Increased bone mineral density for 1 year of romosozumab, vs placebo, followed by 2 years of denosumab in the Japanese subgroup of the pivotal FRAME trial and extension.

Romosozumab, which binds sclerostin, rebuilds the skeletal foundation before transitioning to antiresorptive treatment. This subgroup analysis of an international, randomized, double-blind study in postmenopausal women with osteoporosis showed efficacy and safety outcomes for romosozumab followed by denosumab in Japanese women were generally consistent with those for the overall population. PURPOSE: In the international, randomized, double-blind, phase 3 FRActure study, in postmenopausal woMen with ostEoporosis (FRAME; NCT01575834), romosozumab followed by denosumab significantly improved bone mineral density (BMD) and reduced fracture risk. This report evaluates Japanese women in FRAME. METHODS: Postmenopausal women with osteoporosis (T-score - 3.5 to - 2.5 at total hip or femoral neck) received romosozumab 210 mg or placebo subcutaneously monthly for 12 months, then each group received denosumab 60 mg subcutaneously every 6 months for 24 months. The key endpoint for Japanese women was BMD change. Other endpoints included new vertebral, clinical, and nonvertebral fracture; the subgroup analysis did not have adequate power to demonstrate statistically significant reductions. RESULTS: Of 7180 enrolled subjects, 492 (6.9%) were Japanese (247 romosozumab, 245 placebo). BMD increases from baseline were greater (P < 0.001) for romosozumab-to-denosumab than placebo-to-denosumab at the lumbar spine (36 months, 12.7%), total hip (4.2%), and femoral neck (4.1%). Fracture risk was lower through 36 months for romosozumab-to-denosumab vs placebo-to-denosumab for new vertebral (1.7% vs 4.5%; relative risk reduction (RRR) 63%, P = 0.070), clinical (3.2% vs 7.3%; RRR 53%, P = 0.072), nonvertebral (2.8% vs 6.1%; RRR 50%, P = 0.12), and all other fracture types evaluated. Rates of adverse events and positively adjudicated serious cardiovascular events were generally balanced between groups. CONCLUSIONS: Efficacy and safety for romosozumab-to-denosumab were similar between Japanese women and the overall population. The sequence of romosozumab to rebuild the skeletal foundation before transitioning to antiresorptive treatment with denosumab is a promising regimen for Japanese postmenopausal women with osteoporosis at high risk of fracture.

One Year of Romosozumab Followed by Two Years of Denosumab Maintains Fracture Risk Reductions: Results of the FRAME Extension Study.

Romosozumab, a humanized monoclonal antibody that binds and inhibits sclerostin, has the dual effect of increasing bone formation and decreasing bone resorption. As previously reported in the pivotal FRActure study in postmenopausal woMen with ostEoporosis (FRAME), women with a T-score of ≤ -2.5 at the total hip or femoral neck received subcutaneous placebo or romosozumab once monthly for 12 months, followed by open-label subcutaneous denosumab every 6 months for an additional 12 months. Upon completion of the 24-month primary analysis period, eligible women entered the extension phase and received denosumab for an additional 12 months. Here, we report the final analysis results through 36 months, including efficacy assessments of new vertebral, clinical, and nonvertebral fracture; bone mineral density (BMD); and safety assessments. Of 7180 women enrolled, 5743 (80%) completed the 36-month study (2851 romosozumab-to-denosumab; 2892 placebo-to-denosumab). Through 36 months, fracture risk was reduced in subjects receiving romosozumab versus placebo for 12 months followed by 24 months of denosumab for both groups: new vertebral fracture (relative risk reduction [RRR], 66%; incidence, 1.0% versus 2.8%; p < 0.001), clinical fracture (RRR, 27%; incidence, 4.0% versus 5.5%; p = 0.004), and nonvertebral fracture (RRR, 21%; incidence, 3.9% versus 4.9%; p = 0.039). BMD continued to increase for the 2 years with denosumab treatment in both arms. The substantial difference in BMD achieved through 12 months of romosozumab treatment versus placebo was maintained through the follow-up period when both treatment arms received denosumab. Subject incidence of adverse events, including positively adjudicated serious cardiovascular adverse events, were overall balanced between groups. In conclusion, in postmenopausal women with osteoporosis, 12 months of romosozumab led to persistent fracture reduction benefit and ongoing BMD gains when followed by 24 months of denosumab. The sequence of romosozumab followed by denosumab may be a promising regimen for the treatment of osteoporosis. © 2018 American Society for Bone and Mineral Research.

