Replacement treatment with biosynthetic human growth hormone in growth hormone-deficient hypopituitary adults*

OBJECTIVES The physiological role Of growth hormone in adult life has recently attracted increased Interest. We have studied the clinical effects and the effects on body composition of prolonged replacement with biosynthetic human GH In a large number of hypopituitary adults. DESIGN A randomized double blind placebo controlled trial for 6 months followed by an open trial of GH treatment for 12 months. GH dally dose was 0·04 (0·02-0·05) IU/kg s.c. PATIENTS Forty GH deficient hypopituitary patients (19 M, 21 F; aged 19–67 years) on conventional replacement therapy were studied. MEASUREMENTS Serum insulin like growth factor I (IGF-I), skinfold thickness, total body potassium, total body water (TBW), exercise tolerance and muscle strength, and well-being. RESULTS During the 6-month double blind phase, two GH treated patients withdrew because of adverse events. Lean body mass (LBM) increased and percentage body fat (%BF) decreased on GH but not on placebo (P) (LBM: (GH: from 48·5 ± 9·6 to 49·6 ± 9·5kg; P: from 50·9 ± 9·2 to 50·1 ± 9·0kg, P < 0·05 GH vs P) and TBW (OH: from 34·7 ± 11·4 to 34·2 ± 10·7; P: from 37·4 ± 7·6 to 38·7 ± 8·1, P < 0·05 GH vs P). TBW Increased on GH (P < 0·01) but not on P. No change was observed In waist-to-hip ratio or in muscle strength. During longer-term follow-up combining the double blind and open phase components of the study, 34, 27 and 11 patients received OH for 6,12 and 18 months respectively. Patients dropped out because of adverse events or lack of perceived benefit. Skinfold thicknesses decreased significantly at 6 and 12 months and the waist circumference at 6 months. Waist-to-hip ratio decreased significantly on OH at 12 months. LBM increased on GH treatment from 49·6 ± 9·1 to 51·6 ± 9·4kg (P < 0·0006), 51·9 ± 8·9kg (P < 0·07) and 53·1 ± 10·5 kg (P < 0·0001) at 6, 12 and 18 months respectively. Percentage body fat decreased on GH from 37·2 ± 10·7 to 34·7 ± 10·1 (P < 0·005), 35·1 ± 12·8 (NS) and 34·5 ± 86 (P < 0·04) at 6, 12 and 18 months respectively. TBW also increased at 6 and 12 months of GH treatment. Exercise time increased significantly at 6, 12 and 18 months of GH treatment. Muscle strength in selected muscle groups Increased significantly at 6, 12 or 18 months of GH treatment. Randomization resulted in the placebo group having a greater GHQ score (higher morbidity) than the OH group before therapy. Over the controlled phase, GHQ scores improved on placebo but not on OH and CPRS score was unchanged in either group. In the open phase, the GHQ score did not change on GH therapy but CPRS score improved at 6 and 12 months. CONCLUSIONS Growth hormone replacement therapy in adults for 6 months increased lean body mass, total body water and exercise tolerance, and decreased body fat. Growth hormone replacement for longer than 6 months maintains the advantageous effects seen in shorter-term studies and may have additional effects on body fat distribution, muscle strength and psychological well-being.     

The effects of prolonged growth hormone replacement on bone metabolism and bone mineral density in hypopituitary adults*

