Skeletal changes in rats bearing mammosomatotrophic pituitary tumors: a model of acromegaly with gonadal dysfunction

Growth hormone (GH) exerts potent effects on bone metabolism, resulting in an increased bone formation in animals and humans. Acromegaly has been associated with increased bone turnover, whereas the net effect of the increased bone metabolism has been obscured because patients with acromegaly are often associated with hypogonadism. We investigated changes in cortical and cancellous bone in adult rats implanted mammosomatotrophic pituitary tumor cells (GH3) as a model of acromegaly with gonadal dysfunction. Acromegaly model rats were prepared by implanting GH3 cells into female Wistar-Furth rats at 17 weeks of age. At 28 weeks of age, GH3-bearing rats (GH rats) showed very high serum GH levels and a moderate increase in serum prolactin levels, resulting in low circulating estradiol levels. The GH rats showed significant increases in body weight and in length and volume of both the femur and vertebral body. Bone mineral content values of either the midfemur or the whole lumbar body were significantly greater in the GH rats compared with littermate controls, while the areal bone mineral density values of the respective bones were not different between the two groups. The parameters of mechanical strength of the femur were significantly larger in the GH rats than in controls, whereas those of the lumbar vertebral body cylinder specimen were not different between the two groups. Respective normalized mechanical parameters of the femur and the vertebral body were the same in the GH rats as in controls. In the midfemur, the GH rats showed a significant increase in the total cross-sectional area without influencing the bone marrow area, resulting in an increase in the cortical bone area and the moment of inertia compared with controls. The indices of periosteal bone formation in the midfemur were greater in the GH rats compared with controls, but the endocortical bone formation and resorption were not different between the two groups. In the vertebral body cancellous bone, the GH rats had an increase in bone turnover rate, whereas the structural parameters were not different between the two groups. These results from GH3-bearing rats demonstrate that an excess of GH increases cortical bone mass in rats accompanied with estrogen deficiency, while no large effect on vertebral body cancellous bone mass is seen.     

Growth hormone regulates the balance between bone formation and bone marrow adiposity

Cancellous bone decreases and bone marrow fat content increases with age. Osteoblasts and adipocytes are derived from a common precursor, and growth hormone (GH), a key hormone in integration of energy metabolism, regulates the differentiation and function of both cell lineages. Since an age‐related decline in GH is associated with bone loss, we investigated the relationship between GH and bone marrow adiposity in hypophysectomized (HYPOX) rats and in mice with defects in GH signaling. HYPOX dramatically reduced body weight gain, bone growth and mineralizing perimeter, serum insulin‐like growth factor 1 (IGF‐1) levels, and mRNA levels for IGF‐1 in liver and bone. Despite reduced body mass and adipocyte precursor pool size, HYPOX resulted in a dramatic increase in bone lipid levels, as reflected by increased bone marrow adiposity and bone triglyceride and cholesterol content. GH replacement normalized bone marrow adiposity and precursor pool size, as well as mineralizing perimeter in HYPOX rats. In contrast, 17β ‐estradiol, IGF‐1, thyroxine, and cortisone were ineffective. Parathyroid hormone (PTH) reversed the inhibitory effects of HYPOX on mineralizing perimeter but had no effect on adiposity. Finally, bone marrow adiposity was increased in mice deficient in GH and IGF‐1 but not in mice deficient in serum IGF‐1. Taken together, our findings indicate that the reciprocal changes in bone and fat mass in GH signaling‐deficient rodents are not directly coupled with one another. Rather, GH enhances adipocyte as well as osteoblast precursor pool size. However, GH increases osteoblast differentiation while suppressing bone marrow lipid accumulation. © 2010 American Society for Bone and Mineral Research     

Bone ultrasonometric features and growth hormone secretion in asthmatic patients during chronic inhaled corticosteroid therapy

