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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 6 2614-2618
Copyright © 2003 by The Endocrine Society

The Impact of Congenital, Severe, Untreated Growth Hormone (GH) Deficiency on Bone Size and Density in Young Adults: Insights from Genetic GH-Releasing Hormone Receptor Deficiency

Hiralal G. Maheshwari, Roger Bouillon, Jos Nijs, Victor S. Oganov, Alexej V. Bakulin and Gerhard Baumann

Center for Endocrinology (H.G.M., G.B.), Metabolism and Molecular Medicine, Department of Medicine, Northwestern University Medical School and Veterans Administration Chicago Health Care System, Lakeside Division, Chicago, Illinois 60611; Division of Endocrinology (R.B., J.N.), Catholic University, B3000 Leuven, Belgium; and State Research Center, Institute for Biomedical Problems, Russian Academy of Sciences, 123007 Moscow, Russia

Address all correspondence and requests for reprints to: G. Baumann, M.D., Northwestern University Medical School, 303 East Chicago Avenue, Chicago, Illinois 60611. E-mail: gbaumann{at}northwestern.edu.


   Abstract
Top
 Abstract
Introduction
 Subject and Methods
 Results
 Discussion
 References
 
GH and IGF-I have well recognized effects on bone elongation during development, but their importance for bone mineralization and structure during the growth phase are less well understood. Because children with GH deficiency are generally treated with GH, little detailed information exists in humans about the effects of long-term GH deficiency on bone development. The recently described syndrome of genetic GHRH receptor deficiency in Pakistan (dwarfism of Sindh) affords a unique opportunity to examine the question of GH deficiency on bone development because the affected patients have congenital, severe, isolated GH deficiency, which had never been treated because of societal reasons. We performed dual energy x-ray absorptiometry scans in four adult males (age, 23–30 yr) to address the question of bone mineralization. Areal bone mineral density (BMD) was low (mean Z scores: -3.3, -2.1, -3.7, and -1.7) in the lumbar spine, femoral neck, forearm, and total skeleton, respectively. This low areal BMD is in part caused by the small bone size in these dwarfed patients. When corrected for size, volumetric BMD (bone mineral apparent density) was normal to near normal (mean Z scores: -1.2, +0.8, and +0.8 for lumbar spine, femoral neck and total skeleton, respectively). We conclude that GH/IGF-I deficiency has relatively little impact on bone mineralization during the bone accretion phase. This is in marked contrast to their effect on bone elongation and overall bone size.


   Introduction
Top
 Abstract
 Introduction
Subject and Methods
 Results
 Discussion
 References
 
GH AND IGF-I are well recognized and crucial factors for bone growth and development (1). GH and/or IGF deficiency in childhood results in linear growth failure due in large part to decreased proliferation of growth plate chondrocytes and subsequently impaired bone elongation. GH deficiency (GHD) acquired in adulthood has been reported to result in osteopenia in multiple studies (2, 3, 4), and prolonged treatment with GH can reverse those changes (5, 6, 7, 8, 9). Although there is universal agreement about the role of GH in bone elongation and bone size and therefore accretion of total and regional bone mass, less is known about its effect on bone quality and degree of bone mineralization. Available information is limited by the fact that virtually all GH-deficient children are treated with GH. Adults with GHD frequently lack multiple pituitary hormones, which individually may also contribute to abnormal bone structure (e.g. by causing hypogonadism or hypothyroidism). Additional confounding factors include less than optimal hormone replacement therapy, such as supraphysiological dosing of corticosteroids.

We and others (10, 11, 12, 13) recently described a genetic syndrome of severe GHD caused by a nonsense mutation in the GHRH receptor (dwarfism of Sindh). Affected homozygous patients have severe, congenital, isolated GHD, but no other endocrine or medical abnormalities. The affected kindred we described lives in a rural area of Pakistan, where modern medical care is not readily available. As a consequence, patients affected by the mutation have remained untreated into adulthood, thereby presenting a unique opportunity to assess the effect of congenital, severe, isolated GHD on bone mass, size, and density. We studied four adult affected patients by dual energy x-ray absorptiometry (DEXA) scanning to assess their bone mineral density (BMD). A special challenge was presented by their small size (height, 6–8 SD below normal), which affected DEXA results because of small bone dimensions.


