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Postmenopausal women with severe osteoporosis may require treatment with the bone anabolic drug teriparatide. While changes in bone mineral density (BMD) are one measure of response, BMD changes often require a minimum of one year to observe measureable changes. Biochemical markers of bone turnover change within 1 to 3 months of initiating osteoporosis therapy. Monitoring with a marker such as procollagen type I N propeptide (PINP), an osteoblast-derived protein, during teriparatide treatment may provide clinically useful information for managing patients with osteoporosis. Clinical trials have shown consistent increases in PINP within 3 months of initiating teriparatide, increases that are significantly greater than placebo and significantly different from baseline. Increases in PINP concentrations during teriparatide treatment correlate well with increases in skeletal activity assessed by radioisotope bone scans and quantitative bone histomorphometry parameters. Individuals treated with teriparatide in clinical trials usually experienced an increase in PINP > 10 mcg/L from baseline, while those given placebo usually did not. In the clinical setting, patients experiencing a significant increase in PINP > 10 mcg/L after initiating teriparatide therapy may receive an earlier confirmation of anabolic effect, while those who do not may be assessed for adherence, proper injection technique, or undetected secondary conditions that might mitigate an anabolic response. PINP monitoring may provide information supplemental to BMD monitoring and be a useful aid in managing patients receiving anabolic osteoporosis treatment in the same way that biochemical markers of bone resorption are useful in monitoring antiresorptive therapy. This review examines PINP as a biological response marker during teriparatide treatment for osteoporosis.

OBJECTIVE: To compare the bone anabolic drug teriparatide (20 mug/day) with the antiresorptive drug alendronate (10 mg/day) for treating glucocorticoid-induced osteoporosis (OP). METHODS: This was a 36-month, randomized, double-blind, controlled trial in 428 subjects with OP (ages 22-89 years) who had received >/=5 mg/day of prednisone equivalent for >/=3 months preceding screening. Measures included changes in lumbar spine and hip bone mineral density (BMD), changes in bone biomarkers, fracture incidence, and safety. RESULTS: Increases in BMD from baseline were significantly greater in the teriparatide group than in the alendronate group, and at 36 months were 11.0% versus 5.3% for lumbar spine, 5.2% versus 2.7% for total hip, and 6.3% versus 3.4% for femoral neck (P < 0.001 for all). In the teriparatide group, median percent increases from baseline in N-terminal type I procollagen propeptide (PINP) and osteocalcin (OC) levels were significant from 1 to 36 months (P < 0.01), and increases in levels of C-terminal telopeptide of type I collagen (CTX) were significant from 1 to 6 months (P < 0.01). In the alendronate group, median percent decreases in PINP, OC, and CTX were significant by 6 months and remained below baseline through 36 months (P < 0.001). Fewer subjects had vertebral fractures in the teriparatide group than in the alendronate group (3 [1.7%] of 173 versus 13 [7.7%] of 169; P = 0.007), with most occurring during the first 18 months. There was no significant difference between groups in the incidence of nonvertebral fractures (16 [7.5%] of 214 subjects taking teriparatide versus 15 [7.0%] of 214 subjects taking alendronate; P = 0.843). More subjects in the teriparatide group (21%) versus the alendronate group (7%) had elevated predose serum calcium concentrations (P < 0.001). CONCLUSION: Our findings indicate that subjects with glucocorticoid-induced OP treated with teriparatide for 36 months had greater increases in BMD and fewer new vertebral fractures than subjects treated with alendronate. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The association between vertebral fracture severity and health-related quality of life (HRQOL) was investigated in a subset of patients in the Fracture Prevention Trial. We sought to determine whether vertebral fracture severity was associated with HRQOL scores, and if so, to determine the effects of teriparatide (recombinant human parathyroid hormone 1-34) on vertebral fracture grades that most strongly impact HRQOL in postmenopausal women with osteoporosis. METHODS: Vertebral fracture severity was assessed by the visual semiquantitative (SQ) method. A subset of 444 patients with a baseline radiograph completed the Osteoporosis Assessment Questionnaire. Baseline HRQOL scores were modeled as a function of maximum baseline vertebral fracture grade, while controlling for age, bone mineral density, body mass index, and back pain. RESULTS: The effect of baseline vertebral fracture grade on baseline HRQOL was statistically significant, while interactions between vertebral fracture grade and the other variables were not statistically significant. SQ grade 3 (SQ3) vertebral fractures were associated with a significantly lower overall HRQOL score and with significantly lower physical function, symptoms, and emotional status dimension scores. After a median of 19 months of therapy, new or worsening SQ3 vertebral fractures occurred in 21 of 448 patients (4.7%) in the placebo group compared with 3 of 444 patients (0.7%) in the 20 mug/day teriparatide group. The risk of developing a new or worsened SQ3 vertebral fracture was reduced by 86% (P < 0.001) in patients treated with 20 mug/day teriparatide. CONCLUSION: Compared with prevalent fractures of lesser severity, SQ3 vertebral fractures were associated with reduced HRQOL. Teriparatide treatment significantly reduced the risk of new or worsening SQ3 vertebral fractures. These findings suggest, but do not directly demonstrate, a benefit of teriparatide on HRQOL. [ABSTRACT FROM AUTHOR]

Background: The objective of this analysis was to gain new insights into the patient characteristics and other factors associated with lasmiditan usage and clinical outcomes under conditions resembling the real-world setting., Methods: This was a post hoc analysis of data from the 12-month, open-label extension (OLE) of the phase 3, double-blind, randomized, controlled CENTURION trial, which examined the efficacy and safety of lasmiditan as acute treatment across four migraine attacks. Patients completing the main study who treated ≥ 3 attacks could continue in the OLE. The initial lasmiditan dose was 100 mg, with dose adjustments to 50 mg or 200 mg allowed at the investigator's discretion. Patient and clinical characteristics were summarized by dosing pattern and completion status. Safety was assessed based on adverse event (AE) frequency by number of doses., Results: In total, 445 patients treated ≥ 1 migraine attacks with lasmiditan during the OLE, 321 of whom (72.1%) completed the study. Forty-seven percent of patients remained on the 100-mg initial dose during the OLE whereas 20.2% used both 100 mg and 50 mg, 30.6% used both 100 mg and 200 mg, and 6 (1.3%) used multiple dose levels. All dosing patterns were associated with clinical and patient-reported improvement; however, the 100-mg group had the highest proportion of patients reporting improvement in the Patient Global Impression of Change - Migraine Headache Condition (56.5% vs 33.4%-52.2%). In comparison, all three groups that made dose adjustments had higher rates of completion compared to the 100-mg group (72.1%-83.3% vs 68.9%). The frequency of AEs decreased with continued use of lasmiditan. Concomitant triptans and lasmiditan use did not increase AE frequency., Conclusions: Based on high persistence and patient satisfaction rates, the 100-mg dose appears optimal for most patients. For those who adjusted dose levels, dose adjustments appeared beneficial to improve efficacy or tolerability, retaining patients on treatment. Collectively, the data suggest that patients who experienced efficacy continued to use lasmiditan regardless of the occurrence or frequency of AEs, and continued use appeared associated with fewer AEs., Trial Registration: European Union Drug Regulating Authorities Clinical Trials Database (EudraCT): 2018-001661-17; ClinicalTrials.gov: NCT03670810; registration date: September 12, 2018., (© 2024. The Author(s).)

Background: Following the CENTURION phase 3 randomized controlled trial's four-month double-blind phase, this 12-month open-label extension collected data for up to one year about dose optimization, patterns of use, migraine-related disability, and quality of life during lasmiditan treatment., Methods: Migraine patients ≥18 years completing the double-blind phase and treating ≥3 migraine attacks could continue into the 12-month open-label extension. The initial oral lasmiditan dose was 100 mg; the dose could subsequently be adjusted to 50 mg or 200 mg at the investigator's discretion., Results: 477 patients entered and 321 (72.1%) completed the extension; 445 (93.3%) treated ≥1 attack with lasmiditan. Of 11,327 attacks, 8654 (76.4%) were lasmiditan-treated (84.9% of these involved moderate or severe pain). By study end, 17.8%, 58.7%, and 23.4% of patients were taking lasmiditan 50, 100, and 200 mg, respectively. Mean improvements were observed in disability and quality of life. The most common treatment-emergent adverse event was dizziness (35.7% of patients, 9.5% of attacks)., Conclusions: During this 12-month extension, lasmiditan was associated with a high rate of study completion, most attacks were treated with lasmiditan, and patients reported improvements in migraine-related disability and quality of life. No new safety findings were observed with longer exposure. Trial registration: ClinicalTrials.gov (NCT03670810); European Union Drug Regulating Authorities Clinical Trials Database (EUDRA CT: 2018-001661-17).

