Full text of DOI:10.1359/jbmr.2002.17.6.1081

JOURNAL OF BONE AND MINERAL RESEARCH
Volume 17, Number 6, 2002
© 2002 American Society for Bone and Mineral Research
The Effects of Growth Hormone Replacement Therapy on
Bone Metabolism in Adult-Onset Growth Hormone
Deficiency: A 2-Year Open Randomized Controlled
Multicenter Trial*
MARIE BEX,1 ROGER ABS,2 DOMINIQUE MAITER,3 ALBERT BECKERS,4 GERARD LAMBERIGTS,5
and ROGER BOUILLON1
ABSTRACT
Adult hypopituitary patients with growth hormone deficiency (GHD) show a significant decrease in bone mass and
an increased fracture rate. Replacement therapy with GH increases bone turnover. Most of the long-term data on
bone mineral content (BMC) and bone mineral density (BMD) have been acquired in open, noncontrolled trials
involving limited numbers of patients. To determine whether long-term GH therapy is beneficial for bone despite
the increased bone turnover, 100 patients (59 men and 41 women), aged 25–65 years (mean, 49.7 years) with
adult-onset GHD were randomized to treatment with GH (40 men and 28 women; mean dose, 0.18 IU/kg per week)
or to a nontreated control group (19 men and 13 women) for 24 months. Despite a similar increase in parameters
of bone turnover (osteocalcin [OC], procollagen type I carboxy-terminal propeptide [PICP], and pyridinolines
([PYD]) in male and female GH-treated patients compared with controls, the effects on BMC and BMD as
evaluated by dual-energy X-ray absorptiometry were gender specific. A significant increase in spine BMC and
BMD and total hip BMD and a decrease in BMD at the ultradistal radius over time was observed in male
GH-treated patients compared with the evolution in controls (mean ؎ SEM change at 24 months: ؉6.8 ؎ 1.1%
and p ؍ 0.009, ؉5.1 ؎ 0.8% and p ؍ 0.005, ؉3.5 ؎ 0.7% and p ؍ 0.02, and ؊2.6 ؎ 0.8% and p ؍ 0.008,
respectively). No significant treatment effects were observed in female patients. Despite the increase in the total
remodeling space induced by GH treatment, prolonged GH therapy in adult-onset GHD has a positive effect on
bone balance, maintaining bone mass in women, and even increasing it in men over a 2 year-period. (J Bone Miner
Res 2002;17:1081–1094)
Key words: adult, growth hormone deficiency, bone density, growth hormone therapy, controlled study
(GHD) adults have a decreased bone turnover,(1,2) and GH
replacement therapy in these patients clearly enhances both
INTRODUCTION
ROWTH HORMONE (GH) has well-known effects on
growth and development of the skeleton in children but
also influences bone homeostasis in adults. GH-deficient
bone formation and resorption. GH excess in adults (acro-
megaly) increases bone size especially through periosteal
bone growth. Acquired GHD in adults, either isolated or as
part of panhypopituitarism, also has major adverse effects
on body composition with increase in total fat mass and
decrease in muscle and bone mass.(3) Based on cross-
sectional and retrospective studies, such patients have a
decreased quality of life (QoL), increased morbidity includ-
ing an increased incidence of fractures, and higher mortality
G
*Presented in part as a poster at the 6th International Pituitary
Congress, June 15–17, 1999 Long Beach, California, USA, and the
28th International Symposium GH and Growth Factors in Endo-
crinology and Metabolism, October 23–23, 1999 Boston, Massa-
chusetts, USA.
The authors have no conflict of interest.
1Department of Endocrinology, University Hospital Gasthuisberg, Leuven, Belgium.
2Department of Endocrinology, University Hospital, Antwerp, Belgium.
3Department of Endocrinology, University Hospital St. Luc, Brussels, Belgium.
4Department of Endocrinology, CHU Lie`ge, Lie`ge, Belgium.
5Department of Endocrinology, Algemeen Ziekenhuis St. Jan, Brugge, Belgium.
1081

1082
BEX ET AL.
TABLE 1. CHARACTERISTICS OF PITUITARY DISEASE
Total
GH group
Control group
No. of patients
Men
Women
Mean age (years; range)
Etiology
100
59
41
68
32
40 (59%)
28 (41%)
49 (25–65)
19 (59%)
13 (41%)
51 (28–65)
50
Pituitary adenoma
Nonfunctioning
Prolactinoma
73
47 (65%)
27
26 (82%)
20
11
9
4
2
Cushing’s diseasea
Craniopharyngioma
Other
12
15
16
84
56
53
57
17
1.3
81
9 (13%)
12 (20%)
10 (15%)
58 (85%)
37 (54%)
34 (50%)
37 (54%)
13 (19%)
1.4 (0.1–4.7)
56
3 (9%)
3 (9%)
6 (19%)
26 (81%)
19 (59%)
19 (59%)
20 (62%)
4 (13%)
1.2 (0.1–3.7)
25
IGHD
MPHD, treated for deficiency of
TSH
ACTH
FSH/LH
ADH
Mean peak GH (␮g/liter; range)
0–1.99
2–2.99
13
7
6
3–4.99
6
5
1
Presumed duration of GHD
7.5 Ϯ 6.5
7.0 Ϯ 7 (1–36)
8.5 Ϯ 6 (1–22)
(years; mean Ϯ SD; range)
Percentages (in parentheses) are in reference to each treatment group.
a Median duration postcure, 6.5 years (range, 1–22 years).
from cardiovascular disease.(3) GH replacement in GHD duration were recruited in five Belgian centers (Table 1).
adults now has been accepted as a valuable addition to None of them had been treated with GH before. Mean age
standard pituitary hormone replacement because of its fa-
vorable effects on body composition, improved well being,
and reduction of several risk factors for diseases associated
with GHD.(3)
was 50 years (range, 25–65 years) and suspected mean
duration of GHD was 7.5 years (range, 1–36 years). Diag-
nosis of GHD was based on a peak serum GH response
(assayed by polyclonal competitive radioimmunoassays
(RIAs) of Ͻ5 ␮g/liter (at that time equivalent to10 mU/liter)
after stimulation by either insulin-induced hypoglycemia
(n ϭ 48), GH releasing hormone (RH) (n ϭ 33), or gluca-
gon (n ϭ 19) performed within 5 years before inclusion. All
patients were white except for one Asian man. All patients
had a history of adult-onset hypothalamic pituitary disease.