BACKGROUND: Quantitative ultrasound bone densitometry (QUBD) is a new method to assess bone mineral density and bone microarchitecture. Corticosteroid (CS) therapy may diminish bone mass, alter bone quality and may influence growth hormone (GH) secretion and bone metabolism markers. Therefore, the aim of this study was to evaluate the effects of long-term therapy with inhaled CSs (ICSs) on structural bone characteristics and their correlations with GH secretion and bone markers in asthmatic patients. METHODS: In a cross-sectional study, we enrolled 60 adult patients with mild to moderate persistent asthma: 22 on chronic (>1 year) ICS therapy, 10 naive to ICSs treatment and 28 healthy control subjects. The groups were matched for age and BMI. Each subject underwent to QUBD at the phalanxes to assess bone microarchitecture by ultrasound bone profile index (UBPI), bone density by amplitude-dependent speed of sound (AdSos); test with GH-releasing hormone (GHRH) injection with calculation of peak GH and the Delta GH (peak GH-basal GH); and hormonal and bone markers measurements. RESULTS: Asthmatics treated with long-term ICS therapy showed a lower UBPI (P < 0.01) compared to controls (49.8 +/- 19.3 vs. 77.0 +/- 10.1, respectively) and to asthmatics never taking ICSs (73.2 +/- 9.6). In ICS-treated asthmatics, DeltaGH and GH-peak showed a significant correlation with UBPI. A significant difference was observed comparing asthmatics treated with ICSs to controls and asthmatics naive to ICSs in GH response to GHRH iv bolus. Serum osteocalcin was significantly reduced in asthmatic patients treated with ICSs. CONCLUSIONS: In asthmatic patients, long-term ICSs treatment produces negative effects on bone quality assessed by QUBD, and such effects are associated to an impaired GH secretion.     

Serum leptin values in relation to bone density and growth hormone-insulin like growth factors axis in healthy men

A novel action of leptin on bone formation has recently been described in animals. However, in humans, studies provide data, that, are less conclusive. So far, few studies investigated the leptin-bone density association in males. Moreover, it has been suggested that GH, IGF-1 and IGFBP-3 may be major players in the hormonal or paracrine pathways that regulate bone cell metabolism. Also, leptin has been shown to modulate the GH/IGF pathway. The aim of this study was to clarify further this issue by investigating (a) the influence of serum levels of leptin, GH, IGF-1 and IGFBP-3 on bone mass in various skeletal sites and, (b), the relationship between leptin and the GH/IGF axis. 363 healthy individuals were investigated. BMD and serum leptin, GH, IGF-1 and IGFBP-3 serum levels were assessed. Our results indicate that 11% of healthy males had bone density with T scores 相似文献   

Growth hormone substitution increases gene expression of members of the IGF family in cortical bone from women with adult onset growth hormone deficiency--relationship with bone turn-over

OBJECTIVE: To investigate the effects of growth hormone (GH) replacement therapy on bone matrix gene expression of insulin-like growth factors (IGFs) and markers of bone metabolism in women with adult-onset GH deficiency (GHD). DESIGN AND METHODS: Nineteen women, mean age 45 (range 24-56) years, were included in a double-blind, placebo-controlled parallel group study for 12 months. Biochemical markers were measured at baseline, 6 and 12 months. Bone biopsies were obtained and BMD was measured at baseline and after 12 months. RESULTS: Maximum responses were observed after 6 and 12 months, for bone resorptive and bone formative markers respectively. GH therapy enhanced gene expression in cortical bone of IGFs, GH-and calcitonin-receptor (CR) and osteoprotegerin (OPG), however with the most pronounced effects on CR and IGF-I. Changes in IGF-I gene expression during longitudinal follow-up were significantly correlated with changes in both circulating IGF-I (r = 0.82, p < 0.05), changes in markers of enhanced osteoclastic activity, measured both locally in bone (CR, r = 0.87, p < 0.01) and in serum (CTX-I, r = 0.86, p < 0.05), as well as serum bone ALP (r = 0.96, p < 0.01). CONCLUSIONS: This study indicates that both liver- and bone-derived IGF-I may be significant in mediating the effects of GH on bone metabolism in humans.     