Background: Perimenstrual migraine attacks in women with menstrual migraine is difficult to treat. This post-hoc analysis evaluated the efficacy of lasmiditan, a high affinity and selective 5-HT 1F receptor agonist, for perimenstrual attacks., Methods: Patients from two randomized, double-blind, placebo-controlled clinical trials (MONONOFU and CENTURION) were instructed to treat an attack with a single dose of study medication within four hours of pain onset. After dosing, the proportion of patients who achieved freedom from migraine-related head pain, most bothersome symptom, and disability was reported at baseline up to 48 hours after dose and pooled data were evaluated., Results: A total of 303 patients (MONONOFU N = 78; CENTURION N = 225) treated perimenstrual migraine attacks with lasmiditan 50 mg (N = 24), 100 mg (N = 90), 200 mg (N = 110), and placebo (N = 79). More patients achieved migraine-related head pain freedom with lasmiditan 200 mg versus placebo at all time points assessed. At 2 hours, 33.6% of patients in the 200-mg group (p < 0.001), and 16.7% of patients in the 100-mg (p = 0.11) and 50-mg (p = 0.19) groups were pain free, compared with 7.6% in the placebo group., Conclusions: Lasmiditan treatment of perimenstrual migraine attacks was associated with freedom from migraine-related head pain at two hours, early onset of efficacy, and sustained efficacy. Clinical Trial registration: NCT03962738 and NCT03670810.

The phase 3 trials of the bone anabolic drug teriparatide were prematurely terminated because of a preclinical finding of osteosarcoma in rats treated with high doses of teriparatide for near lifetime. Even so, results from these and subsequent clinical trials showed efficacy and tolerability. Based on the phase 3 results and additional preclinical investigations, Forteo (teriparatide) was approved for use in the United States with an indication for the treatment of osteoporosis in patients at high risk for fracture, a boxed warning regarding potential risk of osteosarcoma, a 2-year lifetime limitation of use, other risk mitigations, and a requirement to assess for risk of osteosarcoma in humans treated with teriparatide. Subsequent investigations included five real-world studies directed at assessing a connection between teriparatide and osteosarcoma risk in humans. The early studies did not identify an increased risk of osteosarcoma but were inadequate to sufficiently characterize risk, given the low incidence of this rare form of bone cancer. Learning from these efforts, two studies were undertaken using claims data to identify large cohorts of patients treated with teriparatide and assess whether these patients were found to have osteosarcoma by linking pharmacy claims data with data from cancer registries. These studies showed no increase in osteosarcoma in patients using teriparatide compared with unexposed groups, as well as to the expected population-based background incidence of the disease. Based on this real-world evidence and the totality of data collected from postmarketing use and other clinical investigations, the label was updated in 2020. The changes included addition of information from large observational studies using real-world evidence, removal of the boxed warning, and a revision of the 2-year lifetime limitation. Thus, observational studies with large sample sizes using real-world data can provide supportive evidence to facilitate regulatory decisions including the elimination of a boxed warning. © 2022 Eli Lilly and Company. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research., (© 2022 Eli Lilly and Company. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.)

Background: In controlled clinical trials, compared with placebo, a significantly greater proportion of participants using lasmiditan to treat a migraine attack achieved 2-h pain freedom (PF) and experienced ≥ 1 treatment-emergent adverse event (TEAE)., Objective: To better inform clinicians about treatment expectations by evaluating the association between TEAEs and efficacy outcomes after lasmiditan treatment., Methods: Pooled data from SAMURAI, SPARTAN, MONONOFU, and CENTURION were analyzed. A common TEAE (CTEAE) was defined as occurring in ≥ 2% in the overall population. Central nervous system (CNS)-CTEAEs were based on Medical Dictionary for Regulatory Activities., Results: At 2 h, a significantly higher percentage of lasmiditan 200 mg-treated participants who achieved PF experienced ≥ 1 CTEAE than non-responders who continued to experience moderate/severe pain (48.2% vs. 28.7%, respectively). Correspondingly, a significantly higher percentage of lasmiditan 200 mg-treated participants who experienced ≥ 1 CTEAE achieved PF at 2 h than those who did not (39.0% vs. 30.2%, respectively). Similar results were generally observed with individual CNS-CTEAEs, but for non-CNS-CTEAEs, this pattern was less evident or in the opposite direction. No consistent differences were observed for migraine-related functional disability freedom. The percentage of participants with improved patient global impression of change (PGIC) was greater with a CNS-CTEAE versus no CNS-CTEAE., Conclusions: Those who had PF at 2 h were more likely to experience a CNS-CTEAE, and those with CNS-CTEAEs were more likely to experience PF. The occurrence of CTEAEs did not seem to negatively affect disability freedom or PGIC., Gov Registration: SAMURAI (NCT02439320), SPARTAN (NCT02605174), MONONOFU (NCT03962738), CENTURION (NCT03670810), ClinicalTrials.gov: NCT02439320, NCT02605174, NCT03962738, NCT03670810., (© 2022. Eli Lilly and Company.)

Introduction: As 5-HT 1B receptor agonists, triptans produce vasoconstriction and have cardiovascular contraindications and precautions. Lasmiditan, a selective 5-HT 1F receptor agonist, has a low affinity for 5-HT 1B receptors, does not cause vasoconstriction, and is free of cardiovascular contraindications and precautions. The objective of this post hoc analysis was to evaluate the efficacy and safety of lasmiditan in patients with and without at least one triptan contraindication., Methods: Patient subgroups, with and without triptan contraindications, were analyzed from pooled patient data from four randomized, double-blind, placebo-controlled clinical trials (SAMURAI, SPARTAN, CENTURION, and MONONOFU). Patients experiencing a single migraine attack of moderate or severe intensity were treated with lasmiditan 50 mg (SPARTAN and MONONOFU only), 100 mg, 200 mg, or placebo, and efficacy data were recorded in an electronic diary., Results: Of 5704 patients, 207 (3.6%) patients had at least one contraindication to triptans. Overall subgroup analysis revealed that the effects of lasmiditan on pain freedom, pain relief, freedom from most bothersome symptom, disability freedom, and Patient Global Impression of Change at 2 h post-dose did not differ in patient groups with and without triptan contraindications. These outcomes generally showed a similar benefit pattern for lasmiditan in both subgroups, with all results being statistically significant in patients without contraindications, and pain relief being statistically significant in patients with contraindications. The safety and tolerability profiles of patients with triptan versus without triptan contraindications were similar, including dizziness in 18.3 to 22.8% and somnolence in 7.9 to 9.9% of patients at the highest dose of lasmiditan., Conclusions: In pooled analyses from four trials, patients with and without triptan contraindications did not differ in their patterns of lasmiditan efficacy. Lasmiditan may be a treatment option in patients with contraindications to triptans., Trial Registration Numbers: SAMURAI, NCT:02439320; SPARTAN, NCT:02605174; CENTURION, NCT:03670810; and MONONOFU, NCT:03962738., (© 2022. The Author(s).)

Background: A significant proportion of triptan users exhibit an insufficient response or inadequate tolerability to a triptan, and some may develop a contraindication. Lasmiditan, a selective 5-HT 1F receptor agonist, may be an option for these individuals. We assessed lasmiditan efficacy in a subgroup of patients in CENTURION (Phase 3 migraine consistency study) who exhibited an insufficient response to triptans, including a subgroup with insufficient response due to efficacy only., Methods: Patients were randomized to lasmiditan 200 mg for four attacks, lasmiditan 100 mg for four attacks, or placebo for three and lasmiditan 50 mg for one attack. Triptan insufficient responders were pre-defined as patients with insufficient efficacy or tolerability, or who developed a contraindication., Results: In triptan insufficient responders, lasmiditan was superior to placebo ( p  < 0.05) for pain freedom beginning at 1 h (both doses); pain relief beginning at 0.5 (200 mg) or 1 h (100 mg); migraine-related disability freedom, much/very much better on the Patient Global Impression of Change, and most bothersome symptom freedom at 2 h; sustained pain freedom; and need for rescue medication. Lasmiditan showed benefit for consistency of effect across attacks for 2-h pain freedom and pain relief. Findings were similar in triptan responders and triptan naïve patients and when the triptan insufficient response definition was based on efficacy only., Conclusions: Lasmiditan was efficacious across multiple clinically relevant endpoints in the acute treatment of migraine independent of prior response to triptans. Trial Registration: CENTURION (NCT03670810); SAMURAI (NCT02439320); SPARTAN (NCT02605174).

Background: While pain freedom at 2 h is a key primary outcome for current trials for acute treatment of migraine, the relationship between the degree of head pain and other efficacy measures at 2 h has rarely been explored. Following lasmiditan treatment of a migraine attack with moderate or severe head pain, we contrast those who achieve pain freedom with those who achieve mild pain but not pain freedom 2 h post dosing., Methods: Patient-level data were pooled across studies and treatment arms from two Phase 3 trials comparing lasmiditan and placebo, SAMURAI and SPARTAN. This post hoc analysis assessed freedom from the most bothersome symptom (MBS), freedom from migraine-related functional disability (disability), and improved patient global impression of change (PGIC) in patients who achieved 2 h pain freedom compared to those who experienced 2 h mild pain. Mild pain differs from pain relief which is defined as either mild pain or pain freedom., Results: Patients who achieved 2 h pain freedom (N = 913), in comparison with those with 2 h mild pain (N = 864), were significantly more likely to experience MBS freedom (91.9% vs. 44.9%), disability freedom (87.1% and 13.4%), and improved PGIC (86.5% and 31.5%) (p < 0.001 for all combinations). In addition, more patients who were pain free experienced both 2 h MBS freedom and 2 h functional disability freedom (83.6%) compared to those with mild pain (10.8%; p < 0.001). The proportion of patients with pain freedom who did not achieve either MBS or disability freedom (4.6%) was lower than in patients with mild pain (52.4%). Lastly, 55.2% of patients experienced mild pain before disability freedom compared to 72.1% who experienced pain freedom and disability freedom at the same time., Conclusions: This study demonstrated that, at 2 h post treatment, patients who were pain free were more likely to achieve other outcomes including freedom from their MBS, freedom from migraine-related functional disability, and improved PGIC compared to those with mild pain, confirming that 2 h pain freedom is more robustly associated with other clinical outcomes than the 2 h mild pain endpoint., Trial Registration: SAMURAI ( NCT02439320 ); SPARTAN ( NCT02605174 )., (© 2021. The Author(s).)

