Potential Role of Pancreatic and Enteric Hormones in Regulating Bone Turnover

Abstract

ADEQUATE NUTRIENT INTAKE and normal gastrointestinal function are essential to bone health. Disorders of nutrient supply caused by either abnormal intake (e.g., anorexia nervosa, starvation) or absorption (e.g., celiac disease, inflammatory bowel disease) may lead to bone disease and an increased fracture risk. (1) The majority of studies examining the effects of nutrients on bone turnover have focused on well-established nutrients (e.g., calcium and phosphate) and homeostatic regulators (e.g., PTH and vitamin D). Three recent observations have suggested the potential involvement of alternative mechanisms regulating the interaction between nutrition and bone turnover. First, bone turnover has a marked circadian rhythm (∼100%), with higher bone resorption at night. The mechanism regulating this rhythm seems to be partially related to the cyclical intake of nutrients. (2-4) Second, there is an acute suppression of bone resorption in vivo (∼50%), which occurs within hours of the ingestion of a mixed meal, glucose, protein, or calcium. (4-7) Third, in a rodent model, providing the normal diet in multiple small fractions decreased bone resorption measured using {3H}tetracycline excretion and increased BMD compared with a matched nutrient load given once a day. (8) These studies suggest acute changes in dietary intake or the pattern of nutrient intake may have an impact on bone homeostasis. This article reviews the evidence supporting an acute nutrient-induced regulation of bone homeostasis, discusses the potential mechanisms involved, and speculates on the possible evolutionary advantage this may confer on animals that have an intermittent supply (or intake) of nutrients. The importance of calcium in maintaining mineral homeostasis is well established. Increased physiological demands result in a reversible demineralization of the skeleton. The maintenance of calcium homeostasis is apparent during acute insufficiency (overnight fast), chronic insufficiency (malnutrition, starvation, anorexia nervosa), or transient increase in demand (e.g., lactation). During these periods, the skeleton acts as a reservoir from which there is rapid mobilization of mineral and buffer. Furthermore, during periods of acute excess (postprandial) or chronic excess (obesity, treatment of anorexia nervosa), mechanisms are in place to restore the balance. Short-term regulators are required to balance acute changes in supply and demand and act to minimize deviations from the set-point. In contrast, longer-term regulators may alter the set-point, resulting in a net increase (or decrease) in bone turnover. The acute nutrient-induced changes in bone turnover may represent the physiological adaptations of the organism to a variable energy and nutrient intake. Bone remodeling is a metabolically demanding process; therefore, mechanisms may exist to ensure that during times of energy (and nutrient) excess bone remodeling is balanced to favor bone formation (in excess of bone resorption), whereas during times of energy insufficiency, bone remodeling is balanced to favor bone resorption (in excess of bone formation) to maintain calcium homeostasis. It is possible that the mechanisms regulating the acute effects of feeding (postprandial) may well be different from (or in addition to) the mechanisms that come in to play during intermediate and long-term changes in nutrient intake (obesity). A similar effect may occur in the regulation of short- and long-term fasting. Similarly, the mechanisms that regulate feeding are likely to be different from those regulating fasting. One intriguing observation is the recent identification of a nutrient responsive signaling system involving SIRT1, which may be involved in energy homeostasis, diabetes, and life span. (9) One or more of the pancreatic or enteric hormones released during a normal physiological response to nutrient ingestion may potentially integrate nutrient intake and bone turnover. Several hormones involved in the postprandial response to nutrients have been shown to regulate bone turnover at pharmacological concentrations. However, the factor(s) regulating the acute postprandial decrease in bone resorption at physiological concentrations remain elusive. Recent studies have shown that a variety of nutrients, including ingestion of a mixed meal, (5) calcium, (10-14) glucose, (4, 6) or protein, (4) result in an acute suppression of bone