Context: Denosumab discontinuation is characterized by an increase in bone turnover overriding pretreatment status, a rapid bone loss in the majority and multiple vertebral fractures (VFx) in some patients. Methods: A working group of the European Calcified Tissue Society performed an updated systematic review of existing literature on changes of bone turnover, bone mineral density (BMD), and fracture risk after denosumab discontinuation and provided advice on management based on expert opinion. Results: Important risk factors for multiple VFx following denosumab cessation are prevalent VFx, longer duration off therapy, greater gain in hip BMD during therapy, and greater loss of hip BMD after therapy according to a retrospective analysis of the FREEDOM Extension Study. Case series indicate that prior bisphosphonate therapy mitigates the biochemical rebound phenomenon after denosumab discontinuation, but it is uncertain whether this attenuation prevents BMD loss and fractures. Current evidence indicates partial efficacy of subsequent antiresorptive treatment with results seemingly dependent on duration of denosumab treatment. Conclusions: A careful assessment of indications to start denosumab treatment is advised, especially for younger patients. A case for long-term treatment with denosumab can be made for patients at high fracture risk already on denosumab treatment given the favorable efficacy and safety profile. In case of denosumab discontinuation, alternative antiresorptive treatment should be initiated 6 months after the final denosumab injection. Assessment of bone turnover markers may help define the optimal regimen, pending results of ongoing randomized controlled trials. Patients who have sustained VFx should be offered prompt treatment to reduce high bone turnover.

Context: Consensus regarding diagnosis and management of osteoporosis in premenopausal women (PW) is still lacking due to few studies carried out in this population. Design: The European Calcified Tissue Society and the International Osteoporosis Foundation convened a working group to produce an updated review of literature published after 2017 on this topic. Results: Fragility fractures in PW are rare and mostly due to secondary osteoporosis (ie, in presence of an underlying disease such as hormonal, inflammatory, or digestive disorders). In absence of another disorder, low bone mineral density (BMD) together with fragility fractures qualifies as idiopathic osteoporosis. In contrast, low BMD alone does not necessarily represent osteoporosis in absence of bone microarchitectural abnormalities. BMD increases in PW with osteoporosis when the underlying disease is treated. For example, in celiac disease, an increase of 9% in radius trabecular volumetric density was achieved after 1 year of gluten-free diet, while anti-tumor necrosis factor alpha improved BMD in PW with inflammatory bowel diseases. In amenorrhea, including anorexia nervosa, appropriately delivered estrogen replacement therapy can also improve BMD. Alternatively, antiresorptive or anabolic therapy has been shown to improve BMD in a variety of conditions, the range of improvement (3%-16%) depending on skeletal site and the nature of the secondary cause. No studies were powered to demonstrate fracture reduction. The effects of bisphosphonates in childbearing women have been scantly studied and caution is needed. Conclusion: The majority of PW with osteoporosis have an underlying disease. Specific therapy of these diseases, as well as antiresorptive and anabolic drugs, improve BMD, but without evidence of fracture reduction.

Osteoporosis is characterized by reduced bone mass and disruption of bone architecture, resulting in increased risk of fragility fractures and significant long-term disability. Although both anti-resorptive treatments and osteoanabolic drugs, such as parathyroid hormone analogues, are effective in fracture prevention, limitations exist due to lack of compliance or contraindications to these drugs. Thus, there is a need for novel potent therapies, especially for patients at high fracture risk. Romosozumab is a monoclonal antibody against sclerostin with a dual mode of action. It enhances bone formation and simultaneously suppresses bone resorption, resulting in a large anabolic window. In this opinion-based narrative review, we highlight the role of sclerostin as a critical regulator of bone mass and present human diseases of sclerostin deficiency as well as preclinical models of genetically modified sclerostin expression, which led to the development of anti-sclerostin antibodies. We review clinical studies of romosozumab in terms of bone mass accrual and anti-fracture activity in the setting of postmenopausal and male osteoporosis, present sequential treatment regimens, and discuss its safety profile and possible limitations in its use. Moreover, an outlook comprising future translational applications of anti-sclerostin antibodies in diseases other than osteoporosis is given, highlighting the clinical significance and future scopes of Wnt signaling in these settings.

Osteocytes, the most abundant bone cell in the adult skeleton, can function as mechanosensors directing osteoblast and osteoclast function in order to maintain optimal load bearing bone in addition to functioning as endocrine cells regulating phosphate metabolism. A controversial function, previously overlooked or denied, has been osteocytes as regulators of calcium metabolism. Early histologists upon observing enlarged osteocyte lacunae in bone sections proposed that mature osteocytes could remove their perilacunar matrix, a term called "osteocytic osteolysis". New insights into this process have occurred during the last decade using novel technology thereby providing a means to identify molecular mechanisms responsible for osteocytic osteolysis. As release of calcium from a mineralized matrix requires a more acidic pH and specialized enzymes, it was proposed that osteocytes may utilize similar molecular mechanisms as osteoclasts to remove mineral. The idea that a cell descended from mesenchymal progenitors (the osteocyte) could function similarly to a cell descended from hematopoietic progenitors (the osteoclast) was challenged as being improbable. Here we review the molecular mechanisms behind this osteocyte function, the role of osteocytic osteolysis in health and disease, and the capacity of the osteocyte to reverse the osteolytic process by replacing the removed matrix, a revived osteoblast function.