OBES SURG (2009) 19:1132–1138DOI 10.1007/s11695-009-9890-y Increase of Bone Resorption and the Parathyroid Hormonein Postmenopausal Women in the Long-termafter Roux-en-Y Gastric Bypass Juan P. Valderas & Soledad Velasco & Sandra Solari &Yessica Liberona & Paola Viviani & Alberto Maiz &Alex Escalona & Gilberto González Received: 13 March 2009 / Accepted: 28 May 2009 / Published online: 11 June 2009 # Springer Science + Business Media, LLC 2009 phosphatases (ALP), parathyroid hormone (PTH), 25- Background The effects of Roux-en-Y Gastric Bypass hydroxyvitamin D (25OHD), and ghrelin.
(RYGB) on bone in the long-term remains unclear. We Results RYGB group, compared to nonoperated women, assessed bone metabolism and bone mineral density (BMD) had higher CTx (0.71±0.21 vs. 0.43±0.15 ng/ml; P<0.01) and PTH (68.3±35 vs. 49.4±16 pg/ml; P=0.02). There Methods We designed a retrospective cohort study in 26 were no differences between RYGB and nonoperated postmenopausal women (58.0±3.9 years old) with RYGB women in: calcium and vitamin D intake (759±457 vs.
3.5±1.1 years before (body mass index (BMI) 29.5± 705±460 mg/day; 176±160 vs. 111±86 UI/day), ghrelin 3.8 kg/m2, presurgery 43.6±5.5 kg/m2) and 26 nonoperated (763±336 vs. 621±274 pg/ml), ALP (101±22 vs. 94± women (57.5 ± 4.7 years old, BMI 29.2 ± 4.1 kg/m2) 25 UI/l), 25OHD (18.8 ±7.6 vs. 17.4±5.9 ng/ml), lumbar matched by age and BMI. The main measures were spine BMD (1.059 ± 0.32 vs. 1.071 ± 0.207 g/cm2), or BMD, serum carboxy telopeptide (CTx), total alkaline femoral neck BMD (0.892 ±0.109 vs. 0.934±1.1 g/cm2).
Conclusions RYGB is associated to high bone resorptionand hyperparathyroidism prevalence in postmenopausal J. P. Valderas (*) Y. Liberona A. Maiz women in the long-term. This occurs independently of the Department of Nutrition, Diabetes, and Metabolism, intake of calcium, vitamin D status, or ghrelin and does not Faculty of Medicine, Pontificia Universidad Católica de Chile, Marcoleta 367,6510260 Santiago, Chilee-mail: [email protected] Keywords Bariatric surgery . Gastric bypass .
Hyperparathyroidism . Bone . Obesity . Menopause S. Velasco G. GonzálezDepartment of Endocrinology, Faculty of Medicine,Pontificia Universidad Católica de Chile,Santiago, Chile Roux-en-Y Gastric Bypass (RYGB) has become one of Department of Clinical Laboratory, Faculty of Medicine, the most common surgical procedures in the treatment of Pontificia Universidad Católica de Chile,Santiago, Chile morbid obesity during the last decade []. This signifi-cant increase of RYGB is explained in part by the fact that this surgery usually induces an excess weight loss (EWL) Department of Digestive Surgery, Faculty of Medicine, greater than 50% with a low rate of regain, compared with Pontificia Universidad Católica de Chile,Santiago, Chile the medical treatment []. RYGB also determines animportant improvement in morbimortality associated with morbid obesity ]. Nevertheless, in the short- and long- Department of Public Health, Faculty of Medicine, term follow-up, several adverse effects of RYGB due to Pontificia Universidad Católica de Chile,Santiago, Chile alterations in the intake, absorption, and metabolism of macronutrients and micronutrients have been described strontium-containing products, active hormonal vitamin D []. Therefore, there is a rising concern regarding the analogs, diuretics). Excess weight was defined as the possible effect of RYGB on bone health and the risk of difference between current body weight and body weight corresponding to a BMI of 25 kg/m2. In the recruitment There are few studies that evaluate the influence of phase, 42 women from the database could not be contacted RYGB on bone mass and bone turnover. The evidence is within the time frame of the study and the other 85 did not mainly limited to short-term follow-up and indicates that meet the inclusion or exclusion criteria, mainly, by not in the first-year postsurgery there is an increase in bone living in Santiago, use of medications known to affect bone resorption and a reduction in bone mineral density metabolism, and having EWL <50%. All RYGB proce- (BMD) []. However, it has not been clearly established dures performed at our institution included a 15- to 30-ml if such negative changes remain beyond the first year after gastric pouch and a 150-cm Roux limb We also RYGB and if they might augment the risk of osteoporosis enrolled 26 nonoperated women, matched by age and in postmenopausal women, subjects per se with a high risk current BMI, selected consecutively with the same inclu- sion and exclusion criteria, among consulting