Bone-Vascular Axis in Chronic Kidney Disease

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Bone-Vascular Axis in Chronic Kidney Disease Pieter Evenepoel, Britt Opdebeeck, Karel David, and Patrick C. D’Haese Patients with chronic kidney disease (CKD) are at increased risk of osteoporosis and vascular calcification. Bone demineralization and vascular mineralization go often hand in hand in CKD, similar to as in the general population. This contradictory association is independent of aging and is commonly referred to as the “calcification paradox” or the bone-vascular axis. Various common risk factors and mechanisms have been identified. Alternatively, calcifying vessels may release circulating factors that affect bone metabolism, while bone disease may infer conditions that favor vascular calcification. The present review focuses on emerging concepts and major mechanisms involved in the bone-vascular axis in the setting of CKD. A better understanding of these concepts and mechanisms may identify therapeutics able to target and exert beneficial effects on bone and vasculature simultaneously. Q 2019 by the National Kidney Foundation, Inc. All rights reserved. Key Words: Bone, Vascular calcification

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pidemiological evidence clearly demonstrates that patients with chronic kidney disease (CKD) are at increased risk of osteoporosis1 and vascular calcification (VC).2 Incorporated in CKD is a state of impaired bone quantity3-9 and quality10 which associates with increased fracture risk.11 Fracture risk increases parallel to CKD severity, with CKD Stage 5D patients showing a nonvertebral fracture risk that is 4- to 6-fold higher than the fracture risk of age- and gender-matched controls.12,13 Fractures are a major cause of morbidity and, compared to CKD patients without fractures, those with fractures experience a multifold increased risk of mortality.14,15 Fractures also impose a large financial burden on healthcare systems. The pathophysiology of osteoporosis in patients with advanced CKD is multifaceted, comprising a mixture of age-related (primary male/postmenopausal), druginduced, and CKD-related bone abnormalities. VC is a condition characterized by calcium-phosphate crystal deposition in the intima, media, or cardiac valves. Especially media calcification is common among patients with CKD, with prevalence and severity paralleling the degree of renal failure.2 VC is observed in more than 60% of patients with CKD Stage 5D and contributes to a huge burden of cardiovascular disease in CKD patients.16,17 VC is increasingly recognized as an active and highly regu-

From the Department of Immunology and Microbiology, Laboratory of Nephrology and University Hospitals Leuven, KU Leuven - University of Leuven, Leuven, Belgium; Department of Nephrology and Renal Transplantation, University Hospital Gasthuisberg - Leuven, Leuven, Belgium; and Department of Biomedical Sciences, Laboratory of Pathophysiology, University of Antwerp, Antwerp, Belgium. Financial Disclosure: The authors declare that they have no relevant financial interests. Support: B.O. (grant 1S22217N) and K.D. (grant 1196520N) are both PhD fellow of the Fund for Scientific Research-Flanders FWO. Address correspondence to Pieter Evenepoel, MD, PhD, Department of Nephrology and Renal Transplantation, University Hospital Gasthuisberg Leuven, Herestraat 49, 3000 Leuven, Belgium. E-mail: pieter.evenepoel@ uzleuven.be Ó 2019 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 https://doi.org/10.1053/j.ackd.2019.09.006

