CV Risk

CVD and fracture risk factors may predict CV risk for older adults with osteoporosis

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Prediction models incorporating both cardiovascular disease and fracture risk factors may be able to predict the risk for major adverse CV events in adults with osteoporosis, according to study data.

“In this study, we evaluated the incidence of major adverse CV events though a composite outcome … and assessed risk factors of CVD to predict this outcome at 1 year in three different cohorts,” Daniel Prieto-Alhambra, MD, PhD, professor of pharmaco- and device epidemiology research at the Centre for Statistics in Medicine in the Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Nuffield Orthopaedic Centre at the University of Oxford in the U.K., and colleagues wrote in a study published in The Journal of Bone and Mineral Research. “The incident fragility fracture cohort can be used for a secondary fracture prevention program, the starting oral bisphosphonates cohort has the potential to be used in primary prevention since it approximates patients newly diagnosed and treated for osteoporosis, while the recently diagnosed with osteoporosis cohort can be used as a general screening in primary care.”

Incidence rates for major adverse CV events among older adults
Older adults with an incident fracture have a higher incidence rate for major adverse CV events than incident bisphosphonate users and those diagnosed with osteoporosis. Data were derived from Pineda-Moncusí M, et al. J Bone Miner Res. 2022;doi:10.1002/jbmr.4648.

Researchers obtained data from the Clinical Practice Research Datalink (CPRD) GOLD database in the U.K. of adults aged at least 50 years at high or imminent fracture risk from 1995 to January 2017. Data were linked to Hospital Episode Statistics Admitted Patient Care data, the Office for National Statistics mortality records and the Index of Multiple Deprivation dataset. The study population was divided into a group of 65,295 adults with an incident diagnosis of osteoporosis (86.8% women; mean age, 73.05 years), a group of 67,065 adults with a first incident fracture at an osteoporotic site (76.7% women; mean age, 79.52 years) and a group of 145,959 incident users of oral bisphosphonates without bisphosphonate use the prior year (79.8% women; mean age, 74.35 years). Participants were followed from the time of diagnosis, incident fracture or start of bisphosphonates for a maximum of 2 years. The main outcome was 1-year occurrence of major CV adverse events, which was defined as the first occurrence of stroke, myocardial infarction or death due to CVD.

At 1 year, the incident fracture group had the highest major adverse CV event (MACE) incidence rate at 52.6 per 1,000 person-years, the oral bisphosphonate group had an incidence rate of 26.3 per 1,000 person-years and the osteoporosis cohort had the lowest incidence rate at 19.6 per 1,000 person-years. Adults experiencing MACE were older, had more comorbidities and a higher prevalence of drug use.

Predictive models using general, CVD and fracture risk factors selected by Lasso regression had an area under the curve of greater than 70% for all three cohorts. These models outperformed models using QRISK factors. Models predicting MACE in the osteoporosis and oral bisphosphonate outcomes had higher discrimination values compared with models predicting stroke or MI, whereas discrimination values within the incident facture cohort were higher for models predicting stroke and MI compared with models predicting MACE.

“The resulting algorithms include risk factors specific to the study population as well as more generic features that can be found easily in primary care data,” the researchers wrote. “Further work will focus on validating these models in external cohorts.”

Women’s CV risk increases with age, not reproductive stage

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Menopausal women tend to have worse cardiovascular risk profiles than premenopausal women, but 5-year increases in CV risk factors are not dependent on reproductive stage, according to data from the CoLaus study.

Pedro Marques-Vidal, MD, PhD, associate professor in the department of nuclear medicine at Lausanne University Hospital, University of Lausanne, Switzerland, and colleagues conducted the prospective, population‐based cohort CoLaus study to better understand whether changes in women’s CVD risk factors differ by reproductive stage independently of underlying aging trajectories.

stethascope heart

Study participants included women who did not use hormone therapy and were followed from 2003 to 2012 for a mean of 5.6 years. Researchers classified women into four categories based on baseline and follow-up comparisons of their menstruation status: premenopausal, menopausal transition, early postmenopausal ( 5 years) and late postmenopausal (> 5 years).

Pedro Marques-Vidal

Researchers used repeated measures of fasting lipids, glucose and CV inflammatory markers for longitudinal analysis, with premenopausal women serving as a reference category, and adjusted analyses for age, medication use and lifestyle factors.

The study featured data from 1,710 women who were aged 35 to 75 years.

The analysis revealed that changes in CVD risk factors did not differ in the other three menopausal categories compared with premenopausal women.

When researchers used age as a predictor variable and adjusted for menopause status, they found that most CVD risk factors rose, whereas interleukin‐6 and interleukin‐1 beta decreased with advancing age.

“All women increase their cardiovascular risk as they get older, and in our study, we found no differences in cardiovascular risk changes comparing women in advanced reproductive stages with premenopausal women,” researchers wrote. “This highlights the strong association between chronological age and the cumulative deleterious effects in CVD risk for women. More longitudinal studies that use novel biomarkers for ovarian age are still needed to disentangle the association between menopause and CVD risk in postmenopausal women and women in the menopause transition. … It would be prudent to do screening and preventive measures during menopause transition as these are also ageing women with inherent cardiovascular risks. Cardiovascular preventive measures should target not only postmenopausal women, but also women in the transition phase while waiting for more conclusive evidence.”

Alfacalcidol Does Not Lower CV Risk in Dialysis, Trial Suggests

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Alfacalcidol does not reduce the risk for cardiovascular events in patients without secondary hyperparathyroidism undergoing maintenance hemodialysis compared with usual care, the Japan Dialysis Active Vitamin D (J-DAVID) trial has found. But experts question the generalizability of the findings.