The role of P2Y1 receptor signaling in central respiratory control.

The profile of P2 receptor signaling in respiratory control has increased substantially since the first suggestions more than 15 years ago of roles in central chemoreception and modulating inspiratory motor outflow. Part of this reflects the paradigm shift that glia participate in information processing and that ATP is a major gliotransmitter. P2 receptors are a diverse family. Here, we review ATP signaling in respiratory control, highlighting G-protein coupled P2Y1 receptors that have been a focus of recent work. Despite strong evidence of a role for glia and P2 receptor signaling in the central chemosensitivity mediated by the retotrapezoid nucleus, P2Y1 receptors do not appear to be directly involved. Evidence that central P2 receptors and glia contribute to the hypoxic ventilatory response is compelling and P2Y1 receptors are the strongest candidate. However, functional significance in vivo, details of the signaling pathways and involvement of other receptor subtypes remain important questions.

Horizontal ridge augmentation using a combination approach.

Resorption of alveolar bone - a common sequel of tooth loss jeopardizes the functional and esthetic outcome of treatment, especially in the maxillary anterior areas. Therefore, augmentation of deficient alveolar ridges is an important aspect of dental implant therapy. A case of severe maxillary ridge deficiency successfully treated with horizontal ridge augmentation to facilitate implant placement is described. Ridge augmentation was achieved using a combination of autogenous block graft, particulate grafting, and guided bone regeneration (GBR). Follow-up was done next day, after ten days, three months, and six months. Various approaches can be followed in order to achieve an increase in the ridge width. In our case, we used a combination of different techniques for ridge augmentation. A significant improvement in ridge width was noticed at six months thus facilitating the placement of implants.

Critical analysis of biomarkers in the current periodontal practice.

Periodontal disease is a chronic microbial infection that triggers inflammation-mediated loss of the periodontal ligament and alveolar bone that supports the teeth. Because of the increasing prevalence and associated comorbidities, there is a need for the development of new diagnostic tests that can detect the presence of active disease, predict future disease progression, and evaluate the response to periodontal therapy, thereby improving the clinical management of periodontal patients. The diagnosis of active phases of periodontal disease and the identification of patients at risk for active disease represent challenges for clinical investigators and practitioners. Advances in diagnostic research are moving toward methods whereby the periodontal risk can be identified and quantified by objective measures using biomarkers. Patients with periodontitis may have elevated circulating levels of specific inflammatory markers that can be correlated to the severity of the disease. Advances in the use of oral fluids as possible biological samples for objective measures of the current disease state, treatment monitoring, and prognostic indicators have boosted saliva- and other oral-based fluids to the forefront of technology. Gingival crevicular fluid (GCF) is an inflammatory exudate that can be collected at the gingival margin or within the gingival crevice. This article highlights recent advances in the use of biomarker-based disease diagnostics that focus on the identification of active periodontal disease from plaque biofilms, GCF, and saliva.

Purinergic modulation of preBötzinger complex inspiratory rhythm in rodents: the interaction between ATP and adenosine.

