This Article Abstract Full Text (PDF) All Versions of this Article: 91/2/432    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Murray, R. D. Articles by Shalet, S. M. Search for Related Content PubMed PubMed Citation Articles by Murray, R. D. Articles by Shalet, S. M. Related Collections Calcium and Bone Metabolism Neuroendocrinology and Pituitary

A Densitometric and Morphometric Analysis of the Skeleton in Adults with Varying Degrees of Growth Hormone Deficiency

Department of Endocrinology (R.D.M., S.M.S.), Christie Hospital, Manchester M20 4BX, United Kingdom; and Clinical Radiology (J.E.A.), Imaging Science and Biomedical Engineering, University of Manchester, Manchester M13 9PL, United Kingdom

Address all correspondence and requests for reprints to: Prof. S. M. Shalet, Department of Endocrinology, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX, United Kingdom. E-mail: stephen.m.shalet{at}man.ac.uk.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context: Low bone mass is a characteristic feature of the adult GH deficiency (GHD) syndrome, but recent dual-energy x-ray absorptiometry (DXA) studies in patients with GH-receptor and GHRH-receptor gene mutations suggest that the situation is more complex.

Objective: The objective was to define bone areal and volumetric densities and morphometry in hypopituitary adults.

Design: The study was a cross-sectional case-controlled study performed between 1999 and 2001.

Setting: The study was undertaken at an endocrine tertiary referral center.

Patients: Thirty patients with GHD, 24 with GH insufficiency (GHI) [peak GH, 3–7 µg/liter (9–21 mU/liter)], and 30 age- and sex-matched controls were included for study.

Main Outcome Measures: DXA and peripheral quantitative computed tomography (pQCT) derived bone density and morphometry were measured.

Results: No densitometric or morphometric abnormalities were detected in GHD patients who acquired their deficiency during adult life. GHD adults of childhood-onset (CO-GHD) showed decreased bone mineral density at the lumbar spine and hip on DXA. pQCT of the radius showed that CO-GHD patients have normal trabecular bone mineral density and only a 2% decrease in cortical density. Radial bone area was reduced 14.5%, cortical thickness 20%, and cortical cross-sectional area 23%, culminating in a reduction in cortical bone of 25%. The "apparent" low DXA bone density in CO-GHD adults therefore relates primarily to reduced cortical thickness and smaller bone area. DXA and pQCT data derived from adults with GHI revealed no evidence of densitometric or morphometric abnormalities.

Conclusions: 1) Adult-onset GHD patients have normal bone density and size. 2) CO-GHD adults have marginally reduced cortical density but significantly reduced cortical bone as a result of reduced cortical thickness and bone size. 3) GHI has no measurable impact on the skeleton.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
LOW BONE MASS is reported to be, and widely accepted, as a characteristic feature of the adult GH deficiency (GHD) syndrome (1, 2). Accumulating data, however, suggest that bone mineral density (BMD) may not be reduced in the majority of individuals with GHD, and low bone mass when present may relate to reduced statural height. Studies of BMD in adults with GHD have predominantly used dual-energy x-ray absorptiometry (DXA), which provides an areal measure of BMD (aBMD) (in grams per square centimeter) that is size dependent, leading to underestimation in small bones and overestimation in large bones (3). Patients with adult-onset GHD (AO-GHD), who by definition are of normal height, show either no abnormality in aBMD or a clinically insignificant reduction (4, 5, 6). In contrast, the majority of studies examining aBMD in GHD adults of childhood-onset (CO-GHD), who despite GH replacement during childhood frequently fail to achieve target genetic height, demonstrate significantly reduced BMD (7, 8, 9). A recent DXA study of GHD adults examined the relationship between age and BMD (10). The data revealed BMD to be dependent on age; low BMD was observed in the young patients, but patients over 60 yr demonstrated a mean BMD Z-score above the reference population. Few patients over 30 yr had a Z-score of less than –2. Additional evidence to support the belief that BMD in GHD adults is normal comes from calculation of bone mineral apparent density (BMAD), in which bone mineral content (BMC) is divided by a calculated volume, assuming the vertebrae are cubes or cylinders (11, 12); BMAD has been reported to be normal in patients with severe GHD resulting from GH-receptor (13, 14) and GHRH-receptor gene mutations (15) and in GHD adults aged less than 30 yr (10), despite reduced BMD Z-scores on DXA.

