Pegvisomant-induced serum insulin-like growth factor-I normalization in patients with acromegaly returns elevated markers of bone turnover to normal

Active acromegaly is associated with increased biochemical markers of bone turnover. Pegvisomant is a GH receptor antagonist that normalizes serum IGF-I in 97% of patients with active acromegaly. We evaluated the effects of pegvisomant-induced serum IGF-I normalization on biochemical markers of bone and soft tissue turnover, as well as levels of PTH and vitamin D metabolites, in 16 patients (nine males; median age, 52 yr; range, 28-78 yr) with active acromegaly (serum IGF-I at least 30% above upper limit of an age-related reference range). Serum procollagen III amino-terminal propeptide (PIIINP) and type I procollagen amino-terminal propeptide, osteocalcin (OC), bone-related alkaline phosphatase, C-terminal cross-linked telopeptide of type I collagen (CTx), albumin-corrected calcium, intact PTH, 25-hydroxy vitamin D, 1,25-dihydroxy vitamin D [1,25-(OH)(2) vit D], urinary type 1 collagen cross-linked N-telopeptide/creatinine ratio, and urinary calcium (24 h collection) were measured (single-batch analysis) at study entry and after IGF-I normalization, along with sera from 32 age- and sex-matched controls. Compared with controls, PIIINP, OC, and CTx were significantly elevated in patients at baseline. Pegvisomant-induced serum IGF-I normalization (699 +/- 76 to 242 +/- 28 micro g/liter, P < 0.001) was associated with a significant decrease in PIIINP, markers of bone formation (type I procollagen amino-terminal propeptide, OC, and bone-related alkaline phosphatase), and resorption (CTx and urinary type 1 collagen cross-linked N-telopeptide/creatinine ratio). 1,25-(OH)(2) vit D decreased and intact PTH increased significantly, but 25-hydroxy vitamin D was unaffected. A significant decline in calculated calcium clearance was observed. The decrease in serum IGF-I correlated positively with the decrease of serum PIIINP (r = 0.7, P < 0.01). After normalization of serum IGF-I, there was no statistical difference between patients and controls for any parameters for which control data were available. In conclusion, GH excess is associated with increased bone and soft tissue turnover. Pegvisomant-induced normalization of serum IGF-I results in a decrease in markers of bone and soft tissue turnover to levels observed in age-matched controls, and these changes are accompanied by an increase in PTH and a decrease in 1,25-(OH)(2) vit D. These data provide further evidence of the effectiveness of pegvisomant in normalizing the altered biological effects of GH hypersecretion.     

Effects of IGF-I combined with GH on glucocorticoid-induced changes of bone and connective tissue turnover in man.

Chronic glucocorticoid therapy results in negative bone and connective tissue balance. To assess the effects of GH and a combination of IGF-I and GH, 24 healthy male volunteers received in a double blind fashion either recombinant human GH (0.3 IU/kg per day s.c.), or a combination of GH (0.3 IU/kg per day s.c.) and IGF-I (80 microgram/kg per day s.c.) or placebo (saline s.c.) during 6 days of methylprednisolone (0.5 mg/kg per day) treatment. Methylprednisolone decreased serum osteocalcin concentrations during placebo treatment from 32.9+/-2.1 to 9.0+/-1.4 microgram/l (P<0.0001), indicating diminished osteoblast activity, and procollagen type I (PICP) and procollagen type III (PIIINP) to 46 and 70% of baseline respectively (P<0.005), indicating diminished bone (PICP) and soft tissue collagen synthesis (PIIINP). Urinary excretion of pyridinoline, deoxypyridinoline and hydroxyproline increased during treatment with methylprednisolone alone, indicating increased bone resorption (P<0.05 or less). The combination of GH and IGF-I resulted in a significant blunting of the methylprednisolone effect on serum PICP and PIIINP concentrations (P<0.005 or less vs placebo); this effect was in part due to IGF-I, since serum PICP concentrations decreased less in the combination group than during GH treatment alone (P<0.05). In the groups receiving GH and GH combined with IGF-I, urinary hydroxyproline excretion increased more when compared with methylprednisolone alone (P<0.05 or less). These findings demonstrate that only the combination of GH and IGF-I, but not GH alone, markedly counteracts diminished bone and body collagen synthesis caused by glucocorticoids, whereas connective tissue resorption is enhanced during treatment with GH alone and in combination with IGF-I.     

Endogenous sex steroid, GH and IGF-I levels in normal elderly men: relationships with bone mineral density and markers of bone turnover.

