Nephrology 23, Suppl.

4 (2018) 88–94

Review Ar ticle

Mineral bone disorders in chronic kidney disease

YI-CHOU HOU,1 CHIEN-LIN LU2 and KUO-CHENG LU2
1
Department of Internal Medicine, Cardinal Tien Hospital, School of Medicine, Fu-Jen Catholic University, and 2Department of Medicine, Fu-Jen Catholic
University Hospital, College of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan

KEY WORDS: ABSTRACT:

renal osteodystrophy, vascular calcification,
vitamin D deficiency.
Correspondence
Dr Kuo-Cheng Lu, Department of Medicine, Fu-
Jen Catholic University Hospital, College of
Medicine, Fu-Jen Catholic University, New Taipei
City, Taiwan. Email: kuochenglu@gmail.com
Accepted for publication 10 August 2018.
doi: 10.1111/nep.13457
SUMMARY AT A GLANCE
This article is a systematic review of the
mechanism of CKDMBD and the
complication about CKDMBD, including
uremic vascular calcification and
osteoporosis. Nutritional vitamin D, should
play a role in managing CKDMBD.
As the GFR loss aggravates, the disturbed mineral metabolism worsens the
bone microstructure and remodelling – scenario, which is known as CKD-
mineral bone disease (MBD). CKD-MBD is characterized by : (i) abnormal
metabolism of calcium, phosphorus, parathyroid hormone (PTH), or vitamin
D; (ii) abnormalities in bone turnover, mineralization, volume linear growth
or strength; (iii) soft-tissue calcifications, either vascular or extra-osseous.
Uremic vascular calcification and osteoporosis are the most common compli-
cations related to CKD-MBD. Disregulated bone turnover by uremic toxin or
secondary hyperparathyroidism disturbed bone mineralization and makes it
difficult for calcium and inorganic phosphate to enter into bone, resulting in
increased serum calcium and inorganic phosphate. Vascular calcification
worsens by hyperphosphatemia and systemic inflammation. Since vitamin D
deficiency plays an important role in renal osteodystrophy, supplement of
nutritional vitamin D is important in treating uremic osteoporosis and vas-
cular calcification at the same time. Its pleotropic effect improves the bone
remodeling initiated by osteoblast and alleviates the risk factors for vascular
calcification with less hypercalcemia than vitamin D receptor analogs. There-
fore, nutritional vitamin D should be considered in managing CKDMBD.

Physiological bone remodelling is an ever-lasting and deli-
cately coordinated process between bone formation and
resorption. It is comprised of continuous removal of old
bone, replacing them with a newly synthesized proteina-
ceous matrix, and to form new bone by subsequent mineral-
ization of the matrix.1 Bone remodelling started with bone
resorption with osteoclast (OC) activation2 and then bone
formation. Both resorption and formation are essential for
repairing micro-fractures and for modifying bone structure
as a stress response.3 In other words, remodelling is the
replacement of bone without changing its previous shape.
Bone turnover occurs in both cortical and trabecular bone
with a relative higher turnover rate in trabecular bone.
