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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 10 4867-4873
Copyright © 2003 by The Endocrine Society

Octreotide Abolishes the Acute Decrease in Bone Turnover in Response to Oral Glucose

Jackie A. Clowes, Heather C. Allen, Donna M. Prentis, Richard Eastell and Aubrey Blumsohn

Bone Metabolism Group, Clinical Sciences (North), University of Sheffield, Sheffield, United Kingdom S5 7AU

Address all correspondence and requests for reprints to: Dr. Jackie A. Clowes, Division of Clinical Sciences (North), University of Sheffield, Northern General Hospital, Herries Road, Sheffield, United Kingdom S5 7AU. E-mail: j.a.clowes{at}sheffield.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Feeding or oral intake of glucose results in an acute suppression of bone turnover. This does not appear to be mediated by insulin. Several gastrointestinal hormones modulate bone turnover in vitro and may mediate this response. We examined whether inhibiting the production of gastrointestinal hormones using octreotide could block glucose-mediated suppression of bone turnover. Fifteen subjects were each studied on four occasions in a randomized, single-blind, crossover study after receiving 1) oral placebo, iv saline; 2) oral glucose, iv saline; 3) oral glucose, iv octreotide; or 4) iv octreotide alone. We measured serum C-terminal telopeptide of type I collagen, urinary N-terminal telopeptide of type I collagen, osteocalcin, procollagen type I N-terminal propeptide, PTH, insulin, ionized calcium, and glucose over 4 h. All bone turnover markers decreased significantly after oral glucose (P < 0.001). At 120 min serum C-terminal telopeptide decreased by 45 ± 2%, urinary N-terminal telopeptide by 31 ± 7%, osteocalcin by 16 ± 1%, and procollagen type I N-terminal propeptide by 8 ± 1%. There was no significant decrease in bone turnover in response to oral glucose during octreotide infusion. Octreotide alone resulted in a significant increase in all bone turnover markers (P < 0.05) and PTH (P < 0.01). We conclude that octreotide completely abolishes the bone turnover response to glucose intake and increases PTH secretion. The apparent bone turnover response to feeding is probably mediated by an octreotide-inhibitable endocrine factor.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
ORAL NUTRIENT INTAKE results in acute suppression of bone turnover (1, 2, 3). This effect is observed with a mixed meal (3), calcium (1), glucose, fat, or protein (2) and results in an acute suppression of bone resorption (~50%) within hours of nutrient ingestion. In addition, fasting attenuates the pronounced circadian rhythm of bone turnover. This suggests that the circadian rhythm is mediated at least in part by cyclical nutrient intake (4, 5). The mechanism of diet-induced suppression of bone resorption is unknown. Conventional regulatory mechanisms do not appear to explain the effect of diet on the circadian rhythm (1, 4, 6, 7).

Potential mechanisms regulating the acute interaction between nutrients and bone metabolism include the postprandial rise in insulin, a direct effect of glucose on bone metabolism, or other postprandial endocrine responses. We have shown that insulin is unlikely to mediate this effect, because hyperinsulinemia induced during a euglycemic clamp did not influence bone turnover (8). Oral glucose results in a substantially greater bone turnover response than iv glucose (2), suggesting that enteric hormones may play a role in mediating this response. Several hormones involved in the postprandial response to nutrients (9, 10, 11) have been shown to modulate bone turnover (12, 13, 14, 15, 16, 17), including amylin, leptin, glucose-dependent insulinotropic peptide (GIP), and glucagon-like polypeptide 1 and 2 (GLP1 and GLP2).