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

Four adult males (patients 4, 5, 23, and 35 in Ref. 11) with a homozygous GHRH-receptor (GHRH-R) defect, aged 23, 28, 28 and 30 yr, participated in the study. All gave informed consent. Their genetic, physical, and endocrine characteristics have been described in detail previously (10, 11). Their nutritional state was considered good (11), and their physical activity level was comparable with that of their normal-statured peers. None had ever been treated with GH or any other form of endocrine therapy. None reported a history of fractures. Their bone age was adult, as assessed by wrist x-rays (14). Although puberty was delayed by 2–3 yr (11), all had completed puberty several years before the present study. There was no element of hypogonadism, as evidenced by normal testicular size, normal serum testosterone, and the siring of two children by one of the patients. They traveled from Pakistan to Chicago and were admitted to the Northwestern University General Clinical Research Center. DEXA was performed on a QDR-4500A scanner (Hologic, Inc., Bedford, MA).

Data acquisition and reduction

Bone mineral content (BMC) and areal BMD were measured for the lumbar spine (L1–L4), nondominant femoral neck, nondominant forearm, and total body, using standardized Hologic software. Areal BMDs were compared with normative values from the United States Caucasian Hologic reference database (Hologic software version 90/25/91), and age- and sex-appropriate Z scores were derived. T scores are identical to Z scores in these patients because of their age.

Because of the small size of the patients and their bones, areal BMD values underestimate true BMD (15). Therefore, volumetric BMD (bone mineral apparent density, BMAD) was calculated as described by Katzman et al. (16), using the following formula:

Lumbar spine: BMAD = BMC/(area)3/2

Hip: BMAD = BMC/area2

Forearm BMAD = BMC/area2

Total body BMAD = BMD/height in meters

To calculate Z scores for volumetric BMD, data were compared with the normative United States Hologic reference database where appropriate data were available (i.e. for the lumbar spine). For the other measurements (femoral neck, radius, and total skeleton), bone area measurements, and hence volumetric BMD data, are not available in the United States Hologic database. Therefore, we used a reference database for body composition of normal Russian Caucasians (n = 821; age 10–92 yr), collected by A.V.B. and V.S.O. as part of the Russian Space Agency Research Program (Bouillon, R., et al., manuscript in preparation). In all cases, Z scores were based on comparison with age- and sex-appropriate reference data.

Because of the small size of the patients, lumbar BMD values were also compared with those of height-matched boys (height-equivalent ages are between 7.4 and 9.5 yr), being cognizant of the inherent differences between a prepubertal bone and a postpubertal bone. (Normative values for pediatric BMDs are available in the Hologic database only for the lumbar spine.)

Percentage body fat, measured by DEXA under exclusion of the head (brain fat), was used as an index of nutritional status (17, 18).

Statistical analysis was performed by t test. Values are expressed as mean ± SD.


   Results
Top
 Abstract
 Introduction
 Subject and Methods
 Results
Discussion
 References
 
Table 1Go summarizes the lumbar spine BMD results for the four patients. All had significantly decreased areal BMD. This finding is at least in part a function of the small bone dimensions. To correct for that limitation, we calculated volumetric BMD (BMAD) as a more accurate index of true bone density. Interestingly, volumetric BMD was much less diminished than areal BMD. Indeed, only one patient (no. 1) had a volumetric BMD outside the normal range. In three of four patients, the lumbar areal BMD values were higher than the average values for height-matched boys (Table 2Go). (No correction for bone size is necessary for this comparison since bone size in the two groups is similar.) This difference likely represents the well recognized bone accretion during puberty.