At the onset of chronic kidney disease (CKD), the sys-
temic mineral metabolism and bone composition start to
change along with glomerular filtration rate (GFR) loss. As
the GFR loss aggravates, the disturbed mineral metabolism
worsens the bone microstructure and remodelling – scenario
that is known as CKD-mineral bone disease (MBD). The
Kidney Disease: Improving Global Outcomes (KDIGO)
defined CKD-MBD as a broader systemic disorder of mineral
and bone metabolism as a result of CKD.4 CKD-MBD is
characterized by the following: (i) abnormal metabolism of
calcium, phosphorus, parathyroid hormone (PTH), or vita-
min D; (ii) abnormalities in bone turnover, mineralization,
volume linear growth or strength; (iii) soft-tissue calcifica-
tions, either vascular or extra-osseous.5
CHARACTERISTICS OF MINERAL AND
HORMONAL DISRUPTION IN CKD
As the GFR falls, free serum calcium levels fall and serum
phosphorus increases. Because of GFR loss, compensatory
production of fibroblast growth factor 23 (FGF-23) decreases
levels of sodium-dependent phosphate transport protein
(Npt)2a and Npt2c in the kidney, resulting in increased uri-
nary excretion of phosphate.6 In response, the parathyroid
glands increase the production of PTH, which decreases the

88 © 2018 Asian Pacific Society of Nephrology


abundance of Npt2a and Npt2c in the proximal tubule, lead-
ing to increased urinary Pi excretion that in turn lowers
serum Pi levels.7 FGF23 also inhibits the production of 1,25
(OH)2D and therefore decreases intestinal Pi absorption, fur-
ther decreasing serum Pi levels.8 The decreased 1,25(OH)2D
induces hypocalcaemia and then stimulated PTH production
persists, which ensues secondary hyperparathyroidism
(SHPT).9 As GFR continues to fall, however, these compensa-
tory mechanisms fail, leading to hyperphosphatemia, hyper-
parathyroidism, and higher serum FGF-23 concentration. The
SHPT and uremic toxin accumulation accelerate bone turn-
over by activating osteoclastogenesis and increased the
release of calcium and phosphate from bone.10 Under physio-
logical condition, FGF-23 decreases the PTH from gland.11 As
progressive GFR loss, PTH was resistant to the suppression by
FGF-23 and sequential nodular parathyroid hyperplasia
formed.12,13 On the aspect of vascular health, hyperphospha-
temia, SHPT, and hypovitaminosis were strongly associated
with increased cardiovascular morbidity and mortality and
increases the risk of calciphylaxis.14 Therefore, the treatment
on SHPT focus on (i) phosphate restriction, (ii) calcimimetics
and (iii) vitamin D analogues supplement.4
Hyperphosphatemia is associated with higher mortality in
CKD/end-stage renal disease (ESRD) patients,15 and phos-
phate restriction is mandatory in treating SHPT, and both
dietary restriction and oral phosphate binders are important
strategies. Among the phosphate binders, calcium-based
phosphate binders hindered the effect of vitamin D because
of the risk of hypercalcemia.16 Calcium-free phosphate
binders such as sevelamer or lanthanum decreases the
intestinal calcium loading, and it provided the benefit in
mortality in contrast to the calcium-based phosphate
binder.17,18 The calcium-sensing receptor (CaSR) is impor-
tant in regulating PTH secretion and therefore, this target
offers the potential to suppress PTH secretion by comple-
mentary mechanism to vitamin D analogues. Calcimimetics
allosterically enhance the sensitivity of CaSR in the parathy-
roid glands to calcium.19 As it direct suppression on PTH,
the serum calcium and phosphate concentration could be
controlled. Current studies involving the use of cinacalcet
include ADVANCE and Evaluation of Cinacalcet HCl Ther-
apy to Lower Cardiovascular Events (EVOLVE) studies, and
the use of calcimimetics provided the benefits on controlling
vascular calcification (VC) in subgroup analysis.20–22
NOVEL CONCEPTS OF ROLE OF
NUTRITIONAL VITAMIN D IN SHPT
Traditionally, active vitamin D compounds were used in
SHPT patients for its inhibitory effects on PTH gene tran-
scription and chief cell hyperplasia.23 As CKD progresses,
vitamin D deficiency or insufficiency was prominent because
of the presence of proteinuria, tubulointerstitial injury and
GFR loss.24 The binding of 25(OH)D to the proximal tubular
epithelium megalin receptor is limited during the
© 2018 Asian Pacific Society of Nephrology
Mineral bone disorders in CKD
proteinuria.25 As GFR loss, the production of FGF-23
inhibits the 1-α-hydroxylase activity in the renal proximal
tubule.8 The damaged tubulointerstitial tissue reduced the
activity of 1-α-hydroxylase and 25-hydroxylase.26 SPTH
itself also inhibits the hepatic production of 25(OH)D. Low
serum 25(OH)D concentration is common in CKD and
ESRD patients,27–29 and the severity of 25(OH)D deficiency
is related to the circulating PTH concentration.30,31 Michaud
et al.32 reported that the SPTH reduced the hepatic produc-
tion of calcidiol. Segersten et al.33 demonstrated 1α-OHase
expression in parathyroid glands, which suppressed parathy-
roid gland hyperplasia in an autocrine/paracrine manner.
