Bone disease in idiopathic hypercalciuria
Ita P. Heilberga and José R. Weisingerb
Purpose of review
Decreased bone mineral density and increased prevalence
of bone fractures have been found in patients with
idiopathic hypercalciuria. The purpose of this review is to
summarize the recent published evidence that supports a
potential role of the bone, and its link to the kidney and
intestine, in the pathogenesis of idiopathic hypercalciuria.
The effects of hypercalciuria on bone and the implications
for treatment are also reviewed.
Recent findings
Evidence suggests that the incidence of a first fracture in
kidney stone patients is fourfold higher than the control
population. Support for the role of bone in the
pathophysiology of hypercalciuria has been corroborated.
New studies have detailed the effects of several cytokines –
increased number and sensitivity of vitamin D receptors,
and increased acid production – upon the bone acting
cells. Similarly, recent clinical and experimental studies have
suggested that genetic factors confer a predisposition to
the formation of renal calcium stones and bone
demineralization.
Summary
Whether hypercalciuria is the result of a primary bone
disorder, a consequence of a persisting negative calcium
balance or a combination of both still remains to be
determined. Nevertheless, bone status must be evaluated
and followed up in patients with idiopathic hypercalciuria.
Keywords
bisphosphonates, bone, bone fractures, bone mineral
density, hypercalciuria, idiopathic hypercalciuria, kidney
stones, lithiasis, osteoporosis, thiazides, urine calcium
Curr Opin Nephrol Hypertens 15:394–402. ß 2006 Lippincott Williams & Wilkins.
a mented bone resorption has been implicated in the
Division of Nephrology, Universidade Federal de São Paulo, São Paulo, Brazil and
b
Division of Nephrology and Renal Transplantation, Hospital Universitario de
Caracas, Universidad Central de Venezuela, Caracas, Venezuela
Correspondence to José R. Weisinger MD, FACP, Division of Nephrology, Hospital
Universitario de Caracas, Universidad Central de Venezuela, Apartado Postal
47365, Los Chaguaramos, Caracas, Venezuela
Tel: +58 212 9869354; fax: +58 212 9856219; e-mail: jweising@telcel.net.ve
This study was supported by Fundação Oswaldo Ramos (FOR), Conselho Nacional
de Desenvolvimento Cientı́fico e Tecnológico (CNPq), Fundação de Amparo à
Pesquisa do Estado de São Paulo (FAPESP), Sao Paulo, Brazil and grant G-97-
008808 of the Fondo Nacional de Ciencia, Tecnologı́a y Innovación de Venezuela
(FONACIT) and Fundarenal-HUC, Caracas, Venezuela.
Current Opinion in Nephrology and Hypertension 2006, 15:394–402
394
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Abbreviations
BMD bone mineral density
GHS genetic hypercalciuric stone-forming rats
RANKL receptor activator of nuclear factor kB ligand
ß 2006 Lippincott Williams & Wilkins
1062-4821
Introduction
About 5% of American women and 12% of men will
develop a kidney stone at some time in their life, and
prevalence has been rising in both sexes [1
]. It is generally
agreed that oversaturation of urine with calcium is one of
the most important risk factors for calcium nephrolithiasis,
and that idiopathic hypercalciuria represents the primary
metabolic alteration in almost one-half of patients [2].
Idiopathic hypercalciuria has been defined as a 24 h
urinary excretion of calcium, in two consecutive collec-
tions, that exceeds 4 mg/kg/day or 140 mg per gram of
urinary creatinine in the absence of other known systemic
diseases that cause normocalcemic hypercalciuria [3].
Although much progress has been made in the diagnosis
and management of idiopathic hypercalciuria during the
past few years, controversies still exist about the definite
pathophysiological events responsible for this condition.
It has become evident that idiopathic hypercalciuria
cannot be explained by a single mechanism, and different
studies have suggested a systemic abnormality in calcium
homeostasis, in which a dysregulation of calcium trans-
port in the intestine, kidney and bone takes place [4–6].
The existence of increased intestinal calcium absorption,
decreased renal tubular calcium reabsorption and aug-
pathophysiology of idiopathic hypercalciuria [7].
Urinary calcium is a determinant of bone mineral density
(BMD), both in women [8] and in men [9
]. Similarly,
reduced BMD has been observed in idiopathic hyper-
calciuria even in the presence of increased calcium intes-
tinal absorption [10]. Interestingly, spine and femoral
neck BMD varied inversely with urine calcium loss in
idiopathic hypercalciuria stone formers but not in non-
stone formers [11].
In this article we will review the evidence that links
the bone with the kidney and intestine as a cause, or even
a consequence, of hypercalciuria. We will try to address a
critical question: is the hypercalciuria the result of a
 Bone disease in idiopathic hypercalciuria Heilberg and Weisinger 395

Table 1 Bone mineral density (BMD) and bone resorption markers in idiopathic hypercalciuria
Number Gender (M/F) Decreased BMD site(s) Method Author (country) Increased resorption markers Year

117 94/23 Radius SPA Lawoyin et al. (USA) [16] 1979

78 41/37 Radius SPA Fuss et al. (Belgium) [17] 1983
70 45/25 Spine QCT Pacifici et al. (USA) [18] HP 1990
42 29/13 Spine QCT Bataille et al. (France) [19] HP 1991
41 27/14 Spine DPA Borghi et al. (Italy) [20] 1991
89 66/23 Radius, spine SPA/DEXA Pietschmann et al. (USA) [21] 1992
55 29/26 Spine DEXA Heilberg et al. (Brazil) [22] 1994
49 all male Tibia DEXA Jaeger et al. (Switzerland) [23] HP, Pyr/DPyr 1994
17 13/4 Spine DEXA Weisinger et al. (Venezuela) [24] 1996
50 20/30 Spine DPA Zanchetta et al. (Argentina) [25] 1996
25 23/2 Spine QCT Ghazali et al. (France) [26] 1997
49 36/13 Spine DEXA Giannini et al. (Italy) [27] HP 1998
14 all male Spine/femur DEXA Trinchieri et al. (Italy) [28] Pyr/DPyr 1998
22 11/11 Spine/femur DEXA Misael da Silva et al. (Brazil) [29] 2002
70 44/26 Spine DEXA Tasca et al. (Italy) [30] HP 2002
Increased urinary hydroxyproline without BMD measurement had been observed by Sutton et al. [31]. SPA, single photon absorptiometry; QCT,
quantitative computed tomography; HP, urinary hydroxyproline; DPA, dual photon absorptiometry; DEXA, dual energy X-ray absorptiometry; Pyr/DPyr,
urinary pyridinoline/deoxypyridinoline.