ATP signalling in the CNS is mediated by a three-part system comprising the actions of ATP (and ADP) at P2 receptors (P2Rs), adenosine (ADO) at P1 receptors (P1Rs), and ectonucleotidases that degrade ATP into ADO. ATP excites preBötzinger complex (preBötC) inspiratory rhythm-generating networks where its release attenuates the hypoxic depression of breathing. Its metabolite, ADO, inhibits breathing through unknown mechanisms that may involve the preBötC. Our objective is to understand the dynamics of this signalling system and its influence on preBötC networks. We show that the preBötC of mouse and rat is sensitive to P2Y(1) purinoceptor (P2Y(1)R) activation, responding with a >2-fold increase in frequency. Remarkably, the mouse preBötC is insensitive to ATP. Only after block of A(1) ADORs is the ATP-evoked, P2Y(1)R-mediated frequency increase observed. This demonstrates that ATP is rapidly degraded to ADO, which activates inhibitory A(1)Rs, counteracting the P2Y(1)R-mediated excitation. ADO sensitivity of mouse preBötC was confirmed by a frequency decrease that was absent in rat. Differential ectonucleotidase activities are likely to contribute to the negligible ATP sensitivity of mouse preBötC. Real-time PCR analysis of ectonucleotidase isoforms in preBötC punches revealed TNAP (degrades ATP to ADO) or ENTPDase2 (favours production of excitatory ADP) as the primary constituent in mouse and rat, respectively. These data further establish the sensitivity of this vital network to P2Y(1)R-mediated excitation, emphasizing that individual components of the three-part signalling system dramatically alter network responses to ATP. Data also suggest therapeutic potential may derive from methods that alter the ATP-ADO balance to favour the excitatory actions of ATP.

Plantar pressure relief in the diabetic foot using forefoot offloading shoes.

PURPOSE: Forefoot offloading shoes (FOS) are commonly used in clinical practice for treatment of plantar forefoot ulcers in the diabetic foot. The aim of this study was to assess the offloading efficacy of four different FOS models in comparison with a cast shoe and control shoe. METHODS: In-shoe plantar pressures were measured during walking in each of the six footwear conditions in 24 neuropathic diabetic patients at high risk for plantar foot ulceration. For each of six foot regions, peak pressure, pressure-time integral, and force-time integral were calculated. Load transfer diagrams were developed to assess the footwear mechanisms of action. Perceived walking comfort was measured using a visual analogue scale (VAS). All comparisons between conditions were tested at P<0.05. RESULTS: Peak pressures and pressure-time integrals at the metatarsal heads and hallux regions were significantly reduced (by 38-58%) in all FOS models when compared with the control shoe. The FOS also relieved metatarsal head peak pressure to a significantly larger extent than the cast shoe (approximately 20%). The load transfer diagrams showed a major transfer of approximately 40% of forefoot load to the midfoot explaining the offloading efficacy of the FOS. Perceived walking comfort was significantly lower in the FOS (VAS score 2.7-5.9) when compared with the control shoe (VAS 8.2) and cast shoe (VAS 6.8). CONCLUSIONS: The data showed that all FOS models were effective in their primary goal, relieving forefoot pressure in at-risk neuropathic diabetic patients. Therefore, these shoes may be effective in offloading and healing plantar forefoot ulcers, although the low comfort scores should be considered as this may potentially affect adherence to treatment.

Peripheral nerve amyloidosis in sural nerve biopsies: a clinicopathologic analysis of 13 cases.