Therefore, active vitamin D has been applied as the essential
treatment in treating SHPT.34,35 However, evidences had
shown that supra-physiological or pharmacological dosage
of active 1,25(OH)2D may aggravate 25(OH)D3 deficiency
because of its feedback inhibition of hepatic 1α-OHase and
25α-OHase resulting in 25(OH)D3 shortage in other tissues
or organs (e.g., colon, osteoblasts (OB), parathyroid gland,
monocytes and immune cells, etc.).36 Active 1,25(OH)2D
inactivates the 1α-OHase through the epigenetic modifica-
tion of VDR gene.37 At the same time, the raising of intracel-
lular 1,25-(OH)2D3 activates the 24-OHase activity to
autoregulates its own catabolism.38 Thus, active 1,25(OH)2D
may not only reduce 25(OH)D3 production but increase
1,25(OH)2D and 25(OH)D3 catabolism. Our study group
provided the evidence that the haemodialysis (HD) patients
had better control on SHPT with combination therapy with
vitamin D analogue and cholecalciferol than those with vita-
min D analogue alone, and the patients with combination
therapy had higher cathelicidin concentration.39 Therefore,
supplement of 25(OH)D during the treatment of SHPT is
important when prescribing active vitamin D or vitamin D
analogue.
VASCULAR AND SOFT TISSUE
CALCIFICATION IN CKD
In CKD, VC will be present at the beginning stage of CKD
because of the impaired bone mineral metabolism.40 VC can
be considered as two major types: intimal calcification asso-
ciated with atherosclerosis, and medial calcification that
involves damaged vascular smooth muscle cells (VSMC),
leading to increased vascular stiffness and decreased vascu-
lar elasticity.41 The factors involving the pathophysiology of
VC in CKD include abnormal serum calcium and phosphate
levels, hyperparathyroidism, increased matrix degradation,
VSMC apoptosis, decreased glutamate protein in matrix, and
systemic inflammation.42–45 The factors above-mentioned
activated the osteoblastic transformation of VSMC and
the VC.
These will make way to let VSMC transdifferentiate to
phenotypic osteoblastic cells. In addition, patients with CKD
usually have bone turnover problems.46 In a high turnover
status, SHPT increases calcium and phosphate release from
89
Y-C Hou et al.
bone by activating bone resorption.47 However, in a low
turnover status (such as adynamic bone disorder), circulat-
ing phosphate and calcium cannot efficiently deposit into
the bone surface and this might maintain serum calcium
and phosphate levels to a higher levels.48 Consequently, cir-
culating phosphate and calcium tend to deposit in soft tissue
other than bone matrix, causing higher probability of
VC. Interestingly, during the VC process, the calcifying
VSMC will secrete sclerostin (SOST), a Wingless/Int-1
(Wnt)-signalling inhibitor that may not only counteract the
local calcification in the artery wall but also destroy bone
mineralization.49,50 These phenomena may lead to reduced
bone mass with a vicious cycle between bone turnover
and VC.
