IngredientesStrontium (Sr) is an alkali-earth metal element located in the fifth cycle, Group IIA of the periodic table, positioned between calcium and barium. It is an element from Group II of the periodic table, discovered in the 19th century. Its atomic number is 38 and its chemical symbol is Sr. The element takes its name from the Scottish village of Strontian, where the mineral strontianite was first identified.
In nature, Sr occurs as a mixture of four stable isotopic forms: 88Sr (82.6%), 86Sr (9.9%), 87Sr (7.0%), and 84Sr (0.6%). This metal is easily oxidized to form strontium oxide; therefore, Sr does not naturally exist in free form. Celestine (SrSO4) and strontianite (SrCO3) are the main minerals present in nature.
Strontium is a natural and commonly occurring element. It can exist in two oxidation states: 0 and +2. Under normal environmental conditions, only the +2 oxidation state is stable enough to be important. Pure strontium is a hard, white-colored metal, but this form is not found in the environment; rather, strontium is usually found in nature in the form of minerals. While natural strontium is stable and not hazardous to health, the synthetic Sr-90 isotope is radioactive and a dangerous component of nuclear fallout. This distinction is important: the strontium used in dietary supplements is the stable, non-radioactive form.
Strontium is a natural element, ubiquitous in the environment, and known to occur in water, food, air, and soils. Strontium is present in these media as a salt or an ionized divalent cation. Food and drinking water are the largest sources of exposure to strontium. Because of the nature of strontium, some of it gets into fish, vegetables, and livestock. Grain, leafy vegetables, and dairy products contribute the greatest percentage of dietary strontium to humans.
In the human body, strontium is a trace element. The daily strontium intake by an adult is approximately 4 mg. The main sources of this element are leafy vegetables, grains, and dairy products (amounting to about 1.2–2.3 mg/day). Ingested strontium can replace calcium in bones, especially during development. Strontium in cooking water is absorbed by foods during preparation.
Sr is mostly deposited in human bones; 99% of strontium is precipitated in the femur, lumbar spine, and iliac bone, while the remaining 0.7% is found in extracellular fluid.
Strontium is not sold in elemental form; it must be bound to a carrier molecule to form a stable salt. Several pharmaceutical and supplement-grade forms have been studied:
Current data indicate that organic strontium salts such as these provide better support for bone health than inorganic salts.
Strontium has been safely used as a medicinal substance for more than a hundred years. It was first listed in Squire's Companion to the British Pharmacopoeia in 1884. Subsequently, strontium was used therapeutically in the United States and Europe. As late as 1955, strontium compounds were still listed in the Dispensatory of the United States of America.
Due to its affinity for bone, Sr isotopes have been used in medicine therapeutically for the past half century to treat bone-related illnesses. Sr-89 has been used since the 1940s to treat bone pain in patients with metastatic bone cancer, adjunctive to chemotherapy, radiation, and hormonal therapy. Sr-85 has been used to study both Sr and Ca metabolism and has also been a powerful tool in the clinical setting for imaging bone lesions in patients with bone cancer.
Though not considered essential for human health, strontium has been used medicinally since the 1950s. Early research in the mid-20th century showed promising results for bone health, but interest waned until more recent decades when studies began exploring its potential for addressing osteoporosis. From the beginning of the 21st century, strontium ranelate began to play an important role in the treatment of osteoporosis.
Although strontium D,L-lactate was marketed as Strontolac® by Wyeth during the 1950s, only one clinical report summarizes its benefits in the treatment of osteoporosis. Unlike strontium ranelate, a strontium-containing drug that has been extensively studied, no recent clinical trials have been conducted with strontium D,L-lactate or the strontium salt of the single L-enantiomer of lactic acid (SrLac).
Early epidemiological interest in strontium's relationship with dental health arose from population observations. Because of reports of an inverse relation between the incidence of dental caries and a high strontium content in drinking water, the use of natural water containing relatively high levels of stable strontium came under consideration.
Strontium is itself the active moiety in all forms used medically and supplementally. The biological activity resides in the divalent strontium ion (Sr2+). The co-molecule (ranelate, citrate, chloride, lactate, etc.) primarily affects bioavailability, tolerability, and rate of absorption rather than conferring independent biological activity.