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  		Table 1. Lumbar spine bone mineralization (L1–L4) and height

 

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  		Table 2. Comparison between areal BMD (L1–L4) in GHRH-R-deficient adults and height/size-matched normal boys

 
Table 3Go lists BMD values for the femoral neck. Similarly discordant data between areal and volumetric density were observed at that site. Z scores for volumetric data were necessarily based on Russian normative data as no corresponding United States data are available. This may not be inappropriate considering that the patients are from South-central Asia, a region closer to Russia than to the United States.


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  		Table 3. Femoral neck bone mineralization

 
Forearm BMD data are given in Table 4Go. The areal BMD of the distal third of the forearm was severely decreased in all four patients, but volumetric BMD values were similar to those in the femoral neck. Unfortunately, no forearm volumetric BMD data are available from a normal control group to calculate a Z score, but the absolute volumetric BMD data (g/cm3) were similar to those in the femoral neck, suggesting relatively normal Z scores.


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  		Table 4. Forearm bone mineralization1

 
Table 5Go shows the BMD findings for the total body. Here again, areal BMD was low, but volumetric BMD was within the normal range in 3, and actually high in one patient. To exclude the disproportionate contribution of the head to overall BMD in small subjects (19), BMD values for the total skeleton minus the head were also determined. The mean (±SD) BMD values for this headless body were 0.848 ± 0.068 g/cm2 for areal BMD, and 0.592 ± 0.058 g/cm3 for volumetric BMD, lower by 15 or 22%, respectively, than the corresponding values including the head.


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  		Table 5. Total body bone mineralization

 
Taken together, correction for the size artifact imposed on areal BMD by the small bones of these patients largely normalized BMD in spine, femoral neck, and total skeleton. Although no Z scores are available for the forearm, the absolute volumetric BMD values for the distal third of radius also appear quite normal.

The percentage body fat (excluding head/brain) was 27.2%, 30.6%, 26.5%, and 18.1%, for subjects 1–4, respectively. These values are either high normal or elevated for young men (17, 18, 20); they confirm adequate nutrition and are consistent with the increased adiposity associated with GH deficiency.


   Discussion
Top
 Abstract
 Introduction
 Subject and Methods
 Results
 Discussion
References
 
The present study demonstrates that volumetric BMD is relatively normal in young adult males with congenital, severe, untreated GHD. This somewhat unexpected result suggests that GH and IGF-I, although crucially important for bone elongation and accretion, are less important for bone mineralization. The patients included in this study had severe GHD due to genetic deficiency of the GHRH-R, which is necessary for somatotrope development, GH synthesis, and GH secretion (see Ref. 21 for review). As a result of their null mutation in the GHRH-R gene, it can be safely assumed that they had never secreted significant amounts of GH, and their severe dwarfism attests to that fact. Because of the environment they grew up in, they had never received exogenous GH or other endocrine therapy, thus presenting a particularly pure paradigm of GHD. Nutrition appears to have been adequate, as judged by several criteria, including nutritional histories, evaluation of food supply in their environment, clinical assessment, and measurement of body fat mass by DEXA. The patients were at or near their peak bone mass in the third decade of life, when peak bone mass is attained in both normal and GH-deficient subjects (22, 23, 24, 25, 26). It appears from this unique experiment of nature that bone mineralization or volumetric BMD in young adult men is relatively independent of GH and IGF-I. Direct measurement of volumetric bone density are possible by quantitative computed tomography (CT) of the lumbar spine and peripheral quantitative CT of the forearm (27). These techniques were not readily available for our patients. However, calculated volumetric density closely reflects true density (28, 29) and is widely used to estimate volumetric density in populations or patient groups that differ in height or bone size (30, 31, 32).

Cortical bone width and mass were not measured separately from trabecular bone. However, since bone size and total body calcium are markedly decreased and since both parameters are reflecting cortical rather than trabecular bone, it can assumed that cortical bone mass must be markedly decreased in these patients without affecting the true density of the existing cortical bone.

