Download Use of bisphosphonates in renal impairment

medication review
The articles in this series are independently researched and compiled by PSA commissioned authors and peer reviewed.
Use of bisphosphonates in
renal impairment
Continuing Professional Development
By Matthew Fanning
Learning objectives
After reading this article you should
be able to:
• Discuss the pathophysiology of
renal osteodystrophy
• Describe the major risks of
bisphosphonate use in renal
impairment and dialysis
• Make recommendations for the
management of osteoporosis in
patients with renal impairment
including those undergoing
dialysis.
Competencies addressed:
3.1.1, 3.1.2, 3.1.3, 3.1.4
Case backgound
Vol. 29 – July #07
Mr MD is an 82-year-old nursing
home resident. His past medical
history includes:
He is currently taking the following
medications:
• right cerebral ischaemic
stroke (2001)
• bilateral carotid stenosis
• chronic renal failure (haemodialysis
Monday, Wednesday and Friday)
• osteoporosis (history of
fragility fractures)
• gastro-oesophageal reflux disease
• ischaemic heart disease
• hypertension
• dyslipidaemia
• gout.
• Alendronate 70 mg tabs – 1 tablet
once weekly
• Allopurinol 100 mg tabs – 1 tablet
every 2nd day
• Aspirin 100 mg tabs – 1 tablet daily
• Atorvastatin 40 mg tabs –
1 tablet daily
• Calcitriol 0.25 mcg caps –
1 capsule after haemodialysis three
times weekly
• Fentanyl 25 mcg/hr patch – 1 patch
every 72 hours
• Metoprolol 50 mg tabs – 1 tablet
twice daily
• Omeprazole 20 mg tabs –
1 tablet daily
• Ramipril 2.5mg tabs – 1 tablet
each morning
• Temazepam 10 mg tabs – 1 tablet
at night.
Matthew Fanning is a consultant pharmacist
with experience in community pharmacy
and clinical pharmacy and the provision of
continuing professional education.
He has recently been admitted to
the aged care facility and the GP has
requested a RMMR as part of his
comprehensive medical assessment.
598
Introduction
Renal osteodystrophy encompasses a
spectrum of metabolic bone disorders
that are common in people with
severe renal impairment. It is caused
by a derangement of normal bone
metabolism arising from reduced
circulating active metabolites of
vitamin D.1 This leads to decreased
intestinal absorption of calcium,
increased serum phosphate and
secondary hyperparathyroidism.1
(Figure 1)
Most patients with renal
osteodystrophy present with osteitis
fibrosa alone or with osteomalacia.
Osteitis fibrosa is a condition
characterised by abnormally high
bone turnover resulting in bone
pain and pathological fractures,
and usually responds well to
treatment with calcitriol.1 Some
of these patients may progress to
tertiary hyperparathyroidism where
parathyroid hormone (PTH) is elevated
despite restoration of serum calcium
Submit your answers online at www.psa.org.au and receive automatic feedback
Figure 1. Pathogenesis of renal
secondary hyperparathyroidism.
Decreased nephron mass
Decreased formation of
1,25(OH)2D
Phosphate
retention
Decreased intestinal
calcium absorption
Increased serum
phosphate
Reduced
suppression
of PTH by
1,25(OH)2D
Decreased serum [Ca2+]
Increased PTH secretion
and cell proliferation
Source: Gardner DG, Shoback D. Greenspan’s Basic and Clinical
Endocrinology, 8th Edition. www.accessmedicine.com
©The McGraw-Hill Companies, Inc. All rights reserved.
