Medicines Q&As
Q&A 124.4
Can strontium ranelate be given to patients with renal impairment
or patients on renal replacement therapies?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp
Date prepared: 20th June 2013
Background
Strontium ranelate is licensed for the treatment of severe osteoporosis
o in postmenopausal women at high risk of fracture to reduce the risk of vertebral and hip
fractures
o in men at increased risk of fracture(1,2). The normal recommended dose is one 2g sachet
once daily by oral administration (3).
Strontium ranelate is made up of 2 atoms of stable strontium and 1 molecule of ranelic acid (3).
Strontium is an alkaline earth element similar to calcium and is naturally present in trace amounts in
healthy bone, so treatment with strontium ranelate is simply making more strontium available for
incorporation into bone (4).
Answer
There are few data on the use of strontium ranelate in patients with renal impairment (RI) or in those
undergoing renal replacement therapies (RRT). Following reviews of the available cardiovascular
safety data by the European Medicines Agency (EMA) in 2012 and 2013, strontium ranelate is now
contra-indicated in patients with
o an established, current or past history of, ischaemic heart disease, peripheral arterial disease,
and/or cerebrovascular disease
o uncontrolled hypertension
o current or previous venous thromboembolic events (VTE) including deep vein thrombosis and
pulmonary embolism
o temporary or permanent immobilisation due to e.g. post-surgical recovery or prolonged bed
rest(2,3)
Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia,
diabetes mellitus), should only be treated with strontium ranelate after careful consideration (2).
Its level of usage in patients with renal impairment is therefore likely to decrease.
Renal Impairment
Strontium ranelate is not recommended for patients with severe RI (creatinine clearance [CrCl] <30
mL/min) (3, 5, 6) due to the absence of bone safety data and pharmacokinetic data in these patients
(3). The BNF states that strontium should be avoided if eGFR < 30mL/min/1.73m 2 (7).In phase III
studies only 6% of patients at inclusion had a CrCl <30mL/min (3). In patients with mild-to-moderate
RI (CrCl 30-70 mL/min), strontium clearance decreases as CrCl decreases. There is approximately a
30% decrease in strontium clearance over the CrCl range 30-70 mL/min, which thereby induces an
increase in strontium plasma levels (3). No dosage adjustment is required in patients with mild-tomoderate RI (CrCl 30-70 mL/min) (3,8).
In accordance with good medical practice, periodic assessment of renal function is recommended in
patients with chronic RI (3). However, no clarification of` ‘periodic’ or ‘chronic’ is included in this
recommendation. Continuation of treatment with strontium ranelate in patients developing severe RI
(CrCl <30mL/min) should be considered on an individual basis (3).
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In both the SOTI and TROPOS trials, patients with severe RI (serum creatinine (Cr) >140 micromol/L)
were excluded. The effect of strontium ranelate on patients with RI was investigated by identifying a
subset of patients with RI (CrCl<30mL/min). This subset was 6.4% of the total safety analysis set (426
patients). The RI subset of patients had a mean age of 83.1 ± 5.1 years (range 70-100 years) and
mean renal clearance of 26.3 ± 3.2mL/min (range 10.8-30mL/min). As expected, patients with RI were
on average older with a higher frequency of reported medical and surgical histories and lower
baseline urinary calcium excretion. At steady state, strontium concentrations increased by
approximately 50% when CrCl <25mL/min and serum Cr >168micromol/L (9,10). As there are no
bone safety data for strontium ranelate in patients with severe RI (CrCl <30mL/min), and the effects of
severe RI are known to be potentially deleterious on bone (11), it is not recommended in patients with
CrCl <30mL/min (3,11).