We recently described abnormalities of body composition and insulin sensitivity in patients with partial GHD [GH insufficiency (GHI), peak GH to stimulation tests of 3–7 µg/liter], although of a lesser degree than observed in severely GHD adults (16, 17). With respect to the skeleton, however, DXA BMD in adults with GHI is reported to be normal (18).

In the present analysis, we used peripheral quantitative computed tomography (pQCT) to study bone density and morphometry in patients with GHD to determine whether the observed "low BMD" of patients with CO-GHD was related to bone size, density, or a combination of these factors. We additionally used DXA and pQCT to confirm whether the milder degree of impaired GH status, GHI, had an impact on the skeleton.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects

The study cohort comprised 54 adults with a history of pituitary disease and 30 age- and sex-matched controls. The patients were subdivided according to their GH secretory status into subgroups defined as GHD and GHI (Table 1). The GH stimulation test of choice was the insulin tolerance test (ITT) (n = 50 of 54). When the ITT was contraindicated and to confirm the patient’s GH secretory status, patients underwent alternate GH stimulation tests using arginine (n = 28), glucagon (GST) (n = 6), or GHRH plus arginine (n = 16). All patients were required to undergo two tests of GH reserve to confirm their GH secretory status, except in the setting of panhypopituitarism and a peak GH response to the ITT of less than 0.33 µg/liter (19) or conversely a normal GH response to the first provocative test (peak GH of >7 µg/liter). GHD was defined as a peak GH response of less than 3 µg/liter to all stimulation tests undertaken (20). GHI was defined by the highest peak GH response to a stimulation test within the range of 3–7 µg/liter. The only exception to the criteria for definition of GH status was for subjects who underwent the GHRH plus arginine test. Respective values, when using the GHRH plus arginine test for the diagnosis of GHD and GHI as defined by previous studies in our unit, were less than 9 and 9–21 µg (16), consistent with the 3-fold greater GH response to the GHRH plus arginine test compared with the ITT (21, 22, 23).

Study protocol

Height was measured using a wall-mounted stadiometer. Weight was measured using an electronic scale (model TBF-305; Tanita, Uxbridge, UK). BMD of the lumbar spine and proximal hip were measured using DXA. At the radius, cortical and trabecular BMD were measured using pQCT. Ethical approval for this study was granted by the South Manchester Local Research Ethics Committee, and written informed consent was obtained from each subject.

DXA

BMD (in milligrams per square centimeter) measurements were made between 1999 and 2001. DXA was performed at the femoral neck, total hip, and lumbar spine (posteroanterior projection, L1–L4). These measures are of integral (cortical and trabecular) bone, and the cortical/trabecular ratios are as follows: lumbar spine, 50:50; femoral neck, 60:40. Scanning was performed using a Hologic (Bedford, MA) QDR-4500 Acclaim fan-beam scanner using software version V8.26f:3.

pQCT

Bone morphometry and vBMD were measured using an XCT 2000 pQCT scanner (Stratec, Pforzheim, Germany), and data analysis was performed with the software package of the manufacturer (version 5.4; Stratec). Cross-sectional (CS) measurements were made in the radius of the nondominant arm at a distance of 4 and 50% of the radial length proximal to the radial growth plate, and results are presented for these sites. A 1-mm-thick, single tomographic slice was taken. At the 4% site, trabecular bone predominates; at the 50% site, there is only cortical bone. Values with a density greater than 710 mg/cm³ were considered to represent cortical bone, and densities of 180–710 mg/cm³ were considered to be trabecular bone. Measurements provided by pQCT include total density (milligrams per cubic centimeter), cortical density (milligrams per cubic centimeter), trabecular density (milligrams per cubic centimeter), bone area (square millimeter), cortical thickness, periosteal circumference, endosteal circumference, and muscle cross-sectional area (CSMA). Due to the thin cortex and inherent difficulty in reliably separating cortical and subcortical bone at the 4% site, "cortical/subcortical" density was measured at this site.

To obtain information on mechanical competence against bending and torsional loads at the mid-diaphysis (50% site), we calculated two composite parameters: axial moment of inertia (AMI) and the stress-strain index (SSI). The AMI is the distribution of bone material around the center of the bone, and the SSI is a combination of AMI and the vBMD of the cortex; both relate well to the fracture load.

