REVIEW ARTICLE
review article
Diabetes, Obesity and Metabolism 16: 1204–1213, 2014. © 2014 John Wiley & Sons Ltd
Skeletal effects of bariatric surgery: examining bone loss, potential mechanisms and clinical relevance L. M. Scibora Health and Human Performance Department, University of St. Thomas, St. Paul, MN, USA
Bariatric surgery is the most effective therapeutic approach to morbid obesity, resulting in substantial weight loss and improved cardiometabolic profiles; however, a growing body of evidence suggests that bariatric procedures increase both skeletal fragility and the risk of related future fracture secondary to excessive bone loss. Prospective evidence shows that areal bone mineral density (BMD) assessed by dual energy X-ray absorptiometry (DXA) declines by as much as 14% in the proximal femoral regions, including the femoral neck and total hip, 12 months postoperatively. Lumbar spine areal BMD outcomes show greater 12-month postoperative variability across surgical procedures (−8 to +6%) and contrast with no change in volumetric BMD outcomes measured by quantitative computed tomography. Diminished mechanical loading, micronutrient deficiency and malabsorption, along with neurohormonal alterations, offer plausible underlying mechanisms to explain these observed post-bariatric bone changes, but most remain largely unsubstantiated in this population. Importantly, DXA-based skeletal imaging may have limited utility in accurately detecting bone change in people undergoing bariatric surgery; partly because excessive tissue overlying bone increases the variability of areal BMD outcomes. Moreover, a paucity of fracture and osteoporosis incidence data raises questions about whether marked post-bariatric surgery bone loss is clinically relevant or a functional adaptation to skeletal unloading. Future studies that use technology which is able to accurately capture the site-specific volumetric BMD and bone architectural changes that underpin bone strength in people undergoing bariatric surgery, that consider mechanical load, and that better quantify long-term fracture and osteoporosis incidence are necessary to understand the actual skeletal effects of bariatric surgery. Keywords: bariatric surgery, body composition Date submitted 28 April 2014; date of first decision 29 May 2014; date of final acceptance 29 July 2014
Introduction The widespread obesity epidemic has resulted in an increased prevalence of bariatric surgical procedures worldwide in the last decade [1,2]. Unlike modest 10% short-term weight reductions after lifestyle-modification interventions [3], bariatric procedures result in an average 56% excess body weight loss (EWL) [4] and attenuate or resolve obesity-related comorbid conditions, including type 2 diabetes, hypertension and dyslipidaemia in the majority of patients [4–6] 2 years after surgery. Despite significant improvements in body weight and cardiometabolic health, growing evidence suggests that bariatric surgery may increase skeletal fragility and the risk of fracture by accelerating bone loss [7–9]. Non-surgical weight loss of 10% is associated with 1–2% greater bone loss as measured by dual energy X-ray absorptiometry (DXA) [10] and an increased risk of hip fracture compared with weight maintenance [11]. Prospective studies suggest that significant bone loss [measured by DXA and quantitative computed tomography (QCT)] is also a consequence of surgery-associated weight loss [12,13]. Numerous plausible explanations could underlie the observed bone loss, such as mechanical unloading, nutrient deficiency and neurohormonal alterations, although direct evidence in this Correspondence to: Dr Lesley M. Scibora, Health and Human Performance Department, University of St. Thomas, 2115 Summit Avenue, Mail #4004, St. Paul, MN 55105, USA. E-mail: [email protected]
population is preliminary [14,15]. Assessing the clinical relevance of post-bariatric surgery bone loss may be hindered by obesity and weight change-related skeleton imaging limitations and inconclusive osteoporosis and fracture data. The present paper provides a brief overview of bone homeostasis, a review of prospective evidence of bariatric surgery on bone outcomes in adult populations and a discussion of the mechanisms that may contribute to post-bariatric surgery skeletal change. Ambiguities in imaging and clinical endpoints, including osteoporosis and fracture are discussed, along with clinical considerations regarding bone health in patients undergoing bariatric surgery. The studies cited in the present review were those published up until 1 March 2014 and were located via PubMed using combinations of the search terms ‘bariatric surgery’, ‘bone’, bone loss’, ‘bone mineral density’, ‘bone turnover’, ‘osteoporosis’ and ‘fracture’. Studies found in the references of the identified literature were also included in the present review.
Bone Homeostasis and Bone Strength The two primary functions of bone are to provide a mineral reservoir and a skeletal structure, acted on by muscles and designed for locomotion that can withstand daily typical mechanical loads. Homeostasis of bone mineral metabolism and bone strength is regulated by interrelated negative feedback systems, influenced by both mechanical and non-mechanical factors such as genetics, gender, age, nutrient availability,
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concurrent disease and drug therapy [16,17]. To remain metabolically efficient, light and strong, bone adaptively alters its mass, architecture and material properties to maintain overall bone strength [18]. Bone remodelling, a tightly coupled activity of osteoblasts and osteoclasts, replaces older, fatigue-damaged bone with new bone, altering its microarchitecture [19,20]. Reflecting independent actions of osteoclasts or osteoblasts, ’formation’ modelling alters bone morphology by adding new bone to a surface (e.g. outer periosteum or inner endosteum) and ‘resorption’ modelling removes bone from a surface over time (e.g. endocortical surface) [19]. Signalling a disruption in bone homeostasis, bariatric prospective studies show remarkable postoperative increases in bone turnover markers (Table 1). Several studies have shown 1-year 43–220% increases in bone resorption markers [12,13,21–26] that remain elevated, although less so, up to 24 months postoperatively [22,27,28], by which time weight stabilizes. Showing greater postoperative variability, bone formation markers decrease [25], remain unchanged [12,29,30] or increase by nearly 100% [21,27,31] in the first postoperative year. This marked increase in bone resorption markers suggests that resorption modelling occurs, supporting the prospective areal bone mineral density (BMD) outcomes discussed below.
