Efficacy and safety results of long-term growth hormone treatment of idiopathic short stature

CONTEXT: Small clinical trials of GH treatment of idiopathic short stature (ISS) show variable efficacy. OBJECTIVE: The study was an analysis of a large GH registry for efficacy and safety of GH treatment of ISS. There was also a comparison with a specific clinical trial. DESIGN: Up to 7 yr of GH treatment of ISS was evaluated for efficacy and safety in the National Cooperative Growth Study (NCGS). SETTING: The NCGS study was conducted at Genentech, Inc. and included 47,226 patients. PATIENTS: The ISS group included maximum stimulated GH 10 ng/ml or more and/or a report of ISS by investigator (n = 8018; all included for safety). Cohort 1 (n = 2520) was similar to the clinical trial, cohort 2 (n = 283) included subjects younger than 5 yr of age, and cohort 3 (n = 940) was pubertal at GH start. INTERVENTION: GH, approximately 0.30 mg/kg.wk, was given. MAIN OUTCOME MEASURES: These included growth velocities and height sd (HtSDS). Results: Mean first-year growth velocities in cohorts 1, 2, and 3 increased 4.6, 3.9, and 4.4 cm/yr over pretreatment, respectively. Measures included: baseline mean HtSDS, -2.9, -3.2, and -2.8; mean HtSDS at 1 yr, -2.4, -2.3, and -2.3, respectively. Mean HtSDS after 7 yr in cohorts 1 (n = 303) and 2 (n = 85) and 5 yr in cohort 3 (n = 58) were: -1.2, -1.0, and -1.5, respectively. Cohort 3 shorter treatment time was due to advanced baseline age (mean 13.8 yr) and puberty. Mean HtSDS gain in cohort 1 was comparable with the clinical trial. No new safety signals specific to the NCGS ISS population were observed. CONCLUSION: ISS patients in the GH registry demonstrate a significant increase in HtSDS with the safety profile similar to GH-deficient patients. Results were similar to the clinical trial.     

The Somatopause

Human aging causes adverse changes in body composition, a fall in bone mineral density, a deterioration in physical performance, a worsening cardiovascular risk profile, and increased morbidity and mortality. In addition, growth hormone (GH) secretion and serum insulin-like growth factor (IGF)-I levels fall. GH deficiency in adults causes similar changes to those observed with aging, which has led to the suggestion that the elderly are GH deficient and would benefit from GH treatment. Randomized controlled studies have demonstrated modest benefits when GH treatment has been used alone or in combination with exercise or sex steroids. GH treatment in adults over 60 years of age is associated with a high incidence of adverse effects, particularly peripheral edema, arthralgia, and carpal tunnel syndrome. Studies to date have been for a maximum of 12 months, so long-term safety data are not available in this setting. There are particular concerns over the links between the GH-IGF-I axis and the development of cancer in the normal population. Long-term studies are required to determine the efficacy and safety of GH treatment in older adults who are not GH deficient. At the present time, there are insufficient data on sustained efficacy, safety, or cost effectiveness to support the use of GH as an anabolic agent in adults over 60 years of age.     

Advantages and disadvantages of GH/IGF-I combination treatment

Growth hormone (GH) is the primary regulator of insulin-like growth factor-I (IGF-I) production in a wide variety of tissues. There is much overlap in the endocrine, metabolic and anabolic effects of GH and IGF-I but both hormones have divergent effects on glucose metabolism, insulin sensitivity and differentiation of prechondrocytes. Theoretically combined administration of GH and IGF-I may be more effective than GH alone or IGF-I alone. Arguments in favor for this are: 1] Clearance of IGF-I may be markedly altered by the co-administration of GH and this will provide sustained actions of IGF-I. 2] Higher serum IGF-I levels are achieved with a combination treatment of GH and IGF-I than with GH treatment alone or IGF-I alone. In addition, combination therapy may have additive or synergistic effects. 3] The combination GH and IGF-I counteracts disadvantageous effects on glucose metabolism of either GH alone or IGF-I alone. 4] GH may exert direct actions on tissues independently from IGF-I. 5] Combination of GH and IGF-I may be more effective in improving tissue IGF-I levels. The combination therapy of GH and IGF-I might be beneficial in growth retardation, in certain specific subgroups of critically ill or catabolic patients and in the treatment of GH-deficient subjects with the metabolic syndrome and/or manifest diabetes. It is at present unknown whether an optimal balance between safety and efficacy can be achieved with the combination therapy of GH and IGF-I, since this combination has been evaluated in only a small number of patient populations and in studies of a relatively short duration. In addition, a disadvantage may be the financial costs of combination therapy of GH and IGF-I. In conclusion, there are many reasons for believing that administration of the combination therapy of GH and IGF-I could have advantages above GH alone or IGF-I alone. However, determination of whether co-administration of GH and IGF-I indeed is superior to either agent alone awaits further study.     