In the majority of patients, pituitary deficiency was caused
by a pituitary tumor: adenoma (n ϭ 73) or craniopharyngi-
oma (n ϭ 12) and/or its treatment (surgery in 75 and
radiotherapy in 33 patients). Pituitary tumor patients in-
cluded 11 patients with inactive Cushing’s disease and 15
patients with treated prolactinomas. Other causes of pitu-
itary deficiency were Sheehan’s syndrome (3), autoimmune
hypophysitis (3), empty sella (3), posttraumatic (2), apo-
plexy (1), basal meningoencephalocele (1), idiopathic (1),
and radiotherapy for cranial neurinoma (1). Eighty-four
patients suffered from at least one additional pituitary HD
(and 60 patients from two or more), and 16 patients had
isolated GHD (IGHD) at inclusion. In the latter, diagnosis
of IGHD had been confirmed by repeated provocative test-
ing. Patients with multiple pituitary HD (MPHD) were on
A large number of short-term (6–12 months) controlled
studies of GH replacement therapy have convincingly de-
termined its capability to increase bone turnover but showed
inconsistent results on bone mass.(1,2) Small-scale uncon-
trolled studies of prolonged GH replacement with follow-up
up to 6 years suggested a progressive increase in bone
mineral density (BMD).(4–12) However, up to now, only one
controlled study of 18 months duration in adult GHD men
has been published.(13) To evaluate the safety and long-term
(i.e., spanning the normal remodeling cycle of bone by
several times) effect of GH replacement therapy on bone
mineral mass and BMD, we performed a prospective con-
trolled 2-year study of 100 adult-onset GHD male and
female patients of which 2⁄
3
were treated randomly with GH
1
and the remaining ⁄
3
was used as a control group. There-
after, all patients were offered GH replacement therapy.
MATERIALS AND METHODS
Patients
One hundred hypopituitary patients (59 men and 41 stable hormone-replacement therapy for at least 6 months.
women) with GHD acquired as adults and of at least 1 year Deficiency of follicle-stimulating hormone (FSH)/

2-YEAR EFFECTS OF GH ON BONE IN GHD
1083
luteinizing hormone (LH), thyroid-stimulating hormone yearly. Laboratory examinations were performed at base-
(TSH), adrenocorticotropic hormone (ACTH), and antidi- line; at 1-, 3-, and 6-month visits; and every 6 months
uretic hormone (ADH) was present in 74, 58, 55, and 17 thereafter. Blood samples were collected in the morning
patients, respectively. All 16 hypogonadal women under the after an overnight fast. Physical examination and drug com-
age of 50 years were on estrogen-replacement therapy but
only 5 of 18 gonadotrophin-deficient women aged Ն50
years were taking estrogens, as were the two postmeno-
pausal women. Because of personal dislike, 4 of 40 hypogo-
nadal men did not receive testosterone-replacement therapy
before or during the study.
Patients with active metabolic disease capable of influ-
encing bone metabolism, previous acromegaly, acute severe
illness during the 6 months before inclusion, pregnancy,
pliance were checked at 3-month intervals. Patients ran-
domized to the control group had an identical follow-up.
All participants gave their written informed consent and
the study was approved by the ethical committees of every
participating hospital and was conducted in accordance with
the guidelines proposed in The Declaration of Helsinki and
with good clinical practice.
hepatic or renal impairment, diabetes mellitus, uncontrolled BMD
hypertension, malignancy, clinically significant cardiopul-
BMD of the lumbar spine (L2–L4), the left hip, the
monary disease, or chronic medication (except for hormone-
replacement therapy, oral contraceptives, bromocriptine,
cabergoline, antacids, H2-receptor-antagonists, proton-
pump inhibitors, mild sedatives, low-dose aspirin, treatment
for mild hypertension, or mild asthma) were excluded from
the study. Pharmacologic doses of glucocorticoids were not
allowed, but lipid lowering drugs and antiepileptic treat-
ment were permitted, if started before and continued for the
duration of the study.
nondominant forearm, and the total body was measured by
dual-energy X-ray absorptiometry. A GE Lunar DPX-L (GE
Lunar Radiation, Inc., Madison, WI, USA) densitometer
was used in one center and different types of the Hologic,
Inc. QDR densitometer (Hologic, Inc. Waltham, MA, USA)
were used in the other centers (a QDR-2000 in two centers
and a QDR-4500 and a QDR-1000/W in one center each).
The longitudinal follow-up of each patient was performed
on the same equipment. In addition to a daily quality control
of the equipment by spine phantom measurements as in-
structed by the manufacturer, the stability of the different
densitometers was verified by yearly measurement of the
ESP phantom 026. The CVs for precision of bone mineral
content (BMC) and BMD measurements of the phantom for
the densitometers used were Յ1.6% and Յ0.6%, respec-
tively. Finally, before statistical analysis, an independent
observer blinded to treatment allocation evaluated the qual-
ity of all scans, recalculating or omitting the data if the
technical aspects of the longitudinal follow-up were not
completely comparable.
BMC and BMD values, expressed in grams and grams per
squared centimeter, respectively, are not directly compara-
ble for Hologic, Inc. (n ϭ 73) and GE Lunar Radiation, Inc.
(n ϭ 26) measurements because of different technical im-
plementations.(14) Therefore, results of treatment are pre-
sented as percent changes from baseline.
The reference values provided by each manufacturer were
used to calculate T scores, which express individual BMD
values as SD scores in relation to the normal mean BMD
values in a young normal population of the same gender.
Patients were considered to be osteopenic when the T score
was between Ϫ1 and Ϫ2.5 and were considered osteopo-
rotic when the T score was Ͻ Ϫ2.5, according to the criteria
defined by the World Health Organization (WHO).(15) Age-,
gender-, and (GE Lunar only) weight-adjusted Z scores
were used for the evaluation of BMD loss attributable to the
GHD state.
Study design
Patients were enrolled into a 24-month prospective open
randomized multicenter trial of either GH-replacement ther-
apy or no treatment. Using a computerized procedure with
seed number, a randomization list and sealed envelopes
were produced by Pharmacia Corp. (Stockholm, Sweden),
1
providing an uneven randomization with ⁄
3
of the patients
into the GH
2
into the nontreatment control group and ⁄
3
group, with gender stratification. Taking into account the
clear effects of GH on bone in short-term double-blind
studies, a placebo-controlled design implying 2 years of
placebo injections was considered unethical. At the time of
the study, reimbursement of GH-replacement therapy had
not been obtained in Belgium.