Octreotide, a long-acting analog of somatostatin, inhibits the postprandial and basal secretion of many gastrointestinal and pancreatic peptides, including insulin, glucagon, gastrin, calcitonin, GIP, GLP1, GLP2, and pancreatic polypeptide (10). The aims of the study were to determine 1) the acute effect of oral glucose on bone turnover and PTH, 2) the effect of octreotide on the response to oral glucose, and 3) the effect of octreotide alone.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Fifteen healthy subjects (nine men and six women; mean age, 27 yr; range, 21–37 yr) were recruited from volunteers, aged 20–40 yr, who responded to local advertisements. Subjects were excluded if they had any disease known to affect bone metabolism, had had a fracture in the previous 12 months, or were taking any medications known to affect bone metabolism, apart from oral contraceptive tablets. The mean body mass index of participants was 23 ± 0.6 kg/m2 (range, 20–27 kg/m2). The study was performed in accordance with current guidelines on good clinical practice and the Declaration of Helsinki. All subjects gave written informed consent, and the North Sheffield research ethics committee approved the study.

Protocol

Each subject was studied in a randomized, single-blind, crossover study on four occasions between 5–21 d apart. On the study day participants received 1) placebo distilled water and iv saline (G°S°), 2) oral glucose and iv saline (G+S°), 3) oral glucose and iv octreotide (G+S+), or 4) oral water and iv octreotide (G°S+). Studies were performed in a randomized order, and subjects were blinded to the study sequence.

Subjects were asked to maintain a normal sleep pattern and to abstain from heavy alcohol use, smoking, or exercise during the 24 h before each study day. On each study day subjects attended the investigation unit at 0830 h after an overnight fast beginning at midnight. Subjects were placed in a semirecumbent position, and a cannula was inserted in the antecubital fossa for the infusion of saline or octreotide. A second cannula in the contralateral arm was used for venous sampling. Cannulas were kept patent using 0.9% saline.

A continuous infusion of 0.9% saline alone (200 ml/h) alone or saline with octreotide (50 µg/h; Sandostatin, Novartis Pharmaceuticals, East Hanover, NJ) was commenced at 0900 h (-30 min) and continued for 270 min. Thirty minutes after the onset of the iv infusion at 0930 h (0 min) subjects were given either 75 g oral glucose (anhydrous glucose; BMS Laboratories Ltd., Beverley, UK) in 250 ml distilled water or 250 ml distilled water alone (placebo). The oral glucose load or placebo was ingested over a maximum of 5 min. Blood samples were collected at -45, -30, 0, 20, 40, 60, 90, 120, 180, and 240 min. Three timed urine samples were collected (-90 to -30 min, -30 to 90 min, and 90 to 240 min). Blood samples were allowed to clot for 30 min and were then centrifuged (10 min at 3000 x g). All samples were snap-frozen in dry ice and then stored at -80 C until assayed.

Biochemical methods

Bone resorption was assessed using serum ß C-terminal cross-linked telopeptide of type I collagen (sßCTX; ß-CrossLaps/serum, Roche Elecsys, Hoffmann-La Roche, Penzberg, Germany) and urinary N-terminal cross-linked telopeptide of type I collagen (uNTX; Vitros ECi, Ortho-Clinical Diagnostics; Rochester, NY). Bone formation was assessed using serum procollagen type I N-terminal propeptide (PINP; Roche Elecsys) and osteocalcin (OC; Roche Elecsys). The analytical coefficients of variation for sßCTX, PINP, and OC were less than 5%, less than 1%, and less than 2%, respectively, over the relevant analytical range. Urinary measurements were expressed as a ratio to creatinine excretion (dry slide method; Ortho-Clinical Diagnostics, Rochester, NY).

Glucose was measured using a glucose oxidase method (Precision Q.I.D., Medisense, Abbott Laboratories, Chicago, IL). PTH was measured using an immunochemiluminometric assay (Roche Elecsys) that measures intact PTH and the 7–84 fragment and has an analytical coefficient of variation of less than 4%. Ionized calcium corrected for pH was measured using an ion-selective electrode (Diagnostic Rapid Lab test 865, Chiron, Halstead, UK) within 2 min of sampling. Insulin was measured using an immunochemiluminometric assay (Roche Elecsys). All biochemical measurements were performed double-blind.