primary disorder of bone metabolism or is the decrease in
bone mineralization in turn a consequence of the hyper-
calciuria with its attendant negative calcium balance?
Is there an increased fracture risk in
hypercalciuric and renal stone patients?
In a population-based retrospective cohort study [12], a
significant number of Rochester, Minnesota residents
with an initial symptomatic episode of urolithiasis were
followed for subsequent age-related fractures. The study
demonstrated that the number of patients with a first
vertebral fracture was over four times the number
expected on the basis of vertebral fracture incidence rates
in the general population of this city. There was no
increase in the risk of hip, pelvis, proximal humerus or
distal forearm fractures, however, in this cohort of patients.
A cross-sectional study [13], using the Third National
Health and Nutrition Examination Survey (NHANES
III) showed that men with kidney stone history have lower
femoral neck BMD than men without kidney stones, after
adjusting for age, body mass index, ethnicity, and other
potential confounders, with a concomitant higher preva-
lence of wrist and spine fractures. The effect of kidney
stone history on BMD or fractures was weaker for women.
Although most studies have demonstrated that BMD is
reduced in idiopathic hypercalciuria patients when com-
pared with other calcium stone formers [14,15
], we still
need to generate data showing that idiopathic hyper-
calciuria patients have increased fracture risk when com-
pared with other stone-forming patients.
Bone mineral density and potential growth
defects in hypercalciuric renal stone-
forming patients
Decreased BMD in trabecular and cortical bone has
been reported in patients with idiopathic hypercalciuria
nephrolithiasis using different methods such as radiologi-
cal evaluation, photon absorptiometry, in-vivo neutron
activation analysis, and whole body counting. Similarly,
some studies [16–31] have demonstrated that these
patients have increased bone resorption markers (Table 1).
Few bone histomorphometric analyses have been
reported in idiopathic hypercalciuria patients and these
have not yielded homogeneous results. While some
studies [22,29,32] have demonstrated low bone volume,
a tendency of low bone formation coupled with increased
bone resorption and delayed bone mineralization, other
reports [33] showed normal bone resorption. Never-
theless, all of these studies have evidenced low bone
formation and a severe mineralization defect.
The underlying mechanisms responsible for possible
higher bone resorption and lower bone formation in this
setting are still unclear and the reasons for the mineraliza-
tion defect are puzzling if one considers that serum
levels of calcium, phosphorus parathyroid hormone,
and vitamin D metabolites are usually normal.
Optimal bone mineral accretion during childhood and
adolescence is critical to the attainment of a healthy
adult skeleton. As in the adult population, reduced
BMD has been detected in a large proportion of idiopathic
hypercalciuria children in studies conducted in the USA,
Venezuela and Spain [34,35]. Interestingly, hypercalciuria
and reduced BMD were uncovered in a substantial num-
ber of their otherwise healthy asymptomatic mothers.
Thus, the diminished BMD observed in adults with idio-
pathic hypercalciuria may start early in life, and may
represent a risk factor for osteoporosis later in life as has
been shown recently in an evaluation of almost 6000 men,
65 years of age or older, in which a history of kidney stones
was associated with lower BMD [36
]. Nevertheless,
growth, including pubertal growth spurt, has been reported

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
 396 Mineral metabolism
to be normal in idiopathic hypercalciuria children and
adolescents [37,38]. Finally, a recent observation [39]
has suggested that children with idiopathic hypercalciuria
and associated hypocitraturia have lower BMD than
similar children with only hypercalciuria.
Pathophysiology of bone alterations in renal
stone formers with hypercalciuria
In addition to either excessive intestinal absorption of
calcium, or a renal calcium leak due to a tubular disturb-
ance, increased mobilization of bone calcium has been
suggested as the explanation for the hypercalciuria in
calcium oxalate stone formers with idiopathic hypercal-
ciuria [14]. Although the pathophysiology of the hyper-
calciuria cannot be explained by a single mechanism or
theory, and mobilization of bone calcium by itself does
not represent the only cause of hypercalciuria, we believe
that bone cells involved in bone formation and resorption
could play a central role in the chain of events leading
to hypercalciuria.
Role of cytokines
Studies by Pacifici et al. [18] have demonstrated that
mononuclear cells from patients with fasting hypercal-
ciuria had an increased spontaneous production of inter-
leukin-1 (IL-1), a potent in-vitro and in-vivo stimulator of
bone resorption. This finding correlated with the lumbar
spine BMD and was not present in those patients with
absorptive hypercalciuria. Subsequently, we demon-
strated that not only IL-1, but other cytokines such as
IL-6, and tumor necrosis factor-a (TNF-a) had increased
expression in idiopathic hypercalciuria patients, with a
significant correlation between in-vitro cytokine pro-
duction and lumbar spine BMD [24]. Based on these
findings, which were corroborated by others [26,29], it has
been suggested that bone resorption induced by elevated
cytokines may represent a primary mechanism leading
to hypercalciuria.
Recently, the interaction between bone formation and
resorption has been further elucidated by the characteri-
zation of a novel glycoprotein called osteoprotegerin, a
soluble secreted receptor of the tumor necrosis factor
superfamily, the receptor activator of nuclear factor kB
(RANK) and its natural ligand, RANKL, which is incor-
porated in the osteoblast membrane [40

