True Fractional Calcium Absorption is
Decreased After Roux-En-Y Gastric Bypass
Surgery
Claudia S. Riedt,* Robert E. Brolin,† Robert M. Sherrell,‡ M. Paul Field,‡ and Sue A. Shapses*
Abstract
RIEDT, CLAUDIA S., ROBERT E. BROLIN, ROBERT
M. SHERRELL, M. PAUL FIELD, AND SUE A.
SHAPSES. True fractional calcium absorption is decreased
after Roux-en-Y gastric bypass surgery. Obesity. 2006;14:
1940 –1948.
Objective: Roux-en-Y gastric bypass (RYGB) is considered
to be the gold standard alternative treatment for severe
obesity. Weight loss after RYGB results primarily from
decreased food intake. Inadequate calcium (Ca) intake and
metabolic bone disease can occur after gastric bypass. To
our knowledge, whether malabsorption of Ca contributes to
an altered Ca metabolism in the RYGB patient has not been
addressed previously.
Research Methods and Procedures: We recruited 25 extremely obese women in order to study true fractional Ca
absorption (TFCA) before and 6 months after RYGB surgery, using a dual stable isotope method (42Ca and 43Ca)
and test load of Ca (200 mg). Hormones regulating Ca
absorption and markers of bone turnover were also measured.
Results: In 21 women (BMI 52.7 ⫾ 8.3 kg/m2, age 43.9 ⫾
10.4 years) who successfully completed the study, TFCA
decreased from 0.36 ⫾ 0.08 to 0.24 ⫾ 0.09 (p ⬍ 0.001)
after RYGB. Bone turnover markers increased significantly
(p ⬍ 0.01). TFCA correlated with estradiol levels (r ⫽
0.512, p ⬍ 0.02) and tended to correlate with 1,25 (OH)2D
(r ⫽ 0.427, p ⬍ 0.06) at final measurement. Stepwise linear
Received for review May 17, 2005.
Accepted in final form August 15, 2006.
The costs of publication of this article were defrayed, in part, by the payment of page
charges. This article must, therefore, be hereby marked “advertisement” in accordance with
18 U.S.C. Section 1734 solely to indicate this fact.
*Department of Nutritional Sciences, Rutgers University, New Jersey; †Princeton Medical
Center, New Jersey; and ‡Institute of Marine and Coastal Sciences, Rutgers University, New
Jersey.
Address correspondence to Sue A. Shapses, Department of Nutritional Sciences, Rutgers
University, 96 Lipman Drive, New Brunswick, NJ 08901.
E-mail: [email protected]
Copyright © 2006 NAASO
1940
OBESITY Vol. 14 No. 11 November 2006
regression indicated that estradiol explained 62% of the
variance for TFCA at 6 months post-surgery (p ⬍ 0.01).
Discussion: TFCA decreases (0.12 ⫾ 0.08) after RYGB
surgery but remains within normal range. Although only
some patients were estimated to have low Ca absorption
after surgery, all of the patients showed a dramatic increase
in markers of bone resorption. The alteration in Ca metabolism after RYGB-induced weight loss appears to be regulated primarily by estradiol levels and might ultimately
affect bone mass.
Key words: bone turnover, calcium absorption, estrogen, gastric bypass, nutrient intake
Introduction
Since the development of bariatric surgery, several surgical methods for the treatment of severe obesity have been
developed over the past decades. Roux-en-Y gastric bypass
(RYGB)1 surgery is considered to be the gold standard
alternative treatment for severe obesity because it should
result in less severe malabsorption and complications than
traditional malabsorptive procedures (i.e., jejuno-ileal bypass) (1–3). The malabsorptive procedures have been recognized as a risk factor for developing bone disease (4 –9)
as a result of altered calcium (Ca) metabolism and compromised Ca absorption (10 –16). Only a few studies have
investigated Ca absorption prospectively in jejuno-ileal bypass patients and have shown that Ca absorption decreases
by ⬃50% after surgery (10,13,16). To our knowledge, the
change in Ca absorption after RYGB surgery has not been
addressed previously. In addition, because inadequate Ca
intake is common after gastric bypass (17–19), this may also
1
Nonstandard abbreviations: RYGB, Roux-en-Y gastric bypass; Ca, calcium; PTH, parathyroid hormone; 25OHD, serum 25-hydroxy-vitamin D; TFCA, true fractional calcium
absorption; CV, coefficient of variation; 1,25(OH)2D, serum 1,25 dihydroxy-vitamin D;
RIA, radioimmunoassay; E1, estrone; E2, estradiol; sNTx, serum n-telopeptide of type I
collagen; PYD, pyridinoline.
Calcium Absorption and Gastric Bypass Surgery, Riedt et al.
contribute to an altered Ca metabolism and bone loss. Understanding the extent to which Ca absorption and intakes
are decreased after gastric bypass surgery was a goal of this
study.
Hormones regulating Ca metabolism are often disturbed
in severe obesity or after bariatric surgery. For example,
serum parathyroid hormone (PTH) is increased in severely
obese subjects, compared with non-obese subjects (20), and
has been shown to decline with dramatic weight loss (21).
Yet, persistently elevated PTH levels are commonly described after bariatric surgery (22–28). Decreased 25-hydroxy-vitamin D (25OHD) levels are also common findings
among patients after bariatric surgery (20,22,25,29 –32). In
addition, serum estrogen levels are typically elevated in
severe obesity (33) and decline with weight loss (26,34,35).
This hormonal profile may be regulating the disturbed Ca
metabolism and the decline in true fractional Ca absorption
(TFCA) (36,37) after weight loss surgery. Bone-regulating
hormones in bariatric patients and their relationship to Ca
absorption and bone loss (9,25,26,30,38) have not been
studied previously in bariatric patients, despite increasing
numbers of this type of obesity treatment (1,39). In this
study, we hypothesized that the decrease in TFCA after
RYGB-induced massive weight loss can be partially explained by bone-regulating hormones.