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lated cellular process. Its pathophysiology varies across vascular beds and remains incompletely understood, despite major progress in the last decade.18-21 Many clinical studies have confirmed the association between low bone mass and VC in patients with CKD, both in cross-sectional22-27 and longitudinal analyses.28 The association between osteoporosis and VC is not specific to CKD and is also commonly observed in the aging general population and in patients with diabetes mellitus or chronic obstructive pulmonary disease.29-34 Importantly, the association between VC and above-mentioned comorbidities persists after adjustment for age in the statistical regression models.24,25,27,29-32,35,36 As (pathological) VC and (physiological) bone mineralization are both actively regulated processes showing many similarities, the coexistence of bone loss with (progressive) VC should be considered a paradoxical phenomenon. It is often referred to as the “calcification paradox.”34 Especially within the context of CKD, VC has also been associated with abnormal bone turnover.35,37,38 The pathophysiology of the bone-vascular axis is complex and multifaceted. Most likely, the relationship reflects common pathogenetic mechanisms in addition to the bone-vascular cross-talk; calcifying vessels may release circulating factors that affect bone metabolism, while bone disease may infer conditions that foster VC (Fig 1). The factors involved are multiple and only partly understood (Table 1). This review does not attempt to present an exhaustive overview but rather focuses on emerging concepts and major mechanisms involved in the bonevascular axis in the setting of CKD. INFLAMMATION CKD is well recognized as a state of microinflammation.23,39 Mounting experimental and clinical evidence points to inflammation as a common soil for bone loss and VC.22,23,40-45 The pathophysiological mechanisms linking inflammation to VC are complex and multifaceted (Fig 2). Inflammatory cytokines can promote vascular smooth muscle cell (VSMC) calcification,46 in part through the activation of Msx2-Wnt/b-catenin signaling.47 In addition, inflammatory cytokines may promote the process of endothelial to mesenchymal transition, leading to Adv Chronic Kidney Dis. 2019;26(6):472-483

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osteogenic gene expression and cytokine production by endothelial cells (ECs).41 Finally, inflammation may repress the important calcification inhibitor fetuin-A.48 VC in turn may also elicit an inflammatory response and as such trigger a self-perpetuating vicious circle as well as damage distant organs, including the bone (Fig 2). Experimental data indicate that inflammatory cytokines, either circulating or locally produced in the bone, such as TNF-a (TNF), IL-6 (interleukin), and IL-1b, may trigger increased bone resorption and decreased bone formation.49-52 These effects are mediated, in part, via cytokine-induced increases in RANKL, a key stimulator of bone resorption, expressed by osteoblasts and T cells.53 TNF-a is also an inhibitor of bone formation,54 tilting the balance toward bone resorption with subsequent bone loss.41 Barreto and colleagues55 conversely reported a positive correlation between TNF-a levels and bone area. These authors speculate that elevated TNF-a expression may represent a homeostatic feedback mechanism to counteract excessive bone mass gain.

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of MGP and osteocalcin in bone biology, however, remains incompletely understood and a matter of ongoing controversy.70-72 Vitamin K may affect bone health directly by targeting the steroid and xenobiotic sensing nuclear receptor, expressed in osteoblasts.71,73 Finally, experimental and clinical evidence furthermore suggests that vitamin K deficiency may trigger microinflammation and as such contribute to the calcification paradox (see above).61,74 Remarkably, the prevention of arterial calcification through targeted overexpression of MGP in the arterial walls was shown to be sufficient to rescue the low bone mass phenotype seen in MGP2/2 mice. This finding supports the hypothesis that arterial calcification, not MGP deficiency itself, causes the low bone mass phenotype in MGP2/2 mice.75

