REVIEW
DOI: 10.5301/jn.5000188
Bisphosphonate therapy in renal osteodystrophy
– a review
Raoul Bergner
Abstract
Bisphosphonates have become a standard treatment
for osteoporosis and malignant bone disease. Most
are contraindicated in severe renal insufficiency be-
cause they are eliminated exclusively by the kidneys.
However, the marked impairment of bone metabo-
lism in many dialysis patients provides a rationale
for their judicious use in this setting. Animal stud-
ies reveal that bisphosphonates inhibit hyperpara-
thyroid bone changes. Clodronate, pamidronate and
ibandronate are also readily dialyzable, enabling
them to be used in dialysis patients. Initial pilot stud-
ies in dialysis patients have confirmed the positive
effect on hyperparathyroid bone disease observed in
animal models. However, large randomized placebo-
controlled trials are required before the use of
bisphosphonates in renal osteopathy can be gener-
ally recommended.
Key words: Bisphosphonate, Dialysis, High turnover os-
teopathy, Hyperparathyroidism, Renal osteodystrophy
Introduction
Bisphosphonates have become a standard treatment for
osteoporosis and malignant bone disease. Their mecha-
nism of action − osteoclast inhibition − makes them a
valuable treatment option in all forms of bone disease as-
sociated with increased osteoclast activity. Since bisphos-
phonates are either bound to bone or excreted intact via the
kidney, there has been reluctance to consider their use in
renal impairment. In addition, some bisphosphonates have
become notorious for nephrotoxic complications, although
this has been confined almost exclusively to their use in ma-
lignant bone disease, in particular multiple myeloma. There
have been no reports as yet of nephrotoxic complications in
the treatment of osteoporosis. Even so, a creatinine clear-
ance below 30-35 mL/min contraindicates the use of most
450 © 2012 Società Italiana di Nefrologia - ISSN 1121-8428
JNEPHROL 2013; 26 ( 3 ) : 450-455
Department of Internal Medicine A, Ludwigshafen General
Hospital, Ludwigshafen am Rhein - Germany
bisphosphonates. For this reason knowledge of the phar-
macokinetics of the various bisphosphonates is a manda-
tory precondition for their use in severe renal impairment or
dialysis dependence.
Bone disease is a frequent finding in severe renal im-
pairment (Kidney Disease: Improving Global Outcomes
[KDIGO] stages IV & V). Most forms are subsumed un-
der the terms renal osteopathy or renal osteodystrophy.
However, they do not form a homogeneous syndrome but
encompass a whole complex of bone changes charac-
terized on the one hand by chronic vitamin D deficiency
and reduced 1-α-hydroxylase activity and on the other by
secondary hyperparathyroidism (1). Other critical deter-
minants of bone metabolism include chronic metabolic
acidosis, raised ß2-microglobulin levels (2, 3) and regu-
lar heparin treatment in dialysis (4) (Fig. 1). Most current
treatments in dialysis patients aim to lower parathyroid
hormone (PTH) levels into the guideline range (Kidney Dis-
ease Outcome Quality Initiative [KDOQI]) (5). Additional
aims are to lower calcium and phosphate levels into their
predefined target ranges. But since this barely influences
the critical determinants just mentioned, such therapy
often has a limited impact on bone. Approaches aimed
at treating bone metabolism directly are only in their
infancy and to be viewed in the main as experimental.
Nevertheless, patients in stage IV or V chronic renal fail-
ure are known to be at above-average fracture risk even
after their PTH levels have been lowered into the KDOQI
guideline range (Tab. I) (6). Hence the need to elucidate
the feasibility of bisphosphonate use in severe renal im-
pairment or dialysis dependence.
Pharmacokinetics
The only bisphosphonates for which targeted pharmacoki-
netic studies are available in dialysis-dependent renal failure
are clodronate (7, 8), an early non-aminobisphosphonate,
and ibandronate (9) and pamidronate (10), both among the
newer aminobisphosphonates.