Research Methods and Procedures
Subjects and Protocol
Twenty-five obese and extremely obese (BMI 39 to 74
kg/m2) women were recruited to participate in a 6-month
prospective clinical trial. Recruitment was completed in
local bariatric support group meetings over a 3-year period
(2001 to 2004) and from individual patient interaction with
the dietitian at the surgeon’s office. From 10 support group
meetings, ⬃70 patients showed initial interest in participating in the study, of which 18 decided to enroll into the
study. Individual meetings with the dietitian resulted in
another 23 potential subjects who were invited to participate
in the study, of which 7 enrolled in the study. Women filled
out questionnaires to assess their medical and nutrition
history. Women were excluded if they were taking any
estrogen, progesterone, or osteoporosis medication, or if
they previously had undergone any type of surgery for
weight loss. The study was approved by Rutgers University
Institutional Review Board, and all subjects signed an informed consent form. Weight loss was achieved through
open or laparoscopic RYGB surgery with an RY-limb
length of 75 or 150 cm. As part of standard practice,
post-surgical patients were advised to take two children’s
chewable multivitamin/mineral tablets daily, containing 400
IU vitamin D/tablet. Furthermore, they were encouraged to
consume 1 g/d Ca supplement in addition to their dietary Ca
intake.
Laboratory Methods
An electronic scale (ScaleTronix ST 5002; ScaleTronix,
White Plains, NY) and a stadiometer (Detecto, Webb City,
MO) were used to measure weight and height to the nearest
0.25 kg and 1.0 cm, respectively. Fasting urine and serum
were collected before surgery (month 0), and again at 1, 3,
and 6 months after surgery, and samples were measured for
markers of bone turnover. Serum hormones were measured
at baseline and at 6 months. TFCA was determined before
and 6 months after surgery using dual stable Ca isotope
methods, inductively coupled plasma mass spectrometry,
and calculations, as described previously (37,40). Briefly,
on the day of the Ca absorption test, women were admitted
at 7 AM after an overnight fast. After blood collection (10
mL), subjects were asked to void and then were served a
standard breakfast. This meal contained a total Ca load of
200 mg, with 43Ca that had been mixed in half cup of skim
milk (153 mg Ca), which had been equilibrated overnight
(⬃12 hours). The milk was consumed in its entirety under
supervision, and the cup was rinsed with deionized water
three times. All of the rinse water was also consumed by
patients. After surgery, although milk was always consumed
in its entirety, some patients were unable to finish all of their
other low Ca breakfast foods. Immediately after breakfast,
an intravenous injection of 42Ca was administered over ⬃3
minutes. Syringes containing the isotopes (that were mixed
with the milk or infused intravenously) were weighed before and after administration on a precision balance scale.
The inductively coupled plasma mass spectrometry instrument precision and accuracy for this method is ⬍⫾1% and
the day-to-day coefficient of variation (CV) for 6 women
measured twice was 1.2%. Serum 1,25 dihydroxy-vitamin
D (1,25(OH)2D) and 25OHD were measured by 125I radioimmunoassay (RIA; DiaSorin, Stillwater, MN) (CV:
⬍15.3% and ⬍6.7%, respectively). Estrone (E1), estradiol
(E2), and cortisol were also measured by 125I RIA (DSL,
Webster, TX) (CV: ⬍9.4%, ⬍8.9%, ⬍8.3%, respectively).
Intact PTH was determined by immuno-radiometric assay
(DSL, Webster, TX) (CV: ⬍5.2%). Serum osteocalcin, a
marker of bone formation, was measured by RIA (BTI,
Stoughton, MA) (CV: ⬍9.0%). Markers of bone resorption
were also measured. Serum n-telopeptide of type I collagen
(sNTx) was measured by enzyme-linked immunosorbent
assay (Osteomark, OSTEX International Inc., Seattle, WA)
(CV: 4.6%). Pyridinoline (PYD, CV: ⬍ 8%) and deoxypyridinoline (CV: ⬍ 10%) were measured in 24-hour urine
samples by reverse phase high performance liquid chromatography and fluorescence detection, as described previously (37). Urinary Ca and creatinine (No. 587, Sigma, St
Louis, MO) (CV: ⬍3.2%; and No. 555, CV: ⬍11.0%) were
also measured in 24-hour urine samples. Urinary creatinine
was used to estimate skeletal muscle mass using the following formula: muscle mass ⫽ creat g/d*29.1 ⫹ 7.38 (41).
OBESITY Vol. 14 No. 11 November 2006
1941
Calcium Absorption and Gastric Bypass Surgery, Riedt et al.
Table 1. Weight, BMI, calcium measurements, and creatinine before and after RYGB surgery (n ⫽ 21)*
Weight (kg)
BMI (kg/m2)
TFCA (estimated from breakfast)
Ca absorbed (mg/d)‡
Urine calcium (mg/d)
Urine creatinine (mg/d)
Baseline
Final
Change (␦)
Change (%)
p value†
139.8 ⫾ 23.0
52.7 ⫾ 8.3
0.36 ⫾ 0.08
416.7 ⫾ 271.3
173.7 ⫾ 87.8
1542 ⫾ 394
101.3 ⫾ 19.9
38.2 ⫾ 7.3
0.24 ⫾ 0.09
227.2 ⫾ 197.0
89.5 ⫾ 39.9
1076 ⫾ 263
⫺38.5 ⫾ 8.0
⫺14.5 ⫾ 2.9
⫺0.12 ⫾ 0.08
⫺189.5 ⫾ 264.2
⫺84.2 ⫾ 76.6
⫺463.2 ⫾ 269.9
⫺27.7 ⫾ 5.4
⫺27.7 ⫾ 5.4
⫺34.0 ⫾ 19.2
⫺38.7 ⫾ 43.8
⫺39.3 ⫾ 38.5
⫺28.2 ⫾ 14.7
⬍0.0001
⬍0.0001
⬍0.0001
0.0006
⬍0.0001
⬍0.0001
RYGB, Roux-en-Y gastric bypass; Ca, calcium; TFCA, true fractional Ca absorption.
* Data (mean ⫾ standard deviation).
† ANOVA 关for changes (%) from baseline to final measurements兴.
‡ Estimated Ca absorbed (TFCA ⫻ total Ca intake in Table 2).
Dietary intakes were monitored by analyzing food
records (3-day averages, at 0, 1, 3, and 6 months). Nutrients
were analyzed by Nutritionist Pro software (version 2.1,
First DataBank, Inc., San Bruno, CA).
Statistics
The Kolmogorov-Smirnov goodness-of-fit-test was applied to test for normal distribution of values at baseline and
final measurement. Non-normally distributed variables
were transformed for subsequent regression analyses. The
changes (%) from baseline to final measurement were analyzed using one-way ANOVA. Pearson’s correlation coefficients were used to evaluate the associations among the
different variables measured at baseline and final measurement, as well as their absolute and percentage changes.