Calibration and quality assurance testing were performed daily. The short-term in vivo precisions [percentage of coefficient of variation (CV)] for the Hologic QDR-4500 were lumbar spine 1.09%, femoral neck 3.29%, and total hip 1.26%. For the Stratec XCT 2000, CVs were less than 1% for vBMD and less than 3% for the biomechanical measures. aBMD and vBMD (11) was measured in grams per square centimeter and grams per cubic centimeter, respectively, and results are expressed as T- and Z-scores. The reference data provided by the relevant scanner manufacturer were used. For femoral neck and total hip Z-scores on the Hologic scanner the National Health and Nutrition Examination Survey (NHANES III, 1988–1991) reference database was used (24).

Assays

IGF-I was determined, after acid-alcohol extraction, by an immunoradiometric assay using a commercially available kit (Diagnostic Systems Laboratories, Webster, TX). Sensitivity was 0.8 ng/ml, and intraassay CVs at 9.3, 55.3, and 263.6 ng/ml were 3.4, 3.0, and 1.5%, respectively. Interassay CVs at 10.4, 53.8, and 255.9 ng/ml were 8.2, 1.5, and 3.7%, respectively.

Data analysis

All data are presented as mean ± SD. Differences across the groups were studied using one-way ANOVA or one-way ANOVA on ranks for parametric and nonparametric datasets, respectively. Differences between groups were examined using a t test or rank-sum test. A P value of <0.05 was considered significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Overall cohort

DXA. DXA performed at the lumbar spine, femoral neck, and total hip confirmed GHD adults to have reduced BMD (grams per square centimeter) at all sites compared with control subjects (P = 0.05, P = 0.05, and P = 0.007) (Table 2). Patients with GHI showed intermediate BMD (grams per square centimeter; T-scores and Z-scores) at the lumbar spine and total hip compared with severely GHD patients and control subjects, with values being not significantly different from either group (Table 2). BMD at the femoral neck demonstrated a trend toward reduced BMD (grams per square centimeter) in GHI adults compared with healthy adults (P = 0.066) but no difference from GHD adults.

Effect of timing of onset of GHD

The impact of GHD during childhood is reported to have a greater effect on BMC than GHD acquired during adult life. We therefore stratified our patients according to their GH status (GHD vs. GHI) and the timing of onset of their deficiency (CO vs. AO) before reanalyzing the data. Demographics of the control and patient groups are presented in Table 4. Of particular relevance is the approximately 8 and 13 cm reduction in height of the CO-GHI and CO-GHD adults, respectively, compared with control subjects.

At the 50% site, cortical density was significantly lower than in control subjects (1.9%; P = 0.045) (Table 5). Additionally, there was a significant reduction in cortical thickness (19.9%; P < 0.001) and CS area (23.4%; P < 0.001) that contributed to an overall reduction in cortical bone content (24.6%; P < 0.001) of the bone slice analyzed (Table 5). Both radial (P = 0.04) and combined radial and ulnar (P = 0.025) area were significantly lower than in control subjects, reflecting their smaller bone size consistent with reduced stature. Periosteal circumference was marginally, but significantly (P = 0.041), lower than control subjects, whereas endosteal circumference was not affected (Table 5). Both calculated measures of biomechanical properties of bone strength, AMI and SSI, were reduced relative to control subjects (P = 0.029 and P = 0.019, respectively).

CO-GHI patients. DXA measures of BMD (grams per square centimeter) were lower than controls at the lumbar spine only (P = 0.002). All DXA values (grams per square centimeter) for the CO-GHI patients were intermediate between those of the CO-GHD and control groups (Table 4). At the 4% pQCT site, CO-GHI adults had reduced cortical/subcortical density (P = 0.034) but normal trabecular density. The modest reduction in cortical/subcortical density was insufficient to significantly impact the total BMD (milligrams per square centimeter). Total, cortical, and trabecular area were not significantly different from the control subjects at this site (Table 5). At the 50% pQCT slice, all values for vBMD, bone size, bone morphometry, and biomechanical measures of bone strength were intermediate between those of the CO-GHD adults and control subjects. No difference in any measure was demonstrated between the CO-GHI subgroup and healthy controls. Cortical thickness (P = 0.006), cortical CS area (P = 0.01), and cortical content (P = 0.012) of the CO-GHI subgroup, however, were significantly greater than in the corresponding CO-GHD patients.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Although there is a wealth of data based on DXA to demonstrate that GHD adults have reduced BMD, clinically relevant decreases in bone mass are confined to CO-GHD adults (7, 8, 9). The BMD of AO-GHD patients has, in the majority of studies, been found to be normal (4, 5, 6). Despite GH replacement in childhood and catch-up growth after initiation of therapy, individuals with CO-GHD often fail to achieve target genetic height. Because DXA provides an areal rather than volumetric measure of BMD, it is highly dependent on bone thickness, which increases in concert with height. The reduced statural height of CO-GHD adults is thus a potential confounder in interpreting DXA measurements. Several methods have been suggested to overcome this size dependency (11, 12, 25, 26, 27, 28, 29, 30). BMAD, a measure of vBMD derived from DXA, is reportedly normal in patients with Larons’s syndrome (13, 14), GHRH-receptor gene mutations (15), and young GHD adults of less than 30 yr of age (10). These observations add weight to the hypothesis that the low bone density measured by DXA in CO-GHD adults relates to bone size rather than indicating a true reduction in bone density. pQCT improves the diagnostic utility of densitometry by providing true vBMD, which is not size dependent. pQCT also provides separate measures of cortical and trabecular BMD and information on the size and morphometry of bones, from which can be derived biomechanical parameters (31, 32).

