Type 2 diabetes mellitus is usually preceded by impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG), which are often referred to as pre-diabetes. Individuals with IGT demonstrate beta-cell dysfunction, insulin resistance, and increased hepatic glucose production; IGT and IFG are risk factors for both diabetes and cardiovascular disease. Type 2 diabetes is associated with micro- and macrovascular complications that lead to excessive mortality and morbidity and the risk of microvascular complications extends to people with pre-diabetes. Maintaining good glycemic control in type 2 diabetes can reduce the risk of developing chronic disease-associated complications. Most individuals who develop type 2 diabetes appear to pass through a stage of IFG or IGT; thus, early intervention (lifestyle and/or pharmacologic) in individuals with pre-diabetes may help prevent cardiovascular disease and the development of type 2 diabetes.The use of exogenous insulin treatment offers the potential to reduce the cardiovascular risk in individuals with type 2 diabetes or pre-diabetes through effective reductions in blood glucose and lipid levels, and in the associated tissue damage resulting from their chronic elevations. However, there are barriers associated with insulin initiation in both type 2 diabetes and pre-diabetes (e.g. hypoglycemia, weight gain, the possible unpredictable action of long-acting insulin, and the need for injections). Insulin glargine, with its flat time-action profile, near 24-hour duration of action, reduced risk of hypoglycemia, and improved glycemic control compared with insulin suspension isophane (neutral protamine hagedorn [NPH] insulin), may help to overcome some of these barriers.Initial results from a small study have indicated the feasibility of treating individuals with pre-diabetes to near-normoglycemia using a regimen of low-dose insulin glargine plus caloric restriction. This is being followed up in the ongoing ORIGIN (Outcomes Reduction with Initial Glargine INtervention) study, which will investigate whether treatment to near-normoglycemia with insulin glargine in individuals with IGT, IFG, or new-onset type 2 diabetes can reduce cardiovascular morbidity and mortality compared with conventional management of these conditions, and whether the rate of progression to type 2 diabetes can be similarly reduced.Further studies are needed to investigate the potential benefits of insulin therapy in individuals with pre-diabetes.

Osteoporosis is a major cause of morbidity, mortality, and healthcare costs. The socioeconomic burden of osteoporosis is likely to increase dramatically if improvements in prevention are not made. Calcium supplementation effectively reduces the rate of bone loss in postmenopausal women, yet most women do not achieve an adequate calcium intake. In fact, use of calcium supplementation appears to have declined as the more effective antiresorptive therapies, such as bisphosphonates, have become available. Among patients prescribed bisphosphonates, calcium intake is often insufficient, despite the fact that adequate calcium intake may be necessary to gain the maximum benefits from antiresorptive therapy. In addition, because calcium interferes with bisphosphonate absorption, incorrect use of calcium may limit the efficacy of bisphosphonate therapy. This underscores the need for new initiatives to reduce the confusion surrounding appropriate calcium use during antiresorptive therapy. Co-packaging of bisphosphonates with calcium supplements is one strategy to help ensure that patients taking bisphosphonates not only achieve adequate calcium intake but also gain the maximum benefit from bisphosphonate therapy.

Recent clinical trials have demonstrated an increase in the risk of cardiovascular disease (CVD) in women using oral hormone replacement therapy (HRT). Bio-identical HRT (BHRT) is widely used by alternative healthcare practitioners for the treatment of symptoms of menopause, with the prevailing assumption that BHRT provides the benefits of HRT while attenuating the risks. However, considering the serious risks of HRT, the use of any form of HRT, including BHRT, without sufficient scientific evaluation may create considerable risk.The main hormone found in BHRT is estriol. Estriol is used alone or in combination with estradiol and estrone. The total daily oral dose of BHRT used is, on average, ten times higher than that used in HRT, and both oral and topical forms are used for bio-identical hormone administration. The clinical trials that have examined cardiovascular outcomes associated with estriol therapy are limited, and there is evidence to demonstrate variable effects on markers associated with cardiovascular risk.Based on the current evidence, the same cardiovascular risks that have recently been found to be associated with oral HRT may also be associated with the administration of oral estriol in BHRT. The use of oral bio-identical hormones cannot be promoted until further evidence is available to demonstrate its safety.