There are studies concerning the association among endogenous sex steroids, growth hormone (GH), insulin-like growth factor-I (IGF-I) and bone mineral density (BMD) in both men and women. However, little is known concerning the association of these parameters with markers of bone turnover in healthy elderly men. We studied the association of BMD (dual energy X-ray absorptiometry of spine, hip and forearm) and markers of bone turnover (bone-specific alkaline phosphatase, serum C-terminal propeptide of type I collagen, and serum osteocalcin reflecting formation, urine deoxypyridinoline and calcium excretion in relation to creatinine excretion reflecting resorption) with endogenous sex steroids, GH and IGF-I in 14 elderly normal men (age range 60-79 years). There was a negative correlation between age and dehydroepiandrosterone sulphate (DHEAS) (r=-0.60, p=0.022) and a positive correlation between GH and IGF-I (r=0.53, p=0.048). Serum estradiol concentrations correlated with BMD at distal 1/3 radius (r=0.41, p=0.1) and mid-radius (r=0.47, p=0.08), and negatively correlated with age (r=-0.45, p=0.09). There was no correlation of estradiol with bone turnover markers, testosterone, free testosterone, DHEAS, GH and IGF-I. Serum GH and IGF-I levels showed no correlation with BMD (all sites) and bone turnover markers. Serum total testosterone concentrations positively correlated with BMD at distal 1/3 radius (r=0.47, p=0.09), femoral neck (r=0.56, p=0.037) and Ward's triangle (r=0.49, p=0.07). These data suggest that serum estradiol and testosterone levels are associated with BMD in elderly men, possibly indicating their contribution to skeletal maintenance in old age. However, correlations of IGF-I, GH and DHEAS with BMD and bone turnover markers are lacking in the group studied.     

Effects of growth hormone-releasing hormone on bone turnover in human immunodeficiency virus-infected men with fat accumulation

GHRH is a potentially appealing strategy to simultaneously improve fat distribution and increase bone turnover in HIV-infected patients. We investigated the effects of GHRH (1 mg sc twice a day over 12 wk) in 31 HIV-infected men with abdominal fat accumulation (age 46 +/- 1 yr, body mass index 26.2 +/- 0.6 kg/m2) in a randomized, double-blind, placebo-controlled study. We previously reported significant effects of GHRH on IGF-I and truncal fat. In this study, we assessed whether GHRH increased markers of bone turnover. At baseline, 32% of our subjects (n = 10) demonstrated a bone density Z score less than -1.0 sd and greater than or equal to -2.5 sd, and 3% (n = 1) demonstrated a Z score of less than -2.5 sd. IGF-I correlated with N-terminal telopeptide (NTx) (r = 0.49, P = 0.005) and tended to correlate with C-terminal telopeptide (CTx) (r = 0.35, P = 0.06) at baseline. Of the bone resorption markers, CTx increased significantly (0.16 +/- 0.07 vs. -0.03 +/- 0.03 ng/ml, GHRH vs. placebo, P = 0.02), and NTx tended to increase in response to GHRH (2.8 +/- 1.4 vs. -0.5 +/- 1.0 nm bone collagen equivalent, GHRH vs. placebo, P = 0.07). Of the bone formation markers, N-terminal propeptide of type 1 procollagen increased (14.6 +/- 9 vs. -6.8 +/- 3.1 microg/liter, GHRH vs. placebo, P = 0.03) and osteocalcin tended to increase (8.4 +/- 3.0 vs. 2.0 +/- 1.6 ng/ml, GHRH vs. placebo, P = 0.06) in response to GHRH. The calciotropic hormones, calcium and phosphorus, did not change significantly. The change in IGF-I correlated with the change in NTx (r = 0.45, P = 0.02), CTx (r = 0.38, P = 0.05), and osteocalcin (r = 0.55, P = 0.002). GHRH improves fat distribution and bone metabolism in men with HIV-related fat accumulation. Long-term studies are needed to determine whether the stimulatory effects of GHRH on bone turnover will translate into increased bone density in this population.     

Early changes in serum N-telopeptide and C-telopeptide cross-linked collagen type 1 predict long-term response to alendronate therapy in elderly women

The aim of this study was to determine whether early changes in serum markers of bone resorption could predict long-term responses in bone mineral density (BMD) after alendronate therapy in elderly women. One hundred and twenty women (mean age, 70 yr) were randomized to alendronate or placebo in this double blind, placebo-controlled clinical trial for 2.5 yr. Outcome measures were hip and spine BMD and biochemical markers of bone resorption, including serum N-telopeptide and C-telopeptide cross-linked collagen type I (NTx and CTx, respectively). Serum NTx and CTx were highly correlated at baseline (r = 0.73; P < 0.001) and remained so throughout the study (range, r = 0.36-0.56; all P < 0.05). After treatment with alendronate, serum NTx decreased 30.4+/-16.0% at 6 months, reaching a nadir of -36.7+/-18.0% by 24 months (P < 0.001). Serum CTx decreased 43.5+/-67.0% at 6 months and continued to decrease to 67.3+/-19.3% at 2.5 yr (P < 0.001). Moreover, decreases in serum NTx and CTx at 6 months were correlated with long-term improvements in vertebral BMD at 2.5 yr in patients receiving alendronate therapy (NTx: r = -0.42; CTx: r = -0.31; both P < 0.05). We conclude that early changes in serum NTx and CTx, markers of bone resorption, predict long-term changes in vertebral BMD in elderly women receiving alendronate therapy and provide a useful tool to assess skeletal health.     