Renal Replacement Therapy (RRT)
No reports describing the therapeutic use of strontium ranelate in patients undergoing RRT were
identified. Since strontium ranelate is not recommended in patients with severe RI (CrCl <30mL/min)
and due to the absence of data, its use in patients undergoing RRT cannot be supported. (See also
‘Strontium Accumulation in Patients with RI or RRT’ below). One source advises avoid in
haemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD)(12). When there is a lack
of data about a medicine’s use in RRT it is possible to look at pharmacokinetic data and predict any
likely removal. For further information please see Q&A 168.5 – What factors need to be considered
when dosing patients on RRT? (13)
Strontium Accumulation in Patients with RI or RRT
In patients with chronic RI or in patients undergoing RRT who are not receiving strontium therapy,
there are some data to suggest that accumulation of naturally occurring strontium may occur
(14,15,16,17,18). Moreover there is some concern that strontium accumulation may have a
detrimental effect on bones including osteomalacia (18). This gives grounds for concern about the
possible safety of strontium ranelate in these groups of patients. The clinical consequences of
strontium accumulation in these populations require clarification.
Strontium may accumulate in patients with chronic renal failure because of:
 impaired renal function,
 contamination of phosphate binders,
 the use of strontium-containing parenteral and dialysis fluids (14).
An epidemiological survey of 75 patients with stable RI, 834 HD patients and 24 control subjects,
found that serum strontium levels are higher in patients with RI and in HD patients when compared to
control subjects (14). Another small study compared 32 patients on HD with 19 control subjects found
that blood plasma strontium concentrations were higher in the HD patients (17). In HD patients, whilst
individual measurements suggest that there is an exchange of strontium between plasma and
dialysate, there was no statistically significant mean change in strontium plasma levels during the
dialysis session (17). The changes in plasma strontium levels during dialysis appear to correlate well
with the difference between dialysis fluid and plasma concentration at the beginning of the session
(17).
Similarly serum strontium levels were statistically significantly higher in a small study of 24 CAPD and
14 chronic renal failure (CRF) patients when compared with 52 healthy controls. It was found that
CAPD was not able to restore strontium plasma levels to normal (16). Another study monitored serum
strontium levels in 1031 patients undergoing RRT (including standard acetate dialysis, bicarbonate
dialysis, haemofiltration and CAPD). The patients were all receiving various aluminium-containing
phosphate-binders. It found that serum strontium levels were significantly higher in those receiving
RRT than in control subjects (19). This suggests that in dialysis patients, strontium overload in the
bone may be possible (19). However, this study should be interpreted with caution, since no detail is
provided about the control arm of the study.
A study of bone biopsies in 100 HD patients and 10 controls showed that HD patients had significantly
higher bone strontium/calcium ratios compared with controls. Additionally, within the dialysis
population, both bone strontium levels and strontium/calcium ratios were significantly higher in
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Medicines Q&As
patients with osteomalacia (18). Conversely, another small study found that the bone strontium
content in 56 patients with chronic HD was not significantly different from control values of patients
with normal renal function (15). However, the HD patients with osteomalacia had slightly, but
significantly increased levels of bone strontium, although the authors state that they found no
correlation between osteoid accumulation and bone strontium content. Further study is needed to
define the relationship between mineralisation defects in renal patients and strontium levels (15) and
to determine whether strontium plays either a primary, secondary or contributive role in the
development of renal osteodystrophy (18).
Therefore the evidence for a possible link between high levels of bone strontium in dialysis patients
with RI and the development of osteomalacia is inconclusive. During the SOTI (20) and TROPOS (21)
trials no evidence of osteomalacia was detected in any bone biopsies (9). However, neither did these
studies provide bone safety data in RI as patients with severe RI (serum Cr >140micromol/L) were
excluded (9). It should also be noted that there were high losses to follow-up in the SOTI and
TROPOS trials (20, 21).
Adverse effects
The following information was discussed by the EMA prior to license approval of strontium ranelate.
Discrete but consistent increases in reporting of nervous system disorders in patients on strontium
ranelate were observed. These included disturbances in consciousness, amnesia, memory loss,
seizures and encephalopathies. Overall, between-group differences for these adverse effects
appeared enhanced in patients ≥ 80 years and in patients with CrCl <30mL/min (11).