]. The role of
the osteoprotegerin/RANKL system in the pathophysiol-
ogy of bone loss of hypercalciuric patients remains to be
disclosed.
Role of the vitamin D receptors and increased sensitivity
to calcitriol
Bushinsky et al. [6] have developed a strain of genetic
hypercalciuric stone-forming rats (GHS rats) with almost
60 generations of inbreeding. These rats excrete eight to
ten times as much calcium as control animals, and almost
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
uniformly form calcium-containing kidney stones.
Increased sensitivity to calcitriol has been observed in
enterocytes and calvariae of these animals, which is
presumably due to the increased number of vitamin D
receptors. This extremely important mechanism will be
discussed in another chapter of this issue.
Role of the diet
While the incidence of renal stone disease has been
shown to be dependent on the dietary habits of affluent
societies, abnormal dietary intake by renal stone formers
remains hypothetical as the cause of the stone disease.
Let us review how calcium excretion can be modified by
changes in calcium, sodium, and protein intake.
Calcium intake
Previous epidemiological data by Curhan et al. [41]
showed that dietary calcium restriction increases the risk
of new symptomatic kidney stone formation. This seems
to occur because of the increased intestinal oxalate
absorption in the absence of calcium in the colon, with
a secondary increase in urinary oxalate, and higher urinary
calcium oxalate supersaturation. Similarly, it has been
shown that this secondary rise in urinary oxalate occurring
from calcium restriction can be avoided by concurrent
dietary oxalate restriction [42].
At the same time, it has been demonstrated that in men
with recurrent calcium oxalate stones and hypercalciuria,
restricted intake of animal protein and salt, combined
with a normal calcium intake, provides greater protection
for new stone formation than the usual low-calcium diet
[43]. Thus, dietary restriction of calcium not only fails to
decrease the incidence of kidney stones, but possibly
further aggravates bone mineral loss. In fact, several
investigators have shown that low-calcium diet in idio-
pathic hypercalciuria patients is associated with reduced
BMD [21,24,28,44].
Sodium intake
The effect of high sodium intake upon volume expan-
sion and increased calcium excretion has been well
documented. This has provided the physiological basis
for the proposed role of increased salt intake as a risk
factor for osteoporosis. A recent study [45
] evaluated the
effect of low sodium diet (2 g/day) during 6 months in
postmenopausal women, showing a reduction in calcium
excretion and the aminoterminal propeptide of type I
collagen.
The effect of a high salt intake in calcium stone formers
and its potential impact on bone have been evaluated with
multiple-regression analysis by Martini et al. [46]. This
study showed that after adjustment for calcium and
protein intakes, age, weight, body mass index, urinary
calcium, citrate, uric acid excretion, and duration of stone
 Bone disease in idiopathic hypercalciuria Heilberg and Weisinger 397
disease, a high salt intake was the single variable that was
predictive of risk of low bone density in calcium stone
formers.
Protein intake
Another factor to be considered that potentially could
lead to increased bone turnover is the subtle metabolic
acidosis resulting from high dietary protein intake. Bone
mineral serves an important role as a reserve of hydroxyl
ions to buffer systemic protons if the kidneys and
lungs are unable to maintain acid–base balance within
narrow physiologic limits. These changes in mineral
composition initiate as physicochemical mineral disso-
lution and later through alterations in bone cell function
[47]. Afterwards, acidosis suppresses osteoblastic activ-
ity with a concomitant acid stimulation of prostaglandin
production by the osteoblasts with a subsequent in-
crease in osteoblastic RANKL synthesis. RANKL then
stimulates osteoclastic activity and the recruitment of
new osteoclasts to promote bone resorption and buffer-
ing of the proton load. At the same time, acidosis causes
a significant increase in TNF-a levels in order to
reduce the acid-induced, cell-mediated net Ca efflux
from bone, with simultaneous inhibition of RANKL
[48

].
The role of high animal protein intake associated with
decreased BMD in idiopathic hypercalciuria has been
suggested by some investigators [19,23]. In an experi-
mental rat model [49] of high protein diet an increase in
both urinary calcium and bone resorption, assessed by
histomorphometric analysis, was observed. Nevertheless,
recent experimental and clinical data concur to indicate
that low protein intake negatively affects bone health.
This controversial issue was initiated by the population-
based Framingham Osteoporosis Study [50], which
showed that even after controlling for known confoun-
ders, including weight loss, women and men with
relatively lower protein intake had increased bone
loss. Thus, selective deficiency in dietary proteins
could cause marked deterioration in bone mass, micro
architecture and strength – the hallmark of osteoporosis
[51

].
It is important to mention that most of the conclusions
obtained from the available work on the role of protein
consumption on bone health in osteoporosis cannot be
extrapolated to bone disease in idiopathic hypercalciuria,
for which further clinical studies are needed.
Role of prolonged immobilization
On the basis of studies in immobilized patient and
experimental in-flight studies, the existence of an imbal-
ance between bone formation and resorption could
induce loss of skeletal mass, leading to osteoporosis,
hypercalcemia, and hypercalciuria, with the attendant
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
risk of nephrolithiasis. Initial studies [52] showed that
the parathyroid-1, 25-dihydroxyvitamin D axis was sup-
pressed in patients with immobilization-induced hy-
percalciuria. A bone histomorphometric study [53]
performed in normal controls who underwent 12 weeks
of complete bed rest demonstrated that the human
skeleton appears to respond to unloading by a rapid
and sustained increase in bone resorption and a more
subtle decrease in bone formation. A recent report [54]
conducted during the Shuttle-Mir Science Program
during 4–6-month space missions indicated that the
bone loss that occurs during space flight is a consequence
of increased bone resorption and decreased intestinal
calcium absorption. Similarly, alendronate was able to
prevent bone loss and avert hypercalciuria when given
in anticipation of 3 weeks of strict bed rest [55], and
intravenous pamidronate in the prevention of femoral
bone loss and renal stone formation during a 90-day bed
rest [56]. A similar approach was taken with the use of
bisphosphonate therapy in order to diminish bone resorp-
tion and reduce bladder stone formation and hypercal-
ciuria in spinal cord injury paraplegics [57].
Role of genetics
It has recently been suggested that a major gene with a
relatively large effect on variation in urine calcium
excretion is segregating in stone-forming families [58
].
As was mentioned previously, idiopathic hypercalciuria
appears to be an autosomal dominant trait and approxi-
mately 40% of patients show a family history of nephro-
lithiasis. We have recently learned that idiopathic
hypercalciuria represents a complex trait, which does
not fit into the classical Mendelian categories, but
represents a polygenic entity [58
,59,60