Effects of growth hormone on bone modeling and remodeling in hypophysectomized young female rats: a bone histomorphometric study

Growth hormone (GH) deficiency causes decreased bone mineral density and osteoporosis, predisposing to fractures. We investigated the mechanism of action of GH on bone modeling and remodeling in hypophysectomized (HX) female rats. Thirty female Sprague–Dawley rats at age 2 months were divided into three groups with 10 rats each: control (CON) group, HX group, and HX + GH (3 mg/kg daily SC) group, for a 4-week study. Hypophysectomy resulted in cessation of bone growth and decrease in cancellous bone mass. Periosteal bone formation decreased and bone turnover rate of endocortical and trabecular surfaces increased as compared to the CON group. GH administration for 4 weeks restored weight gain and bone growth and mitigated decrease in bone density after hypophysectomy. However, trabecular bone mass in the proximal tibial metaphysis remained lower in group HX + GH than in group CON. Dynamic histomorphometric analysis showed that bone modeling of periosteal bone formation and growth plate elongation was significantly higher in group HX + GH than in group HX. New bone formed beneath the growth plate was predominately woven bone in group CON and group HX + GH. Bone remodeling and modeling–remodeling mixed modes in the endocortical and PTM sites were enhanced by GH administration; both bone formation and resorption activities were significantly higher than in group HX. In conclusion, GH administration to HX rats reactivated modeling activities in modeling predominant sites and increased new bone formation. GH administration also increases remodeling activities in remodeling predominant sites, giving limited net gain in the bone mass.     

Growth hormone increases cortical and cancellous bone mass in young growing rats with glucocorticoid-induced osteopenia.

The effects of growth hormone (GH) on linear growth, bone formation, and bone mass have been examined in glucocorticoid (GC)-injected young growing rats. Two-month-old female Wistar rats were injected for 90 days with 1, 3, 6, or 9 mg of methylprednisolone alone or in combination with 5 mg of GH. Bone mass and bone formation parameters were examined in the femoral cortical bone and in cortical bone and cancellous bone of the lumbar vertebra. GC administration dose dependently decreased growth, longitudinal growth of the vertebra, as well as the modeling drift of the cortical bone of the vertebral body and femoral diaphysis. In the vertebral cancellous bone, GC also decreased the mineralizing surface and inhibited the growth-related increase in cancellous bone volume. GH increased growth, longitudinal growth of the vertebra, as well as the modeling drift of the vertebral body and the femoral diaphysis, resulting in an increased cortical bone mass. GH also increased cancellous bone volume and the mineralizing surface of the vertebral body. In GC-injected animals, GH normalized and further increased growth, longitudinal growth, and the modeling drift of both the femoral diaphysis and the vertebral body, resulting in an increased cortical bone mass at both locations. GH also increased cancellous bone volume of the vertebral body in GC-injected animals, but GH did not, however, reverse the decreased mineralizing surface of cancellous bone induced by GC injections. In conclusion, GC administration to growing rats retards normal growth, longitudinal growth, and cortical bone modeling drift. It also decreases the cancellous bone mineralizing surface and inhibits the normal age-related increase in cancellous bone volume of the vertebral body. In the growing rat skeleton, GH can counteract these GC-induced side effects, except for the GC-induced decrease in the mineralizing surface of cancellous bone of the vertebral body, which remained unaffected by GH administration.     

Predictors of Bone Responsiveness to Growth Hormone (GH) Replacement in Adult GH-Deficient Patients

Growth hormone (GH) replacement in adulthood results in variable bone responses as a function of the gonadic hormonal milieu. We performed a retrospective analysis of a large cohort of adult males and females with confirmed GH deficiency (GHD) prior to treatment and during 3 years of replacement therapy. Potential confounders and effect modifiers were taken into account. Sixty-four adult patients with GHD (20 females and 44 males; mean age 34 years, range 18–64) were included in the analysis. GH replacement induced a different effect on bone in males compared to females. Bone mineral content increased in males and decreased in females at the lumbar spine, total femur, and femoral neck; bone mineral density showed a similar trend at the lumbar spine and femoral neck. There was no significant gender difference in bone area at any measured bone site. In both sexes we observed a similar trend for serum markers of bone remodeling. Sex predicted bone outcome on multivariate analysis, as did age, onset of GHD (childhood/adulthood), pretreatment bone mass, baseline body mass index (BMI), and BMI change during GH replacement. Serum IGF-I levels during treatment did not show any relationship with bone outcome at any measured site. This study confirms that bone responsiveness to GH replacement in adult GHD varies as a function of sex even after controlling for potential confounders and highlights the importance of other cofactors that may affect the interaction between GH replacement therapy and bone remodeling.     

