Early Effects of Abaloparatide on Bone Formation and Resorption Indices in Postmenopausal Women With Osteoporosis

Anabolic osteoporosis drugs improve bone mineral density by increasing bone formation. The objective of this study was to evaluate the early effects of abaloparatide on indices of bone formation and to assess the effect of abaloparatide on modeling-based formation (MBF), remodeling-based formation (RBF), and overflow MBF (oMBF) in transiliac bone biopsies. In this open-label, single-arm study, 23 postmenopausal women with osteoporosis were treated with 80 μg abaloparatide daily. Subjects received double fluorochrome labels before treatment and before biopsy collection at 3 months. Change in dynamic histomorphometry indices in four bone envelopes were assessed. Median mineralizing surface per unit of bone surface (MS/BS) increased to 24.7%, 48.7%, 21.4%, and 16.3% of total surface after 3 months of abaloparatide treatment, representing 5.5-, 5.2-, 2.8-, and 12.9-fold changes, on cancellous, endocortical, intracortical, and periosteal surfaces (p < .001 versus baseline for all). Mineral apposition rate (MAR) was significantly increased only on intracortical surfaces. Bone formation rate (BFR/BS) was significantly increased on all four bone envelopes. Significant increases versus baseline were observed in MBF on cancellous, endocortical, and periosteal surfaces, for oMBF on cancellous and endocortical surfaces, and for RBF on cancellous, endocortical, and intracortical surfaces. Overall, modeling-based formation (MBF + oMBF) accounted for 37% and 23% of the increase in bone-forming surface on the endocortical and cancellous surfaces, respectively. Changes from baseline in serum biomarkers of bone turnover at either month 1 or month 3 were generally good surrogates for changes in histomorphometric endpoints. In conclusion, treatment with abaloparatide for 3 months stimulated bone formation on cancellous, endocortical, intracortical, and periosteal envelopes in transiliac bone biopsies obtained from postmenopausal women with osteoporosis. These increases reflected stimulation of both remodeling- and modeling-based bone formation, further elucidating the mechanisms by which abaloparatide improves bone mass and lowers fracture risk. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Burosumab for the Treatment of Tumor-Induced Osteomalacia

Tumor-induced osteomalacia (TIO) is caused by phosphaturic mesenchymal tumors producing fibroblast growth factor 23 (FGF23) and is characterized by impaired phosphate metabolism, skeletal health, and quality of life. UX023T-CL201 is an ongoing, open-label, phase 2 study investigating the safety and efficacy of burosumab, a fully human monoclonal antibody that inhibits FGF23, in adults with TIO or cutaneous skeletal hypophosphatemia syndrome (CSHS). Key endpoints were changes in serum phosphorus and osteomalacia assessed by transiliac bone biopsies at week 48. This report focuses on 14 patients with TIO, excluding two diagnosed with X-linked hypophosphatemia post-enrollment and one with CSHS. Serum phosphorus increased from baseline (0.52 mmol/L) and was maintained after dose titration from week 22 (0.91 mmol/L) to week 144 (0.82 mmol/L, p < 0.0001). Most measures of osteomalacia were improved at week 48: osteoid volume/bone, osteoid thickness, and mineralization lag time decreased; osteoid surface/bone surface showed no change. Of 249 fractures/pseudofractures detected across 14 patients at baseline, 33% were fully healed and 13% were partially healed at week 144. Patients reported a reduction in pain and fatigue and an increase in physical health. Two patients discontinued: one to treat an adverse event (AE) of neoplasm progression and one failed to meet dosing criteria (receiving minimal burosumab). Sixteen serious AEs occurred in seven patients, and there was one death; all serious AEs were considered unrelated to treatment. Nine patients had 16 treatment-related AEs; all were mild to moderate in severity. In adults with TIO, burosumab exhibited an acceptable safety profile and was associated with improvements in phosphate metabolism and osteomalacia. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research..     