Stepwise multiple regression was performed to predict
the dependent variable TFCA at baseline and at month 6,
and independent variables included PTH, 1,25(OH)2D,
25(OH)D, E2, and Ca intake. The total estimated amount of
Ca absorbed (mg/d) was calculated as the product of TFCA
and Ca intake (mg/d). Predictors of the total estimated
amount of Ca absorbed were assessed in a two-stage least
squares analysis, with amounts of Ca absorbed as the dependent variable, and PTH, 1,25(OH)2D, 25(OH)D, and E2
as independent variables. To evaluate the effect of menopausal status on TFCA responses, we conducted separate
analyses of covariance. p Values ⬍0.05 were considered
significant. Data are presented as mean ⫾ standard deviation unless otherwise indicated. All analyses were conducted using the SAS statistical package (version 8.2; SAS
Institute, Inc., Cary, NC).
Results
Of the 25 women recruited, 21 women were included in
the final analysis. One woman was unable to complete the
study due to complications after surgery. Three women had
1942
OBESITY Vol. 14 No. 11 November 2006
to be excluded from analysis because exclusion criteria
were not revealed at the time of screening. On laboratory
analysis of estradiol levels, it was apparent that two postmenopausal women were on hormone-replacement therapy,
and one woman had a history of vertical banded gastroplasty 11 years before RYGB. Of the 21 women included in
the analysis, the Roux-en-Y limb length was 150 cm and 75
cm, in 17 and 4 women, respectively. Five women had the
procedure done through open surgery, and 16 women underwent laparoscopic surgery. Baseline characteristics are
shown in Table 1. The mean age of the 21 subjects was
43.9 ⫾ 10.4 years (range 29 to 62 yrs), and BMI range was
38.9 to 73.5 kg/m2. Based on creatinine levels at baseline,
estimated skeletal muscle mass was 44.9 ⫾ 11.5 kg before
surgery.
Weight Loss and Nutrient Intake
Women lost 38.5 ⫾ 8.0 kg (range: 16.9 to 49.5 kg) 6
months after surgery. Twenty-four hour urinary creatinine
analysis showed a decrease of 463 ⫾ 270 mg/d (p ⬍
0.0001), suggesting an estimated loss of skeletal muscle
mass of 35% of total body weight loss. As expected, caloric
intake decreased after surgery (p ⬍ 0.0001), due to decreases (p ⬍ 0.001) in carbohydrate, protein, and fat intake
(Table 2). Of the micronutrients assessed, only sodium and
phosphorus intakes decreased (p ⬍ 0.0001) after surgery.
Although dietary Ca intake decreased significantly (p ⬍
0.0001) after surgery, total Ca intake remained the same due
to an increase in Ca supplements. Ca supplementation was
consumed by 48% of the subjects before surgery and by
66% after surgery. There tended (p ⬍ 0.08) to be greater
vitamin D intake after surgery (Table 2) that was associated
with greater Ca intake (r ⫽ 0.85, p ⬍ 0.001).
Ca Absorption and Excretion
TFCA and other calcium variables before and 6 months
after surgery (final values) are shown in Table 1. Individual
Calcium Absorption and Gastric Bypass Surgery, Riedt et al.
Table 2. Nutrient intake before and after RYGB surgery (n ⫽ 21)*
Kcal/d
Carbohydrate (g/d)
Protein (g/d)
Fat (g/d)
Total Ca (mg/d)†
Vitamin D (␮g/d)†
Vitamin K (␮g/d)†
Phosphorus (mg/d)†
Magnesium (mg/d)†
Sodium (mg/d)
Baseline
Final
p value
2260 ⫾ 738
247.1 ⫾ 103.6
95.8 ⫾ 37.2
96.1 ⫾ 38.9
1104 ⫾ 516
7.3 ⫾ 5.9
51.9 ⫾ 61.3
1241 ⫾ 583
214 ⫾ 111.2
3785 ⫾ 1418
794 ⫾ 240
92.3 ⫾ 40.2
42.3 ⫾ 12.4
29.0 ⫾ 11.1
935 ⫾ 679
11.0 ⫾ 9.6
37.2 ⫾ 32.9
547 ⫾ 175
218 ⫾ 214
1380 ⫾ 628
⬍0.0001
⬍0.0001
⬍0.0001
⬍0.0001
0.4451
0.1126
0.1084
⬍0.0001
0.2665
⬍0.0001
RYGB, Roux-en-Y gastric bypass; Ca, calcium.
* Data (mean ⫾ standard deviation); ANOVA (for % changes from baseline to final measurements).
† Nutrient amounts for Ca, vitamin D, vitamin K, phosphorus, and magnesium coming from supplement: baseline and final intake,
respectively, for Ca: 209 ⫾ 327 mg/d and 542 ⫾ 699 mg/d; Vitamin D: 5.4 ⫾ 5.9 ␮g/d and 9.7 ⫾ 9.8 ␮g/d; Vitamin K: 4.9 ⫾ 9.6 ␮g/d
and 10.0 ⫾ 14.0 ␮g/d; phosphorus: 38.2 ⫾ 64.9 mg/d and 59.2 ⫾ 115.5 mg/d; magnesium: 32.2 ⫾ 56.9 mg/d and 107.8 ⫾ 219.5 mg/d.
Vitamin D: 1 ␮g ⫽ 40 IU.
changes in TFCA and estimated Ca absorbed from baseline
to 6 months post-surgery are shown in Figure 1. TFCA, total
Ca absorbed, and 24-hour urinary calcium excretion all
decreased (p ⫽ 0.0001) (Table 1). The absolute decrease in
TFCA was 0.12 ⫾ 0.08. When women were divided by
menopausal status, postmenopausal women (n ⫽ 9) had
lower (p ⬍ 0.05) TFCA (0.32 ⫾ 0.06) at baseline compared
with premenopausal women (n ⫽ 12) (0.39 ⫾ 0.08). Postmenopausal women also showed lower urinary Ca excretion
(121.4 ⫾ 61.0 mg/d) compared with premenopausal women
(212.9 ⫾ 86.1 mg/d) at baseline (p ⫽ 0.0003). There was no
significant difference in the response to massive weight loss
in any of the variables measured between pre- and postmenopausal women, whether or not values were corrected
for baseline differences.