Strontium is a naturally occurring metallic element found throughout the earth's crust. It is in the same chemical family as calcium and is physically and chemically similar to calcium. Since strontium ions are chemically similar to calcium and therefore bind tightly to calcium-sensing receptors, strontium can be incorporated into teeth, bones, and seashells in place of calcium.
The transport of Sr ions through enteral and renal tubular cells is mediated by the same membrane carriers as used for calcium, and a highly significant correlation has been observed between Sr and Ca absorption. Therefore, the oral administration of stable Sr is considered suitable for assessing Ca absorption and excretion in clinical practice.
Interest in strontium has persisted over the last three decades due to its unique mechanism of action: it simultaneously promotes osteoblast function and inhibits osteoclast function. However, this dual action has been the subject of ongoing scientific debate.
Strontium ions show physical and chemical similarity to calcium, the basic element that builds the mineral fraction of bone. As a result, strontium acts through the calcium-sensing receptor (CaSR) in bone tissue cells.
Since Sr closely resembles Ca in its atomic and ionic properties, and both are agonists of the CaSR, Sr probably acts on CaSR to influence mature osteoclast apoptosis.
Strontium ranelate increased mRNA and protein levels of OPG (osteoprotegerin) and suppressed those of RANKL. Strontium ranelate also stimulated osteoblast replication and differentiation and increased cell survival under stress. Knocking down CaSR suppressed strontium ranelate-induced stimulation of OPG mRNA, reduction of RANKL mRNA, and increase in replication, indicating the involvement of CaSR in these responses. These results demonstrate that osteoblasts play a key role in the mechanism of action of the anti-fracture agent strontium ranelate, mediating both its anabolic and anti-resorptive actions, at least in part, via activation of CaSR.
Strontium ranelate is an anti-osteoporosis drug with a unique mechanism of action. Unlike other medicines, it has a multidirectional effect on bone tissue, intensifying osteoblastogenesis while inhibiting osteoclastogenesis.
It has been shown that Sr alters the actin cytoskeleton of osteoclasts at the sealing zone, which disrupts ruffled border formation and reduces the surface area available for proton exchange. This disruption has been shown to significantly inhibit resorbing activity, irrespective of changes in osteoclast number.
Sr can increase osteoblastic OPG mRNA expression and reduce RANKL expression in vitro, and knockdown of CaSR results in suppression of this effect. Sr has been shown to dose-dependently stimulate apoptosis in mature osteoclasts, similarly to Ca stimulation.
When stimulated by extracellular Sr2+, the CaSR also activates PLC, which stimulates the diacylglycerol (DAG)-PKCβII signaling pathway, promoting translocation of NF-κB from the cytoplasm to the nucleus in mature osteoclasts in an IP3-independent manner. Sr2+-induced activation of NF-κB could intensify enhanced apoptosis of mature osteoclasts.
Osteoblast-lineage cells produce RANKL, a cytokine that binds the cell surface receptor activator of nuclear factor-kappa B (RANK) of osteoclasts and osteoclast precursors, stimulating their differentiation. Osteoblastic cells also express OPG, which acts as a decoy receptor, protecting bone tissue from excessive resorption by blocking RANKL and preventing it from interacting with RANK, with consequent inhibition of osteoclast differentiation. The OPG/RANKL ratio is therefore pivotal for balanced bone resorption.
OPG has been found to play a central role in Sr's effect on bone, since OPG knockout mice do not have the reduced bone resorption and subsequent increase in trabecular volume that is seen in wild-type mice after Sr treatment.
Strontium ions are incorporated into bone in a similar manner as calcium, improving bone structural parameters. While the dual cellular mechanism of action is strongly supported by in vitro studies and small animal trials, recent large-scale clinical trials have demonstrated that orally administered strontium ranelate may have no anabolic effect on bone formation in humans. Yet, there is a strong correlation between Sr accumulation in bone and reduced fracture risk in post-menopausal women, suggesting Sr acts via a purely physicochemical mechanism to enhance bone strength. This remains an area of active scientific debate.