Background: We present findings from the multicenter, double-blind Phase 3 study, CENTURION. This study was designed to assess the efficacy of and consistency of response to lasmiditan in the acute treatment of migraine across four attacks., Methods: Patients were randomized 1:1:1 to one of three treatment groups - lasmiditan 200 mg; lasmiditan 100 mg; or a control group that received placebo for three attacks and lasmiditan 50 mg for either the third or fourth attack. The primary endpoints were pain freedom at 2 h (first attack) and pain freedom at 2 h in ≥2/3 attacks. Secondary endpoints included pain relief, sustained pain freedom and disability freedom. Statistical testing used a logistic regression model and graphical methodology to control for multiplicity., Results: Overall, 1471 patients treated ≥1 migraine attack with the study drug. Both primary endpoints were met for lasmiditan 100 mg and 200 mg ( p  < 0.001). All gated secondary endpoints were met. The incidence of treatment-emergent adverse events (TEAEs) was highest during the first attack. The most common TEAEs with lasmiditan were dizziness, paresthesia, fatigue, and nausea; these were generally mild or moderate in severity., Conclusions: These results confirm the early and sustained efficacy of lasmiditan 100 mg and 200 mg and demonstrate consistency of response across multiple attacks. Trial Registration Number: NCT03670810.

Introduction: Migraine is associated with substantial functional impairment and affects many aspects of daily life., Methods: Using data from SAMURAI and SPARTAN (double-blind, placebo-controlled, phase 3 studies) and GLADIATOR (an open-label, phase 3 study enrolling patients who had completed SAMURAI or SPARTAN), we assessed the effects of lasmiditan on migraine-related functional disability at multiple time points from 0.5 to 48 h post dose by asking patients to rate how much the migraine was interfering with normal activities. Pooled data from SAMURAI and SPARTAN (SAMURAI + SPARTAN) and data from GLADIATOR were analyzed using the intention-to-treat populations., Results: For SPARTAN + SAMURAI, significantly more patients who received lasmiditan at any dose versus placebo reported freedom from migraine-related functional disability at every timepoint from 2 h post dose, and this difference persisted to 48 h (p < 0.05). Significant differences from placebo in freedom from migraine-related functional disability commenced at 1 h post dose for lasmiditan 200 mg, 1.5 h for lasmiditan 100 mg, and 2 h for lasmiditan 50 mg. Findings from GLADIATOR supported those from SAMURAI + SPARTAN., Conclusion: All doses of lasmiditan resulted in an improvement in migraine-related functional disability that persisted to 48 h. In SAMURAI + SPARTAN, a significant difference from placebo was observed as early as 1 h post dose. TRIAL REGISTRATION AT CLINICALTRIALS.GOV: SAMURAI (NCT02439320), SPARTAN (NCT02605174), and GLADIATOR (NCT02565186).

Objective: To identify factors predicting response (2-hour headache pain freedom or most bothersome symptom freedom) to lasmiditan based on individual patient characteristics, migraine disease characteristics, and migraine attack characteristics. Further, efficacy specifically in difficult-to-treat patient/migraine disease characteristics or attack characteristics (ie, historically considered less responsive to certain acute therapies) subgroups was analyzed., Background: Knowledge of factors associated with a positive or negative response to acute treatment would be useful to practitioners prescribing acute treatments for migraine. Additionally, practitioners and patients would benefit from understanding the efficacy of lasmiditan specifically in subgroups of patients with migraine disease characteristics and migraine attack characteristics historically associated with decreased pain threshold, reduced efficacy of acute treatment, or increased burden of migraine., Methods: Pooled analyses were completed from 2 Phase 3 double-blind clinical trials, SPARTAN and SAMURAI. Data from baseline to 2 hours after taking lasmiditan (50, 100, or 200 mg) or placebo were analyzed to assess efficacy based on patient characteristics, migraine disease characteristics, and migraine attack characteristics. A total of 3981 patients comprising the intent-to-treat population were treated with placebo (N = 1130), lasmiditan 50 mg (N = 598), lasmiditan 100 mg (N = 1133), or lasmiditan 200 mg (N = 1120). Data were analyzed for the following efficacy measures at 2 hours: headache pain freedom and most bothersome symptom freedom., Results: None of the analyzed subgroups based on individual patient characteristics, migraine disease characteristics, or migraine attack characteristics predicted headache pain freedom or most bothersome symptom freedom response at 2 hours following lasmiditan treatment (interaction P ≥ .1). For the difficult-to-treat patient/migraine disease characteristics subgroups (defined as those with ≥24 headache days in the past 3 months, duration of migraine history ≥20 years, severe disability [Migraine Disability Assessment score ≥21], obesity [≥30 kg/m 2 ], and history of psychiatric disorder), single doses of lasmiditan (100 or 200 mg) were significantly more effective than placebo (P ≤ .002) in achieving both endpoints. Headache pain freedom response rates for higher doses of lasmiditan were numerically greater than for lower doses of lasmiditan. For the difficult-to-treat migraine attack subgroups, patients with severe headache, co-existent nausea at the time of treatment, or who delayed treatment for ≥2 hours from the time of headache onset, both endpoint response rates after lasmiditan 100 or 200 mg were significantly greater than after placebo. Among those who delayed treatment for ≥4 hours from the time of headache onset, headache pain freedom response rates for the 200 mg dose of lasmiditan met statistical significance vs placebo (32.4% vs 15.9%; odds ratio = 2.7 [1.17, 6.07]; P = .018). While the predictors of response interaction test showed similar efficacy of lasmiditan vs placebo across subgroups defined by baseline functional disability (mild, moderate, or needs complete bed rest) at the time of treatment, analyses of lasmiditan efficacy within the subgroup "needs complete bed rest" appeared to show less efficacy (eg, in the 200 mg vs placebo group, 25.9% vs 18.5%; odds ratio = 1.56 [0.96, 2.53]; P = .070)., Conclusions: Efficacy of lasmiditan 200 and 100 mg for headache pain freedom and most bothersome symptom freedom at 2 hours post-treatment was generally not influenced by the individual patient characteristics, migraine disease history, or migraine attack characteristics that were analyzed. In the analyses of difficult-to-treat subgroups, patients receiving lasmiditan achieved greater responses (2-hour headache pain freedom and most bothersome symptom freedom) vs placebo recipients., (© 2020 Eli Lilly and Company. Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC, on behalf of American Headache Society.)

Objective: We explore factors that may have contributed to differences in treatment-emergent adverse events in the phase 2 and phase 3 lasmiditan clinical trials., Background: Phase 2 and phase 3 trials showed that the centrally penetrant 5-HT 1F agonist, lasmiditan, was effective; higher frequency and severity of adverse events (AEs) were seen in phase 2., Methods: This work represents a hybrid of a review of primary documents and study reports with additional post hoc analyses. Protocols, informed consents, data collection forms, and methodologies were reviewed. This information was supplemented by results from the clinical study reports and post hoc analyses of individual patient data from each trial., Results: For lasmiditan 100 and 200 mg, in phase 2, the incidence of ≥1 AE was 72-86% (26% severe), while in phase 3 was 36-43% (2% severe). The most common AEs in all studies were CNS-related. The phase 2 consent form was more descriptive of AEs than phase 3. In phase 2, patients recorded AEs and severity in a paper diary that warned about drowsiness and dizziness. In phase 3, patients recorded in electronic diaries whether they experienced unusual feelings after dosing with lasmiditan that they had not felt with a migraine before, and were contacted to determine if an AE had occurred. In phase 2, the AE Schwindel was variably translated from German as "vertigo" or "dizziness," while phase 3 vertigo cases were queried to ensure there was a sensation of rotation or movement. History of recurrent dizziness and/or vertigo was exclusionary in phase 3., Conclusions: This work illustrates how informed consent wording, AE collection methods, translation, exclusion criteria, and other factors may be important determinants for reporting of the frequency and severity of AEs in clinical trials., (© 2020 Eli Lilly and Company. Headache: The Journal of Head and Face Pain published by Wiley Periodicals, Inc., on behalf of American Headache Society.)

