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Bone metabolism and cardiovascular disease: An overlooked association?

      Keywords

      A growing body of evidence suggests that bone mineral metabolism is linked with cardiovascular disease (CVD) [
      • Paul S.
      • Wong M.
      • Akhabue E.
      • et al.
      Fibroblast growth factor 23 and incident cardiovascular disease and mortality in middle-aged adults.
      ]. While confirming a statistically significant association between bone mineral density (BMD) and cardiac valve calcification (CVC), the findings reported by Massera et al. [
      • Massera D.
      • Buzkova P.
      • Bortnick A.E.
      • et al.
      Bone mineral density and long-term progression of aortic valve and mitral annular calcification: the multi-ethnic study of atherosclerosis.
      ] question the clinical relevance of bone mineral derangements as promoters of cardiovascular disease in the general population. In their study, the association between progression of CVC and mineral metabolism was modest and substantially modified by sex, race and renal function. Furthermore, mitral valve calcification progression was more closely associated with calcium and phosphate metabolism than aortic valve calcification.
      Massera et al. [
      • Massera D.
      • Buzkova P.
      • Bortnick A.E.
      • et al.
      Bone mineral density and long-term progression of aortic valve and mitral annular calcification: the multi-ethnic study of atherosclerosis.
      ] utilized the Multi-Ethnic Study of Atherosclerosis (MESA) database, a large observational and longitudinal study of middle-aged men and women free from CVD. While the longitudinal nature of the study is a strength of the current analysis, the relatively low prevalence of CVC as well as the heterogeneity in patients’ follow-up time may have partially masked the signal, despite the fact that data on CVC progression were annualized. In fact, only 55% of the study cohort underwent a repeat scan for CVC assessment after about 10 years, while the rest had a second scan after about 2–4 years from enrolment [
      • Massera D.
      • Buzkova P.
      • Bortnick A.E.
      • et al.
      Bone mineral density and long-term progression of aortic valve and mitral annular calcification: the multi-ethnic study of atherosclerosis.
      ]. The non-linear and time-dependent association of BMD and CVC appears to have been different between individuals with prolonged versus reduced follow-up, and the reported associations were of statistical significance for men only (Supplemental Table 2 and 3) [
      • Massera D.
      • Buzkova P.
      • Bortnick A.E.
      • et al.
      Bone mineral density and long-term progression of aortic valve and mitral annular calcification: the multi-ethnic study of atherosclerosis.
      ].
      Due to the age dependency of both BMD decrease and CVC occurrence, data on the concomitant change of these biomarkers during follow-up would have been of interest to further disentangle the relative contribution of age on the postulated bone-cardiovascular axis. Additionally, information on the longitudinal change of BMD would have helped to overcome the lack of data on use of bone antiresorptive drugs during follow-up. Indeed, it is plausible that patients with osteoporosis received some form of treatment during follow-up, reducing BMD loss and attenuating its association with CVC progression.
      Low BMD may characterize different types of osteodystrophic processes spanning from osteoporosis to osteomalacia [
      • Moe S.
      • Drueke T.
      • Cunningham J.
      • et al.
      Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: improving Global Outcomes (KDIGO).
      ]. Vertebral BMD, even when assessed with computed tomography (CT), and serological biomarkers of calcium and phosphate metabolism do not provide sufficient information on bone remodeling and turn-over [
      • Moe S.
      • Drueke T.
      • Cunningham J.
      • et al.
      Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: improving Global Outcomes (KDIGO).
      ]. Although impractical, bone biopsies would provide useful information on what type of bone mineral metabolism derangement is associated with CVC. In this regard, the literature suggests that in chronic kidney disease (CKD) both low and high bone turn-over states are associated with vascular calcification progression, regardless of BMD levels that may be low in both scenarios [
      • Moe S.
      • Drueke T.
      • Cunningham J.
      • et al.
      Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: improving Global Outcomes (KDIGO).
      ,
      • Ketteler M.
      • Block G.A.
      • Evenepoel P.
      • et al.
      Executive summary of the 2017 KDIGO chronic kidney disease-mineral and bone disorder (CKD-MBD) guideline update: what’s changed and why it matters.
      ,
      Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group
      KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.
      ].
      CVC is characterized by leaflet thickening and deposition of crystals of calcium/phosphate on the valvular cusps or in the annulus of the valve. Although differences in the process of calcification of the aortic and mitral valve may exist, they both involve an active cellular mechanism [
      • Bellasi A.
      • Di Lullo L.
      • Raggi P.
      Cardiovascular calcification: the emerging role of micronutrients.
      ]. Valvular interstitial cells (VIC) transdifferentiate toward osteoblast-like cells in response to traditional as well as non-traditional cardiovascular risk factors [
      • Bellasi A.
      • Di Lullo L.
      • Raggi P.
      Cardiovascular calcification: the emerging role of micronutrients.
      ]. Experimental models suggest that supplementing culture media with phosphate, induces VIC trans-differentiation triggering the calcification process [
      • Bellasi A.
      • Di Lullo L.
      • Raggi P.
      Cardiovascular calcification: the emerging role of micronutrients.
