Denosumab is a potent antiresorptive agent that substantially increases bone mineral density and reduces fracture rates at all skeletal sites for as long as it is administered. However, its favorable skeletal effects reverse quickly upon its discontinuation, because of a vast increase of osteoclast number and activity, which leads to a subsequent profound increase of bone turnover above pre-treatment values, a phenomenon commonly described as “rebound phenomenon”. More importantly, most patients experience rapid, profound bone loss due to this burst of bone resorption that may lead in a minority of these patients to occurrence of fractures, especially multiple vertebral fractures. Therefore, subsequent antiresorptive treatment is mandatory, although the optimal regimen is yet to be clarified. In the present review, we outline what is currently known regarding the negative effects of denosumab discontinuation on different aspects of bone status, the factors that may affect them, and strategies to prevent them.

Context: No defined pre-treatment factors are able to predict the response to radiofrequency ablation (RFA) of an autonomously functioning thyroid nodule (AFTN). Objective: Primary endpoint was to evaluate the success rate of RFA to restore euthyroidism in a cohort of adult patients with small solitary AFTN compared with medium-sized nodules. Secondary endpoints included nodule volume reduction and rate of conversion from hot nodules to cold using scintiscan. Methods: This was a 24-month prospective monocentric open parallel-group trial. Twenty-nine patients with AFTN were divided into two groups based on thyroid volume: 15 patients with small nodules (12 mL) in group B. All patients underwent a single session of RFA and were clinically, biochemically, and morphologically evaluated at baseline and at 1, 6, 12 and 24 months after treatment. Results: After RFA, there was greater nodule volume reduction in group A compared with group B (p < 0.001 for each follow-up point). In group A, there was a greater increase in TSH levels than in group B at 6 (p = 0.01), 12 (p = 0.005), and 24 months (p < 0.001). At 24 months, the rate of responders was greater in group A than in group B (86 vs. 45%; p < 0.001). In group A, 86% of nodules converted from hot to cold compared with 18% in group B (p < 0.001). Conclusions: A single session of RFA was effective in restoring euthyroidism in patients with small AFTNs. Nodule volume seems to be a significant predictive factor of the efficacy of RFA in treating AFTN.

Context: The clinical and radiological aspects of normocalcemic hyperparathyroidism (NHPT) are confounded by the differing methods used to rule out secondary hyperparathyroidism and by the small sample size. Objective: To assess the clinical, biochemical, and radiological profile of NHPT compared with primary hyperparathyroidism (PHPT) and control subjects Design: Multicentric cross-sectional study Setting: Outpatient clinic Patients: 47 NHPT, 41 PHPT, and 39 age- and sex-matched control subjects. Main Outcome Measures: Calcium metabolism and bone turnover markers (BTMs). Lumbar spine, total hip, femoral neck, one-third distal radius bone mineral density (BMD). Morphometric vertebral fracture (VF) assessed by dual-energy X-ray absorptiometry. Results: NHPT patients had significantly higher parathyroid hormone, 25(OH)-vitamin D levels and lower calcium × phosphorus product than controls (P < .001). Compared with PHPT, the NHPT group had significantly higher 25(OH) vitamin D levels (P = .016). NHPT had BTM levels similar to controls and PHPT. NHPT, PHPT, and controls have similar lumbar spine and femoral neck BMD. NHPT and controls had a similar radial BMD, while patients with PHPT had a lower radial BMD than both patients with NHPT (P = .031) and controls (P < .05). Using the control group as the reference, after adjustment for interacting factors, there was no increase in risk of moderate–severe VF in NHPT (odds ratio [OR] 1.04, 95% confidence interval [CI] 0.25-4.55), while PHPT had an increased risk (OR 3.81,95% CI 1.15-15.12). Seventy-nine percent of NHPT and 59% of PHPT patients fulfilled the criteria for asymptomatic hyperparathyroidism. Conclusions: The biochemical phenotype of NHPT is intermediate between PHPT and controls. In contrast, the bone phenotype resembles controls with normal bone turnover, no significant BMD impairment, and no increased risk of VF.

Context Irisin is a hormone like-molecule that is cleaved and secreted by an unknown protease from fibronectin type III domain-containing protein 5 (FNDC5) and it ameliorates bone status, muscle atrophy and influences energy homeostasis. PTH exerts several metabolic effects that may interact with irisin’s ones. Objectives To test the hypothesis that irisin and PTH mutually affect their biological action, we evaluated the FNDC5 mRNA and protein expression in myotubes treated with PTH (1-34) and PTH-r mRNA expression in osteoblasts treated with rec-irisin. To confirm the in vivo impact of PTH on irisin, we evaluated irisin serum concentration in post-menopausal women with primary hyperparathyroidism (PHPT) compared to control subjects. Design and intervention C2C12 myotubes were treated with short-term and continuous 10^-10M teriparatide and MC3T3-E1 osteoblasts with 100 ng/ml r-Irisin for 8 hours. In a cross-sectional, open-label trial, we enrolled 26 PHPT post-menopausal women and 31 age/BMI-matched control subjects without impairment of calcium/phosphate metabolism. Results Teriparatide treatment on myotubes significantly down-regulated FNDC5 expression by acting through its own receptor, which in turn activates Erk1/2 phosphorylation. r-Irisin led to a 50% down regulation of PTH-r mRNA expression compared to untreated cell (p<0.001). Irisin was significantly lower in PHPT group compared to age/BMI-matched controls (4.5±1.1 vs 12±5.2 µg/mL, p<0.001). No significant correlation between Irisin and BMD or PTH was recorded in PHPT group. Conclusion pre-clinical findings suggest the existence of interplay between PTH and irisin metabolism that seems to be confirmed by the significant reduction of irisin concentration in post-menopausal women with PHPT.

Hypovitaminosis D is becoming a notable health problem worldwide. A consensus exists among several different medical societies as to the need for adequate levels of vitamin D for bone and general health. The correct method by which to restore normal vitamin D levels is still a matter of debate. Although cholecalciferol remains the most commonly distributed form of vitamin D supplementation worldwide, several drugs with vitamin D activity are available for clinical use, and making the correct selection for the individual patient may be challenging. In this narrative review, we aim to contribute to the current knowledge base on the possible and appropriate use of calcifediol—the 25-alpha-hydroxylated metabolite—in relation to its chemical characteristics, its biological properties, and its pathophysiological aspects. Furthermore, we examine the trials that have aimed to evaluate the effect of calcifediol on the restoration of normal vitamin D levels. Calcifediol is more soluble than cholecalciferol in organic solvents, due to its high polarity. Good intestinal absorption and high affinity for the vitamin-D-binding protein positively affect the bioavailability of calcifediol compared with cholecalciferol. In particular, orally administered calcifediol shows a much shorter half-life than oral cholecalciferol. Most findings suggest that oral calcifediol is about three- to five-fold more powerful than oral cholecalciferol, and that it has a higher rate of intestinal absorption. Accordingly, calcifediol can be particularly useful in treating diseases associated with decreased intestinal absorption, as well as obesity (given its lower trapping in the adipose tissue) and potentially neurological diseases treated with drugs that interfere with the hepatic cytochrome P-450 enzyme system, resulting in decreased synthesis of calcifediol. Up to now, there has not been enough clinical evidence for its use in the context of osteoporosis treatment.