Growth hormone,insulin-like growth factors,and the senescent skeleton: Ponce de Leon's fountain revisited?

As the population ages, the prevalence of osteoporosis will continue to rise. Yet, the mechanisms leading to age-related bone loss remain poorly defined. Furthermore, extensive logitudinal studies of bone mass, especially in the three decades beyond menopause, have not been completed. Although calciotropic hormones, growth hormone (GH), and insulin-like growth factor-I (IGF-I) change with age, it is not certain if these changes are responsible for age-related bone loss. Nor is it clear if the “sensecent” osteoblast is fully responsive to growth factor stimulation. To complicate matters further, both circulatory and skeletal IFG regulatory systems are extremely redundant. Changes in serum IFGs may lead to compensatory alterations in IGF regulatory systems are extremely redundant. Changes in serum IGFs may lead to compensatory alterations in IGF receptor number, IGF binding protein (IGFBP) synthesis, or IGFBP catabolism. What is measured in serum, maya, in the end, be either a mirror or a rirage of skeletal IGF action! Clinical trials with “replacement” doses of GH or IGF-I are underway. But, critical efidence does not yet support the concept that a true “sommatopause” alters bone remodeling. Moreover, only scarce data exist that GH augments bone formation or prevents bone loss in the elderly. As clinicians expand the use of recombinant growth factors to elders, ethical and clinical issues surrounding administration of the new “fountain of youth” will be revisited. For basic scientists studying skeletal growth factors and their relationship to senescence, significant questions remain unanswered. New technological advances will provide clues about the basic mechanisms of skeletal aging. But, until these findings are validated, scientists and clinicians will have difficulty judging the role of growth factors in halting, or reversing, the inexorable consequences of aging.     

Prepubertal OVX increases IGF-I expression and bone accretion in C57BL/6J mice

It is generally well accepted that the pubertal surge in estrogen is responsible for the rapid bone accretion that occurs during puberty and that this effect is mediated by an estrogen-induced increase in growth hormone (GH)/insulin-like growth factor (IGF) action. To test the cause and effect relationship between estrogen and GH/IGF, we evaluated the consequence of ovariectomy (OVX) in prepubertal mice (C57BL/6J mice at 3 wk of age) on skeletal changes and the GH/IGF axis during puberty. Contrary to our expectations, OVX increased body weight (12-18%), bone mineral content (11%), bone length (4%), bone size (3%), and serum, liver, and bone IGF-I (30-50%) and decreased total body fat (18%) at 3 wk postsurgery. To determine whether estrogen is the key ovarian factor responsible for these changes, we performed a second experiment in which OVX mice were treated with placebo or estrogen implants. In addition to observing similar results compared with our first experiment, estrogen treatment partially rescued the increased body weight and bone size and completely rescued body fat and IGF-I levels. The increased bone accretion in OVX mice was due to increased bone formation rate (as determined by bone histomorphometry) and increased serum procollagen peptide. In conclusion, contrary to the known estrogen effect as an initiator of GH/IGF surge and thereby pubertal growth spurt, our findings demonstrate that loss of estrogen and/or other hormones during the prepubertal growth period effect leads to an increase in IGF-I production and bone accretion in mice.     

Involvement of growth hormone (GH) and insulin-like growth factor (IGF) system in ovarian folliculogenesis

During the last decade, involvement of growth hormone (GH), insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) in ovarian folliculogenesis has been extensively studied. This review provides an update on the GH, IGF system and their role in ovarian follicular development. In vitro studies and knockout experiments demonstrated an important role of GH in preantral follicle growth and differentiation through their binding with GH receptors, which are located both in the oocyte and follicular somatic tissues. Furthermore, GH stimulates the development of small antral follicles to gonadotrophin-dependent stages, as well as maturation of oocytes. With regard to the IGF system, IGF-I has no effects on primordial follicle development, but both IGF-I and IGF-II stimulate growth of secondary follicles. Depending on the species studies and method used, these proteins have been detected in oocytes and/or somatic cells. In antral follicles, these IGFs stimulate granulosa cell proliferation and steroidogenesis in most mammals. The bioavailability of IGFs is regulated by a family of intrafollicular expressed IGF binding proteins (IGFBPs). Facilitation of IGF can be increased through the activity of specific IGFBP proteases, which degrade the IGF/IGFBP complex, resulting in the production of IGFBP fragments and release of attached IGF.     