Hormones and Bone Turnover
Ca-regulating hormones and bone turnover markers before and 6 months after surgery (final values) are shown in
Table 3. Serum levels of 25OHD were low (⬍25 ng/mL) in
11 subjects (52%) before and after surgery, but only 7
patients showed continuously low levels both before and
after surgery (18.9 ⫾ 5.8 ng/mL). Secondary hyperparathyroidism (⬎65 pg/mL) was prevalent in 15 women (71%) at
baseline, as well as 6 months after surgery, of which 13 of
these patients had elevated PTH levels both before and after
surgery (94.1 ⫾ 22.5 pg/mL). Ca absorption was not influenced by serum PTH. Estrogen levels did not differ between
pre- (66.9 ⫾ 51.9 pg/mL) and postmenopausal (36.6 ⫾ 30.5
pg/mL) women at baseline, nor did they differ after weight
loss (41.1 ⫾ 31.0 and 28.4 ⫾ 37.0 pg/mL, pre- and post-
Figure 1: (A) Individual changes (solid lines) in TFCA and (B) total estimated calcium absorbed (mg/d) from baseline to final measurement
6 months after RYGB surgery in 21 extremely obese women. Dashed line and diamonds represent group means at baseline and 6 months
after RYGB surgery.
OBESITY Vol. 14 No. 11 November 2006
1943
Calcium Absorption and Gastric Bypass Surgery, Riedt et al.
Table 3. Calcium-regulating hormones and bone turnover markers before and after RYGB surgery (n ⫽ 21)*
1,25(OH)2D (pg/mL)
25OHD (ng/mL)
PTH (pg/mL)
Cortisol (␮g/dL)
Estradiol (pg/mL)
Estrone (pg/mL)
Osteocalcin (ng/mL)
sNTx (nM BCE)
PYD (nM/d)
DPD (nM/d)
Baseline
Final
Change (⌬)
Change (%)
p value†
42.1 ⫾ 16.4
25.4 ⫾ 9.5
81.3 ⫾ 31.4
9.2 ⫾ 3.0
53.9 ⫾ 45.7
69.6 ⫾ 57.3
10.2 ⫾ 2.8
16.6 ⫾ 5.5
436.8 ⫾ 210.1
50.2 ⫾ 37.1
45.6 ⫾ 20.5
28.6 ⫾ 14.3
77.2 ⫾ 28.3
10.5 ⫾ 6.7
35.7 ⫾ 33.4
48.1 ⫾ 48.6
14.3 ⫾ 2.9
25.6 ⫾ 6.8
849.1 ⫾ 244.5
118.8 ⫾ 71.1
3.4 ⫾ 20.9
3.2 ⫾ 12.1
⫺4.1 ⫾ 30.6
1.3 ⫾ 7.1
⫺18.2 ⫾ 52.5
⫺21.5 ⫾ 73.2
4.1 ⫾ 2.5
9.0 ⫾ 5.3
409.9 ⫾ 210.2
67.9 ⫾ 59.7
17.8 ⫾ 57.4
23.6 ⫾ 68.9
3.4 ⫾ 45.0
31.5 ⫾ 106.8
⫺13.1 ⫾ 73.2
⫺16.5 ⫾ 58.8
45.2 ⫾ 29.0
62.1 ⫾ 44.2
163.9 ⫾ 234.8
203.8 ⫾ 318.2
0.1700
0.1320
0.7354
0.1916
0.4222
0.2139
⬍0.0001
⬍0.0001
⬍0.0001
0.0099
RYGB, Roux-en-Y gastric bypass; 1,25(OH)2D, serum 1,25 dihydroxy-vitamin D; 25OHD, serum 25-hydroxy-vitamin D; PTH, parathyroid
hormone; sNTx, serum N-telopeptide of type I collagen; PYD, pyridinoline; DPD, deoxypyridinoline.
* Data (mean ⫾ standard deviation).
† ANOVA 关for changes (%) from baseline to final measurements兴.
menopausal women, respectively). None of the hormonal
markers measured changed with weight loss.
The bone resorption marker sNTx, was increased (p ⬍
0.0001) as early as 1 month post-surgery, while bone formation marker, serum osteocalcin, showed a gradual rise
and did not increase significantly until 3 months after surgery (p ⬍ 0.0003) (Figure 2). Urinary bone resorption
markers, PYD and deoxypyridinoline, increased by ⬃2-fold
(p ⬍ 0.01) 6 months after surgery.
Correlations and multiple regression analysis
At baseline, TFCA was not correlated to any Ca-metabolism regulating hormones. After six months of weight loss,
TFCA correlated with estradiol levels (r ⫽ 0.512, p ⬍ 0.02)
Figure 2: Changes (%) in bone resorption (sNTx) and bone formation (osteocalcin) markers from baseline to final measurement 6
months after RYGB surgery (p ⬍ 0.0001) in 21 extremely obese
women. Diamonds and solid line represent sNTx; open squares
and dashed line represent osteocalcin.
1944
OBESITY Vol. 14 No. 11 November 2006
and tended to correlate with 1,25(OH)2D (r ⫽ 0.427, p ⬍
0.06) levels. Not surprisingly, a higher TFCA correlated
with increased urinary Ca excretion after surgery (r ⫽
0.681, p ⬍ 0.001). A greater weight loss tended to be
associated with a greater increase in bone resorption (sNTx:
r ⫽ ⫺0.423, p ⬍ 0.06). We found that women who increased dietary Ca intake after surgery (range of % change:
⫺76 to ⫹89) showed an increase in the bone formation
marker osteocalcin (r ⫽ 0.518, p ⬍ 0.02), and tended to
decrease serum PTH levels (r ⫽ ⫺0.403, p ⬍ 0.07), but that
Ca intake had no influence on resorption markers. In addition, total vitamin D intake after surgery (range of 0 to 30.4
␮g/d) tended to correlate with serum 25OHD levels (r ⫽
0.420, p ⬍ 0.06) and inversely correlate with PYD (r ⫽
⫺0.406, p ⬍ 0.08).