However the manufacturer states that there were no differences in the nature of adverse events
between treatment groups regardless of whether patients were aged below or above 80 at inclusion
(3).
Cases of severe hypersensitivity syndromes, including DRESS (drug rash with eosinophilia and
systemic symptoms), sometimes fatal, have been reported with strontium ranelate (3). This has
included systemic involvement such as interstitial nephropathy (3).
In phase III studies of strontium ranelate, over 5 years, nervous system disorders were reported with
higher frequency in patients treated with strontium ranelate compared with placebo: disturbances in
consciousness (2.6% vs. 2.1%), memory loss (2.5% vs. 2.0%) and seizures (0.4% vs. 0.1%) (3). In
phase III studies, the annual incidence of venous thromboembolism (VTE) observed over 5 years was
approximately 0.7%, with a relative risk of 1.4 (95% CI = [1.0 to 2.0]) in strontium ranelate treated
patients as compared to placebo (3). More recent studies and data from post-marketing surveillance
have shown that the risk of VTE is higher in patients with a history of VTE, as well as those who are
permanently or temporarily immobilised(22) . A study in France found that cardiovascular events
(mostly VTE events) and skin reactions accounted for 52 % and 26 %, respectively, of all postmarketing reports in association with strontium ranelate. The risk of VTE in elderly patients >80 years
may also be increased (23,24). Strontium ranelate is now contra-indicated in patients with current or
previous VTE including deep vein thrombosis and pulmonary embolism (2,3) and those who are
temporarily or permanently immobilised e.g. prolonged bed rest or post-surgical recovery (2,3).
Strontium ranelate should be used with caution in patients at increased risk of VTE (3).
A recent routine analysis of available safety data from randomised controlled trials by the EMA has
identified an increased risk of serious cardiac events, including myocardial infarction (MI), but no
observed risk in mortality. This is largely based on data from pooled placebo-controlled studies in
around 7500 post-menopausal women with osteoporosis, which showed a statistically significant
increased risk of MI in strontium ranelate-treated patients compared with those given placebo (1.7%
vs.1.1%), relative risk 1.6 (95% CI 1.07 to 2.38). Strontium ranelate is therefore contra-indicated in
patients with risk factors for MI (1,2) (see above).
A full evaluation of the benefits and risks of strontium ranelate will be conducted by the
Pharmacovigilance Risk Assessment Committee (PRAC) of the EMA (25)
Available through NICE Evidence Search at www.evidence.nhs.uk
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Medicines Q&As
Summary
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The licensed indications for strontium have now been restricted and it is contra-indicated in
patients at risk of cardiac adverse events, as data from clinical trials show an increased risk of
myocardial infarction
Current or previous VTE or presence of risk factors for VTE (immobilisation) are also contraindications
Strontium ranelate is not recommended for use in patients with severe RI (CrCl <30 mL/min)
or in patients undergoing RRT. This is due to:
 an absence of bone safety data and pharmacokinetic data in these patients,
 concerns that natural strontium may accumulate in patients with RI and RRT,
 an inconclusive link between strontium accumulation and bone disease,
 an increased incidence of reported nervous system disorders in patients with severe
RI.
Strontium ranelate can be given to patients with mild-to-moderate renal impairment (CrCl 3070 mL/min) without a need for dosage adjustment.
Periodic assessment of renal function is recommended in patients with chronic RI, but the
frequency of monitoring is not stated.
Continuation of treatment with strontium ranelate in patients developing severe RI (CrCl
<30mL/min) should be considered on an individual basis.
In clinical trials, steady state strontium concentrations were increased by approximately 50%
when CrCl <25mL/min.
There is some evidence to suggest that naturally occurring strontium may accumulate in
patients with RI and in those undergoing RRT, but the clinical consequences of this are
uncertain.
In all patients with RI or receiving RRT, the decision to use strontium ranelate remains a
clinical decision, balancing the potential benefits of therapy against the potential risks.