patients at Multiple mechanisms can affect the bone health post- primary care centers. The study was approved by the RYGB: reduced mechanical load associated to weight School of Medicine Ethics Committee of the Pontificia loss; second, hyperparathyroidism due to inadequate Universidad Católica de Chile and all subjects gave written calcium intake or intestinal calcium and vitamin D malabsorption and; third, changes in hormone or humoral To avoid the seasonal variation in 25OHD levels, half of factors from pancreas (e.g., insulin, amylin), adipose the subjects (operated as well as nonoperated women) were tissue (estradiol, leptin, adiponectin), or digestive tract studied between February and March (summer in the (ghrelin, glucagon-like peptide-2, glucose-dependent insu- Southern Hemisphere) and the other half in the following linotropic peptide), which may influence bone metabo- autumn (April and May) of 2007. Sunlight exposure was lism []. The effects of RYGB on bone independent of estimated using a previously described method Caloric intake was estimated by 24-h dietary recall for 3 days of the The aim of this study was to evaluate bone metabo- last week. For calcium and vitamin D intake, a food lism from 1 year up to 5 years after RYGB in frequency questionnaire was performed. Both dietary postmenopausal women, a high-risk group for osteoporosis, surveys were analyzed using a computer program (Food and characterize the influence of nutritional intake, parathy- Processor II®, ESHA Research, Salem, OR, USA), previ- roid function, vitamin D, and ghrelin on BMD and bone ously validated for Chilean food [].
Body composition was performed in all volunteers (Bioimpedance Analyzer Bodystat 1500 MDD).
A morning-fasted venous blood sample was drawn tomeasure serum total calcium (Ca), phosphorus, total From a total of 2,043 patients who had underwent RYGB in alkaline phosphatases (ALP), gamma glutamyl transferase our hospital at the moment of this study, we identified 284 (GGT), alanine transaminase, total bilirubin, albumin, and Hispanic women aged 50 to 70 and operated 1 to 5 years creatinine by automated analyzer; thyroid-stimulating hor- before. These subjects were randomly ordered and then were mone (TSH) and serum carboxy telopeptide (CTx) by an consecutively called until we reached 26 women who met electrochemiluminescent assay (Modular Analytics E170 de inclusion criteria and accepted to participate. Inclusion Roche Diagnostics, Basel, Switzerland) with an interassay criteria were: body mass index (BMI) previous to the surgery coefficient of variation (CV) for TSH<3.3 and CTx<5.5%; greater than 35 kg/m2; EWL more than 50%; ≥1 of PTH by a chemiluminescent immunoassay (IMMULITE amenorrhea; and living in Santiago, Chile, or 200 km 2000, DPC, Los Angeles, CA, USA) with a CV<6%; round about (to avoid geographic variation of 25OHD 25OHD by radioimmunoassay (RIA; DiaSorin, Stillwater, levels). The exclusion criteria were: having any conditions MN, USA) with a CV<10%; total ghrelin (RIA; Linco known to affect bone (e.g., several renal or hepatic failure, Diagnostics, St. Louis, MO, USA) with a CV<10%. Serum primary hyperparathyroidism, renal stone disease, rheuma- aliquots to measure 25OHD, CTx, and ghrelin were frozen toid arthritis) and taking any medications that affect mineral at −20ºC until they were analyzed at the end of the study.
metabolism, within the past 12 months (e.g., bisphospho- All the assays were done at the Central Laboratory of our nates, estrogens, anticonvulsants, systemic glucocorticoids, institution, which is affiliated to an external quality control program from the College of American Pathologists (USA) statistic analysis was done using a program SAS for and the main methods are published previously [].
Corrected Ca was calculated by subtracting albumin from4.0 and multiplying the difference by 0.8; then, the productwas added to the measured calcium level.
BMD was assessed by dual-energy X-ray absorptiometry There were no differences between groups in age, BMI, (DXA) in the lumbar spine (L2–L4) and both femoral percentage of body fat, years since menopause, solar necks (FN) by a Lunar DPX-L densitometer with a CV< exposure, or calorie intake. Calcium and vitamin D 2% (Lunar DPX Alpha, GE Medical System, Madison, intake were similar in both groups but were below WI, USA). The mean of right and left femoral neck BMD international recommendations [] (Table RYGB women had a presurgical BMI of 43.6 ± 5.5 kg/m2; theypresented a 76.8 ±16.9% of EWL and the elapsed time since RYGB was 3.5 ± 1.1 years (range 18 to 59 months).