Sr absorption and excretion reflect the regulation of Ca metabolism, but some differences in renal handling of the two ions may exist. Plasma concentrations of parathyroid hormone (PTH) negatively correlated with absorption area under the curve (P < 0.01), and plasma concentrations of 1,25-dihydroxyvitamin D correlated positively with Sr absorption when normalized to PTH plasma concentration (P < 0.01). This means that the hormonal regulators of calcium absorption also govern strontium absorption.
The metabolism of strontium consists of binding interactions with proteins, and, based on its similarity to calcium, probably complex formation with various inorganic anions such as carbonate and phosphate, and carboxylic acids such as citrate and lactate.
Absorbed strontium is excreted in both urine and feces. Urine appears to be the major route of excretion, with a urine:fecal ratio of approximately 3:1 in humans. Strontium may also leave the body in breast milk, saliva, or seminal fluid.
With respect to specific strontium salt formulations, data on strontium L-lactate show that after oral administration to fasted men and women, the absorption of Sr was dose-dependent and exhibited a less than proportional increase in Cmax and AUC over a dose range of 0.17 to 0.68 g. For all doses, Tmax occurs between 2.8 and 3.2 hours. Cmax after a 170 mg single dose is approximately 2.6 mg Sr/L. The fraction of absorbed dose of strontium ranged from about 28% to about 33%.
This is by far the best-evidenced clinical application of strontium. The evidence base rests primarily on the pharmaceutical form, strontium ranelate, studied in large randomized controlled trials (RCTs).
Strontium ranelate stimulates bone formation and inhibits bone resorption. Its safety and efficacy for osteoporosis were evaluated in four prospective, randomized, double-blind, placebo-controlled trials.
Phase 2 Trials (PREVOS and STRATOS): Phase 2 clinical trials were conducted in 2002 and included the PREVention Of early postmenopausal bone loss by Strontium ranelate study (PREVOS) and the STRontium Administration for Treatment of Osteoporosis study (STRATOS), which were aimed at determining the minimum effective dose for therapeutic use. In a phase 2 study, the effect of strontium ranelate in postmenopausal women with vertebral osteoporotic fractures was assessed during a double-blind, placebo-controlled trial. Doses of 500 mg, 1 g, and 2 g daily of strontium ranelate or placebo were given to 353 Caucasian women with prevalent osteoporosis. At the conclusion of this 2-year study, the annual increase in lumbar-adjusted bone mineral density of the group receiving 2 g of strontium ranelate was +2.97%, a result significantly different from placebo. All tested doses were superior to placebo, with the highest dose of strontium ranelate (2 g per day) demonstrating the greatest increase in BMD after adjusting for bone strontium content over two years.
Phase 3 Trials (SOTI and TROPOS): Phase 3 clinical trials were conducted in 2004 and 2005, including the Spinal Osteoporosis Therapeutic Intervention study (SOTI) and the TReatment Of Peripheral OSteoporosis study (TROPOS), which were aimed at determining the effectiveness of Sr at preventing new fractures.
The SOTI trial included 1,649 post-menopausal women aged 70 years on average with osteoporosis. The primary efficacy analysis was the incidence of patients with new vertebral fracture over 3 years. Strontium ranelate (2 g/day) reduced the risk of new vertebral fracture by 49% at 1 year as compared with placebo (RR = 0.51; 95% CI 0.36, 0.74; P ≤ 0.001). The benefit after 3 years of strontium ranelate was a reduction of 41% (RR = 0.59; 95% CI 0.48, 0.73; P ≤ 0.001).
The TROPOS study showed a significant (p = 0.05) reduction in the relative risk of experiencing a first non-vertebral fracture in the group treated with strontium ranelate throughout the 3-year study compared with placebo in the intention-to-treat population.
The SOTI and TROPOS studies together suggested that a 2 g daily regimen reduced vertebral fractures by 39% to 41% and nonvertebral fractures by 16% in postmenopausal, osteoporotic women.
Phase III RCTs for the clinical development of strontium ranelate in women with postmenopausal osteoporosis were specifically designed to test the antifracture efficacy of this drug in the long term (5 years), with the main statistical analysis after 3 years of treatment.