The insulin-like growth factor system: towards clinical applications

Insulin-like growth factors (IGF-I and II) are important endocrine, paracrine and autocrine mediators of physiological growth. They promote cellular proliferation, survival and differentiation. Their effects are mediated mainly through the IGF-I receptor, but IGFs also bind to the IGF-II/mannose 6-phosphate and insulin receptors. IGF activity is modulated by a family of six high-affinity IGF binding proteins (IGFBPs); in most situations, IGFBPs inhibit IGF actions but they may also enhance them. Assays are now available for IGF-I, IGF-II and individual IGFBPs. IGF-I and IGFBP-3 assays have some utility in the diagnosis and management of acromegaly and growth hormone deficiency. There is a large body of in vitro and in vivo evidence supporting a pathogenic role for alterations in the IGF system in many diseases, including diabetes, cancer, cardiovascular disease and neuromuscular disease. More recently, epidemiological studies have linked high IGF-I levels with some cancers and low IGF-I levels with ischaemic heart disease. Preliminary studies of recombinant IGF-I as a treatment for diabetes, osteoporosis and neuromuscular disease have been performed in humans. In contrast, there is considerable interest in developing IGF inhibitors for the treatment of cancer. This apparent paradox highlights the need to develop therapeutics beyond the natural ligands and inhibitors, with characteristics such as ligand and tissue specificity. This will only become possible as we increase our understanding of this complex system. Additionally, as IGF and IGFBP assays are becoming more readily available, their role in the diagnosis and monitoring of diseases should be more clearly defined in the near future.     

The role of insulin-like growth factor-I in neuroendocrine function and the consequent effects on sexual maturation: inferences from animal models

It is known that growth hormone (GH) plays an important role in growth and development.Additionally, emerging evidence suggest that it also influences hypothalamic-pituitary-gonadal function. We have found that GH from different species has different effects in mice. In rodents, human GH (hGH) binds to both GH and prolactin (PRL) receptors; it has both somatotrophic and lactotrophic effects. Since PRL has a profound effect on neuroendocrine function, the results obtained from hGH treatment or from transgenic animals expressing the hGH gene reflect PRL-like effects of this hormone. However, bovine GH (bGH) is purely somatogenic and therefore the effects of bGH represent the function of the natural GH produced in rodents. Furthermore, our studies in mice and rats have shown that not all effects of GH are stimulatory and the duration of exposure of the hypothalamo-hypophyseal-gonadal system to GH might influence the secretions of gonadotropins and gonadal steroids. In humans, excess productions of GH in acromegaly and GH resistance in Laron syndrome adversely affect reproduction. Similarly, it has been demonstrated that in transgenic mice expressing various GH genes, in insulin-like growth factor-I (IGF-I) gene-knockout mice, in GH receptor gene-disrupted (GHR-KO) mice, and in Ames dwarf mice the onset of puberty and/or fertility is altered. Therefore, excess or subnormal secretion of GH can affect reproduction. We have shown that the hypothalamic-pituitary functions are affected in transgenic mice expressing the GH genes, Ames dwarf mice and in GH receptor gene knockout mice. The majority of the GH effects are mediated via IGF-I and the aforementioned effects may be due to the GH-induced IGF-I secretion or due to the absence of this peptide production. It is important to realize that the syntheses and actions of IGF binding proteins are controlled by IGF-I. Furthermore, some IGF binding proteins can inhibit IGF-I action. Therefore, the concentrations of IGF binding proteins and the ratio of these binding proteins and IGF-I within the body might play a pivotal role in modulating IGF-I effects on the neuroendocrine-gonadal system.     