At the moment of the study, the women with RYGB The sample size was calculated to find a 10% difference in regained a mean of 6.8 ± 4.9 kg from the minimum weight FN BMD with a power test of 90% and significance level of 95%. For this, we used the DXA data reported by Goodeet al. [] in 21 postmenopausal women with RYGB and 21 postmenopausal control women. The minimal sample sizewas 26 subjects, calculated for each group. Continuous Serum calcium, albumin, phosphorus, creatinine, GGT, variables were analyzed with Student’s t test for indepen- ALT, total bilirubin, and TSH were normal for both dent samples. Categorical variables were compared by chi- groups without statistical differences between them. For squared test. To determine the relation between variables, PTH, the RYGB group had a significantly higher value, simple linear regression and stepwise linear regression were with a greater prevalence of hyperparathyroidism. There performed. Results are shown as mean ± SD otherwise were no differences in 25OHD, but the prevalence of noted. A P value <0.05 was considered significant. The vitamin D deficiency (25OHD < 20 ng/ml) was very high in both groups. There were no differences in fasting Relationship Between BMD, CTx, and PTH and Studied ghrelin levels between RYGB group and nonoperated Correlation coefficients between BMD and bone parameters with all the studied variables in each group are shown inTable . In RYGB group, PTH had significant positive There were no differences in lumbar spine and femoral correlation with ALP, CTx, and corrected Ca in linear neck BMD between both groups. Although the RYGB regression analysis, but a significant negative correlation group had a mean of FN BMD 3% lower than nonoperated with serum phosphorus. The association of PTH with ALP women, there is no statistical significance (P=0.3; Table and serum phosphorus persisted significantly in the There were no differences in ALP between groups.
multiple-regression model (Table ). In the nonoperated RYGB group had a significant higher CTx level (Table ).
group, a significant positive correlation was observed Prevalence of women with high bone turnover, defined by between ghrelin and FN BMD and a negative significant CTx >0.573 ng/ml [, was higher in RYGB group correlation with PTH (Table , Fig. ). Ghrelin persisted as compared to nonoperated women (84.7 vs. 11.5%, P< a predictive factor in the multiple-regression model for FN hydroxyvitamin D, BMI bodymass index, LS lumbar spine, FN Table 4 Regression model of PTH in RYGB women and femoral BMD did not reach statistical significance (r = −0.338, P= A positive significant correlation between CTx and PTH (r = 0.392, P < 0.05) suggests that PTH excess and the greater prevalence of secondary hyperparathyroidism can explain in part the increase of bone resorption in RYGB women. The elevation of PTH and bone resorption could not be explained by low Ca and vitamin D intakes or vitamin D deficiency because these variables did not differsignificantly between women with or without RYGB. The RYGB Roux-en-Y gastric bypass, BMD bone mineral density, FN excess of PTH could be secondary to calcium malabsorp- tion due to the characteristic duodenal exclusion of thistype of surgery [Moreover, the high prevalence of secondary hyperparathyroidism in RYGB women could becaused by a long-standing vitamin D deficiency in In this study, we observed a high bone resorption in morbidly obese patients before surgery, as it has been postmenopausal women, with RYGB surgery 1 to 5 years reported In fact, the RYGB group analyzed before. Bone resorption, measured by CTx, was 65% herein had a negative correlation between 25OHD levels higher in RYGB women compared to nonoperated with BMI (r = −0.410, P=0.04) and positive with EWL women with similar age, body fat percent, BMI, and (r = 0.347, P= 0.08). Therefore, it is possible to speculate years since menopause. This finding was associated to a that these morbidly obese patients had elevated PTH greater prevalence of secondary hyperparathyroidism in previous to surgery, and RYGB worsened the secondary hyperparathyroidism and it may even become tertiary To our best knowledge, there are only two authors that hyperparathyroidism in some patients, as other types of have evaluated and reported bone resorption after RYGB in long-standing states of secondary hyperparathyroidism.
postmenopausal women, a high-risk group for osteoporosis.
Coates et al. found a three-time increase in bone resorption,associated with an 8% decrease in hip BMD, in tenmorbidly obese patients within 3 to 9 months after RYGB]. Goode et al. describes a two-time increase in boneresorption after 3 years post-RYGB in six women whopresented low bone mass Nevertheless, the smallsample size of postmenopausal women included in bothstudies, as well as the bias of selection in the second one,does not allow us to conclude that RYGB in postmeno-pausal women induces negative and persistent changes inbone health after this surgery.
