Distinguished University Professor of Medicine, Department of Medicine, Medical University of South Carolina Charleston, South Carolina 29425
Address all correspondence and requests for reprints to: Norman H. Bell, M.D., Distinguished University Professor of Medicine, Department of Medicine, Medical University of South Carolina, Strom Thurmond Research Building, 114 Doughty Street, Charleston, South Carolina 29425.
The incidence of obesity worldwide has increased markedly in the last decade to decade and a half, with estimates of increases of 50% in the United States and 60% in Europe (1, 2). Studies show that weight loss produced by diet alone is not sustained and that 75% of dieters regain most of the lost weight within 1 yr and 90% within 2 yr (3). Morbid obesity is associated with comorbid conditions and shortened life expectancy (4).
Because of limited success with medical management, surgical treatment of morbid obesity has been used increasingly, especially with the development of laparoscopic surgery. The procedures include laparoscopic vertical-banded gastroplasty, gastric binding, and Roux-Y gastric bypass (5, 6, 7, 8). All are associated with low surgical mortality and result in markedly decreased food intake. Weight loss is significant and sustained. However, there is growing appreciation that these procedures may be associated with the development of bone disease either with or without abnormal vitamin D metabolism.
Several facts must be kept in mind with regard to obesity, vitamin D metabolism, and bone. First, body weight is a major determinant of bone mass, and bone mass is increased in obese subjects, particularly at weight-bearing sites (9, 10). This is attributed to increases in mechanical loading (11). Bones of obese individuals are larger and therefore less likely to fracture (12). Second, compared with lean subjects, obese individuals have low-circulating serum vitamin D and 25-hydroxyvitamin D [25(OH)D] sometimes associated with secondary hyperparathyroidism, presumably because the vitamin is fat soluble and stored in fat (13, 14). Osteomalacia and secondary hyperparathyroidism may occasionally occur even in obese individuals who have not undergone any kind of gastric surgery (15). Third, there is a long-standing recognition of a relationship between gastrointestinal surgery and the development of abnormal vitamin D metabolism and bone disease, osteomalacia, osteitis fibrosa cystica, and osteoporosis (5, 6, 7, 8, 16). Finally, morbid obesity is known to diminish the accuracy of measurement of bone mineral density (BMD) (17).
In the current issue of JCEM, Coates et al. (18) describe the development of marked bone resorption and loss of bone mass in patients who had undergone Roux-Y gastric bypass for morbid obesity. Indeed, by 9 months patients had lost 37 pounds; urinary N-telepeptide of type I collagen had increased by 319%, and BMD had decreased by 7.8% at the total hip, 9.3% at the trochanter, and 1.6% at the total body. Serum immunoreactive PTH and serum 25(OH)D did not change. Patients are to be followed to determine whether bone loss is transient or persistent and requires treatment and prevention. Somewhat similar results were found in two previous studies. Premenopausal women who were either morbidly obese [body mass index (BMI) 40 kg/m2] or severely obese (BMI > 35 kg/m2) and had undergone laparoscopic gastric banding were investigated (6). By 12 months, patients had lost 50 pounds, serum urinary N-telepeptide of type I collagen had doubled, and BMD had decreased at the femoral neck by 3.0% and at the total body by 2.1%. Serum immunoreactive PTH and serum 25(OH)D did not change. In a second study, 14 premenopausal women and two men with morbid obesity who had undergone vertical banded gastroplasty by 12 months had lost weight, had increased urinary total urinary free deoxypyridinoline cross-links, and had lost BMD at the hip (7). Serum immunoreactive PTH did not change. Serum estrogen declined in the women, but their menstrual periods remained regular, and there were no menopausal symptoms. It should be noted that bone loss also occurs in patients who lose weight in response to medical treatment (18).
What could be the mechanism for the increased bone resorption produced by gastric surgery-induced weight loss? It is established that osteoclastic resorption of bone by calcium-regulating and other hormones including estrogen are modulated by cell-to-cell contact between the receptor activator of nuclear factor B ligand (RANKL), a member of the TNF ligand family expressed by osteoblasts, stromal cells, T and B lymphocytes, and RANK, a receptor on the cell surface of osteoclasts and osteoclast precursors. The interaction of RANKL with RANK modulates osteoclastogenesis by enhancing osteoclast differentiation, activation, lifespan, and function (19). Osteoclastogenesis is further regulated by osteoprotegerin (OPG), a soluble decoy receptor produced by osteoblasts, marrow stromal cells, and other cells that interferes with interaction between RANKL and RANK (19). Although estrogen deficiency, vitamin D deficiency, and secondary hyperparathyroidism appear to be ruled out, changes in other systemic hormones such as thyroid hormone and PTH-related protein have not been ruled out.
Osteoclastic bone resorption also is modulated by cytokines, some of which use the RANKL/RANK/OPG system and some of which do not. These include IL-1, IL-6, TNF, IL-11, and prostaglandin E2 (PGE2) (19, 20). Cytokines are produced by fat cells that are in intimate contact with bone cells in bone marrow and modulate fat metabolism. TNF
in particular is a key regulator of fat metabolism (21). It inhibits adipogenesis, the formation of adipocytes from preadipocytes; increases apoptosis of preadipocytes and adipocytes; and stimulates lipolysis (22). TNF
stimulates osteoclastic bone resorption that is not inhibited by OPG and thus is independent of the RANKL/RANK/OPG system (21). Circulating TNF
and TNF
receptor-2 are significantly higher in obese than in nonobese individuals (22). The effects of gastric surgery and weight loss on circulating TNF
or its function in the marrow environment on bone resorption are not known.
Adiponectin is an adipose tissue regulatory protein that is produced by fat cells and inhibits fat cell synthesis, a biochemical event mediated by PGE2 (23). Serum adiponectin is suppressed in obese subjects (8). In men and women with a wide range of age and BMI, there were highly significant inverse correlations between serum adiponectin and BMD of the total body, thoracic and lumbar spine, total hip, and ultra distal radius (24). Furthermore, serum adiponectin gradually increased in obese subjects during the 12 months after gastric bypass surgery (8). If adiponectin negatively modulates bone mass as has been proposed (24), it might act through PGE2 to enhance bone resorption. Increased circulating adiponectin could then account for increased bone resorption and bone loss that follows gastric surgery and weight loss in morbidly obese subjects.
In summary, gastric surgery and weight loss in morbidly obese individuals result in increased bone resorption and bone loss. Recent studies show that circulating adiponectin varies inversely with bone mass and body weight. It is evident that there is still much to be learned about the pathophysiology of bone loss after surgically induced weight loss and the possible influence of fat cell-derived cytokines and hormones on bone metabolism.
Footnotes
Abbreviations: BMD, Bone mineral density; BMI, body mass index; 25(OH)D, 25-hydroxyvitamin D; OPG, osteoprotegerin; PGE2, prostaglandin E2; RANK, receptor activator of nuclear factor B; RANKL, RANK ligand.
Received December 11, 2003.
Accepted December 11, 2003.
References
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