Effect of alendronate and MK-677 (a growth hormone secretagogue), individually and in combination, on markers of bone turnover and bone mineral density in postmenopausal osteoporotic women

GH increases bone turnover and stimulates osteoblast activity. We hypothesized that administration of MK-677, an orally active GH secretagogue, together with alendronate, a potent inhibitor of bone resorption, would maintain a higher bone formation rate relative to that seen with alendronate alone, thereby generating greater enhancement of bone mineral density (BMD) in women with postmenopausal osteoporosis. We determined the individual and combined effects of MK-677 and alendronate administration on insulin-like growth factor I levels and biochemical markers of bone formation (osteocalcin and bone-specific alkaline phosphatase) and resorption [urinary N-telopeptide cross-links (NTx)] for 12 months and BMD for 18 months. In a multicenter, randomized, double blind, placebo-controlled, 18-month study, 292 women (64-85 yr old) with low femoral neck BMD were randomly assigned in a 3:3:1:1 ratio to 1 of 4 daily treatment groups for 12 months: MK-677 (25 mg) plus alendronate (10 mg); alendronate (10 mg); MK-677 (25 mg); or a double dummy placebo. Patients who received MK-677 alone or placebo through month 12 received MK-677 (25 mg) plus alendronate (10 mg) from months 12-18. All other patients remained on their assigned therapy. All patients received 500 mg/day calcium. The primary results, except for BMD, are provided for month 12. MK-677, with or without alendronate, increased insulin-like growth factor I levels from baseline (39% and 45%; P < 0.05 vs. placebo). MK-677 increased osteocalcin and urinary NTx by 22% and 41%, on the average, respectively (P < 0.05 vs. placebo). MK-677 and alendronate mitigated the reduction in bone formation compared with alendronate alone based on mean relative changes in serum osteocalcin (-40% vs. -54%; P < 0.05, combination vs. alendronate) and reduced the effect of alendronate on resorption (NTx) as well (-52% vs. -61%; P < 0.05, combination vs. alendronate). MK-677 plus alendronate increased BMD at the femoral neck (4.2% vs. 2.5% for alendronate; P < 0.05). However, similar enhancement was not seen with MK-677 plus alendronate in BMD of the lumbar spine, total hip, or total body compared with alendronate alone. GH-mediated side effects were noted in the groups receiving MK-677, although adverse events resulting in discontinuation from the study were relatively infrequent. In conclusion, the anabolic effect of GH, as produced through the GH secretagogue MK-677, attenuated the indirect suppressive effect of alendronate on bone formation, but did not translate into significant increases in BMD at sites other than the femoral neck. Although the femoral neck is an important site for fracture prevention, the lack of enhancement in bone mass at other sites compared with that seen with alendronate alone is a concern when weighed against the potential side effects of enhanced GH secretion.     

Serum GH and IGF-I are significant determinants of bone turnover but not bone mineral density in active acromegaly: a prospective study of more than 70 consecutive patients

OBJECTIVE: Acromegaly is characterized by a persistent hypersecretion of GH and provides information on long-term effects of GH on bone metabolism. The aim of this study was to examine the effect of gonadal status and disease activity on bone metabolism in active acromegaly. METHODS: Seventy-three consecutive patients with active acromegaly: 40 women and 33 men (50 +/- 13 (mean +/- s.d.) and 49 +/- 10 years respectively) were evaluated and compared with age-, sex-, and body mass index (BMI)-matched controls by X-ray absorptiometry and biochemical analysis (markers of disease activity and bone turnover). RESULTS: We found that bone turnover, as evaluated by biochemical bone markers, is coupled and markedly increased in relation to disease activity in active acromegaly. Acromegalic women, but not men, were characterized by an increased bone area and slightly decreased bone mineral content resulting in significantly decreased bone mineral density (BMD) in the ultradistal radius, proximal radius, and total body. No differences in bone turnover or BMD were found between eu-and hypogonadal subjects. Multivariate analysis identified age, BMI, and gender as independent predictors of total BMD in acromegaly. CONCLUSION: Our study demonstrates a decreased total body BMD in women, not men, with active acromegaly, regardless of gonadal status or disease activity. Bone turnover is markedly increased in relation to disease activity, possibly counteracting the anabolic effects of excess GH/IGF-I in these subjects. We suggest more focus on biomechanical analyses when investigating endocrine disorders affecting bone size and distribution between compartments.     

Effect of low-dose of recombinant human growth hormone on bone metabolism in elderly women with osteoporosis

BACKGROUND: There has been increasing evidence that the growth hormone (GH)-IGF-I axis plays an important part in the maintenance of bone mass. However, controversy still exists as to the effect of GH treatment on bone mineral density (BMD) in elderly patients with osteoporosis. OBJECTIVE: To investigate the effect of low-dose GH treatment on markers of body composition and bone turnover, serum concentrations of IGF-I and IGF-binding proteins (IGFBPs), and BMD at the radius and lumbar spine in eight elderly Japanese women with osteoporosis. METHODS: Participants were treated with GH as a single daily subcutaneous injection (0.125 IU/kg per week; 0.00595 mg/kg per day) for 48 weeks. RESULTS: Markers of bone formation and bone resorption were both increased up to 24 weeks of GH treatment. The bone formation markers remained increased during GH treatment, whereas the bone resorption markers returned to baseline values after 24 weeks of GH treatment. GH treatment caused a rapid (within 2 weeks) and sustained increase in serum IGF-I concentration. As for IGFBPs, serum concentrations of IGFBPs-2, -3 and -4 did not change significantly during GH treatment. In contrast, GH treatment caused a gradual increase in serum IGFBP-5 concentration, with a significant increase seen 48 weeks after the start of GH treatment. Radial BMD seemed to be increased during the late period of GH treatment, although the change was not significant. Lumbar BMD did not change during GH treatment. GH treatment caused a significant increase in hand grip strength. None of the GH-treated participants had new fractures and side effects such as edema and joint pain. Radial BMD was significantly increased after discontinuation of GH treatment for another 48 weeks and a similar tendency was observed at the lumbar spine (7.1+/-2.3% above pretreatment values for the radius and 3.6+/-2.0% for the lumbar spine). CONCLUSIONS: Low-dose GH treatment attenuated the decrease in muscle strength and bone mass in elderly women without side effects, although changes in nutrition and exercise might affect BMD. The present findings provide useful information regarding the use of low-dose GH treatment in elderly women with osteoporosis.     

