General characteristics of study patients
Demographic and clinical characteristics of the study patients are shown in . A history of CVD was present in 472 (63.3%) of 746 patients included in the study. This group was older (on average 2.2 years) and had a higher proportion of patients with American Society of Anesthesiologists (ASA) score ≥ 3 (+22%) and renal impairment (CKD ≥ 3, +10.9%). No significant differences between patients with and without CVD were observed in regard to sex, residential status, use of walking device, current and former smoking status, alcohol consumption, dementia, type 2 diabetes mellitus, chronic obstructive pulmonary disease, Parkinson’s disease, thyroid dysfunction, anemia, or hypoalbuminemia.
Socio-demographic and clinical characteristics of older patients with hip fracture included in the study (n = 746)
The group with CVD comprised 337 (45.2% of the total cohort) patients with hypertension, 171 (22.9%) with CAD, including 39 (5.2%) with a previous myocardial infarction, 100 (13.4%) with history of stroke, 55 (7.4%) with a history of transient ischemic attack, and 99 (13.2%) with atrial fibrillation (AF). Among the patients with CVDs, one condition was present in 290 (61.4%), two in 121 (25.6%) and three or more in 66 (14.0%) subjects. Chronic heart failure was diagnosed in 384 (59.5% of the total cohort, 81.4% of patients with CVD). Hypertension was associated with CAD (Pearson correlation r = 0.146, P = 0.014) and history of stroke (r = 0.186, P = 0.002). CAD was also associated with history of stroke (r = 0.221, P = 0.033) and AF (r = 0.221, P < 0.001).
Among patients with CVD, angiotensin-converting enzyme (ACE) inhibitors were used by 26.5%, angiotensin 2-receptor blockers (ARBs) by 23.3%, beta blockers by 27.4%, calcium-channel blockers by 12.7%, and statins by 21.5%. Antiosteoporotic medications were used as follows: vitamin D supplement by 19.1% of patients with CVD and 17.7% without CVD, calcium supplement by 22.5% and 19.9%, bisphosphonate by 13.5% and 12.3%, and raloxifene by 1.12% and 0.72%, respectively.
Parameters of mineral and bone metabolism in patients with and without cardiovascular disease
The mean values of serum 25(OH)D concentrations in the group of patients with CVD in total and with each analyzed cardiovascular condition separately were low and did not differ from patients without CVD (). In contrast, serum PTH levels were significantly higher in all groups with CVD compared to non-CVD patients. Patients with hypertension and CAD also had higher serum phosphate levels, and subjects with CAD, history of stroke, and AF demonstrated higher magnesium levels.
Parameters of mineral and bone metabolism in older hip-fracture patients with and without cardiovascular disease
The prevalence of vitamin D deficiency (25[OH] D < 50 nmol/L) was high in both patients without CVD and in the total group with CVD (82.1% and 78.0%, respectively), but slightly lower in patients with CAD (73.1%, P = 0.032) and history of stroke (68.0%, P = 0.006). The percentage of patients with moderate–severe vitamin D deficiency (25[OH] D < 25 nmol/L) did not differ between groups either: 28.9% in the non-CVD group and 31.2% among subjects with CVD, including those with hypertension (34.0%), CAD (33.3%), history of stroke (27.0%), and AF (34.5%).
