Role of bisphosphonates in osteoporosis caused by adult growth hormone deficiency

In recent years,growth hormone and insulin-like growth factors have become key regulators of bone metabolism and remodeling,crucial for maintaining healthy bone mass throughout life.Studies have shown that adult growth hormone deficiency leads to alterations in bone remodeling,significantly affecting bone microarchitecture and increasing fracture risk.Although recombinant human growth hormone replacement therapy can mitigate these adverse effects,improving bone density,and reduce fracture risk,its effectiveness in treating osteoporosis,especially in adults with established growth hormone deficiency,seems limited.Bisphosphonates inhibit bone resorption by targeting farnesyl pyrophosphate synthase in osteoclasts,and clinical trials have confirmed their efficacy in improving osteoporosis.Therefore,for adult growth hormone deficiency patients with osteoporosis,the use of bisphosphonates alongside growth hormone replacement therapy is recommended.

Changes in Serum Leptin Levels during r-hGH Treatment in Growth Hormone-Deficient Children

To observe the effect of growth hormone on serum leptin levels, serum leptin concentrations were measured by enzyme immunoassay in 12 prebutal children with growth hormone deficiency 1, 3 and 6 months before and after the treatment with recombinant human growth hormone (r hGH). For comparison, 34 normal prepubertal children were also investigated. Relationship between leptin levels and body mass index (BMI) was observed at the same time. Our results showed that serum leptin level in normal prepubertal children was 1.22±0.34 ng/ml; the pretreatment serun leptin levels in GHD children was 3.08±2.41 ng/ml, which was significantly different from those 1, 3 and 6 months after GH treatment (i.e. 1.64±1.37 ng/ml,1.57±1.40 ng/ml and 1.35±0.89 ng/ml respectively) (all P <0.001). Our results suggested that r hGH has a suppressive effect on leptin expression.

DIAGNOSTIC VALUE OF SERUM INSULIN- LIKE GROWTH FACTOR BINDING PROTEIN- 3 IN CHILDREN WITH OR WITHOUT GROWTH HORMONE DEFICIENCY

OBJECTIVE: To study the value of serum insulin-like growth factor binding protein-3 (IGFBP-3) levels in differential diagnosis of growth hormone deficiency (GHD). METHODS: To measure serum IGFBP-3 levels by RIA in normal children and adolescents, GHD children and short-stature children without GHD. RESULTS: Serum level of IGFBP-3 in 129 children with untreated GHD and with no pubertal development was 1.6 +/- 0.9 mg/L, which was less than that in normal group of the same age, but overlapped with the normal children in Tanner stage I. After six-month treatment with recombinant human growth hormone (rhGH), serum level of IGFBP-3 in 59 GHD significantly increased from 1.3 +/- 0.7 mg/L to 2.7 +/- 0.9 mg/L, accompanied by an increase of body heights, growth velocities and serum level of IGF-1. Serum level of IGFBP-3 in 55 short-stature children without GHD was 3.3 +/- 2.2 mg/L, which was not significantly different from that in normal group. CONCLUSION: Serum IGFBP-3 level can reflect the status of GH secretion in children with GHD and is a useful marker for differential diagnosis of GHD.

Management of Adult Growth Hormone Deficiency at Peking Union Medical College Hospital:A Survey among Physicians

Objective To evaluate physicians' attitude and knowledge about the management of adult growth hormone deficiency(AGHD) at Peking Union Medical College Hospital and impact factors associated with better decision-making.Methods A 21-question anonymous survey was distributed and collected at Peking Union Medical College Hospital,a major teaching hospital in Chinese Academy of Medical Sciences.Data of physicians' educational background,clinical training,patient workload per year and continuing medical education in AGHD were collected.Factors associated with appropriate answers were further analyzed by multivariate regression models.Results One hundred and eighteen internal medicine residents,endocrine fellows,attending physicians and visiting physicians responded to the survey.Among them,44.9% thought that AGHD patients should accept recombinant human growth hormone replacement therapy.Moreover,56.8% selected insulin tolerance test and growth hormone-releasing hormone-arginine test for the diagnosis of AGHD.Logistic regression analysis of physician demographic data,educational background,and work experience found no consistent independent factors associated with better decision-making,other than continued medical education,that were associated with treatment choice.Conclusions The physicians' reported management of AGHD in this major academic healthcare center in Beijing was inconsistent with current evidence.High quality continued medical education is required to improve Chinese physician management of AGHD.

