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Angela M Cheung,1–3 Heather Frame,4 Michael Ho,5 Erin S Mackinnon,6 Jacques P Brown7 1Department of Medicine, University of Toronto, 2Centre of Excellence in Skeletal Health Assessment, Joint Department of Medical Imaging, University Health Network (UHN), 3Mount Sinai Hospital, University of Toronto, Toronto, ON, 4Assiniboine Clinic, Winnipeg, MB, 5University Health Network, Toronto, 6Amgen Canada, Inc, Mississauga, ON, 7Rheumatology Division, CHU de Québec Research Centre, Laval University, Quebec City, QC, Canada Abstract: Bone strength – and, hence, fracture risk – reflects the structural and material properties of the skeleton, which changes with bone turnover during aging and following effective pharmacotherapy. A variety of powerful new techniques (quantitative computed tomography, as well as peripheral quantitative computed tomography and high-resolution peripheral quantitative computed tomography) provide precise images of bone structure and can be used to model the response of specific bones to different types of mechanical load. This review explores the various components of bone strength and the clinical significance of measures, such as bone mineral density, bone turnover markers, and modern imaging data, with regard to fracture risk in women with postmenopausal osteoporosis, before and after initiating antiresorptive therapy. These imaging and related techniques offer an ever-clearer picture of the changes in bone structure and bone mineral metabolism during normal aging and in osteoporosis, as well as in response to treatment. However, because the newer techniques are not yet available in routine practice, validated tools for absolute fracture risk assessment remain essential for clinical decision making. These tools, which are tailored to patient risk data in individual countries, are based on bone mineral density and other readily available clinical data. In addition, bone turnover marker measurements can be useful in assessing risk and guiding treatment decisions for women with postmenopausal osteoporosis. Such tests may be used before starting a patient on antiresorptive therapy and for ongoing monitoring of treatment effectiveness. Keywords: bone strength, antiresorptive, postmenopausal osteoporosis, bisphosphonate, denosumab, fracture risk

Elevated low-density lipoprotein cholesterol (LDL-C) is a major causal factor for atherosclerotic cardiovascular disease (ASCVD), the leading cause of mortality worldwide. Statins are the recommended first-line lipid-lowering therapy (LLT) for patients with primary hypercholesterolemia and established ASCVD, with LLT intensification recommended in the substantial proportion of patients who do not achieve levels below guideline-recommended LDL-C thresholds with statin treatment alone. The proprotein convertase subtilisin/kexin type 9 inhibitor monoclonal antibody evolocumab has demonstrated significant LDL-C reductions of > 60% in the clinical trial and open-label extension settings, with LDL-C reductions observed early post-evolocumab initiation and maintained long term, during up to 8.4 years of follow-up. Evolocumab therapy, when added to a statin, also conferred a significant reduction in major cardiovascular (CV) events, including a 20% reduction in the composite of CV death, myocardial infarction (MI), or stroke. The absolute benefits were enhanced among various patient types at high and very high risk for secondary ASCVD (e.g., with recent MI, multiple events or peripheral artery disease). Importantly, evolocumab treatment resulted in incremental CV risk reductions during the extended follow-up, including a 23% reduction in CV mortality and no apparent LDL-C level below which there is no further CV risk reduction. Hence, the evolocumab clinical data support the need for early and significant LDL-C lowering, especially in vulnerable ASCVD patients, in order to derive the greatest benefit in the long term. Importantly, evolocumab had no impact on any treatment emergent adverse events apart from a small increase in local injection site reactions. A growing body of real-world evidence (RWE) for evolocumab in heterogeneous populations is consistent with the trial data, including robust LDL-C reductions below guideline-recommended thresholds, a favourable safety profile even at the lowest levels of LDL-C achieved, and a high treatment persistence rate of > 90%. Altogether, this review highlights findings from 50 clinical trials and RWE studies in > 51,000 patients treated with evolocumab, to demonstrate the potential of evolocumab to address the healthcare gap in LDL-C reduction and secondary prevention of ASCVD in a variety of high- and very high-risk patients., Competing Interests: The authors report the following potential conflicts of interest for grants, contracts, consulting fees, honoraria, support for attending meetings, and/or participation on a data safety monitoring board or advisory board. LAL: Amarin, Amgen, AstraZeneca, Esperion, HLS Therapeutics, Kowa, Merck, Novartis, Pfizer, Sanofi; RAH: Acasti, Akcea/Ionis, Amgen, Amryt, Arrowhead, HLS Therapeutics, Medison, Novartis, Pfizer, Regeneron, Ultragenyx; VB: AbbVie, Amgen, BioSyent, Eisai, GSK, Merck, Moderna, Pfizer, Novartis, Novo Nordisk, Sanofi, Seqirus, Sunovion; JB: Amarin, Amgen, Amryt, Arrowhead, Eli Lilly, HLS Therapeutics, Ionis Pharmaceuticals Inc., Kowa, LIB Therapeutics, Medison, New Amsterdam Pharma, Novartis, Novo Nordisk, Regeneron, Sanofi, Ultragenyx; ESM is an employee of and owns stock in Amgen Canada Inc.; GBJM: Amgen, Esperion, HLS Therapeutics, Novartis, Pfizer, Sanofi. The authors declare no conflict of interest., (Copyright: © 2024 The Author(s). Published by IMR Press.)