Background: Migraine is recognized as the second leading cause of disability globally. Lasmiditan is a novel, selective serotonin 5-HT 1F receptor agonist developed for acute treatment of migraine. Here we analyzed effects of lasmiditan on migraine disability assessed with the Migraine Disability Assessment (MIDAS) scale for interim data from a long-term safety study., Methods: Completers of two single-attack parent studies were offered participation in the 1 year GLADIATOR study, that randomized participants to treatment with lasmiditan 100 mg or 200 mg taken as needed for migraine attacks of at least moderate severity. Changes in MIDAS were modeled using a mixed model repeated measures analysis., Results: The sample included 1978 patients who received ≥1 lasmiditan dose and were followed for a median of 288 days. Baseline mean MIDAS scores for the lasmiditan 100-mg and 200-mg groups were 29.4 and 28.9, respectively, indicating severe migraine-related disability. Relative to baseline, MIDAS total scores were significantly lower at 3, 6, 9, and 12 months for both dose groups. At 12 months, changes in MIDAS scores were - 12.5 and - 12.2 for lasmiditan 100 mg and 200 mg, respectively, with 49% and 53% of patients, respectively, achieving at least a 50% decrease in MIDAS total score. Statistically significant improvements were also seen for work and/or school absenteeism and presenteeism, monthly headache days, and mean headache pain intensity at all time points up to 1 year. Findings for patients who completed all visits versus those dropping out early were similar. Responses were generally similar for the lasmiditan 100 mg or 200 mg doses, between subgroups defined based on the number of baseline monthly migraine attacks (≤5 vs. >5), and also between subgroups defined by pain-free response (yes/no) during initial attacks., Conclusions: Long-term treatment with lasmiditan was associated with significant reductions in migraine-related disability, including both work or school absenteeism and presenteeism. The similarity of responses in completers and those who dropped out suggests that selective attrition does not account for the improvements. Benefits were significant at 3 months and maintained through 12 months., Trial Registration: clinicaltrials.govNCT02565186; first posted October 1, 2015.

Background: Lasmiditan demonstrated superiority to placebo in the acute treatment of migraine in adults with moderate/severe migraine disability in two similarly designed Phase 3 trials, SAMURAI and SPARTAN. Post-hoc integrated analyses evaluated the efficacy of lasmiditan in patients who reported a good or insufficient response to triptans and in those who were triptan naïve., Methods: Subgroups of patients reporting an overall response of "good" or "poor/none" to the most recent use of a triptan at baseline (defined as good or insufficient responders, respectively) and a triptan-naïve subpopulation were derived from combined study participants randomized to receive lasmiditan 50 mg (SPARTAN only), 100 mg or 200 mg, or placebo, as the first dose. Outcomes including headache pain-freedom, most bothersome symptom-freedom, and headache pain relief 2 hours post-first dose of lasmiditan were compared with placebo. Treatment-by-subgroup analyses additionally investigated whether therapeutic benefit varied according to prior triptan response (good or insufficient)., Results: Regardless of triptan response, lasmiditan showed higher efficacy than placebo (most comparisons were statistically significant). Treatment-by-subgroup analyses found that the benefit over placebo of lasmiditan did not vary significantly between patients with a good response and those with an insufficient response to triptans. Lasmiditan also showed higher efficacy than placebo in triptan-naïve patients., Conclusions: Lasmiditan demonstrated comparable efficacy in patients who reported a good or insufficient response to prior triptan use. Lasmiditan also showed efficacy in those who were triptan naïve. Lasmiditan may be a useful therapeutic option for patients with migraine., Trial Registration: SAMURAI (NCT02439320); SPARTAN (NCT02605174).

Background: Sustained pain freedom is an important attribute of acute migraine therapies for patients and physicians. Here we report efficacy of the centrally penetrant, highly selective, 5-HT 1F agonist lasmiditan on sustained pain freedom and other outcomes at 24 and 48 hours post-dose., Study Design and Methods: Data from the similarly designed, Phase 3, double-blind studies SAMURAI (NCT02439320) and SPARTAN (NCT02605174) were pooled to more precisely estimate efficacy effects in these post-hoc analyses. In both studies, inclusion criteria were 3-8 migraine attacks per month and Migraine Disability Assessment Score of ≥ 11 (at least moderate disability). Patients were randomized equally to lasmiditan 200 mg, 100 mg, 50 mg (50 mg only in SPARTAN), or to placebo. The study drug was to be taken within 4 hours of onset of pain for non-improving headache of at least moderate severity. Sustained pain freedom was defined as being pain free at 2 hours and at the given time point (24 or 48 hours) post-dose without use of additional study drug or migraine medications. Sustained responses were assessed similarly for most bothersome symptom-free, total migraine-free, and disability-free outcomes. For comparisons with previously published data on other acute medications, an additional endpoint of modified sustained pain freedom at 24 hours was defined as being pain free at 2 hours and no moderate-to-severe headache at 24 hours post-dose without use of additional study drug or migraine medications., Results: Significantly higher proportions of patients treated with lasmiditan versus placebo achieved headache pain freedom at 2 hours post-dose: 200 mg: 35.6%; 100 mg: 29.9%; 50 mg: 28.6%; placebo: 18.3% (all p  < 0.001). Sustained pain freedom was significantly higher in patients treated with lasmiditan versus placebo at 24 hours: 200 mg: 21.2%; 100 mg: 16.9%; 50 mg: 17.4%; placebo: 10.3% (all p  < 0.01); and at 48 hours: 200 mg: 18.4%; 100 mg: 15.2%; 50 mg: 14.9%; placebo: 9.6% (all p  < 0.05). Similar sustained benefits of lasmiditan versus placebo at 24 and 48 hours were noted for most bothersome symptom-free, total migraine-free and disability-free responses. Modified sustained pain freedom at 24 hours was also observed in significantly higher proportions of lasmiditan-treated patients versus placebo: 200 mg: 27.0%; 100 mg: 21.7%; 50 mg: 21.7%; placebo: 12.9% (all p  < 0.01)., Conclusion: Sustained responses at 24 and 48 hours were noted in significantly more patients treated with lasmiditan versus placebo for several efficacy outcomes including pain freedom, most bothersome symptom-free, total migraine-free and disability-free responses., Clinicaltrials.gov Identifier Numbers: SAMURAI: NCT02439320; SPARTAN: NCT02605174.

Objectives: To address the need for long-term lasmiditan data, the GLADIATOR study evaluated the safety (primary) and efficacy (secondary) of lasmiditan for the intermittent, acute treatment of migraine attacks for up to 1 year., Methods: In this prospective, randomized, open-label, Phase 3 study, patients who had completed either of two single-attack studies were offered the opportunity to be randomized 1:1 to lasmiditan 100 mg or 200 mg. Patients were asked to use lasmiditan as the first treatment for each new migraine attack of at least moderate severity. Assessments occurred at baseline and at prespecified time increments up to 48 hours after each dose of study drug using an electronic diary, and safety was assessed throughout the study. Migraine Disability Assessment (MIDAS) was assessed at each visit., Results: As of the cut-off date for this interim analysis (6 March 2018), 1978 patients had received ≥ 1 lasmiditan dose and treated 19,058 migraine attacks. Overall, treatment-emergent adverse events (TEAEs) were similar to those in the single-attack studies and included dizziness (18.6%), somnolence (8.5%), and paresthesia (6.8%). The frequency of TEAEs generally decreased with subsequent attacks. No treatment-related serious adverse events and no cardiovascular TEAEs potentially due to vasoconstriction were observed. For both lasmiditan doses, efficacy measures were generally consistent over study quarters and treated attacks. Overall, across all treated attacks at 2 hours post-dose, pain freedom was observed in 26.9% of the attacks treated with lasmiditan 100 mg and 32.4% of the attacks treated with lasmiditan 200 mg. MIDAS total scores decreased over time., Conclusions: The interim results of this long-term study showed intermittent lasmiditan (100 mg and 200 mg) to be generally well tolerated and efficacious for the acute treatment of migraine over a 1-year period. Trial registration number: NCT02565186; https://clinicaltrials.gov/ct2/show/NCT02565186.

Background: We studied the efficacy and safety of a second dose of lasmiditan for acute treatment of migraine., Methods: SAMURAI and SPARTAN were double-blind, placebo-controlled Phase 3 studies in which individuals with migraine were randomized to oral lasmiditan 50 mg (SPARTAN only), 100 mg, 200 mg, or placebo. Study drug was to be taken within 4 h (h) of onset of a migraine attack (moderate or severe pain). A second dose of study drug was provided for rescue (patient not pain-free at 2 h and took a second dose 2-24 h post-first dose) or recurrence (patient pain-free at 2 h, but experienced recurrence of mild, moderate, or severe migraine pain and took a second dose 2-24 h after first dose). Randomization to second dose occurred at baseline; patients originally assigned lasmiditan were randomized to the same lasmiditan dose or placebo (2:1 ratio), and those originally assigned placebo received placebo. Data from SAMURAI and SPARTAN were pooled for efficacy and safety assessment of a second dose of lasmiditan., Results: The proportion of patients taking a second dose was lower with lasmiditan versus placebo, and decreased with increasing lasmiditan dose; the majority who took a second dose did so for rescue. In patients taking lasmiditan as first dose, outcomes (pain free, most bothersome symptom [MBS] free) at 2 h after a second dose for rescue were similar whether the second dose was lasmiditan or placebo (p > 0.05 in all cases). In patients taking lasmiditan for first dose, outcomes at 2 h after a second dose for recurrence were as follows: lasmiditan pooled versus placebo - pain free, 50% vs 32% (p > 0.05); MBS free, 71% vs 41% (p = 0.02); pain relief, 77% vs 52% (p = 0.03). In patients whose first dose was lasmiditan, the incidence of treatment emergent adverse events (TEAEs) reported after the second dose was similar whether second dose was lasmiditan or placebo., Conclusions: A second dose of lasmiditan showed some evidence of efficacy when taken for headache recurrence. There was no clear benefit of a second dose of lasmiditan for rescue treatment. The incidences of TEAEs were similar whether the second dose was lasmiditan or placebo., Trial Registration: SAMURAI ( NCT02439320 ) [April 2015]. SPARTAN ( NCT02605174 ) [May 2016].

