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Keywords:

  • AORTIC CALCIFICATION;
  • OSTEOPOROSIS;
  • RANKL/OPG;
  • DENOSUMAB;
  • CARDIOVASCULAR

ABSTRACT

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgments
  9. References

Atherosclerosis and osteoporosis are chronic diseases that progress with age, and studies suggest aortic calcification, an indicator of atherosclerosis, is inversely associated with bone mineral density (BMD). The osteoprotegerin (OPG)/receptor activator of NF-κB (RANK)/RANK ligand (RANKL) system has been proposed as a shared regulatory system for bone and vasculature. Denosumab (DMAb), a monoclonal antibody against RANKL, improved BMD and reduced fracture risk in the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial. We evaluated whether or not treatment with DMAb influenced progression of aortic calcification (AC) and incidence of cardiovascular (CV) adverse events. We included 2363 postmenopausal women with osteoporosis (1142 placebo, 1221 DMAb), selected from 7808 participants in the FREEDOM trial (3906 placebo, 3902 DMAb), at high risk of CV events according to modified Raloxifene Use for the Heart (RUTH) criteria. CV adverse events were reported by participants. AC scores were assessed using a semiquantitative method from lateral spine X-rays. Change in AC score from baseline to 12 (n = 1377), 24 (n = 1231), and 36 months (n = 1045) was calculated as AC score at follow-up minus AC score at baseline. AC progression was defined as change in AC score >0. Baseline characteristics, CV risk factors, and AC scores were similar between treatment groups. Mean age of participants was 74 years (range, 60–90), 88% were white, and 77% had AC score >0 at baseline. Frequency of AC progression over 3 years did not differ between women in placebo (22%) and DMAb (22%) groups (p = 0.98). AC progression did not differ between treatment groups when analyzed by baseline estimated glomerular filtration rate or by baseline AC scores. Frequency of CV adverse events did not differ between placebo (40%) and DMAb (38%) groups (p = 0.26). In conclusion, DMAb treatment had no effect on progression of AC or incidence of CV adverse events compared to placebo. © 2014 American Society for Bone and Mineral Research.


Introduction

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgments
  9. References

The presence of aortic calcification (AC) is strongly associated with risk of cardiovascular (CV) events.[1] Epidemiologic studies suggest AC is also associated with decreased bone mineral density (BMD), greater bone loss, and higher risk of fracture.[2-11] Findings can differ by study design, the population and skeletal site studied, as well as the approach used to evaluate AC and measure bone density. In the search for a common mediator capable of influencing bone remodeling and vascular calcification, the osteoprotegerin (OPG)/receptor activator of NF-κB (RANK)/RANK ligand (RANKL) system has received recent attention.[12]

In the bone compartment, RANKL stimulates osteoclast formation, activation, and survival.[13] OPG acts as a decoy receptor preventing RANKL from binding to its receptor RANK on osteoclast and osteoclast precursors and inhibiting bone resorption.[14] Blocking RANKL in preclinical and clinical studies by OPG, and later by denosumab (DMAb), a monoclonal antibody against RANKL, decreases bone resorption and increases bone mineral density.[15] In the randomized, double-blinded Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial, women assigned to treatment with DMAb, compared to placebo, had 68% reduction in risk of vertebral fracture and 40% reduction in hip fracture.[16]

In the vascular compartment, the exact role of RANKL and OPG is more controversial, because preclinical findings are not consistent with human epidemiological observations.[12, 17-19] Genetically modified animals that lack the gene for OPG have increased vascular calcification and osteoporosis, indicating a potential protective role of OPG.[20] Moreover, exogenous OPG has been shown to have mitigating effects on calcification in animal models of atherosclerosis and calcific arteriopathy.[21-24] In contrast, in humans, a large body of epidemiologic literature suggests a positive association between serum OPG and CV outcomes such as atherosclerosis, arterial calcification, or CV disease.[19, 25-28] Low serum RANKL was associated with an increased risk of CV disease in older women and men in the Bruneck Study.[29, 30] Although these findings from observational studies may provide compelling evidence for a link between OPG, RANKL, and cardiovascular disease, randomized trials are needed to help establish causation.