Introduction: The 2021 Canadian Cardiovascular Society (CCS) guidelines recommend intensive low-density lipoprotein cholesterol (LDL-C) reduction for patients with atherosclerotic cardiovascular disease (ASCVD). For patients above LDL-C threshold on maximally tolerated statins, adding ezetimibe and/or a proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) is recommended. This population-based, real-world study examined cardiovascular (CV) events in patients with ASCVD who are on statins and above current guideline threshold LDL-C levels., Methods: Using administrative health data in Alberta, Canada, we identified patients with myocardial infarction (MI), ischemic stroke (IS), or peripheral artery disease with LDL-C > 1.8 mmol/L on statins between April 1, 2010 and March 31, 2016. Exploratory subgroups included very high-risk patients with ASCVD shown to derive the most benefit from PCSK9i intensification as identified by the CCS guidelines, including those with acute coronary syndrome (ACS) or recent MI. Frequencies and rates of individual and composite CV events (primary outcome: MI, IS, hospitalization for unstable angina, coronary revascularization, cardiovascular death; secondary outcome: MI, IS, CV death) were calculated over follow-up., Results: The study included 32,984 patients with a mean (standard deviation) follow-up of 40.8 (21.0) months. Overall, 17.7% and 15.6% experienced a primary and secondary outcome, respectively, with rates of 5.58 and 4.83 per 100 patient-years, respectively. CV death and MI were the most common events. Subgroups with recurrent MI and comorbid diabetes exhibited higher CV event rates (23.6% and 22.2% had a primary outcome, respectively). Rates of CV events were notably high in patients with ACS or recent MI (49.4% and 54.0% had a primary outcome, respectively)., Conclusion: This real-world study confirms that statin-treated high-risk patients with ASCVD and above-threshold LDL-C levels have substantial incidence of recurrent CV events. These findings reinforce the opportunity for lipid-lowering therapy intensification in high-risk patients to levels below guideline-recommended threshold in order to reduce CV risk., (© 2024. The Author(s).)

Introduction: This study characterizes patients receiving evolocumab in clinical practice and assesses treatment effectiveness, safety and persistence outcomes across five countries., Methods: This retrospective and prospective observational study enrolled patients initiated on evolocumab during August 2017 to July 2019 at 49 sites across Canada, Mexico, Colombia, Saudi Arabia and Kuwait. Medical records data were extracted within 6 months prior to (baseline) and every 3 months for 12 months post evolocumab initiation and reported as available., Results: A total of 578 patients were enrolled (40.1% female, median age 60 [interquartile range (IQR) 51-68] years); 83.7% had atherosclerotic cardiovascular disease and/or familial hypercholesterolemia. Median low-density lipoprotein cholesterol (LDL-C) at baseline was 3.4 (IQR 2.7-4.2) mmol/L (131.5 [IQR 104.4-162.4] mg/dL), with 75.6% of patients receiving a statin (59.2% high intensity). Compared to baseline, the median lowest LDL-C was reduced by 70.2% and remained stable over 12 months of treatment. Guideline-recommended LDL-C thresholds < 1.8, < 1.4 and < 1.0 mmol/L (< 70, < 55 and < 40 mg/dL) were achieved by 75.3%, 63.6% and 47.4% of patients. LDL-C outcomes were consistent across high- and very high-risk patients. Background lipid-lowering therapy remained relatively stable. No serious treatment-emergent adverse events were reported, and persistence to evolocumab was 90.2% at 12 months., Conclusion: These findings provide real-world evidence that evolocumab use is in accordance with its international guideline-recommended place in dyslipidemia therapy, as well as confirmation of its effectiveness and safety in a heterogeneous population. Evolocumab can address a healthcare gap in the management of dyslipidemia by increasing the proportion of patients achieving LDL-C goals recommended to lower cardiovascular risk., (© 2023. The Author(s).)