Fig. 1 - Four major mechanisms causing sustained stimula-
tion of osteoclast (OC) activity: in addition to the most impor-
tant stimulating factor, parathyroid hormone (PTH), chronic
metabolic acidosis, increased β2microglobulin (β2MG) and
elevated fibroblast growth factor 23 (FGF 23) also have OC-
activating activity. Heparin administration at each dialysis
session likewise causes OC activation by inhibiting osteopro-
tegerin (OPG). OB = osteoblasts; RANK-L = receptor activator
of nuclear factor kappa B ligand (RANKL).
Clodronate
Two studies used a similar design to determine the dialyz-
ability of clodronate, infusing 300 mg over two hours prior to
four-hour dialysis (7, 8). Calculated clodronate clearances,
86 ± 10 mL/min and 88 ± 16 mL/min, were largely similar to
those for normal renal function. A study of clodronate up-
take into bone found a clear dependency on PTH levels and
bone metabolism: the higher the PTH, the greater the bone
uptake (11).
Ibandronate
Clearance of ibandronate 1 mg administered at the start of
fourhour hemodialysis was 92 ± 19 mL/min, a value like-
wise virtually identical to that for normal renal function (9).
To quantify bone binding in the absence of subsequent di-
Table I
Target parathormone, calcium and phosphate values according to National Kidney Foundation
Kidney Disease Outcome Quality Initiative (KDOQI) guidelines (5)
Parathyroid hormone 150-300 pg/mL
Calcium 8.4-9.5 mg/dL
Phosphate 3.5-5.5 mg/dL
Calcium × phosphate < 55 mg2/dL2
© 2012 Società Italiana di Nefrologia - ISSN 1121-8428
JNEPHROL 2013; 26 ( 3 ) : 450-455
alysis, ibandronate 2 mg was administered at the end of a
dialysis session and bone binding equated with non-renal
clearance (12). Unlike clodronate, ibandronate was 95% to
99% cleared from the circulation (=  bound to bone), but
independently of PTH or other bone metabolism markers.
This naturally carries the risk of the near-total ibandronate
dose being taken up in bone, even in low turnover bone.
Appropriate caution is thus recommended in therapy.
Pamidronate
Clearance of 1 mg radiolabeled pamidronate was 69 ± 
17 mL/min (10). No bone-binding data are available for
pamidronate in dialysis patients.
Thus, all bisphosphonates studied to date have proven to
be readily dialyzable: four-hour dialysis clears 35% to 40%
of the administered dose (Tab. II), which is approximately
equivalent to renal bisphosphonate elimination in normal
renal function. In the case of pamidronate, however, there
is some uncertainty as to whether the clearance of 1 mg is
extrapolable to a standard clinical dose of 60-90 mg. With
the other bisphosphonates the doses were in each case
relatively close to those in clinical use.
Continuous ambulatory peritoneal dialysis (CAPD)
Because bone metabolism in CAPD has only been studied
with methylene-bisphosphonate (13), no figures for bisphos-
phonate clearance via CAPD can be provided.
Animal studies
Initial models of bisphosphonate therapy for hyperparathy-
roid bone disease were explored in animals using ibandro-
nate (14), olpadronate (15), and pamidronate (16).
Ibandronate 1.25 µg/kg or placebo was administered sub-
cutaneously (sc) weekly for three weeks to 2/3 nephrecto-
mized rats and the results compared with sham-operated
controls with normal renal function (14). Ibandronate com-
16.5-33.0 pmol/L Evidence
2.1-2.37 mmol/L Opinion
1.13-1.78 mmol/L Evidence
    Evidence
451
Bergner: Bisphosphonate therapy in renal osteodystrophy
pletely abolished the bone effects of developing hyper-
parathyroidism in nephrectomized rats. Bone resorption
parameters (deoxypyridinoline) and bone volume to total
volume (BV/TV) in the ibandronate group were almost identi-
cal to those in the rats with normal renal function.
A near-identical study design in 5/6 nephrectomized rats
administered olpadronate 1.6 µg sc weekly for five weeks
found a similar effect (15). After an initial increase in de-
oxypyridinoline in nephrectomized animals, levels in the ac-
tive treatment group subsequently declined to those in the
sham-operated animals versus marked bone resorption in
the placebo controls. Olpadronate significantly reduced the
tartrate-resistant acid phosphatase (TRAP) positive osteo-
clast count and significantly increased bone volume.
In the pamidronate study, rats were 5/6 nephrectomized,
uninephrectomized, or left intact; 14 weeks later, the uni and
5/6 nephrectomized rats received pamidronate 3 mg/kg/
week sc or placebo for eight weeks; the intact rats received
placebo (16). Whereas the uninephrectomized rats devel-
oped only mild renal failure with no marked bone metabolic
effects, PTH values increased 5-fold in the 5/6 nephrecto-
mized rats. Bone histology revealed renal osteopathy with
osteitis fibrosa and increased bone turnover. Pamidronate
therapy markedly decreased bone metabolism in all animals
and attained values below the normal range, while bone
density increased significantly. However, no animal devel-
oped osteomalacia.
Clinical studies (Tab. III)
The use of bisphosphonates for hyperparathyroid bone dis-
ease in dialysis patients has been the subject of varied edi-
torials for years. The available animal studies indicate that
such an approach is highly promising. All the more astonish-
ing, therefore, that there should still be virtually no data on the
Table II
Bisphosphonate pharmacokinetics in a four-hour dialysis session
  Beigel
et al (7)
Bisphosphonate Clodronate
Dose (mg) 300
Treatment dosage 3 × 300-600 mg/d
Dialysis clearance (mL/min) 86 ± 10
% administered dose cleared 35
by dialysis
452 © 2012 Società Italiana di Nefrologia - ISSN 1121-8428
use of the various bisphosphonates in this setting. The first
trial of clodronate in dialysis patients dates from 1990 (17).
However, this was a very brief study in nine patients with
severe hyperparathyroid bone disease who received an
infusion of clodronate 300-600 mg at the end of five con-
secutive dialysis sessions. A significant fall was observed
in bone resorption parameters (hydroxyproline) and calcium
and phosphate levels. Alkaline phosphatase (AP) and PTH
values, on the other hand, increased. While some of the pa-
tients were simply followed up, others received clodronate
1.6 g orally daily for a further two weeks. Only these longer-
treated patients showed sustained benefit in terms of their
laboratory parameters.
In a longer, 12-month, open-label and non-placebo-con-
trolled study, 13 patients with persistent severe hyper-
parathyroidism (PTH >500 pg/mL [normal 12-65 pg/mL]),
hypercalcemia (>11 mg/dL), normal phosphate, and osteo-
penia (T-score <1 SD), received an infusion of pamidronate
60 mg every two months during dialysis (18). Bone density
increased significantly in both the lumbar spine and femoral
neck. PTH levels were massively increased at three months,
however, only to reverse subsequently in ten of the 13 pa-
tients: by one year, PTH levels in these 10 patients had fallen
significantly below baseline, while the calcitriol dose had
been increased from 1 µg/week to 3 µg/week without caus-
ing the hypercalcemia that had previously made such an
increase impossible. Whether the PTH-lowering effect was
directly because of the pamidronate or the increased dose
of calcitriol remains an open question.
In another open-label study with no placebo arm, 16 patients
with T-score ≤1.0 SD, PTH ≥2 × normal, and no reduction in
other bone metabolism parameters (TRAP5b, bone-specific
AP and CrossLaps) received an injection of ibandronate 2 mg
after dialysis every four weeks for 1 year; 11 patients were
eventually fit for assessment (19). The study revealed a sig-
Ala-Houhala Bergner Buttazzoni
et al (8) et al (9) et al (10)
Clodronate Ibandronate Pamidronate
300 1 1
2-6 mg 60-90 mg
88 ± 16 92 ± 19 69 ± 17
35 37 32
 JNEPHROL 2013; 26 ( 3 ) : 450-455