OSTEOPROTEGERIN The osteoprotegerin (OPG), receptor activator of nuclear factor-kappaB (RANK) signaling, and RANK ligand (RANKL) signaling pathway play an important role in VITAMIN K bone remodeling. RANKL is produced by stromal cells, Recent data indicate that up to .90% of patients with CKD are osteoblasts, and osteocytes and is the key factor for vitamin K deficient.56-61 Decreased dietary intake, binding by differentiation of monocyte-macrophage osteoclast prephosphate chelators, therapy cursors into multinucleated with vitamin K antagonists, osteoclasts and activation CLINICAL SUMMARY decreased recycling, and of mature osteoclasts. Vesicdecreased production by the ular RANK, which is  Bone demineralization and vascular mineralization often endogenous microbiota may secreted from the matuconcur in CKD. contribute to the high rating osteoclasts, binds prevalence of functional osteoblastic RANKL and  The presence of vascular calcification should flag a patient vitamin K deficiency in promotes bone formation,76 as being at high risk for osteoporosis and vice versa. and may thus be involved CKD.57,58,62,63 Vitamin K plays  Targeting common pathogenic risk factors such as a crucial role as cofactor for in coupling of bone inflammation and vitamin K deficiency may confer bone the carboxylation of Gla proresorption and formation. and vascular benefits. teins. OPG, which is produced Vitamin K deficiency is a by osteoblasts, binds to well-established risk factor of VC and arterial stiffness, RANKL and thereby prevents its interaction with RANK both in the general population and in CKD patients.64,65 through which it inhibits osteoclast differentiation and Accelerated VC in individuals with functional vitamin K suppresses the expression of cathepsin K and tartratedeficiency is explained by incomplete g-carboxylation resistant acid phosphatase (TRAP). Skeletal RANKL and and reduced function of matrix Gla protein (MGP) OPG are regulated by various calcitropic hormones in the vasculature.66 MGP is a 14 kDa secretory (eg, parathyroid hormone77 and estrogens78) and drugs protein synthesized by chondrocytes, VSMCs, ECs, and (eg, glucocorticoids79). The exact role of RANKL-RANK-OPG signaling in the fibroblasts. g-Carboxylated MGP inhibits vascular vasculature is less clear.34,80 Various stimuli including mineralization both directly, as a part of a complex with mediators of inflammation (TNF-a, IL-1, IL-6, transformfetuin-A (also known as a-2-HS-glycoprotein), and indiing growth factor-b) and oxidative stress (oxidized rectly, by interfering with binding of bone morphogenetic low-density lipoprotein [LDL]) trigger the secretion and/ protein-2 to its receptor and thereby inhibiting bone or release of RANKL from T-cells or ECs.81 Secreted/ morphogenetic protein-2-induced osteogenic differentiareleased RANKL through interaction with RANK tion (Fig 3). expressed by the VSMCs subsequently activates their Low dietary intake of vitamin K and circulating paramosteogenic gene expression program.82 OPG is produced eters of vitamin K deficiency are associated with low by VSMCs and ECs, and may be hypothesized to attenuate bone mineral density (BMD) and increased risk of fracthe progression of VC through sequestration of RANKL83 tures, both in the general population and in patients with (Fig 4). CKD.61,67-69 Vitamin K-dependent g-carboxylation of Gla containing bone proteins such as MGP and osteocalcin The finding of OPG-deficient mice developing early(also referred to as bone Gla protein) turns these proteins onset osteoporosis and VC84 supported a central role for dysregulated OPG/RANK/RANKL signaling in the pathointo mineralization inhibitors and promoters in biology of the bone-vascular axis. Although intravenous vasculature and bone respectively. The specific function Adv Chronic Kidney Dis. 2019;26(6):472-483

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Figure 1. Pathogenic factors involved in the bone-vascular axis in aging and CKD. Aging contributes to the development of CKD which in turn increases the risk for vascular calcification (left) and osteoporosis (right) conferring an increased risk of cardiovascular disease and fractures, respectively. The bone-vascular axis reflects common pathogenic mechanisms (ie, inflammation, vitamin D and K deficiency, Klotho deficiency) and cross-talk (ie, osteoprotegerin, sclerostin, calcium, and phosphate). Abbreviation: PTH, parathyroid hormone.