Imperfect use of contraceptive methods notably increases the likelihood of pregnancy. One means of improving user adherence with hormonal contraception is to minimize the dosing schedule. Two forms of hormonal contraceptive have currently achieved this goal: the transdermal patch and the vaginal ring. The first and only transdermal contraceptive patch to receive worldwide regulatory approval (ethinylestradiol/norelgestromin) is a convenient approach to contraception that has a similar efficacy to oral contraceptives (OCs), but with the benefit of once-weekly administration. In addition, transdermal delivery of contraceptive hormones eliminates variability in gastrointestinal absorption, avoids hepatic first-pass metabolism, and prevents the peaks and troughs in serum concentrations that are seen with OCs. Norelgestromin, the progestin contained in the patch, is the active metabolite of norgestimate and is structurally related to 19-nortestosterone. Norgestimate and norelgestromin mimic the physiologic effects of progesterone at the progesterone receptor; however, norelgestromin has negligible direct or indirect androgenic activity, suggesting that it may be suitable for women with disorders related to androgen excess (such as hirsutism, acne, and lipid disorders).Contraceptive effectiveness is usually a function of the efficacy of a contraceptive in combination with compliance with its dosing regimen. The efficacy of the contraceptive patch has been clearly demonstrated in three phase III trials, two of which were randomized comparisons with an OC. The likelihood of pregnancy was similar between these contraceptive methods; however, compliance with the patch was notably better, particularly in younger women. The safety and tolerability profile of the patch was similar to that of the OC. A cost-effectiveness analysis has suggested that the contraceptive patch is more cost effective than the OC, due to decreased costs related to unwanted pregnancy.

Antiresorptive agents for osteoporosis are a cornerstone of therapy, but anabolic drugs have recently widened our therapeutic options. By directly stimulating bone formation, anabolic agents reduce fracture incidence by improving other bone qualities in addition to increasing bone mass. Teriparatide (human parathyroid hormone[1-34]) has clearly emerged as a major approach for selected patients with osteoporosis. Teriparatide increases bone mineral density and bone turnover, improves bone microarchitecture, and changes bone size. The incidence of vertebral and non-vertebral fractures is reduced. Teriparatide is approved in many countries throughout the world for the treatment of both postmenopausal women and men with osteoporosis who are at high risk for fracture. Another anabolic agent, strontium ranelate, may both promote bone formation and inhibit bone resorption. Clinical trials support the use of strontium ranelate as a treatment for postmenopausal osteoporosis and have shown that strontium ranelate reduces the frequency of vertebral and non-vertebral fractures. Other potential anabolic therapies for osteoporosis, including other forms of parathyroid hormone, growth hormone, and insulin-like growth factor-I, have been examined, although less data are currently available on these approaches.

Extremely low birth-weight newborns (<1000g) experience low levels of thyroid hormone that vary inversely with the severity of neonatal illness and the extent of developmental immaturity with levels reaching a nadir at approximate, equals7 days after birth; this phenomenon can persist for several weeks. In the absence of transplacental passage, 30-50% of these neonates cannot generate sufficient quantities of thyroid hormone to meet postnatal demands, placing them at an increased risk for developmental delay and cerebral palsy. Population surveys and interventional trials suggest that a therapeutic opening exists during a 'window of opportunity' corresponding to this period of diminished capacity. Variables to consider before intervention focus on the consideration that supplementation of both the substrate thyroxine and the active hormone triiodothyronine may be necessary in quantities that do not suppress thyroid-stimulating hormone release, yet overcome the persistence of increased conversion to 3,3'5'-triodo-L-thyronine, terminal deiodination, and activity of the sulfation inactivation pathways, as well as the diminished capacity of the newborn to accommodate postnatal physiologic changes. Single daily replacement doses may suppress levels of converting enzymes in the brain, suggesting that physiologic 'mimicry' provided by a constant infusion may be the preferred dosing option. Properly powered clinical trials targeting long-term developmental outcomes are needed to discern whether these interventions will do more than simply elevate blood levels of thyroid hormones to the target values of either the fetus or developing neonate. Identifying the appropriate indications for supplementation may alleviate individual pain and distress due to disability for several hundred extremely low birth-weight neonates each year in the US alone, and save society a pro-rated lifetime cost of nearly $US1 million per child.