turnover markers (Figs. 1 and 2). One study examined the effect of feeding a mixed meal to normal subjects and measured the change in serum markers (osteocalcin {OC}, procollagen type I N-terminal propeptide {PINP}, serum bone alkaline phosphatase {sbALP}, serum C-terminal telopeptide of type I collagen {sβCTX}, and serum N-terminal telopeptide of type I collagen {sNTX}) at 1 h and urine markers (urine immunoreactive free deoxypyridinoline {uifDPD}, urine N-terminal telopeptide of type I collagen {uNTX}, and urine C-terminal telopeptide of type I collagen {uCTX}) at 2 h. (5) The magnitude of the decrease with feeding ranged from 3.8 ± 0.9% for PINP (p < 0.0001) to 17.8 ± 2.6% (p < 0.0001) for sβCTX compared with fasting controls. A time-course was not performed. There was a significant decrease in serum markers (range, 3.8-17.8%) and urine markers (range, 7.0-7.9%). (5) The only exception was sbALP, which showed no effect of feeding. However, the long half-life of sbALP (36 h)(15) may obscure an acute response to feeding. The acute effects of oral glucose, protein, and long-chain triglycerides on sβCTX and osteocalcin in healthy individuals compared to fasting controls presented as AUC0–3h (mean ± SE). ANOVA (all) and p values for the individual groups compared with fasting controls are shown: *p < 0.05, ** p < 0.01, and ***p < 0.001. Reproduced with permission of the American Society for Bone and Mineral Research from J Bone Miner Res 2003:18:2180-2189.20 Percentage change from baseline for (A) the bone turnover marker sβCTX and (B) PINP to oral glucose (G+ So) and oral glucose with intravenous octreotide (G+ S+). The horizontal arrows indicate the onset (←; time -30 minutes) and completion (→; time 240 minutes) of the octreotide or saline infusion, and the vertical arrow (↓; time 0 minutes) indicates oral ingestion of either glucose or distilled water. *p < 0.05, **p < 0.01 comparison with fasting baseline (time -45 to -30 minutes) after adjustment for multiple comparisons (n = 8). (6) Copyright 2003, The Endocrine Society.20 In response to oral glucose, there is a rapid suppression in bone resorption within minutes, with a 50% decrease in sβCTX(6, 7) and uNTX. (4, 6) The postprandial decrease in bone resorption markers is similar in magnitude to that observed with many antiresorptive agents. However, unlike the sustained effect seen with antiresorptive agents, the effect of nutrient intake on bone turnover is only transient, with a maximal effect at 2 h, followed by reversal 4–5 h postprandially. (4, 6) The glucose induced suppression in PINP was 8%(6); however, the results for OC were more variable, with one study showing an 16% decrease(6) with a similar time-course for the response to glucose to the bone resorption markers as for OC and PINP. (6) A second study did not show a significant effect of glucose on OC. (7) This may suggest that the factor(s) released in response to a nutrient load modulate bone resorption and bone formation differently or that more than one bone active factor is modulating nutrient-induced changes in bone turnover. In response to glucose, fat, or protein, the preliminary data presented in one study suggested there was no statistically significant difference in the time-course or magnitude of the postprandial effect on sβCTX, a bone resorption marker. (4) When the same data set was analyzed using a fasting control group, only the response to glucose and protein reached statistical significance for sβCTX (Fig. 1). (7) There was no significant effect on osteocalcin after fat or protein ingestion. (7) The pronounced circadian rhythm of bone turnover markers is also attenuated by fasting (Fig. 3), (2, 3) suggesting that this rhythm is mediated, at least in part, by the cyclical intake of nutrients. In circadian studies, the effect of fasting versus feeding on bone turnover has only been observed for sβCTX and uCTX but not for OC, a bone formation marker. (2, 3) There is also a marked circadian rhythm in bone turnover markers in rodents. (16) One study using CTX was not able to show an acute effect of fasting versus feeding on CTX; however, in a food fractionation study, changing the pattern of nutrient intake significantly modified bone resorption determined using urinary {3H}tetracycline excretion and resulted in a net increase in BMD. (8, 17, 18) Effect of fasting (▪) and feeding (▴) on the circadian rhythm of serum ßCTX, a bone resorption marker. (3)20 One study found that the circadian rhythm in bone