Conversely, compared to patients without CVD, the proportion of subjects with elevated PTH levels (>6.8 pmol/L) indicating SHPT was about two times higher among the patients with CVD (43% vs 23.3%, P < 0.001), and the highest percentages were observed in patients with CAD (53.8%) and history of stroke (51.0%), despite the lower prevalence of vitamin D deficiency in these two groups. Among patients with both vitamin D deficiency and elevated PTH, there was a higher prevalence of subjects with CVD (35.5% vs 21.1%, P = 0.024), including those with hypertension (37.7%, P = 0.012), CAD (46.4%, P = 0.003), history of stroke (37.8%, P = 0.0.13), and AF (35.5%, P = 0.041). Of 267 patients (35.8% of the total cohort) with SHPT, 203 (76.03%) had CVD. Subjects with CVD and SHPT compared to those with normal PTH status (12.3 ± 1.8 vs 4.0 ± 1.6 pmol/L) had a lower level of serum calcium (2.24 ± 0.12 vs 2.30 ± 0.12; P = 0.002) and eGFR (54.4 ± 24.6 vs 68.1 ± 20.0 mL/minute/1.73 m2; P < 0.001), but there were no differences in age or other biochemical and clinical parameters, except a higher proportion of patients with ASA ≥ 3 among the first group (88.3% vs 73.9%; P = 0.038).
The mean serum levels of both bone-formation markers (OC and BAP) and the OC/BAP ratios (indicator of osteoblastic differentiation) did not differ among the groups with and without CVD. Low OC levels (<14 ng/mL, below reference range) were observed in approximately half of the patients (53.1% without CVD and 51.7% with CVD), while low BAP levels (<14 IU) occurred in 9.7% (13.3% and 7.7%, respectively). The different behaviors of OC and BAP, each of which reflects different aspects of bone metabolism and different stages of osteoblastic differentiation, have previously been observed in other clinical settings.55
The urinary excretion of DPD adjusted for creatinine (DPD/Cr), a bone-resorption marker, was significantly higher in patients with CAD (31.9%), history of stroke (27.6%), atrial fibrillation (17.2%), and in the total group with CVD (14.7%). However, the association between CVD and urinary NTx/Cr, the collagen product which resembles DPD, was not significant. In other studies, these two bone-resorption markers have also shown clinically distinct properties.56
The prevalence of elevated DPD/Cr (>7.5 nmol/μmol) was significantly higher in the group with CVD (87.9% vs 74.8%; P
< 0.001), including those with hypertension (87.8%, P
< 0.001), CAD (91.8%, P
< 0.001), history of stroke (94%, P
< 0.001), and AF (90%, P
= 0.002). Among patients with CVD and high DPD/Cr excretion compared to those with DPD/Cr in the normal range, the proportion of subjects with SHPT (40.9% vs 66.7%; P
= 0.038) and low serum OC (49.6% vs 83.3%; P
= 0.007) was lower.
With an increasing number of CVDs, there was a gradient increase in mean levels of serum PTH (in subjects with one CVD 7.4 pmol/L, with two CVDs 9.1 pmol/L, and with three or more CVDs 10.2 pmol/L; P for trend = 0.001), as well as in the prevalence of secondary hyperparathyroidism (35.5%, 45.5%, and 60.0%, respectively; P for trend = 0.001). Similarly, increasing the number of CVDs increased the mean levels of urinary DPD/Cr (12.1, 14.3, and 15.8 nmol/μmol, respectively; P for trend = 0.030) and the proportion of patients with abnormally high bone-resorption status (83.8%, 88.0%, and 95.2%, respectively; P for trend = 0.016).
Correlations between biomarkers of mineral and bone metabolism by cardiovascular disease
To evaluate further the associations between CVD and altered parameters of mineral and bone metabolism in HF patients, Pearson correlation coefficients were estimated separately in subjects with and without CVD. Values for PTH, 25(OH)D, mineral-and bone-metabolism parameters, and eGFR were logarithmically transformed before analysis. This analysis revealed similarities and differences in patients with and without CVD. In both groups, serum PTH levels were positively correlated with age and inversely with serum calcium, eGFR, and cervical type of HF ().