Bone Outcomes of Bariatric Surgery Bariatric Surgical Procedures Each of the following bariatric procedures may differentially influence postoperative bone outcomes. Roux-en-Y gastric bypass (RYGB), the most effective and widely performed bariatric procedure for substantial weight loss (mean 58% EWL) and improved metabolic profiles [4], comprises 47% of the procedures performed currently [2]. RYGB combines intake restriction with a more conservative malabsorptive component of earlier biliopancreatic diversion (BPD) procedures [32] by transecting the stomach to create a small (∼30-ml) proximal gastric pouch anastomosed to the distal small intestine [33]. Although anatomically distinct, increasingly popular sleeve gastrectomy (SG) procedures create a gastric tube by excising much (∼80%) of the stomach [33] and have resulted in sustained weight loss [34] and metabolic improvements similar to those achieved by RYGB [35], including lipid profiles and glucose homeostasis [36]. Originally hypothesized to work though intake restriction (SG and RYGB) and nutrient malabsorption (RYGB), both procedures also appear to exert their cardiometabolic effects, independently of weight loss, through numerous potential neurohormonal mechanisms [37]. By contrast, the restrictive adjustable gastric banding (AGB) procedure uses an inflatable saline-filled band around the proximal stomach to restrict intake and induce early satiety [33]. Resulting in lower, less durable weight loss (mean 46% EWL) [4], and less dramatic cardiometabolic effects compared with RYGB and SG [34], AGB prevalence has declined in recent years [2].
Prospective Bone Outcomes Bone outcomes after bariatric surgery have been recently reviewed [38] and are summarized here along with new data
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[12,13,26,39–42]. Despite restricting investigations to one surgical procedure or population (e.g. premenopausal women) [22,39,43–45] most studies are confounded by heterogeneous populations and lack control groups. Moreover, most studies report areal BMD (g/cm2 ), measured by DXA, as a primary outcome to assess post-bariatric surgery bone health; DXA-based areal BMD is generally accepted as a surrogate marker of bone strength and fracture risk in people of healthy weight [46]. DXA imaging may be limited, however, in obese populations [47,48], particularly as body composition changes during weight loss [12,49] (see Skeletal Imaging in Patients Undergoing Bariatric Surgery section). While technology such as quantitative computed tomography (QCT), peripheral QCT and high-resolution peripheral QCT have the ability to assess compartment-specific volumetric BMD (mg/mm3 ) and geometric variables that underpin bone mechanical strength [50], only two studies have longitudinally assessed skeletal endpoints using these imaging methods.
Areal Density Outcomes The magnitude of skeletal changes varies by skeletal region and surgical procedure (Table 1), although the greatest measured areal BMD loss overall has been reported 1 year after gastric bypass procedures at sites in the proximal femur region, including the total hip and femoral neck. DXA-measured bone loss at the femoral neck and total hip ranges from 5 to 11% 1 year after BPD [51], RYGB [12,13,23,25,26,40,51–53] and some SG [25,39] procedures, while areal BMD changes range widely from no change to 14% reductions after restrictive procedures [7,22,39,45,54]. Spine areal BMD changes are inconsistent with studies reporting 12-month reductions of 3–8% after RYGB [12,25,26,40,44,52], BPD [43] and some SG [25,39] procedures, but no change or even slight gains after restrictive [7,22,39,41,45,55], SG [41], and combined procedures [13]. Forearm bone changes are less widely reported, but some studies suggest that non-weight-bearing radius areal BMD remains stable [12,13,56] or increases slightly (+1.5%) [23,51] 12 months postoperatively. There is a paucity of available studies to establish the longer-term skeletal effects of bariatric procedures. Although some studies suggest that areal BMD loss at the hip may persist [22,53], overall rates of bone loss appear to decrease [40,51] beyond the first postoperative year.
Volumetric Density and Geometry Outcomes Studies reporting QCT derivatives of volumetric BMD and geometry variables are consistent with DXA-based areal BMD outcomes at the spine, tibia and radius sites, but not hip sites. When assessed by QCT, women who have undergone RYGB show similar 3% reductions between spine trabecular volumetric BMD and lumbar spine areal BMD 12 months postoperatively [12]. Reductions in DXA-based proximal femur areal BMD (−9%), however, contrasted with no change in QCT-based proximal femur total volumetric BMD or compartment-specific stability in cortical bone and were greater than the almost 5% trabecular volumetric BMD reductions [12]. In distal appendicular sites, imaging with
doi:10.1111/dom.12363 1205
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RYGB and SG
RYGB and SG
RYGB, AGB, and SG RYGB and AGB RYGB
RYGB
RYGB RYGB
RYGB
RYGB
RYGB
RYGB
RYGB
Carrasco et al. [39]
Nogues et al. [25]
Stein et al. [13]
Riedl et al. [21]
Biagioni et al. [29]
Casagrande et al. [26] Bruno et al. [28]
Carlin et al. [24]
Mahdy et al. [30]
Fleischer et al. [23]
Riedt et al. [31]
Coates et al. [8]
Yu et al. [12]
Surgery
Study author