Effects of 42 months of GH treatment on bone mineral density and bone turnover in GH-deficient adults.

OBJECTIVE: To study the effects of GH treatment for up to 42 months on bone mineral density (BMD) and bone turnover. DESIGN AND METHODS: BMD with dual energy X-ray absorptiometry, serum type I procollagen carboxy-terminal propeptide (PICP), serum type I collagen carboxy-terminal telopeptide (ICTP) and serum IGF-I were assessed in 71 adults with GH deficiency. There were 44 men and 27 women, aged 20 to 59 (median 43) years. Thirty-two patients completed 36 months and 20 patients 42 months of treatment. RESULTS: The BMD increased for up to 30-36 months and plateaued thereafter. In the whole study group, the maximum increase of BMD was 5.0% in the lumbar spine (P<0. 001), 5.9% (P<0.01) in the femoral neck, 4.9% (NS, P>0.05) in the Ward's triangle and 8.2% (P<0.001) in the trochanter area. The serum concentrations of PICP (202.6+/-11.5 vs 116.3+/-5.4 microg/l; mean+/-s.e.m.) and ICTP (10.5+/-0.6 vs 4.4+/-0.3 microg/l) doubled (P<0.001) during the first 6 months of GH treatment but returned to baseline by the end of the study (130.0+/-10.4 and 5.6+/-0.7 microg/l respectively), despite constantly elevated serum IGF-I levels (39. 6+/-4.1 nmol/l at 42 months vs 11.9+/-0.9 nmol/l at baseline; P<0.001). The responses to GH treatment of serum IGF-I, PICP, ICTP (P<0.001 for all; ANOVA) and of the BMD in the lumbar spine (P<0.05), in the femoral neck and the trochanter (P<0.001 for both) were more marked in men than in women. At the end of the study the BMD had increased at the four measurement sites by 5.7-10.6% (P<0.01-0.001) in patients with at least osteopenia at baseline and by 0.1-5.3% (NS P<0.05) in those with normal bone status (P<0.001 for differences between groups; ANOVA). Among patients who completed 36-42 months of treatment, the number of those with at least osteopenia was reduced to more than a half. The response of BMD to GH treatment was more marked in young than in old patients at three measurement sites (P<0. 05-<0.001; ANOVA). In the multiple regression analysis the gender and the pretreatment bone mass appeared to be independent predictors of three measurement sites, whereas the age independently determined only the vertebral BMD. CONCLUSIONS: GH treatment in GH-deficient adults increased BMD for up to 30-36 months, with a plateau thereafter. Concurrently with the plateau in BMD the bone turnover rate normalized. From the skeletal point of view GH-deficient patients exhibiting osteopenia or osteoporosis should be considered as candidates for GH supplementation of at least 3-4 years.     

Effect of recombinant human growth hormone in elderly osteoporotic women

OBJECTIVE: Bone mineral density and growth hormone (GH) secretion rate both decline during normal human ageing. We evaluated the effects of recombinant human GH on markers of body composition and bone turnover in an open study in 8 elderly osteoporotic women aged 68-75 years (mean age 71 years). DESIGN: Subjects were treated with GH as a single daily subcutaneous injection (0.125 IU/kg/week for the first 4 weeks and subsequently 0.25 IU/kg/week) for 48 weeks. RESULTS: GH treatment caused a rapid (within 2 weeks) increase in serum levels of IGF-I and IGF-binding protein-3 (IGFBP-3) which was sustained throughout the study. Markers of bone formation and resorption were both gradually increased up to 24 weeks of GH treatment. The bone formation markers, osteocalcin (OC) and bone alkaline phosphatase, remained high during GH treatment, while the bone resorption marker, deoxypyridinoline (D-Pyr), tended to return to baseline levels after 24 weeks of GH therapy. GH treatment for 48 weeks caused a significant increase in hand grip and a decrease in waist/hip ratio. The mean percentage changes in bone mineral density (BMD) of mid-radius and lumbar spine were + 2.1% and + 1.2%, respectively, although they were not statistically significant. GH treatment was well tolerated and no major side-effects except mild oedema and joint pain were found. Since GH treatment produced durable increases in bone formation markers, BMD continued to be monitored after discontinuation of GH treatment for another 48 weeks, during which significant increases in radial and lumbar BMD (8.1 +/- 2.1 and 3.8 +/- 1.4% above pre- treatment values, respectively) were recorded. CONCLUSION: These results indicate that GH attenuates the decrease in muscle strength and bone mass as well as the gain of abdominal fat with ageing in elderly women. The present data provide useful information about the application of GH treatment in elderly women.     