Pearson correlation coefficients between serum PTH levels and selected clinical, mineral, and bone metabolism factors in older hip-fracture patients with and without cardiovascular disease
However, only in patients with CVD, PTH correlated positively with BAP, troponin I, and in-hospital death, while only in the non-CVD group higher PTH levels were significantly associated with female sex and dementia. BAP correlated positively with serum magnesium (r
= 0.176, P
< 0.022) in the CVD group and with calcium (r
= 0.349, P
< 0.001) and phosphate (r
= 0.286, P
= 0.049) in patients without CVD. Only in the later group, OC correlated positively with BAP (r
= 0.264, P
= 0.009), calcium (r
= 0.240, P
= 0.020), and magnesium (r
= 0.279, P
= 0.007). In both groups, OC correlated inversely with eGFR (r
= −0.456, P
< 0.001 for the CVD group and r
= −0.202, P
= 0.046 for the non-CVD group) and in-hospital death (r
= −0.210, P
= 0.006 and r
= −0.254, P
= 0.012, respectively). In both groups, DPD/Cr positively correlated with serum phosphate (r
= 0.165, P
= 0.048 and r
= 0.268, P
= 0.014, respectively), and the two urinary bone-resorption markers (DPD/Cr and NTx/Cr) were significantly intercorrelated (r
= 0.446, P
< 0.001 and r
= 0.349, P
< 0.001, respectively). 25(OH)D correlated negatively only with NTx/Cr only in the non-CVD patients (r
= −0.260, P
= 0.021). There was no correlation between PTH and resorption markers (DPD/Cr and NTx/Cr), which is consistent with previous reports.59
Factors associated with cardiovascular disease
In univariate analyses of twelve biochemical (25[OH]D, PTH, calcium, phosphate, magnesium, OC, BAP, DPD/Cr, NTx/Cr, hemoglobin, albumin, eGFR) and seven clinical (age, sex, HF type, dementia, smoking, alcohol overuse, use of walking device) parameters, presence of CVD was significantly associated only with age (OR 1.03, 95% confidence interval [CI] 1.00–1.07; P = 0.034), high bone resorption ( urinary DPD/Cr > 7.5 nmol/μmol, OR 2.44, 95% CI 1.23–4.87; P = 0.011), and elevated serum PTH levels (>6.8 pmol/L, OR 2.36, 95% CI 1.35–4.11; P = 0.003). PTH as a continuous variable was also associated with CVD (OR 1.06, 95% CI 1.00–1.13; P = 0.033), indicating that the risk of CVD increases by 6% per 1 pmol/L increment in PTH.
To evaluate further whether higher serum PTH levels were associated with CVD, and given the wide range of PTH in our cohort, age-, sex-and 25(OH)D-adjusted ORs were estimated by quartiles of PTH concentration. For the total CVD group as well as for each of the four studied diseases separately, the adjusted ORs increased with quartiles of serum PTH (P for trends < 0.01 in all groups). Compared to the first quartile (PTH < 3.5 pmol/L), in the fourth quartile (PTH > 8.7 pmol/L) the OR for the total CVD group was 2.5 times higher (95% CI 1.12–5.61; P = 0.006), and the highest values were for CAD (OR 3.34, 95% CI 1.35–8.33; P = 0.009) and history of stroke (OR 2.93, 95% CI 1.04–8.21; P = 0.011).
Using serum PTH at a cutoff of 6.8 pmol/L, it was possible to discriminate between presence and absence of CVD with a sensitivity of 42.9%, specificity of 75.8%, positive predictive value of 76.8% and negative predictive value of 41.6%, and using PTH > 8.7 pmol/L with 30.5%, 84.2%, 78.3%, and 39.4%, respectively. A sensitivity of 88.0%, specificity of 25.0%, positive predictive value of 66.7%, and negative predictive value of 55.0% were yielded using DPD/Cr > 7.5 nmol/μmol. These data suggest that SPTH (more specific) and high bone resorption (more sensitive) may be useful indicators of CVD (if previously not diagnosed).