Table 1. Factors Involved in the Bone-Vascular Axis in CKD (Nonexhaustive) Factor Inflammation Klotho Sclerostin (Wnt-inhibitor) Osteoprotegerin Vitamin K deficiency PTH

BMPs Osteopontin Vitamin D

Role in Bone Metabolism Promotes bone resorption Acts as a Wnt-inhibitor; in addition may modify mineral metabolism Inhibits bone turnover Inhibits osteoclastic bone resorption Reduces bone mineral density Key mediator of bone turnover; effect is dependent on duration and periodicity of PTH exposure and skeletal responsiveness Induce osteoblastic differentiation and bone formation Activates osteoclasts Maintains bone mass, pending sufficient calcium supply

Role in Vascular Calcification Promotes VC Inhibits VC Marker of VC burden; attenuates progression of VC Marker of VC burden; inhibits VC Promotes vascular calcification Complex, composite of incongruent paracrine and systemic effects

Proinflammatory and pro-oxidant effects Inhibits vascular calcification Complex, U-shaped relationship

Abbreviations: BMP, bone morphogenetic protein; PTH, parathyroid hormone; VC, vascular calcification.

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Figure 2. The role of inflammation in the bone-vascular axis. (Vascular axis: upper part) Inflammation triggers 2 processes: (1) the osteogenic/chondrogenic switch of VSMCs through activation of the Msx2-Wnt-signaling pathway and (2) the endothelial to mesenchymal transition of endothelial cells into osteogenic/chondrogenic cells. Both events favor the mineralization of the extracellular matrix of the arterial wall. Inflammation also suppresses the expression of fetuin-A, an important vascular calcification inhibitor. (Bone axis: lower part) Inflammatory cytokines promote bone loss, mainly through increased expression of RANKL, a key stimulator of bone resorption increased interaction. Abbreviations: BMP2, bone morphogenetic protein-2; RANK, receptor activator of nuclear factor-kappaB; RANKL, RANK ligand; VSMC, vascular smooth muscle cell.

injection of recombinant OPG protein and transgenic overexpression of OPG in OPG-deficient mice effectively rescue the osteoporotic bone phenotype, it failed to reverse the arterial calcification, suggesting that local production is important in the inhibition of VC.85 In a rat model, however, it was demonstrated that doses of OPG that inhibit bone resorption also potently inhibit the calcification of arteries induced by warfarin treatment and by vitamin D treatment.86 Data from clinical studies are hard to reconcile with the experimental evidence. Circulating OPG levels in CKD patients do either not87 or negatively88 associate with BMD, while they positively associate with poor cardiovascular outcomes, including VC, arterial stiffness, and mortality.87,89-93 It is currently hypothesized that vascular OPG is part of an anticalcifying defense mechanism, of which the activity parallels the calcification burden. Vascular OPG, spilling over to the circulation, may exert distant skeletal effects, ie, suppression of bone resorption, cum quo (c.q.) bone turnover. Studies with denosumab, a humanized antibody targeting RANKL, show important bone mass gains in postmenopausal women,94 while VC scores are unaffected.95 KLOTHO Klotho is a type I membrane protein that was originally identified as a senescence-related protein because mice carrying hypomorphic Klotho alleles (kl/kl) develop a syndrome that resembles human aging.96 Klotho is mainly expressed in the kidney, and to lesser extent in the parathyroid gland and choroid plexus.97 Cleavage of Klotho in kidney distal tubules sheds the Klotho ectodomain Adv Chronic Kidney Dis. 2019;26(6):472-483

(commonly referred to as soluble Klotho) into body fluids. The principal role of Klotho (both membrane-bound and soluble Klotho) is to form a specific receptor complex with fibroblast growth factor (FGF) receptor 1 through which it mediates the biological function of FGF23.98 Soluble Klotho, in addition, acts as a circulating antiageing hormone independent of FGF23. Clinical studies reveal that patients with kidney disease, already in early CKD have decreased Klotho levels in renal tissue, serum, and urine, and Klotho levels inversely correlate with disease severity and progression.99 The kidney has dual roles in Klotho homeostasis as it produces and releases Klotho in the circulation and clears Klotho from the blood compartment through secretion in the urinary lumen.100 The molecular events that lead to Klotho deficiency after kidney injury are not fully understood. Several pathologic processes and cellular factors have been reported or implied to be associated with Klotho repression, including oxidative stress, the proinflammatory cytokine TNF-a, IL-6, transforming growth factor-b, and epigenetic factors, partly mediated by uremic toxins.101 Recent investigations provide evidence that Klotho is also expressed in osteocytes.102 In bone, osteocytic Klotho may act as a Wnt inhibitor.103 Thus, the low-turnover osteopenia phenotype in Klotho knockout104,105 mice, most probably, results from systemic disturbances in mineral metabolism associated with disrupted FGF23-Klotho signaling rather than from a functional defect of Klotho in osteocytes. Although a matter of ongoing controversy, no compelling evidence currently exists that supports the existence of membrane-bound Klotho in human vasculature.