Table III
Three long-term bisphosphonate studies in dialysis patients
  Wetmore et al (20) Torregrosa et al (18) Bergner et al (19)
Type of study Randomized vs. placebo Open-label Open-label
No. (complete data available) 16/15 (31) 13 (13) 16 (12)
Bisphosphonate Alendronate Pamidronate Ibandronate
Dosage 40 mg/week for 60 mg every 2 mg every
6 weeks 8 weeks 4 weeks
Duration (months) 6 12 12
Route Oral Intravenous during Intravenous after
hemodialysis hemodialysis
Inclusion criteria Age >40 y T-score ≤1 T-score ≤1.5
PTH 100-300 pg/mL PTH > 500 pg/mL PTH >130 pg/mL
Calcium × phosphate Calcium >11 mg/dL TRAP 5b & BAP not
<5.65 Phosphate <6 mg/dL below normal range
Endpoint Bone mineral density Not defined Bone mineral density
Bone density Dual energy X-ray Dual energy X-ray Quantitative computed
measurement absorptiometry absorptiometry tomography
Results Reduced bone density Significantly increased Significantly increased
loss vs. placebo bone density in bone density
lumbar spine & hip  in lumbar spine

BAP = bone-specific alkaline phosphatase; PTH = parathyroid hormone; TRAP5b = tartrate-resistant acid phosphatase 5b.

