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Since the identification of osteoporosis as a major health issue in aging populations and the subsequent development of the first treatment modalities for its management, considerable progress has been made in our understanding of the mechanisms controlling bone turnover and disease pathophysiology, thus enabling the pinpointing of new targets for intervention. This progress, along with advances in biotechnology, has rendered possible the development of ever more sophisticated treatments employing novel mechanisms of action. Denosumab, a monoclonal antibody against RANKL, approved for the treatment of postmenopausal and male osteoporosis, significantly and continuously increases bone mineral density (BMD) and maintains a low risk of vertebral, non-vertebral, and hip fractures for up to 8 years. Currently available combinations of estrogens with selective estrogen receptor modulators moderately increase BMD without causing the extra-skeletal adverse effects of each compound alone. The cathepsin K inhibitor odanacatib has recently been shown to decrease vertebral, non-vertebral, and hip fracture rates and is nearing approval. Romosozumab, an anti-sclerosin antibody, and abaloparatide, a PTH-related peptide analog, are at present in advanced stages of clinical evaluation, so far demonstrating efficaciousness together with a favorable safety profile. Several other agents are currently in earlier clinical and preclinical phases of development, including dickkopf-1 antagonists, activin A antagonists, β-arrestin analogs, calcilytics, and Src tyrosine kinase inhibitors., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Context: The myokine irisin may increase energy expenditure and affect metabolism., Objective: The objective of the study was to elucidate predictors of irisin and study whether circulating irisin may have day-night rhythm in humans., Design: This was an observational, cross-sectional study with an additional 24-hour prospective observational arm (day-night rhythm substudy) and two prospective interventional arms (mixed meal substudy and exercise substudy)., Setting: The study was conducted at the Hellenic Military School of Medicine (Thessaloniki, Greece)., Patients and Interventions: One hundred twenty-two healthy, young individuals were subjected to anthropometric and body composition measurements, and their eating and exercise behavior profiles were assessed with validated questionnaires. Subgroups were subjected to day-night rhythm, standardized meal ingestion, and 30-minute aerobic exercise studies., Main Outcome Measures: Circulating irisin levels were measured., Results: Ιrisin levels were lower in males than females (P = .02) after adjustment for lean body mass, which was its major determinant. Irisin levels followed a day-night rhythm (P < .001) with peak at 9:00 pm. Irisin levels were increased at the end of exercise (84.1 ± 10.0 vs 105.8 ± 14.3 ng/mL; P < .001). Irisin levels were not affected by intake of a standardized meal and were not associated with caloric intake or diet quality., Conclusions: In healthy, young individuals, circulating irisin displays a day-night rhythm, is correlated with lean body mass, and increases acutely after exercise.

Objective: Patients treated with intravenous zoledronate frequently experience an acute phase reaction (APR) characterized by flu-like symptoms and increased levels of inflammatory cytokines. We aimed to define the role of various cytokines/adipocytokines in zoledronate-induced APR and develop a prognostic model for its prediction., Patients and Measurements: Fifty-one postmenopausal women with low bone mass were subjected to zoledronate intravenous infusion. Patients were divided into those who experienced APR (APR+) and those who did not (APR-). APR was clinically defined by body temperature and the visual analogue pain scale for musculoskeletal symptoms. White blood cell count, leucocytic subpopulations, C-reactive protein, interleukin-6, tumour necrosis factor-alpha, visfatin, resistin and leptin were measured before and 48 h following the infusion. The quantitative insulin sensitivity check index (QUICKI) and homoeostasis model of assessment - insulin resistance (HOMA-IR) were calculated to assess insulin sensitivity and resistance, respectively., Results: (APR+) patients were younger and had lower baseline visfatin and higher baseline lymphocytes and phosphate compared with APR- patients. QUICKI decreased and HOMA-IR increased in APR+ patients while remained unchanged in APR- patients. In binary logistic regression analysis, a model containing previous bisphosphonate treatment, age, body mass index, lymphocytes and visfatin, which predicted zoledronate-induced APR with 82·1% sensitivity and 73·9% specificity, was selected. In this model, lymphocytes (P = 0·010) and visfatin (P = 0·029) at baseline could independently predict APR., Conclusions: Zoledronate-induced APR is associated with serum increases of pro-inflammatory cytokines and an increase of insulin resistance. Patients with higher lymphocytes and lower visfatin levels at baseline are at higher risk for APR., (© 2012 Blackwell Publishing Ltd.)