OBJECTIVE Short-term GH replacement in hypopituitary adults increases bone turnover; data on the consequences of longer-term GH treatment are limited. We report on the effects of 12–18 months of GH replacement treatment with biosynthetic human GH on bone metabolism and bone mass in hypopituitary adults. DESIGN Patients were studied before and after GH treatment for 12 months (n= 11) and 18 months (n= 27) respectively in an open trial. GH dose was 0·04±0·01 IU/kg daily. MEASUREMENTS Plasma calcium, phosphate and intact PTH concentrations, 24-hour urinary calcium excretion, 3 markers of bone formation (total alkaline phosphatase, osteocalcin and procollagen 1 carboxy terminal peptide (P1CP)) and serum concentration of carboxyterminal cross-linked telopeptide of type 1 collagen (ICTP), as a marker of bone resorption, were measured at 6-month intervals. Lumbar splne and total body bone mineral mass was measured by dual-energy X-ray absorptiometry. RESULTS Small increases were observed in plasma calcium and phosphate concentrations at 12 months of GH therapy but the differences at 18 months were not statistically significant. Serum intact PTH concentration did not change. Plasma total alkaline phosphatase increased significantly on GH from 75 ± 26 to 92 ± 30 (P<0·01) and 85±31 U/I (NS) at 12 and 18 months respectively. Serum osteocalcin increased from 6·5 ± 3·7 to 15·7 ± 6·2 (P<0·0001) and 16·6±5·7 μg/l (P<0·001) at 12 and 18 months respectively and P1CP increased significantly from 106·0 ± 47·3 μ/l to 165·5 ± 95·3 (P< 0·0001) and 177·2 ± 72·2 μg/l (P<0·01) at 12 and 18 months respectively. Plasma ICTP concentration increased also from 3·4 ± 1·8 to 7·3 ± 3·4 (P < 0·0001) and 7·0 ± 2·7 μg/l (P<0·003) at 12 and 18 months of GH therapy respectively. No significant change was observed in total body or lumbar splne bone mass, over the 18 months of GH treatment CONCLUSIONS Replacement therapy with GH in hypopituitary adults for 6–18 months produced a sustained increase in bone turnover (both formation and resorption). Bone mass was maintained but did not increase over the study period.     

Short and long-term cardiovascular effects of growth hormone therapy in growth hormone deficient adults

OBJECTIVE Since GH substitution therapy is now available for adult GH deficient patients, information on the cardiovascular effects of GH substitution has assumed major clinical interest. We have therefore assessed cardiovascular effects of short and long-term growth hormone substitution therapy in these patients. PATIENTS AND MEASUREMENTS Doppler echocardiography was performed in 21 GH deficient patients after 4 months placebo and 4 months GH therapy, in a double blind cross-over study. In an open design study, 13 patients were reinvestigated following 16 months and 9 patients following 38 months of GH therapy. Twenty-one age and sex-matched normal control subjects were also investigated. RESULTS Heart rate was increased in placebo treated patients as compared to controls. After 4 months of GH treatment, heart rate showed a further Increase (10%, P<0·01) and seemed to remain elevated after 16 months of OH therapy. Systolic and diastolic blood pressures were significantly lower in placebo treated patients than in controls, and did not change significantly after OH treatment. The left ventricular diastolic diameter was reduced in patients as compared to controls, but increased after 4 months GH therapy (P>0·05) and seemed to increase further during prolonged GH treatment. Cardiac index was at the same level in controls and in placebo-treated patients, but increased by 20% following OH therapy and remained elevated after 16 and 38 months (P < 0·05) of GH substitution. CONCLUSION Following GH substitution in GH deficient adult patients, left ventricular diastolic dimensions increased and seemed to normalize, while heart rate and cardiac output were found to be increased to supra-normal levels.     

Bone mineral content and bone mineral metabolism: changes after growth hormone treatment in juvenile chronic arthritis

OBJECTIVE: To determine whether growth hormone (rhGH) affects bone mineral metabolism and bone mineral content (BMC, g/cm) in a therapeutic trial of recombinant growth hormone in growth retarded children with juvenile chronic arthritis (JCA) treated with steroid. METHODS: BMC was measured in 20 children (of whom 17 were treated with corticosteroid) before and after one year of rhGH. Children were randomized to receive either low dose (12 IU/m2/week) or high dose (24 IU/m2/week) for one year. Three monthly assessments were made of disease activity and anthropomorphic measurements. Blood and urine samples were also obtained to measure indicators of disease activity, bone remodeling, and vitamin D and parathyroid hormone (PTH) status. RESULTS: BMC increased during the treatment period and correlated with increasing height. Osteocalcin levels, normally indicators of bone formation, increased after rhGH treatment and correlated significantly with height velocity, particularly for the high dose treatment group. In contrast, osteocalcin levels were negatively correlated with C-reactive protein levels, both before and during treatment. Height velocity, vitamin D, PTH, and osteocalcin levels were significantly lower than age matched controls before treatment. CONCLUSION: Steroid treated children with both JCA and severe growth retardation have reduced vitamin D, PTH, and osteocalcin levels. After treatment with rhGH, height velocity increased, as did BMC. Growth hormone might be a useful adjunct in the treatment of severe growth retardation and osteoporosis in children with JCA. The longterm benefits of rhGH in the treatment of osteoporosis remain unclear.     