Lessons learned from 15 years of KIMS and 5 years of ACROSTUDY

BACKGROUND: Pharmacoepidemiological surveys provide a valuable contribution to the continued monitoring of drug-related effects in patients with rare disorders. One of the earliest examples of this type of survey is KIGS (Pfizer International Growth Study Database), which has monitored the safety and effectiveness of growth hormone (GH) therapy in GH-deficient children since its inception in 1987. Following closely in the footsteps of KIGS is KIMS (Pfizer International Metabolic Database). As of 2009, KIMS has been collecting data on the long-term safety and clinical outcomes of GH replacement in GH-deficient adults for 15 years. Approximately 5 years ago, the ACROSTUDY database was established to monitor the long-term safety and effectiveness of pegvisomant in patients with acromegaly. CONCLUSIONS: By collecting data on the treatment of relatively rare conditions in routine clinical practice, pharmacoepidemiological surveys such as KIMS and ACROSTUDY provide valuable information on the safety and effectiveness of treatment with GH replacement and pegvisomant in the real world.     

A review of guidelines for use of growth hormone in pediatric and transition patients

Growth hormone (GH) is approved by the US Food and Drug Administration (FDA) for use in pediatric patients with disorders of growth failure or short stature and in adults with growth hormone deficiency (GHD) and HIV/AIDS wasting and cachexia. For pediatric patients, guidelines for the use of GH have been developed by several organizations that have identified specific criteria for initiating GH therapy for each FDA-approved indication. Guidelines for adults have also been developed and include recommendations for transition (adolescent) patients with GHD. These patients are often treated with GH as children but may require continued treatment as young adults to attain full skeletal mineralization and improve cardiovascular risk factors. Adult and pediatric guidelines are supported by efficacy and safety studies, which show that, when started at an early age, GH treatment can increase growth velocity and that GH is safe and well-tolerated. We summarize the guidelines that are available for all FDA-approved indications among pediatric and transition patients. Adherence to these guidelines will help to ensure that patients with disorders of growth failure or short stature receive the necessary therapy to increase linear growth and transition smoothly to healthy adulthood.     

Utility of Free IGF-I Measurements

For nearly 30 years, the endogenous bioactivity of insulin-like growth factor I (IGF-I) has been estimated by its circulating concentrations of immunoreactive IGF-I, obtained after either removal or inactivation of the IGF-binding proteins (IGFBPs), and today serum/plasma total IGF-I serves as a useful parameter in the diagnosis and clinical control of growth hormone (GH) disorders. Different assays for the measurement of free, unbound IGF-I were introduced more than a decade ago. Nevertheless, this measurement remains controversial, and in daily clinical practice serum total IGF-I has retained its position as the most widely used IGF-related measurement in GH disorders. This review will provide a survey of data on free versus total IGF-I, with particular reference to GH disorders. As it will be clear, there is reasonable clinical evidence to conclude that both in the diagnosis of as well as during treatment of patients with GH disorders, serum/plasma total IGF-I should remain the primary IGF-related measurement. However, in certain patients the inclusion of free IGF-I may be useful and therefore, some guidelines for the inclusion of free IGF-I measurements will be given.     

Efficacy of medical treatment in Cushing's disease: a systematic review

Due to the positive effects demonstrated in randomized clinical trials on cardiovascular surrogate markers and bone metabolism, a positive effect of growth hormone (GH) treatment on clinically relevant end‐points seems feasible. In this review, we discuss the long‐term efficacy and safety of GH treatment in adult patients with growth hormone deficiency (GHD) with emphasis on morbidity: fatal and nonfatal cardiovascular disease (CVD) and stroke, fractures, fatal and nonfatal malignancies and recurrences, and diabetes mellitus. A positive effect of GH treatment on CVD and fracture risk could be concluded, but study design limitations have to be considered. Stroke and secondary brain tumours remained more prevalent. However, other contributing factors have to be taken into account. Regrowth and recurrences of (peri)pituitary tumours were not increased in patients with GH treatment compared to similar patients without GH treatment. All fatal and nonfatal malignancies were not more prevalent in GH‐treated adults compared to the general population. However, follow‐up time is still relatively short. The studies on diabetes are difficult to interpret, and more evidence is awaited. In clinical practice, a more individualized assessment seems appropriate, taking into consideration the underlying diagnosis of GHD, other treatment regimens, metabolic profile and the additional beneficial effects of GH set against the possible risks. Large and thoroughly conducted observational studies are needed and seem the only feasible way to inform the ongoing debate on health care costs, drug safety and clinical outcomes.     

