Gherardo Mazziotti

Glucocorticoid-induced osteoporosis : pathophysiology and therapy

Glucocorticoid-induced osteoporosis (GIO) is the most common form of secondary osteoporosis. Fractures, which are often asymptomatic, may occur in as many as 30–50% of patients receiving chronic glucocorticoid therapy. Vertebral fractures occur early after exposure to glucocorticoids, at a time when bone mineral density (BMD) declines rapidly. Fractures tend to occur at higher BMD levels than in women with postmenopausal osteoporosis. In human subjects, the early rapid decline in BMD is followed by a slower progressive decline in BMD. Glucocorticoids have direct and indirect effects on the skeleton. The primary effects are on osteoblasts and osteocytes. Glucocorticoids impair the replication, differentiation and function of osteoblasts and induce the apoptosis of mature osteoblasts and osteocytes. These effects lead to a suppression of bone formation, a central feature in the pathogenesis of GIO. Glucocorticoids also favor osteoclastogenesis and as a consequence increase bone resorption. Bisphosphonates are effective in the prevention and treatment of GIO. Anabolic therapeutic strategies are under investigation.

Growth Hormone, Insulin-Like Growth Factors, and the Skeleton

GH and IGF-I are important regulators of bone homeostasis and are central to the achievement of normal longitudinal bone growth and bone mass. Although GH may act directly on skeletal cells, most of its effects are mediated by IGF-I, which is present in the systemic circulation and is synthesized by peripheral tissues. The availability of IGF-I is regulated by IGF binding proteins. IGF-I enhances the differentiated function of the osteoblast and bone formation. Adult GH deficiency causes low bone turnover osteoporosis with high risk of vertebral and nonvertebral fractures, and the low bone mass can be partially reversed by GH replacement. Acromegaly is characterized by high bone turnover, which can lead to bone loss and vertebral fractures, particularly in patients with coexistent hypogonadism. GH and IGF-I secretion are decreased in aging individuals, and abnormalities in the GH/IGF-I axis play a role in the pathogenesis of the osteoporosis of anorexia nervosa and after glucocorticoid exposure.

Glucocorticoid-induced osteoporosis: an update

Glucocorticoid-induced osteoporosis occurs in two phases: a rapid, early phase in which bone mineral density is reduced, possibly as a result of excessive bone resorption, and a slower, progressive phase in which bone mineral density declines because of impaired bone formation. Although the indirect effects of glucocorticoids on bone are evident, their direct effects on osteoblasts, osteoclasts and osteocytes are primarily operative in the pathogenesis of glucocorticoid-induced osteoporosis. The management of patients exposed to glucocorticoids includes general health measures, sufficient calcium and vitamin D, and reducing the therapeutic regimen to the minimal effective dose. The gold standard in the pharmacological treatment of glucocorticoid-induced osteoporosis in postmenopausal women involves the use of bisphosphonates, which should be started soon after beginning chronic glucocorticoid therapy. Anabolic and alternative therapeutic strategies are currently under investigation in glucocorticoid-induced osteoporosis.

Advancing age and insulin resistance: role of plasma tumor necrosis factor-α

In 70 healthy subjects with a large age range, the relationships between plasma tumor necrosis factor-alpha (TNF-alpha) and body composition, insulin action, and substrate oxidation were investigated. In the cross-sectional study (n = 70), advancing age correlated with plasma TNF-alpha concentration (r = 0.64, P < 0.001) and whole body glucose disposal (WBGD; r= -0.38, P < 0.01). The correlation between plasma TNF-alpha and age was independent of sex and body fat (BF; r = 0.31, P < 0.01). Independent of age and sex, a significant relationship between plasma TNF-alpha and leptin concentration (r = 0.29, P < 0.02) was also found. After control for age, sex, BF, and waist-to-hip ratio (WHR), plasma TNF-alpha was still correlated with WBGD (r = -0.33, P < 0.007). Further correction for plasma free fatty acid (FFA) concentration made the latter correlation no more significant. In a multivariate analysis, a model made by age, sex, BF, fat- free mass, WHR, and plasma TNF-alpha concentrations explained 69% of WBGD variability with age (P < 0.009), BF (P < 0.006), fat-free mass (P < 0.005), and plasma TNF-alpha (P < 0.05) significantly and independently associated with WBGD. In the longitudinal study, made with subjects at the highest tertiles of plasma TNF-alpha concentration (n = 50), plasma TNF-alpha concentration predicted a decline in WBGD independent of age, sex, BF, WHR [relative risk (RR) = 2.0; 95% confidence intervals (CI) = 1.2-2.4]. After further adjustment for plasma fasting FFA concentration, the predictive role of fasting plasma TNF-alpha concentration on WBGD (RR = 1.2; CI = 0.8-1.5) was no more significant. In conclusion, our study demonstrates that plasma TNF-alpha concentration is significantly associated with advancing age and that it predicts the impairment in insulin action with advancing age.

Drug-induced Osteoporosis: Mechanisms and Clinical Implications

Drug-induced osteoporosis is common and has a significant impact on the prognosis of patients suffering from chronic debilitating diseases. Glucocorticoids are the drugs causing osteoporotic fractures most frequently, but osteoporosis with fractures is observed also in women treated with aromatase inhibitors for breast cancer, in men receiving anti-androgen therapy for prostate cancer, in postmenopausal women treated with high doses of thyroxine, and in men and women treated with thiazolinediones for type 2 diabetes mellitus. Bone loss with fractures also occurs in patients treated with drugs targeting the immune system, such as calcineurin inhibitors, antiretroviral drugs, selective inhibitors of serotonin reuptake, anticonvulsants, loop diuretics, heparin, oral anticoagulants, and proton pump inhibitors.