      ]. While several steps in these processes await elucidation, it is plausible that regulatory mechanisms that control bone mineralization may also modulate CVC. In this light, the reported differences between women and men as well as between younger and older subjects in the association of BMD and CVC are not surprising. Serum phosphate levels, for example, are generally lower in men than in women and tend to decline with age [
      • Cirillo M.
      • Botta G.
      • Chiricone D.
      • De Santo N.G.
      Glomerular filtration rate and serum phosphate: an inverse relationship diluted by age.
      ,
      • Onufrak S.J.
      • Bellasi A.
      • Cardarelli F.
      • et al.
      Investigation of gender heterogeneity in the associations of serum phosphorus with incident coronary artery disease and all-cause mortality.
      ]. Furthermore, post-menopausal women have higher serum phosphate levels than pre-menopausal women further corroborating the notion that sex-hormones modulate mineral metabolism [
      • Cirillo M.
      • Botta G.
      • Chiricone D.
      • De Santo N.G.
      Glomerular filtration rate and serum phosphate: an inverse relationship diluted by age.
      ,
      • Onufrak S.J.
      • Bellasi A.
      • Cardarelli F.
      • et al.
      Investigation of gender heterogeneity in the associations of serum phosphorus with incident coronary artery disease and all-cause mortality.
      ]. Compared to Whites, Blacks are less prone to osteoporosis and cardiovascular calcification suggesting that there are racial differences in mineral metabolism [
      • Weaver C.M.
      • Gordon C.M.
      • Janz K.F.
      • et al.
      The National Osteoporosis Foundation's position statement on peak bone mass development and lifestyle factors: a systematic review and implementation recommendations.
      ]. Massera et al. [
      • Massera D.
      • Buzkova P.
      • Bortnick A.E.
      • et al.
      Bone mineral density and long-term progression of aortic valve and mitral annular calcification: the multi-ethnic study of atherosclerosis.
      ] confirmed this observation in the Multi-Ethnic Study of Atherosclerosis (MESA). In a previous cross-sectional study of subjects receiving maintenance dialysis, however, race was not associated with vascular calcification implying that CKD affects mineral metabolism control [
      • Bellasi A.
      • Veledar E.
      • Ferramosca E.
      • Ratti C.
      • Block G.
      • Raggi P.
      Markers of vascular disease do not differ in black and white hemodialysis patients despite a different risk profile.
      ]. Indeed, as renal function declines various factors implicated in mineral metabolism regulation such as fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) are altered, and vascular calcification as well as bone mineral derangements are progressively more prevalent [
      • Paul S.
      • Wong M.
      • Akhabue E.
      • et al.
      Fibroblast growth factor 23 and incident cardiovascular disease and mortality in middle-aged adults.
      ,
      • Isakova T.
      • Cai X.
      • Lee J.
      • et al.
      Longitudinal evolution of markers of mineral metabolism in patients with CKD: the chronic renal insufficiency cohort (CRIC) study.
      ]. Hence, in recent years a the new Chronic Kidney Disease - Mineral Bone Disorder (CKD-MBD) moniker was introduced to describe a syndrome that encompasses bone and serum markers of deranged mineral metabolism and vascular calcification [
      • Moe S.
      • Drueke T.
      • Cunningham J.
      • et al.
      Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: improving Global Outcomes (KDIGO).
      ]. Massera et al. [
      • Massera D.
      • Buzkova P.
      • Bortnick A.E.
      • et al.
      Bone mineral density and long-term progression of aortic valve and mitral annular calcification: the multi-ethnic study of atherosclerosis.
      ] documented a similar signal, but the small number of subjects with an estimated glomerular filtration rate below 60 ml/min/1.73 m2 may have attenuated the association and may contribute to explain the reported and partially unexpected differences in directions of the effect modification of eGFR on CVC in men and women.
      Future research endeavors will need to shed more light on the purported bone-cardiovascular axis and explore the effect modulation of age, sex, race and various disease states on mineral metabolism. A better understanding of the pathophysiology underlying BMD decrease and CVC deposition and progression would allow us to identify subjects at risk and ideally propose personalized interventions. However, while available data suggest that mineral metabolism abnormalities are undeniably associated with poor outcome, interventional trials to demonstrate that cardiovascular calcification progression attenuation improves survival are still lacking. In this optic, anti-osteoporotic drug therapies as well as newer compound such as SNF-472 [
      • Bellasi A.
      • Raggi P.
      • Bover J.
      • et al.
      Trial design and baseline characteristics of CaLIPSO: a randomized, double-blind placebo-controlled trial of SNF472 in patients receiving haemodialysis with cardiovascular calcification.
      ,
      • Raggi P.
      • Bellasi A.
      • Bushinsky D.
      • et al.
      Slowing progression of cardiovascular calcification with SNF472 in patients on hemodialysis: results of a randomized phase 2b study.
      ,
      • Raggi P.
      • Bellasi A.
      • Sinha S.
      • et al.
      Effects of SNF472, a novel inhibitor of hydroxyapatite crystallization in patients receiving hemodialysis - subgroup Analyses of the CALIPSO trial.
      ], a direct inhibitor of hydroxyapatite deposition in soft tissues, may offer the opportunity to test whether manipulation of the bone-cardiovascular axis improves outcome in high-risk populations.

      Declaration of competing interests

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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