Therapeutic applications of the insulin-like growth factors.

The potential therapeutic applications of the insulin-like growth factors (IGFs) are broad. This review focuses on treatment of humans with recombinant human IGF-I (rhIGF-I), and with a rhIGF-I/IGF binding protein-3 (IGFBP-3) complex. Several groups of patients have been treated effectively, including individuals with growth hormone insensitivity syndrome (GHIS) secondary to GH receptor deficiency, to IGF-I gene deletion, or to defects in GH signal transduction pathways, patients with type 1 and type 2 diabetes mellitus, or individuals with severe insulin resistance syndromes. In each of these conditions rhIGF-I therapy has been demonstrated to be of clear clinical benefit. Other conditions, which may potential targets for therapy with rhIGF-I or rhIGF-I/IGFBP-3, include chronic inflammatory or nutritional disorders such as Crohn's disease, juvenile chronic arthritis, or cystic fibrosis. Therapy with IGFs has not been attempted in these disorders yet, in part because of lack of adequate supplies. Recently, the newly developed rhIGF-I/IGFBP-3 complex has been used in early clinical studies. Pharmacokinetic analyses in patients with diabetes mellitus and GHIS have suggested that a more physiological profile of serum IGF-I results. Improved glycaemic control has been reported in type 1 and type 2 diabetes in adults. A therapeutic trial in na?ve children with GHIS is currently under way.     

The use of anakinra, an interleukin-1 receptor antagonist, in the treatment of rheumatoid arthritis

Interleukin-1 (IL-1) is a primary cytokine that is involved in the pathogenesis of rheumatoid arthritis; it contributes to inflammation and joint destruction. Anakinra (Kineret) is an IL-1 receptor antagonist that blocks the biologic activity of IL-1. It was approved by the U.S. Food and Drug Administration (FDA) for the treatment of rheumatoid arthritis in 2001. Anakinra is safe and effective in the treatment of rheumatoid arthritis, both as monotherapy and in combination with other disease-modifying antirheumatic drugs.This article reviews the preclinical, clinical, and postmarketing data on the safety and efficacy of anakinra in the treatment of rheumatoid arthritis and focuses on the pivotal clinical trials that led to FDA approval.     

News options and preparations in growth hormone therapy

In the last twenty years, recombinant human Growth hormone (hrGH) has been available for the treatment of Growth Hormone Deficiency (GHD) in children and more recently in adults. However, the necessity of daily injections compromises the patient's compliance. Attempts to improve this compliance includes the use of pens and needle free devices, once the infusion pumps, not always physiologic, are of restricted use. When growth is the purpose of treatment, daily subcutaneous hrGH is still the most indicated. Nevertheless the expansion of GH replacement to new uses and especially in adults will need new preparations. Nowadays, the oral secretagogues have not proved efficacy to be used in clinical practice and the slow- release preparations of GH and GH releasing hormone that could improve the patient's compliance will need to be studied considering long term efficacy and safety.     

Safety of biologics in inflammatory bowel disease

Opinion statement Various biologic agents have been evaluated in patients with inflammatory bowel disease (eg, Crohn’s disease [CD]) and ulcerative colitis (UC). At present, only one, infliximab (humanized monoclonal anti-tumor necrosis factor-á antibody), is approved by the US Food and Drug Administration for induction and maintenance treatment in patients with active moderate to severe and/or fistulizing CD who are refractory to conventional therapy. Two recent trials, Active Ulcerative Colitis Trial (ACT) 1 and ACT 2, observed high efficacy of infliximab in inducting and maintaining clinical remission, mucosal healing, and corticosteroid-sparing effects in patients with moderate to severe UC. A plethora of randomized, double-blind, controlled and open-label, uncontrolled studies on large and small numbers of patients has assessed efficacy and safety of various biologic agents of potential use in treatment of inflammatory bowel disease. With respect to safety of biologic agents used for treatment, the most accurate data are available only in the case of infliximab. This is due to the fact that infliximab was evaluated in many more trials than any other biologic agent. Moreover, postmarketing experience also provides very valuable information about any side effects occurring during treatment with this agent.     