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Figure 3. The role of vitamin K in the bone-vascular axis. Vitamin K stores are low in CKD, mainly as a consequence of decreased recycling and deficient dietary intake and/or microbial generation. (Vascular axis: upper part) Vitamin K deficiency results in decreased c-MGP levels, a well-established inhibitor of vascular calcification. (Bone axis: lower part) Low carboxylated osteocalcin compromises bone mineralization. Decreased activation of SXR, expressed in osteoblasts, may also result in less efficient bone mineralization. Abbreviations: c-MGP, carboxylated matrix Gla protein; SXR, xenobiotic sensing nuclear receptor.

Recombinant Klotho has been shown to decrease oxidative stress and apoptosis in both VSMCs and ECs, to reduce VSMC calcification, and to maintain the contractile VSMC phenotype.106,107 In experimental and clinical studies, including CKD patients, Klotho deficiency associates with hypertension108 and vascular dysfunction.109,110 SCLEROSTIN Wnt-b-catenin signaling plays a central role in bone homeostasis and is tightly regulated by several antagonists, including sclerostin, dickkopf-1, and soluble frizzlerelated proteins. In CKD, circulating sclerostin levels are many-fold higher than in non-CKD counterparts, most probably as a consequence of increased bone production and release. Mechanisms regulating sclerostin synthesis remain poorly defined.111 Circulating and bone sclerostin levels correlate negatively with bone turnover, whether assessed by quantitative bone histomorphometry112-114 or by bone turnover markers.6,115,116 A suppressed bone turnover may explain the positive association between sclerostin and BMD, as observed in the general population117-119 and in CKD patients.120,121 Wnt-b-catenin signaling emerged to be important in vascular (patho)biology as well.122 Of note, the effects of Wnt-b-catenin signaling in cardiovascular tissue are celland stage specific.123 Overall, Wnt-b-catenin signaling promotes atherogenesis and VC.122,124 Mounting experimental125,126 and clinical127 evidence demonstrates increased expression of Wnt-b-catenin signaling inhibitors in calcifying VSMCs and vascular tissue. The calcifying vasculature may prove to be an important source of circulating sclerostin, next to bone.128 Studies exploring the as-

sociation between sclerostin and cardiovascular outcomes have yielded conflicting findings.111,115,129-136 This inconsistency may be explained by case-mix, use of different assays, and different competing factors used in multivariate analysis. Similar to OPG, vascular expression of sclerostin and other Wnt-b-catenin signaling inhibitors may represent a counter-regulatory mechanism to avoid further progression of ossification136,137 (Fig 5). Sclerostin produced in the calcifying vasculature may spill over to the circulation and exert distant skeletal effects, ie, suppression of anabolic Wnt signaling. Whether pharmacological supplementation of (recombinant) sclerostin associates with a specific bone and vascular phenotype remains to be investigated. In clinical trials, romosozumab, a fully human monoclonal antibody against sclerostin, resulted in an increase in BMD to a greater extent than alendronate and teriparatide and a decrease in risk of vertebral and nonvertebral fractures in postmenopausal women.138-140 Saag and colleagues139 showed a numerical increase in serious cardiovascular adverse events (odds ratio 1.31, 95% confidence interval 0.85-2.00) in postmenopausal women with osteoporosis given 12 months of romosozumab followed by 12 months of alendronate vs 24 continuous months of alendronate. It is important to note that cardiovascular events have not been reported in other studies.140,141 Additional studies are required to define whether romosozumab increases cardiac risk or whether alendronate is cardioprotective. Somehow contradictory, neutralization of circulating dickkopf-1 improved vascular function, and decreased osteoblastic transition and VC in an animal of early CKD.142 Thus, the role of Wnt-b-catenin signaling inhibitors on vascular pathobiology remains to be elucidated? Adv Chronic Kidney Dis. 2019;26(6):472-483