Stepwise multiple regression analysis showed that before
surgery, Ca intake alone explained the variance in TFCA
(52%, p ⬍ 0.02), while at six months after surgery only
serum estradiol levels explained the variance in TFCA
(62%, p ⬍ 0.01) (Figure 3) and was independent of weight
loss (r ⫽ 0.132, p ⫽ 0.568). When pre- and postmenopausal
women were analyzed separately, estradiol levels continued
to predict TFCA in the postmenopausal (r ⫽ 0.732, p ⬍
0.05) but not premenopausal women (r ⫽ 0.373, p ⫽
0.283). The estimated amount of Ca absorbed after surgery
was correlated to vitamin D intake (r ⫽ 0.803, p ⬍ 0.0001),
and serum 25(OH)D explained 44% of the variance (r ⫽
0.437, p ⬍ 0.05).
Discussion
The goal of this study was to examine the extent of Ca
malabsorption associated with RYGB surgery and deter-
Calcium Absorption and Gastric Bypass Surgery, Riedt et al.
Figure 3: Association between TFCA and estradiol levels (r ⫽
0.512, p ⬍ 0.02) 6 months after RYGB surgery in 21 extremely
obese women.
mine mechanisms regulating TFCA absorption and bone
turnover before and after RYGB-induced massive weight
loss. The results show that Ca absorption efficiency is
relatively high at baseline, compared with previous reports
(37,42), and although there is a 0.12 reduction of Ca absorption after RYGB surgery, TFCA values remain within
normal range (at 0.24) for most women (42). Although the
decrease in Ca absorption results in inadequate amounts of
Ca absorbed during massive weight loss, we found no
further alteration of the Ca-PTH axis when compared with
before surgery. Furthermore, bone resorption is dramatically increased after surgery, relative to the rise in bone
formation.
In previous studies, the percentage (rather than absolute)
decrease in the fractional Ca absorption is reported. In the
current dataset, there was a 34% decrease, which is less than
that observed by Sellin et al. (10) in jejuno-ileal bypass
patients (⫺50%) that was also measured 6 months after
surgery. Other studies in jejuno-ileal bypass patients that
measured Ca absorption at different time-points reported
decreases in Ca absorption, compared with baseline of 43%,
at 3 months (16), and 34% to 52% (13,16) 1 year after
surgery. Based on these previous reports, we suggest that
there is a less severe decrease of TFCA in RYGB patients
compared with jejuno-ileal bypass, and that this may be due
to more functional small intestine remaining with RYGB.
However, to our knowledge, no study has compared Ca
absorption in different methods of gastric bypass surgery to
traditional jejuno-ileal bypass.
We expected a decrease in TFCA with moderate weight
loss due to decreased caloric intake (37), hence, some of the
decrease in TFCA could be due to a reduction in caloric
intake, rather than solely attributed to intestinal bypass.
Cifuentes et al. (37) found that moderate caloric restriction
and a weight loss of 0.7 kg/wk in postmenopausal women
resulted in a decrease in Ca absorption of 0.02 (baseline
TFCA of 0.23). In the current study, after RYGB surgery,
the more severe caloric restriction resulted in a 1.5 kg
loss/wk and a decrease in absorption of 0.12 (baseline
TFCA of 0.36). Hence, the rate of weight loss in the RYGB
patients is about double compared with moderate weight
loss, yet the decrease in Ca absorption is ⬃6 times greater.
This decrease in Ca absorption could be due to a number of
factors, including a change in gastric physiology due to the
surgery alone, the effect of a more rapid weight loss, or a
different pattern of consuming Ca and other nutrient intake
(i.e., smaller more frequent meals). In addition, the decrease
in Ca absorption spans a wide range (0.03 to 0.34), and the
reasons for this remain unclear. Furthermore, we hypothesize that there is some adaptation to increase the new lower
Ca absorption rate over time, since two patients measured
for a third time at 18 months after RYGB surgery showed an
increase in absorption of 0.05 ⫾ 0.01 (absolute percentage
increase of 5.4 ⫾ 0.8%) from 6 to 18 months after surgery
(preliminary data).
In the extremely obese women before surgery, we found
no specific hormonal regulators of Ca absorption. After
surgery, estradiol was the only hormonal predictor of Ca
absorption. Estrogen has been shown to be a regulator of
active Ca uptake in the duodenum through modulation of
intestinal vitamin D receptors (43,44) and by vitamin Dindependent effects (45), and a more recent finding has now
shown a role of estrogen in Ca uptake in ileal and colonic
cells (46). Ileal and colonic Ca uptake may play a more
important role in gastric bypass patients, whose active Ca
absorption sites in the upper intestine have been bypassed.
The absence of an observed relationship between Ca absorption and estradiol levels in premenopausal women is
likely due to highly fluctuating levels throughout the menstrual cycle. These results are similar to our findings, showing an association between Ca absorption and serum estradiol levels during caloric restriction in estrogen-deplete
conditions but no association with higher estrogen levels
(37,47).
25OHD levels were low in 52% of the subjects before
surgery and did not change significantly after surgery,
which is consistent with other studies (20,25,28,30). Although not a direct predictor of Ca absorption in our study,
we show that subjects with lower 1,25(OH)2D levels tended
to have lower Ca absorption after surgery. 1,25(OH)2D
increases active cellular Ca absorption in the duodenum,
proximal jejunum, and in the colon (48,49), a site that might
become more important for Ca uptake in gastric bypass
patients. For example, Grinstead et al. have shown that
1,25(OH)2D can enhance colonic absorption in short bowel
syndrome (49). There is also evidence that 1,25(OH)2D may
increase the paracellular diffusion of Ca through tight junctions (50 –52). This would be important for the ileum, a site
of passive absorption, where most of the Ca is absorbed due
to the long sojourn time in this intestinal segment (53,54).
Furthermore, there is also newer evidence of vitamin Ddependent active absorption in the ileum (55). Overall,
despite bypassing most of the active absorptive sites of the
duodenum and the majority of the jejunum, there is eviOBESITY Vol. 14 No. 11 November 2006
1945
Calcium Absorption and Gastric Bypass Surgery, Riedt et al.
dence that vitamin D can enhance Ca absorption along the
remainder of the intestine by stimulating active transport as
well as passive diffusion. In addition, a higher vitamin D
intake after surgery, which was associated with greater
serum 25OHD levels, was also associated with greater
amounts of total estimated Ca absorbed. Those patients with
higher vitamin D intake may also have greater nutrient
intake, in general, including dietary Ca. Nevertheless, to
maximize the low serum 25OHD levels in the bariatric
patients and attenuate PTH (56) and bone resorption after
surgery, higher vitamin D intake might be necessary.