During the first 4 weeks of treatment, the intended daily
recombinant human GH (Genotropin; Pharmacia Corp.)
dose was 0.02 IU/kg body weight (BW) per day (Ϸ6.7
␮g/kg) administered subcutaneously at bedtime. Thereafter,
the intended dose was 0.03 IU/kg BW per day (Ϸ10 ␮g/kg)
with a maximum dose of 4 IU/day (Ϸ1.33 mg), irrespective
of BW. In case of adverse events, the dose could be reduced
by stepwise dose reductions of 0.5 IU/day (Ϸ0.17 mg) until
an individualized dose was established. Dose titration ac-
cording to insulin-like growth factor (IGF) I level was not
part of the protocol. Drug compliance was assessed by vial
count and monitoring of medication diaries and retrospec-
tively by a rise in IGF-I during GH therapy. Intake of
minerals, vitamins, or other supplements by either treatment
group was not specifically recommended and remained un-
changed for the duration of the study.
In addition, cortical bone thickness was assessed yearly
by radiogrammetry.(16) All calculations were performed by
a single observer. The metacarpal index is the percent ratio
Bone mass measurements of the spine, the nondominant of cortical area of the metacarpal to the square of periosteal
forearm, and the hip and total body composition were de- diameter (D2 Ϫ d2)/D2 and corrects for differences in skel-
termined at baseline and every 6 months during the study etal size. The reproducibility of the method is 3.1%. Normal
period. A radiograph of the dominant hand was taken values are age-, gender-, and menopause-related.(17)

1084
BEX ET AL.
tions of 21 ng/liter and 53 ng/liter, respectively; the normal
range was 3–30 ng/liter. Serum 1,25-dihydroxyvitamin D
[1,25(OH)2D] levels were measured by RIA after extrac-
tion, as previously described.(23) The between- and within-
assay CVs at a concentration at 42 ng/liter were 14% and
11%, respectively. The mean (ϮSD) value in healthy adults
is 38 Ϯ 12 ng/liter. Serum calcitonin (CT) levels were
measured by IRMA (Medgenix Diagnostics, Fleurus, Bel-
gium). The intra-assay and interassay CVs were 3.1% and
5.3% at 38.3 ng/liter. The normal range in an adult popu-
lation was 0–15 ng/liter. Finally, urinary calcium and phos-
phorus were assayed centrally in this subgroup of patients,
and serum calcium, phosphorus, creatinine, and alkaline
phosphatase (sALP) were assayed in all patients using stan-
dard methods in the five local laboratories.
Body composition, muscle strength, and QoL
Dual-energy X-ray absorptiometry, using the equipment
described previously, was used to measure lean body mass
(LBM) and percentage of body fat. Muscle strength was
evaluated by measuring the grip strength of the dominant
hand with the Jamar hand dynamometer as the average of
three attempts following the instructions of the manufac-
turer. QoL was evaluated using an adult GHD disease–
specific questionnaire Quality of Life Assessment of GHD
in Adults (QoL-AGHDA).(18) This questionnaire provides
information on a range of physical, emotional, and social
issues, relevant to patients with GHD. This QoL-AGHDA
consists of 25 yes/no items. The total score is a simple
summation of the number of “yes” responses, with a high
score indicating greater distress (poor QoL). Baseline values
(mean score of two questionnaires, taken at a 4-week inter-
val) were obtained before patients were informed of their
treatment assignment.
Other biochemical assays
The serum concentrations of IGF-I and IGF binding pro-
tein (BP) 3 (IGFBP-3) in all patients were measured by
Pharmacia Corp. using RIA after acid-alcohol extraction
(Nichols Institute Diagnostics, San Juan Capistrano, CA,
USA) and ELISA (Diagnostic System Laboratories, Web-
ster, TX, USA), respectively. Analysis, using frozen serum
samples, was performed after completion of the study.
IGFBP-3 results were expressed in milligrams per liter and
those of IGF-I were expressed in micrograms per liter and
as a SD score comparing the individual result with those of
Markers of bone turnover
Biochemical markers of bone turnover were analyzed in a
subgroup of 41 patients (28 treated patients and 13 control
patients) from two centers. Fasting serum specimens and
urine samples from an acidified 24-h urine collection were
stored at Ϫ20°C immediately after sampling and all mea-
surements of each individual were performed using the
same batch of assay reagent. Urinary pyridinolines (PYDs)
and deoxypyridinolines (DPDs) normalized for urinary cre-
atinine, markers of bone resorption, were measured in 24-h an age-matched reference population [395 randomly se-
lected healthy Swedes from the Monica study(24): algorithm,
urine collections acidified with hydrochloric acid, by high-
performance liquid chromatography (HPLC) as previously
described.(19) Values are expressed as micromoles per mole
of creatinine, and urinary creatinine was measured colori-
metrically.(20) Interassay CVs were 11.5% and 13.3% for
PYD and DPD, respectively, and the intra-assay CVs were
10.2% and 12.5%. Normal values were 22–89 ␮mol/mol
and 4–21 ␮mol/mol of creatinine for PYD and DPD, re-
spectively. Serum osteocalcin (OC) levels were measured
by a homologous human OC RIA. The within- and between-
assay CVs were 4.5% and 8.6% for a low value (7.6
␮g/liter) and 6.4% and 7.1% for a high value (36 ␮g/liter),
respectively; the mean (ϮSD) values in adults were 25 Ϯ 5
␮g/liter in men, 20 Ϯ 6 ␮g/liter in premenopausal women,
and 29 Ϯ 2 ␮g/liter in postmenopausal women.(21) Serum
procollagen type I carboxy-terminal propeptide (S-PICP)
levels were measured by RIA (Orion Diagnostica, Espoo,
Finland). The between-assay variation coefficient was 4.1%
at 105 ␮g/liter and 6.6% at 216 ␮g/liter; the within-assay
variation was 2.1% at 103 ␮g/liter and 3.2% at 451 ␮g/liter.
The normal ranges were 38–202 ␮g/liter and 50–170 ␮g/
liter in men and women, respectively. Serum intact para-
thyroid hormone (PTH) levels were measured by a human
PTH [hPTH(1-84)] immunoradiometric assay (IRMA) with
polyclonal and monoclonal region–specific antibodies.(22)
The within-assay CVs were 2.4%, 3.7%, and 8.1% for high
(108 ng/liter), medium (20 ng/liter), and low (10 ng/liter)
PTH(1-84) concentrations, respectively. The between-assay
CVs were 6.7% and 6.8% for mean PTH(1-84) concentra-
SDs ϭ (ln(IGF-I) Ϫ (5.92 Ϫ 0.0146 ϫ age))/0.272].
