Strontium

What it is

Strontium is a naturally occurring element found in water, food, air and soil, present as a salt or as a divalent cation that is readily absorbed when swallowed. Chemically it behaves like calcium and is taken up into bone, where it accumulates over years. Two different things are sold under the name: strontium ranelate, a prescription osteoporosis medicine authorised in Europe as Protelos and Osseor, and strontium salts such as strontium citrate sold over the counter as supplements. EFSA has stated that no authority has set dietary reference values for strontium and that there is no evidence it is essential for humans.

What the research says

Almost everything known about strontium and fractures comes from one prescription drug, strontium ranelate, at 2 g a day - not from the citrate salt sold as a supplement. A Cochrane review rated the evidence "silver level" and found a 37 per cent reduction in vertebral fractures and 14 per cent in non-vertebral fractures over three years in postmenopausal women with osteoporosis. Against that, pooled trial data showed more heart attacks and more venous clots, and European regulators restricted the medicine in 2014 to people who cannot take other osteoporosis drugs and have no history of heart or circulatory disease. Severe drug reactions with eosinophilia and systemic symptoms have been reported with the prescription drug and, in at least one case, with an over-the-counter strontium citrate supplement. Strontium also inflates DXA bone density readings for physical reasons, so a rising scan result on strontium does not mean what it usually means.

Evidence grade: Disputed.

What goes wrong

The Cochrane review also found more diarrhoea on 2 g/day and flagged a slight increase in vascular and nervous system side effects over three to four years. (Source 1)

• Meta-analysis, Moderate certainty.
• Size: 4 randomised trials.
• Who: postmenopausal women.
• How long: three to four years.
• Result: Increased risk of diarrhoea at 2 g/day; adverse events did not increase withdrawal, serious side effects, gastritis or death; vascular and nervous system side effects slightly increased.
• Funding: not stated.

An increased risk of diarrhea with 2 g of strontium ranelate was found; however, adverse events did not affect the risk of discontinuing treatment nor did it increase the risk of serious side effects, gastritis or death. Additional data suggests that the risk of vascular and nervous system side-effects is slightly increased with taking 2 g of strontium ranelate daily over three to four years.

Pooled randomised data reviewed by the European Medicines Agency in 2014 showed more myocardial infarctions and more venous thrombotic and embolic events on strontium ranelate than on placebo. (Source 2)

• Official position, Moderate certainty.
• Size: pooled data from randomised studies in around 7,500 postmenopausal women.
• Who: postmenopausal women with osteoporosis.
• How long: not stated in the announcement.
• Result: Myocardial infarction 1.7% versus 1.1%, relative risk 1.6 (95% CI 1.07 to 2.38); venous thrombotic and embolic events 1.9% versus 1.3%, relative risk 1.5 (95% CI 1.04 to 2.19)
• Funding: regulatory review of manufacturer trial data.

The results showed an increased risk of myocardial infarction with Protelos/Osseor as compared with placebo (1.7% versus 1.1 %), with a relative risk of 1.6 (95% CI, 1.07 to 2.38), and an increased risk of venous thrombotic and embolic events — 1.9% versus 1.3 % with a relative risk of 1.5 (95% CI, 1.04 to 2.19).

Pharmacovigilance review of 47 confirmed cases found drug rash with eosinophilia and systemic symptoms is an established reaction to strontium ranelate, fatal in a small proportion. (Source 3)

• Case series, Low certainty.
• Size: 47 confirmed DRESS cases out of 325 hypersensitivity reports.
• Who: patients treated with strontium ranelate, mean age 68.7 years.
• How long: cases reported from 2004 to March 2011; median 33.5 days to skin reaction.
• Result: Maximum incidence 1/24,112 newly treated patients in France (95% CI 1/14,859 to 1/42,194); mortality rate 8.5%; DRESS the direct cause of death in one case.
• Funding: industry (cases reviewed from the Marketing Authorisation Holder's pharmacovigilance database)

For ten patients, persistence of DRESS symptoms was reported at the latest news obtained, and DRESS was identified as the direct cause of death in one case. The maximum incidence of DRESS associated with strontium ranelate was 1/24,112 [95 % CI (1/14,859; 1/42,194)] newly treated patients in France.