Objective: To study the efficacy and safety of lasmiditan for acute treatment of migraine in patients using migraine preventive medications., Background: While lasmiditan has been proven to be an effective acute treatment for migraine, its effectiveness has not been examined when used concurrently with migraine preventives., Methods: SAMURAI and SPARTAN were similarly designed, double-blind, phase 3, placebo-controlled studies of patients 18 years or older with 3 to 8 migraine attacks per month. Patients were randomized to treat a migraine attack with oral lasmiditan 50 mg (SPARTAN only), 100 mg, 200 mg, or placebo. Migraine preventives were allowed as long as doses were stable for 3 months prior to screening and were unchanged during the study. Preventive medications with established or probable efficacy, as recommended by the American Academy of Neurology, the American Headache Society, and the European Headache Federation, plus botulinum toxin type A and candesartan, were included. Within the subgroups of patients using and not using preventive therapies, lasmiditan and placebo groups were analyzed for the outcome of pain-free at 2 h and other efficacy outcomes. The subgroups of patients using and not using preventive therapies were compared and interaction p-values were calculated for safety and efficacy outcomes., Results: In these trials, 698 of 3981 patients (17.5%) used migraine preventive treatments. Among patients using preventives, all lasmiditan doses resulted in significantly more patients being pain-free at 2 h, compared to placebo (p < 0.05). Primary efficacy outcome (pain-free at 2 h), key secondary outcome (most bothersome symptom-free at 2 h) and all other efficacy outcomes were not significantly different between patients using or not using migraine preventives (all interaction p-values ≥0.1). Rates of adverse events were similar for patients using and not using preventive medications., Conclusions: Lasmiditan was more effective than placebo for the acute treatment of migraine in patients concurrently using migraine preventive medications. Lasmiditan efficacy and safety measures were similar for patients using and not using preventive medications., Trial Registration: SAMURAI (NCT02439320) and SPARTAN (NCT02605174). Registered 18 March 2015.

Trial Design: SAMURAI and SPARTAN were double-blind, placebo-controlled Phase 3 studies conducted in the United States, as well as the United Kingdom and Germany (SPARTAN only). Individuals with migraine were randomized to receive oral lasmiditan 50 mg (SPARTAN only), 100 mg, 200 mg, or placebo within 4 hours of onset of a migraine attack. The aim of this analysis was to characterize dizziness reported with lasmiditan treatment., Methods: Data from SAMURAI and SPARTAN were pooled for the current post hoc analyses. Onset time and duration of dizziness were analyzed using descriptive statistics. Subgroup analyses based on presence/absence of dizziness were performed for the endpoints of interference with daily activity, patient global impression of change (PGIC), pain at 2 hours, and most bothersome symptom (MBS) at 2 hours based on adverse events occurring within 2 hours of taking study drug., Results: Dizziness incidence was as follows: Placebo (N = 1262), 2.9% (0.1% severe); lasmiditan 50 mg (N = 654), 8.6% (0.3% severe); lasmiditan 100 mg (N = 1265), 14.9% (0.7% severe); and lasmiditan 200 mg (N = 1258), 16.8% (1.4% severe). Among participants who received lasmiditan as their first dose, risk factors for dizziness were higher lasmiditan dosage, being non-Hispanic/Latino, mild or moderate severity of migraine attack, and lower body mass index. The median time to onset of dizziness was generally 30-40 minutes, and the median duration was 1.5-2 hours. The presence of dizziness did not appear to have a negative influence on lasmiditan's effect on daily activity, PGIC, freedom from pain, or MBS. Overall, 21 participants experienced vertigo: Lasmiditan 50 mg, n = 2 (0.3%); 100 mg, n = 11 (0.9%); 200 mg, n = 7 (0.6%); and placebo, n = 1 (<0.1%)., Conclusion: The incidence of dizziness with lasmiditan increased with dose. Dizziness was generally mild or moderate in severity and of quick onset and short duration. The presence of dizziness did not influence drug efficacy., (© 2019 American Headache Society.)

Background: We assessed the safety profile of lasmiditan, a selective 5-HT 1F receptor agonist without vasoconstrictive activity being developed as an acute therapy for migraine., Methods: SAMURAI and SPARTAN were Phase 3 double-blind studies of patients with migraine, randomized to oral lasmiditan 50 mg (SPARTAN only), 100 mg, 200 mg, or placebo to be taken within 4 hours of onset of migraine pain. Safety data from the studies were integrated. Treatment-emergent adverse events (occurring within 48 hours of first dose) were considered in the analyses., Results: The safety population comprised 1262 patients assigned placebo, and 654, 1265, and 1258 assigned lasmiditan 50 mg, 100 mg, and 200 mg, respectively. There were no deaths; serious adverse events were reported for seven patients (placebo, n = 2 [0.2%]; lasmiditan 50 mg, n = 1 [0.2%]; lasmiditan 100 mg, n = 1 [0.2%]; lasmiditan 200 mg, n = 3 [0.2%]). Patients reporting ≥ 1 treatment-emergent adverse events were: Placebo, n = 174 (13.5%); lasmiditan 50 mg, n = 166 (25.4%); lasmiditan 100 mg, n = 458 (36.2%); and lasmiditan 200 mg, n = 510 (40.6%). Treatment-emergent adverse events were generally mild or moderate in severity. The most common treatment-emergent adverse events with lasmiditan were dizziness, paresthesia, somnolence, fatigue, nausea, muscular weakness and hypoesthesia. There were no ischemic events., Conclusions: As a centrally-penetrant drug, lasmiditan use was associated with neurologic treatment-emergent adverse events; most were mild or moderate in severity and self-limiting., Trial Registration at Clinicaltrials.gov: SAMURAI (NCT02439320) and SPARTAN (NCT02605174).

In randomized clinical trials (RCTs) with teriparatide, the number of patients with incident hip fractures was small and insufficiently powered to show statistically significant differences between groups. We, therefore, conducted a systematic review and meta-analysis of the efficacy of teriparatide in the reduction of hip and upper limb fractures in women and men with osteoporosis. A comprehensive search of databases until 22 November 2017 was conducted for RCTs of at least 6-month duration that reported non-spine fractures (hip, humerus, forearm, wrist), either as an efficacy or safety endpoint. Only RCTs that included patients with the approved treatment indications and dose for use of teriparatide were included; trials with off-label use of teriparatide were excluded. Two independent reviewers performed study selection and data extraction. Statistical procedures included Peto's method and Mantel-Haenszel with empirical correction, as most of the RCTs reported zero events in at least one of the treatment arms. Study results are expressed as odds ratios (OR) with 95% confidence intervals (CI). Publication bias and heterogeneity were evaluated with standard statistical tests. Twenty-three RCTs were included, 19 with an active-controlled arm (representing 64.9% of the patients included in the control group) and 11 double-blind, representing data on 8644 subjects, 3893 of them treated with teriparatide. Mean age (SD) was 67.0 (4.5) years, median treatment duration 18 months (range: 6 to 24 months). A total of 34 incident hip, 31 humerus, 31 forearm, and 62 wrist fractures were included. Meta-analysis results showed an OR (95% CI) for hip fractures of 0.44 (0.22-0.87; p = 0.019) in patients treated with teriparatide compared with controls. The effects on the risk of humerus [1.02 (0.50-2.08)], forearm [0.53 (0.26-1.08)] and wrist fractures [1.21 (0.72-2.04)] were not statistically significant (p > 0.05). This meta-analysis provides evidence of efficacy of teriparatide in reducing hip fractures by 56% in patients with osteoporosis., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

The phase 3 teriparatide Fracture Prevention Trial showed significant reductions in vertebral (VF) and nonvertebral (NVF) fractures; however, patient exposure was insufficient for full analysis of low-incidence fractures, including hip. We assessed fracture results in pooled data from four prospective, observational teriparatide studies. Ambulatory women and men with osteoporosis received subcutaneous teriparatide 20 µg/day for up to 24 months per routine clinical practice. Fracture rates were compared between 6-month periods, using 0 to 6 months of treatment as the reference period. Analyses used a piecewise exponential model for first fracture. Hip, NVF, clinical VF (CVF), any clinical, and wrist fractures were assessed. For 8828 patients analyzed, mean age was 71 years; mean (SD) treatment duration was 17.4 (8.6) months. The rate of hip fracture decreased significantly for the > 12 to 18-month (- 47.7%) and > 18-month periods (-85.2%) versus the first 6 months of therapy, and for the > 18 versus the > 6 to 12-month period. NVF, CVF, and all clinical fractures were all significantly decreased in each post-reference period, with maximum decreases (> 18-month period) of 52.7%, 69.4%, and 61.2%, respectively, versus 0 to 6 months. No significant reduction was seen for rates of wrist fracture. Teriparatide treatment was associated with statistically significant decreases in hip fracture rate, particularly for > 18 months of treatment, and in NVF, CVF, and all clinical fracture rate in real-world patients. These results should be interpreted in the context of the non-controlled design of the source studies.