Treatment efficacy with strontium ranelate has been documented across a wide range of patient profiles: age, number of prevalent vertebral fractures, BMI, as well as family history of osteoporosis and addiction to smoking are not determinants of anti-fracture efficacy.
Four clinical trials demonstrated the efficacy and safety of strontium ranelate for the management of postmenopausal osteoporosis; however, the Food and Drug Administration has not approved it for this indication. Notably, the STRATOS study found that a 1 g daily regimen was associated with a higher incidence of new vertebral deformities, and a 2 g daily regimen reduced lumbar BMD by 3% in postmenopausal, osteoporotic women. This anomaly in the STRATOS data (lumbar BMD reduction at 2 g) is partly attributable to the methodological difficulty of interpreting DXA-measured BMD in the presence of strontium deposition, as the high atomic number of Sr artificially inflates BMD readings.
Evidence strength: For strontium ranelate at 2 g/day in postmenopausal osteoporosis, the evidence is strong and consistent: multiple large Phase III RCTs with several thousand participants demonstrated robust reductions in vertebral and non-vertebral fracture risk. This evidence base supported regulatory approval in Europe (though not the USA). Strontium ranelate was registered for use in postmenopausal osteoporosis in Europe in 2004 on the basis of the two phase 3 trials, and subsequently in more than 70 countries. For non-ranelate supplement forms (citrate, chloride, lactate), direct large-scale human fracture trials are absent and the clinical evidence is far weaker, relying primarily on animal, in vitro, and small human studies.
The effects of strontium ranelate on bone mineral density are similar in men with osteoporosis and postmenopausal women with osteoporosis. The MALEO trial was conducted to extend osteoporosis treatment indications to men; however, the phase 3 clinical evidence base in men is considerably smaller than that in postmenopausal women.
Strontium ranelate is a drug usually prescribed to treat osteoporosis, with proven effects in decreasing the risk of fractures and possible effect in reducing the progression of osteoarthritis (OA).
The largest clinical research ever developed specifically in patients with OA was SEKOIA (Strontium Ranelate Efficacy in Knee Osteoarthritis Trial), a multicenter randomized, double-blind, placebo-controlled study with patients with knee OA who were treated with SrRan.
Outpatients with knee osteoarthritis, Kellgren and Lawrence grade 2 or 3, and joint space width (JSW) of 2.5–5 mm received strontium ranelate 1 g/day (n = 558) or 2 g/day (n = 566), or placebo (n = 559).
Treatment with strontium ranelate was associated with smaller degradations in JSW than placebo (1 g/day: −0.23 mm; 2 g/day: −0.27 mm; placebo: −0.37 mm); treatment-placebo differences were statistically significant for both doses (p < 0.001 and p = 0.018). Fewer radiological progressors were observed with strontium ranelate (p < 0.001 and p = 0.012 for 1 and 2 g/day). There were greater reductions in total WOMAC score (p = 0.045) and pain subscore (p = 0.028) with strontium ranelate 2 g/day.
Strontium ranelate, approved to treat osteoporosis after menopause, has substantial structural-modifying activity in OA; it reduced subchondral bone resorption in preclinical studies and stimulated cartilage matrix formation in vitro and in rat OA models. Results from the SEKOIA trial showed that the treatment group with SrR 1 and 2 g/day had a significant effect on structure, including reduced JSW degradation, and a beneficial effect on symptoms for SrR 2 g/day in knee OA patients after a 3-year follow-up.
Evidence strength: Preliminary to moderate. The SEKOIA trial provides controlled human evidence that strontium ranelate slows structural progression and reduces symptoms in knee OA. However, this finding pertains specifically to strontium ranelate, not to supplement forms such as strontium citrate. Strontium ranelate has been the subject of clinical and experimental studies on OA because of a probable effect on both bone turnover and inflammation associated with this disease, despite current concern with the occurrence of cardiovascular events associated with its long-term use. The drug's restricted regulatory status limits its availability for this indication.