Statistical analysis

Data were log-transformed before analysis. Response or within-group changes over time for each variable were tested using repeated measures ANOVA. The Huynh-Feldt correction was applied when the sphericity assumption was not met (P < 0.05). If the result showed an overall significant effect of time, then each time point was compared with the mean baseline measurement using the Bonferroni method to adjust for multiple comparisons (n = 8).

The trapezoidal rule was used to calculate the area under the curve (AUC) for each protocol and analyte. AUC was compared using two-way ANOVA, and post hoc comparisons were performed using a Scheffé test. Statistical analyses were performed using Statgraphics Plus version 4 (Manugistics, Inc., Rockville, MD) and the Statistical Package for Social Sciences version 10.0 (SPSS, Inc., Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
There was no difference at baseline (-45 and -30 min) for any analyte among the 4 study d (Table 1Go; P > 0.05, by two-way ANOVA).


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  		TABLE 1. Baseline characteristics (mean ± SEM) of subjects in the four protocols

 
The effects of glucose ingestion (G+) with or without octreotide (S+ or S°) on plasma glucose and insulin are shown in Fig. 1Go (left panels). The effects of placebo ingestion (G°) with or without octreotide (S+ or S°) on plasma glucose and insulin are shown in Fig. 1Go (right panels). During fasting (G°S°), plasma glucose remained stable at approximately 5.2 mmol/liter (Fig. 1BGo; P > 0.05). Oral glucose (G+S°) induced a rise in plasma glucose of 9 mmol/liter at 60 min and a 10-fold increase in plasma insulin (Fig. 1Go, A and C; repeated measures ANOVA effect of time, P < 0.01). Infusion of octreotide (G+S+) completely inhibited the insulin response to glucose ingestion (Fig. 1CGo) and resulted in a delayed and exaggerated rise in plasma glucose (Fig. 1AGo). Insulin was suppressed below baseline (5 pmol/liter) for 1 h during the G+S+ protocol (Fig. 1CGo) and throughout the G°S+ protocol (Fig. 1DGo). The AUCs for the four protocols were significantly different for glucose and insulin (two-way ANOVA AUC, all P < 0.0001).



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  		FIG. 1. Left panels, Effects of glucose ingestion (G+) with or without octreotide (S+ or S°) on plasma glucose and insulin. Right panels, Effects of placebo ingestion (G°) with or without octreotide (S+ or S°) on plasma glucose and insulin. *, P < 0.05; **, P < 0.01 repeated measures ANOVA comparison with fasting baseline after adjustment for multiple comparisons (n = 8).

 
The effects of glucose ingestion (G+) with or without octreotide (S+ or S°) on markers of bone turnover are shown in Fig. 2Go (left panels). The effects of placebo ingestion (G°) with or without octreotide (S+ or S°) on markers of bone turnover are shown in Fig. 2Go (right panels). There was a small, but significant, increase in PINP and sßCTX and a small, but significant, decrease in OC during the fasting protocol, G°S° (by repeated measures ANOVA, all P < 0.05), but no change in uNTX (Fig. 2Go, right panels). After oral glucose (Fig. 2Go, left panels; G+S°) there was a marked decrease in all bone turnover markers (P < 0.001). The maximum postprandial suppression in serum markers occurred between 60 and 120 min. At 60 min PINP had decreased by 8 ± 1%, and at 120 min OC had decreased by 16 ± 1% and sßCTX by 45 ± 2%. The maximum postprandial suppression in uNTX occurred between 120 and 240 min, with a decrease of 45 ± 6%. The change in bone turnover in response to glucose was completely abolished by octreotide (Fig. 2Go, left panels; G+S+) for all markers (P > 0.05) except OC (repeated measures ANOVA effect of time, P = 0.001). Octreotide alone (Fig. 2Go, right panels; G°S+) had no effect on OC and uNTX (repeated measures ANOVA effect of time, P > 0.05), but resulted in increases in sßCTX and PINP (P < 0.001).