21 women; mean age 44 years; BMI range 40–74 kg/m2 15 (12 women : 3 men); mean age 51 years; mean BMI 48 kg/m2
22 women; mean age 47 years; mean BMI 44 kg/m2 Group 1: 20 (10 women : 10 men); mean age 33 years; mean BMI 50 kg/m2 Group 2: 19 (10 women : 9 men); mean age 47 years; mean BMI 47 kg/m2 Vitamin D (additional 50 000 IU/week): 30 women; mean age 43 years; mean BMI 50 kg/m2 Control: 30 women; mean age 43 years; mean BMI 51 kg/m2 70 (49 women : 21 men); mean age 35 years; mean BMI 48 kg/m2 23 (18 women : 5 men); age range 20–64 years; mean BMI 47 kg/m2
22 women; age range 18–40 years; BMI >35 kg/m2
22 women; mean age 45 years; mean BMI 44 kg/m2 (RYGB, n = 14; AGB, n = 6; SG, n = 2) RYGB: 30 (27 women : 3 men), mean age 43 years AGB: 10 (8 women : 2 men), mean age 44 years RYGB: 30 (26 women : 4 men); mean age 47 years; mean BMI 45 kg/m2 Control: 20 (18 women : 2 men); mean age 46 years; mean BMI 45 kg/m2
RYGB: 23 women (premenopause); mean age 37 years; mean BMI 42 kg/m2 SG: 20 women premenopause; mean age 34 years; mean BMI 37 kg/m2 15 women; mean age 48 years; mean BMI 43 kg/m2 (RYGB, n = 7; SG, n = 8)
Population
3 m (serum OC): ↑18% 6 m: ↑27% 12 m: ↑39% 3 m (serum OC): NS 6 m: ↑45% 3 m (serum OC): NS 6 m: NS; serum BSAP: NS 3 m (urinary NTx): ↑57% 6 m: ↑86% 12 m: ↑106% 3 m (serum NTx): ↑60% 6 m: ↑60%; urinary DPD: ↑203% 3 m (urinary NTx): ↑174% 9 m: ↑319%
Vitamin D (serum BSAP): 35% Control: ↑46%
Vitamin D (urinary NTx): ↑165% Control: ↑102%
Serum BSAP: NS
Total Cohort(serum BSAP): NS RYGB: NS SG: ↓16% Total cohort (serum BSAP): NS RYGB: ↑20% RYGB (serum OC): ↑183% AGB: ↑68% RYGB: 6 m (serum P1NP): ↑82%; serum OC: NS 12 m:% change not reported, but remained significantly elevated: serum OC: NS Control: NS changes 3 m (serum BSAP): NS 6 m: NS NA Group 1: 6 m: serum BSAP: ↑15% Group 2: 18 m: serum BSAP: ↑26%
Total cohort (urinary NTx): ↑123% RYGB: ↑111% SG: ↑140% Total cohort (serum CTx): ↑144% RYGB: ↑212% RYGB (serum CTx): ↑190% AGB: ↑128% RYGB: 6 m (serum CTx): ↑220% 12 m: % change not reported, but remained significantly elevated Control: NS changes 3 m (serum CTx): ↑174% 6 m: ↑285% Serum NTx: ↑133% Group 1: 6 m:serum NTx: ↑80% Group 2: 18 m:serum NTx: ↑56%
NA
RYGB (serum BSAP): NS SG: NS
Bone formation markers
NA
Bone resorption markers
Table 1. Summary table of prospective bariatric (sleeve gastrectomy, Roux-en-Y gastric bypass and adjustable gastric banding) studies reporting bone turnover markers.*
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AGB Pugnale et al. [45]
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*Bone turnover marker outcomes reflect 12-month changes from baseline unless otherwise noted. For the first time point, the turnover marker is indicated in parentheses. All reported differences significantly different from baseline (at least p < 0.05), unless noted non-significant. AGB, adjustable gastric banding. BPD-DS, biliopancreatic diversion-duodenal switch; BSAP, bone-specific alkaline phosphatase; CTx, C-telopeptide; DPD, deoxypyridinoline; m, month; NA, not available; NS, non-significant; NTx, N-telopeptide; OC, osteocalcin; PINP, procollagen type 1 N-terminal propeptide; RYGB, Roux-en-Y gastric bypass; SG, sleeve gastrectomy.
AGB Giusti et al. [22]
31 women (premenopause), mean age 36 years; mean BMI 44 kg/m2
NA
3 m (serum OC): ↑35%; BSAP: NS for all time points 6 m: ↑92% 9 m: ↑141% 12 m: ↑130% 18 m: ↑95% NA 37 women (premenopause), mean age 37 years; mean BMI 44 kg/m2
Bone formation markers
3 m (urinary NTx): ↑80% 6 m: ↑52% 9 m: ↑78% 12 m: ↑68% 18 m: ↑50% 6 m (urinary NTx): ↑40%; (serum CTx): NS 12 m: ↑61%:↑53% 18 m: ↑38%:↑82% 24 m: ↑46%:↑94% 1 m (urinary NTx): NS; (serum CTx): ↑100% 3 m: ↑35%;↑119% 6 m: ↑41%:↑113% 12 m: ↑58%:↑131% Sinha et al. [27]
75 women : 39 men (AGB, n=18; RYGB, n=50; BPD, n=5); mean age 39 years, mean BMI 48 kg/m2
Surgery
AGB, RYGB and BPD-DS
Study author
Table 1. Continued
Population
Bone resorption markers
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high-resolution peripheral QCT showed endocortical expansion at the distal radius and tibia, with significant cortical (−2%) density and load-share reductions at the tibia in women 12 months after RYGB [13]. That the most remarkable skeletal changes are observed at weight-bearing sites, including the hip (detected by DXA) and tibia (detected by high-resolution peripheral QCT), suggests a strong association with mechanical unloading (Table S1). The current literature supports bone loss after bariatric procedures within the first postoperative year, but longer-term outcomes remain unclear without sufficient data, particularly as body weight stabilizes or if weight regain occurs. Furthermore, inconsistencies with QCT outcomes raise questions regarding the accuracy of DXA in bariatric populations. As discussed later in the present review, whether this observed loss is clinically important or simply an appropriate adaptive response to change in the mechanical environment, is unclear. Several plausible mechanisms to explain these outcomes are first explored below.
Potential Mechanisms Underlying Bone Loss Numerous hypotheses are offered to explain post-bariatric surgery bone loss. Mechanical unloading, calcium and vitamin D insufficiency are frequently cited, while postoperative neurohormonal alterations also offer potential, yet unsubstantiated, preliminary hypotheses. These mechanisms are discussed below.