An investigation of the possible cariostatic effect of strontium—in the absence of effective amounts of fluoride—related the DMFT index of a population to the strontium and fluoride concentrations in drinking water and enamel surfaces. The epidemiological survey was conducted in two neighboring districts in Greece, involving 582 children ranging in age from 11 to 14. The average DMFT values were 5.26 in the high-strontium (2.9–7 ppm Sr) area and 6.95 in the low-strontium (0.2–1.3 ppm Sr) area, while fluoride was low (less than 0.06 ppm) in both districts. The average strontium concentration in surface enamel was higher in the high-strontium area.
Strontium has been used as a radiopacifier in dentistry and incorporated into a variety of dental materials to improve their radiopacity. Furthermore, strontium has been shown to improve the antimicrobial and mechanical properties of dental materials, promote enamel remineralization, alleviate dentin hypersensitivity, and enhance dentin regeneration.
Strontium chloride was the first strontium-based desensitizing agent to be applied in hypersensitivity treatment. However, there was no clinical evidence of the positive effects of this compound as compared to the fluorides employed for the same purpose.
Evidence strength: The epidemiological association between strontium in drinking water and lower caries rates is intriguing but observational and limited. Evidence for strontium compounds in dental materials and dentin sensitivity is primarily in vitro or in small clinical studies. No robust RCT evidence exists for strontium dietary supplementation preventing dental caries in humans.
An increase in density corresponding to the deposition of stable strontium was observed in areas of bone lesions due to metastatic cancer in patients receiving stable strontium supplementation. This suggests the possibility of using strontium to mineralize osteopenic areas and to relieve bone pain.
Separately, radioactive strontium-89 chloride (a non-supplement, intravenously administered radiopharmaceutical) has a documented clinical role. Strontium-89 chloride when administered intravenously reduces pain in metastatic bone cancer. This application is entirely distinct from oral dietary supplement use.
Evidence strength: The use of injectable radioactive Sr-89 for palliation of metastatic bone pain is supported by clinical data, but this is a prescription radiopharmaceutical, not a dietary supplement. Evidence for stable strontium supplementation reducing bone metastasis pain derives from older, smaller clinical observations rather than modern RCTs.
The following dosages are reported in the scientific literature and should not be interpreted as recommendations:
Strontium ranelate is typically administered as a granular sachet dissolved in water, taken at bedtime at least 2 hours after the last meal. Non-pharmaceutical supplement forms (citrate, chloride) are available as capsules or tablets and typically provide elemental strontium doses ranging from approximately 340 mg to 680 mg per day in commercial products, though these doses have not been validated in large-scale fracture endpoint trials.
The most significant safety finding for strontium applies specifically to strontium ranelate, based on pooled analysis of its clinical trials:
The safety profile of strontium ranelate was similar to that of placebo in individual clinical trials, but in recent pooled analyses conducted by the EMA, increased incidences of venous thromboembolism and myocardial infarction have been observed. The EMA also recommended the regular evaluation of cardiovascular conditions in patients using the medication and advised that patients with a history of cardiovascular disease (ischemic heart disease, cerebrovascular disease, uncontrolled hypertension, or peripheral artery disease) not use strontium ranelate.
RCT data indicate a higher incidence of non-adjudicated myocardial infarction with strontium ranelate versus placebo (1.7 vs 1.1%; odds ratio: 1.6; 95% CI: 1.07–2.38; p = 0.020). There was no increase in cardiovascular mortality. MI risk was mitigated by excluding patients with cardiovascular contraindications (OR: 0.99; 95% CI: 0.48–2.04; p = 0.988).
In January 2014, the PRAC recommended the suspension of registration of strontium because of an unfavourable risk/benefit profile (for every 1,000 patient-years of treatment, strontium causes 4 extra cases of serious heart problems and 4 extra cases of blood clots while preventing 5 non-spinal fractures).
This analysis led the EMA to recommend a change in the indication of strontium ranelate, which is now restricted to patients with severe osteoporosis for whom treatment with other medicinal products is not possible. A new contraindication was also added in patients with uncontrolled hypertension and those with established, current, or past history of ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease.
The increased risk for cardiac events with strontium ranelate has been detected in randomized clinical trials but not in real-life observational studies. This discordance between trial and observational data has been a point of ongoing scientific discussion.