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  		FIG. 2. Left panels, Effects of glucose ingestion (G+) with or without octreotide (S+ or S°) on markers of bone turnover. Right panels, Effects of placebo ingestion (G°) with or without octreotide (S+ or S°) on markers of bone turnover. In response to glucose, the maximum postprandiol suppression was 8% ± 1 for PINP, 16% ± 1 for OC, 45% ± 2 for sßCTX, and 45% ± 6 for uNTX (all P< 0.0001). See legend to Fig. 1Go for details.

 
Comparison between protocols was performed by analysis of the AUC and is shown in Fig. 3Go (by two-way ANOVA AUC, all P < 0.0001; except uNTX/creatinine, P = 0.05). There was a large decrease in bone turnover after glucose (G+S°) compared with placebo (G°S°) for all bone turnover markers. The effect of glucose intake with octreotide infusion (G+S+) did not, however, differ from placebo (G°S°) for any marker. Octreotide alone (G°S+) increased bone turnover relative to placebo (G°S°) for all markers except uNTX.



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  		FIG. 3. The AUC for the change in bone turnover markers from baseline was compared between protocols by two-way ANOVA. Barsthat do not contain the same letter are significantly different (post hocScheffé test).

 
The percentage changes in PTH and ionized calcium are shown in Fig. 4Go, and a comparison of protocols for these analytes by AUC is shown in Fig. 5Go. Serum ionized calcium decreased slightly (~0.05 mmol/liter) in all four protocols, but there was no significant difference between protocols (Fig. 5Go; two-way ANOVA of AUC, P > 0.05). Although there was no difference in ionized calcium between protocols, the change in PTH differed significantly (Fig. 5Go; two-way ANOVA of AUC, P < 0.001). There was a small increase in PTH with fasting (G°S°) and after glucose ingestion (G+S°), which were not significantly different (Fig. 5Go). A small transient decrease in PTH was observed at 20 min after glucose ingestion (Fig. 4CGo; G+S°). Octreotide infusion was associated with an exaggerated increase in PTH after the ingestion of oral placebo (Fig. 4DGo, G°S+) or glucose (Fig. 4CGo, G+S+). In addition, there was a transient suppression in PTH after glucose ingestion (G+S+). There was, however, no significant difference in the AUC for PTH between octreotide with or without glucose (Fig. 5Go).



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  		FIG. 4. Percentage changes in ionized calcium (A and B) and PTH (C and D). In response to glucose, the maximum postprandial change was 4 ± 0.5% for ionized calcium and 42 ± 9% for PTH (all (P< 0.0001). See legend to Fig. 1Go for details.

 


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  		FIG. 5. The AUC for the change from baseline in ionized calcium (left) and PTH (right) were compared between protocols by two-way ANOVA (P > 0.0001). Bars that do not contain the same letter are significantly different (post hoc Scheffé test; P < 0.05).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this study oral glucose resulted in a marked suppression of bone resorption markers (sßCTX and uNTX) and a moderate suppression of bone formation markers (PINP and OC). The time course in response to glucose was similar for sßCTX and PINP, with a maximum postprandial suppression at 60–120 min and a delayed response observed for uNTX. Osteocalcin displayed a sustained decrease in response to glucose. Fasting abolished the morning decrease in sßCTX, uNTX, and PINP, but only partially abolished the morning decrease in OC. This suggests that the circadian rhythm of bone markers is mediated at least in part by cyclical nutrient intake (4, 5).

The small difference in the magnitude and time course of the response observed for different bone markers during fasting, after glucose or octreotide is not unexpected. Bone markers reflect different aspects of the remodeling process, with bone turnover influenced by several integrated control mechanisms. A similar difference in magnitude and time course of response has been observed in many acute (e.g.circadian studies) and chronic (e.g.response to antiresorptive agents) clinical models. The delayed response for urine markers compared to serum markers can be explained by the effects of renal clearance and the calculation of an integrated result from timed urine samples. Although qualitatively similar, the small difference in response observed for OC may relate to the effect of cortisol, which increases after cannula insertion. Several previous studies have shown that OC, but not bone resorption markers, are suppressed by cortisol (18, 19).