].
At the same time, it well known that BMD is under
strong genetic control and as much as 75% of its variance
in the normal population has been attributed to genetic
factors [61

]. Thus, attempts to look for common allelic
variations or polymorphisms in genes that link idiopathic
hypercalciuria and decreased BMD have been the focus
of many investigations. Heilberg et al. [62] did not
observe an association between BsmI vitamin D receptor
(VDR) polymorphism with BMD in idiopathic hypercal-
ciuria patients. In a recent report [63], a higher prevalence
of the b rather than the B allele was found in stone
formers with fasting hypercalciuria and reduced BMD.
At the same time, an Arg990Gly polymorphism of the
calcium-sensing receptor gene has been identified in
patients with idiopathic hypercalciuria but BMD was
not assessed in this study [64]. Finally, Reed et al. [65]
found a linkage to chromosome 1q23–24 in three families
with absorptive hypercalciuria and low spinal bone
density, and reported the occurrence of base pair substi-
tutions in the soluble adenylate cyclase gene that segre-
gates with the disease.
 398 Mineral metabolism
What have we learned from recent
experimental models regarding hypercalciuria
and bone demineralization?
As was mentioned previously, the GHS rat model closely
resembles idiopathic hypercalciuria, with the existence of
excessive intestinal calcium absorption, increased bone
resorption, and impaired renal calcium reabsorption. A
quantitative trait locus study [66] in these animals
showed a significant linkage to regions of chromosomes
4, 7, 10, and 14 but none of them mapped to the VDR, or
to the calcium-sensing receptor gene loci. This study
suggests that identification of genes that contribute to
hypercalciuria in this animal model should prove valuable
in understanding idiopathic hypercalciuria and kidney
stone disease in humans.
After years of research, rapid progress was made recently
in the identification and characterization of the Ca(2þ)
and Mg(2þ) transport proteins that contribute to the
delicate balance of divalent cations. Transient receptor
potential cation channel subfamily V, members 5 and 6
(TRPV5 and TRPV6), originally called ECaC1 and
CaT1, have recently been postulated to be the molecular
gatekeepers facilitating Ca2þ influx in the kidney, small
intestine, and bone [67

]. Hoenderop et al. [68] demon-
strated that mice lacking TRPV5 displayed diminished
active Ca2þ reabsorption despite enhanced vitamin D
levels, causing severe hypercalciuria and significant
disturbances in bone structure, including reduced tra-
becular and cortical bone thickness. Similarly, Zebrafish
mutants of TRPm7 have been shown to present both
defective skeletogenesis and kidney stone formation
[69]. Studies performed in nine families with autosomal
dominant idiopathic hypercalciuria, however, showed no
mutations in the human orthologue epithelial Ca2þ chan-
nel (hECaC1) gene [70]. Nevertheless, because of the
heterogeneity of the disease, the involvement of receptor
potential family members in other subtypes of idiopathic
hypercalciuria cannot be excluded and needs further
investigation.
Dent’s disease is a nephrolithiasis disorder associated
with hypercalciuria and low molecular weight pro-
teinuria caused by mutations in the voltage-gated
chloride channel ClC-5. Recent work by Silva et al.
[71] has demonstrated that the hypercalciuria in the
ClC-5 knockout mice on low and high-calcium diets is
of bone and renal origin and is not caused by increased
intestinal calcium absorption, despite an elevated serum
1,25(OH)2D3. Nevertheless, mutation analysis of the
CLCN-5 gene is normal among patients with idiopathic
hypercalciuria and CLCN-5 sequence was shown to be
normal in the GHS rat [72].
Finally, the importance of proteins that interact with
sodium/inorganic phosphate (Na/Pi) cotransporters has
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
begun to emerge. Mice that are null for the sodium-
phosphate cotransporter (NPT) 2a gene exhibit hypo-
phosphatemia, increased urinary phosphate excretion,
hypercalciuria and nephrolithiasis, but no bone deminer-
alization [73]. Heterozygous loss-of-function mutations in
the NPT2a gene in humans, however, induce hypophos-
phatemia, phosphaturia, hypercalciuria, nephrolithiasis in
males, and bone demineralization of variable severity in
both sexes [74]. The link between abnormalities in the
regulation of serum phosphate and NPT2a function and
bone mineralization is complex and warrants further
investigation.
Approach and treatment of the bone
alterations in renal stone disease
Appropriate therapy to prevent bone disease and reduce
renal stone recurrence in patients with idiopathic hyper-
calciuria may include the following.
Thiazides
Thiazide diuretics associated with a reduced sodium
intake represent the first choice of treatment in the
management of idiopathic hypercalciuria stone formers.
A recent metaanalysis [75] revealed that in studies in
which treatment lasted for more than 2 years, the
reduction in stone formation recurrence rate has been
significant. It has been demonstrated [76
,77
,78] that
after adjustment for potential confounders, patients on
thiazide diuretics for other medical conditions showed
improved BMD and reduced forearm and hip fracture
risk. Thus, one would expect that in idiopathic hyper-
calciuria patients the use of thiazides could reduce
urinary calcium excretion, kidney stone recurrence,
and at the same time improve bone metabolism.
Bisphosphonates
When the GHS rats are placed on a low-calcium diet,
urinary calcium excretion exceeds dietary calcium intake,
suggesting that bone may contribute to the excess
calcium excretion. When GSH rats were placed on a
low-calcium diet plus alendronate, Bushinsky et al. [79]
demonstrated a significant decrease in both urinary
calcium and supersaturation. In previous studies [80],
we showed that idiopathic hypercalciuria patients on
alendronate exhibited decreased urinary calcium excre-
tion and bone resorption markers starting 1 month after
treatment, and increased trabecular BMD after 1 year. By
contrast, normocalciuric stone formers showed no signifi-
cant changes in any of these parameters. Similarly, we
have observed [44] that the use of etidronate in male
idiopathic hypercalciuria stone formers with marked
increased bone resorption induced a significant improve-
ment in lumbar spine BMD after 1 year of treatment.
Although the use of bisphosphonates could be of
some benefit in idiopathic hypercalciuria patients with
 Bone disease in idiopathic hypercalciuria Heilberg and Weisinger 399
elevated bone resorption and osteoporosis, it should not
be used for treatment of the hypercalciuria and reduction
of stone events because of the increased risk of osteo-
malacia, especially in those idiopathic hypercalciuria
patients who present low bone formation, as has been
shown in osteoporotic patients [81].
Alkali therapy and citrate
Short-term bicarbonate therapy potently reduces urine
calcium excretion in adult humans, including patients
with hypertension or calcium urolithiasis, and postmeno-
pausal women. In the latter group, potassium bicarbonate
treatment induced a dose-dependent decrease in urinary
calcium that persisted for up to 3 years, with the greatest
decreases occurring in those women with higher baseline
calciuria [82
]. More recently, it has been shown that
combined treatment with potassium citrate and calcium
citrate is more effective than either agent alone in inhib-
iting bone loss, by providing an alkali load and increasing
absorbed calcium [83]. Finally, in a retrospective and
uncontrolled study in patients with recurrent calcium
oxalate nephrolithiasis [84], potassium citrate averted
age-dependent bone loss.
Figure 1 Bone involvement in the pathophysiology of idiopathic hypercalciuria: potential mechanisms
IL-1a, interleukin-1a; IL-6,
interleukin-6; PTH, parathyroid
hormone; TNF-a, tumor necrosis
factor-a; VDR, vitamin D receptor.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Calcium intake
Excess urinary calcium, the fact that some of these patients
have excessive intestinal calcium absorption, and the
knowledge that the majority of stones are composed of
different calcium crystals have led to a customary dietary
calcium restriction, independent of the cause of the kidney
stones. Eventually, this calcium restriction has not re-
solved the kidney stone recurrence. On the contrary, it
may have increased their incidence [41], adding a situation
of persistent negative calcium balance with potential
damage to the bone. Thus, we should not restrict the
calcium intake in patients with idiopathic hypercalciuria.
A frequently asked question by many osteoporotic patients
is whether the supplemental calcium could increase the
risk of kidney stone formation. A recent 8-year prospective
study evaluated the association between dietary factors
and the risk of incident symptomatic kidney stones among
96 245 female participants in the Nurses’ Health Study II
[85]. The study suggested that a higher intake of dietary
calcium decreases the risk of kidney stone formation and
that supplemental calcium was not associated with risk.
Since the timing of calcium supplementation may affect
 400 Mineral metabolism
gastrointestinal absorption of both calcium and oxalate,
interfering in the risk of urinary crystallization, a good
alternative is to take the supplement with meals rather
than at bedtime [86]. The effect of calcium supple-
mentation on osteoporotic women with idiopathic hyper-
calciuria remains to be determined.
Conclusion
In summary, the association of idiopathic hypercalciuria
with decreased bone mass and increased fracture risk is
clear. Whether the decrease in bone mineral mass con-
stitutes the primary event responsible for the hypercal-
ciuria, or its consequence, remains to be clarified.
Although mobilization of bone calcium by itself cannot
be the only cause of hypercalciuria, we believe that bone
cells involved in bone formation and resorption play a
central role in the chain of events leading to hypercal-
ciuria (Fig. 1). Future studies, particularly those employ-
ing molecular biology and genetic techniques, should
improve our understanding of the possible defects that
contribute to the development of hypercalciuria and
nephrolithiasis.
Acknowledgement
We acknowledge the contribution of Sandra Weisinger and Simon da
Franca in the figure design.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:

of special interest


of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (p. 465).
1 Coe FL, Evan A, Worcester E. Kidney stone disease. J Clin Invest 2005;

115:2598–2608.
An excellent review of emerging advances in the pathophysiology of kidney stone
disease.
2 Levy FL, Adams-Huet B, Pak CY. Ambulatory evaluation of nephrolithiasis:
an update of a 1980 protocol. Am J Med 1995; 98:50–59.
3 Coe FL, Parks JH. Nephrolithiasis: pathogenesis and treatment. 2nd ed.
Chicago: Year Book Medical Publishers; 1998. pp. 109–110.
4 Coe FL, Favus MJ, Crockett T, et al. Effects of low calcium diet on urine
calcium excretion, parathyroid function and serum 1, 25(OH)2D3 levels in
patients with idiopathic hypercalciuria and in normal subjects. Am J Med
1982; 72:25–32.
5 Heilberg IP. Hypercalciuria. In: Martini L, editor. Encyclopedia of endocrine
diseases. Vol. 2. San Diego, CA: Academic Press; 2004. pp. 530–536.
6 Bushinsky DA. Genetic hypercalciuric stone-forming rats. Curr Opin Nephrol
Hypertens 1999; 8:479–488.
7 Frick KK, Bushinsky DA. Molecular mechanisms of primary hypercalciuria.
J Am Soc Nephrol 2003; 14:1082–1095.
8 Giannini S, Nobile M, Dalle Carbonare L, et al. Hypercalciuria is a common
and important finding in postmenopausal women with osteoporosis. Eur J
Endocrinol 2003; 149:209–213.
9 Vezzoli G, Soldati L, Arcidiacono T, et al. Urinary calcium is a determinant of

bone mineral density in elderly men participating in the InCHIANTI study.
Kidney Int 2005; 67:2006–2014.
Interesting epidemiological survey on aging performed in Italy showing that
normal men in the highest tertile of calcium excretion had significantly lower
trabecular BMD.
10 Vezzoli G, Rubinacci A, Bianchin C, et al. Intestinal calcium absorption is
associated with bone mass in stone-forming women with idiopathic hyper-
calciuria. Am J Kidney Dis 2003; 42:1177–1183.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
11 Asplin JR, Bauer KA, Kinder J, et al. Bone mineral density and urine calcium
excretion among subjects with and without nephrolithiasis. Kidney Int 2003;
63:662–669.
12 Melton LJ III, Crowson CS, Khosla S, et al. Fracture risk among patients
with urolithiasis: a population-based cohort study. Kidney Int 1998; 53:459–
464.
13 Lauderdale DS, Thisted RA, Wen M, Favus MJ. Bone mineral density and
fracture among prevalent kidney stone cases in the Third National Health and
Nutrition Examination Survey. J Bone Miner Res 2001; 16:1893–1898.
14 Weisinger JR. New insights into the pathogenesis of idiopathic hypercalciuria:
the role of bone. Kidney Int 1996; 49:1507–1518.
15 Giannini S, Nobile M, Sella S, Dalle Carbonare L. Bone disease in primary