Mechanical (Un)loading Unloading subsequent to weight loss is a plausible mediator of bone change and correlates with the magnitude and/or rapidity of weight loss after both RYGB [13,23] and SG [54]. Changes in areal BMD in patients who have undergone bariatric surgery are similar in relative magnitude (∼−1% per month) to those observed in unloading studies after 60 days of bed rest (−4%) [57] and 6 months of space flight (−7%) [58]. Although some studies report no relationship between weight loss and bone change [26,41], there is a strong theoretical framework that helps to explain these relationships if body composition is considered [18,20,59]. Several lines of evidence show that bone density and strength is primarily adapted to lean mass, rather than fat mass [60], in children [61,62], women [63] and men [64]. Requiring more lean mass to move their higher body weight, overweight and obese individuals have greater absolute lean mass than their healthy weight counterparts, which is related to their higher bone mass and strength [63]. While failure to preserve lean mass after bariatric surgery may mediate reductions in bone mass or strength, what constitutes ‘excessive’ lean mass loss is unclear. Potentially 30 ng/ml) and postoperative daily calcium (calcium citrate 1200–2000 mg) and vitamin D (ergocalciferol up to 50 000 IU) supplementation [108,109,112], monitored for normal serum vitamin D, calcium, parathyroid hormone levels and 24-h urinary calcium excretion rates every 6 months postoperatively, is currently recommended to prevent secondary hyperparathyroidism. Along with sufficient protein intake (60–120 g daily) [109,111], changing body composition should be monitored during weight reduction, for the detection and prevention of excessive lean mass loss [96]. Few patients who have undergone bariatric surgery meet the physical activity guidelines for general health [113], so appropriate physical activity designed to maintain or increase muscle mass will facilitate bone strength, optimize weight maintenance after surgery and support overall health and well-being.
Conclusions The skeletal effects of bariatric surgery remain unclear. DXA-based studies consistently show profound bone loss at the proximal femur in the first postoperative year. Newer QCT-based outcomes contradict DXA studies, suggesting that observed bone loss at the femoral neck and hip may be an imaging artifact and that three-dimensional imaging technology may be more accurate in bariatric populations. If bone loss does occur, future studies are needed to fully understand the mechanisms of bone loss and establish if loss is clinically relevant or simply a functional adaptation to skeletal unloading. Without sufficient data regarding fracture endpoints and osteoporosis incidence, the notion that bariatric surgery exerts a clinically relevant impact on the skeleton remains unsupported – although future studies are certainly warranted to better understand long-term postoperative bone structural changes and bone strength outcomes.
Conflict of Interest L. S. solely contributed to the design, conduct/data collection, analysis and writing of this review. No conflict of interest is declared.
Acknowledgements The author would like to thank Dr Moira Petit for her expert and thoughtful review of this manuscript.
Supporting Information Additional Supporting Information may be found in the online version of this article: Table S1. Prospective bariatric regional bone densitometric and geometric outcomes, T- and Z-scores.
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53. Vilarrasa N, San Jose P, Garcia I et al. Evaluation of bone mineral density loss in morbidly obese women after gastric bypass: 3-year follow-up. Obes Surg 2011; 21: 465–472. 54. Cundy T, Evans MC, Kay RG, Downan M, Wattie D, Reid IR. Effects of vertical-banded gastroplasty on bone and mineral metabolism in obese patients. Br J Surg 1996; 83: 1468–1472. 55. von Mach MA, Stoeckli R, Bilz S, Kaaenzlin M, Langer I, Keller U. Changes in bone mineral content after surgical treatment of morbid obesity. Metabolism 2004; 53: 918–921. 56. Censani M, Stein EM, Shane E et al. Vitamin D deficiency is prevalent in morbidly obese adolescents prior to bariatric surgery. ISRN Obes 2013: 284516. 57. Spector ER, Smith SM, Sibonga JD. Skeletal effects of long-duration head-down bed rest. Aviat Space Environ Med 2009; 80(Suppl. 5): A23–A28. 58. LeBlanc AD, Spector ER, Evans HJ, Sibonga JD. Skeletal responses to space flight and the bed rest analog: a review. J Musculoskelet Neuronal Interact 2007; 7: 33–47. 59. Frost HM. Obesity, and bone strength and "mass": a tutorial based on insights from a new paradigm. Bone 1997; 21: 211–214. 60. Zhao LJ, Liu YJ, Liu PY, Hamilton J, Recker RR, Deng HW. Relationship of obesity with osteoporosis. J Clin Endocrinol Metab 2007; 92: 1640–1646.
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63. Beck TJ, Petit MA, Wu G, LeBoff MS, Cauley JA, Chen Z. Does obesity really make the femur stronger? BMD, geometry, and fracture incidence in the women’s health initiative-observational study. J Bone Miner Res 2009; 24: 1369–1379.
