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Metabolic Improvement of Poorly Controlled Noninsulin-Dependent Diabetes Mellitus Decreases Bone Turnover¹

Department of Metabolism and Endocrinology (R.O., Y.T., K.H., M.A.), Kanto Teishin Hospital; Mitsubishi Kagaku Bioclinical Laboratories, Inc. (M.M., Y.H., K.H.); Fourth Department of Internal Medicine (S.F.), University of Tokyo School of Medicine, Tokyo; First Department of Internal Medicine (T.M.), University of Tokushima School of Medicine, Tokushima, Japan

Address correspondence and requests for reprints to: Ryo Okazaki, M.D. Third Department of Medicine, Teikyo University School of Medicine, 3426–3 Anesaki, Ichihara-city, Chiba 299–01, Japan.

	Abstract

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Patients with poorly controlled noninsulin dependent diabetes mellitus (NIDDM) are shown to have higher bone mass. However, the influence of changes in glycemic control on bone turnover is not known. To clarify whether metabolic improvement of poorly controlled NIDDM affects bone turnover, markers for glucose, mineral, and bone metabolism were assessed before and after glycemic control for 3 weeks in 78 poorly controlled NIDDM patients with initial hemoglobin A1c over 8%. Metabolic improvement caused a reduction in urinary calcium (Ca) and phosphate (Pi) and serum 1,25(OH)₂D levels, and an increase in serum Pi without changes in serum Ca or parathyroid hormone levels. Bone resorption markers, urinary deoxypyridinoline (Dpd) and type I collagen carboxy-terminal telopeptide (CTx), as well as a bone formation marker, serum bone type alkaline phosphatase (BALP), were reduced. However, another bone formation marker, serum osteocalcin (OC), was low before treatment and was elevated after treatment. The decrease in Dpd, CTx and BALP, but not the increase in OC, correlated with each other and with the improvement in glycemic indices. In conclusion, metabolic improvement of poorly controlled NIDDM decreases bone turnover within a short period. Thus, glycemic control may protect NIDDM patients from bone loss. It is possible that serum OC is affected by hyperglycemia per se, and may not correctly reflect bone turnover.

	Introduction

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RECENT cross-sectional studies revealed that the presence of noninsulin dependent diabetes mellitus (NIDDM) is associated with higher bone mass and lower fracture rates (1, 2, 3, 4). However, most of those studies were performed in NIDDM patients under fairly controlled and stable conditions; in one of those studies, their mean hemoglobin A1c (HbA1c) was 6.7% (1). Therefore, it is as yet unknown whether changes in glycemic control influence bone turnover in NIDDM patients.

Bone mass is determined by a long-term net balance between bone resorption and bone formation. Therefore, even though the turnover of bone is altered by poor glycemic control, it may not be reflected in bone mass if the duration of the poorly controlled period is short, or if bone mass is evaluated after stable glycemic control is achieved for a certain period. Such a possibility has been in fact pointed out by previous studies using NIDDM patients. For example, poorly controlled NIDDM patients (5, 6) as well as IDDM patients (7, 8, 9) have relative hypercalciuria probably caused by osmotic diuresis associated with glycosuria. This could lead to negative calcium (Ca) balance and secondary hyperparathyroidism, which might result in accelerated bone resorption and loss of bone. Indeed, Selby et al. (10) reported that urinary hydroxyproline excretion, a rather nonspecific resorption marker, is elevated along with urinary Ca in NIDDM patients. It has been also demonstrated that one of the bone formation markers, bone-specific ALP (BALP) tends to be higher in diabetic subjects (11, 12, 13). However, because bone turnover can be affected by many other factors and therefore there is a wide variation among individuals, it has been difficult to evaluate the effects of glycemic control on bone turnover from those cross-sectional studies. In addition, several studies demonstrated that another bone formation marker, serum osteocalcin (OC) is not elevated but is reduced in NIDDM patients (12, 14, 15, 16). In a longitudinal study using NIDDM patients, Sayinalp et al. (17) reported that glycemic control increased serum OC levels but did not affect urinary hydroxyproline excretion. Another longitudinal study by Nagasaka et al. (6) reported that improvement in metabolic control of NIDDM caused a decrease in urinary Ca and serum parathyroid hormone (PTH), while serum OC was elevated. Thus, although there is a possibility that bone turnover is altered by a change in glycemic control, the influence of NIDDM on bone turnover has not been well characterized.