Growth hormone therapy and fracture risk in the growth hormone-deficient adult

Adults with childhood-onset growth hormone deficiency (GHD) and younger adults with adult-onset GHD have a reduced bone mineral content (BMC). Recent trials with prolonged GH replacement therapy have demonstrated increased BMC in such patients. GH treatment in animals increases the amount of bone and the total strength while the density (BMC per unit volume) and the quality of the bone is not increased. A sensitive non-invasive parameter for the detection of effects of GH on bone in clinical studies is therefore to use the BMC from dual-energy X-ray absorption (DEXA) analysis. Bone density is strongly related to fracture risk in women. A number of other risk factors for fractures can be identified in adult GHD patients which, collectively, might explain the increased fracture frequency observed in these patients. The increase in BMC in response to long-term GH replacement therapy is promising. Whether more prolonged treatment will result in a normalization of the bone mass and reduced fracture frequency remains to be established.     

Did growth hormone-deficient children grow up to normal adult height by growth hormone treatment?]

One of the important aims of growth hormone (GH) treatment in GH deficient children is to allow them to grow to their full genetic potential. Usually, however, the final height of GH deficient children does not reach normal adult height and is below their target height. Furthermore, isolated GHD with spontaneous puberty is known to lead to a shorter adult height than that obtained in GHD associated with gonadotropin deficiency. The height at the start of puberty is reported to be well correlated with final height in GHD. Therefore, when isolated GHD subjects treated with GH reached puberty while they were still shorter than normal, they ended up by being shorter than normal as adults. The trial to increase the GH dose during puberty did not seem to increase the final height. The gonadal suppression therapy combined with GH treatment significantly increased the final height in isolated GHD. It is now the consensus that insufficient height at the onset of puberty leads to short final height and that early diagnosis of GHD is thus important to allow catch-up growth to optimal height before puberty. It may also be beneficial to treat GHD with higher doses to overcome the waning phenomenon with GH treatment.     

Long-term effects of growth hormone (GH) on bone mineral status and bone turnover markers in patients with isolated GH deficiency and multiple pituitary hormone deficiency

OBJECTIVE: This study was designed to assess the long-term effects of growth hormone (GH) replacement therapy on bone mass and bone turnover markers in children with isolated GH deficiency (IGHD) and multiple pituitary hormone deficiency (MPHD). MATERIALS AND METHODS: Fifty children (35 IGHD, 15 MPHD) receiving GH replacement therapy were enrolled in the study. The patients were followed for 38.6 +/- 15.7 months (1-5 years). Bone mineral density (BMD) of the lumbar region and bone turnover markers [PTH, osteocalcin, bone-specific alkaline phosphatase (boneALP), and the carboxyterminal propeptide of type-1 collagen (CPP-I)] were assessed annually. RESULTS: The height standard deviation score (SDS) of patients with IGHD and MPHD at diagnosis was statistically significant (P = 0.012), and the change in height SDS during 3 years (Deltaheight SDS(3 years)) was statistically similar between these two groups (P = 0.651). The BMD z-scores of the two groups were comparable at the start of GH therapy (P = 0.083), and then increased in both groups similarly during 5 years of GH replacement therapy (F = 0.349, P = 0.567). When the BMD z-scores during 5 years of GH therapy were analysed in the IGHD and MPHD groups separately, it was found that the BMD z-score increased significantly in IGHD (P < 0.001) but the increase was not significant in MPHD (P = 0.140). Multiple regression analysis showed that the change in BMD z-score during 3 years of GH therapy (DeltaBMD z-score(3 years)) was predicted by the BMD z-score and height SDS at the start of GH therapy and by Deltaheight SDS(3 years) in the IGHD group (t = -2.582, P = 0.02; t = 2.322, P = 0.034 and t = 2.908, P = 0.01, respectively). Age and BMD z-score and height SDS at diagnosis were found to have predictive values for the DeltaBMD z-score(3 years) (t = -3.652, P = 0.022; t = -4.073, P = 0.015 and t = 3.389, P = 0.028, respectively) in the MPHD group. The changes in boneALP, osteocalcin, CPP-1 and PTH levels during the therapy were statistically similar between the IGHD and MPHD groups. CONCLUSION: BMD increased during GH therapy in the IGHD and MPHD groups. GH had a positive effect on bone mass in the short as well as the long term. Early diagnosis and treatment could improve peak bone mass in patients with MPHD. The time and dose of sex steroids for pubertal induction and progression, which mimics physiological secretion, might also contribute to bone accretion in patients with MPHD.     