We assessed the effect of RANKL inhibition, by treatment with DMAb, on progression of AC and incidence of CV adverse events in women participating in the FREEDOM trial, a double-blinded, placebo-controlled, randomized trial.[31, 32]

Subjects and Methods

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgments
  9. References

Participants

The FREEDOM Trial randomized 7808 postmenopausal women (3906 placebo, 3902 DMAb) aged 60 to 90 years, with osteoporosis (baseline BMD T-score <–2.5 at the lumbar spine or total hip and ≥ −4.0 at both sites) to receive 60 mg of DMAb subcutaneously or placebo every 6 months (Q6M) for 3 years (Fig. 1). The inclusion and exclusion criteria have been described by Cummings and colleagues[16] (Clinical trial registration: http://clinicaltrials.gov/show/NCT00089791; A Study to Evaluate Denosumab in the Treatment of Postmenopausal Osteoporosis).

image

Figure 1. Flow diagram of study participants.

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For the current study, we identified 2363 women from the FREEDOM trial (1142 placebo, 1221 DMAb,), who received at least one dose of DMAb and were at increased risk of CV events, defined as a score of ≥4 points according to criteria used in the Raloxifene Use for the Heart (RUTH) trial.[31, 32] We modified the hyperlipidemia criterion, relying on a history of hyperlipidemia, instead of serum lipid measurements, which were not available. The score was determined as follows: prior myocardial infarction, percutaneous coronary intervention, or coronary artery bypass surgery (4 points), diabetes mellitus (3 points), age ≥70 years (2 points), age 65 to 69 years (1 point), current or former smoker (1 point), hypertension (1 point), and hyperlipidemia (1 point).[31, 32] Information on CV risk factors was obtained using a CV-specific medical history questionnaire administered to participants by study staff. These 2363 participants were included in the analysis of DMAb treatment on incidence of CV adverse events (Fig. 1).

Due to inadequate imaging, AC scores could not be determined for 729 of 2,354 participants who had a baseline X-ray, so that 1625 women were included in the analysis of DMAb treatment and AC (Fig. 1). The number of women with both baseline and follow-up AC scores was 1377 women (664 placebo, 713 treatment) at 12 months, 1231 women (583 placebo, 648 treatment) at 24 months, and 1045 women (501 placebo, 544 treatment) at 36 months.

Treatment

Women participating in the FREEDOM trial were randomized to receive placebo or DMAb 60 mg (Q6M) subcutaneously for 36 months. Participants were instructed to take daily calcium (at least 1 g) and vitamin D (400–800 IU).

AC

Two readers, who completed standardized training, independently graded each individual set of four radiographs (baseline, and 12, 24, and 36 months) in a temporal sequence. Calcific deposits in the abdominal aorta, adjacent to each lumbar vertebra (L1–L4), were assessed separately for the posterior and anterior walls of the aorta (8 segments in total). Each aortic segment was graded according to a 4-point severity scale: 0 (no calcification), 1 (less than 1/3 artery wall with calcification), 2 (1/3 to 2/3 artery wall with calcification), or 3 (more than 2/3 of the artery wall with calcification), as described for the Framingham Heart Study.[33] Readers were instructed that, for each aortic segment, the grade could not be lower at a subsequent time point (indicating improvement) than the grade assigned at a previous time point.

AC scores for each individual were calculated by summing the grades for the eight aortic segments. AC scores ranged from a minimum of 0, indicating no aortic calcification, and increasing in severity to a maximum of 24. If any one of the eight aortic segments could not be graded (due to inadequate visualization of soft tissue anterior to spine), then the AC score was considered missing. About 30% of individuals had at least one aortic segment that was not evaluable at each time point and therefore set to missing.