Treatment of Obesity Using GH

The obesity epidemic calls for complementary treatment possibilities in addition to lifestyle changes. One of the important regulators of lipid homeostasis is growth hormone (GH). Clinical trials have tested if GH can reduce obesity in humans. The mechanisms underlying the response to GH administration have also been investigated in animal models of human obesity. A literature search yielded 19 randomized placebo-controlled clinical studies and several animal studies investigating chronic GH treatment of obesity. Significant effects were found in some of the larger trials. One clinical trial showed significantly increased weight loss due to GH treatment, and in seven trials, a significant reduction of fat mass was found. The improvements observed were modest, but even minor improvements have been shown to be beneficial, especially if the reduction in fat mass includes visceral adipose tissue, as was reported in three of six trials. In principle, animal data support the clinical observations although the reduction of fat mass was more dramatic than observed in humans. The mechanisms resulting in lipid mobilization most likely include adipose tissue lipo-protein lipase (LPL) inhibition and antagonization of the anti-lipolytic activity of insulin. By feeding a restricted amount of a high fat diet to GH exposed rats hyper-insulinemia was avoided, loss of body fat was accelerated and metabolic markers were improved. Provision of a diet suitable for the metabolic conditions during GH treatment shows promise for improving metabolic control and can perhaps increase the efficacy and/or widen the therapeutic window of GH.     

Established and novel disease‐modifying treatments in multiple sclerosis

Multiple sclerosis (MS) is a presumed autoimmune disorder of the central nervous system, resulting in inflammatory demyelination and axonal and neuronal injury. New diagnostic criteria that incorporate magnetic resonance imaging have resulted in earlier and more accurate diagnosis of MS. Several immunomodulatory and immunosuppressive therapeutic agents are available for relapsing forms of MS, which allow individualized treatment based upon the benefits and risks. Disease‐modifying therapies introduced in the 1990s, the beta‐interferons and glatiramer acetate, have an established track record of efficacy and safety, although they require administration via injection. More recently, monoclonal antibodies have been engineered to act through specific mechanisms such as blocking alpha‐4 integrin interactions (natalizumab) or lysing cells bearing specific markers, for example CD52 (alemtuzumab) or CD20 (ocrelizumab and ofatumumab). These agents can be highly efficacious, but sometimes have serious potential complications (natalizumab is associated with progressive multifocal leukoencephalopathy; alemtuzumab is associated with the development of new autoimmune disorders). Three new oral therapies (fingolimod, teriflunomide and dimethyl fumarate, approved for MS treatment from 2010 onwards) provide efficacy, tolerability and convenience; however, as yet, there are no long‐term postmarketing efficacy and safety data in a general MS population. Because of this lack of long‐term data, in some cases, therapy is currently initiated with the older, safer injectable medications, but patients are monitored closely with the plan to switch therapies if there is any indication of a suboptimal response or intolerance or lack of adherence to the initial therapy. For patients with MS who present with highly inflammatory and potentially aggressive disease, the benefit‐to‐risk ratio may support initiating therapy using a drug with greater potential efficacy despite greater risks (e.g. fingolimod or natalizumab if JC virus antibody‐negative). The aim of this review is to discuss the clinical benefits, mechanisms of action, safety profiles and monitoring strategies of current MS disease‐modifying therapies in clinical practice and of those expected to enter the market in the near future.     

Surgical treatment of movement disorders

A substantial body of evidence has accumulated regarding the efficacy and safety of neurosurgery for Parkinson's disease, essential tremor, and dystonia. Surgery for movement disorders (thalamotomy, pallidotomy, and subthalamic nucleotomy or subthalamotomy) was largely ablative (lesion-based). Given the safety and anatomy-preservation advantage, long-term electrical stimulation of these same targets (thalamus, globus pallidus, and subthalamic nucleus) is discussed as the treatment of choice. High-frequency deep brain stimulation procedures replicate the effects of ablative interventions, but do not require making a destructive brain lesion. This article outlines patient eligibility for surgery, targeting techniques, intraoperative findings, and potential complications and discusses the outcomes expected for each of the major interventions for which clinical trial data are available.     

Safety of biologic therapy

Several biologic agents have been assessed in patients with inflammatory bowel disease (IBD; Crohn's disease [CD] and ulcerative colitis [UC]). Until recently, only infliximab (humanized monoclonal anti-TNF-alpha antibody) had been approved by the Food and Drug Administration (FDA) to induce and maintain remission in patients with active mild to moderate and/or fistulizing Crohn's disease who are refractory to conventional therapy. Two recent trials, ACT 1 and ACT2, observed high efficacy of infliximab in inducing and maintaining clinical remission, mucosal healing, and corticosteroid-sparing effects in patients with moderate to severe UC. This agent also was recently approved by the FDA for the treatment of ulcerative colitis to reduce signs and symptoms, to induce clinical remission and healing of the intestinal mucosa, and to eliminate the use of corticosteroids in patients with moderately to severely active UC who have had an inadequate response to conventional therapy. There have been many randomized, double-blind, controlled and open-label uncontrolled studies of large and small numbers of patients assessing the efficacy and safety of various biologic agents considered potentially useful in the treatment of IBD. Among all the biologic agents, infliximab has the most robust data on safety. This is because it has been evaluated in many more trials than has any other biologic agent. In addition, postmarketing experience provides very valuable information about adverse events occurring during treatment with this agent.     