Effects of long-term treatment with loop diuretics on bone mineral density, calcitropic hormones and bone turnover

BACKGROUND: Loop diuretics (LD) are widely used in the treatment of cardiovascular diseases and disorders with fluid accumulation. LD are known to increase renal calcium losses and may thereby affect calcium homeostasis and bone metabolism. OBJECTIVE: We studied to what extent long-term treatment with LD affects calcium homeostasis and bone metabolism. DESIGN AND SUBJECTS: In a cross-sectional design we compared 140 postmenopausal women treated with a LD for more than 2 years with 140 age-matched women not in diuretic therapy. RESULTS: Treatment with LD was associated with significantly increased urinary calcium, plasma parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D levels. Per 40 mg day(-1) of furosemide, urinary calcium was increased by 17% (P < 0.05) and plasma PTH levels were increased by 28% (P = 0.04). Users of LD had a 17% higher body weight (P < 0.001) compared with nonusers. This was due to a 32% higher fat mass (P < 0.001) and a 6% higher lean tissue mass (P < 0.001). Moreover, users of LD had a higher bone mineral density (BMD) at the spine (+7.5%, P < 0.001), hip (+4.8%, P = 0.004), forearm (+3.7%, P = 0.01) and whole body (+2.5%, P = 0.06). However, after adjustment for body weight differences, BMD did not differ between groups. Nevertheless, duration of LD treatment was positively associated with BMD at the spine (P = 0.03) and whole body (P < 0.05). BMD at the spine increases by 0.3% per 1 year of treatment. CONCLUSIONS: The increased renal calcium losses in users of LD are compensated for by a PTH-dependent increase in 1,25(OH)(2)D levels. Thereby calcium balance remains neutral without major effects on bone metabolism.     

The effect of growth hormone treatment on somatomedin levels in growth hormone-deficient children

Serum levels of immunoreactive somatomedin (IRSM) and insulin-like activity (ILAs) by receptor assay have been measured in 177 GH-deficient (GHD) children treated with 2 U GH three times weekly for 6-10 months. The overall mean (+/- SD) pretreatment IRSM and ILAs levels were 0.21 +/- 0.30 and 0.39 +/- 0.25 U/ml, respectively. Pretreatment IRSM and ILAs levels were in the normal range for chronological age and sex in 15.8% and 33% of these GHD children. Mean IRSM and ILAs levels increased after 1 month of therapy to 0.36 +/- 0.51 and 0.62 +/- 0.33 U/ml, respectively (P less than .0001). The increase in serum IRSM levels (from 0.2 to 2.0 U/ml) that normally occurs from 1-16 yr of age is also evident in untreated GHD children, albeit to a lesser extent. In addition, the mean increase in IRSM after GH was greater in older patients. However, individual responses varied greatly. An increase in IRSM or ILAs with an increase in height velocity (HV) was observed in the majority of children, but all other combinations occurred, including increased SM with decreased HV, decreased SM with increased HV, and decreased SM with decreased HV. In summary 1) age-dependent factors in GHD children importantly influence basal and treatment SM leels; 2) a basal SM level is not a very sensitive diagnostic test, since a significant proportion of GHD children have SM levels in the normal range; and, 3) SM levels in individual patients may not increase with GH therapy and, thus, cannot be used to predict a clinical response to GH therapy.     

Growth hormone treatment of non-growth hormone-deficient growth disorders.