To evaluate reader reliability, the two readers evaluated AC scores for the same 30 radiographs. The intraclass correlation coefficient (ICC) between readers was ≥0.93, indicating excellent agreement. Change in AC score was calculated as the AC score at follow-up minus the AC score at baseline. The methods used to score AC on the baseline and follow-up radiographs in a temporal sequence prohibited any negative change scores. We defined (any) AC progression as change in AC score >0.

CV adverse events

CV adverse events and CV serious adverse events were reported by participants and/or physicians and were not adjudicated using medical records. These were coded as preferred terms in the Medical Dictionary for Regulatory Activities (MedDRA; Version 11.0). CV adverse events and serious CV adverse events included vascular and cardiac events as categorized by MedDRA that occurred after the first dose of investigational product.

Renal function

Renal function was estimated using the Cockcroft-Gault (mL/min) equation ([140–age {years}] × [weight {kg}] × [0.850 if female]/[72 × plasma creatinine {mg/dL}]). Cockroft-Gault estimation of renal function was chosen instead of the Modification of Diet in Renal Disease (MDRD) Study estimating method because the Cockroft-Gault estimation was used primarily in the analysis of the effects of DMAb on fracture and BMD by level of renal function for the whole FREEDOM study population.[34] In addition, the precision of the Cockroft-Gault estimation of renal function for women over the age of 60 years with truly low renal function appears to be slightly better than that obtained with MDRD estimation.[35-39] An estimated glomerular filtration rate (eGFR) above or less than 45 mL/min was selected to examine the influence of renal function on progression of AC as an eGFR below 45 mL/min has been shown to be associated with an increased prevalence of vascular calcification as well as an increased risk of clinical CV events.[40-42]

Statistical analysis

We compared baseline factors by treatment group in 1625 women who had evaluable AC scores at baseline, using two-sided Student's t tests or chi-square tests as appropriate.

We used a two-sided Wilcoxon rank sum test to compare the mean change in AC score (follow-up AC score minus baseline AC score) at each time point in women in placebo and treatment groups. We compared frequency (%) of any progression (AC score change >0) at each time point by treatment using a two-sided chi-square test with one degree of freedom (df). The number of women included in the analysis of change in AC score at 12, 24, and 36 months was 1377, 1231, and 1045, respectively.

We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between AC progression (AC score change >0) over 3 years and treatment group (n = 1045) adjusted for baseline AC score. We performed stratified analysis to evaluate potential differences in the association between any AC progression at 3 years and treatment group by baseline AC score (<6 versus ≥6) and baseline renal function (<45 versus ≥45 mL/min).

We calculated incidence (%) as the number of women who had one or more CV adverse events divided by 2363, the total number of participants with high CV risk (≥4 points on modified RUTH trial criteria). We compared incidence of CV adverse events by treatment group using a two-sided, chi-square test (1 df).

Analyses were performed based on the actual treatment received, where subjects who received at least one dose of DMAb were analyzed in the DMAb treatment group. Statistical testing was performed at the 5% significance level. Analyses were conducted using SAS software version 9.1.3 (SAS Institute, Cary, NC, USA).

Results

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgments
  9. References

As shown in Table 1, mean age (74 years), race (88% white), body mass index (BMI) (27 kg/m2), and years since menopause (26) were similar in placebo and DMAb groups (all p values >0.05). There were no differences at baseline between treatment groups at baseline in prevalence of vertebral fracture (22% to 24%), mean lumbar spine BMD T-score (–2.8), or eGFR (64 mL/min).

Table 1. Baseline Characteristics, According to Treatment Group, in 1625 Women in the FREEDOM Trial, Scoring ≥4 Points on Modified RUTH Trial Criteria and Who Had Evaluable AC Score at Baseline
 Placebo (n = 782)Denosumab (n = 843)Total (n = 1625)
  1. FREEDOM = Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months; RUTH = Raloxifene Use for the Heart; AC = aortic calcification; BMD = bone mineral density.