Bone turnover increased after surgery, which is consistent with findings by Coates et al. (25). Typically, there is an
increase in bone resorption with moderate weight loss
(35,57). We found a more immediate and dramatic rise in
biomarkers of bone resorption (60 to 200%) relative to bone
formation (45%) with massive weight loss due to gastric
bypass surgery. The observed “uncoupling” of bone formation and resorption markers in this study is similar to findings in bed rest studies, where a significant increase in bone
resorption without concomitant increase in bone formation
has been reported (58,59). Reduced mobilization and/or
increased catabolism associated with surgery (60) in RYGB
patients could partially explain the uncoupling of bone
turnover immediately following surgery. However, the sustained increase in bone biomarkers suggests other regulators
of bone turnover and mobilization and release of Ca from
bone (i.e., decreased mechanical loading due to massive
weight loss). Patients who increased their Ca intake after
surgery showed greater increases in the bone formation
biomarker compared with those consuming less Ca. It might
be possible that a greater rate of bone formation in an
increased state of bone turnover is beneficial in offsetting
bone loss (25,38).
Normally, TFCA is decreased at high Ca intakes (61), yet
this relationship was not observed either before or after
gastric bypass surgery. TFCA is relatively high (0.36) in the
severely obese patient before surgery, and, therefore, the
decrease in TFCA (0.12) due to RYGB remains within
normal range (0.24). This implies that some RYGB patients
could absorb sufficient amounts of Ca after surgery, as long
as dietary Ca intake is high enough. It is estimated that the
total amount of Ca absorbed decreased by 190 mg/d or
perhaps more, since there may be inaccurate reporting of
nutrients, especially in the obese subject at baseline who
often underestimate intakes (62,63). Assuming that 200 and
240 mg Ca absorbed/d is necessary to achieve at least zero
Ca balance in pre- and postmenopausal women, respectively (37,64), a regression equation based on Ca absorbed
and Ca intake shows that, theoretically, a Ca intake of ⬃800
mg/d for premenopausal and ⬃1500 mg/d for postmenopausal women is sufficient to achieve Ca balance after
RYGB surgery. However, some women with lower absorption still would not achieve Ca balance at those intakes. To
1946
OBESITY Vol. 14 No. 11 November 2006
our knowledge, there is no specific recommended Ca intake
after surgery, although most clinics are recommending 1.0
to 1.5 g Ca/d. Despite the fact that this level of Ca intake
should achieve Ca balance in most women, the high levels
of serum PTH both before and after surgery, and a marked
and sustained increase in bone resorption, suggest that another mechanism is regulating bone loss, and this area
requires further investigation.
Several studies have shown that RY limb length influences weight loss, with shorter limb length resulting in less
weight loss (65– 68), which led us to retrospectively examine whether RY limb length influences the degree of malabsorption. Although there were no differences in TFCA
response or the amount of total Ca absorbed/d between
patients with 75 cm compared with the majority with 150
cm RY limb length, our data are limited by the few patients
with the shorter RY limb length.
In conclusion, to our knowledge, this is the first study to
examine TFCA absorption after RYGB surgery. We found
that serum estradiol levels influenced Ca absorption. In
addition, despite the dramatic decrease in absorption due to
surgery, absolute levels of absorption are not remarkably
low due to high rates of Ca absorption before surgery. At
least 50% of the postmenopausal women would have a
negative Ca balance even with 1.2 grams Ca/d. The increased rate of bone turnover in all subjects appears to be
regulated by some other mechanism that was not addressed
in this paper. Although increased Ca intake can positively
influence bone turnover after RYGB surgery, it is unlikely
that further increases in Ca supplementation beyond current
recommendations will attenuate the elevated levels of bone
resorption. Despite bypassing most of the active sites for Ca
absorption in these patients, Ca absorption is influenced by
traditional Ca metabolism regulating hormones, estradiol,
and vitamin D after RYGB surgery.
Acknowledgments
The authors thank Gloria Regis-Andrews, RN, for her
excellent clinical assistance and care, and Ben Dobrzynski,
RPh, for mixing and dispensing the calcium isotopes. Statistical consulting and laboratory assistance by Dr. Yvette
Schlussel and Hasina Ambia-Sobhan is greatly appreciated.
References
1. Barrow CJ. Roux-en-Y gastric bypass for morbid obesity.
AORN J. 2002;76:590, 593– 604.
2. Weber M, Muller MK, Bucher T, et al. Laparoscopic gastric
bypass is superior to laparoscopic gastric banding for treatment of morbid obesity. Ann Surg. 2004;240:975– 82.
3. Jones KB Jr. Bariatric surgery–where do we go from here?
Int Surg. 2004;89:51–7.
4. Mellstrom D, Johansson C, Johnell O, et al. Osteoporosis,
metabolic aberrations, and increased risk for vertebral fractures after partial gastrectomy. Calcif Tissue Int. 1993;53:
370 –7.
Calcium Absorption and Gastric Bypass Surgery, Riedt et al.
5. Eddy RL. Metabolic bone disease after gastrectomy. Am J
Med. 1971;50:442–9.
6. Zittel TT, Zeeb B, Maier GW, et al. High prevalence of bone
disorders after gastrectomy. Am J Surg. 1997;174:431– 8.
7. Compston JE, Horton LW, Laker MF, et al. Bone disease
after jejuno-ileal bypass for obesity. Lancet. 1978;2:1– 4.
8. Halverson JD, Teitelbaum SL, Haddad JG, Murphy WA.
Skeletal abnormalities after jejunoileal bypass. Ann Surg.
1979;189:785–90.
9. Parfitt AM, Miller MJ, Frame B, et al. Metabolic bone
disease after intestinal bypass for treatment of obesity. Ann
Intern Med. 1978;89:193–9.
10. Sellin JH, Meredith SC, Kelly S, Schneir H, Rosenberg IH.
Prospective evaluation of metabolic bone disease after jejunoileal bypass. Gastroenterology. 1984;87:123–9.
11. Nunan TO, Compston JE, Tonge C. Intestinal calcium absorption in patients after jejuno-ileal bypass or small intestinal
resection and the effect of vitamin D. Digestion. 1986;34:9 –
14.