A woman taking an over-the-counter strontium citrate supplement at 1.36 g a day developed DRESS with liver involvement and later granulomatous dermatitis and eye damage; the rash settled after the supplement was withdrawn. (Source 4)

• Case report, Certainty not rated.
• Size: 1 patient.
• Who: 51-year-old woman taking several over-the-counter supplements.
• How long: supplement started 6 weeks before presentation.
• Result: Registry of Severe Cutaneous Adverse Reactions score of 5; aspartate aminotransferase 121 U/L, alanine aminotransferase 188 U/L, eosinophilia 1.25 x 10^9 cells/L.
• Funding: not stated.

We report a novel drug reaction leading to DRESS with subsequent granulomatous dermatitis as a result of taking strontium citrate, which is an over-the-counter supplement.

In the same five-country study, cardiovascular death was significantly more frequent with current strontium ranelate than with current bisphosphonate use, while the venous thromboembolism estimate for that same comparison did not reach statistical significance. (Source 5)

• Case-control study, Low certainty.
• Size: 5,477 AMI cases with 54,674 controls; 5,614 VTE cases with 6,036 controls; 3,019 cardiovascular death cases with 29,871 controls.
• Who: new users of strontium ranelate or oral bisphosphonates in Denmark, Italy, the Netherlands, Spain and the UK.
• How long: database follow-up; current versus past use compared.
• Result: Cardiovascular death OR 1.35 (95% CI 1.02, 1.80) current strontium ranelate versus current bisphosphonate; VTE OR 1.24 (95% CI 0.96, 1.61) for that comparison and 1.30 (1.04, 1.62) for current versus past strontium ranelate.
• Funding: not stated (EU-ADR Alliance collaboration)

Limit of this finding: The paper's own headline does not match its own numbers. It states a "25-30% excess risk of VTE" with current strontium ranelate versus current bisphosphonate, but the figure it reports for that comparison is an odds ratio of 1.24 with a confidence interval of 0.96 to 1.61, which includes 1 and so is compatible with no excess risk at all. The only venous-clot estimate that excluded 1 was the comparison of current with past strontium ranelate use, 1.30 (1.04 to 1.62). The cardiovascular death figure, 1.35 (1.02 to 1.80), does exclude 1. Read the clot result as unresolved in this study rather than as a demonstrated 25-30 per cent increase.

However, current strontium ranelate (compared with current bisphosphonate) appears associated with 25-30% excess risk of VTE and 35% excess risk of CVDeath.

High-dose strontium citrate given by gavage to pregnant rats produced bone and eye abnormalities in the fetuses at the top dose, while maternal organs and the other fetal measures showed no lesions; this is an animal finding at doses far above supplement use and is not a human finding. (Source 6)

• Animal study, Low certainty.
• Size: 20 pregnant Sprague Dawley rats per group.
• Who: pregnant rats.
• How long: gavage on days 6 to 15 of pregnancy.
• Result: Maternal appearance, internal organs, gravid uterus weight, implantation number and implantation loss rate showed no lesions at any dose; fetal weight, sex ratio, resorptions, stillbirths and visceral examination did not differ from control; bone and eye anomalies significantly increased at 2267 mg/kg; NOAEL judged 1360 mg/kg/day.
• Funding: not stated.

However, in 2267 mg/kg strontium citrate group, the fetuses showed the statistical differences in the anomalies of the bones and eyes compared to the control group.