Statistical analysis
The primary efficacy variable was the mean relative
change of BMC at the lumbar spine (L2–L4) after 24
months of treatment. Based on a relevant improvement of
2% per year of the L2–L4 BMC in the GH-treated group
with 90 evaluable patients randomly assigned, 30 to the
control group and 60 to the treatment group, at the end of
the 2-year period, the power of the study was 80% at a 5%
significance level. Secondary objectives were the evaluation
of the mean relative change of BMD at the lumbar spine, the
hip, and the forearm of total body BMC and body compo-
sition.
The effect of GH over time (6, 12, 18, and 24 months) on
BMC and BMD was analyzed using a linear mixed model.(25)
Presence of a gender difference was evaluated. The p values
were corrected for multiple testing using the step-down Bon-
ferroni method of Holm.(26) Statistical significance was as-
sumed for p Ͻ 0.05. Analyses were performed using the SAS
version 6.12 TS 051. Data were analyzed on an intention-to-
treat basis. Two patients in the treated group were excluded
from the efficacy analysis because of protocol violations (a
pharmacologic glucocorticoid replacement dose and start of
oral methylprednisolone for emphysema, respectively).

2-YEAR EFFECTS OF GH ON BONE IN GHD
1085
TABLE 2. BASELINE CLINICAL CHARACTERISTICS IN GH-TREATED AND CONTROL PATIENTS
Males
Females
GH
Control
GH
Control
No. of patients
40
19
28
13
Mean age (years)
Height (cm)**
49 Ϯ 11
174 Ϯ 8
52 Ϯ 11
174 Ϯ 7
50 Ϯ 11
162 Ϯ 6
49 Ϯ 13
163 Ϯ 5
Weight (kg)
84 Ϯ 13
27.8 Ϯ 3.6
29 Ϯ 7
56 Ϯ 9
98 Ϯ 10
83 Ϯ 9
27.4 Ϯ 2.5
28 Ϯ 5
56 Ϯ 7
97 Ϯ 6
81 Ϯ 18
31.3 Ϯ 7.4
45 Ϯ 9
41 Ϯ 7
97 Ϯ 16
78 Ϯ 11
29.2 Ϯ 5.1
44 Ϯ 7
40 Ϯ 3
94 Ϯ 10
BMI (kg/m2)*
% BF (% of BW; DXA)**
LBM (kg; DXA)**
Waist (cm)
Waist/hip ratio**
Hand power (dynamometry)
Metacarpal index
QoL-AGHDA-score**
IGF-I (␮g/liter)**
IGF-I SDs**
0.96 Ϯ 0.06
46.7 Ϯ 8.6
80.6 Ϯ 6.9
7.6 Ϯ 5.2
177.5 Ϯ 76.2
Ϫ0.4 Ϯ 1.6
3.14 Ϯ 0.74a
0.95 Ϯ 0.04
46.8 Ϯ 7.4
79.1 Ϯ 8.5
8.2 Ϯ 5.7
137.7 Ϯ 66.0
Ϫ1.4 Ϯ 1.9
2.62 Ϯ 0.74
0.86 Ϯ 0.06
27.1 Ϯ 4.8
80.7 Ϯ 7.8
12.9 Ϯ 6.5
104.3 Ϯ 60.4
Ϫ2.8 Ϯ 2.7
2.89 Ϯ 1.19
0.87 Ϯ 0.06
30.7 Ϯ 5.6
84.4 Ϯ 10.3
12.0 Ϯ 7.0
92.3 Ϯ 57.0
Ϫ3.2 Ϯ 2.7
2.65 Ϯ 0.72
IGFBP-3 (ng/ml)
Results are the mean Ϯ SD.
BF, body fat; BMI, body mass index; LBM, lean body mass; DXA, dual-energy X-ray absorptiometry.
Asterisks indicate significant differences between genders: * p ϭ 0.005; ** p Ͻ 0.0001.
a GH-treated males had higher baseline IGFBP-3 than nontreated males ( p ϭ 0.014), p Ͼ 0.05 for all other comparisons between
GH and control groups of same gender.
respiratory disorders (in 47% vs. 50%, respectively) being
the most common. The majority (Ͼ70%) of the fluid-related
adverse events in the GH-treated group occurred within the
first 6 months of GH treatment. There was a nonsignificant
gender difference in the occurrence of fluid retention–
related side effects (in 82% of women vs. in 70% of men)
explaining that women needed transient or permanent re-
ductions of their GH dose more frequently (64% of women
vs. 42.5% of men; p ϭ 0.08).
RESULTS
Baseline characteristics, compliance, and tolerance
Clinical characteristics at baseline did not differ between
patients in the GH and the control group, as shown in Table
2. Ninety-two patients completed the study, of whom 62
patients were in the treated group and 30 patients were in
the control group. Three GH-treated patients withdrew
within the first 4 months because of GH-related fluid reten-
tion effects (joint pain and edema with or without carpal
tunnel syndrome, respectively). Reasons for study discon-
tinuation during the second year of treatment were perfor-
mance of gastric banding surgery, emphysema, and non-
compliance. Reasons for discontinuation in the control
GH-dose and IGF-I, IGF-I sodium dodecyl sulfate,
and IGFBP-3
Dose reductions from the intended 0.21 IU/kg per week
group were pregnancy and a demand for GH-replacement (Ϸ10 ␮g/kg per day) were required in over one-half of the
therapy. Overall, compliance in the 62 patients completing patients. The maximum mean dose of GH was 0.19 Ϯ 0.03
the study was very good. Noncompliance, defined as miss- IU/kg per week (Ϸ9 Ϯ 1.4 ␮g/kg per day) at 3 months in
ing 15% of injections or more (one injection per week) was women and 0.19 Ϯ 0.04 IU/kg per week (Ϸ9 Ϯ 1.8 ␮g/kg
present in 4 patients but was caused by treatment interrup- per day) at 6 months in men. Thereafter and for the duration
tions of 3–9 months duration in 3 of these patients. Reasons of the second treatment year, the mean dose of GH was
for interruption were arterial hypertension, a rise in serum 0.17 Ϯ 0.05 IU/kg per week (Ϸ8.1 Ϯ 2.4 ␮g/kg per day) in
creatinine (both noncorrecting after discontinuation), and women and 0.18 Ϯ 0.05 IU/kg per week (Ϸ8.5 Ϯ 2.4 ␮g/kg
treatment fatigue. Only three of the 58 compliant patients per day) in men, equivalent to a daily injected dose of 2 Ϯ
had missed Ͼ5% of the injections.