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Figure 4. The role of osteoprotegerin in the bone-vascular axis. (Vascular axis: upper part) During inflammation and oxidative stress, endothelial cells secrete sRANKL which binds to RANK, expressed on the VSMC. This interaction, together with activation of the Msx2-Wnt-signaling pathway, stimulates the osteogenic/chondrogenic transdifferentiation of the VSMC leading to mineralization of the extracellular matrix of the vessel wall. VSMCs and endothelial cells also produce osteoprotegerin which binds to sRANKL and prevents the RANK-RANKL interaction. (Bone axis: lower part) Both osteocytes and osteoblasts stimulate osteoclast maturation through production of RANKL that binds to osteoclastic RANK. Osteoprotegerin blocks this signaling. Abbreviations: RANK, receptor activator of nuclear factor-kappaB; RANKL, RANK ligand; VSMC, vascular smooth muscle cell.

PARATHYROID HORMONE Secondary hyperparathyroidism (SHPT) is an almost universal complication in patients with advanced CKD. It is less acknowledged that PTH hyporesponsiveness is as much an integral component of CKD-MBD as elevated circulating PTH levels. Recent evidence points to decreased PTH/PTH related peptide (PTHrP) type 1 receptor (PTH1R) expression and function and competing downstream signals in addition to local environmental factors as contributing mechanisms.143 PTH1R is highly expressed in bone and kidney, but also at lower levels in the vasculature. PTH is a key regulator of bone remodeling.144 Direct effects of PTH on osteoblasts and osteocytes, and indirect actions on osteoclasts, promote both bone formation and bone resorption. PTH also regulates the spatial relationship between the bone multicellular units and the microvasculature, localizing capillaries near sites of new bone formation as necessary for bone mass accrual.145 The final effect on bone mass, either anabolic or catabolic, appears to depend on the duration and periodicity of PTH exposure.144 Importantly, PTH hyporesponsiveness may explain why low-turnover bone disease is very prevalent in contemporary CKD patients, although these patients often demonstrate circulating PTH levels far above the upper normal limit.146,147 In the vasculature, PTH and PTHrP exert acute vasodilatory actions and reduce oxidative stress and procalcific and profibrotic signals that drive arteriosclerotic disAdv Chronic Kidney Dis. 2019;26(6):472-483

ease.148,149 These actions may be considered paradoxical when viewed against the backdrop of the hypertension and vascular disease arising in settings of primary hyperparathyroidism. It is suggested that the vasculopathy of SHPT may relate to an arterial desensitization to paracrine PTHrP/PTH1R-dependent regulation of vascular tone in addition to direct toxic effects mediated by high calcium and/or phosphate levels, often accompanying the SHPT. Thus strategies that selectively preserve the paracrine PTHrP/PTH1R pathway are generally predicted to exert cardiovascular benefits.148 Diseases or interventions impeding paracrine PTHrP/PTH1R signaling, conversely, may foster vascular disease. Peripheral artery disease was found to be associated with significant reductions in the skeletal anabolic response to PTH.150 These observations support the thesis that PTH hyporesponsiveness may be the common soil for lowturnover bone disease and vascular disease. Experimental and clinical evidence indicates that correction of severe HPT may confer both vascular151-153 and skeletal154 benefits. PHOSPHATE AND CALCIUM Adequate phosphate and calcium supply is a prerequisite for both normal mineralization and ectopic VC. Elevated phosphate triggers osteochondrogenic differentiation of VSMCs. Transient calcium elevations sensitize VSMCs to phosphate by increasing the expression of the sodiumdependent phosphate cotransporter PIT-1. A decreased