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85. Walicka M, Czerwinska E, Talalaj M, Marcinowska-Suchowierska E. Influence of weight reduction on leptin concentration and bone mineral density in patients with morbid obesity before and 6 months after bariatric surgery. Endokrynol Pol 2009; 60: 97–102. 86. Butner KL, Nickols-Richardson SM, Clark SF, Ramp WK, Herbert WG. A review of weight loss following Roux-en-Y gastric bypass vs restrictive bariatric surgery: impact on adiponectin and insulin. Obes Surg 2010; 20: 559–568. 87. Gomez-Ambrosi J, Rodriguez A, Catalan V, Fruhbeck G. The bone-adipose axis in obesity and weight loss. Obes Surg 2008; 18: 1134–1143. 88. Leblanc AD, Schneider VS, Evans HJ, Engelbretson DA, Krebs JM. Bone mineral loss and recovery after 17 weeks of bed rest. J Bone Miner Res 1990; 5: 843–850. 89. Parfitt AM, Miller MJ, Frame B et al. Metabolic bone disease after intestinal bypass for treatment of obesity. Ann Intern Med 1978; 89: 193–199. 90. Parfitt AM, Podenphant J, Villanueva AR, Frame B. Metabolic bone disease with and without osteomalacia after intestinal bypass surgery: a bone histomorphometric study. Bone 1985; 6: 211–220. 91. Collazo-Clavell ML, Jimenez A, Hodgson SF, Sarr MG. Osteomalacia after Roux-en-Y gastric bypass. Endocr Pract 2004; 10: 195–198. 92. Valderas JP, Velasco S, Solari S et al. Increase of none resorption and the parathyroid hormone in postmenopausal women in the long-term after Roux-en-Y gastric bypass. Obes Surg 2009; 19: 1132–1138. 93. Goode LR, Brolin RE, Chowdhury HA, Shapses SA. Bone and gastric bypass surgery: effects of dietary calcium and vitamin D. Obes Res 2004; 12: 40–47. 94. Marceau P, Biron S, Lebel S et al. Does bone change after biliopancreatic diversion? J Gastrointest Surg 2002; 6: 690–698.
73. Stein EM, Strain G, Sinha N et al. Vitamin D insufficiency prior to bariatric surgery: risk factors and a pilot treatment study. Clin Endocrinol (Oxf) 2009; 71: 176–183.
95. Lalmohamed A, de Vries F, Bazelier MT et al. Risk of fracture after bariatric surgery in the United Kingdom: population based, retrospective cohort study. BMJ 2012; 345: e5085.
74. Pereira FA, de Castro JA, dos Santos JE, Foss MC, Paula FJ. Impact of marked weight loss induced by bariatric surgery on bone mineral density and remodeling. Braz J Med Biol Res 2007; 40: 509–517.
96. Kendler DL, Borges JL, Fielding RA et al. The official positions of the international society for clinical densitometry: indications of use and reporting of DXA for body composition. J Clin Densitom 2013; 16: 496–507.
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97. Madsen OR, Jensen JE, Sorensen OH. Validation of a dual energy X-ray absorptiometer: measurement of bone mass and soft tissue composition. Eur J Appl Physiol Occup Physiol 1997; 75: 554–558.
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77. Beckman LM, Beckman TR, Earthman CP. Changes in gastrointestinal hormones and leptin after Roux-en-Y gastric bypass procedure: a review. J Am Diet Assoc 2010; 110: 571–584. 78. Fukushima N, Hanada R, Teranishi H et al. Ghrelin directly regulates bone formation. J Bone Miner Res 2005; 20: 790–798.
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108. Mechanick JI, Youdim A, Jones DB et al. Clinical practice guidelines for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient–2013 update: cosponsored by American Association of Clinical Endocrinologists, The Obesity Society, and American Society for Metabolic & Bariatric Surgery. Obesity 2013; 21(Suppl 1): S1–S27.
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review article
Diabetes, Obesity and Metabolism 16: 1204–1213, 2014. © 2014 John Wiley & Sons Ltd
Skeletal effects of bariatric surgery: examining bone loss, potential mechanisms and clinical relevance L. M. Scibora Health and Human Performance Department, University of St. Thomas, St. Paul, MN, USA
Bariatric surgery is the most effective therapeutic approach to morbid obesity, resulting in substantial weight loss and improved cardiometabolic profiles; however, a growing body of evidence suggests that bariatric procedures increase both skeletal fragility and the risk of related future fracture secondary to excessive bone loss. Prospective evidence shows that areal bone mineral density (BMD) assessed by dual energy X-ray absorptiometry (DXA) declines by as much as 14% in the proximal femoral regions, including the femoral neck and total hip, 12 months postoperatively. Lumbar spine areal BMD outcomes show greater 12-month postoperative variability across surgical procedures (−8 to +6%) and contrast with no change in volumetric BMD outcomes measured by quantitative computed tomography. Diminished mechanical loading, micronutrient deficiency and malabsorption, along with neurohormonal alterations, offer plausible underlying mechanisms to explain these observed post-bariatric bone changes, but most remain largely unsubstantiated in this population. Importantly, DXA-based skeletal imaging may have limited utility in accurately detecting bone change in people undergoing bariatric surgery; partly because excessive tissue overlying bone increases the variability of areal BMD outcomes. Moreover, a paucity of fracture and osteoporosis incidence data raises questions about whether marked post-bariatric surgery bone loss is clinically relevant or a functional adaptation to skeletal unloading. Future studies that use technology which is able to accurately capture the site-specific volumetric BMD and bone architectural changes that underpin bone strength in people undergoing bariatric surgery, that consider mechanical load, and that better quantify long-term fracture and osteoporosis incidence are necessary to understand the actual skeletal effects of bariatric surgery. Keywords: bariatric surgery, body composition Date submitted 28 April 2014; date of first decision 29 May 2014; date of final acceptance 29 July 2014
Introduction The widespread obesity epidemic has resulted in an increased prevalence of bariatric surgical procedures worldwide in the last decade [1,2]. Unlike modest 10% short-term weight reductions after lifestyle-modification interventions [3], bariatric procedures result in an average 56% excess body weight loss (EWL) [4] and attenuate or resolve obesity-related comorbid conditions, including type 2 diabetes, hypertension and dyslipidaemia in the majority of patients [4–6] 2 years after surgery. Despite significant improvements in body weight and cardiometabolic health, growing evidence suggests that bariatric surgery may increase skeletal fragility and the risk of fracture by accelerating bone loss [7–9]. Non-surgical weight loss of 10% is associated with 1–2% greater bone loss as measured by dual energy X-ray absorptiometry (DXA) [10] and an increased risk of hip fracture compared with weight maintenance [11]. Prospective studies suggest that significant bone loss [measured by DXA and quantitative computed tomography (QCT)] is also a consequence of surgery-associated weight loss [12,13]. Numerous plausible explanations could underlie the observed bone loss, such as mechanical unloading, nutrient deficiency and neurohormonal alterations, although direct evidence in this Correspondence to: Dr Lesley M. Scibora, Health and Human Performance Department, University of St. Thomas, 2115 Summit Avenue, Mail #4004, St. Paul, MN 55105, USA. E-mail: [email protected]
population is preliminary [14,15]. Assessing the clinical relevance of post-bariatric surgery bone loss may be hindered by obesity and weight change-related skeleton imaging limitations and inconclusive osteoporosis and fracture data. The present paper provides a brief overview of bone homeostasis, a review of prospective evidence of bariatric surgery on bone outcomes in adult populations and a discussion of the mechanisms that may contribute to post-bariatric surgery skeletal change. Ambiguities in imaging and clinical endpoints, including osteoporosis and fracture are discussed, along with clinical considerations regarding bone health in patients undergoing bariatric surgery. The studies cited in the present review were those published up until 1 March 2014 and were located via PubMed using combinations of the search terms ‘bariatric surgery’, ‘bone’, bone loss’, ‘bone mineral density’, ‘bone turnover’, ‘osteoporosis’ and ‘fracture’. Studies found in the references of the identified literature were also included in the present review.