0.6 IU (Ϸ0.67 Ϯ 0.2 mg) in both genders.
Adverse events possibly related to fluid retention were
Baseline IGF-I and IGF-I SDs did not differ between
reported in 51 (75%) treated patients versus 5 (15%) control treatment groups (Table 2) but were significantly lower in
patients (␹ test, p Ͻ 0.0001): one or more episodes of female patients than in male patients (mean, IGF-I Ϯ SD of
arthralgia (in 53% vs. 12.5% of controls; p ϭ 0.0001), 100 Ϯ 59 ␮g/liter vs. 165 Ϯ 75 ␮g/liter, respectively; p Ͻ
edema (41% vs. 3%; p Ͻ 0.0001), paresthesia including the 0.0001). The percentage of patients in the entire study group
carpal tunnel syndrome (31% vs. 3%; p ϭ 0.002), and/or at baseline with a low IGF-I (SD Ͻ Ϫ2) was 61% in women
myalgia (21% vs. 3%; p ϭ 0.02) occurred significantly and 24% in men. Four men (7% of men, all MPHD and
more frequently in the GH-treated group. There was no randomized to the GH group) had high IGF-I (SD Ͼ ϩ2) at
difference in the reported frequency of other adverse events, baseline. There was a significant increase in serum IGF-I

1086
BEX ET AL.
with GH treatment for the duration of the study (Fig. 1). The Ϫ2) or normal (SD Ϯ 2) pretreatment levels was 21% and
50% in women and 40% and 83% in men, respectively.
Serum IGFBP-3 concentrations sharply increased from a
mean Ϯ SEM of 3.04 Ϯ 0.12 ng/ml at baseline to 4.08 Ϯ
0.11 ng/ml at 1 month in the GH group and plateaued
thereafter, whereas the control group showed no change
(p Ͻ 0.0001). There was no gender difference for IGFBP-3.
percentage of patients with supraphysiological serum IGF-I
concentrations (SD Ͼ ϩ2) at 24 months who had low (SD Ͻ
Baseline BMD
The mean Z score was significantly different from zero,
indicating a decrease in BMD in GHD patients compared
with their age- and gender-matched controls, at all measured
sites in men and at the lumbar spine and the hip in women
aged Ͻ50 years. This reduction persisted after exclusion of
the 4 men with untreated gonadal insufficiency (Fig. 2) and
of the patients with a previous history of ACTH- or prolac-
tin (PRL)-producing tumors (not shown). In contrast, BMD
in all women was normal at the forearm. Women aged Ն50
years, despite a nonsubstituted hypogonadism in 13 out of
20, showed normal bone density for their age at the lumbar
spine and at the hip as well.
At least osteopenia (T score Ͻ Ϫ1 SD) was present at the
lumbar spine in 52% and 50%, at the femoral neck in 71%
and 63%, at the total hip in 51% and 50%, at the 1⁄
forearm
3
in 47% and 33%, and at the ultradistal forearm in 53% and
23% of men and women, respectively.
The mean (ϮSEM) metacarpal index expressed as an SD
score relative to a gender- and decade-specific mean was
0.09 Ϯ 0.21 and 0.01 Ϯ 0.22 in female (n ϭ 28) GHD
patients and male (n ϭ 43) GHD patients, respectively
(NS).
FIG. 1. Mean IGF-I SDs (absolute value) in male (F) and female (f)
GH-treated patients and in male (E) and female (Ⅺ) control patients in
relation to the mean GH dose in the two treated groups. Error bars
represent Ϯ SEM. p Ͻ 0.0001 for all comparisons of IGF-I SDs during
GH treatment between the GH-treated groups and the control groups.
*p Ͻ 0.01 and **p Ͻ 0.001 for differences in IGF-I SDs with GH
treatment between the male- and female-treated groups.
Effect of GH on bone metabolism
The effects of GH treatment on serum bone formation and
urinary bone resorption markers are shown in Fig. 3. The
serum OC concentration doubled during the first 6 months
FIG. 2. Baseline Z score in
GHD patients, stratified accord-
ing to age and gender (Hologic,
Inc.; measurements only; n ϭ
73). Values are mean Ϯ SEM.
The value of p Ͻ 0.05 for all
measured sites in male patients
and for the lumbar spine, femoral
neck, and total hip in female pa-
tients Ͻ50 years old.

2-YEAR EFFECTS OF GH ON BONE IN GHD
1087
FIG. 3. Evolution of (A) serum
bone formation markers (n ϭ 41),
(B) urinary bone resorption mark-
ers (n ϭ 38), and (C) serum cal-
cium, phosphorus (n ϭ 100), and
PTH (n ϭ 41) in GH-treated (F)
and control (E) patients over the
2-year period. Error bars repre-
sent ϮSEM *p Ͻ 0.05, **p Ͻ
0.01, ***p Ͻ 0.001 for differ-
ences between the groups. §p Ͻ
0.05 and §§p Ͻ 0.01 for differ-
ences in change from baseline be-
tween the groups.
of GH treatment from 31 Ϯ 9 ␮g/liter to 64 Ϯ 5 ␮g/liter month of GH treatment (from 52 Ϯ 4 ␮mol/mol to 108 Ϯ
(p Ͻ 0.00001 vs. controls) and gradually decreased there- 17 ␮mol/mol of creatinine and from 11 Ϯ 1 ␮mol/mol to
after but remained significantly elevated at 24 months at 24 Ϯ 4 ␮mol/mol of creatinine, respectively) and persisted
52 Ϯ 4 ␮g/liter (p Ͻ 0.01 vs. controls). Serum PICP values for 1 year (p Ͻ 0.0001 at 3, 6 and 12 months vs. controls)
showed a similar evolution with a maximum at 3 months whereafter the change from baseline no longer significantly
(from 103 Ϯ 8 ␮g/liter to 153 Ϯ 10 ␮g/; p Ͻ 0.0001 vs. differed between the two treatment groups.
controls) and a persistent elevation for the duration of the
The serum calcium level increased by a mean of 0.18 Ϯ
study, although at 24 months, the value (121 Ϯ 6 ␮g/liter) 0.06 mg/dl at 1 month of GH treatment (p Ͻ 0.01 vs.
was no longer significantly different (p ϭ 0.07) from the controls) and remained higher than in the control group for
control group. sALP concentration increased with GH treat- the duration of the study. These effects were even more
ment only in men (from 103 Ϯ 8 IU/liter to 118 Ϯ 10 pronounced for the serum phosphate level that was signif-
IU/liter at 6 months; p Ͻ 0.05 vs. all other groups) and icantly higher with GH treatment (p Յ 0.001 vs. controls) at
returned to baseline levels during the second treatment year all time points with a maximal increase of 0.69 Ϯ 0.08
whereas in both controls and GH-treated women, sALP mg/dl at 3 months. There was a significant decrease in
significantly declined from 12 months onward (not shown). serum PTH concentration during GH treatment with a max-
The increase of urinary PYD and DPD was maximal at 1 imal decrease of Ϫ10.0 Ϯ 1.6 pg/ml at 3 months (p Ͻ 0.01

1088
BEX ET AL.
