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.

Background: Circulating microRNAs (miRs) are currently being investigated as novel biomarkers for osteoporosis and osteoporotic fractures. Aim: The aim of this study was to investigate serum levels of specific microRNAs, known regulators of bone metabolism, in postmenopausal women with low bone mass and with or without vertebral fractures (VFs). Methods: For the analysis, 14 miRs were isolated from the serum of 35 postmenopausal women with low bone mass and with at least one moderate VF and 35 postmenopausal women with low bone mass without fractures. Thirty postmenopausal women with normal BMD values and no history of fractures served as controls. Main outcome parameters were changes in the expression of selected miRs in the serum of patient population and compared with controls. Results: From the 14 miRs that were selected, we identified 5 miRs, namely miR-21-5p, miR-23a, miR-29a-3p, miR-124-3p and miR-2861 that were significantly deregulated in the serum of patients with low bone mass compared with controls. Serum miR-124 and miR-2861 were significantly higher, whereas miR-21, miR-23 and miR-29 were lower in patients compared with controls. In a sub-group analysis of the patient population, the expression of miR-21-5p was significantly lower among osteoporotic/osteopenic women with VFs, showing 66% sensitivity and 77% specificity in distinguishing women with a vertebral fracture. Conclusion: This study identifies a differential expression pattern of miR-21-5p in the serum of women with low BMD and VFs.

Hypophosphatasia (HPP) is an inherited metabolic disease caused by loss-of-function mutations in the tissue non-specific alkaline phosphatase (TNAP) gene. Reduced activity of TNAP leads to the accumulation of its substrates, mainly inorganic pyrophosphate and pyridoxal-5′-phosphate, metabolic aberrations that largely explain the musculoskeletal and systemic features of the disease. More than 400 ALPL mutations, mostly missense, are reported to date, transmitted by either autosomal dominant or recessive mode. Severe disease is rare, with incidence ranging from 1:100,000 to 1:300,000 live births, while the estimated prevalence of the less severe adult form is estimated to be between 1:3100 to 1:508, in different countries in Europe. Presentation largely varies, ranging from death in utero to asymptomatic adults. In infants and children, clinical features include skeletal, respiratory and neurologic complications, while recurrent, poorly healing fractures, muscle weakness and arthropathy are common in adults. Persistently low serum alkaline phosphatase is the cardinal biochemical feature of the disease. Management requires a dedicated multidisciplinary team. In mild cases, treatment is usually symptomatic. Severe cases, with life-threating or debilitating complications, can be successfully treated with enzyme replacement therapy with asfotase alfa.

Context Expression of microRNAs (miRs) related to bone metabolism in the serum maybe affected by anti-osteoporotic treatment. Objective To investigate the effect of two anti-osteoporotic agents with opposite effects on bone metabolism on microRNA expression profile in the serum. Design Observational, open label, non-randomized clinical trial. Setting The outpatient clinics for Metabolic Bone Diseases of 424 General Military Hospital, Thessaloniki, Greece. Patients and Interventions Postmenopausal women with low bone mass were treated with either teriparatide (n=30) or denosumab (n=30) for 12 months. Main outcome measures Changes in the serum expression of selected miRs linked to bone metabolism at 3 and 12 months of treatment. Secondary measurements: associations of measured miRs with changes in bone mineral density (BMD) at 12 months and the bone turnover markers (BTM) C-terminal telopeptide of type I collagen (β-CTX) and procollagen type I N-terminal propeptide (P1NP) at 3 and 12 months. Results We found significantly decreased therelative expression of miR-33-3p at 3 months (p=0.03) and of miR-133a at 12 months (p=0.042) of teriparatide treatment. BMD values at 12 months of teriparatide treatment were significantly and inversely correlated with miR-124-3p expression at 3 months (p=0.008). Relative expression of miR-24-3p and miR-27a was correlated with changes in BTM during teriparatide treatment and of miR-21-5p, miR-23a-3p, miR-26a-5p, miR-27a, miR-222-5p and miR-335-5p with changes in BTM during denosumab treatment. Conclusions Circulating miRs are differentially affected by treatment with teriparatide and denosumab. Teriparatide affects the relative expression of mirRs related to the expression of RUNX-2 (miR-33) and DKK-1 gene (miR-133).

Non-functioning pituitary adenomas, recently alternatively termed pituitary neuroendocrine tumours (NFpitNETs), are mostly benign neoplasms that are not associated with a hormonal hypersecretory syndrome. The clinical spectrum of NFpitNETs varies from completely asymptomatic to the development of panhypopituitarism and manifestations attributed to mass effects on nearby structures. NFpitNETs follow generally an indolent course, but in 5–10% of cases they exhibit more aggressive behaviour, characterised by rapid growth, invasiveness and early recurrence. The initial size of the adenoma, the presence of symptoms and the histological subtype are related to the natural course of NFpitNETs. Active surveillance is usually the strategy of choice in the case of an asymptomatic NFpitNET, while surgical resection is recommended in case of visual and/or neurological abnormalities or rapid tumour growth. Based on previous and emerging data, approximately 50% of patients show tumour growth, while 20% of patients with NF-macroadenomas on active surveillance may require further intervention during a follow-up period of 7 years. Adjuvant radiotherapy is usually considered for large residual tumours or recurrent and/or aggressive adenomas, but there is evidence that medical therapy, especially with cabergoline, can occasionally be beneficial, whereas newer molecular agents are under investigation. Thus, while highly effective medical therapy is awaited, a move towards a more conservative approach seems appropriate, at least until we have better molecular markers of progressiveness.