Inhaled human insulin (Exubera((R)) [insulin human (rDNA origin)] Inhalation Powder) has recently been approved in the EU and the US for preprandial use in adult patients with diabetes mellitus. This formulation of insulin has a more rapid onset, but similar duration, of glucose-lowering activity compared with subcutaneously administered regular human insulin.Preprandial inhaled human insulin provided glycemic control that was comparable to preprandial subcutaneous regular insulin when added to long- or intermediate-acting subcutaneous basal insulin in patients with type 1 diabetes. Inhaled human insulin is also effective when administered alone, when combined with oral antihyperglycemic therapy, or when combined with basal subcutaneous insulin in patients with type 2 diabetes. Comparable rates of hypoglycemia occurred in patients treated with inhaled human insulin and in those treated with subcutaneous regular human insulin. Patients treated with inhaled human insulin demonstrated a greater decline in pulmonary function (forced expiratory volume in 1 second, carbon monoxide diffusing capacity) than patients treated with comparator antihyperglycemic agents; the mean difference between the treatment groups that favored the comparators was noted within the first several weeks of treatment, and did not change over a 2-year treatment period. This agent has also been associated with significant improvements in some quality-of-life and treatment satisfaction scores, especially when compared with subcutaneous mealtime insulin regimens.

black triangle An oral formulation of paricalcitol has been developed for the prevention and treatment of secondary hyperparathyroidism in patients with stage 3 or 4 chronic kidney disease.black triangle Paricalcitol is a synthetic vitamin D analog that binds to the vitamin D receptor inducing suppression of parathyroid hormone (PTH) secretion.black triangle Oral paricalcitol was significantly more effective than placebo in treating secondary hyperparathyroidism in patients with stage 3 or 4 chronic kidney disease. In a pooled analysis of three well designed, 24-week trials, two consecutive reductions from baseline in intact PTH levels of >/=30% were achieved by significantly more paricalcitol than placebo recipients (91% vs 13%).black triangle In addition, mean levels of the biochemical bone markers serum bone-specific alkaline phosphatase, serum osteocalcin, and urinary pyridinoline were reduced from baseline to a significantly greater extent with paricalcitol than with placebo, indicating a reduction in bone turnover.black triangle Oral paricalcitol was well tolerated; there was no significant difference between paricalcitol and placebo recipients in the incidence of hypercalcemia, hyperphosphatemia, or elevated calcium-phosphorus product.

Metabolic bone disease in children includes many hereditary and acquired conditions of diverse etiology that lead to disturbed metabolism of the bone tissue. Some of these processes primarily affect bone; others are secondary to nutritional deficiencies, a variety of chronic disorders, and/or treatment with some drugs. Some of these disorders are rare, but some present public health concerns (for instance, rickets) that have been well known for many years but still persist. The most important clinical consequences of bone metabolic diseases in the pediatric population include reduced linear growth, bone deformations, and non-traumatic fractures leading to bone pain, deterioration of motor development and disability. In this article, we analyze primary and secondary osteoporosis, rickets, osteomalacia (nutritional and hereditary vitamin D-dependent, hypophosphatemic and that due to renal tubular abnormalities), renal osteodystrophy, sclerosing bony disorders, and some genetic bone diseases (hypophosphatasia, fibrous dysplasia, skeletal dysplasia, juvenile Paget disease, familial expansile osteolysis, and osteoporosis pseudoglioma syndrome). Early identification and treatment of potential risk factors is essential for skeletal health in adulthood. In most conditions it is necessary to ensure an appropriate diet, with calcium and vitamin D, and an adequate amount of physical activity as a means of prevention. In secondary bone diseases, treatment of the primary disorder is crucial. Most genetic disorders await prospective gene therapies, while bone marrow transplantation has been attempted in other disorders. At present, affected patients are treated symptomatically, frequently by interdisciplinary teams. The role of exercise and pharmacologic therapy with calcium, vitamin D, phosphate, bisphosphonates, calcitonin, sex hormones, growth hormone, and thiazides is discussed. The perspectives on future therapy with insulin-like growth factor-1, new analogs of vitamin D, strontium, osteoprotegerin, and calcimimetics are presented.