A Novel HR-pQCT Image Registration Approach Reveals Sex-Specific Changes in Cortical Bone Retraction With Aging

During aging, changes in endosteal and periosteal boundaries of cortical bone occur that differ between men and women. We here develop a new procedure that uses high-resolution peripheral quantitative CT (HR-pQCT) imaging and 3D registration to identify such changes within the timescale of longitudinal studies. A first goal was to test the sensitivity of the approach. A second goal was to assess differences in periosteal/endosteal expansion over time between men and women. Rigid 3D registration was used to transform baseline and all follow-up (FU) images to a common reference configuration for which the region consisting of complete slices (largest common height) was determined. Periosteal and endosteal contours were transformed to the reference position to determine the net periosteal and endosteal expansion distances. To test the sensitivity, images from a short-term reproducibility study were used (15 female, aged 21 to 47 years, scanned three times). To test differences between men and women, images from a subset of the Geneva Retirees Cohort were used (248 female, 61 male, average age 65 years, 3.5 and 7 years FU). The sensitivity study indicated a least significant change for detecting periosteal/endosteal expansion of 41/31 microns for the radius and 17/26 microns for the tibia. Results of the cohort study showed significant net endosteal retraction only in females at the radius and tibia after 3.5 years (38.0 and 38.4 microns, respectively) that further increased at 7 years FU (70.4 and 70.8 microns, respectively). No significant net periosteal changes were found for males or females at 7 years. The results demonstrate that it is possible to measure changes in endosteal contours in longitudinal studies within several years. For the investigated cohort, significant endosteal retraction was found in females but not in males. Whether these changes in cortical geometry are related to fracture risk remains to be investigated in larger cohorts © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

COX-inhibiting nitric oxide donators (CINODs) -- a new paradigm in the treatment of pain and inflammation

The clinical utility of non-selective non-steroidal anti-inflammatory drugs (NSAIDs) for pain relief is tempered by their propensity to cause gastrointestinal toxicity. Cyclooxygenase (COX)-inhibiting nitric oxide donators (CINODs) are a new class of drugs designed to provide analgesic efficacy through COX inhibition and gastrointestinal safety through the protective effects of controlled nitric oxide donation. Pre-clinical studies assessing the pharmacology, efficacy and gastrointestinal safety of AZD3582 [4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl)propanoate] support this concept. Based on these studies, AZD3582 was the first CINOD to enter clinical development for the treatment of acute and chronic pain. The potential clinical utility of this new class is illustrated by a study of AZD3582 in healthy volunteers in which it caused significantly less acute gastrointestinal toxicity than an equimolar dose of naproxen. The results of the animal studies and the initial clinical study warrant long-term tolerability studies of AZD3582 along with evaluation of its anti-inflammatory and analgesic effects in humans.     

The CINOD, AZD3582, exhibits an improved gastrointestinal safety profile compared with naproxen in healthy volunteers

COX-inhibiting nitric oxide donators (CINODs) are a new class of drugs in development for the treatment of acute and chronic pain. They comprise a COX-inhibiting moiety linked to a nitric-oxide-donating component and are designed to provide an innovative mechanism of action of balanced COX inhibition and controlled nitric oxide donation. Through these pathways, CINODs should provide analgesic and anti-inflammatory efficacy, while offering gastrointestinal safety through the tissue-protective effects of nitric oxide donation. AZD3582 [4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl)propanoate] is the first agent in the CINOD class to enter extensive clinical development. Pre-clinical studies demonstrate that AZD3582 has a superior gastrointestinal safety profile to naproxen, while demonstrating analgesic and anti-inflammatory efficacy. In healthy human volunteers, AZD3582 caused little gastrointestinal damage compared with equimolar doses of naproxen. Studies to evaluate the longer-term gastrointestinal safety of AZD3582, alongside its efficacy in alleviating chronic and acute pain, are ongoing.     

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]     

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.     

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.     

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.     

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.