Limitations
There are very few data available for patients with RI and no data for patients undergoing RRT
receiving strontium ranelate. The information that is available is largely from small studies with poor
design. Further investigation is needed to confirm the safety and efficacy of strontium ranelate in
patients with CRF or undergoing RRT. Additional study of the clinical consequences of accumulation
of strontium in patients with RI or on RRT, and the possible link between high strontium levels and
bone disease is required.
References
1)
Medicines and Healthcare Products Regulatory Agency. Drug Safety Update April 2013 vol 6,
issue 9: S1.Accessed via
http://www.mhra.gov.uk/Publications/Safetyguidance/DrugSafetyUpdate/index.htm on 11/06/13
2) Servier Laboratories. Direct Healthcare Professional Communication. 13th May 2013. Accessed
via http://www.mhra.gov.uk/home/groups/pl-p/documents/drugsafetymessage/con282759.pdf on
11/06/13
3) Summary of product characteristics for Protelos 2g granules for oral suspension. Servier
Laboratories Limited. Date of revision of text: .October 2012 Accessed online via:
http://emc.medicines.org.uk on 11/06/13
4) Fogelman I, Blake GM. Strontium ranelate for the treatment of osteoporosis. British Medical
Journal 2005; 330: 1400-1401.
5) National Institute for Health and Clinical Excellence. NICE technology appraisal guidance 160
(amended). Alendronate, etidronate, risedronate, raloxifene and strontium ranelate for the
primary prevention of osteoporotic fragility fractures in postmenopausal women (amended). Issue
Available through NICE Evidence Search at www.evidence.nhs.uk
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Medicines Q&As
Date: October 2008 (amended January 2010 and January 2011). Accessed online via
www.nice.nhs.uk on 10/05/11.
6) National Institute for Health and Clinical Excellence. NICE technology appraisal guidance 161
(amended). Alendronate, etidronate, risedronate, raloxifene, strontium ranelate and teriparatide
for the secondary prevention of osteoporotic fragility fractures in postmenopausal women
(amended). Issue Date: October 2008 (amended January 2010 and January 2011). Accessed
online via www.nice.org.uk on 10/05/11.
7) Khanderia S, Managing Editor. British National Formulary No. 65 June 2012. London: BMJ
Group and Pharmaceutical Press. Accessed online via: www.medicinescomplete.com on
12/06/13.
8) Ashley, C. Currie, A. editors. Renal Drug Handbook 3rd Edition. Oxford, Radcliffe Medical Press
Ltd; 2009, p.688.
9) Personal Communication with Therapeutic Information Officer for Servier Laboratories Ltd, 17th
May 2011
10)
Personal Communication with Scientific & Medical Information Advisor for Servier Laboratories
Ltd, 14th June 2013.
11) European Medicines Agency. Protelos. European Public Assessment Report 2005. Scientific
Discussion. Accessed via: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Scientific_Discussion/human/000560/WC500045522.pdf on 10/06/11.
12)
Levy J et al. Oxford Handbook of Dialysis 3rd edition. Oxford University Press ; 2009 p.614
13) Leung R. Q&A 168.5 - What factors need to be considered when dosing patients on renal
replacement therapies? South West Medicines Information & Training. Prepared January 2013.
Accessed via www.evidence.nhs.uk on 12/06/13.
14) Schrooten I, Elseviers MM, Lamberts LV et al. Increased serum strontium levels in dialysis
patients: An epidemiological survey. Kidney International 1999; 56: 1886-1892.
15) Cohen-Solal ME, Augry F, Mauras Y et al. Fluoride and strontium accumulation in bone does not
correlate with osteoid tissue in dialysis patients. Nephrology Dialysis Transplantation 2002; 17:
449-454.
16) Apostolidis N, Paradellis T, Karydas A et al. Calcium and strontium metabolic studies in patients
on CAPD. Peritoneal Dialysis International 1998; 18: 410-414.