Our data are consistent with another, similar example of largely untreated GHD in Russia (33). In that case, a cohort of GH deficient patients received either no GH treatment or was only sporadically treated. Although areal BMD was low, volumetric BMD was relatively normal. Additional support for the present conclusion can be found in the literature. DeBoer et al. (25) studied 70 young adult patients with childhood onset GHD (25 with isolated GHD) and found that volumetric BMD was more normal (mean lumbar Z score, –0.9) than areal BMD (mean lumbar Z score, –1.59). Of note, this volumetric BMD is within the normal range. Baroncelli et al. (30) examined the relationship between body/bone size and areal vs. volumetric BMD in children and concluded that volumetric BMD is unaffected by anthropometric parameters. However, they found that volumetric BMD was decreased in children with GHD, although to a much lesser degree than areal BMD. Low areal BMD was reported in five Israeli adult patients with genetic GH insensitivity (Laron syndrome), but no corrections were made for body/bone size (34). Bachrach et al. (35) assessed BMD and histomorphometry in young adults with genetic GH insensitivity from Ecuador. These patients are functionally similar to ours in that they had complete absence of GH action due to GH receptor deficiency, with a similar degree of dwarfism and severe IGF-I deficiency (36). Whereas their areal BMD was reduced in the spine, femoral neck, and total body, corresponding volumetric BMD was normal or even increased (35). Histomorphometry of iliac crest biopsies demonstrated essentially normal cortical and trabecular bone, with the exception of poor trabecular connectivity (35). Another example is the single patient with genetic IGF-I deficiency, who had severely reduced areal BMD of the lumbar spine, but normal or near-normal volumetric BMD (37). This patient is unique because he has high GH levels and normal direct (i.e. non-IGF-I dependent) GH action. The aggregate of these observations confirms the importance of both GH and/or IGF-I for bone growth but raises questions about the importance of these hormones for normal bone mineralization. It also illustrates that conventional (areal) BMD can be misleading in underestimating bone mineral in cases where bone size is reduced. The large majority of studies do not address this issue.

Appropriate animal models are also helpful in illuminating our findings. The closest model for our patients is the little (lit/lit) mouse, which harbors a severely inactivating missense mutation in the GHRH-R and thus represents the murine homolog (38, 39, 40). Its dwarfed phenotype is very similar to the human phenotype, both physically and biochemically (21). One study using carcass analysis showed that the percentage of body mineral was lower in homozygous little mice than in their heterozygous littermates, but the difference was relatively small (41). Recent studies have shown that the little mouse has relatively normal volumetric bone density and trabecular structure, as measured by micro-CT, compared with heterozygous littermates (Rosen, C. J., personal communication). Detailed histomorphometric as well as DEXA and quantitative computerized tomography data are available in the GH receptor knockout (Laron) mouse (42). In that model, BMC, areal BMD, and bone dimensions are significantly reduced, but trabecular volumetric BMD and trabecular bone volume are not significantly different from normal (43, 44).

It is intriguing that these conditions of severe, congenital GHD, or GH resistance are associated with relatively normal bone mineralization, whereas milder, acquired forms of GHD appear to be associated with true osteopenia. In particular, adults with acquired GHD frequently exhibit decreased areal BMDs, and their normal bone size minimizes geometric artifacts such as the one encountered in this study. Therefore, reports of osteopenia based on areal BMD in adults are probably accurate but should and can be verified by direct measurements. Because of the complex effects of GH and IGF-I on bone growth, maturation, and components of bone turnover (1), the possibility, albeit unlikely, must be considered that mild GHD leads to greater bone loss than severe GHD. Another potential explanation for the apparent discrepancy between the present data and those in adult GHD may lie in the age of onset of GHD. Our patients were in their third decade, when peak bone mass is achieved. They were GH-deficient during a period in their life when bone accretion took place. Most adult patients with GHD are older and spend all or at least part of their GH-deficient time during a period of physiological bone loss. It is possible that GHD with an onset after peak bone mass is achieved results in accelerated bone loss, whereas an onset before that phase may not exhibit the same effect.