During a median of 4 years, the composite outcome of select cardiovascular events was 21.1% in those who took oral alfacalcidol, a vitamin D receptor agonist (VDRA), compared with 17.9% in the usual-care group, a difference that was not statistically different.

“[O]ral alfacalcidol compared with usual care did not reduce the risk of a composite measure of select cardiovascular events. These findings do not support the use of vitamin D receptor activators for patients such as these,” the researchers write.

The study, by Tetsuo Shoji, MD, PhD, from the Department of Vascular Medicine, Osaka City University Graduate School of Medicine, Japan, and colleagues, was published online December 10 in JAMA.

The study was conducted in Japan, and the results are not generalizable to other countries, Rasheeda K. Hall, MD, MBA, MHS, and Julia J. Scialla, MD, MHS, from the Department of Medicine, Duke University School of Medicine, Durham, North Carolina, write in an accompanying editorial.

“Although the use of phosphate binders, VDRAs, and cinacalcet in Japan are comparable to the use in the United States, dialysate calcium and selection of calcium-based vs non–calcium-based phosphate binders tends to be higher in Japan. These patterns were observed in the J-DAVID trial, with approximately 70% of participants using dialysate calcium of 3.0 mEq/L and approximately 80% using calcium-based phosphate binders,” Hall and Scialla explain.

“These practices may be so different from those in the United States and internationally that generalization is not feasible,” they continue.

No Difference in Cardiovascular Outcomes

Vitamin D activation is impaired and cardiovascular risk is elevated in patients with chronic kidney disease. Observational studies have suggested that VDRAs reduce this risk, but the approach had not been tested in randomized trials.

Therefore, Shoji and colleagues conducted a randomized, open-label, blinded endpoint trial that compared the effect of the oral VDRA alfacalcidol with usual care (no VDRAs) on cardiovascular events in patients without secondary hyperparathyroidism receiving maintenance hemodialysis at 108 dialysis centers. For the patients in the study, serum intact parathyroid hormone levels were ≤180 pg/mL.

The investigators randomly assigned 976 patients to receive either alfacalcidol, beginning at a dose of 0.5 μg per day (n = 495) or usual care (n = 481). The intention-to-treat analysis included 964 patients, of whom 944 (97.9%) completed the trial. The median age of the participants was 65 years, and 386 were women (40.0%).

“All participants were eligible to receive any medications other than VDRAs, including phosphate binders and cinacalcet, for standard medical care as recommended by the JSDT [Japanese Society for Dialysis Therapy] Clinical Practice Guidelines,” the researchers explain.

Cardiovascular events, the primary composite outcome, occurred in 103 of 488 patients (21.1%) in the alfacalcidol group, compared with 85 of 476 patients (17.9%) in the usual-care group (absolute difference, 3.25%; 95% confidence interval [CI], −1.75% to 8.24%; hazard ratio [HR], 1.25; 95% CI, 0.94 – 1.67; P = .13). This difference was not statistically significant.

The secondary outcome of all-cause mortality did not differ significantly between the groups (18.2% vs 16.8%, respectively; HR, 1.12; 95% CI, 0.83 – 1.52; P = .46).

Among those in the alfacalcidol group, 76.0% experienced serious adverse events (SAEs), including cardiovascular-related (40.8%), infection-related (13.1%), and malignancy-related SAEs (4.5%).

Among those in the usual-care group, 79.2% experienced SAEs, including events that were cardiovascular- (40.1%), infection- (13.2%), and malignancy-related (4.4%).

“The number of cardiovascular SAEs was higher than the number of occurrences of the primary outcome because some participants had more than 2 cardiovascular SAEs,” the researchers explain.

Predefined laboratory abnormalities differed between the two groups. Corrected serum calcium levels >10.0 mg/dL and phosphate levels >6.0 mg/dL occurred more frequently in the group that received alfacalcidol compared with the control group. Intact parathyroid hormone levels >240 pg/mL occurred less commonly, especially during the first year of follow-up.

Generalizability May Be Limited

“[T]he results cannot be generalized to patients with secondary hyperparathyroidism or to non-Japanese populations, particularly not to US patients undergoing hemodialysis, who have much higher levels of intact PTH [parathyroid hormone] than the participants of this trial,” the researchers note.

Hall and Scialla reiterate that point. “As the J-DAVID investigators acknowledge, VDRAs may plausibly yield different results when accompanied by less calcium loading in the form of dialysate and exogenous calcium,” they write.

The editorialists say that although the researchers excluded patients “with clear indications or contraindications for VDRAs,” approximately one third of participants crossed over during the study; 35% of patients in the usual-care group and 32% of those in the alfacalcidol group dropped out of their assigned treatment. The study did not account for this in power calculations, they explain.

“In addition, the composite cardiovascular end point in the J-DAVID trial was broad. Although this broad end point may improve power for the study, the pathophysiology of many of the end point components, such as sudden cardiac death, peripheral amputation, and stroke, including hemorrhagic stroke, may be heterogeneous and not clearly modified by 1,25[OH]2D-responsive pathways,” Hall and Scialla observe.

“Future studies are needed, both observational and randomized, to understand who should be treated with VDRAs, to what biochemical target levels patients should be treated, and what therapeutic combinations of VDRAs and mineral metabolism cointerventions should be used to prevent CVD in patients with ESKD [end-stage kidney disease] undergoing hemodialysis,” they conclude.