Stergios A. Polyzos

Clinical vertebral fractures following denosumab discontinuation.

Denosumab treatment has an established antifracture efficacy for osteoporosis, but there is recent concern for increased vertebral fracture risk following its discontinuation. We would like to present our clinical experience, adding two new cases of clinical vertebral fractures following denosumab discontinuation. Informed consent was obtained from both participants included in the study. A 62-year woman was presented (March 2016) after a lowenergy vertebral (L3) fracture (December 2015), which caused prolonged, severe pain. She was treatment naive, when osteoporosis complicated with a previous asymptomatic vertebral fracture (T8) was diagnosed (April 2013), and she received four denosumab injections (60mg), but no calcium and vitamin D supplementation. In April 2015, her physician discontinued denosumab after bone mineral density (BMD) improvement. The fracture occurred 14 months after the last denosumab injection. At presentation, her serum calcium (9.1 mg/dl), phosphate (3.7mg/dl) albumin (4.4 g/dl), and total alkaline phosphatase (84 U/l; range 35–104) were normal, but intact parathyroid hormone was high (102 pg/ml; range 14–88) and 25(OH)-vitamin D was low (9.7 ng/ml). No parathyroid gland was evident in neck ultrasonography. After the diagnosis of secondary hyperparathyroidism, the patient received calcium (1000mg/day) and cholecalciferol supplements (2000 U/day), and analgesics for pain relief. We aim to administer zoledronic acid soon after the vitamin D levels restoration. A 61-year woman was presented (April 2016) after two low-energy vertebral fractures (T12, L1). Osteoporosis was diagnosed soon after her menopause (51 years) and she had received strontium ranelate for 1 year and raloxifene for 5 years, since June 2012, when she started denosumab (60mg). She had received two injections of denosumab, when a second physician stopped denosumab because of BMD improvement. In December 2013 (12 months after the last denosumab injection), she experienced spontaneous, severe, prolonged lumbar pain, persistent despite analgesics. A third physician diagnosed the vertebral fractures and performed multiple tests for secondary osteoporosis, which were all negative. Subsequently, she restarted denosumab, which resulted in progressive disappearance of lumbar pain (within 2 months). She continues denosumab until today, selfreporting well-being. There are three recently published articles reporting on five women (53–59 years) previously being on denosumab for postmenopausal osteoporosis (n= 4) [1, 2] or aromatase inhibitor-induced bone loss (n= 1) [3]. The reason for denosumab discontinuation was the improvement in BMD in three cases [1, 2], patient’s decision in one case [2] and discontinuation of denosumab reimbursement in one case [3]. All women were treatment naive for osteoporosis and four of five experienced more than one (up to nine) clinical vertebral fracture within 8–16 months after denosumab discontinuation [1–3]. The fact that all reported fractures were vertebral supports the “severe rebound effect” hypothesis, which is expected to affect primarily trabecular bone [1]: denosumab result in inactivation of osteoclasts and a pool of osteoclast precursors are simultaneously activated after its discontinuation, leading to a rapid rebound in remodeling rates. Although it remains to be shown, this high turnover rate may increase the fracture risk in trabecular bone. This mechanism does not occur after bisphosphonate discontinuation, possibly because bisphosphonates remain * Stergios A. Polyzos stergios@endo.gr

Annual Seminar of Hellenic Osteoporosis Foundation Basic Knowledge of biological responses to musculoskeletal trauma

The Systemic Inflammatory Response Syndrome (SIRS) represents the generalized response of the host to a variety of significant clinical insults, such as infection and trauma. There are specific criteria in the definition, such as: a) hyperor hypothermia, b) heart rate >90/min, c) respirations >20/ minute or PaCO2 <32 mmHg and d) WBC >12,000/mm or <4,000/mm or >10% immature form, with ≥2 of these criteria being necessary. Trauma is one of the more common causes of mortality worldwide. Death is the result of a chain of events starting with the “first hit”, which includes severe organ trauma, hypovolemia, hypoxemia or head injury among others. These can lead to the activation of the immune system and the initial inflammatory immune response after trauma can lead to SIRS. If more insults follow, they become the “second hit”, which can include infection, ischemia/reperfusion or surgical operations, then the inflammatory response is augmented, together with the mortality of the patient. Musculoskeletal injury through the activation of SIRS can lead to multi-organ failure with the loss of organ systems that were not directly involved by the initial trauma. The result is the activation of various parts/subsets of the immune system, including the neuroendocrine system, and the involvement of hormones or molecules such as ACTH, catecholamines, corticosteroids, cytokines and chemokines. The goal of this presentation is to stress the fact the musculoskeletal trauma is not an isolated injury, as it can lead to the activation of a mechanism meant to protect the organism; however, if it goes “unchecked” then it can easily lead to death. endocrine And metAbolic reSPonSe to muSculoSkeletAl trAumA Panagiotis Anagnostis Unit of Reproductive Endocrinology, First Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki, Greece