TRADITIONAL FACTORS RELATED TO THE
OSTEOGENIC TRANS-DIFFERENTIATION OF
VASCULAR SMOOTH MUSCLE CELLS IN CKD
As GFR decline, the secretion of FGF-23 from osteocytes
increases to augment the renal excretion of phosphate.8
However, FGF-23 inhibits the activity of angiotensin-
converting enzyme 2 (ACE2). FGF-23 blocks the conversion
of angiotensin-II into angiotensin (1–7).51 The increase in
FGF23 disturbs the renin-angiotensin aldosterone system
(RASS) system and lessens the angiotensin receptor blocker
(ARB) efficacy.52 The activated angiotensin-II will enhance
the production of aldosterone. Phosphate and calcium stim-
ulate the Na-Pi cotransporter, and aldosterone also contrib-
utes to activate the Na-Pi cotransporter, resulting in
increased phosphate entrance into VSMC.53,54 In addition,
aldosterone accentuates the inflammatory status in part by
tumour necrosis factor alpha (TNFα). Both oxidative/inflam-
matory status and increased intracellular phosphate levels
promote VSMC to transdifferentiate into phenotypic OB
cells, which causes the ossification of the vascular wall to
progress.54 As a whole, the calcified vessels have more
prominent bone formation characteristic than bone resorp-
tion ones. In addition, osteogenic cells may secrete SOST
and FGF23. The secreted FGF23 from the calcified vessel
may contribute further increased FGF23 serum levels. These
high serum levels of FGF23, SOST will contribute to
decreasing OB function with resulted in further decrease
bone turnover in CKD patients.
LINKAGE BETWEEN BONE TURNOVER AND
VC IN CKD
Basically, bone cells have less vitality in patients with CKD
than in normal persons because of accumulation of uremic
toxin and insulin resistance. Thus, low bone turnover is part
of the innate character of CKD.55–57 High PTH serum levels
will overcome the indolent bone cells and lead to high turn-
over bone disease with the characteristics of relatively
higher bone resorption than bone resorption.7 The high
90
turnover status in SHPT can induce increased bone deminer-
alization, which will increase calcium and inorganic phos-
phate release from bone into circulation. In contrast,
overtreatment of CKD patients with Ca-salts, vitamin D
receptor analogue (VDRA), or aluminium may cause them
to develop low turnover bone disorders and low serum PTH
levels. The decreased bone mineralization makes it difficult
for calcium and inorganic phosphate to enter into bone,
resulting in increased serum calcium and inorganic phos-
phate.58 Both high and low bone turnover disorders are
characterized by a relatively higher degree of bone resorp-
tion than bone formation, which may contribute to the ele-
vated serum calcium and inorganic phosphate levels, and
aggravate VC/ossification.
NOVEL CONCEPTS OF NUTRITIONAL
VITAMIN D IN VASCULAR CALCIFICATION
IN CKD
In the study of cardiovascular disease with childhood onset
of ESRD, the Berlin paediatricians Briese et al.59 pointed out
interesting differences (with a relatively similar study result
reported by Pilz et al.60): the prevalence of coronary calcifi-
cations (10% vs 92%) and of cardiac valve calcifications
(0% vs 32%) was quite lower in the Berlin study (more use
of cholecalciferol) than in the Heidelberg one (less use of
cholecalciferol). In contrast to active vitamin D, the inci-
dence of hypercalcaemia is less in CKD patients,61,62 and it
might avoid extra-osseous calcium deposition in the vessels.
These findings suggest that nutritional vitamin D supple-
ment may prevent the development of VC.
VITAMIN D DEFICIENCY MAY CONTRIBUTE
TO VASCULAR CALCIFICATION THROUGH
INCREASE IN GLI1 EXPRESSION IN CKD
Mesenchymal stem cell (MSC)-like cells reside in the vascu-
lar wall, especially in the inner layer of tunica adventitia.
Perivascular Gli1+ progenitors are key contributors to
injury-induced organ fibrosis.63 Kramann et al.64 provided
the evidence that Gli1+ adventitial cells have a critical role
in VC in CKD. It has been noticed that both active and
nutritional vitamin D serve as the suppressor of Gli1 gene.