hypercalciuria. Crit Rev Clin Lab Sci 2005; 42:229–248.
Extensive review about the underlying mechanisms involved in the bone loss
associated with hypercalciuria.
16 Lawoyin S, Sismilich S, Browne R, Pak CY. Bone mineral content in patients
with calcium urolithiasis. Metabolism 1979; 28:1250–1254.
17 Fuss M, Gillet C, Simon J, et al. Bone mineral content in idiopathic renal stone
disease and in primary hyperparathyroidism. Eur Urol 1983; 9:32–34.
18 Pacifici R, Rothstein M, Rifas L, et al. Increased monocyte interleukin-1 activity
and decreased vertebral bone density in patients with fasting idiopathic
hypercalciuria. J Clin Endocrinol Metab 1990; 71:138–145.
19 Bataille P, Achard JM, Fournier A, et al. Diet, vitamin D and vertebral mineral
density in hypercalciuric calcium stone formers. Kidney Int 1991; 39:1193–
1205.
20 Borghi L, Meschi T, Guerra A, et al. Vertebral mineral content in diet-
dependent and diet-independent hypercalciuria. J Urol 1991; 146:1334–
1338.
21 Pietschmann F, Breslau NA, Pak CY. Reduced vertebral bone density in
hypercalciuric nephrolithiasis. J Bone Miner Res 1992; 7:1383–1388.
22 Heilberg IP, Martini LA, Szejnfeld VL, et al. Bone disease in calcium stone
forming patients. Clin Nephrol 1994; 42:175–182.
23 Jaeger P, Lippuner K, Casez JP, et al. Low bone mass in idiopathic renal stone
formers: magnitude and significance. J Bone Miner Res 1994; 9:1525–1532.
24 Weisinger JR, Alonzo E, Bellorin-Font E, et al. Possible role of cytokines on the
bone mineral loss in idiopathic hypercalciuria. Kidney Int 1996; 49:244–250.
25 Zanchetta JR, Rodriguez G, Negri AL, et al. Bone mineral density in patients
with hypercalciuric nephrolithiasis. Nephron 1996; 73:557–560.
26 Ghazali A, Fuentes V, Desaint C, et al. Low bone mineral density and
peripheral blood monocyte activation profile in calcium stone formers with
idiopathic hypercalciuria. J Clin Endocrinol Metab 1997; 82:32–38.
27 Giannini S, Nobile M, Sartori L, et al. Bone density and skeletal metabolism are
altered in idiopathic hypercalciuria. Clin Nephrol 1998; 50:94–100.
28 Trinchieri A, Nespoli R, Ostini F, et al. A study of dietary calcium and other
nutrients in idiopathic renal calcium stone formers with low bone mineral
content. J Urol 1998; 159:654–657.
29 Misael da Silva AM, Dos Reis LM, Pereira RC, et al. Bone involvement in
idiopathic hypercalciuria. Clin Nephrol 2002; 57:183–191.
30 Tasca A, Cacciola A, Ferrarese P, et al. Bone alterations in patients with
idiopathic hypercalciuria and calcium nephrolithiasis. Urology 2002; 59:
865–869.
31 Sutton RAL, Walker VR. Bone resorption and hypercalciuria in calcium stone
formers. Metabolism 1986; 35:485–488.
32 Steiniche T, Mosekilde L, Christensen MS, Melsen F. A histomorphometric
determination of iliac bone remodeling in patients with recurrent renal stone
formation and idiopathic hypercalciuria. APMIS 1989; 97:309–316.
33 Malluche HH, Tschoepe W, Ritz E, et al. Abnormal bone histology in idiopathic
hypercalciuria. J Clin Endocrinol Metab 1980; 50:654–658.
34 Freundlich M, Alonzo E, Bellorin-Font E, Weisinger JR. Reduced bone mass in
children with idiopathic hypercalciuria and in their asymptomatic mothers.
Nephrol Dial Transplant 2002; 17:1396–1401.
35 Garcia-Nieto V, Navarro JF, Monge M, Garcia-Rodriguez VE. Bone mineral
density in girls and their mothers with idiopathic hypercalciuria. Nephron Clin
Pract 2003; 94:89–93.
36 Cauley JA, Fullman RL, Stone KL, et al., for the Mr. OS Research Group.

Factors associated with the lumbar spine and proximal femur bone mineral
density in older men . Osteoporos Int 2005; 16:1525–1537.
Cross-sectional analysis performed in BMD in a large population-based sample of
older men enrolled in the Osteoporotic Fractures in Men Study (Mr. OS), showing
that a history of kidney stones was associated with lower BMD.
37 Polito C, Iolascon G, Nappi B, et al. Growth and bone mineral density in long-
lasting idiopathic hypercalciuria. Pediatr Nephrol 2003; 18:545–547.
 Bone disease in idiopathic hypercalciuria Heilberg and Weisinger 401
38 Skalova S, Palicka V, Kutilek S. Bone mineral density and urinary N-acetyl-
beta-D-glucosaminidase activity in paediatric patients with idiopathic hyper-
calciuria. Nephrology (Carlton) 2005; 10:99–102.
39 Penido MG, Lima EM, Souto MF, et al. Hypocitraturia: a risk factor for reduced
bone mineral density in idiopathic hypercalciuria? Pediatr Nephrol 2006;
21:74–78.
40 Raisz LG. Pathogenesis of osteoporosis: concepts, conflicts, and prospects.