Because synthesis and secretion of OC from osteoblasts is affected by ambient glucose levels, serum OC may not reflect bone formation correctly in diabetic patients (18). Therefore, bone turnover has to be assessed with consideration of the specificity and sensitivity of each biochemical marker. With the recent development of various specific markers of bone resorption and formation, it has become possible to evaluate bone turnover more precisely by measuring a combination of these markers. The present study was undertaken to clarify the influence of glycemic control on bone turnover using several specific bone markers. Poorly controlled NIDDM patients were placed under a rigid control program, and these bone markers were evaluated simultaneously before and 3 weeks after treatment. Urinary Dpd and CTx were used as bone resorption markers, and serum BALP and OC as bone formation markers.

	Subjects and Methods

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Patients

From September 1 1995 to March 31 1996, all the NIDDM patients with HbA1c above 8.0% who gave informed consent to the study were enrolled and admitted to the Department of Metabolism and Endocrinology, Kanto Teishin Hospital. Exclusion criteria were: 1) use of drugs known to affect bone and Ca metabolism during the previous 6 months, including sex steroids, corticosteroids, vitamin D metabolites, calcitonin, warfarin, vitamin K, thiazides, and anti-convulsants; 2) IDDM patients with urinary C-peptide excretion less than 27.6 nmol/day in 2 consecutive determinations; and 3) serum creatinine level of 132.6 mmol/L or more. Twenty-nine female and 49 male patients were analyzed. The ages of patients ranged from 28 to 73 yr (54.7 ± 1.2, mean ± SEM). Of the 29 female patients, 25 were postmenopausal. On admission all the subjects were put on a diet program. The calcium content of the diet was 600–800 mg/day depending on the caloric intake, which was 27–28 kcal/kg ideal body weight. At admission, 37 patients had not previously been under any medications. Among the remaining 41 patients, 26 were on sulfonylurea agents (including 5 combined with -glucosidase inhibitors, 1 with metformin, 1 with -glucosidase inhibitor and metformin), 3 were on -glucosidase inhibitors, and 12 on insulin. At discharge, 13 patients were on diet alone, 14 on sulfonylurea agents (including 3 combined with -glucosidase inhibitors, 1 with metformin, 1 with -glucosidase inhibitor and metformin), 17 on -glucosidase inhibitors, 1 on metformin, and 33 on insulin (including 5 combined with -glucosidase inhibitors, 1 with metformin).

On the second day after admission and the day before discharge, blood was obtained after overnight fasting. Mean blood glucose (MBG) concentrations were calculated by measuring plasma glucose levels at 30 min before and 2 h after each meal and before bed time (7 points). Twenty-four hour urine samples were collected at 0800 on the following day. The interval between the 2 determinations was 21 ± 1.2 days.

