Obesity and bone metabolism.

The interaction between obesity and bone metabolism is complex. The effects of fat on the skeleton are mediated by both mechanical and biochemical factors. Though obesity is characterized by higher bone mineral density, studies conducted on bone microarchitecture have produced conflicting results. The majority of studies indicate that obesity has a positive effect on skeletal strength, even though most likely the effects are site-dependent and, in fact, obese individuals might be at risk of certain types of fractures. Mechanical loading and higher lean mass are associated with improved outcomes, whereas systemic inflammation, observed especially with abdominal obesity, may exert negative effects. Weight loss interventions likely lead to bone loss over time. Pharmacological treatment options seem to be safe in terms of skeletal health; however, the skeletal effects of bariatric surgery are dependent on the type of surgical procedure. Malabsorptive procedures are associated with higher short-term adverse effects on bone health. In this narrative review, we discuss the effects of obesity and weight loss interventions on skeletal health.

Treatment of osteoporosis: whom, how and for how long?

Identification of patients at risk for fragility fractures is the first important step in the management of osteoporosis. Bisphosphonates have been the mainstay of treatment for decades, whereas denosumab and selective oestrogen receptor modulators are other available licensed antiresorptive drugs. Currently teriparatide is the only approved anabolic agent in Europe, while abaloparatide and romosozumab are awaiting approval and might be available in the near future. For bisphosphonates, current guidance suggests an initial treatment course of 3-5 years and more prolonged treatment should be pursued in patients with higher fracture risk. For patients with lower risk, a period off treatment might be considered after this initial course to minimize the risks associated with more prolonged treatment, but this only applies to bisphosphonates and not denosumab or teriparatide. This review discusses strategies for case finding of patients at risk, currently available treatment options, recent developments in pharmacological management and duration of treatment.

Osteogenesis imperfecta - A clinical update.

Osteogenesis imperfecta (OI) is the most common inherited form of bone fragility and includes a heterogenous group of genetic disorders which most commonly result from defects associated with type 1 collagen. 85%-90% of cases are inherited in an autosomal dominant manner and are caused by mutations in the COL1A1 and COL1A2 genes, leading to quantitative or qualitative defects in type 1 collagen. In the last decade, defects in several other proteins involved in the normal processing of type 1 collagen have been described. Recent advances in genetics have called for reconsideration of the classification of OI, however, most recent classifications align with the classic clinical classification by Sillence. The hallmark of the disease is bone fragility but other tissues are also affected. Intravenous bisphosphonates (BPs) are the most widely used intervention, having significant favorable effects regarding areal bone mineral density (BMD) and vertebral reshaping following fractures in growing children. BPs have a modest effect in long bone fracture incidence, their effects in adults with OI concerns only BMD, while there are reports of subtrochanteric fractures resembling atypical femoral fractures. Other therapies showing promising results include denosumab, teriparatide, sclerostin inhibition, combination therapy with antiresorptive and anabolic drugs and TGF-ß inhibition. Gene targeting approaches are under evaluation. More research is needed to delineate the best therapeutic approach in this heterogeneous disease.

Type 2 Diabetes and Osteoporosis: A Guide to Optimal Management.

Context: Both type 2 diabetes (T2D) and osteoporosis are affected by aging and quite often coexist. Furthermore, the fracture risk in patients with T2D is increased. The aim of this article is to review updated information on osteoporosis and fracture risk in patients with T2D, to discuss the effects of diabetes treatment on bone metabolism, as well as the effect of antiosteoporotic medications on the incidence and control of T2D, and to provide a personalized guide to the optimal management. Evidence Acquisition: A systematic literature search for human studies was conducted in three electronic databases (PubMed, Cochrane, and EMBASE) until March 2017. Regarding recommendations, we adopted the grading system introduced by the American College of Physicians. Evidence Synthesis: The results are presented in systematic tables. Healthy diet and physical exercise are very important for the prevention and treatment of both entities. Metformin, sulfonylureas, dipeptidyl peptidase-4 inhibitors, and glucagon-like peptide-1 receptor agonists should be preferred for the treatment of T2D in these patients, whereas strict targets should be avoided for the fear of hypoglycemia, falls, and fractures. Insulin should be used with caution and with careful measures to avoid hypoglycemia. Thiazolidinediones and canagliflozin should be avoided, whereas other sodium-dependent glucose transporter 2 inhibitors are less well-validated options. Insulin therapy is the preferred method for achieving glycemic control in hospitalized patients with T2D and fractures. The treatment and monitoring of osteoporosis should be continued without important amendments because of the presence of T2D. Conclusions: Patients with coexisting T2D and osteoporosis should be managed in an optimal way according to scientific evidence.

Investigational anabolic agents for the treatment of osteoporosis: an update on recent developments.