In the current analysis of patients with GHD, BMD, as assessed by DXA, was reduced at the lumbar spine, femoral neck, and total hip. After stratification in patients with AO- and CO-GHD, it was notable that the reductions in DXA-derived BMD were confined to the CO-GHD adults. Similarly, the reductions in pQCT values for cortical thickness, cortical bone CS area, and cortical content in GHD adults were, after stratification by timing of onset, found to exist exclusively in the CO-GHD patients. No abnormality of bone density or structure was found in AO-GHD patients. The data relating to patients with AO-GHD are in agreement with previous reports and suggest that GH does not play a significant role in physiological maintenance of bone mineralization during adult life (4, 5, 6).

Although DXA BMD is significantly reduced in CO-GHD adults, the question remaining to be answered is whether the "apparent" low BMD is a consequence of the smaller stature of these patients or represents a true reduction in BMD. Trabecular density, measured at the 4% site, was normal. The reduction in total density at the 4% site therefore reflects the reduced cortical/subcortical bone density. Additional analysis of the cortical bone morphometry at the 50% radial site revealed a reduction in cortical thickness, cortical bone CS area, and cortical content, suggesting that not only is the density of cortical bone reduced in CO-GHD adults but also the amount of cortical bone present is reduced. This latter finding is not unexpected given that total radial area (i.e. bone size) of CO-GHD adults is reduced by about 14.5%. The reduction in cortical thickness and cortical bone CS area equate to 20 and 23%, respectively, whereas the decrease in cortical density was in the region of 2%. These relative reductions in the CO-GHD adults suggest that the major component leading to the apparent low BMD observed with DXA is a reduction in cortical bone volume and not density. Assuming that the 8% reduction in stature of these patients is translated into a similar reduction in radial diameter and that the radius is circular, mathematically an approximately 15% reduction in radial area would have been expected, in keeping with the observed 14.5% decrease demonstrated in CO-GHD adults. The reduction in cortical thickness and cortical bone CS area, which account for the majority of the 25% decrease in cortical bone, are however greater than expected from the decrease in radial area. It is therefore possible that GHD during childhood results in suboptimal bone acquisition that is reflected by a decrease in cortical thickening rather than in cortical density.

Although postmenopausal osteoporosis is not a perfect paradigm, the salient pQCT features are similar to our patients with CO-GHD, including reduced cortical density, thickness, CS area, and cortical content (33, 34, 35, 36, 37, 38). The reduction in cortical thickness, CS area, and cortical content of our CO-GHD patients, despite only a minor reduction (2%) in cortical density, likely places these patients at significantly increased risk of fracture. It is well recognized that, for a given mass, the strength of a tubular structure increases with its diameter, and therefore an additional feature that needs to be considered when assessing the risk of fracture of CO-GHD adults is their smaller bone diameter. The SSI provides a measure of resistance to bending and of torsional strength, being relevant to fracture risk of the bone measured. AMI provides a measure of distribution of bone material around the axis of the bone. Both SSI and AMI have been reported to be reduced in postmenopausal patients with osteoporosis (33, 36), although it remains unclear whether these measures will provide a better prediction of fracture risk than pQCT-derived densitometry or morphometric measures alone. Both SSI and AMI values were reduced in CO-GHD adults, supporting the hypothesis that these patients are at increased risk of fracture despite near-normal volumetric densities.