to within the normal range.1 These
patients are prone to developing
hypercalcaemia despite normal
replacement doses of calcium.1
Due to these differences in
pathophysiology, the body of evidence
for the treatment of osteoporosis
in patients with unimpaired renal
function may not be applicable.2 This is
further complicated by a lack of safety
data for bisphosphonates in people
with a creatinine clearance (CrCl) of
less than 30 mL/min.2
Osteoporosis in chronic
renal failure
Although the risk factors and
outcomes of renal osteodystrophy are
well understood, less is known about
osteoporosis in chronic kidney disease
(CKD).3 Diagnosis of osteoporosis is
complicated by the abnormal bone
density associated with all types of
renal osteodystrophy, making standard
diagnostic criteria less relevant.2
Bone biopsy is usually required for a
firm diagnosis of osteoporosis and to
exclude adynamic bone disease.2
Bisphosphonate use
in CKD
Due to the above concerns, patients
with elevated serum creatinine
were excluded from the large
clinical trials with alendronate and
risedronate.5 However, a recent
analysis of the clinical trials identified
a subgroup of patients receiving
risedronate 5 mg daily who had an
overestimated glomerular filtration
rate (GFR) despite having an actual
CrCl <30 mL/min (n=301). The
analysis showed no significant
difference in efficacy (in terms of
fracture risk reduction) or adverse
effects (including renal adverse
drug reactions (ADRs)) between the
cohort with CrCl <30 mL/min and
the cohort with CrCl >30 mL/min.5
The study authors concluded that
risedronate may be used in those
with CrCl <30 mL/min but possibly at
50% of the normal dose based on the
known pharmacokinetics in patients
with intact renal function.5
Bisphosphonates use
in dialysis
There is limited evidence for
the safety and efficacy of
bisphosphonates for osteoporosis
in dialysis. However, there is a
moderate amount of experience
with bisphosphonates used for
hypercalcaemia associated with
secondary hyperparathyroidism in
this population. In a recent study,
clodronate appeared to be cleared
In a short term trial, 31 healthy
haemodialysis patients were
treated with low dose alendronate
(40 mg/week) for six weeks.7 This
appeared to be well tolerated and
was associated with a small increase
in vertebral bone mineral density.7
However, further trials with longer
durations are necessary to establish
the safety and efficacy of alendronate
in this cohort of patients.7
Additional management
issues of renal
osteodystrophy in CKD
Calcitriol, calcium supplementation
(if necessary, guided by serum
calcium) and phosphate restriction
form the mainstay of treatment of
renal osteodystrophy.2 For treatment
of hypocalcaemia in patients
undergoing haemodialysis, calcitriol
should be dosed three times a week
after each treatment.8
Case discussion
Mr MD is at an increased risk of
fracture due to chronic renal failure
and subsequent osteodystrophy.
Furthermore, use of fentanyl,
temazepam and anti-hypertensives
increases his risk of falling. As all
forms of osteodystrophy are
associated with a reduced bone
mineral density, diagnosis of
osteoporosis should only be made
after excluding other related disorders
of deranged bone metabolism
(e.g. osteitis fibrosa, osteomalacia).
The safety and efficacy of alendronate
has not been well established in renal
impairment. However, small studies
and expert opinion suggests that
they are well tolerated and confer an
increased bone mineral density in all
stages of renal impairment and during
haemodialysis. While there is some
consensus that bisphosphonates
may be used in those with a CrCl of
20–30 mL/min at a reduced dose, the
use of alendronate is discouraged in
599
Vol. 29 – July #07
Bisphosphonates form the mainstay
of treatment of post-menopausal
osteoporosis. However there is
very little evidence for their use in
osteoporosis in those with CKD.
There is general agreement that the
proven benefits are likely to translate
to people with CKD. However,
i. Direct nephrotoxicity: This appears
to be of main concern in the
oncological setting where high
doses of bisphosphonates are
used.4 While there is no strong
evidence to support their safety,
expert opinion generally agrees
the risks are small when used in
appropriate doses and according to
guidelines for osteoporosis.4
ii. Effects on the skeleton itself:
Since bisphosphonates potently
inhibit bone resorption, there is
a risk that this may worsen bone
quality in a population that has
a very low bone turnover rate.4
However, subgroup analyses have
failed to prove this as clinically
significant except in adynamic
bone disease.4
by haemodialysis in a similar manner
to that in individuals with normal
renal function.6 The kinetics of other
bisphosphonates are less well
understood, but should be similar
to that of clodronate.6 However,
the authors cautioned against using
repeated doses of bisphosphonates
because of a lack of safety data.6
Continuing Professional Development
Secondary
hyperparathyroidism
current recommendations limit
their use in patients with advanced
renal impairment because of safety
concerns. There are two broad
areas of concern about the safety of
bisphosphonates in CKD.
medication review
The articles in this series are independently researched and compiled by PSA commissioned authors and peer reviewed.
patients undergoing dialysis due to a
lack of quality safety data.
Actions and
recommendations
Continuing Professional Development
The following recommendations
were carried out after discussion with
Mr MD, his GP and nursing staff:
1. Alendronate is predominately
renally cleared and is
contraindicated by the
manufacturer in patients with a
creatinine clearance less then
35 mL/min.8 Although there is
limited data suggesting it may
be well tolerated in patients
undergoing haemodialysis, its
use is discouraged due to the
lack of safety data.7 Studies have
shown a persistence of benefit of
alendronate in non-renally impaired
patients for a significant time
after cessation, most likely due
to its long half-life within bone.9
This is likely to apply to those
with CKD also, although there
is no direct evidence to support
this. Consider ceasing alendronate.
Calcitriol should be continued for
management of hypocalcaemia.
2. There is significant evidence for
atorvastatin for the reduction of
cardiovascular risk in people with
normal renal function.8 However,
there is doubt as to whether
statins improve outcomes in
patients undergoing haemodialysis.
A recent study of atorvastatin used
in diabetic patients undergoing
haemodialysis showed no
improvement in mortality in the
treatment group.10 The authors
concluded that due to the very
high short term cardiovascular
Questions 1. Renal osteodystrophy is a
result of:
Vol. 29 – July #07
a)
b)
c)
d)
Secondary hyperthyroidism.