Our observations and hypothesis about the GH/IGF-1 effects on volumetric bone density do not contradict observations on increased fracture risk in GHD patients. Indeed, it is possible that fractures, and particularly cortical bone-related fractures, are more dependent on bone size and mass than on volumetric density, especially in patients with either very short or tall stature.

In summary, we report that congenital, severe, untreated GHD results in relatively normal BMD in young (23–30 yr old) adult men affected by genetic GHRH-R deficiency. While bone size and hence areal BMD is substantially reduced, estimated volumetric BMD is near normal. Although GH and IGF-I are critical for bone growth and skeletal development, the present data raise questions about the role of these hormones in bone mineralization during the bone accretion phase of life.


   Acknowledgments
 
We thank Dr. Mary Leonard for helpful discussions.


   Footnotes
 
This work was supported in part by a merit review grant from the Department of Veterans Affairs (to G.B.), by a travel grant from Pharmacia Corp. (to G.B.), by the Flemish Research Foundation, FWO (to R.B.), and by General Clinical Research Center Grant RR-00048 from the NIH. This work was presented in part at the 23rd Annual Meeting of the American Society of Bone and Mineral Research, Phoenix, Arizona, and reported in abstract form (J Bone Miner Res 2001; 16:S399).

Abbreviations: BMAD, Bone mineral apparent density; BMC, bone mineral content; BMD, bone mineral density; CT, computed tomography; DEXA, dual energy x-ray absorptiometry; GHD, GH deficiency; GHRHR, GHRH receptor.

Received July 18, 2002.

Accepted March 10, 2003.


   References
Top
 Abstract
 Introduction
 Subject and Methods
 Results
 Discussion
 References
 