Bone Homeostasis and Bone Strength The two primary functions of bone are to provide a mineral reservoir and a skeletal structure, acted on by muscles and designed for locomotion that can withstand daily typical mechanical loads. Homeostasis of bone mineral metabolism and bone strength is regulated by interrelated negative feedback systems, influenced by both mechanical and non-mechanical factors such as genetics, gender, age, nutrient availability,
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concurrent disease and drug therapy [16,17]. To remain metabolically efficient, light and strong, bone adaptively alters its mass, architecture and material properties to maintain overall bone strength [18]. Bone remodelling, a tightly coupled activity of osteoblasts and osteoclasts, replaces older, fatigue-damaged bone with new bone, altering its microarchitecture [19,20]. Reflecting independent actions of osteoclasts or osteoblasts, ’formation’ modelling alters bone morphology by adding new bone to a surface (e.g. outer periosteum or inner endosteum) and ‘resorption’ modelling removes bone from a surface over time (e.g. endocortical surface) [19]. Signalling a disruption in bone homeostasis, bariatric prospective studies show remarkable postoperative increases in bone turnover markers (Table 1). Several studies have shown 1-year 43–220% increases in bone resorption markers [12,13,21–26] that remain elevated, although less so, up to 24 months postoperatively [22,27,28], by which time weight stabilizes. Showing greater postoperative variability, bone formation markers decrease [25], remain unchanged [12,29,30] or increase by nearly 100% [21,27,31] in the first postoperative year. This marked increase in bone resorption markers suggests that resorption modelling occurs, supporting the prospective areal bone mineral density (BMD) outcomes discussed below.
Bone Outcomes of Bariatric Surgery Bariatric Surgical Procedures Each of the following bariatric procedures may differentially influence postoperative bone outcomes. Roux-en-Y gastric bypass (RYGB), the most effective and widely performed bariatric procedure for substantial weight loss (mean 58% EWL) and improved metabolic profiles [4], comprises 47% of the procedures performed currently [2]. RYGB combines intake restriction with a more conservative malabsorptive component of earlier biliopancreatic diversion (BPD) procedures [32] by transecting the stomach to create a small (∼30-ml) proximal gastric pouch anastomosed to the distal small intestine [33]. Although anatomically distinct, increasingly popular sleeve gastrectomy (SG) procedures create a gastric tube by excising much (∼80%) of the stomach [33] and have resulted in sustained weight loss [34] and metabolic improvements similar to those achieved by RYGB [35], including lipid profiles and glucose homeostasis [36]. Originally hypothesized to work though intake restriction (SG and RYGB) and nutrient malabsorption (RYGB), both procedures also appear to exert their cardiometabolic effects, independently of weight loss, through numerous potential neurohormonal mechanisms [37]. By contrast, the restrictive adjustable gastric banding (AGB) procedure uses an inflatable saline-filled band around the proximal stomach to restrict intake and induce early satiety [33]. Resulting in lower, less durable weight loss (mean 46% EWL) [4], and less dramatic cardiometabolic effects compared with RYGB and SG [34], AGB prevalence has declined in recent years [2].
Prospective Bone Outcomes Bone outcomes after bariatric surgery have been recently reviewed [38] and are summarized here along with new data
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[12,13,26,39–42]. Despite restricting investigations to one surgical procedure or population (e.g. premenopausal women) [22,39,43–45] most studies are confounded by heterogeneous populations and lack control groups. Moreover, most studies report areal BMD (g/cm2 ), measured by DXA, as a primary outcome to assess post-bariatric surgery bone health; DXA-based areal BMD is generally accepted as a surrogate marker of bone strength and fracture risk in people of healthy weight [46]. DXA imaging may be limited, however, in obese populations [47,48], particularly as body composition changes during weight loss [12,49] (see Skeletal Imaging in Patients Undergoing Bariatric Surgery section). While technology such as quantitative computed tomography (QCT), peripheral QCT and high-resolution peripheral QCT have the ability to assess compartment-specific volumetric BMD (mg/mm3 ) and geometric variables that underpin bone mechanical strength [50], only two studies have longitudinally assessed skeletal endpoints using these imaging methods.
