Oxytocin as a novel therapeutic option for type I diabetes and diabetic osteopathy.

OBJECTIVE: The aim of the present study was to highlight the newly discovered metabolic role of oxytocin (OT) in the type I diabetic rats. Previous studies have demonstrated that OT has a beneficial role on bone physiology and therefore, the OT effect on the diabetic osteopathy will be assessed as well. METHODS: Induction of the type I diabetes was carried out by an intraperitoneal injection of 60 mg/kg body weight of streptozotocin. The metabolic role of OT on diabetic rats after OT treatment with intramuscular injection of 40 µIU/kg body weight for 6 weeks was assessed. Histological and ultrastructural studies of rat pancreas samples, before and after the OT injection, were performed and compared with the obtained physiological results. RESULTS: Oxytocin treatment had positive metabolic effects in diabetic rats. This is based on the change in glucose metabolism, lipid profile, and insulin sensitivity in experimental animals. In addition, OT treatment showed histological regenerative changes of pancreatic islet cells of diabetic rats. Moreover, OT administration showed that it has an anabolic effect on the bone biology. CONCLUSIONS: The results suggest that activation of the oxytocin receptor (OTR) pathway by infusion of OT, OT analogs, or OT agonists may represent a promising approach for the treatment of diabetes and some of its complications, including diabetic osteopathy.

Stem cells in skeletal physiology and endocrine diseases of bone.

Self-renewing, multipotent progenitors of skeletal tissues are found within skeletal segments (skeletal stem cells) and coincide with adventitial reticular cells of bone marrow vessels in situ and with explanted clonogenic stromal cells ex vivo. These cells, which can be identified and prospectively isolated based on a minimal surface phenotype noted for expression of CD146, CD105 and alkaline phosphatase, are established during bone development through interactions with developing sinusoids. They represent a crucial crossroad of skeletal and hematopoietic physiology, as well as of endocrine regulation of bone growth and remodeling. In addition, they are central to major endocrine functions of bone itself, such as regulation of renal phosphate handling. Skeletal stem cells represent a central model system for investigating skeletal diseases, as tools for in vitro and in vivo models, for cell therapy-based strategies, or as targets for drugs.

'Old' bones in young bodies: the tale of cystic fibrosis.

PURPOSE OF REVIEW: Cystic fibrosis (CF) is the most common genetic disease within the white population and leads to premature respiratory failure. Approximately, 60 000 individuals are currently living with CF in North America and Europe, almost half of whom are adults. RECENT FINDINGS: Dozens of studies across the globe indicate that CF adults have low bone density and increased rates of fractures. This genesis of the problem appears to be in late childhood to adolescence. SUMMARY: Prevention and treatment of CF-related bone disease must address the myriad risk factors (decreased absorption of fat-soluble vitamins due to pancreatic insufficiency, altered sex hormone production, chronic lung infection with increased serum levels of proinflammatory, bone-active cytokines, malnutrition and low body weight, physical inactivity and glucocorticoid therapy) for poor bone health. This review will address the pathogenesis, diagnosis and treatment of bone disease in CF. It will also discuss best practice guidelines for optimizing bone health in patients with CF.

[Effect of glucose and bone metabolism in endocrinal disorder].

It is well known that endocrine disorders; glucocorticoid excess including Cushing syndrome, high dose or long term steroid therapy and hyperthyroidism, induce secondary osteoporosis. These common endocrinal disorders affect not only bone metabolism but also glucose metabolism. Glucose metabolisms also play a important role in the progression of osteoporosis. To prevent secondary osteoporosis, multifocal intervention such as correction of insulin resistance or glucose metabolism, lifestyle, and drug therapy, need to be added to current management of endocrinal system.

Endocrine parameters of cystic fibrosis: back to basics.

Dramatic changes in the life expectancy of cystic fibrosis (CF) patients are occurring, creating a cohort of aging individuals experiencing long-term complications of this chronic disease. The two most common of these complications include CF-related diabetes and CF bone disease. The clinical implications of each have become better understood, as have potential therapies. However, data obtained from the basic science studies of both diseases have not been widely recognized. In this review, we focus on the known and hypothesized pathogenesis of these two disorders. Additionally, the molecular underpinnings of CF will be explained along with the potential interactions with endocrine disease phenotypes.

Devastating skeletal effects of delayed diagnosis of complicated primary hyperparathyroidism because of ectopic adenoma.