Vitamin D activated receptor regulates specific microRNA
and secrets hedgehog (Hh) pathway inhibitors suppressor of
fused (SuFu).65 Cholecalciferol could repress the Hh signal-
ling by directly inhibiting extra-cellular domain of smooth-
ened.66,67 The vitamin D deficiency may contribute to VC
through increase in Gli1 expression in CKD.
BONE DISORDERS IN CKD
In patients with early CKD (stages 1 and 2), Wnt-signalling
inhibitors, such as dickkopf WNT-signalling pathway inhibi-
tor 1 (DKK1), SOST and secreted frizzled related protein 1
© 2018 Asian Pacific Society of Nephrology

(sFRP) were secreted from kidneys, or osteocyte in bone/cal-
cified soft tissue, which could act on the OBs resulting in
decreased OB viability.68,69 In addition, retention of protein-
bound uremic toxins (PBUT), such as indoxyl sulphate/p-
cresol sulphate (IS/PCS), further attenuated the OB/OC via-
bility and function.55,70 Uremic osteoporosis was used to
describe the effects of PBUT on the qualitative bone loss
with normal bone quantity. When renal function declined
progressively, metabolic acidosis and hyponatremia also
result in the bone quantity loss.71 When the severity of CKD
progresses (≥stage 3) with calcium, phosphate, vitamin D
and PTH dysregulation, patients may present with high or
low PTH levels. High PTH levels drive the indolent OB into
high viability and function but poor quality in behaviour,
resulting in both bone quality and quantity loss.72,73 How-
ever, medical or surgical treatment of SHPT which largely
remove much of the PTH hypersecretion, the bone cells may
return back to the innate low bone cell viability status –the
low bone turnover disorders.74,75
UREMIC OSTEOPOROSIS-RELATED BONE
QUALITY LOSS
End-stage renal disease patients also are at an extremely
high risk of bone fractures because of the high incidence of
uremic osteoporosis and MBD.76,77 Compared with normal
population, uremic patients are more prone to having
abnormal bone metabolism, a disarranged bone microarchi-
tecture, lower bone mass and musculoskeletal fragility.78,79
The concept of ‘uremic osteoporosis’ was recently intro-
duced by Fukagawa et al.5,80 to explain the role of uremic
toxins in influencing bone quality in CKD patients. Accumu-
lative uremic toxins exhibit noxious effects on bone metabo-
lism and function, and attenuate the bone quality and
quantity. A representative uremic toxin, IS, accumulates in
CKD patients with progressive renal dysfunction.81 IS could
down-regulate the expression of PTH receptor on OB and
decrease the bone turnover.82 It also represses the bone for-
mation signalling by enhancing the secretion of Wnt antago-
nist from osteocyte.57 A previous clinical study showed a
positive correlation between IS levels and bone formation
rate, osteoid volume, OB surface area and bone fibrosis vol-
ume. Multivariate regression analysis further confirmed the
associations between IS levels and bone formation rate, OB
surface area, and bone fibrosis volume.83 They revealed that
the mineral-to-matrix ratio and carbonate substitution
increased with the number of immature crystals in CKD
rats.10 The enzymatic cross-link ratio was also increased
abnormally. Accumulated uremic toxins, especially IS, might
also be responsible for pathological collagen cross-links with
disarrayed orientation and weakened mechanical proper-
ties.84 Although the benefit of oral absorbent AST-120 for
uremic osteoporosis is still lacking in the clinical studies, the
AST-120 significantly reduces serum IS levels and can abol-
ish the bone effects noted in CKD animals.10,84 Therefore, to
© 2018 Asian Pacific Society of Nephrology
Mineral bone disorders in CKD
decrease gastrointestinal absorption and increase clearance
the uremic toxin may be important in treating the uremic
osteoporosis.