The most common adverse events reported with strontium ranelate were nausea and diarrhea. These gastrointestinal effects were generally mild to moderate in the clinical trials.
Because strontium is excreted primarily by the kidney, absorbed strontium is excreted in both urine and feces, with urine appearing to be the major route of excretion at a urine:fecal ratio of approximately 3:1 in humans. Impaired renal clearance would therefore be expected to lead to elevated strontium accumulation in bone, an effect of particular concern in patients with chronic kidney disease. The EMA's prescribing information for strontium ranelate includes a contraindication in severe renal impairment.
A methodological limitation affecting interpretation of strontium's efficacy is that strontium ions are incorporated into bone in a similar manner as calcium, improving bone structural parameters. However, the availability of this element varies depending on the salt concentration. Because strontium has a higher atomic number than calcium, its incorporation into hydroxyapatite artificially inflates BMD values measured by dual-energy X-ray absorptiometry (DXA). This means that raw BMD gains in strontium-treated patients overestimate true bone density improvements, and studies must adjust for strontium bone content to obtain valid estimates.
It is important to maintain a normal dietary intake of calcium when taking strontium supplements. High concurrent calcium intake may reduce strontium absorption, since both ions compete for the same intestinal transport mechanisms. At low exposure levels (below 100 mg/kg/day), ingestion of stable strontium poses no harm to organisms with access to adequate calcium, phosphorus, and vitamin D. Strontium ranelate prescribing information and clinical trial protocols typically mandated concurrent calcium and vitamin D supplementation to ensure adequate mineral status.
Strontium may leave the body in breast milk, saliva, or seminal fluid. Strontium ranelate has not been approved for use during pregnancy or lactation. The ability of strontium to substitute for calcium in developing bone and teeth means that exposures during critical developmental windows merit caution.
Strontium's reliance on the same intestinal and renal transport carriers as calcium means that drugs and nutrients affecting calcium metabolism — including active vitamin D analogues, PTH-based therapies, bisphosphonates, and antacids — may alter strontium pharmacokinetics. Plasma concentrations of PTH negatively correlated with strontium absorption (P < 0.01), and multiple stepwise regression showed that PTH and phosphatemia were significantly related to absorption values at 240 min (P < 0.01).
It is important to emphasize that the safety concerns documented above — particularly the cardiovascular signals — are based on clinical trial data for strontium ranelate at 2 g/day, administered to a specific patient population over multi-year periods. Other strontium salts including strontium citrate, strontium gluconate, and strontium malonate have been safely administered as supplements at daily oral doses as high as 1.7 g strontium for periods from several months to over a decade. Daily administration of a strontium salt to over 200,000 women for periods exceeding a decade has been shown to have low risk of potential side effects and has proven free of unexpected adverse events. Nonetheless, because controlled cardiovascular endpoint data for supplement-form strontium at high doses are absent, the cardiovascular caution observed with ranelate cannot be definitively excluded for other long-term high-dose strontium formulations in populations at cardiovascular risk.
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Strontium, as strontium ranelate, has been studied in large Phase III RCTs (SOTI, TROPOS) demonstrating significant reductions in vertebral fractures (41%) and non-vertebral fractures in postmenopausal women with osteoporosis. Strontium ranelate was approved for osteoporosis treatment in Australia and most of Europe, though restricted in some EU countries due to cardiovascular risks. OTC strontium citrate lacks equivalent RCT data.
Strontium can be incorporated into bone cells in place of calcium, increasing bone density and reducing the risk of osteopenia and osteoporosis. Strontium ranelate is an approved pharmaceutical for osteoporosis in several countries, though elemental strontium supplements are less well-studied. Preclinical and mechanistic research supports strontium's dual action of promoting bone formation and inhibiting resorption.
Strontium substitutes for calcium in the hydroxyapatite lattice, forming strontium-substituted hydroxyapatite with reduced acid solubility. Strontium chloride (10%) is used clinically in desensitizing toothpastes and has documented effects on dentinal tubule occlusion. Strontium-fluoride co-doped bioactive glasses show superior remineralization and dentinal tubule sealing in multiple studies.
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