Long-term treatment of acromegaly with lanreotide: evidence of increased serum parathormone concentration

The somatostatin analogue lanreotide is effective in reducing growth hormone levels in patients with acromegaly. Acromegaly is characterized by calcium homeostasis alterations. The aim of our study was to evaluate the effects of lanreotide on bone turnover markers in a group of acromegalic patients and to verify a possible increase of intact parathormone (iPTH) levels in a transient or persistent way. Serum GH, IGF-I and serum and urinary markers of bone metabolism were measured before treatment and on months 3 and 24. In short-term treatment (3 months), lanreotide significantly decreased GH, IGF-I, serum calcium, osteocalcin and alkaline phosphatase levels, but increased iPTH level (49 +/- 16.7 vs pre-treatment 28.3 +/- 7.6 ng/L, p<0.001). During long-term study (24 months) GH and IGF-I were significantly still low; serum calcium and alkaline phosphatase levels returned to pre-treatment levels. iPTH level was significantly still higher compared with pre-treatment (46.4 +/- 9.2 vs 28.3 +/- 7.6 ng/L, p<0.05). No changes were seen in serum albumin, creatinine and vitamin D during short and long term treatment. The changes of most bone markers during lanreotide treatment can be explained by the decrease of GH and IGF-I. The increase of iPTH concentration suggests that lanreotide has ulterior and long-standing actions on calcium homeostasis: intestinal malabsorption of calcium due to the lanreotide could contribute to this "secondary" hyperparathyroidism. The clinical relevance of these long-standing effects needs to be further investigated.     

Increased urinary N-telopeptide cross-linked type 1 collagen predicts bone loss in patients with inflammatory bowel disease

OBJECTIVE: Reduced bone mineral density (BMD) is common in patients with inflammatory bowel disease (IBD), but the factors associated with its longitudinal rate of change have not been established. We prospectively assessed the rate of change in BMD, and its association with biochemical markers of bone turnover. METHODS: Twenty-two patients with Crohn's disease and 14 ulcerative colitis patients age 37.1 +/- 11.6 yr were followed for 2 yr. Lumbar spine (L2-L4) and femoral neck BMD were measured by dual x-ray absorptiometry at baseline and 24 months. Bone-specific alkaline phosphatase, osteocalcin, urinary N-telopeptide crosslinked type 1 collagen (NTx), parathyroid hormone, and 25-hydroxyvitamin-D were determined at baseline. RESULTS: At baseline, 59% of Crohn's patients and 43% of ulcerative colitis patients were osteoporotic, with spine or femoral neck BMD T-score < -2.5. Spine BMD, and spine and femoral neck T-scores were lower and disease duration was longer in nine patients with ileal resection compared with nonoperated patients (0.84 +/- 0.15 g/cm2 vs 0.96 +/- 0.11 g/cm2, -3.0 +/- 1.5 vs -1.7 +/- 1.3, -3.2 +/- 1.5 vs -2.2 +/- 1.0, respectively; all p < 0.05). At 24 months, 13/36 (36%) and 14/36 (39%) patients experienced spinal and femoral neck bone loss, respectively, with mean annual percent BMD changes of -2.0% and -1.5%, respectively. NTx, a bone resorption marker, inversely correlated with spinal BMD rate of change (r = -0.4, p < 0.05). Using quartiles analysis, patients with the highest NTx (Q4) experienced the greatest decrease in spine BMD compared with patients with the lowest NTx (Q1). CONCLUSIONS: Spine and femoral neck bone loss continues over time in more than one-third of IBD patients. Increased NTx level predicts spinal bone loss in IBD patients.     

胰岛素、胰岛素原对胰岛素抵抗状态下HepG2细胞PAI-1分泌的影响

目的研究胰岛素、胰岛素原对胰岛素抵抗状态下ＨｅｐＧ２细胞ＰＡＩ１分泌的影响。方法选择在合成ＰＡＩ１方面与肝细胞相似的ＨｅｐＧ２细胞，以高浓度胰岛素诱导胰岛素抵抗后，分别用生理浓度的胰岛素、胰岛素原刺激２４小时，以观察胰岛素抵抗状态下ＰＡＩ１活性的变化。结果基础状态下胰岛素抵抗ＨｅｐＧ２细胞与非胰岛素抵抗ＨｅｐＧ２细胞相比，ＰＡＩ１活性差异不明显；胰岛素、胰岛素原刺激后，胰岛素抵抗ＨｅｐＧ２细胞ＰＡＩ１活性明显高于非胰岛素抵抗ＨｅｐＧ２细胞。当培液中同时加入１０－４Ｍ二甲双胍后，胰岛素、胰岛素原介导的ＰＡＩ１过量分泌得到明显抑制。结论在胰岛素抵抗状态下，胰岛素、胰岛素原刺激后ＨｅｐＧ２细胞ＰＡＩ１活性明显增加，而二甲双胍可明显抑制此现象。     

Bone mineral content and bone metabolism during physiological GH treatment in GH-deficient adults--an 18-month randomised, placebo-controlled, double blinded trial