Measurements

Urinary total Dpd was assayed using Pyrilinks-D kit (Metra Biosystems, Inc., Mountain View, CA) after acid hydrolysis. Aliquots of urine samples were incubated at 107 C for 18 h after acidification with an equal volume of 12 mol/L hydrochloric acid. One tenth of the mixture was neutralized by adding 4 vol 1N sodium hydroxide and 20 vol assay buffer, and the assays were performed according to the manufacturer’s instructions. The intra- and interassay coefficients of variations (CVs) were 2.0 and 6.0%, respectively. Urinary CTx was assayed using CrossLaps kit (Osteometer Biotech A/S, Copenhagen, Denmark) according to the manufacturer’s instructions. The intra- and interassay CVs were 5.0 and 6.6%, respectively. Serum BALP was assayed by an immunoassay using Alkphase-B kit (Metra Biosystems). The intra- and interassay CVs were 3.0 and 3.5%, respectively. Serum OC was assayed by an immunoradiometric assay (Mitsubishi BGP-IRMA kit, Mitsubishi Chemical Co., Tokyo, Japan) as previously described (19). The intra- and interassay CVs were 4.6 and 6.3%, respectively.

Serum intact PTH levels were measured by an immunoradiometric assay (Allegro Intact PTH kit, Japan Mediphysics Co., Nishinomiya, Japan). Serum 1,25(OH)₂D levels were assayed using a radioreceptor assay kit (1, 25VD kit-Medi, Japan Mediphysics) as previously described (19). Samples before and after glycemic control were assayed as paired samples for metabolic bone markers, intact PTH, and 1,25(OH)₂D. The other biochemical markers were measured by usual methods on the day or the day after the samples were collected.

Statistical analyses

All statistical analyses were performed using StatView software (Version 4.5, Abacus Concepts Inc, Berkeley, CA). The differences between two groups were analyzed by Student’s t test. The differences between the values before and after treatment were analyzed by Student’s paired t test. Probability values below 0.05 were defined as significant. The coefficients of correlation were calculated by the Pearson’s method.

	Results

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Changes in glucose, mineral, and bone metabolic markers

Table 1 summarizes changes in glucose and mineral metabolic markers. Initial diabetic control was poorer in insulin-treated compared with noninsulin-treated subjects as assessed by HbA1c (10.30 ± 0.3 vs. 9.6 ± 0.2%), fasting blood glucose (FBG) (11.5 ± 0.7 vs. 9.2 ± 0.4 mmol/L), MBG (15.4 ± 1.3 vs. 12.7 ± 0.4 mmol/L), or urinary sugar (US) (31.3 ± 5.6 vs. 16.3 ± 2.1 mol/molCr), whereas urinary C-peptide (uCPR) levels were lower in insulin-treated than in noninsulin treated subjects (2.07 ± 0.19 vs. 2.86 ± 0.20 mol/molCr). Glycemic control was markedly improved by any of the treatments, which was associated with a decrease in uCPR levels.

Table 2 summarizes the values for metabolic bone markers before treatment. When the data were compared between males and females, females had higher mean values for urinary Ca (0.52 ± 0.05 vs. 0.37 ± 0.03 mol/mol Cr), urinary Pi (2.42 ± 0.15 vs. 2.04 ± 0.06 mol/mol Cr), Dpd, CTx, and serum total ALP before treatment. However, there were essentially no gender differences in the effects of glycemic improvement on mineral and bone metabolic markers (Fig. 1). The types of treatment (i.e. with insulin or without insulin) also did not affect the changes in any of the markers except for urinary Ca excretion, which was significantly reduced in insulin-treated subjects but tended to decrease only slightly in noninsulin treated subjects (Fig. 1). Urinary Dpd was initially high in 27 out of 78 patients, and the mean value was at a high normal range (Fig. 2A). Urinary CTx was more widely distributed (Fig. 2B). After the improvement of glycemic control, both of these resorption markers decreased significantly. Serum BALP was initially high in 16 out of 78 patients, and the mean value was also at a high normal range (Fig. 2C). Metabolic improvement significantly decreased serum BALP as well as total ALP (Fig. 1). In contrast, serum OC, another bone formation marker, was below the normal range in 25 out of 78 patients before treatment and was significantly increased after treatment (Fig. 2D).