Osteoporosis and the growth hormone-insulin-like growth factor axis

Osteoporosis is the result of an imbalance between bone resorption and bone formation. Currently, mainly drugs that inhibit bone resorption are available for the treatment of osteoporosis. A new approach in the treatment of osteoporosis is the use of anabolic agents that increase bone turnover, both bone formation and resorption. Growth hormone (GH) and insulin-like growth factors (IGFs) are essential in the development and growth of the skeleton and for the maintenance of bone mass and density. We will review the evidence of GH and IGF-I in the pathophysiology and treatment of osteoporosis.     

How robust are laboratory measures of growth hormone status?

Biochemical assessment of growth hormone (GH) status is required in both suspected GH deficiency and GH excess. GH secretion can either be measured through investigation of the pituitary or by monitoring markers that change as a consequence of GH action on its target tissues. The two most widely used and, to date, best validated biochemical parameters are immunoassay measurement of either human GH (hGH) or insulin-like growth factor (IGF)-I. The fundamental difference between measurement of hGH and IGF-I is that the first reflects GH secretion while the second reflects GH action. However, because GH secretion is pulsatile in nature, random blood sampling for determination of hGH levels is only minimally informative. Analytical methods for measuring GH and IGF-I show considerable between-method variability. Since these parameters are used in establishing diagnoses and in monitoring GH-related diseases, the endocrinologist should be aware of the specifications and limitations of the analytical methods available.     

From mouse to man: redefining the role of insulin-like growth factor-I in the acquisition of bone mass

The insulin-like growth factor system (IGF) has been linked to the process of bone acquisition through epidemiologic analyses of large cohorts and in vitro studies of bone cells. But the exact relationship between expression of IGF-I in bone and skeletal homeostasis or pathologic conditions, such as osteoporosis, remains poorly defined. Recent advances in genomic engineering have resulted in the development of better in vivo models to test the role of IGF-I during development and maintenance of the adult skeleton. It is now established that skeletal expression of IGF-I is critical for differentiative bone cell function. It may also be essential for the full anabolic effects of parathyroid hormone on trabecular bone and for some component of biomineralization. Evidence from conditional mutagenesis studies suggests that serum IGF-I may represent more than a storage depot or permissive factor during the final phase of skeletal acquisition. This work re-examines the original tenets of the "somatomedin hypothesis" in light of these newer mouse models and their remarkable skeletal phenotypes. The implications are far reaching and suggest that newer approaches for manipulating the IGF regulatory system may one day be useful as therapeutic adjuncts for the treatment of osteoporosis.     

Insulin-like growth factor-I is internalized after binding to the type I insulin-like growth factor receptor

Receptor-mediated endocytosis may represent an important mechanism whereby peptide hormones exert their biological effects. The ability of recombinant insulin-like growth factor (IGF)-I to be internalized by cultured cells was evaluated in BRL-3A2 cells, a rat liver-derived cell line which lacks insulin receptors. Since recombinant IGF-I does not bind to the Type II IGF receptor, all specific binding of 125I-IGF-I in BRL-3A2 cells represents binding to the Type I receptor. Exposure of BRL-3A2 cells to IGF-I resulted in a rapid 50% downregulation of Type I IGF receptors. Only one-half of these binding sites were sensitive to treatment with trypsin, a phenomenon which indicates that the peptide and its receptor were internalized after the cells were exposed to IGF-I. In conclusion, these experiments demonstrate that IGF-I can be internalized by cultured cells via the Type I IGF receptor, and suggest that IGF hormone action may be exerted by receptor-mediated endocytosis.     

Chronic upper airway resistive loading induces growth retardation via the GH/IGF-I axis in prepubescent rats.