Teriparatide increases bone mass primarily through remodeling of older or damaged bone and abundant replacement with new mineralizing bone. This post hoc analysis investigated whether dual-energy X-ray absorptiometric (DXA) areal bone mineral density (aBMD) measurement adequately reflects changes of mineral and organic matrix content in cortical and trabecular bone. Paired biopsies and aBMD measurements were obtained before and at end of 2 years of teriparatide treatment from postmenopausal women with osteoporosis who were either alendronate pretreated (mean, 57.5 months) or osteoporosis-treatment naive. Biopsies were assessed by micro-computed tomography (μCT) to calculate mean cortical width (Ct.Wi), cortical area (Ct.Ar), and trabecular bone volume fraction (BV/TV). Fourier transformed infrared imaging (pixel size ∼6.3 × 6.3 μm 2 ) was utilized to calculate mineral and organic matrix density (mean absorption/pixel), as well as total mineral and organic contents of cortical and cancellous compartments (sum of all pixels in the compartment). Effect of pretreatment over time was analyzed using mixed model repeated measures. μCT derived Ct.Wi and BV/TV increased, accompanied by similar increases in the overall mineral contents of their respective bone compartments. Mineral density did not change. Marked increases in the total content of both mineral and organic matrix associated with volumetric growth in both compartments consistently exceeded those of aBMD. Increases in organic matrix exceeded increases in mineral content in both cortical and trabecular compartments. For percent changes, only change in Ct.Wi correlated to change in femoral neck aBMD (r = .38, p = 0.043), whereas no other significant correlations of Ct.Wi or BV/TV with lumbar spine, total hip, or femoral neck aBMD were demonstrable. These data indicate that 2 years of teriparatide treatment leads to an increased bone organic matrix and mineral content in the iliac crest. The magnitude of these increases in the iliac crest were not detected with conventional aBMD measurements at other skeletal sites. © 2018 American Society for Bone and Mineral Research., (© 2018 American Society for Bone and Mineral Research.)

Introduction: Teriparatide significantly reduces fracture rates in clinical trials; however, those study populations were relatively restricted and included too few patients to analyze fracture outcomes within clinically important patient subgroups. We assessed fracture outcomes in subgroups of osteoporosis patients from 4 real-world teriparatide observational studies., Methods: Patients received teriparatide 20 μg/day for up to 24 months. Fracture rates were compared between 0 to 6 months versus >6 months using a piecewise exponential model for first fracture. Analyses included incident clinical vertebral fractures (CVF) and nonvertebral fractures (NVF), and clinical fractures (CVF and NVF) by subgroups of gender, age <75 or ≥75 years, diabetes, prior bisphosphonates use, rheumatoid arthritis (RA), glucocorticoid use, prior hip, and prior vertebral fracture., Results: The population included 8828 patients (8117 women, 92%) with mean (SD) age 71 (10.6) years and teriparatide treatment duration 17.4 (8.6) months. Overall, CVF, NVF, clinical fracture, and hip fracture rates decreased by 62%, 43%, 50%, and 56%, respectively (all p < .005) for >6 months versus 0 to 6 months. Subgroup analyses all showed significantly decreased rates after >6 months except for NVF reduction in males (n = 710, fracture rate low during months 0 to 6) and in patients using glucocorticoids, and CVF in patients with prior hip fracture. The effects of teriparatide on CVF, NVF, and clinical fractures over time were statistically consistent in all subgroups except age for CVF (p = .074, patients <75 years of age responded better), and diabetes for clinical fractures (p = .046, patients with diabetes responded better), although all of these subgroups experienced significant reductions over time. Glucocorticoids, prior bisphosphonate, and prior vertebral fracture were associated with increased CVF, NVF, and clinical fracture rates; RA, prior hip fracture and female gender were associated with higher NVF and clinical fracture rates; increased age was associated with higher CVF and clinical fracture rates., Conclusions: Data from 4 real-world observational studies showed statistically significant reductions during teriparatide treatment in rates of CVF, NVF, and clinical fractures in clinically relevant patient subgroups. These results should be interpreted in the context of the non-controlled design of the source studies., (Copyright © 2018 Elsevier Inc. All rights reserved.)

There has been renewed interest of late in the role of modeling-based formation (MBF) during osteoporosis therapy. Here we describe early effects of an established anabolic (teriparatide) versus antiresorptive (denosumab) agent on remodeling-based formation (RBF), MBF, and overflow MBF (oMBF) in human transiliac bone biopsies. Postmenopausal women with osteoporosis received subcutaneous teriparatide (n = 33, 20 μg/d) or denosumab (n = 36, 60 mg once/6 months), open-label for 6 months at 7 US and Canadian sites. Subjects received double fluorochrome labeling at baseline and before biopsy at 3 months. Sites of bone formation were designated as MBF if the underlying cement line was smooth, RBF if scalloped, and oMBF if formed over smooth cement lines adjacent to scalloped reversal lines. At baseline, mean RBF/bone surface (BS), MBF/BS, and oMBF/BS were similar between the teriparatide and denosumab groups in each bone envelope assessed (cancellous, endocortical, periosteal). All types of formation significantly increased from baseline in the cancellous and endocortical envelopes (differences p < 0.001) with teriparatide (range of changes 2.9- to 21.9-fold), as did MBF in the periosteum (p < 0.001). In contrast, all types of formation were decreased or not significantly changed with denosumab, except MBF/BS in the cancellous envelope, which increased 2.5-fold (difference p = 0.048). These data highlight mechanistic differences between these agents: all 3 types of bone formation increased significantly with teriparatide, whereas formation was predominantly decreased or not significantly changed with denosumab, except for a slight increase in MBF/BS in the cancellous envelope. © 2017 American Society for Bone and Mineral Research., (© 2017 American Society for Bone and Mineral Research.)

Objective: The Japan Fracture Observational Study (JFOS), a prospective observational study, investigated the real-world effectiveness of daily teriparatide to reduce clinical fracture risk in osteoporotic patients., Methods: In routine clinical practice, Japanese patients initiated on teriparatide 20 μg/day by subcutaneous injection were enrolled. The primary end-point was the rate of clinical fractures at 6-month intervals over 24 months. Bone mineral density (BMD), procollagen type 1 aminoterminal propeptide (P1NP), back pain, and health-related quality-of-life (HRQoL) information was collected., Results: Of 1,996 patients at baseline, 90.1% were female, and mean age was 76.9 years. Teriparatide persistence at 12 and 24 months was 68.0% and 51.6%, respectively. Compared to the first 6-month treatment interval, the odds ratio of fractures decreased by 56.4% during 6-12 months, 51.6% during 12-18 months, and 58.8% during 18-24 months (all p < .01). After 24 months, BMD increased by 17.2% (lumbar spine) and 7.9% (total hip). After 6 months, P1NP levels increased by 259.3%. A reduction in back pain (100 mm visual analog scale) of 16.1 mm at 3 months was maintained through 24 months. HRQoL (pain, daily living activities, general health) improved by ≥10% at each post-baseline time point. Of 279 (14.6%) patients with ≥1 adverse event (AE), 71 (3.7%) experienced ≥1 drug-related AE (investigator assessed), including nausea (0.7%), dizziness (0.4%), and decreased appetite (0.3%). Osteosarcoma was not reported; there were no new safety signals., Conclusions: JFOS demonstrated effectiveness of teriparatide 20 μg/day to reduce the risk of clinical fractures in Japanese patients in a real-world setting.

Spine fracture prevalence is similar in men and women, increasing from <5 % in those <60 to 11 % in those 70-79 and 18 % in those ≥80 years. Prevalence was higher with age, lower bone mineral density (BMD), and in those meeting criteria for spine imaging. Most subjects with spine fractures were unaware of them., Introduction: Spine fractures have substantial medical significance but are seldom recognized. This study collected contemporary nationally representative spine fracture prevalence data., Methods: Cross-sectional analysis of 3330 US adults aged ≥40 years participating in NHANES 2013-2014 with evaluable Vertebral Fracture Assessment (VFA). VFA was graded by semiquantitative measurement. BMD and an osteoporosis questionnaire were collected., Results: Overall spine fracture prevalence was 5.4 % and similar in men and women. Prevalence increased with age from <5 % in those <60 to 11 % in those 70-79 and 18 % in those ≥80 years. Fractures were more common in non-Hispanic whites and in people with lower body mass index and BMD. Among subjects with spine fracture, 26 % met BMD criteria for osteoporosis. Prevalence was higher in subjects who met National Osteoporosis Foundation (NOF) criteria for spine imaging (14 vs 4.7 %, P < 0.001). Only 8 % of people with a spine fracture diagnosed by VFA had a self-reported fracture, and among those who self-reported a spine fracture, only 21 % were diagnosed with fracture by VFA., Conclusion: Spine fracture prevalence is similar in women and men and increases with age and lower BMD, although most subjects with spine fracture do not meet BMD criteria for osteoporosis. Since most (>90 %) individuals were unaware of their spine fractures, lateral spine imaging is needed to identify these women and men. Spine fracture prevalence was threefold higher in individuals meeting NOF criteria for spine imaging (∼1 in 7 undergoing VFA). Identifying spine fractures as part of comprehensive risk assessment may improve clinical decision making.