Lipids,blood pressure and bone metabolism after growth hormone therapy in elderly hemodialysis patients

BACKGROUND: Previously we have demonstrated anabolic effects and improved functional status after growth hormone (GH)-therapy in elderly patients in chronic hemodialysis. The aim of this study is to elucidate the effects of GH-therapy on lipid profiles, blood pressure and bone metabolism. METHODS: Twenty patients, mean age 73 years, were randomized into two groups i), growth hormone (rHuGH) therapy at a dose of 0.2 IU/kg/BW, or ii) placebo subcutaneously after each dialysis session in a scheme of 3 dialysis per week during 6 months. Two patients in the GH group died (92 and 79 years old) and 1 patient was transplanted. Ten placebo treated patients and 7 GH treated patients were evaluable. RESULTS: The uremic lipid profile with increased triglycerides (TG), low high density lipoproteins, normal lipo-protein Apo-B and relatively low Apo-E values was changed after GH therapy. An unexpected decrease of TG and an indication of decrease of Apo-E values was noted. This differs from GH-treatment to non-uremic adults. Ambulatory 24-hr blood pressures showed a normal circadian rhythm in all patients (GH:n=7, placebo:n=7) at the start and the end of the study. Bone metabolism was increased in the GH group reflected in significant increases of the osteocalcin and telopeptide of type I collagen values. An indication of increased values of propeptide of type I procollagen did not reach statistical significance. CONCLUSIONS: Our study of GH-therapy to elderly patients on hemodialysis demonstrated decreased triglyceride levels, no effect on 24-hr blood pressure and increased bone metabolism.     

Impact of androgens, growth hormone, and IGF-I on bone and muscle in male mice during puberty.

The interaction between androgens and GH/IGF-I was studied in male GHR gene disrupted or GHRKO and WT mice during puberty. Androgens stimulate trabecular and cortical bone modeling and increase muscle mass even in the absence of a functional GHR. GHR activation seems to be the main determinant of radial bone expansion, although GH and androgens are both necessary for optimal stimulation of periosteal growth during puberty. INTRODUCTION: Growth hormone (GH) is considered to be a major regulator of postnatal skeletal growth, whereas androgens are considered to be a key regulator of male periosteal bone expansion. Moreover, both androgens and GH are essential for the increase in muscle mass during male puberty. Deficiency or resistance to either GH or androgens impairs bone modeling and decreases muscle mass. The aim of the study was to investigate androgen action on bone and muscle during puberty in the presence and absence of a functional GH/insulin-like growth factor (IGF)-I axis. MATERIALS AND METHODS: Dihydrotestosterone (DHT) or testosterone (T) were administered to orchidectomized (ORX) male GH receptor gene knockout (GHRKO) and corresponding wildtype (WT) mice during late puberty (6-10 weeks of age). Trabecular and cortical bone modeling, cortical strength, body composition, IGF-I in serum, and its expression in liver, muscle, and bone were studied by histomorphometry, pQCT, DXA, radioimmunoassay and RT-PCR, respectively. RESULTS: GH receptor (GHR) inactivation and low serum IGF-I did not affect trabecular bone modeling, because trabecular BMD, bone volume, number, width, and bone turnover were similar in GHRKO and WT mice. The normal trabecular phenotype in GHRKO mice was paralleled by a normal expression of skeletal IGF-I mRNA. ORX decreased trabecular bone volume significantly and to a similar extent in GHRKO and WT mice, whereas DHT and T administration fully prevented trabecular bone loss. Moreover, DHT and T stimulated periosteal bone formation, not only in WT (+100% and +100%, respectively, versus ORX + vehicle [V]; p < 0.05), but also in GHRKO mice (+58% and +89%, respectively, versus ORX + V; p < 0.05), initially characterized by very low periosteal growth. This stimulatory action on periosteal bone resulted in an increase in cortical thickness and occurred without any treatment effect on serum IGF-I or skeletal IGF-I expression. GHRKO mice also had reduced lean body mass and quadriceps muscle weight, along with significantly decreased IGF-I mRNA expression in quadriceps muscle. DHT and T equally stimulated muscle mass in GHRKO and WT mice, without any effect on muscle IGF-I expression. CONCLUSIONS: Androgens stimulate trabecular and cortical bone modeling and increase muscle weight independently from either systemic or local IGF-I production. GHR activation seems to be the main determinant of radial bone expansion, although GHR signaling and androgens are both necessary for optimal stimulation of periosteal growth during puberty.     