An acute phase response (APR) is frequently observed in patients treated with intravenous (i.v.) zoledronate (ZOL). We aimed to define clinical and laboratory parameters that may predict ZOL-induced APR in women with low bone mass. Fifty-one postmenopausal women with low bone mass were given a single i.v. infusion of ZOL 5mg. APR was clinically defined by the visual analog pain scale (VAS) for the musculoskeletal symptoms and body temperature. White blood cell count (WBC), leucocyte subpopulations, C-reactive protein (CRP), parathyroid hormone (PTH), 25-hydroxyvitamin D [25(OH)D], interleukins (IL)-1b and -6, tumor necrosis factor (TNF)α and interferon (IFN)γ were measured before and 48 h following the infusion. Subsequently, patients were divided into those experiencing APR (APR+) or not (APR-). WBC, granulocytes, CRP, IL-1b and IL-6 were significantly increased, whereas lymphocytes, eosinophils, calcium, phosphate and 25(OH)D decreased 48h after ZOL infusion. Twenty-eight of the 51 patients (54.9%) experienced an APR. APR+ patients were younger and had higher baseline lymphocytes compared to APR- patients. There was no difference (p=0.405) in the development of APR between treatment-naive patients (19/32, 59.4%) and patients previously treated with another oral nitrogen-containing bisphosphonate (9/19, 47.4%). In conclusion, our data suggest that pre-treatment higher lymphocyte number increases the risk of APR while previous treatment with another nitrogen-containing bisphosphonate does not significantly reduce the risk. Serum 25(OH)D concentrations decrease significantly after the infusion, possibly as part of the inflammatory response to ZOL., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Intermittent exogenous parathyroid hormone (PTH) is a potent osteoanabolic agent used for the treatment of severe osteoporosis. Two molecules of recombinant PTH are commercially available: the full-length PTH (PTH 1-84) and teriparatide (PTH 1-34). We present the first report of PTH-induced mild, asymptomatic, normochromic normocytic anemia in a postmenopausal woman treated sequentially with PTH 1-84 and PTH 1-34. Anemia was more pronounced with PTH 1-84 compared to PTH 1-34 and was reversed with each regimen discontinuation. We suggest monitoring of hematocrit and hemoglobin in PTH-treated patients, especially when PTH 1-84 is used.

There is only limited evidence for biological parameter abnormalities in subclinical hypothyroidism. The aim of this study was to investigate the impact of varying degrees of thyroid failure on the stapedial reflex as a biological index, and establish its role in the evaluation of the hypothyroid patient. We studied 10 patients with subclinical hypothyroidism, 10 patients with clinical hypothyroidism, and 20 controls. All three parameters of stapedial reflex (amplitude, decay, and threshold) were measured before and after restoration of euthyroidism through thyroxine administration. Data are given as mean +/- SEM. Stapedial reflex maximal amplitudes were different among the groups studied (p < 0.0001), as values in subclinical (4.3 +/- 0.4 mm) and clinical (3.7 +/- 0.3 mm) groups before treatment were lower (p < 0.05) than those of control (5.7 +/- 0.3 mm), and subclinical (6.4 +/- 0.5 mm) and clinical (5.6 +/- 0.4 mm) groups after treatment. Similarly, stapedial reflex decays were different among the groups studied (p < 0.001), as values in subclinical (81 +/- 7 ms) and clinical (89 +/- 4 ms) groups before treatment were higher (p < 0.05) than those in control (65 +/- 2 ms), subclinical (56 +/- 8 ms), and clinical (61 +/- 8 mm) groups after treatment. There was no significant difference among the groups for stapedial reflex threshold or significant correlation between stapedial reflex parameters and thyroid function tests. Stapedial reflex, a biological parameter that reflects neuromuscular status, is abnormal in patients with subclinical and clinical hypothyroidism and returns to normal when clinical and biochemical euthyroidism has been achieved through thyroxine administration.