EFFECTS OF CHINA-MADE RECOMBINANT HUMAN GROWTH HORMONE ON THE TREATMENT OF GROWTH HORMONE DEFICIENCY

To evaluate the therapeutic effect of China-made recombinant human growth hormone (r-hGH) in children with growth hormone deficiency (GHD) and to investigate the utilities of various biochemical parameters in GHD diagnosis and treatment. Methods Our study comprises of 30 normal children and 71 GHD children treated with China-made r-hGH substitution therapy 0.1 IU·kg-1·d-1 for 6 months. Serum insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3), bone turnover markers (Ost, ICTP), and anti-growth hormone antibody (GHAb) were detected before and after r-hGH treatment. Results After the first 3 and 6 months of treatment, growth velocities of GHD children were significantly increased (13.1 ± 3.7 and 12.6 ± 3.6 cm/year) compared with pretreatment values (2.9 ± 0.8 cm/year, P < 0.01). GHD Children had obviously reduced serum levels of IGF-1, IGFBP-3, and bone turnover markers (Ost, ICTP) compared with normal controls (P < 0.01), and these biochemical parameters improved significantly after treatment (P < 0.01). Growth hormone antibodies were positive in 17 of 45 cases after treatment by binding capacity detection. The binding percentage of growth hormone an-tibody which was increased more than 30% after the treatment showed a negative correlation with growth velocity (P < 0.01). Conclusions (1) The growth stimulating effect and safety were confirmed in using China-made r-hGH in the treatment of GHD children for 6 months. (2) The measurements of serum IGF-1 and IGFBP-3 may serve as useful parameters in the diagnosis of GHD. (3) Serum Ost and ICTP are useful laboratory criteria for evaluating the effect of r-hGH therapy in the early stage. (4) It is necessary to monitor serum levels of GHAb during r-hGH therapy.

Effects of different doses of long-acting growth hormone in treating children with growth hormone deficiency

BACKGROUND With the improvement of economy and living standards,the attention paid to short stature in children has been increasingly highlighted.Numerous causes can lead to short stature in children,among which growth hormone deficiency(GHD)is a significant factor.AIM To investigate the long-term efficacy and safety of different doses of long-acting polyethylene glycol recombinant human growth hormone(PEG-rhGH)in the treatment of GHD in children.METHODS We selected 44 pediatric patients diagnosed with GHD who were treated at Wuhu First People's Hospital from 2014 to 2018.Total 23 patients were administered a high dose of long-acting PEG-rhGH at 0.2 mg/kg subcutaneously each week,forming the high-dose group.Meanwhile,21 patients were given a lower dose of long-acting PEG-rhGH at 0.14 mg/kg subcutaneously each week,establishing the low-dose Group.The total treatment period was 2 years,during which we monitored the patients’height,annual growth velocity(GV),height standard deviation score(HtSDS),chronological age(CA),bone age(BA),and serum levels of insulin-like growth factor-1(IGF-1)and insulin-like growth factor-binding protein-3(IGFBP-3)before treatment and at 6 mo,1 year,and 2 years after treatment initiation.We also monitored thyroid function,fasting plasma glucose,fasting insulin,and other side effects.Furthermore,we calculated the homeostatic model assessment for insulin resistance.RESULTS After 1 year of treatment,the GV,HtSDS,IGF-1,BA,and IGFBP-3 in both groups significantly improved compared to the pre-treatment levels(P<0.05).Moreover,when comparing GV,HtSDS,IGF-1,BA,and IGFBP-3 between the two groups,there were no statistically significant differences either before or after the treatment(P>0.05).During the treatment intervals of 0-1.0 years and 1.0-2.0 years,both patient groups experienced a slowdown in GV and a decline in HtSDS improvement(P<0.05).CONCLUSION The use of PEG-rhGH in treating GHD patients was confirmed to be effective,with similar outcomes observed in both the high-dose group and low-dose groups,and no significant differences in the main side effects.