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Figure 5. The role of sclerostin in the bone-vascular axis. (Vascular axis: upper part) Activation of the Msx2-Wnt-signaling pathway stimulates the vascular smooth muscle cell (VSMC) to transdifferentiate into osteogenic/chondrogenic cells. Calcifying VSMCs express sclerostin, attenuating the progression of vascular calcification. (Bone axis: lower part) Osteocytic sclerostin blocks Wnt-b catenin signaling, which results in decreased osteoblastogenesis and increased osteoclastogenesis, finally cumulating in a low turnover osteopenia phenotype. Abbreviation: VSMC, vascular smooth muscle cell.

skeletal calcium/phosphate buffering capacity and high skeletal calcium/phosphate efflux may explain the association between VC and, respectively, low and high bone turnover.35,37 HYPOGONADISM Gonadal dysfunction is a common finding in patients with CKD. It is reported in one-third to one-half of men with CKD Stage 3-5, increasing to 50%-75% of men undergoing dialysis.155-157 In these patients, low total testosterone and/ or free testosterone levels likely result from a combination of primary testicular failure and secondary hypothalamicpituitary dysfunction. Similarly, in premenopausal women with CKD, menstrual irregularities are common. Oligomenorrhea ensues with declining renal function, and approximately 50% of patients with Stage 5 CKD experience amenorrhea and low estrogen levels, and few regain menses following commencement of dialysis once amenorrhoeic.158,159 The pathogenesis of gonadal dysfunction in CKD is multifaceted; it includes inhibition of luteinizing hormone signaling as a consequence of the uremic state, increased prolactin production, reduced renal prolactin clearance, and direct toxic effects of uremia on the gonads. In addition, comorbid conditions such as obesity and diabetes mellitus, and several coprescribed medications, including glucocorticoids, can contribute to these gonadal disturbances.160 Finally, also end-organ resistance to the action of sex steroids may contribute to a state of hypogonadism in CKD.161 Only few studies so far investigated the link between hypogonadism and bone outcomes in men and women with CKD. Overall, these studies yielded inconclusive results,

most probably as a consequence of analytical limitations and heterogeneity of study population and bone outcomes.160,162 Estradiol and testosterone deficiency associate with poor cardiovascular outcomes, including VC, both in the general population163 and CKD patients.156,164,165 The strength of the association is rather weak and both direct166 and indirect mechanisms may be involved.164 With regard to androgens, a complex (U-shaped) relationship may be hypothesized, with signaling at the extremes causing cardiovascular harm.167 Hormone replacement therapy has a beneficial impact on BMD; whether testosterone supplementation confers cardiovascular risks, and if so on what conditions, remains a matter of ongoing debate.168 CONCLUSIONS Osteoporosis, VC, and cardiovascular events are highly prevalent in CKD patients and closely interrelated, independent of age. This close relationship may be explained by common risk factors. In addition, the relationship may reflect “collateral damage”; calcifying vessels may release circulating factors that affect bone metabolism, while bone disease may infer conditions that foster VC. Clinicians should be aware of the close relationship between osteoporosis and VC. The reasons are 2-fold; first, clinical suspicion for VC and related morbidity should be high in a patient presenting with osteoporosis and vice versa; second, it should be acknowledged that any therapy affecting bone metabolism may affect vascular health directly or indirectly often in a negative way. The bone-vascular axis furthermore should be an incentive to Adv Chronic Kidney Dis. 2019;26(6):472-483