resorption in vitro was abolished if the serum used was heat treated, suggesting that the factor(s) controlling the nutrient-induced changes in the circadian rhythm were heat labile. (19) In addition, the conventional regulatory mechanisms do not seem to explain the effect of diet on the circadian rhythm of bone turnover. (10, 20-22) The amplitude of the circadian rhythm for bone resorption markers is generally greater than observed for bone formation markers. During the day, feeding results in a net positive balance for bone formation, with a greater suppression in bone resorption compared with bone formation. In contrast, during the night, when energy and nutrient supply is inadequate, there is a net negative balance with bone resorption occurring in excess of bone formation, which may be required to maintain calcium homeostasis. There are multiple hormones released in the postprandial response to nutrient intake. (22-24) Many of these potential mediators have been shown to regulate bone turnover in vitro(25-28) and in vivo, (29) including insulin, glucagon, calcitonin, gastric inhibitory polypeptide (GIP), glucagon-like polypeptide 2 (GLP 2), leptin, and amylin. (7, 28, 30-34) The time-course of change and specificity of response to glucose suggest that adrenaline (Ad), noradrenaline (NA), and growth hormone (GH)(23, 35) are unlikely to mediate the acute nutrient-induced decrease in bone resorption, which is first apparent 20 minutes postprandial. (6) The postprandial increase in GH is first observed at 50 minutes and Ad at 120 minutes, and NA does not change at any time-point. (23, 35) The delayed increase in these hormones suggests that they are unlikely to mediate the acute nutrient-induced changes in bone resorption. In addition, if the morning rise in cortisol is inhibited using metyrapone, there is no effect on the bone resorption markers (DPD, uNTX, and PYD), although the effect on OC is significant. (36) In contrast, in in vitro studies, mifepristone, a glucocorticoid receptor antagonist, partially abolished the amplitude of the circadian rhythm of bone resorption present in serum. (37) Gastrin is released in response to calcium and amino acids but not glucose or fat ingestion. (38) Because a decrease in bone resorption is observed in response to each of these macronutrients, it suggests that gastrin could only have a role in mediating the postprandial decrease in bone resorption if it were acting together with another bone active factor(s). Although exogenous glucagon decreases bone resorption by 10%, (4) glucagon is unlikely to mediate the acute effects of meal ingestion on bone turnover, because there is either no change(22) or a postprandial decrease in glucagon with feeding. (23) In vitro insulin dose-dependently inhibited pit formation by up to 80%, and glucose resulted in a concentration-dependent change in osteoclast activity. (39, 40) In vivo, an intravenous infusion of insulin alone decreased bone resorption by ∼30%, (4) suggesting a role for insulin in the nutrient-induced suppression in bone turnover. However, during a euglycemic hyperinsulinemic clamp study, bone resorption did not change, suggesting that hypoglycemia rather than insulin per se caused the previously observed decrease in bone resorption. (41) Nonetheless, longer-term effects of hyperglycemic hyperinsulinemia may be mediated by indirect effects such as the stimulation of renal calcium excretion(42-45) and intestinal calcium absorption. (46) In another study, the bone turnover response to oral glucose was substantially greater than that after intravenous glucose, (4) suggesting a role for the incretin hormones (GIP and GLP 1). In addition, octreotide abolished the nutrient-induced suppression in bone turnover (Fig. 2), which suggests a potential role for the pancreatic or enteric hormones in the acute suppression of bone turnover. (6) Octreotide is a long-acting analog of somatostatin, which inhibits the basal and postprandial secretion of many pancreatic, enteric, and pituitary hormones. These include insulin, glucagon, gastrin, calcitonin, GLP 1, GLP 2, GIP, GH, and ghrelin. (22, 47-49) The effect did not seem to be mediated by changes in PTH or ionized calcium levels. (6) This raised the possibility of novel endocrine mechanisms mediating an “entero-osseous” interaction between the gastrointestinal tract and bone, which was first proposed by Bollag et al. (26) The evidence suggests that the factor(s) that regulate the acute interaction between