What the evidence supports

A Cochrane review of four randomised trials found 2 g/day strontium ranelate reduced vertebral and, to a lesser extent, non-vertebral fractures over three years in postmenopausal women with osteoporosis; the reviewers rated this "silver level" evidence. (Source 1)

• Meta-analysis, Moderate certainty.
• Size: 4 randomised trials (two contributing about 5,082 women to the vertebral fracture analysis)
• Who: postmenopausal women in what the review calls a treatment population, defined by the review as women with prevalent vertebral fractures and/or lumbar spine BMD T score < -2.5 SD.
• How long: at least one year; main results over three years.
• Result: Vertebral fracture RR 0.63 (95% CI 0.56, 0.71), a 37% reduction; non-vertebral fracture RR 0.86 (95% CI 0.75, 0.98), a 14% reduction.
• Funding: not stated; additional data were sought from authors and, in the earlier version, industry sponsors.

A 37% reduction in vertebral fractures (RR 0.63, 95% CI 0.56, 0.71) and a 14% reduction in non-vertebral fractures (RR 0.86, 95% CI 0.75, 0.98) were demonstrated over three years with 2 g of strontium ranelate daily in a treatment population.

What the evidence does not support

A five-country nested case-control study found no excess risk of myocardial infarction with strontium ranelate compared with bisphosphonates in patients who had no contraindication to it. (Source 5)

• Case-control study, Low certainty.
• Size: 5,477 AMI cases with 54,674 controls; 5,614 VTE cases with 6,036 controls; 3,019 cardiovascular death cases with 29,871 controls.
• Who: new users of strontium ranelate or oral bisphosphonates in Denmark, Italy, the Netherlands, Spain and the UK.
• How long: database follow-up; current versus past use compared.
• Result: AMI OR 0.89 (95% CI 0.70, 1.12); VTE OR 1.24 (0.96, 1.61) current SR versus current bisphosphonate and 1.30 (1.04, 1.62) current versus past SR; cardiovascular death OR 1.35 (1.02, 1.80)
• Funding: not stated (EU-ADR Alliance collaboration)

No excess risk of AMI (5477 cases/54,674 controls) was found with current SR vs current BP (OR 0.89 (95%CI 0.70, 1.12)) nor with current vs past SR use (0.71(0.56, 0.91)).

Where the evidence is mixed

In the TROPOS randomised trial, strontium ranelate 2 g/day reduced non-vertebral fractures by 16 per cent overall, but the hip fracture reduction reached significance only in a high-risk subgroup. (Source 7)

• Randomized trial, Moderate certainty.
• Size: 5,091 postmenopausal women (1,977 in the high hip-fracture-risk subgroup)
• Who: postmenopausal women with osteoporosis.
• How long: 5-year study with main analysis over 3 years.
• Result: All non-vertebral fractures RR reduced 16% (P = 0.04); major fragility fractures 19% (P = 0.031); hip fracture reduced 36% (P = 0.046) only in women aged 74 or over with femoral neck T score at or below -3; femoral neck BMD +8.2%, total hip +9.8%.
• Funding: not stated (manufacturer-sponsored phase III programme)

Limit of this finding: This trial's abstract reports percentage risk reductions and p-values but no confidence intervals, so the precision of each figure cannot be judged. Two numbers need care. The 36 per cent hip fracture reduction (P = 0.046) comes from a subgroup of 1,977 of the 5,091 women - those aged 74 or over with a low femoral neck T score - and was not the trial's primary endpoint, so it is not a result for all women. The 45 per cent reduction in vertebral fractures in women without a prevalent vertebral fracture is reported with no confidence interval and no p-value at all, unlike every other estimate, so it should not be read as equally firm.

In the entire sample, relative risk (RR) was reduced by 16% for all nonvertebral fractures (P = 0.04), and by 19% for major fragility fractures (hip, wrist, pelvis and sacrum, ribs and sternum, clavicle, humerus) (P = 0.031) in strontium ranelate-treated patients in comparison with the placebo group.

