A Randomized Double-Blind Placebo-Controlled First-In-Human Phase 1 Trial of TransCon PTH in Healthy Adults

TransCon PTH is a sustained-release, essentially inactive prodrug transiently bound to an inert carrier, designed to release PTH(1-34), and in development for hypoparathyroidism (HP). This phase 1, randomized, placebo-controlled, single and multiple ascending dose (SAD and MAD, respectively) trial evaluated safety, tolerability, pharmacodynamics (PD), and pharmacokinetics (PK) of TransCon PTH in healthy adults. SAD and MAD cohorts consisted of 10 subjects (eight active, two placebo) who received up to seven single or six multiple ascending doses of TransCon PTH, respectively. TransCon PTH doses ranged from 3.5 to 124 μg PTH(1-34) for the SAD cohorts and 3.5 to 24 μg PTH(1-34)/day for the MAD cohorts. The primary PK endpoint was Free PTH. The PD endpoints included albumin adjusted serum calcium (sCa), fractional excretion of calcium (FECa), intact endogenous PTH(1-84), bone turnover markers, renal tubular maximum reabsorption of phosphate/glomerular filtration rate (TMP/GFR), serum phosphate (sP) and magnesium, and 1,25 dihydroxyvitamin D. TransCon PTH was generally well tolerated; there were no drug-related serious adverse events (SAEs), and all AEs were transient in nature. Free PTH demonstrated an effective half-life of approximately 60 hours and a dose-dependent, sustained exposure with an infusion-like profile within the calculated physiologic range for active PTH at steady-state. Albumin-adjusted sCa demonstrated a dose-dependent, sustained response with complete control of FECa despite modest hypercalcemia at higher doses. Renal tubular maximum reabsorption of phosphate/glomerular filtration rate (TMP/GFR) showed a dose-dependent decrease, resulting in a dose-dependent decrease in sP. TransCon PTH administered daily for 10 days showed no increase in the osteoblastic bone formation markers, serum bone-specific alkaline phosphatase (BSAP) or P1NP, or the osteoclastic bone resorption marker, urine NTx, but modestly and transiently increased the osteoclast marker, serum CTx. These phase 1 data support TransCon PTH as a daily replacement therapy for HP providing physiological levels of PTH 24 hours per day and advancement into phase 2 clinical development. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.     

Effects of Odanacatib on Bone Structure and Quality in Postmenopausal Women With Osteoporosis: 5-Year Data From the Phase 3 Long-Term Odanacatib Fracture Trial (LOFT) and its Extension

Odanacatib (ODN), a selective oral inhibitor of cathepsin K, was an investigational agent previously in development for the treatment of osteoporosis. In this analysis, the effects of ODN on bone remodeling/modeling and structure were examined in the randomized, double-blind, placebo-controlled, event-driven, Phase 3, Long-term Odanacatib Fracture Trial (LOFT; NCT00529373) and planned double-blind extension in postmenopausal women with osteoporosis. A total of 386 transilial bone biopsies, obtained from consenting patients at baseline (ODN n = 17, placebo n = 23), month 24 (ODN n = 112, placebo n = 104), month 36 (ODN n = 42, placebo n = 41), and month 60 (ODN n = 27, placebo n = 20) were assessed by dynamic and static bone histomorphometry. Patient characteristics at baseline and BMD changes over 5 years for this subset were comparable to the overall LOFT population. Qualitative assessment of biopsies revealed no abnormalities. Consistent with the mechanism of ODN, osteoclast number was higher with ODN versus placebo over time. Regarding bone remodeling, dynamic bone formation indices in trabecular, intracortical, and endocortical surfaces were generally similar in ODN-treated versus placebo-treated patients after 2 years of treatment. Regarding periosteal modeling, the proportion of patients with periosteal double labels and the bone formation indices increased over time in the ODN-treated patients compared with placebo. This finding supported the observed numerical increase in cortical thickness at month 60 versus placebo. In conclusion, ODN treatment for 5 years did not reduce bone remodeling and increased the proportion of patients with periosteal bone formation. These results are consistent with the mechanism of action of ODN, and are associated with continued BMD increases and reduced risk of fractures compared with placebo in the LOFT Phase 3 fracture trial. © 2020 American Society for Bone and Mineral Research.     