nutrient ingestion and bone should be heat labile, (19) respond within minutes of nutrient ingestion, (4, 6) either decrease if the factor stimulates bone resorption or increase if the factor inhibits bone resorption, (4, 6) and must show a reversal in the process within 4–5 h. (4, 6) The majority of studies have focused on the effects of the pancreatic or enteric hormones on osteoblast and osteoclast differentiation in vitro or long-term effects on BMD and bone turnover markers in vivo. Pharmacological doses of GIP, GLP 2, amylin, and leptin have been shown to regulate bone turnover in vitro(26, 50, 51) and in vivo. (7, 31, 33, 34) Both in vitro and in vivo studies suggest there is an acute, reversible decrease in bone resorption in response to GLP 2. (7, 52) However, whereas the normal postprandial concentration of GLP 2 after ingestion of protein, fat, or glucose is ∼40 pM, to produce a significant decrease in the area under the curve (AUC) for bone resorption, a pharmacological dose of GLP 2 (800 μg) was required, which resulted in a peak plasma concentration of GLP 2, which was 100-fold higher (∼3500 pM) than the normal physiological postprandial levels (Fig. 4). (7) In contrast, GLP 1 receptors have not been identified on osteoblasts, (26) and an intravenous bolus of GLP 1 in humans did not result in a change in sβCTX, although this study was difficult to interpret because of the absence of an adequate control group. (7) The effect of GLP 2 injections on (A) serum GLP 2 and (B) percentage change in sβCTX levels in humans. The normal postprandial increase in GLP 2 is ∼40 pM (A, broken line). GLP injections were given subcutaneously at 100, 200, 400, and 800 μg and compared with placebo (saline). (7) Reproduced with permission of the American Society for Bone and Mineral Research from J Bone Miner Res 2003:18:2180-2189.20 One study showed that GIP receptors are present on osteoblasts and GIP increased cyclic AMP and intracellular calcium release, resulting in an increase in the synthesis of type I collagen and bALP. (26) Furthermore, GIP administration has been shown to prevent oophorectomy-induced bone loss in rats. (33) A transgenic mouse model overexpressing GIP had increased bone formation markers and increased BMD. (53) Conversely, the GIP receptor knockout model had a significant decrease in BMD. (53) Although an intravenous bolus of GIP in humans did not result in a change in sβCTX, this study was difficult to interpret because of the absence of a control group, the short infusion (2 minutes) of GIP (which is very rapidly metabolized), and the very short (45 minutes) duration of follow-up, which may have masked an effect on bone turnover. (7) Amylin is a 37 amino acid peptide that is co-secreted with insulin from the β cells in the pancreas and increases acutely after a meal. In vitro, amylin stimulates osteoblast numbers(51) and inhibits osteoclast differentiation. (27) In addition, pharmacological doses of amylin result in an anabolic effect on bone in vivo. (31) An amylin knockout model resulted in decreased BMD, (54) an effect that seemed to be mediated through an inhibition of osteoclastogenesis with no apparent effect on osteoblast differentiation or function. (54) There is also substantial evidence suggesting a role for leptin in central and peripheral regulation of bone metabolism, which may, at least in part, explain the protective effect of obesity on bone. (28) Leptin receptors have been identified on osteoblasts. (55) Although leptin may modulate bone turnover, the postprandial increase in leptin in response to nutrient intake is delayed by several hours, (56, 57) suggesting that leptin is not the primary factor mediating the very early nutrient-induced reduction in bone turnover. There is, however, evidence that leptin is a key hormone involved in the intermediate and long-term balance between energy and bone metabolism. (28) The role of PTH as a mediator of acute food-induced changes in bone turnover is unclear. PTH receptors have recently been identified on human osteoclasts. (58) Glucose decreases PTH secretion and insulin increases PTH secretion in vitro. (59, 60) PTH secretion is increased by a mixed meal, (61) decreased by glucose, (62) and in the majority of studies, decreased by insulin(41, 44, 63, 64) independently of serum calcium. (41, 44, 45, 61) We were unable to identify a difference in the AUC for PTH during fasting compared with glucose ingestion, although the time-course of response did show a small