In contrst to previous circadian study (4, 5), we observed a small increase in CTX and PINP during fasting. Both studies were conducted while subjects were fasting, however we gave a 1.25-liter iv fluid load over 5 h compared to a small oral fluid load in the circadian study. The potential impact of this is unknown.

There are a number of possible mechanisms controlling the acute nutrient-induced suppression in bone resorption, including 1) a direct effect of enteroendocrine hormones on osteoclast and osteoblast function; 2) an indirect effect of enteroendocrine hormones on calcium homeostatic mechanisms, e.g. PTH; and 3) changes in the metabolism of bone turnover markers.

Potential candidates include insulin and glucose, which may modulate bone turnover directly (20, 21). However in vivo hyperinsulinemia did not result in an acute decrease in bone turnover during a euglycemic clamp (8). The time course of change and specificity of response to glucose suggests that noradrenaline, adrenaline, cortisol, and GH (9, 22) are unlikely to mediate the postprandial suppression of bone turnover.

Pharmacological doses of calcitonin inhibit bone resorption (12). However, a postprandial increase in calcitonin probably only occurs in food containing calcium (12). Although leptin may modulate bone turnover, the postprandial response to nutrient intake is delayed by several hours (16, 23). Changes in acid-base balance associated with fasting and feeding may modulate calcium excretion (24), but nutrient intake in rats appears to inhibit bone resorption independently of changes in acid-base balance (25).

There is a postprandial increase in amylin, GLP1, GLP2, and GIP. In addition, the observation that oral glucose resulted in a greater suppression of bone resorption compared with iv glucose (2) suggests a possible role for the incretin hormones in the postprandial suppression of bone turnover. Functional receptors for hormones involved in glucose homeostasis (e.g. amylin and GIP) have been identified on osteoclasts and osteoblasts. In addition, several enteroendocrine hormones (e.g. amylin, GLP1, GLP2, and GIP) regulate bone turnover in vitro (13, 14, 15) and at pharmacological doses in vivo (17, 26, 27).

GH and IGF modulate bone turnover (28) and are modified by somatostatin and octreotide (10, 29). However, although fasting suppressed the nocturnal increase in bone resorption (4, 5), fasting exaggerated the nocturnal increase in GH secretion (30). In addition, octreotide does not alter the nocturnal increase in OC (31). Therefore, short-term changes in GH are unlikely to mediate the acute effect of feeding on bone turnover. Although nutrient supply is an important determinant of serum IGF-I (30), acute postprandial changes are largely limited to an effect on IGF-binding protein-1 (29).

There are a number of possible mechanisms controlling the reversal of nutrient-induced suppression in bone resorption by octreotide, including 1) inhibition of enteroendocrine hormones; 2) a direct stimulatory effect of octreotide on osteoclast and osteoblast function; 3) changes in blood flow and, hence, metabolism of bone markers; and 4) an indirect effect on calcium homeostatic mechanisms, e.g. PTH.

There is a postprandial increase in many enteroendocrine hormones that is abolished by octreotide (10, 11). Somatostain receptors have only been identified on the metaphyses of long bones of neontal rats (32, 33). This suggests that octreotide does not have a direct effect on bone cells in this context. There is a postprandial increase in blood flow in the splanchnic artery that is inhibited by octreotide and a decrease in renal blood flow (34, 35). Bone markers are cleared by different routes, e.g. PINP primarily by the liver, OC primarily by the kidney, and CTX and NTX primarily by glomerular filtration (37, 38, 39). We observed a concordant response to octreotide and glucose. This suggests, indirectly, that altered clearance is not the mechanism driving the acute nutrient-induced suppression in bone resorption.