Primary hyperparathyroidism.
Secondary hyperparathyroidism.
Insufficient cutaneous synthesis of
vitamin D.
2. Theoretical safety concerns of
bisphosphonates in CKD do
not include:
a) Inhibition of bone resorption,
resulting in a worsening of bone
quality.
600
risk and all cause mortality in
this group, statin therapy may
not have sufficient time to
improve outcomes consistently.10
Furthermore, there is a significant
risk of myopathy in renally impaired
individuals.8
While Mr MD does not have
diabetes, his short term
cardiovascular risk due to his renal
failure and past medical history is
also very high. Since the benefits
of atorvastatin are most likely to be
gained over a long period of time,
it may no longer be beneficial and
may pose a significant risk of harm.
Consider ceasing atorvastatin.
3. While temazepam is hepatically
cleared, CNS effects may be more
pronounced people with renal
impairment and may contribute
to cognitive impairment, ataxia
and falls.8 Furthermore, long term
use may result in tolerance and
dependence. Consider gradually
reducing the dose of temazepam
with the view of eventual cessation
or PRN use.
Outcomes
Mr MD’s doctor elected to cease
alendronate due to the discussed
safety concerns. Atorvastatin was
continued with close monitoring
of clinical signs of myopathy and
serum creatine kinase. Mr MD was
resistant to ceasing temazepam
but agreed to review this with his
doctor periodically.
Summary
Renal osteodystrophy encompasses
a spectrum of metabolic bone
disorders which can be difficult to
distinguish using standard diagnostic
techniques. Osteoporosis is common
in patients with CKD but there is little
evidence for the safety and efficacy
of bisphosphonates in this cohort.
The manufacturer of alendronate
contraindicates its use in individuals
with a CrCl <35 mL/min, however
evidence suggests that it may be
well tolerated in individuals with a
CrCl >20 mL/min. While there is weak
evidence to suggest bisphosphonates
may be well tolerated in patients
undergoing haemodialysis, use of
these agents is discouraged due to
lack of safety data.
References
1. Shoback D, Sellmeyer D, Bikle D. Chapter 9: Metabolic
bone disease. In: Greenspan’s Basic and Clinical
Endocrinology. 8th edn. [Online]. [Accessed 19 Mar
2010]. At: www.accessmedicine.com/content.
aspx?aID=2632277
2. Miller P. Treatment of osteoporosis in chronic
kidney disease and end stage renal disease. Current
Osteoporosis Reports. 2005; 3(1)5–12.
3. Stehman-Breen C. Osteoporosis and chronic kidney
disease. Semin Nephrol. 2004; 24(1):78–81.
4. Cunningham J. Bishphosphonates in the renal patient.
Nephrol Dial Transplant. 2007; 22:1505–7.
5. Cohen S. Preferred treatment for osteoporosis in
patient with renal failure. Medscape Today. [Online].
[Accessed 19 Mar 2010]. At: www.medscape.com/
viewarticle/500058
6. Rodd C. Bisphosphonates in dialysis and
transplantation patients: efficacy and safety issues.
Peritoneal Dialysis International. 2001; 21(3):S256–60.
7. Wetmore J, Benet L, Kleinstuck D et al. Effects of
short term alendronate on bone mineral density in
haemodialysis patients. Nephrology. 2005; 10(4):393–9.
8. Rossi S, ed. Australian Medicines Handbook. Adelaide:
Australian Medicines Handbook; 2010.
9. Black D, Schwartz A, Ensrud K et al. Effects of
continuing or stopping alendronate after 5 years of
treatment. The fracture intervention trial long term
extension (FLEX): A randomised trial. Obstetrical and
Gynecological Survey. 2007; 62(4):251–2.
10. Wanner C, Crane V, Marz W et al. Atorvastatin in
patients with Type 2 Diabetes Mellitis undergoing
haemodialysis. NEJM. 2005; 353:238–48.
A score of 3 out of 4 attracts three quarters of a credit point.
b) Direct nephrotoxic effects.
c) Hypocalcaemia.
d) Hypercalcaemia.
3. Which statement is false?
a) Approved product information
contraindicates the use of
bisphosphonates in individuals
with CrCl <35 mL/min.
b) Reanalysis of risedronate trial data
showed no significant differences
in efficacy or ADRs in a cohort of
patients with CrCl 20–30 mL/min.
c) Bone mineral density is useful
for defining the type of metabolic
bone disease in patients with CKD.
d) There is insufficient safety data to
support using bisphosphonates in
dialysis.
4. Which of the following is
unlikely to increase a patient’s
risk of falling?
a)
b)
c)
d)
Fetanyl.
Omeprazole.
Temazepam.
Ramipril.