  2. a

    Placebo, n = 317; denosumab, n = 355; total, n = 672.

  3. b

    Placebo, n = 465; denosumab, n = 487; total, n = 952.

Age (years), n (%)74 (5)74 (5)74 (5)
White, n (%)688 (88)743 (88)1431 (88)
Body mass index (kg/m2), mean (SD)27 (4)27 (4)27 (4)
Years since menopause (years), mean (SD)26 (7)26 (7)26 (7)
Prevalent vertebral fracture, n (%)175 (22)201 (24)376 (23)
Lumbar spine BMD T-score, mean (SD)–2.75 (0.75)–2.79 (0.71)–2.77 (0.73)
Lumbar spine BMD (g/cm2), Hologica, mean (SD)0.738 (0.077)0.733 (0.063)0.735 (0.070)
Lumbar spine BMD (g/cm2), Lunarb, mean (SD)0.855 (0.093)0.850 (0.096)0.852 (0.094)
Total hip BMD T-score, mean (SD)–1.97 (0.82)–1.89 (0.84)–1.93 (0.83)
Total hip BMD (g/cm2), Hologica, mean (SD)0.715 (0.101)0.731 (0.098)0.724 (0.100)
Total hip BMD (g/cm2), Lunarb, mean (SD)0.755 (0.097)0.760 (0.101)0.757 (0.099)
Estimated glomerular filtration rate (mL/min), mean (SD)64 (19)64 (20)64 (20)

The distribution of baseline AC score was highly skewed (Fig. 2) with nearly one-fourth of participants having no evidence of aortic calcification at baseline (AC score = 0: 22% placebo, 24% DMAb; p = 0.24). Median baseline AC scores were similar between placebo (AC = 6) and DMAb (AC = 5) groups (p = 0.20; Table 2). Further, median AC score at baseline was similar between treatment groups in women with low (<45 mL/min) and high (≥45 mL/min) eGFR, and in women with baseline AC scores below the median (<6) and equal to or above the median (≥6); all p values >0.05.

image

Figure 2. Frequency distribution of baseline AC score in 1625 participants. AC = aortic calcification.

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Table 2. Baseline AC Score, According to Treatment Group, in Overall Study Group and Stratified by Baseline eGFR and by Baseline AC Score Category, in 1625 Women in the FREEDOM Trial, Scoring ≥4 Points on Modified RUTH Trial Criteria and Who Had Evaluable AC Score at Baseline
 Placebo (n = 782)Denosumab (n = 843)Total (n = 1625)
  1. Values are median (interquartile range).

  2. AC = aortic calcification; eGFR = estimated glomerular filtration rate; FREEDOM = Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months; RUTH = Raloxifene Use for the Heart.

  3. a

    Aortic calcification score has no units and ranges from 0 to 24.

AC scorea6 (11)5 (11)6 (11)
AC score by eGFR   
eGFR <45 mL/min8 (12)8 (13)8 (13)
eGFR ≥45 mL/min6 (11)5 (11)5 (11)
AC score by median AC score   
AC score <61 (3)1 (2)1 (3)
AC score ≥611 (6)12 (7)12 (7)

The distribution of CV risk factors (RUTH criteria) used to select participants for the current study was similar in placebo and DMAb groups (Table 3). Ninety-one percent were 70+ years old, and baseline prevalence of hypertension was 83%, high cholesterol 66%, and diabetes 26%. Thirteen percent of women in the DMAb group and 12% in the placebo group had a history of myocardial infarction, coronary artery bypass grafting, or percutaneous coronary intervention.

Table 3. Distribution of Cardiovascular Risk Factors, According to Treatment Group, in 1625 Women in the FREEDOM Trial, Scoring ≥4 Points on Modified RUTH Trial Criteria and Who Had Evaluable AC score at baseline
 PointsPlacebo (n = 782)Denosumab (n = 843)Total (n = 1625)
  1. FREEDOM = Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months; RUTH = Raloxifene Use for the Heart; AC = aortic calcification.