Areal Density Outcomes The magnitude of skeletal changes varies by skeletal region and surgical procedure (Table 1), although the greatest measured areal BMD loss overall has been reported 1 year after gastric bypass procedures at sites in the proximal femur region, including the total hip and femoral neck. DXA-measured bone loss at the femoral neck and total hip ranges from 5 to 11% 1 year after BPD [51], RYGB [12,13,23,25,26,40,51–53] and some SG [25,39] procedures, while areal BMD changes range widely from no change to 14% reductions after restrictive procedures [7,22,39,45,54]. Spine areal BMD changes are inconsistent with studies reporting 12-month reductions of 3–8% after RYGB [12,25,26,40,44,52], BPD [43] and some SG [25,39] procedures, but no change or even slight gains after restrictive [7,22,39,41,45,55], SG [41], and combined procedures [13]. Forearm bone changes are less widely reported, but some studies suggest that non-weight-bearing radius areal BMD remains stable [12,13,56] or increases slightly (+1.5%) [23,51] 12 months postoperatively. There is a paucity of available studies to establish the longer-term skeletal effects of bariatric procedures. Although some studies suggest that areal BMD loss at the hip may persist [22,53], overall rates of bone loss appear to decrease [40,51] beyond the first postoperative year.
Volumetric Density and Geometry Outcomes Studies reporting QCT derivatives of volumetric BMD and geometry variables are consistent with DXA-based areal BMD outcomes at the spine, tibia and radius sites, but not hip sites. When assessed by QCT, women who have undergone RYGB show similar 3% reductions between spine trabecular volumetric BMD and lumbar spine areal BMD 12 months postoperatively [12]. Reductions in DXA-based proximal femur areal BMD (−9%), however, contrasted with no change in QCT-based proximal femur total volumetric BMD or compartment-specific stability in cortical bone and were greater than the almost 5% trabecular volumetric BMD reductions [12]. In distal appendicular sites, imaging with
doi:10.1111/dom.12363 1205
1206 Scibora
RYGB and SG
RYGB and SG
RYGB, AGB, and SG RYGB and AGB RYGB
RYGB
RYGB RYGB
RYGB
RYGB
RYGB
RYGB
RYGB
Carrasco et al. [39]
Nogues et al. [25]
Stein et al. [13]
Riedl et al. [21]
Biagioni et al. [29]
Casagrande et al. [26] Bruno et al. [28]
Carlin et al. [24]
Mahdy et al. [30]
Fleischer et al. [23]
Riedt et al. [31]
Coates et al. [8]
Yu et al. [12]
Surgery
Study author
21 women; mean age 44 years; BMI range 40–74 kg/m2 15 (12 women : 3 men); mean age 51 years; mean BMI 48 kg/m2
22 women; mean age 47 years; mean BMI 44 kg/m2 Group 1: 20 (10 women : 10 men); mean age 33 years; mean BMI 50 kg/m2 Group 2: 19 (10 women : 9 men); mean age 47 years; mean BMI 47 kg/m2 Vitamin D (additional 50 000 IU/week): 30 women; mean age 43 years; mean BMI 50 kg/m2 Control: 30 women; mean age 43 years; mean BMI 51 kg/m2 70 (49 women : 21 men); mean age 35 years; mean BMI 48 kg/m2 23 (18 women : 5 men); age range 20–64 years; mean BMI 47 kg/m2
22 women; age range 18–40 years; BMI >35 kg/m2
22 women; mean age 45 years; mean BMI 44 kg/m2 (RYGB, n = 14; AGB, n = 6; SG, n = 2) RYGB: 30 (27 women : 3 men), mean age 43 years AGB: 10 (8 women : 2 men), mean age 44 years RYGB: 30 (26 women : 4 men); mean age 47 years; mean BMI 45 kg/m2 Control: 20 (18 women : 2 men); mean age 46 years; mean BMI 45 kg/m2
RYGB: 23 women (premenopause); mean age 37 years; mean BMI 42 kg/m2 SG: 20 women premenopause; mean age 34 years; mean BMI 37 kg/m2 15 women; mean age 48 years; mean BMI 43 kg/m2 (RYGB, n = 7; SG, n = 8)
Population
3 m (serum OC): ↑18% 6 m: ↑27% 12 m: ↑39% 3 m (serum OC): NS 6 m: ↑45% 3 m (serum OC): NS 6 m: NS; serum BSAP: NS 3 m (urinary NTx): ↑57% 6 m: ↑86% 12 m: ↑106% 3 m (serum NTx): ↑60% 6 m: ↑60%; urinary DPD: ↑203% 3 m (urinary NTx): ↑174% 9 m: ↑319%
Vitamin D (serum BSAP): 35% Control: ↑46%
Vitamin D (urinary NTx): ↑165% Control: ↑102%
Serum BSAP: NS
Total Cohort(serum BSAP): NS RYGB: NS SG: ↓16% Total cohort (serum BSAP): NS RYGB: ↑20% RYGB (serum OC): ↑183% AGB: ↑68% RYGB: 6 m (serum P1NP): ↑82%; serum OC: NS 12 m:% change not reported, but remained significantly elevated: serum OC: NS Control: NS changes 3 m (serum BSAP): NS 6 m: NS NA Group 1: 6 m: serum BSAP: ↑15% Group 2: 18 m: serum BSAP: ↑26%
Total cohort (urinary NTx): ↑123% RYGB: ↑111% SG: ↑140% Total cohort (serum CTx): ↑144% RYGB: ↑212% RYGB (serum CTx): ↑190% AGB: ↑128% RYGB: 6 m (serum CTx): ↑220% 12 m: % change not reported, but remained significantly elevated Control: NS changes 3 m (serum CTx): ↑174% 6 m: ↑285% Serum NTx: ↑133% Group 1: 6 m:serum NTx: ↑80% Group 2: 18 m:serum NTx: ↑56%
NA
RYGB (serum BSAP): NS SG: NS
Bone formation markers
NA
Bone resorption markers
Table 1. Summary table of prospective bariatric (sleeve gastrectomy, Roux-en-Y gastric bypass and adjustable gastric banding) studies reporting bone turnover markers.*
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AGB Pugnale et al. [45]
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*Bone turnover marker outcomes reflect 12-month changes from baseline unless otherwise noted. For the first time point, the turnover marker is indicated in parentheses. All reported differences significantly different from baseline (at least p < 0.05), unless noted non-significant. AGB, adjustable gastric banding. BPD-DS, biliopancreatic diversion-duodenal switch; BSAP, bone-specific alkaline phosphatase; CTx, C-telopeptide; DPD, deoxypyridinoline; m, month; NA, not available; NS, non-significant; NTx, N-telopeptide; OC, osteocalcin; PINP, procollagen type 1 N-terminal propeptide; RYGB, Roux-en-Y gastric bypass; SG, sleeve gastrectomy.