Background: Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of morbidity and mortality in Canada. The COVID-19 pandemic altered the usual care of ambulatory and acute cardiac patients. This study aimed to describe ASCVD-related clinical outcomes and healthcare resource utilization (HCRU) patterns during the coronavirus disease 2019 (COVID-19) pandemic in Alberta, Canada, relative to the three preceding years., Methods: A repeated cross-sectional study design was conducted over three-month periods using administrative health data between March 15, 2017, and March 14, 2021. ASCVD-related clinical outcomes included major adverse cardiovascular events (MACE) endpoints. HCRU was assessed through general practitioner and other healthcare professional visits (including telehealth claims) for ASCVD events, emergency department visits, ASCVD diagnostic imaging tests, laboratory tests, and hospital length of stay., Results: Relative to the control year period (March to June 2019) ASCVD-related events (i.e., hospitalizations, emergency department (ED) visits and physician office visits) declined by 23% during the three-months COVID-19 period (March to June 2020). Acute declines were not sustained following June 2020. In contrast, in-patient mortality rates involving a primary MACE endpoint increased from March to June 2020 COVID-19 period., Conclusions: This study demonstrates the COVID-19 pandemic and corresponding public health restrictions impacted ASCVD-related care. While many clinical outcomes returned to pre-pandemic levels at the end of the observation period, our results suggest that patients' HCRU declined, which could lead to further CV events and mortality. Understanding the impact of COVID-19 restrictions on ASCVD-related care may help improve healthcare resiliency., (© 2023 Published by Elsevier Inc. on behalf of the Canadian Cardiovascular Society.)

Introduction: A high proportion of Canadian patients with acute myocardial infarction (AMI) do not achieve the threshold low-density lipoprotein cholesterol (LDL-C) levels recommended by the Canadian Cardiovascular Society in 2021. This increases the risk of subsequent atherosclerotic cardiovascular disease (ASCVD) events. Here, we assess LDL-C levels and threshold achievement among patients by lipid-lowering therapies (LLT) received post-AMI., Methods: A retrospective cohort study of patients identified with AMI between 2015 and 2019 was conducted using administrative health databases in Alberta, Canada. Patients were grouped by their highest-intensity LLT post-AMI (proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) + another LLT; PCSK9i alone; ezetimibe + statin; statins (high, moderate, low intensity); or ezetimibe alone), and available LDL-C levels were examined in the year before and after LLT dispense date., Results: The cohort included 15,283 patients. In patients on PCSK9i + LLT, the median [95% confidence interval (CI)] LDL-C levels decreased from 2.7 (2.3-3.4) before to 0.9 (0.5-1.2) mmol/l after treatment, the largest decrease among treatment groups. In the ezetimibe + statin and high-intensity statin groups, median (95% CI) values after treatment were 1.5 (1.5-1.6) and 1.4 (1.4-1.4) mmol/l, respectively. The proportion of patients below the 1.8 mmol/l threshold increased by 77.7% in the PSCK9i + LLT group after treatment, compared to 45.4 and 32.4% in the ezetimibe + statin and high-intensity statin groups, respectively., Conclusions: Intensification with PCSK9i in AMI patients results in a greater proportion of patients achieving below the recommended LDL-C threshold versus statins and or ezetimibe alone. Increased focus on achieving below the LDL-C thresholds with additional LLT as required may benefit patient cardiovascular outcomes., (© 2022. The Author(s).)