12. Charles P, Mosekilde L, Sondergard K, Jensen FT. Treatment with high-dose oral vitamin D2 in patients with jejunoileal bypass for morbid obesity. Effects on calcium and magnesium metabolism, vitamin D metabolites, and faecal lag
time. Scand J Gastroenterol. 1984;19:1031– 8.
13. Dano P, Christiansen C. Calcium malabsorption and absence
of bone decalcination following intestinal shunt operation for
obesity. A comparison of two types of operation. Scand J
Gastroenterol. 1978;13:81–5.
14. Rannem T, Hylander E, Jarnum S, et al. Calcium absorption and bone mineral content in patients subjected to ileal
bypass because of familial hypercholesterolaemia. Scand J
Gastroenterol. 1990;25:897–905.
15. Lindsjo M, Danielson BG, Fellstrom B, Lithell H, Ljunghall S. Intestinal absorption of oxalate and calcium in patients
with jejunoileal bypass. Scand J Urol Nephrol. 1989;23:
283–9.
16. Hylander E, Jarnum S, Kempel K, Thale M. The absorption
of oxalate, calcium, and fat after jejunoileal bypass. A prospective study. Scand J Gastroenterol. 1980;15:343– 8.
17. Brolin RL, Robertson LB, Kenler HA, Cody RP. Weight
loss and dietary intake after vertical banded gastroplasty and
Roux-en-Y gastric bypass. Ann Surg. 1994;220:782–90.
18. Alvarez-Leite JI. Nutrient deficiencies secondary to bariatric
surgery. Curr Opin Clin Nutr Metab Care. 2004;7:569 –75.
19. El-Kadre LJ, Rocha PR, de Almeida Tinoco AC, Tinoco
RC. Calcium metabolism in pre- and postmenopausal morbidly obese women at baseline and after laparoscopic Rouxen-Y gastric bypass. Obes Surg. 2004;14:1062– 6.
20. Hey H, Stokholm KH, Lund B, Lund B, Sorensen OH.
Vitamin D deficiency in obese patients and changes in circulating vitamin D metabolites following jejunoileal bypass. Int
J Obes. 1982;6:473–9.
21. Andersen T, McNair P, Hyldstrup L, et al. Secondary
hyperparathyroidism of morbid obesity regresses during
weight reduction. Metabolism. 1988;37:425– 8.
22. Ott MT, Fanti P, Malluche HH, et al. Biochemical evidence
of metabolic bone disease in women following roux-Y gastric
bypass for morbid obesity. Obes Surg. 1992;2:341– 8.
23. Shaker JL, Norton AJ, Woods MF, Fallon MD, Findling
JW. Secondary hyperparathyroidism and osteopenia in
women following gastric exclusion surgery for obesity. Osteoporos Int. 1991;1:177– 81.
24. Sorensen HA, Frandsen NJ, Hyldstrup L. Late calcium
metabolic consequences of jejuno-ileal bypass. Obesity Surgery. 1992;2:219 –23.
25. Coates PS, Fernstrom JD, Fernstrom MH, Schauer PR,
Greenspan SL. Gastric bypass surgery for morbid obesity
leads to an increase in bone turnover and a decrease in bone
mass. J Clin Endocrinol Metab. 2004;89:1061–5.
26. Guney E, Kisakol G, Ozgen G, Yilmaz C, Yilmaz R,
Kabalak T. Effect of weight loss on bone metabolism: comparison of vertical banded gastroplasty and medical intervention. Obes Surg. 2003;13:383– 8.
27. Goode LR, Brolin RE, Chowdhury HA, Shapses SA. Bone
and gastric bypass surgery: effects of dietary calcium and
vitamin D. Obes Res. 2004;12:40 –7.
28. Hamoui N, Kim K, Anthone G, Crookes PF. The significance of elevated levels of parathyroid hormone in patients
with morbid obesity before and after bariatric surgery. Arch
Surg. 2003;138:891–7.
29. Mosekilde L, Melsen F, Hessov I, et al. Low serum levels of
1.25-dihydroxyvitamin D and histomorphometric evidence of
osteomalacia after jejunoileal bypass for obesity. Gut. 1980;
21:624 –31.
30. Rickers H, Christiansen C, Balslev I, Rodbro P. Impairment of vitamin D metabolism and bone mineral content after
intestinal bypass for obesity. A longitudinal study. Scand J
Gastroenterol. 1984;19:184 –9.
31. Slater GH, Ren CJ, Siegel N, et al. Serum fat-soluble vitamin deficiency and abnormal calcium metabolism after malabsorptive bariatric surgery. J Gastrointest Surg. 2004;8:48 –
55.
32. Newbury L, Dolan K, Hatzifotis M, Low N, Fielding G.
Calcium and vitamin D depletion and elevated parathyroid
hormone following biliopancreatic diversion. Obes Surg.
2003;13:893–5.
33. Kirschner MA, Samojlik E, Drejka M, Szmal E, Schneider
G, Ertel N. Androgen-estrogen metabolism in women with
upper body versus lower body obesity. J Clin Endocrinol
Metab. 1990;70:473–9.
34. Kopelman PG, White N, Pilkington TR, Jeffcoate SL. The
effect of weight loss on sex steroid secretion and binding in
massively obese women. Clin Endocrinol (Oxf). 1981;15:
113– 6.
35. Ricci TA, Heymsfield SB, Pierson RN, Jr., Stahl T,
Chowdhury HA, Shapses SA. Moderate energy restriction
increases bone resorption in obese postmenopausal women.
Am J Clin Nutr. 2001;73:347–52.
36. Cifuentes M, Advis JP, Shapses SA. Estrogen prevents the
reduction in fractional calcium absorption due to energy restriction in mature rats. J Nutr. 2004;134:1929 –34.
37. Cifuentes M, Riedt CS, Brolin RE, Field MP, Sherrell RM,
Shapses SA. Weight loss and calcium intake influence calcium absorption in overweight postmenopausal women. Am J
Clin Nutr. 2004;80:123–30.
OBESITY Vol. 14 No. 11 November 2006
1947
Calcium Absorption and Gastric Bypass Surgery, Riedt et al.
38. von Mach MA, Stoeckli R, Bilz S, Kraenzlin M, Langer I,
Keller U. Changes in bone mineral content after surgical
treatment of morbid obesity. Metabolism. 2004;53:918 –21.