Corneal properties in children with congenital isolated growth hormone deficiency

AIM:To compare the corneal parameters of children with congenital isolated growth hormone deficiency and healthy subjects.METHODS:In this cross-sectional,prospective study,50 cases with growth hormone(GH)deficiency treated with recombinant GH and 71 healthy children underwent a complete ophthalmic examination.The corneal hysteresis(CH),corneal resistance factor(CRF),Goldmann-correlated intraocular pressure(IOPg)and corneal-compensated intraocular pressure(IOPcc)were measured with the Ocular Response Analyzer(ORA).Central corneal thickness(CCT)was measured by a ultrasonic pachymeter.RESULTS:The mean age was 13.0±3.0 years in the GH deficiency group consisting of 21 females and 29 males and 13.4±2.4 years in the healthy children group consisting of 41 females and 30 males.There was no statistically significant difference between the groups for gender or age(Chi-square test,P=0.09;independent ttest,P=0.28,respectively).The mean duration of recombinant GH therapy was 3.8±2.4y in the study group.The mean CH,CRF,IOPg and IOPcc values were 11.0±2.0,10.9±1.9,15.1±3.3,and 15.1±3.2 mm Hg respectively in the study group.The same values were 10.7±1.7,10.5±1.7,15.2±3.3,and 15.3±3.4 mm Hg respectively in the control group.The mean CCT values were 555.7±40.6,545.1±32.5μm in the study and control groups respectively.There was no statistically significant difference between the two groups for CH,CRF,IOPg,IOPcc measurements or CCT values(independent t-test,P=0.315,0.286,0.145,0.747,0.13 respectively).CONCLUSION:Our study suggests that GH deficiency does not have an effect on the corneal parameters and CCT values.This observation could be because of the duration between the beginning of disease and the diagnosis and beginning of GH therapy.

Benefit of Growth Hormone Replacement in Adults Older than 60 Years

Objective: Benefits of replacement therapy in growth hormone deficiency (GHD) are well documented in younger and middle-aged patients. The aim of our investigation was to prove the benefit of GH replacement for patients older than 60 years especially in terms of health-related quality of life (HRQoL) of age as well. Design: Data of 743 consecutively recruited patients (394 men, 349 women) with GHD aged 20 - 49 (n = 606) and 60 - 69 (n = 137) years enrolled from KIMS Germany (Pfizer International Metabolic Database) were compared. Treatment effects over the 12 months dose-finding and the subsequent phase up to three years were analysed using mixed models. Serum insulin-like growth factor I (IGF-I), fasting blood glucose, fasting serum total cholesterol and low-density lipoprotein cholesterol (LDL-C) as well as body mass index (BMI) at baseline and at last visit were studied. HRQoL was assessed using the Quality of Life-Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA). Results: For both age groups and genders the IGF-I level and standardized IGF-I increased over the dose-finding phase. In women, the overall QoL-AGHDA score at the baseline examination was 8.7 (95% CI: 7.7 - 9.7) and decreased to 6.3 (95% CI: 5.1 - 7.6) at the end of the dose-finding phase (p < 0.001). In men, the corresponding values were 8.8 (95% CI: 7.8 - 9.8) and 6.4 (95% CI: 5.1 - 7.6;p < 0.001) without differences between the age groups. The therapy benefit for elderly was supported by the non-impairment after the dose-finding phase. In total cholesterol, LDL-C and fasting blood glucose, no significant changes were detected, whereas an increase in BMI did not differ between age groups. Conclusion: We could show positive effects of GH replacement on HRQoL in patients older than 60 years of age. Therefore, GH replacement should be considered in elderly GHD adults without difference compared to younger age groups.