This study demonstrates real-world effectiveness of teriparatide in reducing the risk of hip and other fragility fractures. Fracture incidence significantly decreased as adherence and persistence increased for any clinical, vertebral, nonvertebral, and hip fractures among patients who were observed for 2 years after teriparatide initiation., Introduction: Examine the relationship of treatment adherence and persistence to teriparatide with hip and other fractures., Methods: Truven MarketScan Research Databases, 2004 through 2014, provided teriparatide users ≥18 years old with continuous coverage 12 months pre- and 24 months post-teriparatide prescription. Adherence (medication possession ratio, MPR) groups were defined as high (≥0.80), medium (0.50 ≤ MPR < 0.80), and low (<0.50). Persistence, allowing for ≤90-day gaps between prescriptions, was defined as 1-6, 7-12, 13-18, and 19-24 months. Fracture incidence was summarized and compared by using ANOVA and logistic regression models; the effects of adherence were examined with Cox proportional hazard models with time-dependent covariates for teriparatide exposure., Results: Among 14,284 teriparatide subjects, mean age was 68.4 years, 89.8% were female, and 29.6% had a fracture in the previous year; these characteristics were similar across MPR and persistence groups. The effects of adherence and persistence to teriparatide were statistically significant (P < .001) for all fracture types except wrist (P ≥ .125). By logistic regression, high vs low adherence was associated with reduced risk for any (OR = 0.67; P < .001); vertebral (OR = 0.64; P < .001); nonvertebral (OR = 0.71; P < .001); and hip fractures (OR = 0.52; P < .001) and longer (19-24 months) vs shorter persistence (1-6 months) was associated with reduced risk for any (OR = 0.63, P < .001); vertebral (OR = 0.56, P < .001); nonvertebral (OR = 0.69, P < .001); and hip fractures (OR = 0.48, P < .001). Cox models revealed a significantly reduced risk between high and low adherence for any (OR = 0.69, P < .001); vertebral (OR = 0.60, P < .001); nonvertebral (OR = 0.77, P < .001); and hip fractures (OR = 0.55, P < .001)., Conclusion: Fracture incidence significantly decreased as persistence and adherence to teriparatide increased., Competing Interests: Compliance with ethical standards Funding The study was funded by Eli Lilly and Company. Conflict of interest All authors are employees of Eli Lilly and Company and minor stockholders. Ethical approval For this type of study, formal consent is not required (retrospective study).

Despite evidence for higher fracture risk, clinical effects of osteoporosis treatments in type 2 diabetes (T2D) are largely unknown. Post hoc analyses of the DANCE observational study compared T2D patients and patients without diabetes to assess the effect of teriparatide, an osteoanabolic therapy on skeletal outcomes and safety. Patients included ambulatory men and women with osteoporosis receiving teriparatide 20μg/day SQ up to 24months followed by observation up to 24months. Main outcome measures included nonvertebral fracture incidence comparing 0-6months with 6+ months of teriparatide, change from baseline in BMD and back pain severity, and serious adverse events. Analyses included 4042 patients; 291 with T2D, 3751 without diabetes. Treatment exposure did not differ by group. For T2D patients, fracture incidence was 3.5 per 100 patient-years during 0-6months treatment, and 1.6 during 6months to treatment end (47% of baseline, 95% CI 12-187%); during similar periods, for patients without diabetes, fracture incidence was 3.2 and 1.8 (57% of baseline, 95% CI 39-83%). As determinants of fracture outcome during teriparatide treatment, diabetes was not a significant factor (P=0.858), treatment duration was significant (P=0.003), and the effect of duration was not significantly different between the groups (interaction P=0.792). Increases in spine and total hip BMD did not differ between groups; increase in femoral neck BMD was greater in T2D patients than in patients without diabetes (+0.34 and +0.004g/cm(2), respectively; P=0.014). Back pain severity decreased in both groups. Teriparatide was well tolerated without new safety findings. In conclusion, during teriparatide treatment, reduction in nonvertebral fracture incidence, increase in BMD, and decrease in back pain were similar in T2D and non-diabetic patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)

An increase in procollagen type I amino-terminal propeptide (PINP) early after teriparatide initiation was shown to correlate with increased lumbar spine areal BMD and is a good predictor of the anabolic response to teriparatide. Few data exist correlating PINP and bone microstructure, and no data exist in patients on teriparatide following prior potent antiresorptive treatment. This exploratory analysis aimed to investigate the effects of teriparatide on cancellous bone microstructure and correlations of bone markers with microstructure in alendronate-pretreated patients. This was a post hoc analysis of changes in bone markers and three-dimensional indices of bone microstructure in paired iliac crest biopsies from a prospective teriparatide treatment study in postmenopausal women with osteoporosis who were either treatment-naïve (TN, n=16) or alendronate-pretreated (ALN, n=29) at teriparatide initiation. Teriparatide (20μg/day) was given for 24months; biopsies were taken at baseline and endpoint, and serum concentrations of PINP and type 1 collagen cross-linked C-telopeptide (βCTX) were measured at intervals up to 24months. In the TN and ALN groups, respectively, mean (SD) increases in three-dimensional bone volume/tissue volume were 105 (356)% (P=0.039) and 55 (139)% (P<0.005) and trabecular thickness 30.4 (30)% (P<0.001) and 30.8 (53)% (P<0.001). No significant changes were observed in trabecular number or separation. In the ALN patients, 3-month change of neither PINP nor βCTX correlated with indices of cancellous bone microstructure. However, 12-month changes in biochemical bone markers correlated significantly with improvements in bone volume/tissue volume, r=0.502 (P<0.01) and r=0.378 (P<0.05), trabecular number, r=0.559 (P<0.01) and r=0.515 (P<0.01), and reduction of trabecular separation, r=-0.432 (P<0.05) and r=-0.530 (P<0.01), for PINP and βCTX, respectively. We conclude that cancellous bone microstructure improved with teriparatide therapy irrespective of prior antiresorptive use., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Teriparatide (TPTD) is the only currently available therapeutic agent that increases the formation of new bone tissue and can provide some remediation of the architectural defects in the osteoporotic skeleton. The use of teriparatide clinically is limited to 24 months. We review clinical findings during daily teriparatide treatment over time. Teriparatide appears to increase bone formation more than bone resorption as determined biochemically and histologically. Teriparatide exerts its positive effects on bone formation in two distinct fashions. The first is direct stimulation of bone formation that occurs within active remodeling sites (remodeling-based bone formation) and on surfaces of bone previously inactive (modeling-based bone formation). The second is an increase in the initiation of new remodeling sites. Both processes contribute to the final increase in bone density observed by non-invasive tools such as DXA. Remodeling is the repair process by which skeletal tissue is maintained in a young healthy state, and when stimulated by TPTD is associated with a positive bone balance within each remodeling cavity. It seems likely therefore that this component will contribute to the anti-fracture efficacy of TPTD. Teriparatide reduces the risk of fracture, and this effect appears to increase with longer duration of therapy. The use of novel treatment regimens, including shorter courses, should be held in abeyance until controlled clinical trials are completed to define the relative fracture benefits of such approaches in comparison to the 24-month daily use of the agent. Summary In patients with osteoporosis at high risk for fracture, the full continuous 24-month course with teriparatide results in improved skeletal health and outcomes than shorter time periods.

We compared effects of teriparatide and denosumab on PTH, bone turnover markers, and bone histomorphometry in osteoporotic postmenopausal women. The findings were inconsistent with an early indirect anabolic effect of denosumab.

Summary: In patients in the Direct Assessment of Nonvertebral Fractures in Community Experience (DANCE) observational study with and without a prior vertebral or hip fracture, the incidence of nonvertebral fractures was lower with >6 months of teriparatide treatment than during the first 6 months., Introduction: Clinical evidence on the effect of teriparatide in patients with prior fracture is limited. In the DANCE observational study, the incidence of nonvertebral fragility fractures (NVFX) decreased significantly in patients receiving teriparatide for >6 months (6-24 months) versus >0 to ≤6 months (reference period)., Methods: We performed a post hoc analysis to assess the effect of teriparatide 20 μg/day in patients who entered DANCE with prior vertebral or hip fractures. The incidence of patients experiencing a NVFX for four 6-month intervals during and after treatment was compared with the reference period., Results: Overall, 4085 patients received ≥1 dose of teriparatide. Of 3720 with sufficient data for efficacy analysis, 692 had prior vertebral fracture, including 179 with previous kyphoplasty/vertebroplasty; 290 had prior hip fracture. These patients were older, and those with prior vertebral fractures had more comorbid conditions at baseline than those without prior vertebral fractures. The incidence of patients experiencing NVFX declined over time in all patient groups. The fracture incidence rate declined 49 and 46%, respectively, in patients with and without prior vertebral fracture and was 63 and 46% lower in patients with previous kyphoplasty/vertebroplasty and without prior vertebral fracture. NVFX declined 43 and 48% in patients with and without prior hip fracture. The reduced incidence over time was consistent in the subgroups (all interaction p values >0.05). Patients with prior fracture were more likely to experience serious adverse events., Conclusion: The incidence of NVFX decreased over time in patients receiving teriparatide in DANCE regardless of prior fracture status.