The effect of upper airway loading on longitudinal bone growth and various components of the growth hormone (GH)/insulin-like growth factor I (IGF-I) axis has not been fully elucidated. In the present study, the effect of chronic resistive airway loading (CAL) in a prepubescent rat model on linear bone growth and weight gain was investigated. We hypothesize that CAL induced in prepubescent rats will lead to impaired longitudinal growth due to impairment in circulating and liver GH/IGF-I parameters. The tracheae of 22-day-old rats were obstructed by tracheal banding to increase inspiratory esophageal pressure. The GH/IGF-I markers were analyzed using ELISA, RT-PCR, and Western immunoblot analysis 14 days after surgery. Animals exhibited impaired longitudinal growth as demonstrated by reduction of tibia and tail length gains by 40% (P < 0.0001) and body weight gain by 24% (P < 0.0001). No differences were seen in total body energy balance, i.e., oxygen consumption, daily food intake, or arterial blood gases. Circulating GH, IGF-I, and IGF binding protein-3 (IGFBP-3) levels were reduced by 40% (P = 0.037), 30% (P < 0.006), and 27% (P = 0.02), respectively, in the CAL group. Liver IGF-I mRNA level decreased by 20% (P < 0.0002), whereas GH receptor mRNA and protein expression were unchanged. We conclude that impaired longitudinal growth in prepubescent CAL rats is related to a decrease in GH, IGF-I, and IGFBP-3 levels.     

Insulin-like growth factor-binding protein-5 inhibits osteoblast differentiation and skeletal growth by blocking insulin-like growth factor actions

Signaling through the IGF-I receptor by locally synthesized IGF-I or IGF-II is critical for normal skeletal development and for bone remodeling and repair throughout the lifespan. In most tissues, IGF actions are modulated by IGF-binding proteins (IGFBPs). IGFBP-5 is the most abundant IGFBP in bone, and previous studies have suggested that it may either enhance or inhibit osteoblast differentiation in culture and may facilitate or block bone growth in vivo. To resolve these contradictory observations and discern the mechanisms of action of IGFBP-5 in bone, we studied its effects in differentiating osteoblasts and in primary bone cultures. Purified wild-type (WT) mouse IGFBP-5 or a recombinant adenovirus expressing IGFBP-5WT each prevented osteogenic differentiation induced by the cytokine bone morphogenetic protein (BMP)-2 at its earliest stages without interfering with BMP-mediated signaling, whereas an analog with reduced IGF binding (N domain mutant) was ineffective. When added at later phases of bone cell maturation, IGFBP-5WT but not IGFBP-5N blocked mineralization, prevented longitudinal growth of mouse metatarsal bones in short-term primary culture, and inhibited their endochondral ossification. Because an IGF-I variant (R3IGF-I) with diminished affinity for IGFBPs promoted full osteogenic differentiation in the presence of IGFBP-5WT, our results show that IGFBP-5 interferes with IGF action in osteoblasts and provides a framework for discerning mechanisms of collaboration between signal transduction pathways activated by BMPs and IGFs in bone.     

Insulin-like growth factor-I and central nervous system development.

Insulin-like growth factor-I (IGF-I), a 70-amino acid-protein structurally similar to insulin, promotes cell proliferation and differentiation in multiple tissues. Most of its effects are mediated by the Type I IGF receptor (IGF-IR), a heterotetramer that has tyrosine kinase activity and phosphorylates insulin receptor substrates (IRS-1 and 2) which leads to the activation of two downstream signaling cascades: the MAP kinase and the phosphatidylinositol 3-kinase (P3K) cascades. The growth-promoting effects of IGF-I are prominent in the nervous system, qualifying this molecule as a neurotrophin. Although the primary regulator of IGF-I expression is growth hormone (GH), the developmental expression of IGF-I in various tissues precedes that of GH, supporting an independent role of IGF-I in embryonic and fetal life [1]. This review will examine the effect of IGF-I on central nervous system (CNS) development. The specialized structure of the CNS is the product of a complex series of biological events which result from the interaction between the cells' genetic program and environmental influences. CNS development begins in the embryo with dorsal ectodermal cell proliferation to form the neural plate, and, with its closure, the neural tube, followed by the rapid division of pluripotential cells, their migration to the periphery of the neural tube, and differentiation into neural or glial cells. During the latter stages, cells form special structures such as nuclei, ganglia, cerebral cortical layers, and they also develop a network with their cytoplasmic extensions, neurites. Many more cells and connections are generated in fetal life than are found in the mature organism. This excessive production of some cell groups and neurites may compensate for tissue loss due to various injuries, and their selective elimination also constitutes an efficient way to organize the architecture of the CNS. This elimination is believed to be accomplished by apoptosis. The cells' intrinsic program for development includes the expression of various genes at different times. Environmental influences, such as extracellular matrix (ECM) molecules that attract or repel cells, afferent inputs, and target-derived diffusible molecules modify and modulate cellular behavior. IGF-I is among the molecules which affect several steps involved in development.     