Cardiovascular (RUTH) score, mean (SD)Range, 4–135.3 (1.7)5.3 (1.7)5.3 (1.7)
Myocardial infarction, percutaneous intervention, or coronary bypass, n (%)494 (12.0)113 (13.4)207 (12.7)
Diabetes mellitus, n (%)3203 (26.0)217 (25.7)420 (25.8)
Age ≥70 years, n (%)2705 (90.2)766 (90.9)1471 (90.5)
Age 65–69 years, n (%)164 (8.2)67 (7.9)131 (8.1)
Former or current smoker, n (%)1351 (44.9)404 (47.9)755 (46.5)
Hypertension, n (%)1652 (83.4)692 (82.1)1344 (82.7)
High cholesterol, n (%)1525 (67.1)542 (64.3)1067 (65.7)

Mean change in AC score was 0.1 at 12 months, 0.2 at 24 months, and 0.4 at 36 months of follow-up in both placebo and DMAb groups (all p values >0.05; Table 4). DMAb had no effect on frequency of AC progression (change in AC score >0) at 12 months (4% placebo, 5% DMAb), 24 months (10% placebo, 12% DMAb), or 36 months (22% placebo, 22% DMAb) of follow-up. The OR for AC progression over 3 years associated with DMAb was 1.00 (95% CI, 0.74–1.34, Fig. 3). Further, odds of 3-year progression of AC did not differ according to baseline renal function (eGFR of ≥45 mL/min or <45 mL/min) or baseline AC score (<6 or ≥6).

Table 4. Comparison of Mean Change in AC Score and Frequency of Any Progression in AC Score, According to Treatment Group and Months of Follow-Up, in Women in the FREEDOM Trial Scoring ≥4 Points on Modified RUTH Trial Criteria
Follow-up, monthsChange in AC (follow-up minus baseline)Frequency of any progression (change in AC >0)Total
Placebo, mean (SD)Denosumab, mean (SD)pPlacebo, % (n/N)Denosumab, % (n/N)pn
  1. AC = aortic calcification; FREEDOM = Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months; RUTH = Raloxifene Use for the Heart.

120.1 (0.6)0.1 (0.4)0.384% (26/664)5% (35/713)0.371377
240.2 (0.7)0.2 (0.8)0.2710% (60/583)12% (78/648)0.331231
360.4 (1.0)0.4 (1.1)0.9722% (109/501)22% (118/544)0.981045
image

Figure 3. ORs and 95% CIs for association between treatment and any progression of AC (change in AC score >0) over 36 months for overall study group and stratified by baseline AC score category and baseline eGFR in 1045 participants. OR = odds ratio; CI = confidence interval; eGFR = estimated glomerular filtration rate.

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Incidence of CV adverse events (38% to 40%) and incidence of serious CV adverse events (9% to 10%) did not differ between women in the placebo and DMAb groups (Table 5).

Table 5. Comparison of Incidence of Cardiovascular Adverse Events (Number of Women With at Least 1 Cardiovascular Adverse Event) Over 36 Months of Follow-Up, According to Treatment Group, in 2363 Women in the FREEDOM Trial Scoring ≥4 Points on Modified RUTH Trial Criteria
 Placebo (n = 1142)Denosumab (n = 1221)p
  1. Values are n (%).

  2. FREEDOM = Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months; RUTH = Raloxifene Use for the Heart.

Cardiovascular events456 (40)460 (38)0.26
Vascular337 (30)325 (27)0.12
Cardiac193 (17)214 (18)0.69
Serious cardiovascular events105 (9)122 (10)0.51
Vascular35 (3)36 (3)0.87
Cardiac79 (7)98 (8)0.31

Discussion

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgments
  9. References

This is the largest study to evaluate the effect of DMAb, an inhibitor of RANKL, on the progression of vascular calcification in a large, randomized clinical trial. We found no evidence that treatment with this drug contributed to the progression of abdominal aortic calcification or to increased risk of CV adverse events in 60- to 90-year-old women with osteoporosis and high CV risk.

