Low prevalence of osteoporosis treatment in patients with recurrent major osteoporotic fracture

International audienceThe majority of patients do not receive anti-osteoporotic treatment following a major osteoporotic fracture, despite the guidelines and the availability of effective anti-osteoporotic treatments. The fight against factors limiting the diagnosis and treatment of osteoporosis should become a priority to improve secondary prevention after an initial osteoporotic fracture. PURPOSE: Despite the availability of effective anti-osteoporotic treatments, osteoporosis management is currently insufficient. The main objective of this study was to assess the prevalence of anti-osteoporotic treatments introduced after an initial prior major osteoporotic fracture during hospitalization for recurring fractures. METHODS: We conducted an observational, cross-sectional, bicentric study that included all patients aged over 50 years who were hospitalized or seen in consultation for major osteoporotic fracture. RESULTS: One hundred twenty-eight out of two hundred four (62.7%) patients had a past history of major osteoporotic fracture and therefore had an indication of treatment based on guidelines. Among these patients, only 43/128 (33.5%) had received anti-osteoporotic treatment as secondary prevention after the initial fracture. The main causes of non-prescription identified were the attending physicians' ignorance of the indication of treatment (n = 30; 35.3%), ignorance of the fracture (n = 17; 20%), and comorbidities (n = 12; 14.1%). The failure to introduce treatment was associated with the presence of comorbidities with a Charlson Comorbidity Index ≥6 (OR = 0.34 [0.16-0.73], p < 0.05), dementia (OR = 0.23 [0.08-0.72], p < 0.05), and past history of proximal femur fracture (OR = 0.20 [0.04-0.91], p < 0.05). CONCLUSIONS: Two thirds of patients with a past history of major osteoporotic fracture presenting with a new fracture were not treated. The main reason for lack of treatment seems to stem from the incorrect assessment of the patient's fracture risk. Although major osteoporotic fracture leads to an increased risk of mortality and requires treatment, the significance of patient comorbidities was an independent risk factor leading to non-treatment

TAAR1 dependent and independent actions of the potential antipsychotic and dual TAAR1/5-HT1A receptor agonist SEP-383856

SEP-383856 (SEP-856) is a novel antipsychotic under clinical development. It displays a unique pattern of receptor interaction, with only weak (partial agonist) activity at dopamine D2 receptors, yet more potent agonist activity at the trace amine associated receptor (TAAR1) and 5-hydroxytryptamine 1 A receptor (5-HT1A). Nonetheless, these observations await independent confirmation and more detailed characterization of the in vitro and in vivo actions of SEP-856 at TAAR1 and 5-HT1A receptors would be instructive. Herein, we employed luminescence complementation technology in heterologous live cell systems, confocal microscopy, voltage clamp electrophysiology, behavioral readouts and TAAR1 knockout (KO) mice to study SEP-856 in further detail. We provide evidence for the ability of SEP-856 to activate TAAR1 at the surface plasma membrane, and show that this interaction results in Gαs recruitment (pEC50: 6.08 ± 0.22 EMAX: 96.41% ± 15.26) and by extension, to G-protein inwardly rectifying potassium (GIRK) channel activation. Using TAAR1-KO mice, we find TAAR1 to be indispensable for SEP-856 control of body temperature, baseline locomotion reduction and for “antipsychotic-like” efficacy as characterized by a reversal of dizocilipine (MK-801) mediated disruption of pre-pulse inhibition. Conversely, the inhibition by SEP-856 of MK-801 induced locomotion was unaffected in TAAR1 KO mice. SEP-856 behaved as a low-potency, partial agonist at the 5-HT1A receptor, while it partially inhibited recruitment of D2 receptor-coupled Gα and GIRK by DA and acted as a weak partial agonist with low potency at the same receptor when applied alone. Our findings corroborate and extend previous observations on the molecular substrates engaged by this unique, dual TAAR1/5-HT1A receptor agonist and potential antipsychotic that could prove to have major advantages in the treatment of schizophrenia and other psychotic disorders