Effects of Somatostatin Analogs on Glucose Homeostasis: A Metaanalysis of Acromegaly Studies

BACKGROUND Somatostatin analogs (SSA) may influence glucose metabolism, but the clinical relevance of this effect is uncertain because trials performed so far are limited in terms of number of patients and heterogeneity for length and type of follow-up. PURPOSE The purpose of the study was to assess, via the metaanalysis of acromegaly studies, the clinical impact of SSA on glucose metabolism. The outcomes analyzed were fasting plasma glucose, fasting plasma insulin, hemoglobin A(1c), and plasma glucose concentrations during oral glucose tolerance test. STUDY SELECTION Eligibility criteria were: 1) duration of SSA treatment of at least 3 wk; 2) available numerical data for at least one of the four biochemical outcomes investigated; 3) measurement of the outcomes before and after SSA treatment; and 4) no selection of acromegalic patients for their responsivity to SSA. After revision, only 31 studies fulfilled eligibility criteria and were therefore selected for data extraction and analysis. DATA SYNTHESIS SSA treatment was found to induce statistically significant decrease in fasting plasma insulin [effect size -0.45, 95% confidence interval (CI) from -0.58 to -0.32, P < 0.001], without any significant change of fasting plasma glucose (effect size +0.04, 95% CI from -0.07 to +0.15, P = 0.52) and hemoglobin A(1c) (effect size +0.11, 95% CI from -0.02 to +0.23, P = 0.09). Serum glucose values during the oral glucose tolerance test were shown to significantly change during SSA treatment (effect size +0.31, 95% CI from +0.17 to +0.45, P < 0.001), although with high inconsistency among trials. CONCLUSIONS Our data suggest that modifications of glucose homeostasis induced by SSA may have an overall minor clinical impact in acromegaly.

Long‐term effects of lanreotide SR and octreotide LAR® on tumour shrinkage and GH hypersecretion in patients with previously untreated acromegaly

background and objective The therapeutic efficacy of lanreotide SR and octreotide LAR® has been studied widely in patients treated previously with neurosurgery and/or radiotherapy. These therapies limit the evaluation of the long‐term effects of somatostatin analogues on tumour shrinkage. Neurosurgical and radiotherapy treatments cause irreversible anatomical changes in pituitary morphology, which can make accurate evaluation of tumour shrinkage difficult. The aim of this study was to investigate the therapeutic efficacy of lanreotide SR and octreotide LAR® in previously untreated patients with acromegaly. We aimed to investigate the long‐term effects of these drugs on tumour shrinkage and growth hormone (GH) hypersecretion without the confounding influences of previous therapy.

Cushing's Syndrome and Bone

Structural and functional impairment of skeletal system is a relevant cause of morbidity and disability in patients with Cushings syndrome (CS). Approximately 30–50% of patients with CS experience fractures (particularly at the spinal level) consistent with the 50% incidence of osteoporosis. Growth failure, pubertal arrest are the hallmarks of CS in children and growing adolescents leading to reduced final adult height and peak bone mass. The decrease in osteoblast number and function, through different mechanisms, seems to play a central role in the bone loss in CS. Patients with CS have decreased serum levels of osteocalcin and alkaline phosphatase. Considering the preferential bone loss in the cancellous skeleton it is reasonable to measure BMD, possibly with Dual X-rays absorptiometry (DEXA) at lumbar spine, in all patients with CS.Patients cured from CS have increased prevalence of spine damage: therefore, a radiological follow-up of the skeleton should be included in the management of patients with CS not only during the active phase but also after cure.Glucocorticoid-induced osteoporosis is reversible. The recovery of bone loss in CS is slow, taking approximately ten years to become complete. In the meanwhile, patients with severe osteopenia are exposed to a high risk of fracture. Alendronate may induce a more rapid improvement in BMD than cortisol normalization alone and it could be useful in patients with persistent postsurgical hypercortisolism to prevent further bone loss. The decision to discontinue antiresorptive therapy should be based on clinical monitoring and DEXA measurements.

New understanding and treatments for osteoporosis.

To summarize promising areas of investigation in osteoporosis and to stimulate further research in this area, as discussed in a recent international conference. Over the recent years, there has been an improvement in the knowledge of molecular pathways involved in bone formation and resorption with the development of new drugs to treat osteoporosis. Intact parathyroid hormone, teriparatide, and anti-sclerostin monoclonal antibody are anabolic drugs, whereas denosumab and odanacatib are anti-resorptive drugs with more reversible effects as compared to bisphosphonates. Anabolic and anti-resorptive agents have different effects on bone, and research in this area includes the efficacy of combination and sequential therapies with them. New insights in the molecular pathways of bone remodeling have clarified the mechanisms responsible for skeletal fragility in several forms of secondary osteoporosis, such as that occurring in type 2 diabetes, following drug exposure and systemic inflammatory diseases. Future research is needed to address the efficacy of anti-osteoporotic drugs in these more recently recognized conditions of skeletal fragility. Osteoporosis continues to be an important field of biomedical research.

Increased prevalence of radiological spinal deformities in adult patients with GH deficiency: influence of GH replacement therapy.

This cross‐sectional study shows that a high number of untreated adult patients with GHD develop radiological vertebral deformities. Patients undergoing GH replacement treatment showed a significantly lower prevalence of vertebral deformities versus treated patients in the presence of similar BMD, as assessed by DXA.