Primary hyperparathyroidism is a disease caused by exaggerated secretion of the parathyroid gland hormone, produced by an adenoma in 80% of cases. Ectopic adenomas occur in a small proportion of cases. Herein, the authors report a 72-year-old woman with a delayed diagnosis of primary hyperparathyroidism, produced by an intrathoracic adenoma, with a longstanding course, presenting with severe osteoporosis, multiple fractures, bone deformities, and neurologic impairments. Persistent hypercalcemia, high levels of alkaline phosphatase, and parathyroid hormone were documented and a paratracheal mass was found on a helicoidal tomography of the thorax. After surgical removal, the histopathological examination confirmed an ectopic adenoma of the parathyroid gland and the patient achieved some improvement in her clinical picture.

Vitamin D receptor activators can protect against vascular calcification.

An apparent conflict exists between observational studies that suggest that vitamin D receptor (VDR) activators provide a survival advantage for patients with ESRD and other studies that suggest that they cause vascular calcification. In an effort to explain this discrepancy, we studied the effects of the VDR activators calcitriol and paricalcitol on aortic calcification in a mouse model of chronic kidney disease (CKD)-stimulated atherosclerotic cardiovascular mineralization. At dosages sufficient to correct secondary hyperparathyroidism, calcitriol and paricalcitol were protective against aortic calcification, but higher dosages stimulated aortic calcification. At protective dosages, the VDR activators reduced osteoblastic gene expression in the aorta, which is normally increased in CKD, perhaps explaining this inhibition of aortic calcification. Interpreting the results obtained using this model, however, is complicated by the adynamic bone disorder; both calcitriol and paricalcitol stimulated osteoblast surfaces and rates of bone formation. Therefore, the skeletal actions of the VDR activators may have contributed to their protection against aortic calcification. We conclude that low, clinically relevant dosages of calcitriol and paricalcitol may protect against CKD-stimulated vascular calcification.

Posttransplant metabolic acidosis: a neglected factor in renal transplantation?

PURPOSE OF REVIEW: The occurrence and pathogenesis of metabolic acidosis after renal transplantation is reviewed. Posttransplant acidosis is shown to be a key mechanism for major metabolic complications in mineral and muscle metabolism, and for anemia, discussed in the context of both acidosis and renal transplantation. RECENT FINDINGS: Continuous improvement in kidney transplant survival has shifted attention to long-term outcomes, specifically to disorders linked to cardiovascular disease, physical capacity and quality of life. Metabolic acidosis is gaining growing acceptance as a clinical entity and has occasionally come into focus in the context of renal transplantation. The possible link to metabolic disturbances resulting in impairment of musculoskeletal disorders and physical limitations, however, has not been considered specifically. SUMMARY: Available evidence suggests a high prevalence of (compensated) metabolic acidosis after renal transplantation, presenting as low serum bicarbonate and impaired renal acid excretion. This condition is associated with relevant disorders in mineral metabolism and muscle function. Current knowledge about the effects of acidosis on renal electrolyte handling, mineral metabolism and protein synthesis suggests that acid/base derangements contribute to the muscle and bone pathology, as well as anemia, encountered after kidney transplantation. Consequently, posttransplant acidosis may be a relevant factor in the causal pathway of impaired physical capacity observed in this patient group.

P450 oxidoreductase deficiency: a new form of congenital adrenal hyperplasia.

PURPOSE OF REVIEW: P450 oxidoreductase deficiency--a newly described form of congenital adrenal hyperplasia--typically presents a steroid profile suggesting combined deficiencies of steroid 21-hydroxylase and 17alpha-hydroxylase/17,20-lyase activities. These and other enzymes require electron donation from P450 oxidoreductase. The clinical spectrum of P450 oxidoreductase deficiency ranges from severely affected children with ambiguous genitalia, adrenal insufficiency and the Antley-Bixler skeletal malformation syndrome to mildly affected individuals with polycystic ovary syndrome. We review current knowledge of P450 oxidoreductase deficiency and its broader implications. RECENT FINDINGS: Since the first report in 2004, at least 21 P450 oxidoreductase mutations have been reported in over 40 patients. The often subtle manifestations of P450 oxidoreductase deficiency suggest it may be relatively common. P450 oxidoreductase deficiency, with or without Antley-Bixler syndrome, is autosomal recessive, whereas Antley-Bixler syndrome without disordered steroidogenesis is caused by autosomal dominant fibroblast growth factor receptor 2 mutations. In-vitro assays of P450 oxidoreductase missense mutations based on P450 oxidoreductase-supported P450c17 activities provide excellent genotype/phenotype correlations. The causal connection between P450 oxidoreductase deficiency and disordered bone formation remains unclear. SUMMARY: P450 oxidoreductase mutations cause combined partial deficiency of 17alpha-hydroxylase and 21-hydroxylase. Individuals with an Antley-Bixler syndrome-like phenotype presenting with sexual ambiguity or other abnormalities in steroidogenesis should be analyzed for P450 oxidoreductase deficiency.