Role and molecular mechanism of ghrelin in degenerative musculoskeletal disorders

Ghrelin is a brain-gut peptide, and the first 28-peptide that was found in the gastric mucosa. It has a growth hormone (GH)-releasing hormone-like effect and can potently promote the release of GH from pituitary GH cells; however, it is unable to stimulate GH synthesis. Therefore, ghrelin is believed to play a role in promoting bone growth and development. The correlation between ghrelin and some degenerative diseases of the musculoskeletal system has been reported recently, and ghrelin may be one of the factors influencing degenerative pathologies, such as osteoporosis, osteoarthritis, sarcopenia and intervertebral disc degeneration. With population ageing, the risk of health problems caused by degenerative diseases of the musculoskeletal system gradually increases. In this article, the roles of ghrelin in musculoskeletal disorders are summarized to reveal the potential effects of ghrelin as a key target in the treatment of related bone and muscle diseases and the need for further research.     

Recent advances in the biochemistry and physiology of the insulin-like growth factor/somatomedin family

The insulin-like growth factors (IGF) or somatomedins (Sm) are a family of low molecular weight circulating growth factors which have a major, but not absolute, dependence on GH, and have been shown to stimulate body growth and skeletal metabolism in vivo. They are thus considered to mediate the effects of GH on skeletal growth. In humans, the family consists of two well-characterized forms--IGF-I or SmC (a basic peptide) and IGF-II (a "neutral" peptide)--as well as perhaps two less well characterized forms--SmA (a neutral peptide) and an acidic insulin-like activity (ILA pI 4.8). Similar IGF/Sm species have been found and well-characterized in rat serum. Some higher mol wt forms also exist in tissues and body fluids and may represent possible precursor forms. On the basis of in vitro, clinical and in vivo evidence it has been postulated that IGF-I is the primary growth factor in the adult, whilst IGF-II is probably a major foetal growth factor. In vitro the IGF/Sms have a variety of effects including (1) acute insulin-like metabolic actions, which are observed primarily in insulin target tissues and are initiated largely at insulin receptors, and (2) longer term effects, associated with cell growth and skeletal tissue metabolism, and which occur in traditionally non-insulin target tissues, primarily via IGF/Sm receptors. These observations, together with the circumstantial clinical evidence favouring a close association between IGF levels and growth status, clearly indicate a role for IGF/Sms in growth regulation. This concept is now fully supported by the demonstration that IGF-I infused into hypophysectomized (GH-deficient) rats results in increased growth and skeletal metabolism. The physiological regulation of the expression of net IGF activity in vivo is complex and is controlled by the following three determinants: the levels of IGFs, the levels of the specific carrier-proteins and the levels of IGF inhibitors. Both IGFs and their carrier-proteins are influenced by the GH status of the animal as well as by other hormones, nutritional status and chronic illness. Little is known yet about the control of the various IGF inhibitors that have been described. Of importance, however, is the general concept that normal growth is dependent on an adequate balance between all three determinants and that some regard must be had for the contribution of each in determining the overall potential for growth under given circumstances.     