Back Pain-Inducing Test,a Novel and Sensitive Screening Test for Painful Osteoporotic Vertebral Fractures: A Prospective Clinical Study

To detect painful vertebral fractures (VFs) in back pain populations at risk of osteoporosis, we designed a physical examination test (the Back Pain-Inducing Test [BPIT]) that included three movements: lying supine, rolling over, and sitting up. If back pain is induced during any of these movements, the result is defined as positive, thereby establishing a presumptive diagnosis of painful VFs. Pain severity is quantified using a self-reported numerical rating scale (NRS). The presence or absence of painful VFs is verified by whole-spine magnetic resonance imaging (MRI), the gold standard for final diagnosis. According to the standards for reporting diagnostic accuracy, a real-world, prospective, and observational study was performed on 510 back pain patients (enrolled from a single institute) at risk of osteoporosis. The sensitivity, specificity, and accuracy of the BPIT for identifying painful VFs were 99.1% (95% CI, 97.5% to 99.8%), 67.9% (95% CI, 60.4% to 74.5%), and 89.0%, respectively. The positive and negative predictive values were 86.6% (95% CI, 82.9% to 89.6%) and 97.4% (95% CI, 92.6% to 99.3%), respectively. Cutoff NRS scores for lying supine, rolling over, and sitting up were 3, 0, and 2, respectively. The corresponding area under the receiver operating characteristic curves (AUROCs) of each movement was 0.898 (95% CI, 0.868 to 0.922), 0.884 (95% CI, 0.854 to 0.911), and 0.910 (95% CI, 0.882 to 0.933), respectively. Although the high prevalence of VFs in the enrolled cohort partially limits the external validity of the predictive value in the general population, we conclude that the BPIT is potentially effective for detecting painful VFs in back pain populations at risk of osteoporosis. This test may be used as a stratification tool in decision-making on subsequent imaging procedures: a negative BPIT rules out painful VFs and indicates that an MRI should be spared, whereas a positive BPIT means that an MRI is necessary and is likely to identify painful VFs. © 2019 American Society for Bone and Mineral Research.     

Acetylcholinesterase Inhibitors Are Associated with Reduced Fracture Risk among Older Veterans with Dementia

Acetylcholinesterase inhibitors (AChEIs) have been noted to increase bone density and quality in mice. Human studies are limited but suggest an association with improved bone healing after hip fracture. We examined the relationship between AChEI use and fracture risk in a national cohort of 360,015 male veterans aged 65 to 99 years with dementia but without prior fracture using Veterans Affairs (VA) hospital, Medicare, and pharmacy records from 2000 to 2010. Diagnosis of dementia, any clinical fracture (excluding facial and digital), comorbidities, and medications were identified using ICD-9 and drug class codes. Cox proportional hazard models considering AChEI use as a time-varying covariate and adjusting for fall and fracture risk factors compared the time-to-fracture in AChEI users versus non-AChEI users. Potential confounders included demographics (age, race, body mass index), comorbidities associated with fracture or falls (diabetes, lung disease, stroke, Parkinson's, seizures, etc.) and medications associated with fracture or falls (bisphosphonates, glucocorticoids, androgen deprivation therapy [ADT], proton pump inhibitors [PPIs], selective serotonin receptor inhibitors [SSRIs], etc.). Competing mortality risk was considered using the methods of Fine and Gray. To account for persistent effects on bone density or quality that might confer protection after stopping the medication, we completed a secondary analysis using the medication possession ratio (MPR) as a continuous variable in logistic regression models and also compared MPR increments of 10% to minimal/no use (MPR 0 to <0.10). Among older veterans with diagnosis of dementia, 20.1% suffered a fracture over an average of 4.6 years of follow-up. Overall, 42.3% of the cohort were prescribed AChEIs during the study period. The hazard of any fracture among AChEI users compared with those on other/no dementia medications was significantly lower in fully adjusted models (hazard ratio [HR] = 0.81; 95% confidence interval [CI] 0.75–0.88). After considering competing mortality risk, fracture risk remained 18% lower in veterans using AChEIs (HR = 0.82; 95% CI 0.76–0.89). © 2019 American Society for Bone and Mineral Research. Published 2019. This article is a U.S. Government work and is in the public domain in the USA.     