Primary hyperparathyroidism: new concepts in clinical, densitometric and biochemical features.

Primary hyperparathyroidism (PHPT) is characterized most commonly now as an asymptomatic disorder with hypercalcaemia and elevated levels of parathyroid hormone (PTH). The elevation in PTH is detected by both the standard immunoradiometric assays (IRMA) and a more recent IRMA that detects only the 1-84 full-length PTH molecule. The serum calcium concentration is usually <1 mg dL(-1) above normal. Recently, another variant of PHPT (normocalcaemic PHPT) has been described in which the serum calcium is normal but the serum PTH is elevated, in the absence of any secondary cause for PTH elevation. Although usually sporadic, PHPT also occurs in inherited syndromes. Skeletal manifestations are appreciated by densitometry showing a typical pattern in which cancellous bone of the lumbar spine is reasonably well preserved whilst the cortical bone of the distal third of the radius is preferentially reduced. Although reduced in incidence, renal stones remain the most common overt complication of PHPT. Other organs are theoretical targets of PHPT such as the neurobehavioural axis and the cardiovascular system. Vitamin D looms as an important determinant of the activity of the PHPT state. The 2002 NIH Workshop on asymptomatic PHPT has led to revised guidelines to help doctors determine who is best advised to have parathyroid surgery and who can be safely followed without surgery. New information about the natural history of PHPT in those who did not undergo surgery has helped to define more precisely who is at-risk for complications. At the NIH workshop, a number of items were highlighted for further investigation such as pharmacological approaches to controlling hypercalcaemia, elevated PTH levels and maintaining bone density.

Growth hormone in musculoskeletal pain states.

Growth hormone is essential for normal linear growth and the attainment of an adult mature height. It also plays an important role in cartilage growth and the attainment of normal bone mass. There is only one rheumatic disorder, namely acromegaly, in which abnormalities of growth hormone production play a major etiologic role. However, there is increasing appreciation that suboptimal growth hormone secretion, leading to a state of adult growth hormone deficiency, may occur in the setting of chronic inflammatory disease, chronic corticosteroid use, and fibromyalgia. Therefore, the evaluation and effective management of growth hormone oversecretion and undersecretion is relevant to practicing rheumatologists.

Endocrine changes after burns: the bone involvement.

Any major burn is followed by a pronounced endocrine and metabolic response, by an acute phase response. In 30 burn subjects whose bone status was studied after burn trauma with the densitometer HOLOGIC 2000, bone involvement was found 6 and 12 months postburn: the Bone Mineral Density (BMD) of their lumbar vertebrae L1-4 and of their left hip dropped significantly in most of them. Elevated levels of cortisol both in blood and in urine (free cortisol) were found, accompanied by very low testosterone, dihydrotestosterone (DHT) and free testosterone levels in blood of the burned males, but not of the females. Elevated 17beta-estradiol levels were found in many burned males; they were generally not low in the burned females. DHEA-S levels were generally low. Very low levels of the triiodothyronine (T3) and of the free thyroxine (FT4) were found. Increased, even very high, PTH values were occasionally present. hGH and IGF-1 were generally normal, with a few exceptions (low or increased levels). Total and ionized calcium levels were low after burn, 250H vitamin D (calcidiol) was usually low or low normal too. Prolonged and very high levels of CTX and of NTX (both are indicators of bone resorpcion, of collagen catabolism) were found, as well as of the ACP (acid phosphatases), but the latter were less manifest, if compared with the CTX and NTX. ALP (alkaline phosphatases) were elevated too, but their elevated levels were much less pronounced than the levels of CTX and NTX. Osteocalcin levels were initially low to low normal, to increase later to the normal levels. As for the cytokines that had been investigated, mostly the elevated levels of TNFalpha were found, as well as those of IL-2, IL-6 and IL-8. Finally, a few suggestions have been given regarding the additional possibilities how to treat the burned patients: the use of anabolics, of vitamin D, of calcium, eventually of calcitonin.