IGFs and human cancer: implications regarding the risk of growth hormone therapy

Perturbations of the insulin-like growth factor (IGF) axis, including the autocrine production of IGFs, IGF binding proteins (IGFBPs) and IGFBP proteases such as prostate specific antigen (PSA), and cathepsin D have been identified in prostate, lung and breast cancer cells and tissues. Serum IGFBP-3 levels have been found to be negatively correlated to the risk of cancer. Interestingly, IGFBP-3 is a potent inhibitor of IGF action and also mediates apoptosis via an IGF-independent mechanism. Recent case-control studies have found an approximately 10% increase in the serum levels of IGF-I in patients with prostate, breast and lung cancers, which are among the most frequently diagnosed cancers. While the studies indicate an association between serum IGF-I levels and cancer risk, causality has not been established. Thus, serum IGF-I level may actually be a confounding variable, serving as a marker for autocrine tissue IGF-I production. Growth hormone (GH) therapy raises both IGF-I and IGFBP-3 levels in serum. However, the role of GH in controlling prostate, breast and lung growth and carcinogenesis remains unclear from animal studies. Increased GH levels as seen in acromegaly have been associated with benign prostatic hyperplasia but not with prostate, breast or lung cancers, although colon cancer mortality may be increased. Should serum IGF-I levels be proven to play a causal role in the pathogenesis of cancer, interpreting the risk associated with therapies such as GH replacement must take into account both the duration of exposure and the risk magnitude associated with the degree of serum IGF-I elevation. Since GH-deficient patients often have a subnormal IGF-I serum level, which normalizes on therapy, their cancer risk on GH therapy probably does not increase substantially above that of the normal population. Until further research in the area dictates otherwise, ongoing surveillance and routine monitoring of IGF-I levels in GH recipients should become standard of care.     

Serum leptin, insulin-like growth factor-I components and sex-hormone binding globulin. Relationship with sex, age and body composition in healthy population

Leptin plays an important role in the regulation of food intake and thermogenesis, regulates long term energy balance and reproductive function and its concentrations are closely linked to body mass index. Leptin secretion is influenced by many factors and the age-related changes in different hormones might modify circulating leptin concentrations. Sex dimorphism in leptin concentrations has been clearly shown in previous studies and its concentrations were lower in men than in women in all decades of life. Insulin growth factor-I (IGF-I) is a peptide growth factor that is present in all types of physiologic fluids and is also produced by connective tissue cell types and its autocrine/paracrine secretion is nearly always present within tissues. There is a physiological decline of the growth hormone (GH)/IGF-I axis with ageing and in addition, insulin, thyroid hormones and the supply of dietary energy may directly regulate the circulating levels of the IGFs and growth hormone binding protein (GHBP). Furthermore, there is no doubt that GH participates in the regulation of body composition, and with advanced age there is a decrease in muscle and an increase in adiposity associated with a decline in GH and total IGF-I. The biological activities of the IGF ligands are modulated by the family of high affinity GHBP. Sex hormone binding globulin (SHBG) concentrations are thought to be regulated primarily through opposing actions of sex steroids on hepatic SHBG production, with oestrogen stimulating and androgen inhibiting SHBG production, and thyroid hormones are also a potent stimulator of SHBG production concentrations. Some studies support an independent IGFBP3 contribution to SHBG variability and these findings are compatible with the hypothesis that some of the anabolic effects ascribed to the GH/IGF axis may be caused by SHBG-mediated changes in testosterone activity or SHBG/total testosterone index.     

Optimizing growth hormone efficacy: an evidence-based analysis

For almost two decades, recombinant growth hormone (GH) has been in abundant supply to treat GH-deficient subjects to final height, yet the results continue to be suboptimal. Although there are numerous potential causes for this underachievement, the issues of poor compliance, ineffective dosing and lack of efficacy monitoring have been frequently promulgated to explain the phenomenon. Compliance is tied to knowledge, which is best promoted at the time of diagnosis by hospital-based personnel. GH pens have improved acceptability, but data on improvement in compliance are lacking. No GH device or delivery system has yet been shown to increase final height. Daily (or six times per week) dosing is clearly more effective, but increasing GH dose, especially during puberty, has a tendency to advance bone age and pubertal progression, which mitigates many of the effects. Finally, titration of dose to the insulin-like growth factor (IGF)-I level may prove to be useful in promoting final height; however, the converse is not true, i.e. increments in IGF-I level have not been shown to correlate with increments in height velocity. Thus, these issues with respect to achievement of final height are far from solved.     