In vivo PTH secretion is increased by a mixed meal (41), decreased by glucose (42), and, in the majority of studies, decreased by insulin (8, 43) independently of calcium (8, 41, 43). We were unable to demonstrate a significant difference in the PTH response to glucose compared with fasting, although there was a transient decrease in PTH immediately after glucose ingestion. The role of PTH as a mediator of acute food-induced changes in bone turnover is uncertain. Continuous fasting decreases serum PTH and abolishes the nocturnal increase in PTH (4, 6), suggesting that PTH might explain the decreased circadian rhythm of bone resorption observed during fasting (4, 5). However, reversal of the nocturnal increase in PTH by timed evening calcium administration only partially suppresses the nocturnal peak in bone resorption (1). Furthermore, continuous suppression of PTH using a calcium infusion does not abolish the circadian rhythm of bone turnover (7). We were unable to demonstrate any change in ionized calcium among the four study protocols despite acute perturbations in PTH. This is not unexpected, because resorption-mediated calcium efflux from bone is approximately 0.4 mmol/h (40). Therefore, a 2% decrease in serum calcium is the maximum expected over 2 h.

We found that octreotide alone increased serum PTH. The mechanism for this is uncertain. Somatostatin receptors have been identified in parathyroid tissue (44). In acromegaly there is an increase in PTH secretion in response to octreotide (45); however, this has not been observed in normal subjects (46, 47). In this study bone resorption did not decrease after the ingestion of glucose with octreotide infusion, although the increase in PTH was similar to that observed after octreotide alone.

The observations in this study raise the possibility of an interaction between nutrient intake and bone turnover, which may be mediated through the enteroendocrine hormones. The potential biological significance of these observations is supported by several studies (13, 14, 15, 17, 26, 27). For example, functional receptors for hormones involved in glucose homeostasis have been identified on osteoclasts and osteoblasts. In addition, several enteroendocrine hormones modulate osteoclast and osteoblast function both in vitro and at pharmacological doses in vivo. Furthermore, a study in rats has demonstrated that an identical diet given in fractions results in a net gain in bone mineral density and a net decrease in bone resorption (48).

In conclusion, we have shown that oral glucose intake is associated with an acute suppression of bone turnover, which is completely reversed by octreotide. These effects are unlikely to be explained by the observed changes in PTH or ionized calcium. Octreotide may either inhibit a factor that stimulates bone turnover or stimulate a factor that inhibits bone turnover. The mechanism(s) mediating these effects remains unclear. However, our observations have raised the possibility of a novel endocrine mechanism(s) mediating an entero-osseous interaction between the gastrointestinal tract and bone; this requires further investigation.


   Acknowledgments
 
We thank the volunteers for generously participating in this study; Alison Eagleton and Kim Naylor for assisting with biochemical analysis; Roche Diagnostics for provision of biochemical reagents for the measurement of sßCTX, PINP, OC, and PTH; and Novartis Pharmaceuticals, UK for providing the octreotide.


   Footnotes
 
This work was supported by Roche Diagnostics GmbH (Mannheim, Germany), which supplied reagents for automated analysis of sßCTX, OC, PINP, and PTH, and a fellowship from the National Health Service Executive (to J.A.C.). Presented at the American Society for Bone and Mineral Research, San Antonio, TX, September 2002.

Abbreviations: AUC, Area under the curve; GIP, glucose-dependent insulinotropic peptide; GLP, glucagon-like polypeptide; G+S+, oral glucose and iv octreotide; G+S°, oral glucose and iv saline; G°S+, oral water and iv octreotide; G°S°, oral water and iv saline; OC, osteocalcin; PINP, procollagen type I N-terminal propeptide; sßCTX, serum C-terminal telopeptide of type I collagen; uNTX, urinary N-terminal telopeptide of type I collagen.

Received September 16, 2002.

Accepted July 3, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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