transient decrease in PTH at 20 minutes. (6) Fasting resulted in either a decrease or no change in the mean 24-h PTH level; however, it abolished the nocturnal increase in PTH, (2, 20) suggesting that PTH might explain the decreased circadian rhythm of bone resorption observed during fasting. (2, 3) When PTH release was suppressed by a continuous calcium infusion, there was no change in the circadian rhythm in bone resorption, (21) and reversal of the nocturnal increase in PTH by timed evening calcium administration only partially suppressed the nocturnal peak in bone resorption. (10) In addition, blocking the effect of PTH using neutralizing antibodies in vitro did not abolish the circadian rhythm of bone resorption present in serum. (37) Several studies have been unable to show a change in ionized calcium levels in response to glucose or insulin infusion, despite acute changes in PTH, and it is likely that this is a caused by the relatively slow efflux of calcium from bone. (65) We were unable to identify an effect of glucose ingestion compared with fasting on ionized calcium levels. (6) PTH/PTH-related peptide (PTHrP) receptors have been identified in both intestinal epithelial cells and the pancreas. (66, 67) PTHrP is most likely to have an autocrine function rather than influencing bone homeostasis through the systemic circulation. However, to our knowledge, PTHrP has not been measured in the serum of normal individuals after nutrient ingestion. Calcitonin receptors are present on osteoclasts but not on osteoblasts. Calcitonin gene-related peptide (CGRP) seems to stimulate osteoblasts and inhibit osteoclast numbers in vitro. (27, 51) Although pharmacological doses of calcitonin inhibit bone resorption, (25, 68) it is unclear whether feeding results in a postprandial increase in calcitonin secretion in either rats or humans. (25) If an increase in calcitonin does occur after food intake, (69) this is likely related to the calcium content of the meal. (25, 61, 70, 71) The calcitonin/calcitonin gene-related peptide (CT/CGRP) knockout mice had a normal basal rate of bone resorption, increased sensitivity of the osteoclast to PTH stimulation, and increased BMD, with no bone loss after ovariectomy. (72) In addition, the calcitonin receptor knockout heterozygote mouse had an increase in bone formation indices with no apparent changes in bone resorption in vivo. (54) GH and IGFs modulate bone turnover, (73) and these hormones are regulated by somatostatin and octreotide. (49, 74) During fasting, there is a marked increase in the nocturnal secretion of GH, (75, 76) which is suppressed by feeding. (75, 76) In addition, octreotide suppresses the nocturnal increase in GH but does not alter the nocturnal increase in osteocalcin. (77) Furthermore, the increase in GH in response to glucose is delayed for at least 50 minutes, (23, 35) which suggests that the short-term changes in GH are unlikely to mediate the effect of feeding on bone turnover. Although nutrient supply is an important determinant of serum IGF-1 levels, (76) acute postprandial changes are largely limited to an effect on IGF-binding protein-I. (74) During fasting, there is a marked increase in the nocturnal secretion of ghrelin, a GH secretagogue that is suppressed by feeding. (78) In addition, ghrelin regulates the proliferation and differentiation of osteoblasts(79) and interestingly, may also modulate the effect of leptin on monocyte and T-lymphocyte function. (80) Moreover, a long-acting GH secretagogue, hexarelin, prevents bone loss in the setting of androgen deficiency; however, after estrogen deficiency, efficacy of this compound seemed to be restricted to specific bone compartments in rats. (81, 82) In a ghrelin knockout model, there was no effect on bone size, BMD, or fat deposition in 8-week-old mice. (83) In children, ghrelin secretion is not suppressed in response to diet, and thus, it is possible that skeletal effects of ghrelin are masked during growth, and a bone phenotype may only become apparent during aging. (84) Ghrelin is, however, released from the gastric fundus, and because total gastrectomy failed to abolish the postprandial decrease in sβCTX, it is unlikely that ghrelin mediates the acute nutrient-induced decrease in bone resorption. (85) Physiological effects may influence bone resorption, including changes in acid-base balance, which may modulate calcium excretion. (86) Although controversial, some studies have suggested that high dietary protein may