The purpose of this analysis was to assess the association of osteoporosis-related vertebral fracture burden and pulmonary function. This study also examined the relationship between vertebral fracture burden and height loss, estimated by arm span - height. This was a single-site and single-visit study. Patients had a history of at least 1 moderate or severe vertebral fracture. Vertebral fracture burden was quantified using the spinal deformity index (SDI). Pulmonary function during inspiration was determined by spirometry. Forty-one women aged 70-91 completed the study. Vertebral fracture burden negatively correlated with forced inspiratory vital capacity and inspiratory time. For each unit increase in SDI, forced inspiratory vital capacity decreased by 1.62%, and inspiratory time decreased by 2.39%. There was no correlation between SDI and measures of inspiratory flow. For each unit increase in SDI, height decreased by about 0.5 cm. Vertebral fractures were associated with decreased lung volume and height loss., (Copyright © 2015 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

Sclerostin, a SOST protein secreted by osteocytes, negatively regulates formation of mineralized bone matrix and bone mass. We report the results of a randomized, double-blind, placebo-controlled multicenter phase 2 clinical trial of blosozumab, a humanized monoclonal antibody targeted against sclerostin, in postmenopausal women with low bone mineral density (BMD). Postmenopausal women with a lumbar spine T-score -2.0 to -3.5, inclusive, were randomized to subcutaneous blosozumab 180 mg every 4 weeks (Q4W), 180 mg every 2 weeks (Q2W), 270 mg Q2W, or matching placebo for 1 year, with calcium and vitamin D. Serial measurements of spine and hip BMD and biochemical markers of bone turnover were performed. Overall, 120 women were enrolled in the study (mean age 65.8 years, mean lumbar spine T-score -2.8). Blosozumab treatment resulted in statistically significant dose-related increases in spine, femoral neck, and total hip BMD as compared with placebo. In the highest dose group, BMD increases from baseline reached 17.7% at the spine, and 6.2% at the total hip. Biochemical markers of bone formation increased rapidly during blosozumab treatment, and trended toward pretreatment levels by study end. However, bone specific alkaline phosphatase remained higher than placebo at study end in the highest-dose group. CTx, a biochemical marker of bone resorption, decreased early in blosozumab treatment to a concentration less than that of the placebo group by 2 weeks, and remained reduced throughout blosozumab treatment. Mild injection site reactions were reported more frequently with blosozumab than placebo. In conclusion, treatment of postmenopausal women with an antibody targeted against sclerostin resulted in substantial increases in spine and hip BMD. These results support further study of blosozumab as a potential anabolic therapy for osteoporosis., (© 2014 American Society for Bone and Mineral Research.)

Objectives: This report from the Japan Fracture Observational Study (JFOS) describes the design of the study, baseline characteristics of the patients, and interim results., Research Design and Methods: This is an interim analysis from an ongoing observational study of male and female patients with osteoporosis initiating daily teriparatide treatment observed at baseline, 3, 6 and 12 months. There was no control group. Baseline data were collected on demographic characteristics, medical and osteoporosis history, prior use of medications and health-related quality of life (HRQoL). This interim analysis includes preliminary information concerning incidence of clinical fractures, bone mineral density (BMD), procollagen type 1 aminoterminal propeptide (P1NP), back pain, HRQoL, and adverse events., Results: Baseline observations were completed for 1810 patients; 90.1% were female. Compared with osteoporotic patients treated with teriparatide in other observational studies, those in JFOS were older but had fewer osteoporosis risk factors. The incidence of clinical fractures was 2.9% at 6 months and 3.7% at 12 months. At 12 months, mean BMD was 8.9% higher at the lumbar spine and 0.8% higher at the total hip compared to baseline. At 6 months, the median serum concentration of P1NP was 187.7% higher than at baseline. At 12 months, back pain scores assessed by visual analog scale (VAS) were lower and HRQoL scores were higher than at baseline. No new safety signals were observed., Conclusions: This is the first report from an observational study of daily teriparatide in Japanese osteoporotic patients at high risk of fractures. Patients in JFOS were older but had fewer osteoporosis risk factors than those treated with teriparatide in other observational studies. The interim analysis suggests that the clinical profile of teriparatide in the real world is similar to that observed in clinical trials and observational studies conducted in Europe and the United States.

Teriparatide is a skeletal anabolic treatment for patients with osteoporosis at high risk for fracture. Because adequate clinical trials have not yet been conducted to assess the efficacy of teriparatide for reducing the risk of hip fracture, we review here the literature regarding how treatment with teriparatide affects the hip in patients with osteoporosis. Teriparatide increases cancellous bone volume, improves bone architecture, and - uniquely among osteoporosis treatments - increases cortical thickness and cortical porosity. By bone scan and positron emission tomography, teriparatide increases bone formation throughout the skeleton, including the hip. Consistent with these findings, studies using dual-energy X-ray absorptiometry and quantitative computed tomography for longitudinal assessment of changes at the hip have consistently shown increases in areal and volumetric bone mineral density, cortical thickness, and finite element-estimated hip strength in patients treated with teriparatide. Finally, in clinical fracture-outcome trials, treatment with teriparatide has been shown to reduce the risk of nonvertebral fracture, a composite endpoint that includes hip fracture. Taken together, this body of evidence suggests that teriparatide positively affects the hip in patients with osteoporosis., (Copyright © 2014. Published by Elsevier Inc.)

Our purpose was to identify factors for a parsimonious fracture risk assessment model considering morphometric spine fracture status, femoral neck bone mineral density (BMD) and the World Health Organization (WHO) clinical risk factors. Using data from 2761 subjects from the Canadian Multicentre Osteoporosis Study (CaMos), a prospective, longitudinal cohort study of randomly selected community-dwelling men and women aged ⩾50 years, we previously reported that a logistic regression model considering age, BMD and spine fracture status provided as much predictive information as a model considering these factors plus the remaining WHO clinical risk factors. The current analysis assesses morphometric vertebral fracture and/or nonvertebral fragility fracture at 5 years using data from an additional 1964 CaMos subjects who have now completed 5 years of follow-up (total N=4725). Vertebral fractures were identified from lateral spine radiographs assessed using quantititative morphometry at baseline and end point. Nonvertebral fragility fractures were determined by questionnaire and confirmed using radiographs or medical records; fragility fracture was defined as occurring with minimal or no trauma. In this analysis, a model including age, BMD and spine fracture status provided a gradient of risk per s.d. (GR/s.d.) of 1.88 and captured most of the predictive information of a model including morphometric spine fracture status, BMD and all WHO clinical risk factors (GR/s.d. 1.92). For comparison, this model provided more information than a model considering BMD and the WHO clinical risk factors (GR/s.d. 1.74). These findings confirm the value of age, BMD and spine fracture status for predicting fracture risk.

Many postmenopausal women treated with teriparatide for osteoporosis have previously received antiresorptive therapy. In women treated with alendronate (ALN) or raloxifene (RLX), adding versus switching to teriparatide produced different responses in areal bone mineral density (aBMD) and biochemistry; the effects of these approaches on volumetric BMD (vBMD) and bone strength are unknown. In this study, postmenopausal women with osteoporosis receiving ALN 70 mg/week (n = 91) or RLX 60 mg/day (n = 77) for ≥18 months were randomly assigned to add or switch to teriparatide 20 µg/day. Quantitative computed tomography scans were performed at baseline, 6 months, and 18 months to assess changes in vBMD; strength was estimated by nonlinear finite element analysis. A statistical plan specifying analyses was approved before assessments were completed. At the spine, median vBMD and strength increased from baseline in all groups (13.2% to 17.5%, p < 0.01); there were no significant differences between the Add and Switch groups. In the RLX stratum, hip vBMD and strength increased at 6 and 18 months in the Add group but only at 18 months in the Switch group (Strength, Month 18: 2.7% Add group, p < 0.01 and 3.4% Switch group, p < 0.05). In the ALN stratum, hip vBMD increased in the Add but not in the Switch group (0.9% versus -0.5% at 6 months and 2.2% versus 0.0% at 18 months, both p ≤ 0.004 group difference). At 18 months, hip strength increased in the Add group (2.7%, p < 0.01) but not in the Switch group (0%); however, the difference between groups was not significant (p = 0.076). Adding or switching to teriparatide conferred similar benefits on spine strength in postmenopausal women with osteoporosis pretreated with ALN or RLX. Increases in hip strength were more variable. In RLX-treated women, strength increased more quickly in the Add group; in ALN-treated women, a significant increase in strength compared with baseline was seen only in the Add group., (Copyright © 2013 American Society for Bone and Mineral Research.)