RENAL OSTEODYSTROPHY
The prevalence of osteoporosis varies according to CKD
stages. Fractures in early-stage CKD patients (stages 1–3 A
CKD) are more resemblance as traditional osteoporosis
rather than CKD-MBD.85,86 However, most patients in stage
4 or 5 CKD exhibit certain degree of decreased bone mineral
density (BMD) and/or certain level of CKD-MBD.87,88 At
the time of dialysis initiation, as many as up to half of the
patients, might have experienced a fracture.89 Together,
vitamin D deficiency, poor nutrition, inactivity, myopathy,
and peripheral neuropathy play a role in muscle weakness
and falls.90 Since vitamin D is crucial for bone health, and
vitamin D supplement is protective in fracture prevention in
CKD, the role of vitamin D should be stratified.
VITAMIN D DEFICIENCY-RELATED BONE
QUANTITY LOSS
Vitamin D is essential for normal bone formation and miner-
alization, and plays a critical role in bone biology.91,92 Disor-
dered vitamin D metabolism plays a crucial role in SHPT
along with other changes of mineral metabolism. Vitamin D
deficiency is common in advanced CKD, and the BMD is pos-
itively correlated with the serum 25(OH)D concentration.93
In another study, Mucsi et al.94,95 demonstrated a correlation
between 25 (OH) vitamin D deficiency and low radial BMD
in HD patients. ESRD patients with 25 (OH) D deficiency
(<15 nmol/L) had a lower bone formation rate and decreased
trabecular mineralization surface, independent of PTH and
calcitriol levels.95,96 Vitamin D can suppress the parathyroid
gland, and vitamin D deficiency worsens SHPT and increased
bone turnover, bone loss, and mineralization defects. Mili-
nkovic et al.97 have been noted the bone resorption increased
in HD patients with serum 25-(OH) D levels <50 nmol/L In a
retrospective study, Ambrus et al.95 revealed the association
between fractures and significant low vitamin D status among
maintenance HD patients. Lower 25 (OH) vitamin D levels
have been shown to be associated with subperiosteal resorp-
tion and reduced BMD in ESRD patients. Vitamin D defi-
ciency might also cause frailty presenting muscle weakness,
non-vertebral and hip fractures.90,98,99 Although high-quality
studies are needed to validate the effect of vitamin D on bone
quantity in CKD, supplement of vitamin D is important in
treating quantity bone loss.
VITAMIN D DEFICIENCY-RELATED BONE
QUALITY LOSS
Vitamin D deficiency is associated with an impaired bone
mineralization process, resulting in a larger volume of the
91
Y-C Hou et al.
unmineralized bone matrix, called osteoid. A group of US
and German scientists100,101 demonstrated that vitamin D
deficiency speeds up the premature aging of existing bone
and consequently reduces its quality. In vitamin D defi-
ciency patients, the mineralized bone was composed of
higher degree of mature collagen cross-link ratio and
carbonate-to-phosphate ratio, characteristics of aging and
brittle bone. The premature mineralized bone has significant
loss in the mechanical integrity and toughness, and the
vitamin-D-deficient bone is less resistant to the crack initia-
tion. Vitamin D-deficient bone tissue has a straighter crack
path with fewer crack bridges compared with normal.101
Furthermore, vitamin D deficiency inhibits normal bone
remodelling in the remaining mineralized bone tissue.102,103
Therefore, vitamin D levels should be maintained at well-
balanced levels to maintain the structural integrity of bone,
especially in CKD patients.
In conclusion, the underlying mechanisms of bone loss
and fractures in CKD patients are complex and remain
incompletely understood. In contrast to bone biopsy, the
presently available non-invasive investigative measures to
detect both bone quantity and quality losses are clinically
insufficient as screening or diagnostic techniques. Bone-
targeted pharmacotherapy was shown to only marginally
affect the incidence of fractures, and might be associated
with unexpected adverse effects in this specific population.
Classical but individualized therapy, including vitamin D
supplementation, phosphate control with phosphate binders,
anti-resorptive agents, dialysis and medical and surgical PTX,
might differentially benefit these patients. Researchers
should keep on investigating the detailed mechanisms of
pathophysiology, and look for the targeted therapy for both
quality- and quantity-related bone losses in CKD patients.
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