We then examined which factors are independently associated with CVD. Multiple logistic regression analysis with PTH, 25(OH)D, DPD/Cr, albuminemia, eGFR, smoking status, alcohol consumption, HF type, dementia, and sex entered as independent categorical variables and corrected for age showed that elevated serum PTH (>6.8 pmol/L), high urinary DPD/Cr (>7.5 nmol/μmol), and advanced age were the only significant indicators of presence of CVD (), and together explained 32.1% of the variability in presence of CVD. Elevated PTH levels were independently and significantly associated with each of the analyzed CVDs (), and the OR ranged between 1.91 (for AF) and 3.43 (for CAD). Of note, in our models we did not include medication use (see below) as independent variables, as their use was a consequence of presence of CVD.
Independent factors associated with the presence of cardiovascular disease in older hip-fracture patients
Multivariate-adjusted odds ratio for the presence of cardiovascular disease in older hip-fracture patients with elevated serum parathyroid hormone levels (>6.8 pmol/L)
Further, we examined the unique and combined effects of abnormally high PTH and DPD/Cr levels as indicators of presence of CVD (). Compared to subjects with normal serum PTH and urinary DPD/Cr levels (reference group), the age-and sex-adjusted OR for CVD (model 1) was significantly greater in patients with high DPD/Cr and normal PTH levels (OR 4.26, P = 0.005), but the highest risk of CVD was in patients with elevated PTH and both normal (OR 10.27, P = 0.004) and high DPD/Cr (OR 7.61, P < 0.001). After adjustment for seven additional factors was made, the OR for the presence of CVD further increased (model 2, ): 17.32 in patients only with SHPT, 9.68 in patients with SHPT and high DPD/Cr, and 5.33 in subjects only with excess bone resorption. These associations are displayed in . In total, the OR for presence of CVD among HF patients with SHPT or excess bone resorption compared to those with both parameters in the normal range was 7.54 ().
Odds ratios for presence of cardiovascular disease according to serum PTH concentrations as urinary deoxypyridinoline excretion in older patients with hip fracture
Odds ratios for presence of cardiovascular disease in older patients with hip fracture according to serum parathyroid hormone and urinary deoxypyridinoline levels.
Independent factors associated with serum PTH elevation and high bone resorption
Multivariate logistic regression analyses were performed to determine independent factors associated with elevated PTH (SHPT) and high bone resorption (DPD/Cr > 7.5 nmol/μmol) in older HF patients. These models included age, sex, CVD (yes/no), dementia (yes/no), type 2 diabetes mellitus (yes/no), HF type, smoking status, alcohol consumption, eGFR < 60 mL/minute/1.73 m2 (yes/no), albumin < 33 g/L (yes/no), OC < 14 ng/mL (yes/no), 25(OH)D, calcium, phosphate, magnesium, and DPD/Cr > 7.5 nmol/μmol (in the first model) or PTH > 6.8 pmol/L (in the second model) as independent variables. Independent predictors of SHPT were CVD (any) (OR 2.76, 95% CI 1.30–5.86; P = 0.008), renal impairment (OR 4.70, 95% CI 2.10–10.56; P < 0.001), female sex (OR 2.42, 95% CI 1.03–5.71; P = 0.043), 25(OH) D (OR 0.97, 95% CI 0.95–0.99; P = 0.014), serum calcium corrected for albumin (OR 0.003, 95% CI 0.0002–0.054; P < 0.001), and serum phosphate (OR 4.07, 95% CI 1.26–13.18; P = 0.019). The combined effect of these factors explained 48.7% of the variability in SHPT. These associations remained significant when the analyses were repeated with each CVD separately: OR ranged between 1.7 for AF and 2.9 for CAD.
Independent indicators of high bone resorption were the presence of CVD (OR 2.57, 95% CI 1.11–6.00; P
= 0.028), low eGFR (OR 0.19, 95% CI 0.07–0.52; P
= 0.001), and low OC (OR 6.20, 95% CI 2.23–17.25; P
< 0.001), which explained 38.3% of the variability in high DPD/Cr. The “preventive” effect of renal impairment reflects the fact that DPD is mainly released by degradation of peptide-bound cross-links through renal metabolism61
and is not directly generated from osteoclastic bone resorption.62
Of note, CVD emerged as the second-most significant independent predictor (after eGFR < 60 mL/minute/1.73 m2
) of both SHPT and excess bone resorption in this cohort.