Analysis of the effects of growth hormone, voluntary exercise, and food restriction on diaphyseal bone in female F344 rats.

The aim of this study is to examine the effects of growth hormone, exercise, and weight loss due to food restriction on tibial diaphyseal bone and on tibial muscle mass. Thirteen-month-old female F344 rats were divided into six groups: group 1, baseline controls (B); group 2, age-matched controls (C); group 3, GH treated (GH); group 4, voluntary wheel running exercise (EX); group 5, GH + EX; and group 6, food restricted (FR). The dose of GH was 2.5 mg recombinant human (rh) GH/kg body weight/day, 5 days per week, given in two divided doses of 1.25 mg at 9-10 A.M. and 4-5 P.M. Food-restricted rats were fed 60% of the mean food intake of the age-matched controls. All animals except the baseline controls were killed after 4.5 months. The baseline controls were killed at the beginning of the study. Growth hormone increased the body weight and tibial muscle mass of the rats markedly, while EX caused only a slight decrease in body weight and partially inhibited the increase caused by GH in the GH + EX group. Food restriction greatly decreased body weight below that of age-matched controls, but neither FR nor EX had a significant effect on the mass of the muscles around the tibia. Growth hormone and EX independently increased tibial diaphyseal cortical bone area (p < 0.0001, p < 0.0001), cortical thickness (p < 0.0001, p < 0.0001), cortical bone mineral content (p < 0.0001, p < 0.0001), periosteal perimeter (p < 0.0001, p < 0.0001), and bone strength-strain index (SSI) (p < 0.0001, p < 0.0001). The effects of GH were more marked and resulted in a greater increase in the weight of the mid tibial diaphysis (p < 0.0001). The combination of GH and EX produced additive effects on many of the tibial diaphyseal parameters, including bone SSI. GH + EX, but not GH or EX alone, caused a significant increase in endocortical perimeter (p < 0.0001). In the FR rats, cortical bone area and cortical mineral content increased above the baseline level (p < 0.001, p < 0.0001) but were below the levels for age-matched controls (p < 0.0001, p < 0.0001). In addition, marrow area, endocortical perimeter, and endocortical bone formation rate increased significantly in the FR rats (p < 0.01, p < 0.0001, p < 0.0001). Three-point bending test of right tibial diaphysis resulted in maximum force (Fmax) values that reflected the group differences in indices of tibial diaphyseal bone mass, except that GH + EX did not produce additive effect on Fmax. The latter showed good correlation with left tibial diaphyseal SSI (r = 0.857, p < 0.0001), and both indices of bone strength correlated well with tibial muscle mass (r = 0.771, Fmax; r = 0.700, SSI; p < 0.0001). GH increased serum IGF-I (p < 0.0001), and the increase was partially reduced by EX. Serum osteocalcin was increased by GH with or without EX (p < 0.01, p < 0.01), and FR or EX alone did not alter serum IGF-I and osteocalcin levels. The bone anabolic effects of GH with or without EX may relate, in part, to increased load on bone from tibial muscles and body weight, which were increased by the hormone. The osteogenic effect of EX with or without GH may relate, in part, to increased frequency of muscle load on bone as EX decreased body weight (p < 0.05), but had no significant effect on tibial muscle mass. The enhanced loss of endocortical bone by FR may relate, in part, to decreased load on bone due to low body weight (p < 0.0001), as FR did not cause a significant decrease in tibial muscle mass (p = 0.357). The roles of humoral and local factors in the bone changes observed remain to be established.     

The effect of ovariectomy and ovarian steroid treatment on growth hormone and insulin-like growth factor-I levels in the rat femur.