J Clin Invest 2005; 115:3318–3325.
This excellent review encompasses the emerging data on pathogenetic mechan-
isms underlying osteoporosis. It examines the regulation of bone remodeling,
involving the osteoblastic and osteoclastic bone lineages and their interac-
tion with systemic hormones, local cytokines, and growth and transcription
factors.
41 Curhan GC, Willett WC, Rimm EB, Stampfer MJ. A prospective study of
dietary calcium and other nutrients and the risk of symptomatic kidney stones.
N Engl J Med 1993; 328:833–838.
42 Pak CY, Odvina CV, Pearle MS, et al. Effect of dietary modification on urinary
stone risk factors. Kidney Int 2005; 68:2264–2273.
43 Borghi L, Schianchi T, Meschi T, et al. A comparison of two diets for the
prevention of recurrent stones in idiopathic hypercalciuria. N Engl J Med
2002; 346:77–84.
44 Heilberg IP, Martini LA, Teixeira SH, et al. Effect of etidronate treatment on
bone mass of male nephrolithiasis patients with idiopathic hypercalciuria and
osteopenia. Nephron 1998; 79:430–437.
45 Carbone LD, Barrow KD, Bush AJ, et al. Effects of a low sodium diet on bone

metabolism. J Bone Miner Metab 2005; 23:506–513.
Interesting study showing that in postmenopausal women with sodium intakes
equal to or greater than the average sodium intake in the United States 3.4 g/
day), a low sodium intake could benefit skeletal health.
46 Martini LA, Cuppari L, Colugnati FA, et al. High sodium chloride intake is
associated with low bone density in calcium stone-forming patients. Clin
Nephrol 2000; 54:85–93.
47 Krieger NS, Frick KK, Bushinsky DA. Mechanism of acid-induced bone
resorption. Curr Opin Nephrol Hypertens 2004; 13:423–436.
48 Frick KK, LaPlante K, Bushinsky DA. RANK ligand and TNF-alpha mediate


acid-induced bone calcium efflux in vitro. Am J Physiol Renal Physiol 2005;
289:F1005–F1011.
Important experimental study demonstrating that the simultaneous inhibition of
RANKL and TNF-a is necessary to reduce acid-induced, cell-mediated net calcium
efflux from bone. The authors also emphasize that additional osteoblast-produced
factors are involved in this process.
49 Amanzadeh J, Gitomer WL, Zerwekh JE, et al. Effect of high protein diet on
stone-forming propensity and bone loss in rats. Kidney Int 2003; 64:2142–
2149.
50 Hannan MT, Tucker KL, Dawson-Hughes B, et al. Effect of dietary protein on
bone loss in elderly men and women: the Framingham Osteoporosis Study.
J Bone Miner Res 2000; 15:2504–2512.
51 Bonjour JP. Dietary protein: an essential nutrient for bone health. J Am Coll


Nutr 2005; 24:526S–536S.
This excellent review puts into perspective the recent controversial data suggest-
ing that low protein intake can negatively affect bone health. It concludes that
protein intake may be as essential as calcium and vitamin D for bone health and
osteoporosis prevention.
52 Stewart AF, Adler M, Byers CM, et al. Calcium homeostasis in immobilization:
an example of resorptive hypercalciuria. N Engl J Med 1982; 306:1136–
1140.
53 Zerwekh JE, Ruml LA, Gottschalk F, Pak CY. The effects of twelve weeks of bed
rest on bone histology, biochemical markers of bone turnover, and calcium
homeostasis in eleven normal subjects. J Bone Miner Res 1998; 13:1594–
1601.
54 Smith SM, Wastney ME, O’Brien KO, et al. Bone markers, calcium metabo-
lism, and calcium kinetics during extended-duration space flight on the mir
space station. J Bone Miner Res 2005; 20:208–218.
55 Ruml LA, Dubois SK, Roberts ML, Pak CY. Prevention of hypercalciuria and
stone-forming propensity during prolonged bedrest by alendronate. J Bone
Miner Res 1994; 10:655–662.
56 Watanabe Y, Ohshima H, Mizuno K, et al. Intravenous pamidronate prevents
femoral bone loss and renal stone formation during 90-day bed rest. J Bone
Miner Res 2004; 19:1771–1778.
57 Vaidyanathan S, Watson ID, Jonsson O, et al. Recurrent vesical calculi,
hypercalciuria, and biochemical evidence of increased bone resorption in
an adult male with paraplegia due to spinal cord injury: is there a role for
intermittent oral disodium etidronate therapy for prevention of calcium
phosphate bladder stones? Spinal Cord 2005; 43:269–277.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
58 Loredo-Osti JC, Roslin NM, Tessier J, et al. Segregation of urine calcium

excretion in families ascertained for nephrolithiasis: evidence for a major gene.
Kidney Int 2005; 68:966–971.
This article discloses that a major gene with a relatively large effect on variation
in urine calcium excretion is segregating in families of stone formers, further
suggesting that it should be feasible to genetically map the quantitative trait
locus.
59 Gambaro G, Vezzoli G, Casari G, et al. Genetics of hypercalciuria and calcium
nephrolithiasis: from the rare monogenic to the common polygenic forms. Am
J Kidney Dis 2004; 44:963–986.
60 Moe OW, Bonny O. Genetic hypercalciuria. J Am Soc Nephrol 2005;


16:729–745.
This is an outstanding and extensive review of the current clinical and experi-
mental data concerning monogenic causes of hypercalciuria. The review outlines
the newest results from attempts to study polygenic hypercalciuria as a complex
trait.
61 Zmuda JM, Sheu YT, Moffett SP. Genetic epidemiology of osteoporosis: past,