Background: The 2021 Canadian Cardiovascular Society guidelines recommend proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor therapy in patients with atherosclerotic cardiovascular disease whose low-density lipoprotein cholesterol (LDL-C) concentration remains ≥ 1.8 mmol/L despite maximally tolerated statin therapy. This retrospective and prospective observational study characterizes Canadian patients treated with evolocumab and describes its effectiveness and safety., Methods: Between August 2017 and July 2019, a total of 131 patients initiated on evolocumab therapy were enrolled at 15 sites in Canada. Data were extracted from medical records every 3 months between 6 months prior to, and for 12 months following evolocumab therapy initiation, until July 6, 2020. Baseline and prospectively collected data are reported as available., Results: A total of 131 patients were enrolled (59.5% male; mean age [standard deviation (SD)] 64.7 ± 10.6 years), most with a diagnosis of atherosclerotic cardiovascular disease and/or familial hypercholesterolemia (93.4%). Mean (± SD) LDL-C concentration at baseline was 3.7 (± 1.7) mmol/L (n = 119), with 58.0% of patients receiving a statin (36.6% high intensity). Mean (± SD) LDL-C concentration after evolocumab treatment was 1.6 (± 1.0) mmol/L (n = 120), representing a 58.7% decrease from baseline (n = 109). This level remained stable over 12 months. An LDL-C concentration < 1.8 mmol/L was achieved by 77.5% of patients. Persistence was 92%, and no serious treatment-emergent adverse events were reported., Conclusions: These findings provide real-world evidence of guideline-recommended initiation of evolocumab therapy, as well as confirmation of its effectiveness and safety in a Canadian population. Evolocumab therapy can address a healthcare gap in the management of dyslipidemia, by increasing the proportion of patients achieving LDL-C goals recommended to lower cardiovascular risk., (© 2022 The Authors.)

Background: Cardiovascular disease is the second-leading cause of death in Canada. However, limited data are available on the prevalence of atherosclerotic cardiovascular disease (ASCVD) in Canada. The study objective was to describe the incidence and prevalence of ASCVD in adult patients in Ontario, Canada, and to evaluate temporal trends for subsequent ASCVD events among those with new-onset ASCVD., Methods: This retrospective, observational study identified ASCVD incidence and prevalence data from the Institute for Clinical Evaluative Sciences Data Repository for adults from Ontario. Overall prevalence was established for the period from 2002 to 2018. Incident cases from April 1, 2005 to March 2016 were then identified, and followed up to 2018. Primary outcomes were date and type of index event/procedure, patient characteristics/baseline demographics, and comorbidities. Secondary outcomes assessed were time from first to second ASCVD event, subsequent event(s) and/or mortality, and type of subsequent event(s) relative to the type of index/primary event., Results: A total of 1,042,621 eligible prevalent ASCVD cases were identified; of these, 743,309 patients (69%) were newly diagnosed with incident ASCVD. The 10-year prevalence rates for all ASCVD subtypes increased over the study period. Overall event incidence rates per 1000 person-years were mostly stable or increased. Among incident cases, 50% experienced subsequent events over the study period., Conclusions: This observational study demonstrated increasing prevalence and high incidence of new ASCVD diagnoses in adults from Ontario, over the study period. These data, together with the substantial number of subsequent events in ASCVD patients, demonstrate significant clinical burden of this disease in Ontario., (© 2021 The Authors.)