In ten women self-supplementing with over-the-counter strontium, bone strontium kept rising throughout the study and beyond four years without levelling off, but the amount deposited varied widely between individuals - after three years the highest finger signal was roughly nine times the lowest. (Source 8)

• Case series, Low certainty.
• Size: 10 female volunteers, nine with osteopenia or osteoporosis.
• Who: women self-supplementing with strontium supplements of their choice.
• How long: up to 1,535 days of measurement.
• Result: Mean baseline finger and ankle signal 0.42±0.13 and 0.39±0.07, rising to 1.43±1.12 and 1.17±0.51 at 24 h (p=0.0043 and p=0.000613); after three years the highest individual signal was 28.15±0.86 at the finger against 3.15±0.15 in another volunteer; levels still rising beyond 4 years.
• Funding: not stated (university research study)

Bone Sr levels continued to increase throughout the length of the study. However the Sr signal varied widely between the individuals such that after three years, the highest Sr signal observed was 28.15±0.86 for the finger and 26.47±1.22 for the ankle in one volunteer compared to 3.15±0.15 and 4.46±0.36, for the finger and ankle, respectively in another.

What official bodies say

On the strength of that cardiovascular signal the European Medicines Agency restricted strontium ranelate in 2014 to patients who cannot take other osteoporosis medicines, and contraindicated it in anyone with ischaemic heart disease, peripheral arterial disease, cerebrovascular disease or uncontrolled hypertension. (Source 9)

• Official position, Certainty not rated.
• Size: not applicable.
• Who: postmenopausal women and men with severe osteoporosis in the EU.
• How long: ongoing use, with review every 6 to 12 months.
• Result: Not a measured effect; a regulatory restriction. The PRAC had initially recommended suspension.
• Funding: regulatory (European Medicines Agency, CHMP and PRAC)

Protelos/Osseor must not be used in patients with established, current or past history of ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease, or those with uncontrolled hypertension;

EFSA stated in 2009 that no authority has set dietary reference values for strontium and that there is no evidence it is essential for humans, and that it could not assess the safety or bioavailability of a strontium supplement source put before it. (Source 10)

• Official position, Certainty not rated.
• Size: not applicable.
• Who: EU food supplement consumers.
• How long: not applicable.
• Result: No dietary reference values exist; safety and bioavailability of strontium-enriched yeast could not be assessed.
• Funding: independent (EFSA ANS Panel, adopted 13 May 2009)

There is no evidence that strontium is essential for humans.

Where the research disagrees

Whether strontium ranelate raises cardiovascular risk

• European Medicines Agency CHMP and PRAC (2014), pooled analysis of randomised trials in around 7,500 postmenopausal women: The results showed an increased risk of myocardial infarction with Protelos/Osseor as compared with placebo (1.7% versus 1.1 %), with a relative risk of 1.6 (95% CI, 1.07 to 2.38) (Source 2)
• EU-ADR Alliance multi-database study (2020), nested case-control studies in five EU healthcare databases, comparing strontium ranelate with bisphosphonates rather than placebo: Strontium ranelate use, compared with oral bisphosphonates, is not associated with increased risk of AMI in patients with no contraindications for SR use. (Source 5)

Whether over-the-counter strontium citrate can be treated as equivalent to prescription strontium ranelate

• Cochrane review authors (2006), the fracture evidence base is entirely strontium ranelate; no strontium citrate fracture trial was included: We included randomized controlled trials (RCTs) of at least one year duration comparing strontium ranelate versus placebo reporting fracture incidence, bone mineral density (BMD), health related quality of life or safety in postmenopausal women. (Source 11)
• EFSA ANS Panel (2009), assessment of a supplement-grade strontium source, which the Panel could not evaluate for safety or bioavailability: The Panel notes that neither safety data nor suitable supporting references were provided (Source 10)