  1. Ohlsson C, Bengtsson BA, Isaksson OG, Andreassen TT, Slootweg MC 1998 Growth hormone and bone. Endocr Rev 19:55–79[Abstract/Free Full Text]
  2. Rosen T, Hansson T, Granhed H, Szucs J, Bengtsson BA 1993 Reduced bone mineral content in adult patients with growth hormone deficiency. Acta Endocrinol (Copenh) 129:201–206
  3. Holmes SJ, Economou G, Whitehouse RW, Adams JE, Shalet SM 1994 Reduced bone mineral density in patients with adult onset growth hormone deficiency. J Clin Endocrinol Metab 78:669–674[Abstract]
  4. Colao A, Di Somma C, Pivonello R, Loche S, Aimaretti G, Cerbone G, Faggiano A, Corneli G, Ghigo E, Lombardi G 1999 Bone loss is correlated to the severity of growth hormone deficiency in adult patients with hypopituitarism. J Clin Endocrinol Metab 84:1919–1924[Abstract/Free Full Text]
  5. Baum HB, Biller BM, Finkelstein JS, Cannistraro KB, Oppenhein DS, Schoenfeld DA, Michel TH, Wittink H, Klibanski A 1996 Effects of physiologic growth hormone therapy on bone density and body composition in patients with adult-onset growth hormone deficiency. A randomized, placebo-controlled trial. Ann Intern Med 125:883–890[Abstract/Free Full Text]
  6. Johannsson G, Rosen T, Bosaeus I, Sjostrom L, Bengtsson BA 1996 Two years of growth hormone (GH) treatment increases bone mineral content and density in hypopituitary patients with adult-onset GH deficiency. J Clin Endocrinol Metab 81:2865–2873[Abstract/Free Full Text]
  7. Rahim A, Holmes SJ, Adams JE, Shalet SM 1998 Long-term change in the bone mineral density of adults with adult onset growth hormone (GH) deficiency in response to short or long-term GH replacement therapy. Clin Endocrinol (Oxf) 48:463–469[CrossRef][Medline]
  8. Valimaki MJ, Salmela PI, Salmi J, Viikari J, Kataja M, Turunen H, Soppi E 1999 Effects of 42 months of GH treatment on bone mineral density and bone turnover in GH-deficient adults. Eur J Endocrinol 140:545–554[Abstract]
  9. Biller BM, Sesmilo G, Baum HB, Hayden D, Schoenfeld D, Klibanski A 2000 Withdrawal of long-term physiological growth hormone (GH) administration: differential effects on bone density and body composition in men with adult-onset GH deficiency. J Clin Endocrinol Metab 85:970–976[Abstract/Free Full Text]
  10. Baumann G, Maheshwari H 1997 The dwarfs of Sindh: severe growth hormone (GH) deficiency caused by a mutation in the GH-releasing hormone receptor gene. Acta Paediatr Suppl 423:33–38[Medline]
  11. Maheshwari HG, Silverman BL, Dupuis J, Baumann G 1998 Phenotype and genetic analysis of a syndrome caused by an inactivating mutation in the growth hormone-releasing hormone receptor: dwarfism of Sindh. J Clin Endocrinol Metab 83:4065–4074[Abstract/Free Full Text]
  12. Wajnrajch MP, Gertner JM, Harbison MD, Chua Jr SC, Leibel RL 1996 Nonsense mutation in the human growth hormone-releasing hormone receptor causes growth failure analogous to the little (lit) mouse. Nat Genet 12:88–90[CrossRef][Medline]
  13. Netchine I, Talon P, Dastot F, Vitaux F, Goossens M, Amselem S 1998 Extensive phenotypic analysis of a family with growth hormone (GH) deficiency caused by a mutation in the GH-releasing hormone receptor gene. J Clin Endocrinol Metab 83:432–436[Abstract/Free Full Text]
  14. Tanner JM, Whitehouse RW, Cameron N, Marshall WA, Healy MJR, Goldstein H 1983 Assessment of skeletal maturity and prediction of adult height (TW2 method). London: Academic Press
  15. Carter DR, Bouxsein ML, Marcus R 1992 New approaches for interpreting projected bone densitometry data. J Bone Miner Res 7:137–145[Medline]
  16. Katzman DK, Bachrach LK, Carter DR, Marcus R 1991 Clinical and anthropometric correlates of bone mineral acquisition in healthy adolescent girls. J Clin Endocrinol Metab 73:1332–1339[Abstract/Free Full Text]
  17. Bray GA, Bouchard C, James WPT 1998 Definitions and proposed current classification of obesity. In: Bray GA, Bouchard C, James WPT, eds. Handbook of obesity. New York: Marcel Dekker; 31–40