Unlabelled: To date, no intervention studies have been published demonstrating the effect of the antioxidant lycopene on bone. Postmenopausal women supplemented with lycopene had significantly increased antioxidant capacity and decreased oxidative stress and the bone resorption marker N-telopeptide (NTx). Lycopene decreases bone resorption markers and may reduce the risk of osteoporosis., Introduction: We have previously shown in vitro and in vivo that lycopene from tomato is associated with a protective effect on bone, but lycopene intervention studies have not been reported. Our aim was to carry out a randomized controlled intervention study to determine whether lycopene would act as an antioxidant to decrease oxidative stress parameters, resulting in decreased bone turnover markers, thus reducing the risk of osteoporosis in postmenopausal women., Methods: Sixty postmenopausal women, 50-60 years old, were recruited. Following a 1-month washout without lycopene consumption, participants consumed either (N = 15/group): (1) regular tomato juice, (2) lycopene-rich tomato juice, (3) tomato Lyc-O-Mato lycopene capsules, or (4) placebo capsules, twice daily for total lycopene intakes of 30, 70, 30, and 0 mg/day respectively for 4 months. Serum collected after the washout, 2 and 4 months of supplementation, was assayed for cross-linked aminoterminal N-telopeptide, carotenoid content, total antioxidant capacity (TAC), lipid, and protein oxidation., Results: Participants who consumed juice or lycopene capsules were analyzed in one group designated "LYCOPENE-supplemented". Repeated measures ANOVA showed that LYCOPENE-supplementation for 4 months significantly increased serum lycopene compared to placebo (p < 0.001). LYCOPENE-supplementation for 4 months resulted in significantly increased TAC (p < 0.05) and decreased lipid peroxidation (p < 0.001), protein oxidation (p < 0.001), and NTx (p < 0.001). These decreases in lipid peroxidation, protein oxidation, and NTx were significantly different from the corresponding changes resulting from placebo supplementation (p < 0.05, p < 0.005, and p < 0.02, respectively)., Conclusions: Our findings suggest that the antioxidant lycopene is beneficial in reducing oxidative stress parameters and the bone resorption marker NTx.

Background and Objectives: Lycopene is a carotenoid commonly found in tomatoes and tomato products which acts as an antioxidant to decrease oxidative stress and osteoporosis risk. We wanted to determine the effects of a lycopene-restricted diet on oxidative stress parameters and bone turnover markers in postmenopausal women., Setting: St. Michael 's Hospital, Toronto, ON, Canada. PARTICIPANTS AND STUDY DESIGN: 23 healthy postmenopausal women, 50-60 years old, provided blood samples at baseline and following a one-month lycopene-depletion period., Measurements: Serum samples were analyzed for carotenoids; the oxidative stress parameters protein thiols and thiobarbituric-malondialdehyde reactive substances; the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), and the bone turnover markers bone alkaline phosphatase and crosslinked N-telopeptide of type I collagen (NTx). A paired t-test was used to test for significant differences in bone turnover markers, oxidative stress parameters and antioxidant status after lycopene restriction., Results: Dietary lycopene restriction resulted in significantly decreased serum lycopene (p < 0.0001), lutein/zeaxanthin (p < 0.01), and α -/β -carotene (p < 0.05). GPx (p < 0.01), lipid and protein oxidation increased (not significant), while CAT and SOD were significantly depressed (p < 0.05 and p < 0.005, respectively). These changes coincided with significantly increased NTx (p < 0.05)., Conclusions: These findings suggest that the daily consumption of lycopene may be important as it acts as an antioxidant to decrease bone resorption in postmenopausal women and may therefore be beneficial in reducing the risk of osteoporosis.

Background/aims: Polymorphisms of the paraoxonase 1 (PON1) enzyme affect the ability to protect LDL from oxidation. Oxidative stress is a risk factor for osteoporosis and antioxidants may be beneficial for prevention. The aim of this study was to determine whether PON1 genotypes modified the association between lycopene and bone turnover markers and oxidative stress parameters., Methods: Blood samples from 107 women 25-70 years of age were analyzed for serum carotenoid concentrations, bone-specific alkaline phosphatase (BAP), N-telopeptide of type I collagen (NTx) and oxidative stress parameters. Subjects were genotyped for the 172T→A and 584A→G polymorphisms of PON1., Results: The 172T→A polymorphism modified the association between lycopene and NTx (p < 0.05 for interaction). In the 172TT genotype, high serum lycopene was associated with decreased NTx (p < 0.05). The 584A→G polymorphism modified the association between lycopene and BAP (p < 0.05 for interaction). Additionally, in participants with the 584GG genotype, high serum lycopene was associated with high TBA-reactive substances (p < 0.05)., Conclusions: These findings show that PON1 polymorphisms modify the association between serum concentrations of lycopene and oxidative stress parameters and bone turnover markers and may, therefore, moderate the risk of osteoporosis., (Copyright © 2010 S. Karger AG, Basel.)