OBJECTIVE: To evaluate the effect of physiological adult growth hormone (GH) replacement on bones. DESIGN: Thirty-six prospective severely growth hormone-deficient (GHD) adults (22 females and 14 males) were randomised to either 18 months of GH (0.03 mU/kg/day) or placebo treatment. METHODS: Bone mineral density and content (BMD, BMC) and body composition were evaluated by dual energy X-ray absorptiometry at baseline and after 6, 12 and 18 months. Serum concentrations of insulin-like growth factor-I (IGF-I), IGF binding protein 3, osteocalcin, carboxyterminal propeptide of type I collagen, carboxyterminal crosslink telopeptide of type I collagen, amino-terminal propeptide of type III procollagen and urine pyridinolin and deoxypyridinolin were determined. RESULTS: IGF-I levels increased from 63.2 microg/l (+/-10.1) to 193.6 (+/- 25.8) microg/l (mean (+/-s.e.)) (P<0.001 compared with placebo). Markers of bone turnover increased significantly from 142% to 227% of baseline values (all P<0.001 compared with placebo). Body composition changes were an increase of lean body mass and a decrease of fat mass resulting in a reduction of percentage body fat of +/- 1.8 (+/- 3.8) in the GH-treated group vs an increase of 1.0 (+/-2.9)) in the placebo-treated group (P=0.002). CONCLUSIONS: No significant difference in BMD or BMC between the GH and placebo groups was found after 18 months. At several sites the variances of changes from baseline were significantly greater in the GH than in the placebo group, indicating an impact of the treatment. From baseline to 6 months an insignificant reduction of total BMD was seen while an increase of BMD was found from 6 to 18 months in the GH group compared with the placebo group.This placebo-controlled trial confirmed the longer term open studies on the effect on bones in patients with GHD, with an initial overrepresentation of bone resorption followed by an increase in BMD which at 18 months had reached baseline level.     

Chronic idiopathic neutropenia of adults is associated with decreased bone mineral density and alterations in bone turnover biochemical markers.

The aim of this study was to assess bone mineral density (BMD) and biochemical indices of bone metabolism in patients with chronic idiopathic neutropenia of adults (CINA) and define the relationships, if any, between these parameters and serum levels of interleukin-1beta (IL-1beta) and tumour necrosis factor-alpha (TNF-alpha), two cytokines normally involved in bone metabolism. Femoral neck BMD, serum osteocalcin (OC), bone-specific alkaline phosphatase (BAP) and type I procollagen carboxy-terminal propeptide (PICP), as well as urine-free deoxypyridoline (Dpd) cross-links, N-telopeptide (NTx) and C-telopeptide (CTx) cross-links of type I of collagen were measured in 45 CINA patients and 36 normal subjects. Patients were arbitrarily classified in two groups, A and B, as having mild (neutrophils 1700-2500/microl) or 'pronounced' (neutrophils<1700/microl) neutropenia, respectively. BMD values were found significantly reduced in both groups of patients, compared to controls, and they strongly correlated with the number of circulating neutrophils. Serum OC and urinary NTx were significantly increased in patients of group B. Both serum OC and urinary NTx correlated inversely with the number of circulating neutrophils. Serum BAP and PICP and urine Dpd and CTx were within normal range. Serum IL-1beta and TNF-alpha were elevated in both groups of patients and correlated inversely with the number of circulating neutrophils and the values of BMD. In addition, TNF-alpha, but not IL-1beta, inversely correlated with OC and NTx. These findings indicate that CINA patients have biochemical evidence of increased bone turnover which leads to decreased BMD. The elevated serum IL-1beta and TNF-alpha concentrations, suggestive of an underlying chronic inflammatory process in these patients, may be part of a mechanism accelerating bone turnover which, if prolonged, causes lowering of BMD.     

The effect of short- and long-term growth hormone treatment on bone mineral density and bone metabolism of prepubertal children with idiopathic short stature: a 3-year study

OBJECTIVE: We recently reported that children with idiopathic short stature (ISS) have decreased lumbar spine bone mineral density (BMD) that increases after 1 year of GH therapy. The aim of this study was to confirm these short-term results and to evaluate the effect of long-term GH therapy on the BMD of children with ISS. PATIENTS AND DESIGN: We treated a group of 16 short, slow-growing but otherwise healthy non-GH-deficient prepubertal children (8 girls and 8 boys) with a chronological age of 9.5 +/- 0.9 years, a bone age of 8.1 +/- 1.2 years and a height of 124.3 +/- 6.3 cm (height-SDS of -2.1 +/- 0.6) with GH at a dose of 0.1 IU/kg/day for 3 consecutive years. MEASUREMENTS: Height was determined at 3-month intervals and annual growth velocities were calculated. Bone ages and BMD were measured every 12 months by dual-energy X-ray absorptiometry, as were serum concentrations of the carboxy-terminal propeptide of type 1 collagen (PICP) and the carboxy-terminal cross-linked telopeptide of type 1 collagen (ICPT). RESULTS: Growth velocity increased from 4.0 +/- 0.8 cm/year to 8.7 +/- 1.5 and 8.0 +/- 1.7 cm/year at 12 and 36 months of GH therapy, respectively, while height-SDS improved from -2.1 +/- 0.6 to -1.6 +/- 0.4 after 36 months of GH (P < 0.0001). Baseline lumbar spine BMD was decreased when compared to that of a control group of healthy children paired for gender, bone age and height (0.640 +/- 0.08 g/cm2vs. 0.730 +/- 0.08 g/cm2; P < 0.003). Lumbar spine BMD increased after 1 year of GH from 0.640 +/- 0.08 to 0.749 +/- 0.08 g/cm2 (P < 0.05), reaching levels similar to that of controls followed for 1 year without therapy (0.749 +/- 0.04 g/cm2vs. 0.760 +/- 0.08 g/cm2). During this period lumbar spine BMD increased 14.5% in the ISS subjects and 3.9% in the controls. Over the following 2 years of GH therapy the lumbar spine BMD of our ISS patients increased at a rate similar to that of the control population, so that after 3 years of consecutive GH therapy the lumbar spine BMD of ISS children was comparable to that of the controls (0.784 +/- 0.12 g/cm2vs. 0.785 +/- 0.09 g/cm2). Femoral neck BMD of our patients was similar to that of the controls at baseline and at 36 months. Following 1 year of GH treatment serum concentrations of PICP increased from 229.6 +/- 63.5 to 358.6 +/- 87.9 micro g/l, while levels of ICTP increased from 9.6 +/- 5.9 to 13.7 +/- 2.1 micro g/l. After 36 months of GH therapy, PICP and ICTP values had decreased to 303.3 +/- 67.2 micro g/l and 11.3 +/- 3.3 micro g/l, respectively, and were no longer significantly different from baseline. CONCLUSIONS: Children with ISS have decreased lumbar spine BMD, which normalized after 1 year of GH. Over the next 2 years of therapy lumbar spine BMD increased at a normal rate, so that after 3 consecutive years of GH the lumbar spine BMD of children with ISS was similar to that of controls. Bone turnover increased with treatment as indicated by a rise in bone formation and bone resorption markers.     