  18. Friedl KE, Moore RJ, Martinez-Lopez LE, Vogel JA, Askew EW, Marchitelli LJ, Hoyt RW, Gordon CC 1994 Lower limit of body fat in healthy active men. J Appl Physiol 77:933–940[Abstract/Free Full Text]
  19. Brismar TB, Lindgren AC, Ringertz H, Rosenborg M, Ritzen ME 1998 Total body bone mineral measurements in children with Prader-Willi syndrome: the influence of the skull’s bone mineral content per area (BMA) and of height. Pediatr Radiol 28:38–42[CrossRef][Medline]
  20. Segal KR, Dunaif A, Gutin B, Albu J, Nyman A, Pi-Sunyer FX 1987 Body composition, not body weight, is related to cardiovascular disease risk factors and sex hormone levels in men. J Clin Invest 80:1050–1055
  21. Baumann G 2001 Growth hormone releasing hormone receptors and pituitary development. In: Rappaport R, Amselem S, eds. Hypothalamic-pituitary development genetic and clinical aspects. Vol 4. Basel, Switzerland: Karger; 48–60
  22. Matkovic V, Jelic T, Wardlaw GM, Ilich JZ, Goel PK, Wright JK, Andon MB, Smith KT, Heaney RP 1994 Timing of peak bone mass in Caucasian females and its implication for the prevention of osteoporosis. Inference from a cross-sectional model. J Clin Invest 93:799–808
  23. Lu PW, Cowell CT, SA LL-J, Briody JN, Howman-Giles R 1996 Volumetric bone mineral density in normal subjects, aged 5–27 years. J Clin Endocrinol Metab 81:1586–1590[Abstract]
  24. Kaufman JM, Taelman P, Vermeulen A, Vandeweghe M 1992 Bone mineral status in growth hormone-deficient males with isolated and multiple pituitary deficiencies of childhood onset. J Clin Endocrinol Metab 74:118–123[Abstract]
  25. de Boer H, Blok GJ, van Lingen A, Teule GJ, Lips P, van der Veen EA 1994 Consequences of childhood-onset growth hormone deficiency for adult bone mass. J Bone Miner Res 9:1319–1326[Medline]
  26. Benbassat CA, Wasserman M, Laron Z 1999 Changes in bone mineral density after discontinuation and early reinstitution of growth hormone (GH) in patients with childhood-onset GH deficiency. Growth Horm IGF Res 9:290–295[CrossRef][Medline]
  27. Faulkner KG 1998 Bone densitometry: choosing the proper skeletal site to measure. J Clin Densitom 1:279–285[CrossRef][Medline]
  28. Reinbold WD, Genant HK, Reiser UJ, Harris ST, Ettinger B 1986 Bone mineral content in early-postmenopausal and postmenopausal osteoporotic women: comparison of measurement methods. Radiology 160:469–478[Abstract/Free Full Text]
  29. Jergas M, Breitenseher M, Gluer CC, Yu W, Genant HK 1995 Estimates of volumetric bone density from projectional measurements improve the discriminatory capability of dual x-ray absorptiometry. J Bone Miner Res 10:1101–1110[Medline]
  30. Baroncelli GI, Bertelloni S, Ceccarelli C, Saggese G 1998 Measurement of volumetric bone mineral density accurately determines degree of lumbar undermineralization in children with growth hormone deficiency. J Clin Endocrinol Metab 83:3150–3154[Abstract/Free Full Text]
  31. Melton 3rd LJ, Atkinson EJ, O’Connor MK, O’Fallon WM, Riggs BL 1998 Bone density and fracture risk in men. J Bone Miner Res 13:1915–1923[CrossRef][Medline]
  32. Looker AC, Beck TJ, Orwoll ES 2001 Does body size account for gender differences in femur bone density and geometry? J Bone Miner Res 16:1291–1299[CrossRef][Medline]
  33. Bouillon R, Koledova K, Bezlepkina O, Chernikhova E, Nagajeva E, Bakulin A, Nijs J, Peterkova VA, Dedov I, Oganov O, Attanasio A Lifelong hypopituitarism and growth hormone deficiency decreases bone size but not volumetric density yet increases prevalence of fractures. Program of the 23rd Annual Meeting of the American Society of Bone and Mineral Research, Phoenix, AZ, 2001, p S224
  34. Laron Z, Klinger B 1994 IGF-I treatment of adult patients with Laron syndrome: preliminary results. Clin Endocrinol (Oxf) 41:631–638[Medline]