Neurological manifestations of HIV infection in Nigerians

Nervous system complications commonly accompany HIV infection and are associated with significant morbidity and mortality. HIV incidence has been progressively increasing in Nigeria, yet the neurological manifestations of the disease have not been systematically studied in Nigerians. This study aimed to describe the nature and frequency of neurological manifestations associated with HIV infection in a sample of 202 Nigerians. This was a prospective study of patients with documented HIV infection who attended a referral centre clinic in Abuja in 2003. A personal history, general and neurological examinations, and other relevant medical investigations were carried out for all subjects. A mini mental-state exam was carried out with those willing to cooperate. In all, 89 patients (44%) were diagnosed with at least one neurological disorder. Herpes zoster and cognitive impairment were the most frequent, each present in 12.3% of the study group. Peripheral neuropathy and facial palsy were also present, in 10.4% and 3.9% of subjects, respectively. Brain mass lesions, seizure disorder, cryptococcal meningitis, cord compression syndrome, and trigeminal neuralgia were also documented. There was no significant difference demographically between subjects with or without neurological impairment. Future studies in this area should utilise nerve conduction studies and more detailed testing of cognitive function to further characterise the neurological manifestations of HIV infection.     

The Natural History of Flare‐Ups in Fibrodysplasia Ossificans Progressiva (FOP): A Comprehensive Global Assessment

Fibrodysplasia ossificans progressiva (FOP) leads to disabling heterotopic ossification (HO) from episodic flare‐ups. However, the natural history of FOP flare‐ups is poorly understood. A 78‐question survey on FOP flare‐ups, translated into 15 languages, was sent to 685 classically‐affected patients in 45 countries (six continents). Five hundred patients or knowledgeable informants responded (73%; 44% males, 56% females; ages: 1 to 71 years; median: 23 years). The most common presenting symptoms of flare‐ups were swelling (93%), pain (86%), or decreased mobility (79%). Seventy‐one percent experienced a flare‐up within the preceding 12 months (52% spontaneous; 48% trauma‐related). Twenty‐five percent of those who had received an intramuscular injection reported an immediate flare‐up at the injection site, 84% of whom developed HO. Axial flare‐ups most frequently involved the back (41.6%), neck (26.4%), or jaw (19.4%). Flare‐ups occurred more frequently in the upper limbs before 8 years of age, but more frequently in the lower limbs thereafter. Appendicular flare‐ups occurred more frequently at proximal than at distal sites without preferential sidedness. Seventy percent of patients reported functional loss from a flare‐up. Thirty‐two percent reported complete resolution of at least one flare‐up and 12% without any functional loss (mostly in the head or back). The most disabling flare‐ups occurred at the shoulders or hips. Surprisingly, 47% reported progression of FOP without obvious flare‐ups. Worldwide, 198 treatments were reported; anti‐inflammatory agents were most common. Seventy‐five percent used short‐term glucocorticoids as a treatment for flare‐ups at appendicular sites. Fifty‐five percent reported that glucocorticoids improved symptoms occasionally whereas 31% reported that they always did. Only 12% reported complete resolution of a flare‐up with glucocorticoids. Forty‐three percent reported rebound symptoms within 1 to 7 days after completing a course of glucocorticoids. This study is the first comprehensive global assessment of FOP flare‐ups and establishes a critical foundation for the design and evaluation of future clinical trials. © 2015 American Society for Bone and Mineral Research.     