39. Wei Y, Goldfaden A, Birkmeyer JD. Characteristics of
hospitals performing bariatric surgery. JAMA 2006;295:282–
4.
40. Field MP, Cifuentes M, Sherell RM, Shapses SA. Determination of Ca isotope ratios in metabolic studies using sector
field HR-ICPMS. J Anal Atomic Spec. 2003;18:727–33.
41. Keshaviah PR, Nolph KD, Moore HL, et al. Lean body
mass estimation by creatinine kinetics. J Am Soc Nephrol.
1994;4:1475– 85.
42. Heaney RP, Recker RR. Distribution of calcium absorption
in middle-aged women. Am J Clin Nutr. 1986;43:299 –305.
43. Chen C, Noland KA, Kalu DN. Modulation of intestinal
vitamin D receptor by ovariectomy, estrogen and growth
hormone. Mech Ageing Dev. 1997;99:109 –22.
44. Liel Y, Shany S, Smirnoff P, Schwartz B. Estrogen increases
1,25-dihydroxyvitamin D receptors expression and bioresponse
in the rat duodenal mucosa. Endocrinology. 1999;140:280 –5.
45. Van Cromphaut SJ, Rummens K, Stockmans I, et al.
Intestinal calcium transporter genes are upregulated by estrogens and the reproductive cycle through vitamin D receptorindependent mechanisms. J Bone Miner Res. 2003;18:1725–36.
46. Arjmandi BH, Khalil DA, Hollis BW. Ipriflavone, a synthetic phytoestrogen, enhances intestinal calcium transport in
vitro. Calcif Tissue Int. 2000;67:225–9.
47. Cifuentes M, Morano AB, Chowdhury HA, Shapses SA.
Energy restriction reduces fractional calcium absorption in
mature obese and lean rats. J Nutr. 2002;132:2660 – 6.
48. Hylander E, Ladefoged K, Jarnum S. Calcium absorption
after intestinal resection. The importance of a preserved colon.
Scand J Gastroenterol. 1990;25:705–10.
49. Grinstead WC, Pak CY, Krejs GJ. Effect of 1,25-dihydroxyvitamin D3 on calcium absorption in the colon of
healthy humans. Am J Physiol. 1984;247(2 Pt 1):G189 –92.
50. Chirayath MV, Gajdzik L, Hulla W, Graf J, Cross HS,
Peterlik M. Vitamin D increases tight-junction conductance
and paracellular Ca2⫹ transport in Caco-2 cell cultures. Am J
Physiol. 1998;274(2 Pt 1):G389 –96.
51. Kutuzova GD, DeLuca HF. Gene expression profiles in rat
intestine identify pathways for 1,25-dihydroxyvitamin D(3)
stimulated calcium absorption and clarify its immunomodulatory properties. Arch Biochem Biophys. 2004;432:152– 66.
52. Karbach U. [New findings on the mechanism and regulation of
intestinal calcium transport]. Z Gastroenterol. 1994;32:500 –13.
53. Duflos C, Bellaton C, Pansu D, Bronner F. Calcium solubility, intestinal sojourn time and paracellular permeability
codetermine passive calcium absorption in rats. J Nutr. 1995;
125:2348 –55.
1948
OBESITY Vol. 14 No. 11 November 2006
54. Marcus CS, Lengemann FW. Absorption of Ca45 and Sr85
from solid and liquid food at various levels of the alimentary
tract of the rat. J Nutr. 1962;77:155– 60.
55. Wasserman RH. Vitamin D and the dual processes of intestinal calcium absorption. J Nutr. 2004;134:3137–9.
56. Steingrimsdottir L, Gunnarsson O, Indridason OS, Franzson L, Sigurdsson G. Relationship between serum parathyroid hormone levels, vitamin D sufficiency, and calcium intake. JAMA. 2005;294:2336 – 41.
57. Riedt CS, Cifuentes M, Stahl T, Chowdhury HA, Schlussel
Y, Shapses SA. Overweight postmenopausal women lose
bone with moderate weight reduction and 1 g/day calcium
intake. J Bone Miner Res. 2005;20:455– 63.
58. Zerwekh JE, Ruml LA, Gottschalk F, Pak CY. The effects
of twelve weeks of bed rest on bone histology, biochemical
markers of bone turnover, and calcium homeostasis in eleven
normal subjects. J Bone Miner Res. 1998;13:1594 – 601.
59. Baecker N, Tomic A, Mika C, et al. Bone resorption is
induced on the second day of bed rest: results of a controlled
crossover trial. J Appl Physiol. 2003;95:977– 82.
60. Shapses SA, Weissman C, Seibel MJ, Chowdhury HA.
Urinary pyridinium cross-link excretion is increased in critically ill surgical patients. Crit Care Med. 1997;25:85–90.
61. Bronner, F. Calcium absorption. In: Johnson L, ed. Physiology of the Gastrointestinal Tract. 2nd ed. New York: Raven
Press; 1987, pp. 1419 –35.
62. Blundell JE. What foods do people habitually eat? A dilemma
for nutrition, an enigma for psychology. Am J Clin Nutr.
2000;71:3–5.
63. Goris AH, Westerterp-Plantenga MS, Westerterp KR. Undereating and underrecording of habitual food intake in obese
men: selective underreporting of fat intake. Am J Clin Nutr.
2000;71:130 – 4.
64. Heaney RP, Recker RR, Stegman MR, Moy AJ. Calcium
absorption in women: relationships to calcium intake, estrogen
status, and age. J Bone Miner Res. 1989;4:469 –75.
65. Brolin RE, LaMarca LB, Kenler HA, Cody RP. Malabsorptive gastric bypass in patients with superobesity. J Gastrointest Surg. 2002;6:195–203.
66. Freeman JB, Kotlarewsky M, Phoenix C. Weight loss after
extended gastric bypass. Obes Surg. 1997;7:337– 44.
67. Bruder SJ, Freeman JB, Brazeau-Gravelle P. Lengthening
the Roux-Y limb increases weight loss after gastric bypass: a
preliminary report. Obes Surg. 1991;1:73–7.
68. Choban PS, Flancbaum L. The effect of Roux limb
lengths on outcome after Roux-en-Y gastric bypass: a prospective, randomized clinical trial. Obes Surg. 2002;12:
540 –5.