Growth hormone (GH) and insulin-like growth factor-I (IGF-I) are known to play an important role in bone metabolism. The regulation of plasma levels of GH and IGF-I by ovarian steroids is well known, however, their effect on local GH and IGF-I is still unclear. In this study, we investigated the effect of ovariectomy and ovarian steroid treatment on the femur GH and IGF-I levels as well as on bone density in the rat. Nine month-old rats were ovariectomized (OVX) or sham-operated (SHAM) and 9 weeks after the surgery they were treated with daily s.c. injections of either 17beta-estradiol (OVX + E), progesterone (OVX + P), or vehicle (OVX + V) for another 10 weeks. GH and IGF-I levels in the femur extracts were measured by specific radioimmunoassay (RIA). Ovariectomy decreased GH and had no effect on IGF-I levels. Estradiol treatment increased femur GH and IGF-I levels compared to SHAM rats. Progesterone restored GH and increased IGF-I levels. Ovariectomy decreased, estrogen restored and progesterone partially restored femur bone density. Our results demonstrate that ovariectomy and ovarian steroids modulate the levels of GH and IGF-I in the bone of aged OVX rats. However, these effects appear to be limited to supraphysiological concentrations of estradiol and progesterone.     

Similar effects of long-term exogenous growth hormone (GH) on bone and muscle parameters: a pQCT study of GH-deficient and small-for-gestational-age (SGA) children

BACKGROUND AND AIMS: Treatment with GH in short children has focused on height development. Little is known about the concomitant changes in muscle mass, bone structure and bone strength. METHODS: Muscle area as well as parameters of bone architecture (bone mineral content, BMC; volumetric cortical density, total bone area, TBA; cortical area, cortical thickness, CT; and marrow area) were measured by means of pQCT (Stratec) at 65% of the proximal length of the forearm. The strength-strain index (SSI) was calculated as an indicator of bone strength. RESULTS: Prepubertal children with GHD (mean values: age; 7.2 years; height SDS=-2.9 SDS; GH dose: 30 microg/kg/d) were followed at 0, 6, 12 (n=74) and 24 (n=55) months. Prepubertal children with SGA (mean values: age: 7.1 years; height SDS=-3.4 SDS; GH dose: 55 mug/kg/d) were followed at 0, 6, 12 (n=47) and 24 (n=35) months. Both groups showed a similar increase in height. At GH start, muscle mass and bone characteristics were lower than normal but similar in SGA vs. GHD. Muscle area (mean values, SDS) increased from -3.0 to -1.5 in SGA and from -2.4 to -1.0 in GHD. Bone geometry changed in a biphasic mode, with an increase in total bone area and lowering of bone mineral content (BMC) during the first 12 months, followed by an increase of BMC and CT thereafter. SSI (mean values, mm(3)) improved from 78 to 114 in GHD and from 62 to 101 in SGA after 24 months on GH. The increment in terms of SDS did not reach significance in SGA. SSI correlated positively with muscle area before and during GH treatment. CONCLUSIONS: Bone strength and muscle mass are impaired in prepubertal children with GHD and SGA. Exogenous GH can indirectly improve bone structure and strength by inducing an increase in muscle mass. Our findings support the assumption that, in SGA, there is impaired tissue responsiveness to GH.     

Effects of 24 Months of Growth Hormone (GH) Treatment on Serum Carboxylated and Undercarboxylated Osteocalcin Levels in GH-Deficient Adults

We studied the effect of growth hormone (GH) replacement on bone mineral density (BMD) and some parameters of bone metabolism, including undercarboxylated osteocalcin (ucOC), an independent predictive marker of fracture risk, which has not been previously determined or compared during GH treatment. Measurements were performed at baseline and after 6, 12, 18 and 24 months of the initiation of the GH therapy in 21 adult patients with GH deficiency. Significant increases were observed in BMD after 1 year at the lumbar spine and after 1.5 years at the femoral neck. Serum total OC and carboxylated (c) OC increased and reached the maximum at 6 months, but the values remained over the baseline at both 12 and 18 months. The ucOC:total OC ratio changed contrarily: it decreased at 6 months, then increased again and reached the baseline level during the next 18 months. Serum calcium (Ca), phosphate (P) and total alkaline phosphatase (ALP) levels increased after 6 months, thereafter the Ca and P values decreased, while the total ALP remained elevated until 12 months. Serum parathormone decreased at 12 months and increased again thereafter. GH replacement therapy is associated with improvement of ucOC, a marker of fracture risk, which in addition to the increase of BMD, might contribute to the beneficial effect of GH replacement therapy on bone metabolism.     