How much

• Reference intake: EFSA ANS Panel, 2009: no dietary reference values for strontium have been established by EFSA's nutrition panel or any other authority, and there is no evidence strontium is essential for humans. (Source 10)
• Upper limit: No tolerable upper intake level or acceptable daily intake for strontium was found in the sources searched. EFSA stated in 2009 that it could not even assess the safety of a proposed strontium supplement source because no safety data were supplied. The nearest thing to a ceiling in the literature is a regulatory one: the European Medicines Agency restricted the 2 g/day prescription salt strontium ranelate in 2014. (Source 10)
• Studied: Strontium ranelate 2 g/day for 3 to 5 years in 5,091 postmenopausal women with osteoporosis (TROPOS). (Source 7)
• Studied: Strontium ranelate 0.125 g, 0.5 g, 1 g and 2 g daily across the four trials pooled by Cochrane. (Source 1)
• Studied: Over-the-counter strontium citrate self-administered at 1.36 g daily in a reported case of DRESS. (Source 12)

A common belief, and what the research shows

The belief: Strontium supplements build bone, and you can tell because your DXA bone density score goes up.

What the research shows: Much of that rise is a measurement artefact rather than new bone. Because strontium sits in bone in place of calcium and blocks X-rays more strongly, "X-ray absorptiometry measurements of BMD are overestimated because strontium attenuates X-rays more strongly than calcium." Bone strontium also keeps climbing for years - "Bone Sr levels continued to increase throughout the length of the study." Separately, the fracture evidence belongs to a prescription drug at 2 g a day, not to the citrate salt in supplements, and that drug carried an increased risk of myocardial infarction and venous clots: "an increased risk of venous thrombotic and embolic events — 1.9% versus 1.3 % with a relative risk of 1.5 (95% CI, 1.04 to 2.19)." Stable strontium in supplements is also not the radioactive strontium-90 of fallout, which is a different isotope of the same element.

Questions and answers

What is it?

Strontium is a naturally occurring element found in water, food, air and soil. It behaves chemically like calcium and is absorbed as a divalent ion, then deposited in bone. No authority has set dietary reference values for it and there is no evidence it is essential for people, so it is not a nutrient in the way calcium is. (Source 10)

What does it do in the body?

Strontium substitutes for calcium in bone mineral and accumulates there. The one form studied for fractures, the prescription salt strontium ranelate at 2 g a day, reduced vertebral and non-vertebral fractures in postmenopausal women with osteoporosis over three years and raised measured bone density. There is no equivalent fracture evidence for the strontium salts sold as supplements. (Source 1)

Is it good or bad for you?

It depends heavily on the form, the dose and the person. At 2 g a day as a prescription medicine it cut fractures, but pooled trials showed more heart attacks and more venous clots, and European regulators in 2014 confined it to people with no history of heart or circulatory disease who cannot take other osteoporosis medicines. Severe hypersensitivity reactions have been reported with both the prescription salt and an over-the-counter strontium citrate supplement. (Source 13)

How do you get more of it?

Strontium comes into the diet with water and food, and tap water used in cooking adds to it - strontium transferred into broccoli, lentils and spaghetti cooked in strontium-containing water. Beyond diet, people take it as strontium citrate supplements or, where it was prescribed, as strontium ranelate at 2 g a day. (Source 14)

If it is harmful, what reduces it?

Stopping the source is what the reports describe: in the strontium citrate hypersensitivity case the skin lesions subsided once the supplement was withdrawn, alongside intravenous steroids. Strontium already laid down in bone leaves slowly, and measured bone strontium kept rising for years in women who kept taking supplements. No validated way of clearing strontium from bone was found in what we searched. (Source 12)

Why might someone be low in it or missing it?

The question does not apply in the usual sense. Strontium is not an essential nutrient, no reference intake exists and no deficiency state has been described, so being "low" in it is not a recognised condition. Intake varies mainly with the strontium content of local water and of food cooked in it. (Source 10)

Which whole foods contain it or feed it?

Strontium is ubiquitous rather than concentrated in particular foods: it occurs in water, food, air and soils, and food cooked in strontium-containing water picks more up. In a cooking experiment 33 to 64 per cent of the strontium remained in the pour-off water, showing transfer into broccoli, lentils and spaghetti. (Source 14)

What happens if you do not have it?