There are different mechanisms that could explain our results. First of all, multiple epidemiological and clinicaldata have shown that a 10% weight loss, independent ofits cause, results in 1% to 2% bone loss, increase of bonemarkers, and risk of fracture [In RYGB, themaximum cumulative weight loss corresponds to the 1-to 2-year period . Our study was performed mostlyafter that period (mean 3.5 years after RYGB) when thewomen had already reached their minimal weight andeven had a regain. Thus, the increase of bone resorption inthis group compared with nonoperated women should notbe explained by the active weight loss process. Further-more, no correlation was observed between percentage ofEWL and bone markers neither between time since Fig. 1 a Pearson correlation between serum ghrelin and femoral neckBMD in nonoperated women. b Pearson correlation between serum surgery and bone markers, and the negative correlation ghrelin and femoral neck BMD in RYGB women. RYGB Roux-en-Y observed between percentage of EWL and lumbar spine There are two facts that support this possibility: first, higher bone mass before surgery due to the positive effect Goode et al. and Carlin et al. were unable to lower PTH of obesity in BMD. This positive correlation of body levels with adequate Ca and vitamin D supplementation in weight and BMD was observed in our cohort (Table as their studies [] and, second, we found a significant already reported in several epidemiological studies [ positive correlation between PTH levels and corrected Therefore, a possible higher BMD before RYGB in calcium (r = 0.409, P< 0.05) in the RYGB group.
morbidly obese patients could protect them of osteoporosis In our institution, all RYGB surgeries are performed development despite the fact of elevated PTH levels and with a long-limb Roux-en-Y (150 cm), unlike standard procedures performed in other centers that include a short Our study has some limitations. First, a larger sample of limb (70–100 cm). This difference could produce different patients could allow the detection of significant differences nutritional outcomes. Johnson et al. [] observed higher in BMD between women with and without RYGB. But the PTH and lesser 25OHD levels in subjects with a long-limb interpretation of small differences in BMD, as the 3% of Roux-en-Y compared to their counterparts with a short this study, is limited by the precision of DXA method that limb. Jin et al. ] described a similar finding concerning decreased moreover in overweight subjects [We did not vitamin D levels. On the other hand, Fleisher et al. [ measure a specific bone formation marker, such as bone- described a decrease of calcium absorption and an increase specific alkaline phosphatases or osteocalcin. However, in in PTH without changes in 25OHD levels in patients with a the presence of other normal liver tests, as was found in our 150-cm Roux-en-Y limb. Riedt et al. described a decrease patients, total alkaline phosphatases should be an adequate in calcium absorption without changes in PTH and 25OHD bone formation marker [Moreover, due to budget levels without differences between patients with short or limitations, we did not assess calcium absorption or urinary long Roux-en-Y limb ]. It is possible to speculate that calcium excretion. Identifying the cause of the secondary the length of Roux-en-Y limb might affect vitamin D hyperparathyroidism was beyond the objective of this absorption mainly and thus produce hyperparathyroidism and increase of bone resorption. However, our patients had We conclude that, in postmenopausal women, RYGB is similar 25OHD levels than controls and therefore it would associated in the long-term to an increase in bone resorption and parathyroid hormone. These observations, together Ghrelin is an orexigenic peptide mainly produced in the with a high prevalence of vitamin D deficiency, are stomach fundus, whose serum levels may increase, de- independent risk factors for osteoporosis , ]. For crease, or not change over 24-month follow-up after RYGB these reasons, and in spite of no decreased in BMD, we ].The possibility that ghrelin could be involved in the postulate that, in the long-term, postmenopausal women control of bone metabolism was initially supported by the with RYGB may have an increased risk of osteoporotic observation that gastrectomy induces osteopenia and that fractures. In addition, we detected a lack of positive effects the bone structure is preserved by retaining the oxyntic of ghrelin on bone metabolism after RYGB. We emphasize gland area ]. In the last years, it has been described that the need of a complete bone evaluation in postmenopausal ghrelin has positive effects on the osteoblast proliferation in rat, mouse, and human and, in cohort studies, fastingghrelin levels has a positive correlation with BMD and a This study was supported by funds from the Department of Nutrition, Diabetes, and Metabolism, School of Medicine, negative one with bone markers [In our study, we Pontificia Universidad Católica de Chile. We would like to thank Ms.
observed that women with RYGB performed 5 years ago Susan Smalley M. for her critical review in English of our manuscript and had similar ghrelin levels than nonoperated women, but the to Ms. Jacqueline Parada for the CTx measurements.
protective effect of this peptide on bone, expressed as apositive correlation with BMD (Fig. and as a negative The authors have nothing to disclose.
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