Bone mineral density in early-onset hypogonadism and the effect of hormonal replacement.

Hypogonadism is associated with reduction of bone mineral density (BMD), especially if sex steroid deficiency occurs early in life. In this situation, the effect of hormonal replacement therapy on bone mass is controversial. We evaluated the BMD through dual-energy X-ray absorptiometry (DXA) in patients with genetically determined hypogonadism or hypogonadism acquired in adulthood. The results of the BMD of patients never treated (pretreatment) or under treatment were compared with population standards and were submitted to pair analysis. Thirty-three patients were evaluated: group 1: BMD evaluated pretreatment (24); group 2: BMD evaluated under treatment (21); group 3: BMD evaluated pretreatment and under treatment (12). In group 1, there was a significant reduction of bone mass in all regions, with no gender differences. In patients with concomitant growth hormone (GH) deficiency, the total body (-3.60) and lumbar spine (-4.10) BMDs were significantly reduced compared to patients without associated GH deficiency (-2.37 and -2.35, respectively). In group 2, a significant reduction of bone mass was detected in all regions. In group 3, the patients showed statistically significant improvement in BMD with hormonal replacement therapy in all regions in both sexes. We conclude that the early onset of hypogonadism reduces the BMD significantly. This effect is increased when there is associated GH deficiency. Gonadal steroid replacement therapy increases the BMD in all bone regions, and the increase is similar in both sexes. However, although hormone replacement improves bone mass, it still remains significantly lower in comparision with population standards.     

Effects of 24 Months of Growth Hormone (GH) Treatment on Serum Carboxylated and Undercarboxylated Osteocalcin Levels in GH-Deficient Adults

We studied the effect of growth hormone (GH) replacement on bone mineral density (BMD) and some parameters of bone metabolism, including undercarboxylated osteocalcin (ucOC), an independent predictive marker of fracture risk, which has not been previously determined or compared during GH treatment. Measurements were performed at baseline and after 6, 12, 18 and 24 months of the initiation of the GH therapy in 21 adult patients with GH deficiency. Significant increases were observed in BMD after 1 year at the lumbar spine and after 1.5 years at the femoral neck. Serum total OC and carboxylated (c) OC increased and reached the maximum at 6 months, but the values remained over the baseline at both 12 and 18 months. The ucOC:total OC ratio changed contrarily: it decreased at 6 months, then increased again and reached the baseline level during the next 18 months. Serum calcium (Ca), phosphate (P) and total alkaline phosphatase (ALP) levels increased after 6 months, thereafter the Ca and P values decreased, while the total ALP remained elevated until 12 months. Serum parathormone decreased at 12 months and increased again thereafter. GH replacement therapy is associated with improvement of ucOC, a marker of fracture risk, which in addition to the increase of BMD, might contribute to the beneficial effect of GH replacement therapy on bone metabolism.     

Longitudinal in vivo effects of growth hormone overexpression on bone in transgenic mice.

In this study we examined the effect of systemic overexpression of GH on bone in transgenic mice longitudinally in vivo over a period of 9 months. We observed substantially increased BMC in GH transgenic mice and a significant reduction in serum osteocalcin. GH effects on bone were strongly dependent on gender and developmental stage. INTRODUCTION: State-of-the-art bone marker and microimaging technology was applied in this longitudinal study to examine bone metabolism, BMC, bone density, and cortical bone structure over the life span of growth hormone (GH) transgenic (tg) mice. MATERIALS AND METHODS: Thirty-eight mice from four genetic groups (male, female, tg, and controls) were examined with DXA, and their femur and tibia were examined with peripheral QCT (pQCT). Osteocalcin (formation) and collagen cross-links (resorption) from serum and urine were also measured at postnatal weeks 3, 6, 9, 12, 18, 26, and 38. RESULTS: GH tg mice displayed a significant increase in body weight (up to 50%) and BMC (up to 90%), but serum osteocalcin was significantly reduced compared with controls. GH tg females (but not males) displayed increased trabecular density over controls up to week 12. In contrast, male (but not female) GH tg mice displayed a higher cortical cross-sectional area than controls. Cortical density was significantly lower in both male and female GH tg mice compared with control mice. CONCLUSIONS: The increase in BMC in GH tg mice is associated with reduced serum osteocalcin levels, indicating that bone turnover may be lower than in the control mice. On a structural level, bone responds to GH excess in a gender-specific manner, with alterations varying substantially between different developmental stages.     