have a potentially adverse effect on the skeleton that could be mediated, at least in part, through increased urinary acid production and hence increased urinary calcium excretion. (87) However, nutrient intake in rats seems to inhibit bone resorption independently of changes in acid-base balance. (88) Surgical resection of the fundus, which is involved in acid secretion and the production of histamine, pancreastatin, and ghrelin, leads to osteopenia, suggesting a role for one or more of these factors in the pathogenesis of chronic postgastrectomy bone disease, (89) if not the acute suppression of bone resorption. Furthermore, there is little evidence to support an acute effect of fasting versus diet on the reproductive system, at least in women, (90) although in men, decreases in mean leuteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone levels have been observed. (91) Finally, it is worth considering the possibility of a response mediated by the enteric and central nervous system, similar to that proposed for leptin. (28) Altered metabolism of bone markers may potentially occur because of postprandial changes in blood flow or enzyme induction. (92, 93) However, it is unlikely that changes in the metabolism of markers have a significant effect, because the direction of the bone marker response in the majority of studies is the same, (2-6) despite their different routes of clearance. (94-96) Importantly uDPD, which is believed to represent an end product of collagen breakdown, showed a similar time-course of response as found with other bone resorption markers (uCTX, uNTX) measured in the urine. In addition, the magnitude of the decrease in DPD in response to nutrients was similar to both urinary and serum bone resorption markers. (5-7) A number of studies have shown an acute change in urinary {3H}tetracycline excretion in response to dietary modifications. (17, 8) This is important because urinary {3H}tetracycline excretion measures bone remodeling using a different approach and yet provides results that are concordant with the nutrient-induced changes observed using bone resorption markers. It will be valuable to further verify the effect of nutrient-induced changes on bone turnover using bone histomorphometry; however, this approach will require long-term feeding studies. It is possible that some of the differences between the fasting and postprandial measurements may be caused by analytical factors such as postprandial hypertriglyceridemia, affecting analytical recovery. However, dietary status had only a minimal effect on the analytical variability of measurements. (5) In addition, other dietary factors such as gelatin have been shown to increase excretion of hydroxyproline, which is one of the early less specific bone resorption markers, but not for urinary PYD. (97) A large number of dietary components have been found to be bone active, including some vegetables, salads, and herbs. (88, 98-100) These seem, at least in rats, to relate to a bone-active compound rather then an effect of the base excess buffering metabolic acid. (88) In addition, the essential oils and their monoterpene components can inhibit bone resorption in rats. Furthermore, the monoterpene borneol can acutely and reversibly inhibit bone resorption in rats both in vivo and in vitro. (100) The oxysterols, which are oxygenated derivatives of cholesterol derived from the diet and endogenous sources, have been shown to inhibit adipocyte differentiation and stimulate osteoblast differentiation from mesenchymal stem cells. (101) Finally, the flavanoid, quercetin, which has antioxidant properties, can inhibit osteoclast differentiation in vitro through the inhibition of NF-κB and activator protein 1 (AP-1). (102) Epidemiological studies have traditionally focused on the effect of calcium intake on bone health, and there is convincing evidence that calcium supplements prevent osteoporosis and probably fractures. (103) There is also increasing evidence that intake of fruit and vegetables may enhance BMD and suppress bone turnover in adults(104, 105) and increase BMC in children. (106) The impact of dietary protein and the source of dietary protein on bone health is widely debated. (87) It is also clear that decreased nutritional intake in the elderly or anorexia nervosa in the young is detrimental to bone health. It is, however, currently unknown whether the composition, timing, and size of the meal is important or whether there is a synergistic effect of