Vitamin D Supplementation in Young White and African American Women

There is limited information on the effects of vitamin D on serum 25 hydroxyvitamin D (25OHD) in young people and none on African Americans. The main objective of this trial was to measure the effect of different doses of vitamin D3 on serum 25OHD and serum parathyroid hormone (PTH) in young women with vitamin D insufficiency (serum 25OHD ≤ 20 ng/mL (50 nmol/L). A randomized double‐blind placebo‐controlled trial of vitamin D3 was conducted in young white and African American women, age 25 to 45 years. A total of 198 healthy white (60%) and African American (40%) women were randomly assigned to placebo, or to 400, 800, 1600, or 2400 IU of vitamin D3 daily. Calcium supplements were added to maintain a total calcium intake of 1000 to 1200 mg daily. The primary outcomes of the study were the final serum 25OHD and PTH levels at 12 months. The absolute increase in serum 25OHD with 400, 800, 1600, and 2400 IU of vitamin D daily was slightly greater in African American women than in white women. On the highest dose of 2400 IU/d, the mixed model predicted that mean 25OHD increased from baseline 12.4 ng/mL (95% confidence interval [CI], 9.2–15.7) to 43.2 ng/mL (95% CI, 38.2–48.1) in African American women and from 15.0 ng/mL (95% CI, 12.3–17.6) to 39.1 ng/mL (95% CI, 36.2–42.0) in white women. There was no significant effect of vitamin D dose on serum PTH in either race but there was a significant inverse relationship between final serum PTH and serum 25OHD. Serum 25OHD exceeded 20 ng/mL in 97.5% of whites on the 400 IU/d dose and between 800 and 1600 IU/d for African Americans. The recommended dietary allowance (RDA) suggested by the Institute of Medicine for young people is 600 IU daily. The increase in serum 25OHD after vitamin D supplementation was similar in young and old, and in white and African American women. © 2014 American Society for Bone and Mineral Research.     

Single‐ and Multiple‐Dose Randomized Studies of Blosozumab,a Monoclonal Antibody Against Sclerostin,in Healthy Postmenopausal Women

Two clinical studies were conducted to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple doses (intravenous [iv] and subcutaneous [sc]) of blosozumab in postmenopausal women, including prior/current bisphosphonate (BP) users. In these phase 1, randomized, subject‐ and investigator‐blind, placebo‐controlled studies, subjects received escalating doses of blosozumab: single iv doses up to 750 mg, single sc doses of 150 mg, multiple iv doses up to 750 mg every 2 weeks (Q2W) for 8 weeks, multiple sc doses up to 270 mg Q2W for 8 weeks, or placebo. Six subjects were randomized to each dose in the single‐dose study (12 to placebo) and up to 12 subjects to each arm in the multiple‐dose study. Blosozumab was well tolerated with no safety concerns identified after single or multiple administrations up to 750 mg. Dose‐dependent responses were observed in sclerostin, N‐terminal propeptide of procollagen type 1, bone‐specific alkaline phosphatase, osteocalcin, C‐terminal fragment of type 1 collagen, and bone mineral density (BMD) after single and multiple (up to 5) administrations of blosozumab. There was up to a 3.41% (p = 0.002) and up to a 7.71% (p < 0.001) change from baseline in lumbar spine BMD at day 85 after single or multiple administrations of blosozumab, respectively. Prior BP use did not appear to have a clear impact on the effects of single doses of blosozumab when considering bone biomarker and BMD responses. Antibodies to blosozumab were detected by a screening assay, but no patterns with regard to dose or route of administration and no clear impact on blosozumab exposure or PD responses were identified. In summary, blosozumab was well tolerated and exhibited anabolic effects on bone. These findings support further investigation of blosozumab as a potential anabolic therapy for osteoporosis. © 2014 American Society for Bone and Mineral Research.     