Although a large body of data on efficacy and safety of growth hormone (GH) treatment for various non-growth hormone-deficient (GHD) growth disorders has accumulated from a combination of clinical trial and postmarketing sources in the last 20 years or more, there remain limitations. Clinical trial data have the advantage of direct comparison of well-matched, randomized patient groups receiving treatment (or not) under comparable conditions and, as such, provide the highest quality evidence of efficacy. Clinical trials, however, are typically too small for any statistically valid assessment for safety, which is more comprehensively addressed using postmarketing data. Consequently, while the efficacy of GH treatment in children with non-GHD growth disorders has been solidly established and, based on the combination of the rigor of the clinical trial data and numerical power of the postmarketing data, no major concerns exist regarding safety, additional long-term data are required.     

The effects of growth hormone treatment on bone mineral density and body composition in girls with turner syndrome

BACKGROUND: Many girls with Turner syndrome (TS) are treated with GH to increase adult height. In addition to promoting longitudinal bone growth, GH has effects on bone and body composition. OBJECTIVE: The objective was to determine how GH treatment affects bone mineral density (BMD) and body composition in girls with TS. METHOD: In a cross-sectional study, we compared measures of body composition and BMD by dual energy x-ray absorptiometry, and phalangeal cortical thickness by hand radiography in 28 girls with TS who had never received GH and 39 girls who were treated with GH for at least 1 yr. All girls were participants in a National Institutes of Health (NIH) Clinical Research Center (CRC) protocol between 2001 and 2006. RESULTS: The two groups were similar in age (12.3 yr, sd 2.9), bone age (11.5 yr, sd 2.6), and weight (42.8 kg, sd 16.6); but the GH-treated group was taller (134 vs. 137 cm, P = 0.001). The average duration of GH treatment was 4.2 (sd 3.2) yr (range 1-14 yr). After adjustment for size and bone age, there were no significant differences in BMD at L1-L4, 1/3 radius or cortical bone thickness measured at the second metacarpal. However, lean body mass percent was higher (P < 0.001), whereas body fat percent was lower (P < 0.001) in the GH-treated group. These effects were independent of estrogen exposure and were still apparent in girls that had finished GH treatment at least 1 yr previously. CONCLUSIONS: Although GH treatment has little effect on cortical or trabecular BMD in girls with TS, it is associated with increased lean body mass and reduced adiposity.     

Growth hormone replacement is important for the restoration of parathyroid hormone sensitivity and improvement in bone metabolism in older adult growth hormone-deficient patients

Alterations in PTH circadian rhythm and PTH target-organ sensitivity exist in adult GH-deficient (AGHD) patients and may underlie the pathogenesis of AGHD-related osteoporosis. GH replacement (GHR) results in increased bone mineral density, but its benefit in AGHD patients over 60 yr old has been debated. To examine the effect of age on changes in PTH circadian rhythm and target-organ sensitivity after GHR, we recruited 22 AGHD patients (12 were <60 yr of age, and 10 were >60 yr of age). Half-hourly blood samples were collected for PTH, calcium, phosphate, nephrogenous cAMP (marker of renal PTH activity), type-I collagenbeta C-telopeptide (bone resorption marker), and procollagen type-I amino-terminal propeptide (bone formation marker) before and after 1, 3, 6, and 12 months of treatment with GHR. Significant PTH circadian rhythms were present in both age groups throughout the study. After GHR, PTH decreased and nephrogenous cAMP, adjusted calcium, and bone turnover markers increased in both groups, suggesting increased PTH target-organ sensitivity. In younger patients, the changes were significant after 1 month of GHR, but, in older patients, the changes were delayed until 3 months, with maximal changes at 12 months. Older AGHD patients derive benefit from GHR in terms of improvement in PTH sensitivity and bone metabolism. Their response appears delayed and may explain why previous studies have not shown a positive effect of GHR on bone mineral density in older AGHD patients.     

Bone mineral status in growth hormone-deficient males with isolated and multiple pituitary deficiencies of childhood onset.