There are no previous data analyzing trabecular and cortical density or morphometric and biomechanical properties of long bones in patients with adult GHD. Schweizer et al. (39) examined these parameters using pQCT in 45 prepubertal children with GHD and compared them with those of a reference population. Cortical density was observed to be normal (SD score, 0.03), but, similar to the current analysis of GHD adults, total radial area, cortical thickness, and cortical area were significantly lower than predicted (SD scores, –0.43, –1.32, and –1.38, respectively). Their findings are near identical to the findings of the current study and suggest that the abnormalities of bone structure associated with GHD during childhood persist through to adult life.

We additionally examined BMD by DXA and pQCT in patients with GHI. No abnormalities of bone density or structure were detected in the AO-GHI patients. In the CO-GHI adults, although BMD was reduced if DXA values were expressed as Z-scores, with the exception of the lumbar spine, this was not confirmed when absolute values (grams per square centimeter) were analyzed. pQCT data failed to detect any notable abnormalities, confirming that the impact of this lesser degree of GHD on the skeleton is negligible. This is in agreement with a previous study in which only severe GHD was found to have an influence on BMD (18).

There are a number of caveats when scientifically analyzing the data that may have impacted on the results of this study. It is notable that the T- and Z-scores for the trabecular bone density at the 4% site were in the region of –0.70 to –0.95 in the control group. This likely represents inadequacy of the reference data when compared with the local population rather than truly reduced BMD in the control subjects in light of the normal bone density when assessed by DXA. The concept of type 2 error should also be considered when the cohort is stratified by timing of onset and GH status because the subgroups contain as few as 11 patients.

In summary, the present study provides a wealth of bone densitometric and morphometric data that 1) confirm AO-GHD adults to have normal bone density and morphometry; 2) show that lesser degrees of GHD (such as GHI), whether present during childhood or acquired during adult life, have a negligible impact on the skeleton; and 3) show that CO-GHD adults have normal trabecular density, marginally reduced cortical density, but significant reductions in cortical thickness, cortical CS area, and overall cortical content, which along with the smaller bone size, account for the reduced BMD observed in DXA studies and place these patients at increased risk of fracture. Reduced values for the biomechanical measures of bone strength (SSI and AMI) also suggest an increased risk of fracture in this subset of GHD adults.

	Acknowledgments

 
We thank Mr. Mike Machin for preparing the DXA and pQCT databases for analysis, and Mrs. Mel Hodgkinson and other radiographers in the clinical radiology scanning unit for performing the scans.

	Footnotes

 
This work was supported by the Pfizer Corporation.

First Published Online November 8, 2005

Abbreviations: aBMD, Areal bone mineral density; AMI, axial moment of inertia; AO, adult onset; BMAD, bone mineral apparent density; BMC, bone mineral content; BMD, bone mineral density; CO, childhood onset; CS, cross-sectional; CSMA, muscle CS area; CV, coefficient of variation; DXA, dual-energy x-ray absorptiometry; GHD, GH deficiency; GHI, GH insufficiency; GST, glucagon stimulation test; ITT, insulin tolerance test; pQCT, peripheral quantitative computed tomography; SSI, stress-strain index; vBMD, volumetric bone mineral density.

Received April 25, 2005.