present, and future. Curr Osteoporos Rep 2005; 3:111–115.
This excellent article focuses on several genetic approaches in order to identify
the genes and allelic variants that confer susceptibility to osteoporosis, includ-
ing genome-wide linkage mapping in families, candidate gene association
studies in unrelated individuals, and quantitative trait locus mapping in animal
models.
62 Heilberg IP, Teixeira SH, Martini LA, Boim MA. Vitamin D receptor gene
polymorphism and bone mineral density in hypercalciuric calcium-stone-
forming patients. Nephron 2002; 90:51–57.
63 Rendina D, Mossetti G, Viceconti R, et al. Association between vitamin D
receptor gene polymorphisms and fasting idiopathic hypercalciuria in recur-
rent stone-forming patients. Urology 2004; 64:833–838.
64 Vezzoli G, Tanini A, Ferrucci L, et al. Influence of calcium-sensing receptor
gene on urinary calcium excretion in stone-forming patients. J Am Soc Nephrol
2002; 13:2517–2523.
65 Reed BY, Gitomer WL, Heller HJ, et al. Identification and characterization of a
gene with base substitutions associated with the absorptive hypercalciuria
phenotype and low spinal bone density. J Clin Endocrinol Metab 2002;
87:1476–1485.
66 Hoopes RR Jr, Reid R, Sen S, et al. Quantitative trait loci for hypercalciuria in
a rat model of kidney stone disease. J Am Soc Nephrol 2003; 14:1844–
1850.
67 Hoenderop JG, Bindels RJ. Epithelial Ca2þ and Mg2þ channels in health and


disease. J Am Soc Nephrol 2005; 16:15–26.
This review describes the characteristics of epithelial Ca(2þ) and Mg(2þ) trans-
port, and highlights in particular the distinctive features, and the physiologic
relevance and pathophysiologic implications of the new epithelial channels, the
transient receptor potential channels (TRPV5 and TRPV6) and Mg(2þ) channels
(TRPM6 and TRPM7).
68 Hoenderop JG, van Leeuwen JP, van der Eerden BC, et al. Renal Ca2þ
wasting, hyperabsorption, and reduced bone thickness in mice lacking
TRPV5. J Clin Invest 2003; 112:1906–1914.
69 Elizondo MR, Arduini BL, Paulsen J, et al. Defective skeletogenesis with
kidney stone formation in dwarf zebrafish mutant for trpm7. Curr Biol 2005;
15:667–671.
70 Muller D, Hoenderop JG, Vennekens R, et al. Epithelial Ca(2þ) channel
(ECAC1) in autosomal dominant idiopathic hypercalciuria. Nephrol Dial
Transplant 2002; 17:1614–1620.
71 Silva IV, Cebotaru V, Wang H, et al. The ClC-5 knockout mouse model of
Dent’s disease has renal hypercalciuria and increased bone turnover. J Bone
Miner Res 2003; 18:615–623.
72 Scheinman SJ, Cox JP, Lloyd SE, et al. Isolated hypercalciuria with mutation
in CLCN5: relevance to idiopathic hypercalciuria. Kidney Int 2000; 57:
232–239.
73 Prie D, Beck L, Friedlander G, Silve C. Sodium–phosphate cotransporters,
nephrolithiasis and bone demineralization. Curr Opin Nephrol Hypertens
2004; 13:675–681.
74 Prie D, Huart V, Bakouh N, et al. Nephrolithiasis and osteoporosis associa-
ted with hypophosphatemia caused by mutations in the type 2a sodium-
phosphate cotransporter. N Engl J Med 2002; 347:983–991.
75 Pearle MS, Roehrborn CG, Pak CY. Meta-analysis of randomized trials for
medical prevention of calcium oxalate nephrolithiasis. J Endourol 1999; 13:
679–685.
76 Lau EM, Leung PC, Kwok T, et al. The determinants of bone mineral density in

Chinese men-results from Mr. Os (Hong Kong), the first cohort study on
osteoporosis in Asian men. Osteoporos Int 2006; 17:297–303.
An interesting epidemiological study showing that in Asian men thiazide diuretics
were associated with a higher BMD at the spine.
 402 Mineral metabolism
77 Rejnmark L, Vestergaard P, Mosekilde L. Reduced fracture risk in users of

thiazide diuretics. Calcif Tissue Int 2005; 76:167–175.
This is a well designed nationwide, population-based, case–control study that
assessed the use of thiazide diuretics and fracture risk in almost 65 000 fractured
patients. The study demonstrated that after adjustment for potential confounders, the
use of thiazides was associated with a significantly reduced fracture risk.
78 Schoofs MW, van der Klift M, Hofman A, et al. Thiazide diuretics and the risk
for hip fracture. Ann Intern Med 2003; 139:476–482.
79 Bushinsky DA, Neumann KJ, Asplin J, Krieger NS. Alendronate decreases
urine calcium and supersaturation in genetic hypercalciuric rats. Kidney Int
1999; 55:234–243.
80 Weisinger JR, Alonzo E, Machado C, et al. Papel del hueso en la fisiopatologı́a
de la hipercalciuria idiopática: Efecto del aminobisfosfonato alendronato
[Role of the bone in the pathophysiology of idiopathic hypercalciuria: Effect
of the aminobisphosphonate alendronate]. MEDICINA 1997; 57:45–48.
81 Odvina CV, Zerwekh JE, Rao DS, et al. Severely suppressed bone turnover: a
potential complication of alendronate therapy. J Clin Endocrinol Metab 2005;
90:1294–1301.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
82 Frassetto L, Morris RC Jr, Sebastian A. Long-term persistence of the urine

calcium-lowering effect of potassium bicarbonate in postmenopausal women.
J Clin Endocrinol Metab 2005; 90:831–834.
This study demonstrates that potassium bicarbonate induces a dose-dependent
decrease in urinary calcium, with greatest decreases in those with higher baseline
urinary calcium excretion.
83 Sakhaee K, Maalouf NM, Abrams SA, Pak CY. Effects of potassium alkali and
calcium supplementation on bone turnover in postmenopausal women. J Clin
Endocrinol Metab 2005; 90:3528–3533.
84 Pak CY, Peterson RD, Poindexter J. Prevention of spinal bone loss
by potassium citrate in cases of calcium urolithiasis. J Urol 2002; 168:
31–34.
85 Curhan GC, Willett WC, Knight EL, Stampfer MJ. Dietary factors and the risk
of incident kidney stones in younger women: Nurses’ Health Study II. Arch
Intern Med 2004; 164:885–891.
86 Domrongkitchaiporn S, Sopassathit W, Stitchantrakul W, et al. Schedule of
taking calcium supplement and the risk of nephrolithiasis. Kidney Int 2004;
65:1835–1841.