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maximize efforts controlling common pathogenetic factors. Research, so far, is hampered by analytical issues169,170 and uncertainties as to whether mechanistic factors act strictly autocrine/paracrine or also function as systemic factors affecting distant tissues. Whatsoever, on the basis of available data it might be prudent for clinicians to adapt a low threshold to assess cardiovascular risk in patients with osteoporosis or vice versa, to assess fracture risk in patients with VCs. REFERENCES 1. Moe SM, Nickolas TL. Fractures in patients with CKD: time for action. Clin J Am Soc Nephrol. 2016;11:1929-1931. 2. Budoff MJ, Rader DJ, Reilly MP, et al. Relationship of estimated GFR and coronary artery calcification in the CRIC (Chronic Renal Insufficiency Cohort) Study. Am J Kidney Dis. 2011;58:519-526. 3. Stein MS, Packham DK, Ebeling PR, Wark JD, Becker GJ. Prevalence and risk factors for osteopenia in dialysis patients. Am J Kidney Dis. 1996;28:515-522. 4. Rix M, Andreassen H, Eskildsen P, Langdahl B, Olgaard K. Bone mineral density and biochemical markers of bone turnover in patients with predialysis chronic renal failure. Kidney Int. 1999;56:1084-1093. 5. Urena P, Bernard-Poenaru O, Ostertag A, et al. Bone mineral density, biochemical markers and skeletal fractures in haemodialysis patients. Nephrol Dial Transpl. 2003;18:2325-2331. 6. Evenepoel P, Claes K, Meijers B, et al. Bone mineral density, bone turnover markers, and incident fractures in de novo kidney transplant recipients. Kidney Int. 2019;95(6):1461-1470. 7. Chen H, Lips P, Vervloet MG, van Schoor NM, de Jongh RT. Association of renal function with bone mineral density and fracture risk in the Longitudinal Aging Study Amsterdam. Osteoporos Int. 2018;29:2129-2138. 8. Klawansky S, Komaroff E, Cavanaugh PF Jr, et al. Relationship between age, renal function and bone mineral density in the US population. Osteoporos Int. 2003;14:570-576. 9. Ishani A, Blackwell T, Jamal SA, Cummings SR, Ensrud KE. The effect of raloxifene treatment in postmenopausal women with CKD. J Am Soc Nephrol. 2008;19:1430-1438. 10. Malluche HH, Porter DS, Monier-Faugere MC, Mawad H, Pienkowski D. Differences in bone quality in low- and highturnover renal osteodystrophy. J Am Soc Nephrol. 2012;23:525-532. 11. Pimentel A, Urena-Torres P, Zillikens MC, Bover J, Cohen-Solal M. Fractures in patients with CKD-diagnosis, treatment, and prevention: a review by members of the European Calcified Tissue Society and the European Renal Association of Nephrology Dialysis and Transplantation. Kidney Int. 2017;92:1343-1355. 12. Jadoul M, Albert JM, Akiba T, et al. Incidence and risk factors for hip or other bone fractures among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study. Kidney Int. 2006;70:1358-1366. 13. Rodriguez GM, Naves DM, Cannata Andia JB. Bone metabolism, vascular calcifications and mortality: associations beyond mere coincidence. J Nephrol. 2005;18:458-463. 14. Tentori F, McCullough K, Kilpatrick RD, et al. High rates of death and hospitalization follow bone fracture among hemodialysis patients. Kidney Int. 2014;85:166-173. 15. Naves M, Diaz-Lopez JB, Gomez C, Rodriguez-Rebollar A, Rodriguez-Garcia M, Cannata-Andia JB. The effect of vertebral fracture as a risk factor for osteoporotic fracture and mortality in a Spanish population. Osteoporos Int. 2003;14:520-524. 16. Okuno S, Ishimura E, Kitatani K, et al. Presence of abdominal aortic calcification is significantly associated with all-cause and cardiovascular mortality in maintenance hemodialysis patients. Am J Kidney Dis. 2007;49:417-425.

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