In order to determine whether growth hormone (GH) deficiency of childhood onset affects the adult bone mineral status, we assessed bone mineral content (BMC) by photon absorptiometry in 30 full-grown GH-deficient men (8 with isolated GH deficiency and 22 with multiple pituitary deficiencies; 28 previously treated with GH) and in 30 male controls matched for age (within 4 yr) and height (within 10 cm). Forearm BMC was measured by single photon absorptiometry just proximally of the distal one third of the nondominant forearm (PBMC-2 in arbitrary units and PBMC/bone width (BW) after normalization for bone width) and at a more distal site, close to the carpal joint (DBMC-2 and DBMC/BW). Lumbar BMC was measured by dual photon absorptiometry and reported as total BMC for L2-L4 (LBMC in g) and after normalization for projected area (LBMD in g/cm2). The patients had a significantly lower BMC, both at the forearm (P less than 0.0001) and at the lumbar spine (P less than 0.005): 35.7 +/- 1.0 vs. 50.0 +/- 1.6 and 36.9 +/- 1.2 vs. 52.8 +/- 1.9 (mean +/- SEM) for PBMC-2 and DBMC-2 in patients and controls, respectively; 1.36 +/- 0.03 vs. 1.70 +/- 0.04 and 1.07 +/- 0.03 vs. 1.35 +/- 0.04 for PBMC/BW and DBMC/BW; 34.00 +/- 1.08 vs. 42.02 +/- 1.27 g for LBMC and 0.886 +/- 0.016 vs. 0.976 +/- 0.018 g/cm2 for LBMD. Both the patients with isolated GH deficiency and the patients with multiple pituitary deficiencies were osteopenic when compared to their respective controls (P less than 0.01 to P less than 0.0001 for the patients with multiple deficiencies; statistical significance reached for PBMC-2, DBMC-2, and DBMC/BW only, P less than 0.05, in the small group of patients with isolated GH deficiency). For the patients (n = 19) who had at least three serial measurements over a period of 6 to 28 months, no decrease in BMC was detected. Our findings indicate that men with GH deficiency of childhood onset present with a low adult bone mass, despite prior GH substitution in most of these subjects. The observations of a more pronounced bone mineral deficit at the forearm (20-30% lower mean values, depending on the type of measurements) than at the lumbar spine (9-19%) and the findings of osteopenia in both the patients with isolated GH deficiency and multiple pituitary deficiencies, support the view that GH deficiency per se is responsible for part of the observed deficit.(ABSTRACT TRUNCATED AT 400 WORDS)     

Gender variation in PTH sensitivity and rhythmicity following growth hormone replacement in adult growth hormone-deficient patients

BACKGROUND: Adult GH deficiency (AGHD) is associated with osteoporosis and reduced bone turnover; factors improved by GH replacement (GHR), with men gaining greater benefit than women. Reduction in sensitivity of bone and kidney to the effects of PTH may underlie AGHD changes in bone turnover. We determined the gender difference in PTH target-organ sensitivity following GHR in AGHD patients. DESIGN, PATIENTS AND MEASUREMENTS: Twenty AGHD patients (10 men) were admitted to hospital before and after GHR initiation. Half-hourly blood samples were collected for PTH, calcium, nephrogenous cyclic AMP (NcAMP, marker of PTH activity), type-I collagen C-telopeptide (CTX, bone resorption marker) and procollagen type-I amino-terminal propeptide (PINP, bone formation marker). RESULTS: The 24-h mean PTH concentration decreased in both genders (P < 0.001), with maximal changes seen 6 and 12 months following GHR in men and women, respectively. Increases in 24-h mean NcAMP (P < 0.05), calcium (P < 0.001) and bone turnover markers (P < 0.001) occurred in both genders following GHR, with maximal changes at 1 month in men, but at 3 months for NcAMP, calcium and CTX and 12 months for PINP in women. Maximal NcAMP increase was higher in men (P = 0.009). CONCLUSIONS: Following GHR, PTH target-organ sensitivity increased in both genders, demonstrated by simultaneous reduction in PTH concentration and increase in NcAMP, calcium and bone turnover. In women, improvement in renal PTH sensitivity was delayed and reduced, and changes in bone turnover were delayed, with increase in bone resorption preceding bone formation. Both factors may contribute to the reduced bone mineral density (BMD) response to GHR observed in women.     