Bone density and turnover in young adult patients with growth hormone deficiency after 2-year growth hormone replacement according with gender

GH deficiency (GHD) in adults is accompanied by reduced bone mass that may revert only after 2 yr of GH replacement. However, it is unclear whether the gender may modify bone responsiveness to GH replacement in adults. In this study we have evaluated whether bone mineral density (BMD) and turnover improve after GH replacement according to patients' gender. BMD at lumbar spine (LS) and femoral neck (FN), serum osteocalcin (OC), and urinary cross-linked N-telopeptides of type I collagen (Ntx) were assessed in 64 hypopituitaric patients (35 men, 30-50 yr) before and 2 yr after the beginning of GH replacement. Values of IGF-I and BMD at LS and at FN were expressed as Zscores. At study entry, IGF-I and BMD resulted similar among men and women with GHD. During GH replacement, IGF-I levels increased in both men and women without any difference in the percentage of IGF-I increase between the genders (p=0.47). In women receiving estrogen replacement, however, the percentage of IGF-I increase (p<0.05), and the Z IGF-I score (p<0.001) were significant lower than estrogen untreated women, although IGF-I levels were similar in the 2 groups (p=0.53). The GH dose adjusted for body weight required to restore normal age- and sex- matched IGF-I levels was lower in men than in women (p<0.001), and was higher in women receiving than in those not receiving estrogen replacement (p<0.05). In contrast, hypogonadal men treated with testosterone and eugonadal men received a similar GH dose (p=0.97). Also OC, Ntx levels, lumbar and femoral BMD improved (p<0.001) in all patients. Nevertheless, a greater increase in lumbar BMD increase was observed in men than in women (8.0+/-2.1 vs 2.6+/-0.4%; p<0.05). No significant difference was revealed in bone parameters in women treated or untreated with estrogen replacement and in men treated or not with testosterone replacement for concomitant hypogonadism. At the multiple correlation analysis, gender was a stronger predictor for the required GH dose than the age (p<0.001 and p=0.02, respectively). In conclusion, a 2-yr GH replacement normalizes IGF-I levels, increases bone mass and improves bone turnover both in men and in women with GHD without any difference between the 2 groups, provided that the dose of GH was modulated on the basis of IGF-I levels. Women receiving oral estrogens should receive a GH dose approximately doubled, as compared to men and women not receiving oral estrogens, to achieve similar effects on bone density and turnover. In particular, GH replacement dose, to be successful on bone mass and turnover, depends on gender in hypopituitary patients aged below 50 yr.     

Bone turnover in hyperthyroidism before and after thyrostatic management

Hyperthyroidism is associated with enhanced osteoblastic and osteoclastic activity, and patients frequently have low bone mineral density and high bone turnover. The aim of this study was to examine the bone formation and resorption markers trend in 12 female patients, before and after normalization of thyroid activity. The following measurements were made at baseline and 1 and 6 months after hormone normalization induced by methimazole treatment: total alkaline phosphatase (ALP), bone alkaline phosphatase (BALP), collagen type C-terminal propeptide (PICP), osteocalcin (BGP), telopeptide (ICTP), urinary-hydroxyproline/urinary creatinine (uOHP/uCreat), urinary calcium/urinary creatinine (uCa/uCreat) and deoxypyridinoline crosslinks (D-Pyr). Compared with controls, all of these parameters were significantly increased (ALP p = 0.014; BALP p = 0.0001; PICP p = 0.013; BGP p = 0.009; ICTP p = 0.0001; uOHP/uCreat p = 0.002; uCa/uCreat p = 0.044; crosslinks p = 0.0001). After treatment the values of ALP, BALP and PICP in hyperthyroid patients showed an initial slight increase and then a significant downwards trend (ALP p = 0.008, BAP p = 0.001, PICP p = 0.026). Furthermore, resorption markers showed a significant decrease (uOHP/ uCreat p < 0.005 and D-Pyr p < 0.008). As regards lumbar BMD patients, measurements were significantly reduced in comparison with the control group (p = 0.005). Six months after serum thyroid hormones level normalization, we observed a significant increase (p=0.014 vs baseline). Both neoformation and resorption markers are useful to assess pathological bone turnover and bone involvement in hyperthyroidism. They could also be employed to monitor the effect of antithyroid treatment on bone and to indicate if bone antiresorption therapy should be considered.     