Low IGF-I levels in hip fracture patients: A comparison of 20 coxarthrotic and 23 hip fracture patients

We measured total body bone density and body composition with dual energy x-ray absorptiometry in 43 elderly patients, 23 with hip fracture and 20 with coxarthrosis, after surgery and after 6 months. Insulin-like growth factor-1 (IGF-I), a polypeptide known to affect bone metabolism, and two of its binding proteins (IGFBP-1, IGFBP-3) were measured preoperatively and after 6 months. Normal serum IGF-I levels are dependent on adequate nutrition and normal secretion of growth hormone (GH). We found consistently lower levels of IGF-I and IGFBP-3 and a tendency to higher levels of IGFBP-1 in the patients with hip fractures, who also had a lower total body mass, lower fat mass and bone mineral density than the coxarthrosis group, indicating a more catabolic state in the patients with hip fracture, even 6 months after the trauma.     

Hormonal effects on the morphology of bone defect healing.

Standard defects were produced in the radii of hypophysectomized immature rats. All animals were injected with Methimazole, and grouped according to hormone supplementation, growth hormone (GH), thyroxine (T4), the combination, or no hormones. Lack of GH and T4 caused a retardation of defect healing and callus formation but not a total cessation. The presence of GH in the hypophysectomized animal caused a larger callus due to greatly increased chondrogenesis throughout the 6 week study. Thyroxine in the hypophysectomized animal increased bone metabolism and caused more cartilage and bone formation than seen in the hormone deficient group, but not as great as that seen in the GH injected animals or the T4 and GH injected animals. Growth hormone allowed greater chondrogenesis; T4 enhanced maturation to bone. The combination allowed the development of a callus similar in stage and proportion of tissue to that observed in the pituitary intact animals. The influences of GH and T4 on the healing of a bone defect in the immature rat correspond to influences of GH and T4 on growing epiphyseal plate.     

Effect of long-term growth hormone treatment on bone mass and bone metabolism in growth hormone-deficient men.

Long-term GH treatment in GH-deficient men resulted in a continuous increase in bone turnover as shown by histomorphometry. BMD continuously increased in all regions of interest, but more in the regions with predominantly cortical bone. INTRODUCTION: Adults with growth hormone (GH) deficiency have reduced rates of bone turnover and subnormal BMD. GH treatment is effective in enhancing bone turnover as shown by biochemical markers and bone histomorphometric studies. However, it is uncertain whether long-term treatment will result in higher bone mass. In this study, we present BMD and histomorphometric data on 5 years of GH treatment in GH-deficient men. MATERIALS AND METHODS: Thirty-eight adult men with childhood onset GH deficiency (20-35 years) were included in the study. Twenty-six of these had multiple pituitary hormone deficiencies and were on stable conventional hormone replacement. BMC (total body) and BMD (lumbar spine and hip) were measured before and after 1, 2, 3, 4, and 5 years of treatment. BMD in various regions of the total body was calculated by computer software (head, trunk, arms, and legs). Transiliac bone biopsies were obtained before and after 1 and 5 years of GH treatment. RESULTS: Total body BMC increased 18% after 5 years of treatment. This increase was observed in all regions of interest: head, 13.7%; trunk, 27.8%; arms, 24.4%; legs, 13.8%. BMD also increased in all separately measured regions: lumbar spine, 9%; femoral neck, 11%; femoral trochanter, 16%. Lumbar spine area significantly increased (p=0.0002). Histomorphometric data showed increased osteoid surface (p<0.02), osteoid volume (p<0.01), and activation frequency (p<0.006), but trabecular bone volume did not increase significantly. Qualitative assessment of the cortical bone showed endosteal and periosteal bone formation. CONCLUSIONS: In conclusion, GH considerably increases BMC after long-term treatment. The combination of BMD and histomorphometric data suggests that GH has a greater effect on cortical than on trabecular bone.