (mcg/day), caf-
feine (mg/day), and multivitamin use (yes/no). Models for
panel b were further adjusted for total calcium intake (mg/
day). Values are means ± SE, n = 201. Analysis was based
on a general linear model with Dunnett’s adjustment for
multiple comparisons. *Different from T1, P < 0.05
S. Sahni et al.
95
on bone density loss is unclear. While these two
studies show promising results for vitamin C
intake (at dosages much higher than usual dietary
intake), they did not examine the effect of vita-
min C alone and the study by Chuin et al. was not
double blinded. The studies had small sample
size and limited duration of treatment. Future tri-
als are needed to examine interventions of vita-
min C supplementation in larger studies of longer
duration. Such good-quality double blinded ran-
domized controlled trials will aid in confi rming
the epidemiological fi ndings reported thus far
and will help in ascertaining optimal intakes for
osteoporosis prevention.
Vitamin C and Fracture Risk
As noted above, several studies have examined
dietary vitamin C’s effect on bone density but
relatively fewer studies have examined effects
on fracture. Most of the studies with fracture
outcomes had either cross-sectional or case-
control designs. Some fracture studies also
reported signifi cant interactions with smoking
or estrogen use (Table
8.3 ). In a case cohort
study from the Swedish Mammography Cohort
[ 17 ], Melhus et al. examined 247 cases (44 cur-
rent and 42 former smokers) and 873 controls
(93 current and 127 former smokers) aged
40–76 years. Signifi cant interaction between
current smoking status and both dietary vitamin
E ( P = 0.02) and vitamin C ( P = 0.03) intake was
reported. Among current smokers, hip fracture
risk increased with low intake of vitamin E [3.0
(95 % CI: 1.6–5.4)] or vitamin C [3.0 (1.6–
5.6)]. In contrast, the OR decreased to 1.1 (0.5–
2.4) and 1.4 (0.7–3.0) with high intakes of
vitamin E and C, respectively. Current smokers
with a low intake of both vitamins E and C, the
risk of hip fracture was much higher; OR = 4.9
(2.2–11.0).
The only prospective cohort study on this
topic was from the Framingham Osteoporosis
study. This study evaluated associations of vita-
min C intake (total, dietary, and supplemental)
with incident hip fracture and non-vertebral
osteoporotic fracture, over a 15- to 17-year
follow- up [ 40 ]. 366 men and 592 women (mean
age 75 ± 5 years) completed a food frequency
questionnaire (FFQ) in 1988–1989 and were fol-
lowed for non-vertebral fracture until 2003 and
hip fracture until 2005. Tertiles of vitamin C
intake were created after adjusting for total
energy (residual method). Over follow-up 100
hip fractures occurred and 180 non-vertebral
osteoporotic fractures occurred. Among men and
women in this study, subjects in the highest tertile
of total vitamin C intake (median = 313 mg/day)
had a signifi cantly lower risk of hip fracture as
compared to subjects in the lowest tertile of
intake (median = 94 mg/day) (HR T3 = 0.56, 95 %
CI = 0.31–0.98, P = 0.04, HR T2 = 0.73, 95 %
CI = 0.44–1.20, P = 0.21, P for trend = 0.04,
Global test P value = 0.0001). Similarly, subjects
in the highest tertile of total vitamin C intake
(median = 308 mg/day) had lower risk of non-
vertebral osteoporotic fracture as compared to
subjects in the lowest tertile of intake
(median = 95 mg/day) (HR T3 = 0.66, 95 %
CI = 0.43–1.01, P = 0.06, HR T2 = 0.93, 95 %
CI = 0.65–1.36, P = 0.73, P for trend = 0.05,
Global test P value < 0.0001). Subjects in the
highest category of supplemental vitamin C
intake (median = 260 mg/day) had signifi cantly
lower risk of hip fracture as compared to non-
supplement users (HR T3 = 0.31, 95 % CI = 0.13–
0.73, P = 0.007, HR T2 = 0.50, 95 %
CI = 0.20–1.24, P = 0.13, P for trend = 0.02,
Global test P value < 0.0001). Similarly, subjects
in the highest category of supplemental vitamin
C intake (median = 260 mg/day) tended to have
lower risk of non-vertebral osteoporotic fracture
as compared to non-supplement users, but this
only approached signifi cance (HR T3 = 0.58,
95 % CI = 0.30–1.11, P = 0.10, HR T2 = 0.80,
95 % CI = 0.38–1.71, P = 0.57, P for trend = 0.07,
Global test P value < 0.0001). Dietary vitamin C
intake was not associated with fracture risk
(all P > 0.22).