Gonadotropin-releasing hormone (GnRH) analog therapy relies primarily on the ability of these compounds to bind to and modulate GnRH-receptor activity. GnRH analogs have been used in pediatric patients where endogenous gonadotropin release is undesirable or potentially harmful, such as in: (i) patients with central precocious puberty (CPP); (ii) healthy short children where pubertal delay would provide an opportunity to supplement pre-pubertal linear growth; and (iii) children with malignancies and other disorders where treatment requires the use of gonadotoxic compounds. In the first two groups of patients, GnRH agonists may be used alone or in conjunction with somatropin (growth hormone [GH]) to prevent early skeletal maturation and increase the subsequent adult height, while in the latter case, GnRH agonists are used alone or in conjunction with GnRH antagonists in an attempt to preserve gonadal function.In children and adolescents with CPP, timely use of GnRH agonists alone can result in an adult height within the genetic potential of the individual (target height); however, minimal height is gained when GnRH agonist therapy is commenced after a marked advancement of skeletal age. This provides the rationale for combined therapy with GnRH agonists and somatropin in such patients, and studies have shown improved growth with this approach compared with GnRH agonists alone. Combination therapy with GnRH agonists and somatropin has also been shown to increase adult heights to a greater extent than GnRH agonists alone in pediatric patients with concomitant CPP and GH deficiency, those with idiopathic short stature, and those born small for gestational age; however, such combination therapy has shown no increased benefit over somatropin alone in pediatric patients with GH deficiency. Limited results in children and adolescents with congenital adrenal hyperplasia and chronic primary hypothyroidism have also shown increased growth rates, while no growth benefit was seen in pediatric renal transplant recipients.GnRH analogs also have potential as gonadoprotective agents; studies of GnRH agonists used alone and in combination with GnRH antagonists in women undergoing cytotoxic therapy have shown increased preservation of reproductive potential in patients who were receiving GnRH analog therapy versus those who were not.The adverse effects of GnRH analogs mainly consist of menopausal-like complaints. Increases in bodyweight and body mass index in children receiving GnRH agonist therapy have been shown; however, these increases do not persist after discontinuation of therapy. Adult bone mineral density and fertility are also not adversely affected by childhood GnRH agonist therapy.GnRH analog therapy appears to be both well tolerated and effective in pediatric patients, as it allows the preservation or improvement of adult height, and shows no longstanding negative effects on body composition, bone density, reproductive function, or endocrine physiology. These agents may also be useful for preservation of gonadal function in children and adolescents undergoing cytotoxic therapy.

Obesity and type 2 diabetes mellitus have reached epidemic proportions in the US, and indeed, globally. While microvascular complications contribute to considerable morbidity, much of the excess mortality (around 70%) is due to macrovascular disease. Hyperglycemia has predictable toxic effects on multiple organs ('glucotoxicity') including the pancreas, where it impairs insulin secretion and insulin gene expression through mechanisms that lead to glucose densensitization and beta-cell exhaustion, eventually resulting in irreversible beta-cell failure. There is robust evidence to suggest that strict glycemic control reduces diabetic microvascular complications (retinopathy, nephropathy, and neuropathy) in both primary- and secondary-prevention settings. While unequivocal evidence that intensive glycemic control reduces the risk of death due to macrovascular disease is lacking, meta-analytic data and controlled clinical trial data suggest there may still be clinically significant lowering of the risk for macrovascular endpoints through strict glycemic control. Cardiovascular disease in a diabetic patient is a collusion of several factors besides hyperglycemia, such as hypertension, dyslipidemia, diffuse endothelial dysfunction, hypercoagulability, and inflammation. It is important to address lifestyle issues such as maintenance of ideal bodyweight, good dietary practice, smoking cessation, and regular exercise in the comprehensive risk management of a diabetic patient, in order to reduce the vascular complications. Large, ongoing clinical trials such as ACCORD (Action to Control Cardiovascular Risk in Diabetes) are likely to establish the potential benefits of glycemic control in preventing or postponing macrovascular complications of diabetes.