nificant increase in the primary endpoint, lumbar spine bone

density. At three months, as in the two studies above, PTH
levels were markedly increased. However, as in the pamidro-
nate study, they had fallen below baseline by the end of the
study. Unlike in the pamidronate study, PTH levels remained
within the KDOQI guideline range (5) throughout the study.
Bone metabolism markers, except for CrossLaps, showed
only a slight non-significant fall. Calcitriol doses underwent
a slight but non-significant increase during the study.
The only placebo-controlled study of bisphosphonates in
the treatment of renal osteopathy was performed with oral
alendronate 40 mg/week for six weeks in 31 dialysis pa-
tients over 40 years of age with PTH levels between 100 and
300 pg/mL (20). Hip and lumbar spine densities were mea-
sured at baseline and six months, and osteocalcin, PTH,
calcium, phosphorus and AP at baseline, one, three, and six
months. Here again PTH levels increased on bisphospho-
nate therapy. Hip density remained stable in the alendronate
group while decreasing significantly in the placebo group.
The other parameters did not differ between the groups.
Discussion
All studies to date have shown the bisphosphonates to be
readily dialyzable. Despite higher protein binding in some
cases, bisphosphonate clearance during a fourhour dialy-
sis session is consistently equivalent to that for normal renal
function. Thus, a single dialysis session can largely clear a
dose of bisphosphonate. For this reason, if the aim is not
to lose much of the dose immediately, bisphosphonates
should be administered after dialysis. To date, binding to
bone in dialysis patients has only been studied for clodro-
nate and ibandronate. The results revealed a marked differ-
ence between the aliphatic first-generation bisphosphonate
clodronate and the aminobisphosphonate ibandronate.
Ibandronate showed a very high affinity for bone indepen-
dently of bone metabolism, whereas with clodronate there
was a close correlation with bone turnover. This carries the
great danger that the near totality of the ibandronate dose
binds to bone even if bone metabolism is already low.

© 2012 Società Italiana di Nefrologia - ISSN 1121-8428 453

Bergner: Bisphosphonate therapy in renal osteodystrophy
Several animal studies have clearly shown that bisphos-
phonate therapy reverses both the histologic changes of
experimental hyperparathyroidism and the changes in bone
metabolism parameters. Osteomalacia was not induced
despite the substantial reduction in bone remodeling. Bone
density increased markedly, as in the osteoporosis studies.
Yet despite these pharmacokinetic findings and experimen-
tal renal osteopathy results, clinical study data are meager:
just three studies in small numbers of dialysis patients re-
ceiving bisphosphonates. Doubtless all three studies have
substantial weaknesses here and there and are no substi-
tute for large randomized placebo-controlled clinical trials,
but they do point to a trend.
In terms of weaknesses, none of the studies incorporated
the gold standard investigation for diagnosing high turnover
osteopathy, namely bone biopsy, and all patient numbers
were very low. The studies also relied on bone density and
surrogate markers of bone metabolism (21), not the fracture
rates used in the pivotal studies of bisphosphonates in the
treatment of osteoporosis.
In the pamidronate study it is also unclear how much of the
drug administered during dialysis was even taken up in bone,
since pamidronate is readily dialyzable. The alendronate
study can be criticized for the ultralow dose used. Neverthe-
less, some observations remain that are consistent across
all three studies. Thus, bisphosphonates increase or stabi-
lize bone density compared to placebo in dialysis patients
too. They also increase PTH levels, according to a study of
this phenomenon by Lu et al (22), because of a transient de-
crease in calcium. However, PTH levels subsequently fall to
below baseline, i.e. the effect is only transient.
Many questions remain open – treatment dose, for a start.
It could be argued that the higher bone metabolism than in
osteoporosis requires a higher dose of bisphosphonate. On
the other hand, the absence of renal excretion means that no
bisphosphonate gets lost, with virtually the entire dose being
available to bone. Dose-finding studies are clearly needed.
It is also uncertain whether low bone density alone, as in
osteoporosis, is a sufficient indication for bisphosphonate
therapy in dialysis patients (23-25). The danger in low-turn-
over osteopathy is that the bisphosphonate radically inhibits
residual bone turnover, resulting in adynamic bone. Since
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454 © 2012 Società Italiana di Nefrologia - ISSN 1121-8428
PTH elevation alone does not exclude low-turnover oste-
opathy (26, 27), every dialysis patient would ideally need a
bone biopsy before commencing bisphosphonate therapy.
Other unresolved questions concern the duration of bisphos-
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appropriate parameters for monitoring treatment.
Special attention should be given to potential side effects
of the bisphosphonates, especially the osteonecrosis of the
jaw. This severe side effect is reported mainly in patients
with high dose bisphosphonate treatment for malignant
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and phosphorus levels. On the other hand, several studies
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A case can be made on the basis of the data presented for
extending bisphosphonate therapy to dialysis patients with
certain forms of renal osteopathy. However, in the complete
absence to date of large randomized placebo-controlled tri-
als, such therapy can only be recommended at best as an
individual management decision. In such cases, prior bone
biopsy to confirm high-turnover osteopathy is mandatory.
Financial support: None.
Conflict of interest statement: Dr. Bergner received speakers fee from
Abbott, Amgen, Bristol-Myers-Squibb, Lilly and Roche Pharma.
Address for correspondence:
Raoul Bergner, MD
Medizinische Klinik A
Klinikum der Stadt Ludwigshafen GmbH
Bremserstraße 79
67063 Ludwigshafen, Germany
bergnerr@klilu.de
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Accepted: May 08, 2012
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