Taken together, these studies suggest that vita-
min C intake may be protective against hip frac-
ture as well as other fractures. These protective
effects were more evident among current smok-
ers and estrogen using women. Larger prospec-
tive cohort studies are required to further clarify
8 Vitamin C and Bone Health
96
Table 8.3 Studies of vitamin C and relative risk of fractures of the hip and other sites
Type of Fracture/Study Study design Sample Results
Hip fracture
Michaelsson et al. (1995) [
42 ] Case-control study, the Swedish
Mammography Cohort
247 cases and 893 matched
controls aged 40–75 years
Higher vitamin C intake was associated with increased hip
fracture risk compared to low intake (adjusted OR = 1.9, 95 % CI:
1.2–3.1)
Melhus et al. (1999) [
17 ] Case cohort study, the Swedish
Mammography Cohort
247 cases (44 current and 42
former smokers) and 873 controls
(93 current and 127 former
smokers) aged 40–76 years
Effect modifi cation by smoking. Among current smokers, low
dietary vitamin C was associated with a higher hip fracture risk;
OR = 3.0 (1.6–5.6). No association was seen with high dietary
vitamin C; OR = 1.4 (0.7–3.0).
Effect modifi cation by vitamin E. Current smokers with a low
intake of both vitamins E and C, had increased risk of hip
fracture; OR = 4.9 (2.2–11.0)
Zhang et al. (2005) [
12 ] Case-control 1215 male and female cases aged
50 years and 1349 age- and
sex-matched controls without hip
fracture
Effect modifi cation by smoking. Ever smokers: Vitamin C intake
did not have a signifi cant linear association with hip fracture.
Never smokers: Protective trends seen with higher intake (5th
quintile, OR = 0.65 (95 % CI, 0.38–1.13), P trend = 0.02
Sahni et al. (2009) [
40 ] Prospective cohort, the
Framingham Osteoporosis Study
366 men and 592 women (mean
age 75 years)
Over follow-up 100 hip fractures occurred. Subjects in the highest
tertile of total vitamin C intake had signifi cantly fewer hip
fractures (P trend = 0.04) compared to those in the lowest tertile of
intake. Subjects in the highest category of supplemental vitamin
C intake had signifi cantly fewer hip fractures (P trend = 0.02)
compared to non-supplement users. Dietary vitamin C intake was
not associated with fracture risk (all P > 0.22)
Any fracture
Simon and Hudes, (2001) [
11 ] Cross-sectional, third National
Health and Nutrition
Examination Survey (NHANES
III)
3778 pre-menopausal women,
3165 post- menopausal women
and 6137 men aged 20–90 years
Effect modifi cation by smoking and history of estrogen use in
post- menopausal women. Among ever smokers with a history of
estrogen use, a standard deviation increase in serum ascorbic acid
was associated with a 49 % decrease in fracture prevalence
Sahni et al. (2009) [
40 ] Prospective cohort, the
Framingham Osteoporosis Study
366 men and 592 women (mean
age 75 years)
Over follow-up, 180 non-vertebral osteoporotic fractures
occurred. Subjects in the highest tertile of total vitamin C intake
had signifi cantly fewer non-vertebral fractures (P trend = 0.05)
compared to subjects in the lowest tertile of intake. Subjects in
the highest category of supplemental vitamin C intake had
signifi cantly fewer non-vertebral fractures (P trend = 0.07)
compared to non-supplement users. Dietary vitamin C intake was
not associated with fracture risk (all P > 0.22)
S. Sahni et al.
97
these interactions with hip fracture as well as
other fractures.
Conclusion
Dietary and lifestyle factors have important
contributions to skeletal health. Higher vita-
min C intake appears to be associated with
higher BMD and lower bone loss. These asso-
ciations seem to be modifi ed by other nutri-
tional and non- nutritional factors. Limited
work suggests that usefulness of vitamin C
intake in bone loss prevention, particularly in
men with concomitant low intakes of calcium
or vitamin E. However, more studies are
needed to confi rm these fi ndings. Vitamin C
intake also appears to be protective against hip
fractures and other fractures, though there is a
dearth of prospective cohort studies in this
area. Some studies have suggested that asso-
ciation of vitamin C with bone measures is
non-linear. Overall the protective effects of
vitamin C have been observed at levels much
higher that the dietary recommended intakes.
Well designed randomized controlled trials
are needed to confi rm these epidemiological
ndings and to ascertain optimal intakes for
osteoporosis prevention.
Acknowledgments S Sahni and MT Hannan have unre-
stricted institutional research grants from General Mills
Bell Institute of Health and Nutrition and PAI, Inc. /
Amgen. DP Kiel is on the scientifi c advisory board of
Merck Sharp and Dohme, Amgen, Eli Lilly, Ammonett
Pharma, and Novartis, has institutional grants from Merck
Sharp and Dohme, Amgen, PAI, Inc., and Eli Lilly, and
receives royalties from Springer for editorial work and
author royalties from UpToDate.
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