Benefit of postponing normal puberty for improving final height

Experiments of nature and clinical observations have provided indications that postponing puberty may increase final height in short children. In children with central precocious puberty, a GnRH analog (GnRHa) alone is efficacious in increasing final height, but in other conditions a combination of growth hormone (GH) and GnRHa is needed. In GH-deficient children with early onset of puberty and poor height prediction, the combination of GH and GnRHa increases final height by 1.0-1.3 s.d. In children with idiopathic short stature and persistent short stature after intrauterine growth retardation, the combination also appears to be beneficial. Potential side effects include weight gain, a negative effect on bone mineralization, and psychosocial consequences. More data on long-term safety have to be collected before the combination of GH and GnRHa in children with idiopathic short stature should be considered for clinical use outside clinical trials.     

生长激素治疗特发性矮小症的研究进展

特发性矮小症(ISS)是一种病因未明的矮小症,目前较常用的治疗药物是生长激素(GH),本文就GH治疗ISS的适应证、有效性、安全性及目前的争议进行综述.     

A multicenter study of the efficacy and safety of sustained release GH in the treatment of naive pediatric patients with GH deficiency

Treatment of naive children with GH deficiency has relied upon long-term replacement therapy with daily injections of GH. The daily schedule may be inconvenient for patients and their caregivers, possibly promoting nonadherence with the treatment regimen or premature termination of treatment. We studied a new sustained release GH formulation, administered once or twice monthly, to determine its efficacy and safety in this population. Seventy-four prepubertal patients with documented GH deficiency were randomized to receive sustained release recombinant human GH at either 1.5 mg/kg once monthly or 0.75 mg/kg twice monthly by sc injection in a 6-month open-label study. Efficacy was determined by growth data from 69 patients completing 6 months and 56 patients completing 12 months in an extension study. Growth rates were significantly increased over baseline and were similar for the two dosage groups. The mean (+/-SD) annualized growth rate (pooled data) was 8.4 +/- 2.1 cm/yr at 6 months, and the growth rate was 7.8 +/- 1.8 at 12 months compared with 4.5 +/- 2.3 at baseline. Standardized height, bone age, and predicted adult height assessments demonstrated catch-up growth without excessive skeletal maturation. Injection site-related events (including pain, erythema, and nodules) were the most commonly reported adverse events; no serious adverse events related to treatment were reported. Laboratory studies documented no accumulation of trough GH or IGF-I levels during treatment, nor did glucose intolerance or persistent hyperinsulinism develop. Sustained release recombinant human GH is safe and effective for long-term GH replacement in children with GH deficiency. Patients achieved similar growth velocities when sustained release GH was given once or twice monthly. The enhanced convenience of this dosage form may result in greater long-term adherence to the treatment regimen.     

Management of growth hormone deficiency in adults.

Growth hormone (GH) deficiency in adults is a recognised clinical entity. There is still, however, an ongoing debate of the clinical need and the importance of replacing GH in adults with severe GH deficiency. This review will focus on the overall management of adults with GH deficiency and highlight published data on dose management and treatment goals for various age groups. The efficacy data on quality of life and well-being is discussed and available and growing experience on long-term effects of GH replacement in adults and safety in terms of diabetes mellitus, pituitary tumour recurrence/regrowth and malignancy risk will be reviewed.     

Optimal use of growth hormone therapy for maximizing adult height in children born small for gestational age

Growth retardation is a well-known complication of being born small for gestational age (SGA). Approximately 10% of children born SGA do not experience postnatal catch-up growth and are at risk for short adult height. The use of growth hormone (GH) therapy in these short children appears to increase their adult height, but modalities of GH administration remain controversial. Numerous therapeutic strategies have been developed to optimize the efficacy of GH treatment. Data concerning the influence of age at start of GH treatment, duration of GH treatment, GH dosage and method of GH administration on height gain and adult height are reported in this chapter. Longitudinal studies addressing the safety of GH treatment in SGA children are reassuring, but long-term follow-up remains necessary. Recommendations on the management of SGA children during GH treatment are given.