Accepted November 2, 2005.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Carroll PV, Christ ER, Bengtsson BA, Carlsson L, Christiansen JS, Clemmons D, Hintz R, Ho K, Laron Z, Sizonenko P, Sonksen PH, Tanaka T, Thorne M 1998 Growth hormone deficiency in adulthood and the effects of growth hormone replacement: a review. Growth Hormone Research Society Scientific Committee. J Clin Endocrinol Metab 83:382–395[Abstract/Free Full Text]
2. de Boer H, Blok GJ, Van der Veen EA 1995 Clinical aspects of growth hormone deficiency in adults. Endocr Rev 16:63–86[CrossRef][Medline]
3. Mughal Z, Ward K, Adams JE 2004 Assessment of bone status in children by densitometric and quantitative ultrasound techniques. In: Carty H, Brunelle F, Stringer DA, Kao SC, eds. Imaging children. 2nd ed. Chap 2. Oxford, UK: Elsevier
4. Janssen YJ, Hamdy NA, Frolich M, Roelfsema F 1998 Skeletal effects of two years of treatment with low physiological doses of recombinant human growth hormone (GH) in patients with adult-onset GH deficiency. J Clin Endocrinol Metab 83:2143–2148[Abstract/Free Full Text]
5. Fernholm R, Bramnert M, Hagg E, Hilding A, Baylink DJ, Mohan S, Thoren M 2000 Growth hormone replacement improves body composition and increases bone metabolism in elderly patients with pituitary disease. J Clin Endocrinol Metab 85:4104–4112[Abstract/Free Full Text]
6. Toogood AA, Adams JE, O’Neill PA, Shalet SM 1997 Elderly patients with adult-onset growth hormone deficiency are not osteopenic. J Clin Endocrinol Metab 82:1462–1466[Abstract/Free Full Text]
7. O’ Halloran DJ, Tsatsoulis A, Whitehouse RW, Holmes SJ, Adams JE, Shalet SM 1993 Increased bone density after recombinant human growth hormone (GH) therapy in adults with isolated GH deficiency. J Clin Endocrinol Metab 76:1344–1348[Abstract]
8. 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]
9. 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]
10. Murray RD, Columb B, Adams JE, Shalet SM 2004 Low bone mass is an infrequent feature of the adult growth hormone deficiency syndrome in middle-age adults and the elderly. J Clin Endocrinol Metab 89:1124–1130[Abstract/Free Full Text]
11. Carter DR, Bouxsein ML, Marcus R 1992 New approaches for interpreting projected bone densitometry data. J Bone Miner Res 7:137–145[Medline]
12. Kroger H, Kotaniemi A, Vainio P, Alhava E 1992 Bone densitometry of the spine and femur in children by dual-energy x-ray absorptiometry. Bone Miner 17:75–85[CrossRef][Medline]
13. 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]
14. Benbassat CA, Eshed V, Kamjin M, Laron Z 2003 Are adult patients with Laron syndrome osteopenic? A comparison between dual-energy X-ray absorptiometry and volumetric bone densities. J Clin Endocrinol Metab 88:4586–4589[Abstract/Free Full Text]
15. Maheshwari HG, Bouillon R, Nijs J, Oganov VS, Bakulin AV, Baumann G 2003 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. J Clin Endocrinol Metab 88:2614–2618[Abstract/Free Full Text]
16. Murray RD, Adams JE, Shalet SM 2004 Adults with partial growth hormone deficiency have an adverse body composition. J Clin Endocrinol Metab 89:1586–1591[Abstract/Free Full Text]
17. Murray RD, Shalet SM 2005 Insulin sensitivity is impaired in adults with varying degrees of GH deficiency. Clin Endocrinol (Oxf) 62:182–188[CrossRef][Medline]
18. 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]
19. Toogood AA, Beardwell CG, Shalet SM 1994 The severity of growth hormone deficiency in adults with pituitary disease is related to the degree of hypopituitarism. Clin Endocrinol (Oxf) 41:511–516[Medline]
20. Growth Hormone Research Society 1998 Consensus guidelines for the diagnosis and treatment of adults with growth hormone deficiency: summary statement of the Growth Hormone Research Society Workshop on Adult Growth Hormone Deficiency. J Clin Endocrinol Metab 83:379–381.[Abstract/Free Full Text]
21. Aimaretti G, Corneli G, Razzore P, Bellone S, Baffoni C, Arvat E, Camanni F, Ghigo E 1998 Comparison between insulin-induced hypoglycemia and growth hormone (GH)-releasing hormone + arginine as provocative tests for the diagnosis of GH deficiency in adults. J Clin Endocrinol Metab 83:1615–1618[Abstract/Free Full Text]
22. Darzy KH, Aimaretti G, Wieringa G, Gattamaneni HR, Ghigo E, Shalet SM 2003 The usefulness of the combined growth hormone (GH)-releasing hormone and arginine stimulation test in the diagnosis of radiation-induced GH deficiency is dependent on the post-irradiation time interval. J Clin Endocrinol Metab 88:95–102[Abstract/Free Full Text]