vs. controls), persisting at 18 months and 24 months (p Ͻ the female GH-treated group, no significant changes in the
0.001 compared with baseline) although the ⌬PTH no number of patients with at least osteopenia were observed.
longer differed from the control group. Serum CT levels The metacarpal index, evaluated in 59 patients, did not
remained unchanged whereas the 1,25(OH)2D concentra- change significantly over time.
tion did not show consistent changes (not shown). Urinary
calcium excretion in male patients increased only tran-
siently in response to GH treatment (from 102 Ϯ 19 mg/g to
151 Ϯ 25 mg/g of creatinine at 1 month; p Ͻ 0.01 compared
Effect on other measures: body composition, muscle
strength, and QoL
with controls), whereas in female patients the increase was
more pronounced (from 124 Ϯ 21 mg/g to 219 Ϯ 39 mg/g
creatinine at 3 months; p Ͻ 0.001 vs. controls) and persisted
over the 2-year period (p Ͻ 0.05 vs. male treated patients).
No gender differences in response to GH treatment were
observed unless otherwise indicated.
At the end of the 2-year period, both GH-treated and
control patients had increased their BW by a mean of 1.5 Ϯ
0.7 kg. GH administration resulted in a significant decrease
in body fat and an increase in lean mass. As shown in Fig.
5, these beneficial changes in body composition were ini-
tially greater in male GH patients compared with female GH
patients, but the gender difference lessened over time. In
contrast, only GH-treated women showed a significant in-
crease in grip strength from 12 months onward (ϩ8.3 Ϯ
3.8% at 18 months; p Ͻ 0.05).
Female patients participating in the protocol experienced
greater psychological distress as shown by a higher mean
baseline QoL-AGHDA score (12.7 Ϯ 1.0 vs. 7.8 Ϯ 0.7 in
men; p Ͻ 0.001). However, GH treatment was associated
with a similar improvement of the QoL-AGHDA score in
both genders, which was significantly different compared
with nontreated controls from 18 months onward (mean
decrease in score of 3.5 Ϯ 0.8 and 4.5 Ϯ 0.8 at 18 months
and 24 months, respectively, vs. no change in controls; p Ͻ
0.001).
Effect of GH on bone mass and density
The effects on BMC and BMD of GH administration for
2 years are shown in Table 3 and the significant effects are
illustrated in Fig. 4. A significant difference in evolution
between the GH-substituted and the control groups was
observed at the lumbar spine (BMC, p ϭ 0.036; BMD, p ϭ
0.006) and at the ultradistal radius (radial BMD, p ϭ 0.004).
The difference in spine BMC and BMD over time was
significant in men only, after 24 months of GH therapy
(BMC, p ϭ 0.009; BMD, p ϭ 0.005, for the treatment effect
in men). The mean Ϯ SEM increase in spine BMC and
BMD in GH-treated male patients at 2 years was 6.8 Ϯ
1.1% and 5.1 Ϯ 0.8%, respectively. In women, administra-
tion of GH for 2 years did not result in a significant treat-
ment effect for the spine BMC (p ϭ 0.87), whereas a
significant treatment effect for spine BMD (p ϭ 0.046) was
caused by a transient decrease in BMD in the control group
DISCUSSION
We examined the effects of GH-replacement therapy on
at 6 months. Although female and to a lesser degree male bone in the largest population of adult-onset GHD patients
GH-treated patients showed a progressive decline in ultra- studied so far. By including patients with adult-onset GHD
distal (UD) radial BMD compared with baseline (Ϫ5 Ϯ only, a randomly selected GHD control group for the total
1.6% and Ϫ2.6 Ϯ 0. 8% at 24 months, respectively), the duration of the study and a sufficient number of patients of
evolution in GH-treated women did not significantly differ both genders, we were able to deal with several of the
from their controls (p ϭ 0.08; p ϭ 0.008 for treatment effect limitations of previous studies.
in women and men, respectively). Female GH-treated pa-
Bone density at baseline was decreased in GHD patients
tients showed a less pronounced decline in BMD at the at the lumbar spine (Ϫ0.4 Z score), femoral neck (Ϫ0.5 Z
1
distal ⁄
3
radius as well, although once again, no difference score), total hip (Ϫ0.5 Z score), and distal forearm (Ϫ0.4 Z
score). These data are in line with previous data in simi-
with controls could be shown.
Total hip BMD, although not statistically significant for lar(27,28) or smaller(29–31) groups of patients aged 55 years or
the total group (treatment effect, p ϭ 0.057), showed a less with adult- or mixed-onset GHD and indicate that bone
significant progressive increase in GH-treated males remodeling, even at a lower rate than normal,(32) is suffi-
(ϩ3.5 Ϯ 0.7% at 24 months, p ϭ 0.019 for treatment effect ciently imbalanced to produce a small but significant loss of
in men). The evolution of bone density measurements at the BMD. Whether this is caused by a direct effect of GH/IGF-I
other sites (femoral neck BMD and total body BMC) did not on bone cells or mediated by the GH/IGF-I effects on other
show any treatment or gender effects. The control group did body tissues is unclear. Usually, obesity is associated with
not show any significant changes throughout the 24 months an increased bone mass. Despite their absolute and relative
of the study. Patients with lower initial bone mass (Z increase in fat mass, GHD adults make an exception to this
score Ͻ Ϫ1 SDs) did not show more marked increases in rule. The associated relative decrease in LBM or muscle
BMD.
mass could be an indirect mechanism contributing to their
Among the 33 male patients who completed the 24 lower bone mass.
months of GH treatment, the percentage with at least os-
The decreased baseline BMD was observed in men as
teopenia decreased from 52 to 36% at the lumbar spine, well as in premenopausal women at weight-bearing sites but
from 79 to 70% at the hip, from 54 to 50% at the femoral not in postmenopausal women. Others(33,34) also have ob-
neck, was unchanged (53%) at the ultradistal radius, and served that elderly subjects with acquired GHD have no
increased from 38 to 47% at the proximal radius (all NS). In significant bone deficit at the time of diagnosis. The reasons

2-YEAR EFFECTS OF GH ON BONE IN GHD
1089

1090
BEX ET AL.