MAGNETIC RESONANCE IMAGES OF THE HYPOTHALAMIC-PITUITARY AREA IN IDIOPATHIC GROWTH DEFICIENCY

In order to describe the magnetic resonance imaging (MRI) findings in hypothalamic-pituitary area and its clinical relevance in patients with idiopathic growth hormone deficiency (IGHD), the MR imagings of 26 patients with IGHD were analyzed. On MRI, 24 out of 26 cases (92. 3%) showed apparent pituitary upper margin depression; 8 out of 26 cases (30. 8%) showed definite pituitary stalk transection; 22 out of 26 cases (84. 6%) showed absence of the normal posterior pituitary bright spot. The bright lipidlike signal on T1W1 images at the median eminence distal to the breaking point (so-called ectopic posterior lobe) was found in 4 out of 26 cases (15. 4%). According to the MRI findings of the pituitary stalks, the 26 cases were divided into three groups; group A of 8 cases (31%) characterized by the definite transaction of stalk; group B of 13 cases (50%) defined by the possible stalk transection; and group C of 5 cases (19%) with no definite stalk transection.MRI findings were consistent with the clinical and endocrine tests. The stalk transection was statistically significantly difference in insulin test, L-dopa/p test, and height standard deviation score (P< 0.05). The MRI of hypothalamic-pituitary area may differentiate partial IGHD form stalk-transected, doubtful transection and without transection.

Actively separated microneedle patch for sustained-release of growth hormone to treat growth hormone deficiency

Growth hormone deficiency(GHD)has become a serious healthcare burden,and presents a huge impact on the physical and mental health of patients.Here,we developed an actively separated microneedle patch(PAA/NaHCO_(3)^(-)Silk MN)based on silk protein for sustained release of recombinant human growth hormone(rhGH).Silk protein,as a friendly carrier material for proteins,could be constructed in mild full-water conditions and ensure the activity of rhGH.After manually pressing PAA/NaHCO_(3)^(-)Silk MN patch to skin for 1 min,active separation is achieved by absorbing the interstitial fluid(ISF)to trigger HCO_(3)^(-)in the active backing layer to produce carbon dioxide gas(CO_(2)).In rats,the MN patch could maintain the sustained release of rhGH for more than 7 days,and produce similar effects as daily subcutaneous(S.C.)injections of rhGH in promoting height and weight with well tolerated.Moreover,the PAA/NaHCO_(3)^(-)Silk MN patch with the potential of painless self-administration,does not require cold chain transportation and storage possess great economic benefits.Overall,the PAA/NaHCO_(3)^(-)Silk MN patch can significantly improve patient compliance and increase the availability of drugs,meet current unmet clinical needs,improve clinical treatment effects of GHD patients.

Clinical evaluation of recombinant human growth hormone injection in children with growth hormone deficiency

Recombinant human growth hormone(rhGH)has been widely used in the clinical treatment of growth hormone deficiency.To simplify the injection process and increase drug compliance,application of the GH injection has become a new treatment plan in recent years.The purpose of the current study was to evaluate the efficacy and safety of rhGH injection for the treatment of growth hormone deficiency(GHD)in children in China.In a nationwide,noncomparative,prospective,randomized,open trial,31 children with confirmed complete GHD received subcutaneous injection of rhGH at 0.25 mg/kg$wk(0.107 IU/kg$d).The injection was given daily and the total weekly amount was separated into 6–7 injections.The patients were followed up at 3-month intervals and the treatment duration was 12 months.The height(HT),annual growth velocity(GV),mean height standard deviation score(HT SDS),blood serum insulin-like growth factor I(IGF-I),insulin-like growth factor binding protein 3(IGFBP-3),and bone maturity before and after treatment were compared,and the safety of the treatment was analyzed.The mean HT,GV,and HT SDS were increased from 109.0�14 cm,2.7�0.9 cm/yr,and–4.62�1.46 at baseline to 121.8�13.4 cm,12.9�3.3 cm/yr,and–2.47�1.86 after 12 months of treatment,respectively(P<0.001).At the same time,blood IGF-I and IGFBP-3 were increased significantly[41.27�64.43μg/L vs 159.21�167.92μg/L and 1540.00�1325.11 mg/L vs 3533.93�1413.82 mg/L,respectively(P<0.001)].The bone age assessments performed 6 and 12 months after the treatment showed that no advanced bone maturation was noted.No serious adverse events occurred during the treatment,and the drug-related adverse events were mainly decreased thyroid function.We conclude that rhGH injection is a safe and effective drug for treatment of growth hormone deficiency in children.