17) Mauras Y, Ang KS, Simon P et al. Increase in blood plasma levels of boron and strontium in
hemodialyzed patients. Clinica Chimica Acta 1986; 156: 315-320.
18) D’Haese PC, Schrooten I, Goodman WG et al. Increased bone strontium levels in hemodialysis
patients with osteomalacia. Kidney International 2000; 57: 1107-1114.
19) Canavese C, Pacitti A, Salomone M et al. Strontium overload in uremic patients on regular
dialytic treatment. Trans Am Soc Artif Intern Organs 1986; 32: 120-122.
20) Meunier PJ, Roux C, Seeman E et al. The effects of strontium ranelate on the risk of vertebral
fracture in women with postmenopausal osteoporosis. (The Spinal Osteoporosis Therapeutic
Intervention [SOTI] study). New England Journal of Medicine 2004; 350 (5): 459-468.
21) Reginster JY, Seeman E, De Vernejoul MC et al. Strontium ranelate reduces the risk of
nonvertebral fractures in postmenopausal women with osteoporosis: treatment of peripheral
osteoporosis (TROPOS) study. J Clin Endocrinol Metab 2005; 90; 2816-2822.
22) European Medicines Agency. Questions and answers on the review of Protelos and Osseor
(strontium ranelate) 15 March 2012 Accessed via
http://www.ema.europa.eu/docs/en_GB/document_library/Medicine_QA/2012/03/WC500124208.pdf
on 18/06/13
23) Medicines and Healthcare Products Regulatory Agency. Drug Safety Update May 2012 vol 5,
issue 10: A3. Accessed via
http://www.mhra.gov.uk/home/groups/dsu/documents/publication/con152742.pdf on 12/06/13
24) Servier Laboratories Limited. Direct Healthcare Professional Communication-New contraindications for strontium ranelate (Protelos). 30 March 2012. Accessed via
http://www.mhra.gov.uk/home/groups/comms-ic/documents/websiteresources/con152561.pdf on
12/06/13
25) European Medicines Agency. Review of Protelos/Osseor (strontium ranelate) started.
EMA/291972/2013. 16 May 2013. Accessed via
Available through NICE Evidence Search at www.evidence.nhs.uk
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Medicines Q&As
http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Protelos_and_Osseor/
Procedure_started/WC500143497.pdf on 18/06/13
Quality Assurance
Prepared by
Julia Kuczynska (based on earlier work by Michèle Skipp), South West Medicines Information, Bristol
Date prepared
20th June 2013
Checked by
Trevor Beswick, South West Medicines Information, Bristol
Date of check
1st July 2013
Search strategy
 Embase [*STRONTIUM RANELATE/ OR (strontium AND ranelate).ti,ab] AND [exp *KIDNEY
FAILURE/ OR exp *RENAL REPLACEMENT THERAPY/] Limit to: Humans and Year = 20112013
 Medline [*STRONTIUM ISOTOPES/ OR *STRONTIUM/ OR (strontium AND ranelate).ti,ab]
AND [exp *RENAL REPLACEMENT THERAPY/ OR exp *RENAL INSUFFICIENCY/ OR exp
*ACUTE KIDNEY INJURY] Limit to: Humans and Year = 2011-2013
 In-house database / resources Keyword – Strontium.
 In-house renal files and texts.
 DRUGDEX Drug Evaluations. Accessed via www.thomsonhc.com on 13/06/13.
 Manufacturer (Servier Laboratories Ltd. Personal Communication. Letters dated 17/05/11 and
14/06/13).
 Internet Search (National Library for Health; Prodigy; Cochrane Library; NICE; SIGN, NHS
Evidence, Clinical Knowledge Summaries).
 Clinical Expert: Specialist Renal Pharmacist, Royal Devon & Exeter Hospital (personal
communication June 2011).
Available through NICE Evidence Search at www.evidence.nhs.uk
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