FIG. 4. Evolution of BMC/
BMD at three sites according to
treatment group and gender. F,
male GH-treated; f, female GH-
treated; E, male controls; Ⅺ, fe-
male controls. Values are the per-
centages of the baseline values;
error bars represent Ϯ SEM. The
p values for the treatment effect
in male patients were p ϭ 0.009,
p ϭ 0.005, p ϭ 0.019, and p ϭ
0.008 for spine BMC, spine
BMD, total hip BMD, and radial
BMD, respectively.
are not well understood but the important bone loss gener- mass in the male GH-treated group compares favorably with
ated by estrogen deficiency may mask the less important the data of the only published placebo-controlled study for
GH-mediated bone loss in postmenopausal women. The 18 months in men,(13) despite a maintenance GH dose
degree of osteopenia observed should predispose adult nearly twice as high in our study. At a dose of 9 ␮g/kg per
GHD patients to a 1.5- to 2-fold increased risk of fracture, day and in agreement with studies observing gender differ-
if bone quality and other risk factors are the same as in ences in GH requirements published after the start of our
prospective controlled studies.(35) Two small-scale cross- study,(44–47) the male GH-treated patients and the 9 GH-
sectional studies of adult-onset GHD patients(36,37) have treated hypogonadal females acquired supraphysiological
suggested such an increased prevalence of fractures. More- IGF-I levels whereas at the same GH dose the subgroup of
over, the Pharmacia Corp. International Metabolic Database 13 women treated orally with estrogen increased their IGF-I
KIMS, a large-scale pharmacoepidemiological survey, also into the desired high normal age-related reference range.
indicated an increased fracture risk in adult GHD pa- Fluid-related adverse events during GH treatment were
tients.(38)
common (75%), but their early occurrence and even distri-
The “normal” baseline IGF-I values in 39% of women and bution among both genders (despite supraphysiological vs.
76% of men are not unexpected in this older group of patients normal IGF-I levels during treatment in men and women,
with adult-onset GHD. In a similar population of adult-onset respectively) indicate that the rate of GH dosing causing
GHD patients (mean age of 45 years), 70% of IGF-I and 72% rapid IGF-I increase rather than the absolute level of IGF-I
of IGFBP-3 estimations were within the range of normal obtained was related to the occurrence of side effects. A
subjects.(39) The time of onset of GHD(40,41) and the age of the more gradual increase of the GH dose spanning several
patient(42,43) are two factors determining baseline IGF-I, with months, as is the current practice,(46) titrated to IGF-I levels
significantly lower values in childhood-onset GHD and at a might have prevented a large number of events.
lower age (Ͻ40 years), resulting in an increasing overlap
GH-replacement therapy had a clear effect on all bone
between GHD patients and the normal range with age.
parameters studied. Markers of bone formation, OC (ϩ100%)
Both male and female patients responded to the GH and collagen synthesis, PICP (ϩ50%), increased signifi-
treatment with the expected changes in body composition.(3) cantly from the start of GH-replacement therapy onward
However, women showed a less pronounced decrease in and this increase, although slowly waning over time, was
body fat percentage during the period of 0–18 months, in still significant after 2 years of continuous GH therapy. The
keeping with previous observations in a 9-month crossover bone resorption parameters PYD (ϩ150%) and DPD
study,(44) whereas the relative increase in LBM in treated (ϩ150%) also increased significantly, but this increase
women did not differ from that in men. The decrease of waned off during the second year of treatment (Fig. 3).
body fat percentage by 4% and the net 6% increase of lean Serum phosphate concentration increased significantly

2-YEAR EFFECTS OF GH ON BONE IN GHD
1091
(Ϫ2–3% at 2 years of treatment). No significant changes
between treated and untreated groups were detectable for
total body BMC (Table 3). Cortical bone thickness as mea-
sured by quantitative radiogrammetry of the metacarpal was
not significantly modified by GH treatment either.
The increase in BMD of the anteroposterior spine in the
present controlled study was fairly similar to the effects of
GH in adult-onset GHD men studied in the only other
(placebo) controlled study reported by Baum.(13) In contrast,
they observed no significant changes at the total hip or
radius and a 2.4% increase at the femoral neck at 18 months
was significant. However, numerous uncontrolled studies
(Table 4; see Ohlsson et al.(2)) have revealed a much larger
increase of BMC and/or BMD after 2 years or more of
GH-replacement therapy. Therefore, it seems likely that
prolonged GH-replacement therapy of GHD patients may
slowly increase bone mass. The magnitude of such an
increase might have been overestimated because of the lack
of a suitable control group. Indeed, the GHD control pop-
ulation in the only two controlled long-term studies
(Baum(13) and this study) clearly shows that BMC and BMD
evolution apparently does not follow the classical expected
age-related bone loss. This might be related to a lower bone
turnover or to a better compliance to androgen-replacement
therapy. A minimum of 6 months of androgen-replacement
therapy also may be of too short a duration to allow for
complete restoration of the hypogonadal bone loss.(50) On
the other hand, the lack of a significant bone loss in the
control groups over an 18- to 24-month period confirms
previous observations that bone loss in GHD is an early
event, independent of the duration of the disease.
Why female patients, despite a more than adequate GH-
replacement dose, do not react similarly as GH-treated male
patients is unclear. In previous studies lasting 24 months or
more and aiming at high normal IGF-I values, women were
not included(12,51) or were of low number and not analyzed
separately.(8) Some uncontrolled studies mentioned a simi-
lar increase in both genders(5,6) or even a small female
advantage at the total body.(5) However, more recently,
Johansson et al.(10) and Va¨lima¨ki(11) observed a significant
increase in BMC/BMD in GH-treated men but not in
women after a follow-up of 33 months and 42 months,
respectively. The gender effect observed in our study cannot
be ascribed to an insufficient GH dose. Moreover, GH-
treated women showed the same relative changes in lean
and fat mass, a comparable improvement in QoL, and
similar changes in bone turnover markers as GH-treated
male patients. Some studies(5,11,52) claimed larger incre-
ments in BMD in patients with lower initial Z scores,
although this effect has not been confirmed by others.(6,7,10)
We did not observe such an effect in our male-treated
group; therefore, the higher (normal) initial Z score in our
postmenopausal women cannot explain the apparent lack of
significant treatment effect in the female group. However,
the number of GH-treated women was too small to allow
valuable analysis and conclusions regarding the possible
confounding effects of age, gonadal status, or (mode of)
replacement therapy as modifying factors for their bone
FIG. 5. Change in percentage of body fat (absolute value) and LBM
(percentage of baseline) determined by dual-energy X-ray absorption in
male (F) and female (f)GH-treated patients and in male (E) and
female (Ⅺ) control patients. Error bars represent Ϯ SEM. Baseline
values of percent body fat and LBM differ between genders (Table 2).