Effect of growth hormone and pamidronate on bone blood flow, bone mineral and IGF-I levels in the rat

So far it is not known whether the growth hormone (GH) has an effect on the local blood circulation in bones. Using male rats we studied the local blood circulation in the tibia and the distal end of the femur (by means of the uptake of 85Sr-microspheres), the density and ash weight of the tibia, the urinary excretion of pyridinoline (PD) and deoxypyridinoline (DPD) as an indicator of bone resorption and the blood levels of IGF-I after the administration of human GH (4 mg/kg s.c. daily for 4 weeks) and/or bisphosphonate pamidronate (Aredia, CIBA-Geigy, administered in the dose of 3 mg/kg i.p. on day 1, 2, 9 and 10). The rats were divided into four groups: 1. controls, 2. GH, 3. pamidronate, 4. GH plus pamidronate. After the administration of GH, we observed a significant increase in bone blood flow (and in the uptake of 85Sr-microspheres), a decrease in the density and ash weight of the tibia and increased urinary excretion of PD and DPD; IGF-I levels in the blood were non-significantly elevated. Simultaneously administered pamidronate inhibited all significant effects of GH and it also decreased the IGF-I levels in rats treated with GH. After the administration of pamidronate itself the bone density and ash weight of the tibia were increased and urinary DPD excretion was decreased. In view of the known vascular effects of IGF-I, we assume that the increase in bone blood flow after the administration of GH and its reduction after simultaneous administration of pamidronate could be mediated by the changes of IGF-I blood levels, although the effect of pamidronate on IGF-I is still not clear. Regarding the role of blood circulation in rat bones, we consider that our present results are further evidence for the relationship between the blood circulation in bones and bone resorption, although these results do not show how active is bone blood circulation in the regulation of bone tissue metabolism.     

Scintigraphie osseuse et déficit en IGF1 : présentation d’un cas clinique

Growth delay in adults with GH (growth hormone) or insulin-like growth factor 1 (IGF1) deficiency is often associated to low bone mineral density (BMD), osteoporosis and a higher risk of fractures (Tritos et al., 2011 [1]; Wüster et al., 2001 [2]; Bex et Bouillon, 2003 [3]). However to date, the risk of fractures in children with GH or IGF1 deficiency is not clearly evaluated (Högler and Shaw, 2010 [4]). This is the case of a young woman aged 21, with a syndrome including a severe mental, growth and weight retardation (–4 SD), facial dysmorphism and partial epilepsy, who recently presented walking and muscle strength loss, without history of trauma. Bone scan revealed several hot spots related to cortical bone fractures and biological data showed an IGF1 deficiency. Through this case, we discuss the role played by GH and IGF1 in bone growth, and the basic procedures to follow in children when measuring BMD with dual absorptiometry X ray technique (DXA).     

The effects of growth hormone on cortical and cancellous bone

Growth hormone (GH) has profound effects on linear bone growth, bone metabolism and bone mass. The GH receptor is found on the cell surface of osteoblasts and osteoclasts, but not on mature osteocytes. In vitro, GH stimulates proliferation, differentiation and extracellular matrix production in osteoblast-like cell lines. GH also stimulates recruitment and bone resorption activity in osteoclast-like cells. GH promotes autocrine/paracrine insulin-like growth factor 1 (IGF-I) production and endocrine (liver-derived) IGF-I production. Some of the GH-induced effects on bone cells can be blocked by IGF-I antibodies, while others cannot. In animal experiments, GH administration increases bone formation and resorption, and enhances cortical bone mass and mechanical strength. When GH induces linear growth, increased cancellous bone volume is seen, but an unaffected cancellous bone volume is found in the absence of linear growth. Patients with acromegaly have increased bone formation and resorption markers. Bone mass results are conflicting because many acromegalics have hypogonadism, but in acromegalics without hypogonadism, increased bone mineral density (BMD) is seen in predominantly cortical bone, and normal BMD in predominantly cancellous bone. Adult patients with growth hormone deficiency have decreased bone mineral content and BMD. GH therapy rapidly increases bone formation and resorption markers. During the first 6-12 months of therapy, declined or unchanged BMD is found in the femoral neck and lumbar spine. All GH trials with a duration of two years or more show enhanced femoral neck and lumbar spine BMD. In osteoporotic patients, GH treatment quickly increases markers for bone formation and resorption. During the first year of treatment, unchanged or decreased BMD values are found, whereas longer treatment periods report enhanced or unchanged BMD values. However, existing trials comprising relatively few patients and limited treatment periods do not allow final conclusions to be drawn regarding the effects of GH on osteoporosis during long-term treatment.