Combined treatment of growth hormone and the bisphosphonate pamidronate, versus treatment with GH alone, in GH-deficient adults: the effects on renal phosphate handling, bone turnover and bone mineral mass

OBJECTIVE A potential drawback of GH replacement therapy In GH deficient (GHD) patients is the Initial decrease in bone mass. The present study Investigates the effects of the addition of pamidronate to GH replacement therapy in adult GHD subjects, on serum PTH and 1,25-dihydroxyvitamin D₃ (1,25-(OH)₂D₃) levels, renal phosphate handling, bone turnover and bone mineral content (BMC). DESIGN Six GHD adult patfents were studied for two periods of 6 months with a wash-out period of 3 years. In the first period they were treated with conventional replacement therapy and GH. In the second study period GH treatment was Identical, whlle after 2 weeks 150 mg pamidronate per day was added. RESULTS In the first study period (GH only) there was a slgniflcant increase of phosphate reabsorption, without a change In serum PTH and 1,25-(OH)2D3 levels. Thls suggests a specific effect of GH or IGF-l on renal phosphate handling. This was supported by the close correlatlon between serum IGF-I levels and TmPlGFR (r=0·75, P < 0.0001). When GH was administered together with pamldronate, this correlation was less, but remained signiflcant (r=0·44, P < 0001). The Increase In bone turnover and decrease in BMC, as Initially observed during GH replacement therapy alone, were attenuated by simultaneous pamidronate administration. The decline in lumbar spine BMC (measured with dual-photon absorptiometry) at 6 months was ?3.1 ± 1.5% during GH replacement therapy alone vs an increase of +3.8 ± 2.0% during the admlnistratlon of the comblnatlon of GH and pamldronate (measured with dual-energy X-ray absorptlometry). At the distal and proximal forearm the changes amounted to ?0.5 ± 3.4% vs +4.5 ± 1.8% and ?1 ± 1.2% vs +1.2 ± 1.1 % respectively. CONCLUSIONS This study shows that the addition of a bisphosphonate to GH replacement therapy in GHD adults counteracts the GH (or IGF-I) Induced Increase In renal phosphate reabsorptlon. Furthermore, It reduces OH induced bone turnover and prevents the lnitlal decrease in bone mineral content seen during GH treatment alone, resultlng In a beneflclal effect on bone mlneral mass. Pamidronate might therefore be an important adjunct to GH replacement therapy in adults with GHD and severe osteopenia during the early phase of GH Induced stlmulation of bone turnover.     

Responses of markers of bone and collagen turnover to exercise, growth hormone (GH) administration, and GH withdrawal in trained adult males

To examine the interactions between acute exercise and GH on markers of bone and collagen turnover and to assess the potential for detecting GH abuse in athletes using these markers, we studied 17 aerobically trained males (age, 26.9+/-1.5 yr). Sequential studies of exercise, GH administration, and GH withdrawal were undertaken. A randomized, controlled study of rest vs. exercise showed that exercise did not change serum osteocalcin; other markers of formation increased transiently (each P<0.001): bone-specific alkaline phosphatase (+16.1%), carboxyterminal propeptide of type I procollagen (+14.1%), and procollagen III N-terminal extension peptide (+5.0%). The carboxyterminal cross-linked telopeptide of type I collagen, a bone resorption marker, increased 9.7% (P = 0.018) in response to exercise. A randomized, double blind, placebo-controlled, parallel study of recombinant human GH treatment (0.15 IU/kg x day) for 1 week increased serum osteocalcin (net increase preexercise, +/-10.0%; P = 0.017), carboxyterminal propeptide of type I procollagen (+17.6%; P = 0.002), procollagen III N-terminal extension peptide (+48.4%; P = 0.001), and carboxyterminal cross-linked telopeptide of type I collagen (53.3%; P = 0.009). Disappearance half-times after cessation of recombinant human GH for pre- and postexercise markers ranged from 248-770 h. We conclude 1) endurance exercise transiently activates bone and collagen turnover; 2) brief GH administration results in similar but quantitatively greater augmentation; and 3) these data will assist in designing a GH detection strategy.     