OBJECTIVE: Amyloidosis is a well-recognized but uncommon cause of peripheral neuropathy. Our objectives were to determine the overall prevalence of peripheral nerve amyloidosis in sural nerve biopsies and to evaluate the clinical and pathologic features of these lesions. METHODS: All available histologic and ultrastructural materials on biopsy tissue from 13 cases of peripheral nerve amyloidosis were examined. Muscle biopsies performed at the same time as the nerve biopsy were reviewed when available. Clinical data were collected on all patients. RESULTS: The prevalence of amyloidosis in sural nerve biopsies at our institution was 13 (1.2%) of 1098 cases over a 15.8-year period. These patients ranged in age from 41 to 82 years (median, 61 years) at initial presentation and included 10 men and 3 women. Presenting neuropathy symptoms were sensory in 6 of the 13 patients, motor in 2 cases, and mixed in 5 cases. Cardiac, renal, or gastrointestinal involvement was present in 7 of 13 cases. Two patients had myeloma and 7 had systemic autonomic symptoms. Two patients had probable familial amyloid polyneuropathy, and 1 patient demonstrated an alanine 60 point mutation. Amyloid, identified as amorphous eosinophilic extracellular deposits demonstrating apple green birefringence on Congo red stain or recognized by its characteristic fibrillar ultrastructure by electron microscopy, was identified in the endoneurium in 12 nerves, perineurium in 2 nerves, and epineurium in 9 nerves. Chronic inflammation was identified in 5 nerves. Axonal loss was recorded as mild (<25%) in 1 nerve, moderate (25% to 75%) in 8 nerves, and severe (>75%) in 4 nerves. Axonal degeneration predominated over demyelination in 8 of 10 cases that could be evaluated. Concomitant muscle biopsies contained amyloid deposits in 8 of 9 cases. CONCLUSIONS: Amyloidosis is a rare (1.2% in our series) cause of peripheral neuropathy with a distinct microscopic and ultrastructural appearance. Just over half the patients in our study had visceral organ involvement and systemic autonomic symptoms. The peripheral neuropathy was associated with axonal degeneration and a moderate to severe axonal loss in the majority of cases. Amyloid deposition was present in 8 out of 9 muscle biopsies performed at the same time.

Attenuation of epinephrine-induced dysrhythmias by bradykinin: role of nitric oxide and prostaglandins.

Cardiac dysrhythmias are common during anesthesia and surgery. An important precipitating factor of clinically relevant arrhythmias is the introoperative use of epinephrine. Bradykinin acts as an endogenous cardioprotective substance because it suppresses ventricular dysrhythmias induced by ischemia. In this study, we investigated whether bradykinin has a protective effect, preventing the development of dysrhythmias after epinephrine infusion in rats. Because kinins are potent stimulators of the release of nitric oxide and prostaglandins from the endothelium, we investigated whether the protective effect of bradykinin is mediated by these 2 autacoids. Male Sprague-Dawley rats anesthetized with sodium pentobarbital had catheters placed into a carotid artery and both jugular veins. Arterial blood pressure and lead II of the electrocardiogram (ECG) were continuously monitored and recorded. After a steady state was achieved, 1 mg/kg enalapril, an inhibitor of angiotensin I-converting enzyme/kininase II, was given intravenously to all groups except the one treated with losartan. Bradykinin was infused at the initial rate of 0.5 microg/kg per min. Cardiac arrhythmia was induced with 7.5 microg/kg epinephrine intravenously. Dysrhythmia was assessed by counting the number of premature ventricular contractions (PVCs), runs of ventricular tachycardia (V Tach), and missing beats during the first minute after epinephrine. In untreated, control rats, epinephrine caused 10.8 +/- 2.7 PVCs, 0.8 +/- 0.2 runs of V tach, and 11.6 +/- 7.4 missing beats/min. In rats pretreated with bradykinin, the same dose of epinephrine elicited 1.2 +/- 0.5 PVCs, no runs of V tach, and 0.4 +/- 0.4 missing beats/min. This beneficial effect of bradykinin was partially reversed by N-nitro-L-arginine methyl ester (L-NAME) or indomethacin, and completely by L-NAME plus indomethacin or icatibant, but it was not affected by des-Arg9[Leu8]-bradykinin. We conclude that bradykinin, acting on the B2 receptor, attenuates epinephrine-induced dysrhythmia via a mechanism that involves the release of NO and prostaglandins. Although the mechanism is not clear, NO and prostaglandins may prevent epinephrine-induced dysrhythmia and protect the myocardium via a direct action on cardiac neurons.