  35. Bachrach LK, Marcus R, Ott SM, Rosenbloom AL, Vasconez O, Martinez V, Martinez AL, Rosenfeld RG, Guevara-Aguirre J 1998 Bone mineral, histomorphometry, and body composition in adults with growth hormone receptor deficiency. J Bone Miner Res 13:415–421[CrossRef][Medline]
  36. Rosenbloom AL, Guevara Aguirre J, Rosenfeld RG, Fielder PJ 1990 The little women of Loja—growth hormone-receptor deficiency in an inbred population of southern Ecuador. N Engl J Med 323:1367–1374[Abstract]
  37. Woods KA, Camacho-Hubner C, Bergman RN, Barter D, Clark AJ, Savage MO 2000 Effects of insulin-like growth factor I (IGF-I) therapy on body composition and insulin resistance in IGF-I gene deletion. J Clin Endocrinol Metab 85:1407–1411[Abstract/Free Full Text]
  38. Eicher EM, Beamer WG 1976 Inherited ateliotic dwarfism in mice. Characteristics of the mutation, little, on chromosome 6. J Hered 67:87–91[Free Full Text]
  39. Godfrey P, Rahal JO, Beamer WG, Copeland NG, Jenkins NA, Mayo KE 1993 GHRH receptor of little mice contains a missense mutation in the extracellular domain that disrupts receptor function. Nat Genet 4:227–232[CrossRef][Medline]
  40. Lin SC, Lin CR, Gukovsky I, Lusis AJ, Sawchenko PE, Rosenfeld MG 1993 Molecular basis of the little mouse phenotype and implications for cell type-specific growth. Nature 364:208–213[CrossRef][Medline]
  41. Donahue LR, Beamer WG 1993 Growth hormone deficiency in ’little’ mice results in aberrant body composition, reduced insulin-like growth factor-I and insulin-like growth factor-binding protein-3 (IGFBP-3), but does not affect IGFBP-2, -1 or -4. J Endocrinol 136:91–104[Abstract/Free Full Text]
  42. Zhou Y, Xu BC, Maheshwari HG, He L, Reed M, Lozykowski M, Okada S, Cataldo L, Coschigamo K, Wagner TE, Baumann G, Kopchick JJ 1997 A mammalian model for Laron syndrome produced by targeted disruption of the mouse growth hormone receptor/binding protein gene (the Laron mouse). Proc Natl Acad Sci USA 94:13215–13220[Abstract/Free Full Text]
  43. Sjögren K, Bohlooly YM, Olsson B, Coschigano K, Tornell J, Mohan S, Isaksson OG, Baumann G, Kopchick J, Ohlsson C 2000 Disproportional skeletal growth and markedly decreased bone mineral content in growth hormone receptor minus]/- mice. Biochem Biophys Res Commun 267:603–608[CrossRef][Medline]
  44. Sims NA, Clement-Lacroix P, Da Ponte F, Bouali Y, Binart N, Moriggl R, Goffin V, Coschigano K, Gaillard-Kelly M, Kopchick J, Baron R, Kelly PA 2000 Bone homeostasis in growth hormone receptor-null mice is restored by IGF-I but independent of Stat5. J Clin Invest 106:1095–1103[Medline]



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[Abstract] [Full Text] [PDF]

Home page
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Home page
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M. J. E. Walenkamp, M. Karperien, A. M. Pereira, Y. Hilhorst-Hofstee, J. van Doorn, J. W. Chen, S. Mohan, A. Denley, B. Forbes, H. A. van Duyvenvoorde, et al.
Homozygous and Heterozygous Expression of a Novel Insulin-Like Growth Factor-I Mutation
J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2855 - 2864.
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Home page
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R. Bouillon, E. Koledova, O. Bezlepkina, J. Nijs, E. Shavrikhova, E. Nagaeva, O. Chikulaeva, V. Peterkova, I. Dedov, A. Bakulin, et al.
Bone Status and Fracture Prevalence in Russian Adults with Childhood-Onset Growth Hormone Deficiency
J. Clin. Endocrinol. Metab., October 1, 2004; 89(10): 4993 - 4998.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
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Are Adult Patients with Laron Syndrome Osteopenic? A Comparison between Dual-Energy X-Ray Absorptiometry and Volumetric Bone Densities
J. Clin. Endocrinol. Metab., October 1, 2003; 88(10): 4586 - 4589.
[Abstract] [Full Text] [PDF]

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