INTRODUCTION: Teriparatide, a PTH analogue, was the first anabolic agent to be approved for the treatment of osteoporosis in 2002. Abaloparatide was also recently approved by the FDA. The need for other anabolic agents is still unmet. Areas covered: In this review, we discuss target molecules and recent advances in the field of anabolic therapy for osteoporosis. PTH and PTHrP analogues binding to the PTH receptor and different routes of administration of teriparatide to avoid the burden of daily subcutaneous injections are discussed. We also review antibodies targeting suppressors of the Wnt pathway such as sclerostin and Dickopff-1. Expert opinion: The development of alternative ways of administering PTH receptor ligands is a promising field, especially via the transdermal route. Other more promising molecules are still at very early stages of development. FDA recently requested more data on Romosozumab.

Adrenal malignant melanoma masquerading as a pheochromocytoma in a patient with a history of a multifocal papillary and medullary thyroid carcinoma.

OBJECTIVE: Adrenal masses usually represent benign and nonfunctional adrenal adenomas; however, primary or metastatic malignancy should also be considered. Discovery of an adrenal mass needs further evaluation in order to exclude malignancy and hormonal secretion. We present a rare case of a possibly primary adrenal malignant melanoma with imaging and biochemical features of a pheochromocytoma. CASE REPORT: A 61-year-old male farmer was referred for evaluation of a mass in the right supraclavicular region and a left adrenal lesion. The patient had a history of a multifocal papillary and medullary thyroid carcinoma. Laboratory tests revealed increased 24hour urinary dopamine and also increased serum calcitonin and neuron specific enolase. A pathology report of the resected right supraclavicular mass and left adrenal showed a malignant melanoma. CONCLUSION: This is a case of a possibly primary adrenal malignant melanoma with imaging and biochemical features of a pheochromocytoma. Although this case is very rare and there are rigid diagnostic criteria for the diagnosis of primary adrenal melanoma, it underlines the fact that the differential diagnosis of a dopamine secreting adrenal mass should include primary or metastatic malignant melanoma in order to determine the best diagnostic approach for the patient and select the most appropriate surgical management.

Effects of teriparatide retreatment in a patient with ß-thalassemia major.

BACKGROUND: Bone disease is a frequent complication of ß-thalassemia major (ß-ΤΜ) and its etiology is multifactorial. Marrow expansion, chronic hypoxia, endocrine complications, and iron overload caused chiefly by chronic transfusion treatment are significant factors affecting skeletal health. Bone disease is prevalent even among patients on regular transfusions and adequate iron chelation. The life expectancy of patients with ß-thalassemia has increased during the past decade and so, nowadays, patients with thalassemia-associated bone disease (TBD) often require long-term management. There are limited data concerning their pharmacologic treatment. Bisphosphonates represent the most widely studied agents in such patients and there are no published studies about the effects of anabolic treatment. Retreatment with teriparatide has only occasionally been studied in patients with osteoporosis. CASE REPORT: We present a male adult patient with ß-ΤΜ with a history of low bone mass and multiple vertebral fractures, who required sequential treatment for his longstanding bone disease. He had exhibited considerable, albeit delayed, response to a course of teriparatide treatment for 18 months but subsequently, and while on alendronate, sustained an insufficiency fracture at the left ischiopubic ramus. A second trial of teriparatide treatment resulted in further remarkable increase in total hip and femoral neck bone mineral density. We present the patient's response to sequential treatment during an 8-year follow-up. CONCLUSION: Teriparatide could represent an alternative treatment for adults with TBD especially when long-term, sequential treatment is needed. Although there are limited data concerning retreatment, in selected cases, this might be considered.

Type 2 diabetes mellitus and fracture risk.

Increased fracture risk, traditionally associated with type 1 diabetes, has lately been of great concern in patients with type 2 diabetes. A variable increase in fracture risk has been reported, ranging from 20% to 3-fold, depending on skeletal site, diabetes duration and study design. Longer disease duration, the presence of diabetic complications, inadequate glycemic control, insulin use and increased risk for falls are all reported to increase fracture risk. Patients with type 2 diabetes display a unique skeletal phenotype with either normal or more frequently increased, bone mineral density and impaired structural and geometric properties. Recently, alterations in bone material properties seem to be the predominant defect leading to increased bone fragility. Accumulation of advanced glycation end-products and changes in collagen cross-linking along with suppression of bone turnover seem to be significant factors impairing bone strength. FRAX score has been reported to underestimate fracture risk and lumbar spine BMD is inadequate in predicting vertebral fractures. Anti-diabetic medications, apart from thiazolidinediones, appear to be safe for the skeleton, although more data are needed. Optimal strategies to reduce skeletal fragility in type 2 diabetic patients are yet to be determined.

Bone disease in anorexia nervosa.

Anorexia nervosa is a serious psychiatric disorder accompanied by high morbidity and mortality. It is characterized by emaciation due to self-starvation and displays a unique hormonal profile. Alterations in gonadal axis, growth hormone resistance with low insulin-like growth factor I levels, hypercortisolemia and low triiodothyronine levels are almost universally present and constitute an adaptive response to malnutrition. Bone metabolism is likewise affected resulting in low bone mineral density, reduced bone accrual and increased fracture risk. Skeletal deficits often persist even after recovery from the disease with serious implications for future skeletal health. The pathogenetic mechanisms underlying bone disease are quite complicated and treatment is a particularly challenging task.