In our study, we used the most conservative criterion for evaluating AC progression defined as change in AC score >0. Thus, even the smallest increase would be considered as progression in AC score. However, AC is a slow process, and we cannot rule out that the 3-year duration of follow-up may not have been long enough to detect a potential difference between treatment and placebo groups.

Our results are similar to a small, randomized trial of ibandronate in 474 women with osteoporosis 55 to 80 years old,[43] which reported no differences in 3-year progression of AC (evaluated using the same methods as the current study) between treatment and placebo groups. Although both ibandronate and DMAb are antiresorptive drugs, the mechanisms of action are distinctly different. Nevertheless, we have demonstrated that 3 years of DMAb treatment in postmenopausal women, although preventing fractures, does not increase the risk for progression of vascular calcification. Because patients with chronic kidney disease are predisposed to vascular calcification, we also studied the effects of treatment on progression of vascular calcification in participants with lower eGFR.[28, 44] Even in this higher risk group of women with eGFR <45 mL/min, there was no evidence that DMAb led to acceleration in the progression of abdominal AC. Moreover, DMAb did not significantly affect eGFR in this study (data not shown).

Multiple reports demonstrate an inverse relationship between the degree of calcification in the aorta and the degree of calcification of the skeleton.[2-11] A biological link has long been hypothesized between bone metabolism pathways and vascular calcification and most recently the OPG/RANK/RANKL system has been proposed as a plausible shared regulatory system.[17, 18] Although elevated OPG levels have been associated with increased coronary calcification scores in hemodialysis patients, the association has never been causally established.[28]

Numerous epidemiological studies have found a positive association between serum OPG concentrations and CV outcomes[25-27]; however, the biological implications remain unclear. First, it has never been clear whether or not the elevated serum concentrations of OPG cause vascular calcification or represent a response to the calcification. Further, the serum concentrations of OPG might not reflect OPG levels in the vessel wall.

One possible explanation for increased serum OPG levels in women with vascular disease is that they represent an incomplete or insufficient regulatory mechanism to counteract disease progression.[18] This is supported by preclinical findings demonstrating a protective role of RANKL inhibitors on both vascular calcification and bone loss.[20, 21, 23, 45] Of note, low-density lipoprotein receptor knockout mice with atherosclerosis and vascular calcification, induced by an atherogenic diet, had high levels of endogenous OPG. However, treatment of these mice with recombinant OPG resulted in reduced incidence of vascular calcification without changes in atherosclerosis lesion size or number in comparison to a group treated with the vehicle.[22] Additional preclinical evidence indicated that blocking RANKL by DMAb inhibited aortic calcium deposition and prevented bone loss following glucocorticoid exposure in the human RANKL knock-in mice.[46]

Until recently, studies in humans have been limited to measuring circulating OPG (and not RANKL), as OPG is easily measurable and circulates at a higher level than RANKL. OPG levels reflect total OPG (both bound and unbound to RANKL) and cannot be used as a surrogate for either RANKL activity or inhibition. Although an inverse association has been observed between levels of circulating RANKL and symptomatic coronary artery disease in small, cross sectional studies,[29, 47] high baseline serum concentrations of RANKL increased the risk for incident CV disease (myocardial infarction, stroke, transient ischemic attack, and vascular death) in a large, 15-year population-based study in 909 participants in the Bruneck Study.[30]