Subgroup Variations in Bone Mineral Density Response to Zoledronic Acid After Hip Fracture

Minimizing post‐fracture bone loss is an important aspect of recovery from hip fracture, and determination of factors that affect bone mineral density (BMD) response to treatment after hip fracture may assist in the development of targeted therapeutic interventions. A post hoc analysis of the HORIZON Recurrent Fracture Trial was done to determine the effect of zoledronic acid (ZOL) on total hip (TH) and femoral neck (FN) BMD in subgroups with low‐trauma hip fracture. A total of 2127 patients were randomized (1:1) to yearly infusions of ZOL 5 mg (n = 1065) or placebo (n = 1062) within 90 days of operation for low‐trauma hip fracture. The 1486 patients with a baseline and at least one post‐baseline BMD assessment at TH or FN (ZOL = 745, placebo = 741) were included in the analyses. Percentage change from baseline in TH and FN BMD was assessed at months 12 and 24 and compared across subgroups of hip fracture patients. Percentage change from baseline in TH and FN BMD at months 12 and 24 was greater (p < 0.05) in ZOL‐treated patients compared with placebo in most subgroups. Treatment‐by‐subgroup interactions (p < 0.05) indicated that a greater effect on BMD was observed for TH BMD at month 12 in females, in patients in the lower tertile body mass index at baseline (≤22.6 kg/m²), and in patients with baseline FN BMD T‐score of ≤ –2.5; for FN BMD in patients who received ZOL for >6 weeks post‐surgery; and for TH and FN BMD in patients with a history of one or more prior fractures. All interactions were limited to the first 12 months after treatment with none observed for the 24‐month comparisons. (Clinical trial registration number NCT00046254.) © 2014 American Society for Bone and Mineral Research.     

Outcome of extracranial cervicocephalic arterial dissections: A follow-up study

Abstract

Cervicocephalic arterial dissections (CCAD) are an increasingly recognized cause of ischemic stroke in young adults. Various treatments have been suggested but no controlled trial has ever been performed. Medical treatment has included anticoagulant or platelet antiaggregant therapy. Surgical correction has been proposed for selected patients who have failed medical therapy. Percutaneous balloon angioplasty and stenting have been increasingly used in some patients, although long-term results are unknown. The objective of the study was to review our recent experience with the management and outcome of extracranial CCAD. We identified 27 patients with extracranial CCAD who were evaluated, treated and/or followed by our Stroke Service from September 1995 to August 2001. Clinical presentation, diagnostic evaluation, management, and outcome were reviewed. There were 15 men (56%) and 12 women (44%) with mean ages of 38 and 43 years respectively. Diagnosis was made by cerebral angiography in 15 (56%) patients and by MRI/ MRA only in 12 (44%) patients. Twenty-two patients had spontaneous and five had traumatic extracranial CCAD. Most common associated disorders were arterial hypertension (37%) and migraine (26%). One patient presented only with a painful post-ganglionic Horner syndrome, another patient with neck pain and post-ganglionic Horner syndrome, another patient solely with protracted unilateral headaches, three with transient ischemic attacks (TIA), and 21 with ischemic strokes. The internal carotid artery (ICA) was the most frequently involved vessel (63%), followed by the vertebral artery (30%), and multivessel involvement in two patients (7%). Eighteen patients received anticoagulant therapy and nine platelet anti-aggregants. Follow-up extended from 2 to 115 months, with a mean of 58 months. At the end of follow-up, 23 (85%) patients had either no disability or only minor sequelae (modified Rankin score: 0 to 1), and four (15%) patients had moderate limitations (modified Rankin score: 2 to 3). Two patients had a recurrent ischemic stroke, one unrelated to recurrent CCAD, and the other following percutaneous balloon angioplasty/stenting for treatment of a persistent vertebral artery pseudoaneurysm. Most CCAD involved the extracranial ICA. The clinical presentation is variable, most patients having an ischemic stroke or TIAs. The short- and long-term outcome are usually favorable with either anticoagulant or platelet antiaggregant therapy. A medical initial approach to the management of extracranial CCAD is recommended for most patients. [Neurol Res 2002; 24: 395-398]