Bone mineral metabolism in adults with beta-thalassaemia major and intermedia

Bone disease is an important cause of morbidity in older patients with beta-thalassaemia major and intermedia. We studied 27 women and 23 men with beta-thalassaemia major (37) and intermedia (13) whose mean age was 32.3 +/- 9.7 years. Bone mineral density (BMD) of the lumbar spine, femoral neck and distal radius was determined by dual-energy X-ray absorbiometry (DXA). The longitudinal change in BMD over a mean of 5.6 years was determined in 19 patients. Serum 25-hydroxyvitamin D, insulin growth factor-1 (IGF-1), bone formation markers bone-alkaline phosphatase, osteocalcin and the resorption marker urinary N-telopeptide cross-linked type 1 collagen (NTx) were determined. The BsmI vitamin D receptor (VDR) gene polymorphism was analysed. Reduced BMD (Z-score < -2) was present in 89%, 62% and 73% of patients in the spine, hip and radius respectively. Vitamin D deficiency was found in 62%, decreased IGF-1 in 72% and increased urinary NTx in 84% of patients. Serum IGF-1 correlated with spine and hip BMD (r = 0.4, r = 0.39, P < 0.01 respectively), and NTx correlated with the hip BMD Z-score (r = 0.35 P < 0.05). The mean annual percentage change in spine BMD was -1.36%. Patients with the VDR BB genotype had lower spine BMD than patients with the bb genotype. In conclusion, bone loss continues in adult thalassaemia patients and is associated with increased bone resorption and decreased IGF-1. The BsmI VDR gene polymorphism is associated with osteopenia in thalassaemia.     

Cardiovascular risk factors in acromegaly before and after normalization of serum IGF-I levels with the GH antagonist pegvisomant

Acromegaly is associated with premature cardiovascular mortality. GH replacement therapy decreases inflammatory markers of cardiovascular risk, but little is known about these markers in patients with acromegaly. The GH receptor antagonist, pegvisomant, reduces IGF-I levels in 98% of patients treated. We investigated the effects of GH receptor blockade on inflammatory and other cardiovascular risk markers in active acromegaly. Forty-eight patients with acromegaly and 47 age- and body mass index-matched controls were included. The study consisted of 3 parts: a cross-sectional study, a prospective randomized 12-wk placebo-controlled study, and a longitudinal open-label study of up to 18 months of pegvisomant treatment. After baseline evaluation, patients with acromegaly were randomized to placebo (n = 14), 10 mg (n = 12), 15 mg (n = 10), or 20 mg (n = 12) daily pegvisomant for 12 wk. Subsequently, all patients received at least 10 mg pegvisomant daily for up to 18 months, with dose adjustments to achieve a normal IGF-I level. Anthropometry, GH, IGF-I, and pegvisomant levels were measured monthly. C-reactive protein (CRP), IL-6, homocysteine, lipoprotein(a), glucose, insulin, triglycerides, total cholesterol, and high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol were determined at baseline, 4 and 12 wk in the placebo-controlled study and at 3-month intervals (during which IGF-I levels were normal) in the longitudinal study. In the cross-sectional study, patients had lower CRP than did controls [median, 0.3 (range, 0.2-0.8) vs. 2.0 (0.6-3.7) mg/liter; P < 0.0001] and had higher insulin [78.6 (55.8-130.2) vs. 54.5 (36.6-77.5) pM, P = 0.0051]. IL-6, homocysteine, triglycerides, lipoprotein(a), LDL cholesterol and HDL cholesterol were not different between groups. In the placebo-controlled study, CRP increased in patients treated with 20 mg pegvisomant, compared with placebo (mean +/- SEM, 13.7 +/- 3.6 vs. 0.5 +/- 3.3 mg/liter; P = 0.010). There were no significant differences in IL-6, homocysteine, glucose, insulin, triglyceride, total cholesterol, LDL cholesterol and HDL cholesterol levels. In the longitudinal open-label study (median duration, 15.6 months), CRP increased by 2.0 +/- 0.5 mg/liter (P = 0.0002). Total cholesterol and triglycerides increased (0.22 +/- 0.11 mM, P = 0.050; and 0.25 +/- 0.09 mM, P = 0.007, respectively), whereas lipoprotein(a) decreased (-70 +/- 33 mg/liter, P = 0.039). Glucose, insulin, homocysteine, HDL cholesterol, and IL-6 did not change. We conclude that patients with active acromegaly have lower CRP and higher insulin levels than healthy controls. Administration of pegvisomant increases CRP levels. We propose that GH secretory status is an important determinant of serum CRP levels, although additional studies are needed to determine the mechanism and significance of this finding.