View larger version (36K): [in this window] [in a new window]   Figure 1. The changes in the markers for bone turnover and calcium (Ca) metabolism in the subgroups. Percent changes in the urinary deoxypyridinoline (Dpd), urinary type I collagen carboxy-terminal telopeptide (CTx), urinary Ca, serum bone-type alkaline phosphatase (BALP), serum total ALP, serum osteocalcin (OC), and serum 1,25(OH)2D levels in 78 NIDDM patients after glycemic control are plotted in the first bar in each column. The changes in male (n = 49) and female (n = 29) patients are plotted in the second and third bar; insulin-treated (n = 33) and noninsulin-treated (n = 45) patients are plotted in the fourth and fifth bar in each column respectively. Data are expressed as mean SEM. Asterisks denote significance of difference before treatment. *** P < 0.001, **P < 0.01, *P < 0.05.

View larger version (53K): [in this window] [in a new window]   Figure 2. The changes in the markers for bone turnover. Urinary Dpd [A], type I collagen CTx [B], serum BALP [C], and serum OC [D] levels in 78 NIDDM patients are plotted before and after glycemic control. The bold circles (•) represent the mean, and the vertical lines represent the SEM for each marker. The shaded area represents reference range. P, results of Student’s paired t-test.

As shown in Table 3, changes in both Dpd and CTx correlated significantly with the changes in all the glycemic indices, i.e. HbA1c, MBG, and US, as well as those in urinary Ca and serum 1,25(OH)₂D. No correlation was found between the changes in bone resorption markers and serum intact PTH. Change in serum BALP also correlated with the changes in glycemic indices and urinary Ca. Changes in urinary Ca and Pi (r = 0.242, P < 0.05) were correlated with the change in US. There was a weak negative correlation between the change in the serum 1,25(OH)₂D and Pi levels (r = -0.287, P < 0.05). However, the change in serum OC did not correlate with the changes in any of the indices of glucose and mineral metabolism other than urinary Pi (r = -0.258, P < 0.05).

	Discussion

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The present studies demonstrate that metabolic improvement of poorly controlled NIDDM is associated with a decrease in markers of bone resorption and formation except for OC, and that the changes in all the bone markers other than OC correlated with each other as well as with the changes in glycemic indices.

The decrease in OC among diabetic patients has been previously reported (12, 14, 15, 16) and is interpreted to represent a reduction in bone formation. In contrast, BALP, another bone formation marker, tends to be elevated in diabetic patients (11, 12). Because OC expression becomes high after a decline in ALP expression with maturation of osteoblasts at mineralization phase (20), Bouillon, et al. (12) suggested that hyperglycemia causes a suppression of osteoblast maturation. If this is the case, poorly controlled diabetics should have a defect in bone mineralization. However, histomorphometric analyses of bones from IDDM or NIDDM patients do not show such changes (21, 22, 23). Alternatively, because OC is known to be glycosylated (24), this may affect the measurement of serum OC level. In addition, Inaba, et al. (18) demonstrated that high glucose in culture medium attenuates the stimulation of OC gene expression by 1,25(OH)₂D in an osteoblast-like cell line, MG-63, suggesting that the production of OC by osteoblasts is suppressed by hyperglycemia. Therefore, in poorly controlled diabetics, OC may not properly reflect bone formation. Such a possibility is corroborated by the present observation that OC was not correlated with any other metabolic bone markers or indices of glycemic control. From these previous and present observations it is plausible to assume that both the resorption and formation of bone can be reduced by an improvement of diabetic control. Histomorphometric studies showing normal or increased bone turnover have also been reported in NIDDM patients (22, 23), although a recent study reported reduced bone formation in a small fraction (8 patients) of NIDDM as well as IDDM patients (21). In normal postmenopausal women, an increase in bone turnover accelerates the reduction in bone mass, whereas a decrease in bone turnover is associated with the preservation of bone mass (25, 26, 27). Therefore, our findings suggest that improvement of glycemic control has protective effects on bone in NIDDM patients. The fact that the degree of metabolic improvement correlates with the decrease in bone turnover also suggests that the better glycemic control would be associated with the lower bone loss.