AGB Giusti et al. [22]
31 women (premenopause), mean age 36 years; mean BMI 44 kg/m2
NA
3 m (serum OC): ↑35%; BSAP: NS for all time points 6 m: ↑92% 9 m: ↑141% 12 m: ↑130% 18 m: ↑95% NA 37 women (premenopause), mean age 37 years; mean BMI 44 kg/m2
Bone formation markers
3 m (urinary NTx): ↑80% 6 m: ↑52% 9 m: ↑78% 12 m: ↑68% 18 m: ↑50% 6 m (urinary NTx): ↑40%; (serum CTx): NS 12 m: ↑61%:↑53% 18 m: ↑38%:↑82% 24 m: ↑46%:↑94% 1 m (urinary NTx): NS; (serum CTx): ↑100% 3 m: ↑35%;↑119% 6 m: ↑41%:↑113% 12 m: ↑58%:↑131% Sinha et al. [27]
75 women : 39 men (AGB, n=18; RYGB, n=50; BPD, n=5); mean age 39 years, mean BMI 48 kg/m2
Surgery
AGB, RYGB and BPD-DS
Study author
Table 1. Continued
Population
Bone resorption markers
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high-resolution peripheral QCT showed endocortical expansion at the distal radius and tibia, with significant cortical (−2%) density and load-share reductions at the tibia in women 12 months after RYGB [13]. That the most remarkable skeletal changes are observed at weight-bearing sites, including the hip (detected by DXA) and tibia (detected by high-resolution peripheral QCT), suggests a strong association with mechanical unloading (Table S1). The current literature supports bone loss after bariatric procedures within the first postoperative year, but longer-term outcomes remain unclear without sufficient data, particularly as body weight stabilizes or if weight regain occurs. Furthermore, inconsistencies with QCT outcomes raise questions regarding the accuracy of DXA in bariatric populations. As discussed later in the present review, whether this observed loss is clinically important or simply an appropriate adaptive response to change in the mechanical environment, is unclear. Several plausible mechanisms to explain these outcomes are first explored below.
Potential Mechanisms Underlying Bone Loss Numerous hypotheses are offered to explain post-bariatric surgery bone loss. Mechanical unloading, calcium and vitamin D insufficiency are frequently cited, while postoperative neurohormonal alterations also offer potential, yet unsubstantiated, preliminary hypotheses. These mechanisms are discussed below.
Mechanical (Un)loading Unloading subsequent to weight loss is a plausible mediator of bone change and correlates with the magnitude and/or rapidity of weight loss after both RYGB [13,23] and SG [54]. Changes in areal BMD in patients who have undergone bariatric surgery are similar in relative magnitude (∼−1% per month) to those observed in unloading studies after 60 days of bed rest (−4%) [57] and 6 months of space flight (−7%) [58]. Although some studies report no relationship between weight loss and bone change [26,41], there is a strong theoretical framework that helps to explain these relationships if body composition is considered [18,20,59]. Several lines of evidence show that bone density and strength is primarily adapted to lean mass, rather than fat mass [60], in children [61,62], women [63] and men [64]. Requiring more lean mass to move their higher body weight, overweight and obese individuals have greater absolute lean mass than their healthy weight counterparts, which is related to their higher bone mass and strength [63]. While failure to preserve lean mass after bariatric surgery may mediate reductions in bone mass or strength, what constitutes ‘excessive’ lean mass loss is unclear. Potentially 30 ng/ml) and postoperative daily calcium (calcium citrate 1200–2000 mg) and vitamin D (ergocalciferol up to 50 000 IU) supplementation [108,109,112], monitored for normal serum vitamin D, calcium, parathyroid hormone levels and 24-h urinary calcium excretion rates every 6 months postoperatively, is currently recommended to prevent secondary hyperparathyroidism. Along with sufficient protein intake (60–120 g daily) [109,111], changing body composition should be monitored during weight reduction, for the detection and prevention of excessive lean mass loss [96]. Few patients who have undergone bariatric surgery meet the physical activity guidelines for general health [113], so appropriate physical activity designed to maintain or increase muscle mass will facilitate bone strength, optimize weight maintenance after surgery and support overall health and well-being.
Conclusions The skeletal effects of bariatric surgery remain unclear. DXA-based studies consistently show profound bone loss at the proximal femur in the first postoperative year. Newer QCT-based outcomes contradict DXA studies, suggesting that observed bone loss at the femoral neck and hip may be an imaging artifact and that three-dimensional imaging technology may be more accurate in bariatric populations. If bone loss does occur, future studies are needed to fully understand the mechanisms of bone loss and establish if loss is clinically relevant or simply a functional adaptation to skeletal unloading. Without sufficient data regarding fracture endpoints and osteoporosis incidence, the notion that bariatric surgery exerts a clinically relevant impact on the skeleton remains unsupported – although future studies are certainly warranted to better understand long-term postoperative bone structural changes and bone strength outcomes.
Conflict of Interest L. S. solely contributed to the design, conduct/data collection, analysis and writing of this review. No conflict of interest is declared.
Acknowledgements The author would like to thank Dr Moira Petit for her expert and thoughtful review of this manuscript.
Supporting Information Additional Supporting Information may be found in the online version of this article: Table S1. Prospective bariatric regional bone densitometric and geometric outcomes, T- and Z-scores.
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