Nothing is known to go wrong from not having extra strontium, because it is not essential and no deficiency disease exists. What the trials show is the reverse: adding a high dose of one particular strontium salt reduced fractures in women who already had osteoporosis, and the Cochrane reviewers graded even that as "silver level" evidence. (Source 15)

How can you test for it?

Bone strontium can be measured non-invasively by in vivo X-ray fluorescence in research settings, but that is not a routine clinical test and there is no status range to interpret it against. The more practical point is that strontium corrupts the usual bone test: DXA bone density readings are overestimated when strontium replaces calcium in bone, by roughly 10 per cent for each 1 per cent molar replacement. (Source 16)

References

1. Cochrane Database of Systematic Reviews. Strontium ranelate for preventing and treating postmenopausal osteoporosis. 2006. PMID 17054253, DOI 10.1002/14651858.CD005326.pub3. Read the source
2. European Medicines Agency. Protelos / Osseor (strontium ranelate) Article-20 referral: Protelos/Osseor to remain available but with further restrictions. 2014. Read the source
3. Osteoporosis International. Drug rash with eosinophilia and systemic symptoms (DRESS) in patients receiving strontium ranelate. 2013. PMID 23361875, DOI 10.1007/s00198-013-2265-1. Read the source
4. JAAD Case Reports. Strontium citrate associated drug reaction with eosinophilia and systemic symptoms syndrome with granulomatous dermatitis. 2021. PMID 33778142, DOI 10.1016/j.jdcr.2021.02.002. Read the source
5. Osteoporosis International. Comparative cardiovascular safety of strontium ranelate and bisphosphonates: a multi-database study in 5 EU countries by the EU-ADR Alliance. 2020. PMID 32757044, DOI 10.1007/s00198-020-05580-0. Read the source
6. Regulatory Toxicology and Pharmacology. Prenatal developmental toxicity study of strontium citrate in Sprague Dawley rats. 2019. PMID 30529436, DOI 10.1016/j.yrtph.2018.12.003. Read the source
7. The Journal of Clinical Endocrinology and Metabolism. Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: Treatment of Peripheral Osteoporosis (TROPOS) study. 2005. PMID 15728210, DOI 10.1210/jc.2004-1774. Read the source
8. Bone. Monitoring bone strontium intake in osteoporotic females self-supplementing with strontium citrate with a novel in-vivo X-ray fluorescence based diagnostic tool. 2014. PMID 24434614, DOI 10.1016/j.bone.2014.01.002. Read the source
9. European Medicines Agency. Protelos / Osseor (strontium ranelate) Article-20 referral: Protelos/Osseor to remain available but with further restrictions. 2014. Read the source
10. EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS), The EFSA Journal (2009) 1085. Inability to assess the safety of strontium-enriched yeast added for nutritional purposes as a source of strontium in food supplements and the bioavailability of strontium from this source, based on the supporting dossier. 2009. Read the source
11. Cochrane Database of Systematic Reviews. Strontium ranelate for preventing and treating postmenopausal osteoporosis. 2006. PMID 17054253, DOI 10.1002/14651858.CD005326.pub3. Read the source
12. JAAD Case Reports. Strontium citrate associated drug reaction with eosinophilia and systemic symptoms syndrome with granulomatous dermatitis. 2021. PMID 33778142, DOI 10.1016/j.jdcr.2021.02.002. Read the source
13. European Medicines Agency. Protelos / Osseor (strontium ranelate) Article-20 referral: Protelos/Osseor to remain available but with further restrictions. 2014. Read the source
14. Journal of Trace Elements in Medicine and Biology. Absorption of strontium by foods prepared in drinking water. 2019. PMID 30910202, DOI 10.1016/j.jtemb.2019.01.001. Read the source
15. Cochrane Database of Systematic Reviews. Strontium ranelate for preventing and treating postmenopausal osteoporosis. 2006. PMID 17054253, DOI 10.1002/14651858.CD005326.pub3. Read the source
16. Journal of Clinical Densitometry. Effect of bone strontium on BMD measurements. 2007. PMID 17289524, DOI 10.1016/j.jocd.2006.10.004. Read the source