Because the radiographs were acquired to assess vertebral fracture, AC scoring was difficult due to the convexity of the lumbar lordosis adjacent to L3 and L4. We conservatively considered AC score as missing if any one of the eight aortic segments could not be graded. Although we used a reliable and validated method of scoring AC based on evaluation of lateral vertebral spine radiographs,[33] 25% to 30% of women were missing longitudinal AC scores. However, baseline characteristics (age, BMI, years since menopause, BMD T-scores, and eGFR) were similar in women with radiographs that could be assessed and women with radiographs that could not be evaluated. The frequency of women who were white and who had prevalent vertebral fractures was somewhat lower in women with radiographs that could not be assessed (88% white, 23% prevalent vertebral fracture) versus those with radiographs that could be assessed (94% white, 27% fracture). More importantly, there were no differences in baseline characteristics between placebo and treatment groups in women who did not have evaluable radiographs. The amount of missing data also did not differ between treatment groups, although it is possible that the lower sample size could have reduced our ability to detect a potential treatment effect.

In our study, we instructed the radiologist readers to consider only stable or progressively more severe scores in evaluating the longitudinal sets of radiographs; therefore, we were unable to exclude the possibility of a small protective effect of DMAb on radiographic progression of vascular calcification. Our imaging approach, although valid for predicting incident CV events, may not be the most sensitive method for detecting progressive disease. However, we found no treatment effect on incidence of CV adverse events, which occurred in nearly 40% of participants, given the selection criteria to include high-risk subjects.

This study provides evidence that DMAb treatment over 3 years in women with osteoporosis does not affect risk of progression of AC or subject incidence of CV adverse events. The findings are based on a subset of women at high risk of CV disease from a large, randomized clinical trial and robust methods were used to assess AC and CV adverse events. Although the relation between OPG/RANK/RANKL and vascular calcification is not yet fully elucidated, findings from the FREEDOM trial demonstrate that the benefits in BMD accrual and fracture risk reduction conferred by DMAb treatment are not accompanied by increased risk of vascular calcification and cardiovascular adverse events.

Disclosures

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgments
  9. References

AMC has served as a consultant to and/or has received grant funding from Amgen, Eli Lilly, Merck, Novartis, and Warner Chilcott. LG has served as a consultant for Otsuka, was an Amgen employee, and owned Amgen Inc. stock and/or stock options at the time of collaboration on the manuscript. NF was an Amgen employee and owned Amgen Inc. stock and/or stock options at the time of collaboration on the manuscript, and is presently a Biogen Idec employee. DPK has served as a consultant to Amgen, received grant funding from Amgen, has served as a consultant for Eli Lilly, Novartis, and Merck, and has received grant funding from Novartis and Merck. PDM has served as a consultant to and received grant funding from Amgen, Lilly, Merck, Radius, and GE-Lunar. MSA, NSD, OE, SS, and AW are employees at Amgen Inc. and own Amgen Inc. stock and/or stock options. CC is an employee of Nordic Bioscience A/S and CCBR/Synarc, has served as consultant to Amgen, Roche, Wyeth-Ayerst, Eli Lilly, Novartis, Novo Nordisk, Proctor and Gamble, Groupe Fournier, Besins EscoVesco, MSD, Chiesi, Boehringer Mannheim, and Pfizer, has received speaking fees from Pfizer and owns stock in Nordic Bioscience and CCBR/Synarc.

Acknowledgments

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgments
  9. References

This study was funded by Amgen Inc. EJS's work on this study was supported by NIH K01 AR053118. AMC's work is supported by a senior investigator award from the Canadian Institutes of Health Research. We thank the investigators of the FREEDOM trial as well as the participants who participated in the trial.

Authors' roles: Study design: SS, LG, AC, PM, NF, CC, OE, ND, AW, and DPK. Study conduct and data collection: SS and LG. Data analysis: AW and ND. Data interpretation: EJS, DPK, SS, and MSA. Drafting manuscript: EJS, DPK, NF, SS, and OE. Revising manuscript content: EJS, DPK, SS, OE, AW, ND, MSA, LG, AC, PM, and CC. Approving final version of manuscript: EJS, PM, CC, ND, LG, MSA, OE, AW, SS, AC, NF, and DPK.

References

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgments
  9. References
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