Lycopene is an antioxidant associated with a reduced risk of chronic diseases common in women such as osteoporosis and cancer; however, no official recommendation for lycopene consumption exists, and intake data from Canadian women are limited. This study was designed to generate information about average lycopene intake in Canadian women of different ages. A cross-sectional study was conducted at St. Michael's Hospital in Toronto, Ontario, Canada. One hundred one women, between the ages of 25 and 70 years, who were not on any medications, were recruited to record their diet for 7 days. Statistical analyses were performed to compare the types of lycopene-containing foods consumed, associations between intake of lycopene and macro/micronutrients, and whether participant characteristics, such as body mass index, could predict lycopene intake. Average lycopene intake was 6.14 +/- 5.35 mg/day, which is higher than reported in other countries. Intake was similar among age groups but was highly variable. Raw tomatoes were the most frequently consumed source of lycopene, while participants with the highest lycopene intake consumed more cooked/processed tomato products than those with lower intake (P < .005). Participants 25-49 years old consumed more dried/powdered tomatoes (P < .05), pizza (P < .002), and ketchup (P < .10) than 50-70 year olds. Lycopene intake could not be predicted by any participant characteristics. In older participants, lycopene intake was positively correlated with intake of calcium, niacin, and vitamins A, D, and K (P < or = .05). These findings are significant to women's health and may contribute to the establishment of nutritional and health recommendations regarding consumption of lycopene by Canadian women to prevent chronic diseases.

Fracture healing requires coordinated coupling between osteogenesis and angiogenesis in which vascular endothelial growth factor (VEGF) plays a key role. We hypothesized that targeted over-expression of angiogenic and osteogenic factors within the fracture would promote bone healing by inducing development of new blood vessels and stimulating/affecting proliferation, survival, and activity of skeletal cells. Using a cell-based method of gene transfer, without viral vector, 5.0 x 10(6) fibroblasts transfected with VEGF were delivered to a 10-mm bone defect in rabbit tibiae (Group 1) (n = 9); control groups were treated with fibroblasts (Group 2) (n = 7), or saline (Group 3) (n = 7) only. After 12 weeks, eight tibial fractures healed in Group 1, compared to four each in Groups 2 and 3. In Group 1, ossification was seen across the entire defect; in Groups 2 and 3, the defects were fibrous and sparsely ossified. Group 1 had more positively stained (CD31) vessels than Groups 2 and 3. MicroCT 3-D showed complete bridging of the new bone for Group 1, but incomplete healing for Groups 2 and 3. MicroCT bone structural parameters showed significant differences between VEGF treatment and control groups (p < 0.05). These results indicate that the cell-based VEGF gene therapy has significant angiogenic and osteogenic effects to enhance healing of a segmental defect in the long bone of rabbits.

Introduction: Oxidative stress induced by reactive oxygen species (ROS) is associated with the risk of osteoporosis, and can be reduced by certain dietary antioxidants. Lycopene is an antioxidant known to decrease the risk of age-related chronic diseases, such as cancer. However, the role of lycopene in osteoporosis has not yet been investigated., Materials and Methods: In a cross-sectional study, 33 postmenopausal women aged 50-60 years provided seven-day dietary records and blood samples. Serum samples were used to measure serum lycopene, lipid peroxidation, protein thiols, bone alkaline phosphatase (BAP), and cross-linked N-telopeptides of type I collagen (NTx). The serum lycopene per kilogram body weight of the participants was grouped into quartiles and associated with the above serum parameters using one-way ANOVA and the Newman-Keuls post-test., Results: The results showed that groups with higher lycopene intake, as determined from the dietary records, had higher serum lycopene (p<0.02). A higher serum lycopene was found to be associated with a low NTx (p<0.005). Similarly, groups with higher serum lycopene had lower protein oxidation (p<0.05)., Discussion: In conclusion, these results suggest that the dietary antioxidant lycopene reduces oxidative stress and the levels of bone turnover markers in postmenopausal women, and may be beneficial in reducing the risk of osteoporosis.