23. Colao A, Cerbone G, Pivonello R, Aimaretti G, Loche S, Di Somma C, Faggiano A, Corneli G, Ghigo E, Lombardi G 1999 The growth hormone (GH) response to the arginine plus GH-releasing hormone test is correlated to the severity of lipid profile abnormalities in adult patients with GH deficiency. J Clin Endocrinol Metab 84:1277–1282[Abstract/Free Full Text]
24. Looker AC, Wahner HW, Dunn WL, Calvo MS, Harris TB, Heyse SP, Johnston Jr CC, Lindsay R 1998 Updated data on proximal femur bone mineral levels of US adults. Osteoporos Int 8:468–489[CrossRef][Medline]
25. 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]
26. Prentice A, Parsons TJ, Cole TJ 1994 Uncritical use of bone mineral density in absorptiometry may lead to size-related artifacts in the identification of bone mineral determinants. Am J Clin Nutr 60:837–842[Abstract/Free Full Text]
27. Molgaard C, Thomsen BL, Prentice A, Cole TJ, Michaelsen KF 1997 Whole body bone mineral content in healthy children and adolescents. Arch Dis Child 76:9–15[Abstract/Free Full Text]
28. Nevill AM, Holder RL, Maffulli N, Cheng JC, Leung SS, Lee WT, Lau JT 2002 Adjusting bone mass for differences in projected bone area and other confounding variables: an allometric perspective. J Bone Miner Res 17:703–708[CrossRef][Medline]
29. Lu PW, Cowell CT, Lloyd-Jones SA, 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]
30. Warner JT, Cowan FJ, Dunstan FD, Evans WD, Webb DK, Gregory JW 1998 Measured and predicted bone mineral content in healthy boys and girls aged 6–18 years: adjustment for body size and puberty. Acta Paediatr 87:244–249[CrossRef][Medline]
31. Rauch F, Schoenau E 2001 Changes in bone density during childhood and adolescence: an approach based on bone’s biological organization. J Bone Miner Res 16:597–604[CrossRef][Medline]
32. Specker B, Binkley T 2003 Randomized trial of physical activity and calcium supplementation on bone mineral content in 3- to 5-year-old children. J Bone Miner Res 18:885–892[CrossRef][Medline]
33. Di Leo C, Tarolo GL, Bagni B, Bestetti A, Tagliabue L, Pietrogrande L, Pepe L 2002 Peripheral quantitative computed tomography (PQCT) in the evaluation of bone geometry, biomechanics and mineral density in postmenopausal women. Radiol Med (Torino) 103:233–241
34. Nijs J, Westhovens R, Joly J, Cheng XG, Borghs H, Dequeker J 1998 Diagnostic sensitivity of peripheral quantitative computed tomography measurements at ultradistal and proximal radius in postmenopausal women. Bone 22:659–664[Medline]
35. Schneider P, Reiners C, Cointry GR, Capozza RF, Ferretti JL 2001 Bone quality parameters of the distal radius as assessed by pQCT in normal and fractured women. Osteoporos Int 12:639–646[CrossRef][Medline]
36. Hasegawa Y, Schneider P, Reiners C, Kushida K, Yamazaki K, Hasegawa K, Nagano A 2000 Estimation of the architectural properties of cortical bone using peripheral quantitative computed tomography. Osteoporos Int 11:36–42[CrossRef][Medline]
37. Crabtree N, Loveridge N, Parker M, Rushton N, Power J, Bell KL, Beck TJ, Reeve J 2001 Intracapsular hip fracture and the region-specific loss of cortical bone: analysis by peripheral quantitative computed tomography. J Bone Miner Res 16:1318–1328[CrossRef][Medline]
38. Tsurusaki K, Ito M, Hayashi K 2000 Differential effects of menopause and metabolic disease on trabecular and cortical bone assessed by peripheral quantitative computed tomography (pQCT). Br J Radiol 73:14–22[Abstract]
39. Schweizer R, Martin DD, Schwarze CP, Binder G, Georgiadou A, Ihle J, Ranke MB 2003 Cortical bone density is normal in prepubertal children with growth hormone (GH) deficiency, but initially decreases during GH replacement due to early bone remodeling. J Clin Endocrinol Metab 88:5266–5272[Abstract/Free Full Text]

This article has been cited by other articles:

				R. D. Murray, M. Bidlingmaier, C. J. Strasburger, and S. M. Shalet The Diagnosis of Partial Growth Hormone Deficiency in Adults with a Putative Insult to the Hypothalamo-Pituitary Axis J. Clin. Endocrinol. Metab., May 1, 2007; 92(5): 1705 - 1709. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 91/2/432    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Murray, R. D. Articles by Shalet, S. M. Search for Related Content PubMed PubMed Citation Articles by Murray, R. D. Articles by Shalet, S. M. Related Collections Calcium and Bone Metabolism Neuroendocrinology and Pituitary