Although bone mass is reduced in IDDM patients (28), recent cross-sectional studies demonstrate that the presence of NIDDM is associated with normal or higher bone mass (1, 2, 3, 4). These observations appear contradictory to the present results. However, many of those studies were performed in NIDDM patients under fairly controlled and stable conditions, although details of diabetic control were not presented in some studies. Therefore, those studies failed to address the issue of whether glycemic control of NIDDM affects bone turnover and, consequently, bone mass. Krakauer, et al. (21) reported a longitudinal study that followed bone density in IDDM and NIDDM patients using single photon absorptiometry. Although the initial radial bone density was low in both IDDM and NIDDM patients, the deficit was completely corrected after 2.5 or 12.5 yr of diabetic control in NIDDM patients, whereas bone density continued to be low in IDDM patients. These results are in agreement with the present results, and support the notion that poor glycemic control of NIDDM reduces bone mass, and metabolic improvement can prevent the reduction in bone mass in NIDDM patients.

In the present study, metabolic improvement of NIDDM patients had similar effects on bone turnover regardless of the way these patients were treated, i.e. diet, oral hypoglycemic agents, insulin, or combination. In addition, the changes in any of the bone markers did not correlate with the amount of daily insulin injections, serum insulin, serum insulin-like growth factor (IGF)-I, or IGF-binding protein 3 levels (data not shown). Therefore, the effect of metabolic improvement on bone turnover appears not to be caused by changes in insulin or IGF actions but is the result of correction of hyperglycemia per se. If this is the case, better control of not only NIDDM but also IDDM can prevent bone loss caused by poor glycemic control. For preventing diabetic microvascular complications, the importance of rigid glycemic control has been emphasized since the disclosure of results by Diabetes Control and Complications Trial in IDDM patients (29, 30). The present observations further emphasize the importance of good diabetic control for preventing not only microvascular complications but also osteoporosis by reducing bone loss.

The mechanism whereby bone turnover is affected by glycemic control status is not clear at the moment. The decrease in urinary Ca excretion after metabolic control correlated with the decrease in urinary glucose excretion as previously reported (5, 6, 7, 9). The decrease in urinary Ca excretion was also correlated with the reduction in bone resorption markers. It is tempting to speculate from these data that renal hypercalciuria by osmotic diuresis caused stimulation of bone resorption caused by secondary hyperparathyroidism. However, parathyroid function was not enhanced in patients before glycemic control as reported previously (28, 31, 32, 33), and no significant changes could be detected in either serum Ca or intact PTH levels after metabolic improvement. Without significant changes in serum Ca or PTH, serum 1,25(OH)₂D was reduced after glycemic control, which may partly explain the reduction in urinary Ca and bone resorption markers. The reduction in serum 1,25(OH)₂D was correlated with the increase in serum Pi, suggesting that the increase in serum Pi suppressed renal 1,25(OH)₂D production. Thus, although the possibility cannot be ruled out that there are subtle changes in PTH-Ca axis that could not be detected by the present study protocol, the mechanism of changes in bone turnover in diabetics under different glycemic control remains unclear. Bone turnover is regulated by many local cytokines, cell-cell, and cell-matrix interactions as well as systemic hormones, and hyperglycemia may affect any of these local microenvironments that regulate bone turnover. Takagi et al. (34) reported that advanced glycosylation endproducts (AGEs) stimulate production of interleukin-6, a bone resorbing cytokine, in human and mouse osteoblast-like cells in culture. However, because the formation of AGEs is considered irreversible, this mechanism can not explain the rapid reduction in bone resorption markers after glycemic control of NIDDM. Further studies are needed to clarify these issues.

	Footnotes

 
¹ The present study was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Culture of Japans.

Received March 6, 1997.

Revised June 2, 1997.

Accepted June 16, 1997.

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