Taken together, these data indicate that in older HF patients both SHPT and high bone resorption are significant independent indicators of the presence of CVD and vice versa. The OR for the presence of CVD is 2.68 times higher among subjects with SHPT and 2.58 times higher among patients with high bone resorption compared to patients without such a condition. Furthermore, compared to subjects with both PTH and DPD/Cr in the normal range, the OR for presence of CVD is 17.3 times higher in patients with SHPT and 5.3 times higher in subjects with excess bone resorption. On the other hand, CVD predicts SHPT (OR 2.82) and excess bone resorption (OR 2.53). These findings suggest bidirectional links between CVD and mineral/bone parameters related to osteoporosis. As the 25(OH)D levels in patients with and without CVD were low and did not differ significantly, our results highlight the significance of the independent associations between SHPT, high bone resorption, and CVD, supporting the hypothesis that osteoporosis and CVD share common biological mechanisms.
PTH and use of cardiovascular medications
In order to determine potential effects of different cardiovascular medications on vitamin D and PTH status, the serum mean values of 25(OH)D and PTH in patients receiving and not receiving such drugs were compared. shows that if compared with nonusers, serum PTH levels were significantly higher in users of ACE inhibitors (65.7%) and beta blockers (49.3%), but significantly lower in patients receiving calcium channel blockers (34.6%). PTH levels did not differ in respect to use of ARBs. No significant associations between serum 25(OH)D concentrations and use of any of the five classes of cardiovascular medications have been found.
Use of cardiovascular medications and serum parathyroid hormone and vitamin D status
Multiple logistic regression analyses with use of the aforementioned medications as independent variables and controlling for age, sex, CVD, renal impairment, HF type, 25(OH)D, calcium, phosphate, magnesium, and DPD/Cr showed that among these five medication classes only the use of ACE inhibitors was significantly and independently associated with elevated PTH (SHPT) (OR 3.76, 95% CI 1.01–14.16; P = 0.049).
Cardiovascular disease and PTH as predictors of short-term outcomes
In multivariate regression models that considered age, sex, preexisting comorbidities including CAD, hypertension, history of stroke, AF, dementia, CKD ≥ 3 stage, ASA score ≥ 3, and smoking status, having CVD was a strong independent predictor of postoperative myocardial injury (cTnI rise) (OR 6.13, 95% CI 1.57–24.00; P = 0.009) and prolonged hospital stay (LOS > 20 days) (OR 4.27, 95% CI 1.53–11.88; P = 0.005). After further adjusting for SHPT, vitamin D deficiency, and high urinary DPD/Cr excretion, patients with CVD were 2.3 times more likely to develop postoperative myocardial injury (OR 2.25, 95% CI 1.10–4.58; P = 0.006); however, the association between CVD and prolonged length of stay was no longer significant. In fully adjusted models (all clinical and laboratory parameters), CVD did not predict long-term residential care facility need or in-hospital death either. In contrast, SHPT was a strong independent predictor of in-hospital mortality (OR 17.39, 95% CI 3.32–78.63; P < 0.001), LOS > 20 days (OR 2.82, 95% CI 1.47–5.41; P = 0.002). and myocardial injury (OR 1.42, 95% CI 1.25–1.88; P < 0.001). This does not mean that CVD is unrelated to outcomes. It does imply that SHPT is an important pathway contributing to and mediating poorer outcomes. Elevated PTH (>6.8 pmol/L) occurred in 76.9% of in-hospital deaths, 59.2% of postoperative cTnI rises, and in 45.3% of prolonged hospital stays.