Further increase in forearm cortical bone mineral content after discontinuation of growth hormone replacement

OBJECTIVE Growth hormone replacement of adults with childhood onset GH deficiency results In an Increase In bone mineral density (BMD) after 6-12 months of OH replacement. By measuring BMD 12 months after discontinuation of GH replacement we aimed to Investigate whether there is an effect of GH replacement on BMD persisting after GH has been withdrawn. DESIGN BMD was measured 13 ± 1 (mean ± SE, range 11-16) months after discontinuation of OH replacement. PATIENTS Ten adults, age 23·;2 ±1·;4 (range 18·8-32·4) years, with childhood onset isolated GH deficiency (2 idiopathic, 8 irradiation induced) who had previously completed a study of the effect of 12 months of OH replacement on BMD. MEASUREMENTS Forearm cortical bone mineral content (BMC) was measured using single-photon absorptlometry at the proximal site of the distal forearm. Forearm integral BMC at the ultradistal site of the forearm and bone width at both proximal and ultradistal rites of the distal forearm were measured by the same technique. Vertebral trabecular BMD was measured using quantitative computed tomography. RESULTS Forearm cortical BMC was significantly greater than that measured at the time of discontinuation of OH (1·48 ±0·04 vs 1·44 ± 0·05 g/cm). There was no significant change in forearm integral BMC or in vertebral trabecular BMD after discontinuation of OH. There was no significant change in bone width at proximal and ultradistal sites of the distal forearm after discontinuation of GH. CONCLUSION After discontinuation of OH replacement the further increase In forearm cortical bone mineral content without a significant Increase In forearm bone width suggests that the Increase In cortical bone mineral content Is due to a persisting effect of previous GH replacement, and not to further spontaneous attainment of bone mass before peak bone mass lo reached. These findings emphasize the importance of continuing to monitor bone mass after the stimulus to Increase bone turnover has been withdrawn.     

Comparative effects of antiresorptive agents on bone mineral density and bone turnover in postmenopausal women

Postmenopausal osteoporosis is a common clinical entity; its complications represent a significant burden to society. In recent years the choice of therapies available for the treatment of postmenopausal osteoporosis has increased dramatically. There are a number of antiresorptive agents currently available including hormone replacement therapy (HRT), selective estrogen receptor modulators (SERMs), bisphosphonates, and dual action bone agents. It is difficult to truly compare these therapies given the lack of direct head-to head studies. The efficacy of antiresorptive therapies can be assessed in a number of ways including measurement of bone mineral density (BMD), assessment of bone turnover markers, and fracture reduction. Other important factors include ease of administration and consequent patient compliance. This article reviews the currently available antiresorptive agents and their effects on the above outcome measures.     

Effects of growth hormone treatment on very-low density lipoprotein apolipoprotein B100 turnover in adult hypopituitarism

Adult hypopituitarism is associated with hyperlipidemia, mainly due to an increase of very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) levels. Recent studies have shown that such patients exhibit increased hepatic secretion of VLDL apolipoprotein B100 (VLDL apo B100). To examine the effects of growth hormone (GH) replacement on VLDL apo B100 turnover, 13 GH-deficient hypopituitary patients (8 women and 5 men; aged 47 +/- 3 years, mean +/- SEM; body mass index [BMI], 30 +/- 2 kg/m2) entered a double-blind placebo-controlled study for 6 months (GH 0.125 IU/kg/wk for 4 weeks, and then 0.25 IU/kg/wk). GH was subsequently used in all patients for a further 6 months. A 6-hour [1-13C] leucine infusion was administered at baseline and at 6 months. The secretion rate of VLDL apo B100 was derived by kinetic analysis following quantitation of isotopic enrichment by gas chromatography/mass spectrometry. The GH-treated group (6 patients) demonstrated a similar fractional secretion rate (FSR) for VLDL apo B100 at 0 and 6 months. The pool size and absolute secretion rate (ASR) also were unaffected significantly by GH therapy. No significant changes were observed in the placebo group (7 patients). Treatment with GH for 6 months caused an increase in the high-density lipoprotein (HDL) cholesterol concentration (13 patients, 1.27 +/- 0.13 v 1.16 +/- 0.10 mmol/L, respectively, P = .05), whereas total cholesterol and triglyceride concentrations did not change. Nonesterified fatty acids (NEFAs) increased during GH therapy (471 +/- 43 micromol/L at 6 months v 349 +/- 49 micromol/L at baseline, P < .0005). The data suggest that GH does not affect VLDL apo B100 turnover in a significant way.