All values in GH-treated males and females are significantly different
from baseline. In addition **p Ͻ 0.001 for GH-treated males compared
with control males. Significant differences in response between GH-
treated male and female groups are indicated; *p Ͻ 0.01.
throughout GH-replacement therapy, reflecting the well-
known effect of GH on the tubular reabsorption of phos-
phate. Serum calcium also slightly but significantly in-
creased (Fig. 3), probably reflecting increased intestinal
calcium absorption and accelerated calcium kinetics.(48) All
bone parameters increased similarly in GH-treated women
and men. The relative extent of accelerated bone turnover as
measured by specific biochemical markers corresponds well
with histomorphometric data of bone formation and turn-
over measured in either childhood(49) or adult-onset GHD
patients(32) after 1 year of GH-replacement therapy.
Despite a similar increase in bone turnover, only GH-
treated males showed a significant increase in bone mass.
This positive effect was limited to weight-bearing regions:
the lumbar spine (BMC ϩ 7% after 2 years, BMD ϩ 5%;
both p Ͻ 0.001 compared with controls) and the hip (BMD
total hip ϩ 3.5%; p Ͻ 0.05). The increase of 2% at the
femoral neck was not significant. At the radius (as measured
at two sites), a slight decrease was observed in both genders
that was significant versus control group at the UD radius response to GH therapy.

1092
BEX ET AL.
TABLE 4. CONTROLLED AND UNCONTROLLED STUDIES OF AT LEAST 18 MONTHS IN PATIENTS WITH GHD
Percent change in BMD
No. of patients
Duration
(months)
Reference
(No. at final evaluationb)
Study design
Lumbar spine
Femoral neck
Baum et al.(13)
Bex et al.
32 M
59 M
41 F
18
24
SBPC
randomized,
open controlled
Open
5.1
5.1
NS
3.8
2.1
1.6c
3.7
5.0
4.8
11.8d
5.5
5
2.4
NS
NS
4.1
Johansson et al.(5)
Janssen et al.(6)
24 M ϩ 20 F
20 M ϩ 27 F
20 M ϩ 13 F (18)
4 M ϩ 3 F
44 M ϩ 27 F (32)
(20)
11 M ϩ 9 F
31 M ϩ 21 F
20 M CHO (6)
38 M CHO (13)
24
24
33
36
36
42
48
48
30
60
Open
Open
Open
Open
Johansson et al.(10)
Rahim et al.(7)
3.5c
NS
5.9
5.7
Va¨lima¨ki et al.(11)a
Kann et al.(8)
Open
Open
Open
Open
Johannsson et al.(9)
Vandeweghe et al.(4)
ter Maaten et al.(12)
7.2
9.6
11.1
M, male; F, female; SBPC, single-blind placebo-controlled; CHO, childhood onset.
a Including 12 patients with CHO.
b If Ͻ50% of included patients evaluated at indicated study duration.
c Change versus month 15 of GH replacement.
d Nonstable equipment; change in normal controls of 4% at 48 months.
The major limitation of this study is the use of a prede- ble at that low lower level as long as GH therapy is given.
termined GH dose titrated to adverse events and not to Because BMC/BMD remains about unchanged (in
measured IGF levels. In retrospect, male and hypogonadal women) and increases significantly (in men), bone bal-
female patients were treated with higher GH doses than ance must be positive during prolonged (Ͼ12 months)
recommended nowadays to avoid IGF-I levels above the GH-replacement therapy. The further increase in BMC/
age-related normal range.(46) Therefore, the results on bone BMD observed several months after stopping GH-
might not be applicable to the current practice. However, replacement therapy in Baum’s patients,(51) probably be-
despite the supraphysiological dosing, the increase in bone cause of refilling of the extra remodeling space, is in line
mass is comparable with the results of the only single-blind with this hypothesis.
placebo-controlled study or even less than in numerous
The 2-year increase in BMC/BMD in bone areas most
open studies (Table 4), using smaller GH doses aiming at at risk for fracture is at first sight lower than what can be
normal IGF-I. Furthermore, although randomized and con- obtained by classical antiresorptive agents (estrogens,
trolled, the study was not placebo-controlled. However, the CT, or bisphosphonates). However, taking into account
obvious changes in body composition and the occurrence of that the latter agents decrease the remodeling space and
side effects would soon have revealed treatment assignment GH-replacement therapy increases the remodeling space,
to most patients (and physicians, in case of a double-blind the net effect on adult bone balance probably is very
protocol). Finally, because of the unequal inclusion of fe- similar. Longer-term (Ͼ2 year) yet uncontrolled studies
male versus male patients (enforced by the “no pregnancy” suggest indeed that continuous GH therapy further in-
exclusion criterion) the female subgroup analysis might not creases BMD by ϳ2%/year. This increase is not substan-
have had sufficient power to prove a treatment effect.
tially lower than the yearly BMD increment observed in es-
In conclusion, two controlled studies have now shown trogen, SERM, CT, or even bisphosphonate- treated
a significant positive effect on bone mass and density postmenopausal women.(35)
over an 18- to 24-month GH treatment period in men but
Thus, prolonged GH-replacement therapy in adult-onset
no controlled study has yet shown a similar effect in GHD patients has a positive effect on bone balance and not
GHD women. However, the true GH effect on bone is only maintains (women) but even increases (men) bone
underestimated because GH therapy clearly stimulates mass, despite a significant increase in bone remodeling.
bone remodeling and thus increases the bone remodeling
space (the total volume of osteoclastic resorption pits
present at any given time) by ϳ2%. If bone formation
would simply remain in perfect balance with the in-
ACKNOWLEDGMENTS
creased bone resorption during prolonged treatment,
We acknowledge the contribution of Jos Nys in the qual-
BMC and BMD should decrease by ϳ2% shortly after ity control of the dual-energy X-ray absorptiometry mea-
introduction of GH-replacement therapy and remain sta- surements and the calculation of the metacarpal index. We

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1093
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Jans and Willy Coopmans for laboratory assistance; Dr.
Sylva Van Imschoot, St. Jan, Brugge, for including some
patients; and Alexandra Van Aelst for her dedication to this
study. Genotropin was generously provided by Pharmacia.
This study was supported by Pharmacia.
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Address reprint requests to:
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Laboratorium voor Experimentele Geneeskunde en
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Herestraat 49
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F 1996 New approach to the diagnosis of growth hormone Received in original form July 6, 2001; in revised form January 7,
deficiency in adults. Eur J Endocrinol 134:352–356. 2002; accepted February 6, 2002.