different bone active nutrients. In addition, disease models of malnutrition (e.g., anorexia nervosa) or malabsorption (e.g., gastrectomy, celiac disease, inflammatory bowel disease, and short bowel syndrome) result in osteoporosis and osteomalacia. (34, 89, 107) It is particularly interesting that GLP 2 infusion can reverse the bone phenotype observed in patients with short bowel syndrome. (34) GLP 2 causes mucosal hypertrophy; therefore, this effect may, at least in part, relate to a relative increase in nutrient absorption rather than a direct effect on bone turnover. (108) These observations may well be relevant to the clinical management of secondary causes of osteoporosis related to inadequate nutrient intake, malabsorption, and chronic inflammatory diseases. Prolonged starvation in mice and humans suppresses bone turnover and decreases BMD. (28, 109) Low body weight or a decrease in weight are associated with an increased risk of osteoporosis, bone loss, and fracture. (110, 111) The mechanism for this association is unknown but may include genetic factors, mechanical loading, or effects of estrogen and leptin. (28, 112-114) The observation that obese subjects are frequently “grazers” with a short interval between nutrient ingestion suggests an important alternative hypothesis. The increased frequency in dietary intake may result in a more prolonged suppression in bone turnover, resulting in an increase in BMD in obese subjects. Certainly, one study in rats has showed that an identical diet given in fractions results in a suppression of bone resorption and a net gain in bone mass. (8, 17) This suggests that frequent small meals may benefit the skeleton. Conversely, the complete absence of enteral feeding, as in total parenteral nutrition, is associated with significant skeletal deficits. (115, 116) Whereas this is likely caused by multiple factors, certainly loss of effects of enteric hormones on bone is a possibility that warrants further study. It is clear that the traditional nutrients and classical regulators of bone metabolism are no longer adequate to explain all the observed interactions between diet and bone health (or disease). The evidence supports a role for the pancreatic or enteric hormones in both the acute and chronic regulation of bone metabolism (Table 1). Despite this, the physiological regulator(s) involved in the acute nutrient-induced suppression of bone turnover remain elusive. There are a substantial number of bone-active peptides that are acutely responsive to nutrients, and current evidence suggests that these may represent a highly complex, integrated network of physiological regulators acting on bone metabolism. The model in Fig. 5 summarizes the information currently available, showing a stimulatory, inhibitory, or potential effect of the pancreatic and enteric hormones on bone metabolism. Potential role of pancreatic and enteric hormones in osteoclast and osteoblast differentiation and function. The figure summarizes the stimulatory (+), inhibitory (−), and potential (?) effects of the pancreatic and enteric hormones on bone metabolism.20 Preliminary evidence suggests that the effects of pancreatic or enteric hormones may be through direct modulation of osteoblast and osteoclast function. In addition, studies support effects on maturation and differentiation of osteoblasts and osteoclasts. These actions may include regulation of monocyte and lymphocyte function, with indirect effects on osteoblasts and osteoclasts. Several transgenic and knock models for the gut and pancreatic hormones or their receptors showed a bone phenotype in vivo in response to a number of stressors (e.g., oophorectomy), suggesting a functional role for the hormone (or receptor) in bone metabolism. However, feeding studies have not yet been performed in these transgenic and knock models, and until these data are available, it will not be possible to implicate these hormones in the regulation of nutrient-induced changes in bone turnover. Furthermore, the factors regulating the integration of energy and bone metabolism are clearly multifactorial and are likely to exhibit significant redundancy. It is possible, therefore, that double knockout mouse models as well as complex human studies may be required to elucidate the full impact of the pancreatic or enteric hormones on bone physiology. What is clear is that we have a significant amount to learn about the impact of nutrients on bone health and the factors regulating these responses.