Strontium Ranelate (DB09267): A Comprehensive Pharmacological and Clinical Monograph

Section 1: Introduction and Drug Profile

1.1. Overview: A Novel Agent with a Complex Legacy

Strontium ranelate represents a unique chapter in the history of osteoporosis treatment. Developed by the French pharmaceutical company Servier Laboratories and first introduced to the European market in 2004 under brand names such as Protelos® and Osseor®, it was positioned as a groundbreaking therapeutic agent for severe osteoporosis.[1] Its primary indication was for the treatment of postmenopausal women, with a later expansion to include adult men at high risk of fracture.[4]

What set strontium ranelate apart was its novel mechanism of action. It was promoted as the first in a new class of "dual action bone agents" (DABA).[5] This classification stemmed from its purported ability to simultaneously stimulate bone formation by osteoblasts and, to a lesser extent, inhibit bone resorption by osteoclasts.[4] This uncoupling of the normal bone remodeling cycle, which in osteoporosis is imbalanced in favor of resorption, theoretically leads to a net gain in bone mass and an improvement in bone strength.[4] This dual-action narrative was a powerful differentiator in a therapeutic landscape dominated by anti-resorptive agents like bisphosphonates, which primarily work by inhibiting osteoclast function.[9] The promise of a more physiological approach that could "rebalance" bone turnover was scientifically compelling and held significant clinical appeal.[8]

Initial clinical data from large-scale trials appeared to validate this promise, demonstrating significant reductions in both vertebral and non-vertebral fractures.[4] However, the drug's trajectory was profoundly altered by the emergence of serious safety concerns during post-marketing surveillance. An increased risk of cardiovascular events, particularly myocardial infarction, venous thromboembolism (VTE), and rare but severe skin reactions, led to a series of stringent regulatory actions.[6] These safety signals fundamentally changed the drug's risk-benefit assessment, leading to its clinical use being heavily restricted. Today, strontium ranelate is considered a second-line or last-resort treatment, reserved for a very specific subset of high-risk patients for whom all other approved osteoporosis therapies are deemed unsuitable.[5] Its story serves as a significant case study in drug development, pharmacovigilance, and the complex interplay between efficacy, safety, and market viability.

1.2. Chemical and Physical Properties

Strontium ranelate is an organometallic compound, specifically the distrontium salt of ranelic acid.[3] The molecule consists of two atoms of stable, non-radioactive strontium (

Sr2+) ionically bonded to one molecule of ranelic acid. Upon ingestion, the compound dissociates in the gastrointestinal tract, and it is the strontium ion that is considered the pharmacologically active moiety responsible for the effects on bone metabolism.[9] The ranelic acid component serves as a carrier and is rapidly cleared from the body.[9]

Key Identifiers:

• DrugBank ID: DB09267 [5]
• Type: Small Molecule [5]
• CAS Number: 135459-87-9 [1]
• Molecular Formula: C12​H6​N2​O8​SSr2​ [7]
• Molecular Weight: 513.49 g/mol [7]

Nomenclature and Synonyms:

• IUPAC Name: distrontium; 5-[bis(carboxylatomethyl)amino]-3-(carboxylatomethyl)-4-cyanothiophene-2-carboxylate [7]
• Common Synonyms and Brand Names: S 12911, S 12911-2, Protelos, Protos, Osseor, Bivalos, Protaxos [1]

Physical Characteristics:

Strontium ranelate is described as a white to light yellow powder or crystalline powder. It is characterized as being slightly soluble in water and almost insoluble in ethanol, but it is easily soluble in dilute hydrochloric acid.1 It is typically administered as granules for oral suspension.15

1.3. Therapeutic Classification

Strontium ranelate occupies a distinct position in pharmacological classification systems, reflecting its unique mechanism.

• Pharmacotherapeutic Group: It is broadly categorized under "Drugs for treatment of bone diseases" and more specifically as a "Bone Density Conservation Agent".[5] In the Anatomical Therapeutic Chemical (ATC) classification system, it is assigned the code M05BX03.[20]
• Mechanism-Based Classification: The most descriptive classification, and the one central to its clinical identity, is as a "dual action bone agent" (DABA).[5] This distinguishes it from the two major classes of osteoporosis drugs:

1. Anti-resorptive agents: These drugs, such as bisphosphonates, denosumab, and selective estrogen receptor modulators (SERMs), primarily function by inhibiting the activity of bone-resorbing osteoclasts.[9]
2. Anabolic agents: This class, primarily represented by parathyroid hormone analogs like teriparatide, functions by directly stimulating bone-forming osteoblasts.[9]

Strontium ranelate is unique in that it combines both of these actions, aiming to shift the entire bone remodeling balance toward net bone formation.[4]

Section 2: Mechanism of Action: A Dual Effect on Bone Remodeling

The pharmacological activity of strontium ranelate is defined by its unique ability to modulate both sides of the bone remodeling equation. This dual mechanism was the cornerstone of its development and initial clinical positioning, offering a departure from existing therapies that targeted either bone formation or resorption, but not both.

2.1. The Core Principle: Rebalancing Bone Turnover

Postmenopausal osteoporosis is fundamentally a disease of imbalance within the bone remodeling unit. In a healthy state, the process of bone resorption by osteoclasts is tightly coupled to subsequent bone formation by osteoblasts, ensuring skeletal integrity is maintained.[4] In osteoporosis, this coupling is disrupted, and the rate of resorption exceeds the rate of formation, leading to a progressive loss of bone mass, deterioration of the bone's microarchitecture, and a consequent increase in fragility and fracture risk.[4]

Strontium ranelate was the first agent developed to directly address this imbalance by uncoupling bone turnover in a beneficial way. Preclinical and clinical studies have consistently shown that treatment with strontium ranelate leads to an increase in markers of bone formation while simultaneously causing a decrease in markers of bone resorption.[4] This rebalancing effect in favor of bone formation results in a net accretion of bone tissue, an improvement in bone microarchitecture, and an increase in overall bone strength, which collectively form the physiological basis for its observed anti-fracture efficacy.[4]

2.2. Anabolic Effects: Stimulation of Bone Formation

The anabolic, or bone-forming, component of strontium ranelate's action is mediated through its direct effects on osteoblasts and their precursors. In vitro experiments have provided substantial evidence for these mechanisms:

• Osteoblast Proliferation and Differentiation: Strontium ranelate has been shown to enhance the replication of pre-osteoblastic cells, the progenitors of mature osteoblasts. It also promotes their differentiation into fully functional osteoblasts, thereby increasing the pool of bone-building cells.[8]
• Increased Osteoblast Activity and Survival: Beyond increasing their numbers, the drug stimulates the metabolic activity of mature osteoblasts. This leads to an increased synthesis of key bone matrix proteins, including type I collagen and non-collagenous proteins such as osteocalcin and bone sialoprotein, which are essential for constructing the organic scaffold of new bone.[1] Furthermore, strontium ranelate promotes osteoblast survival by inhibiting apoptosis (programmed cell death), thus prolonging their functional lifespan.[21]
• Molecular Pathways: The anabolic effects are mediated through complex signaling pathways. One identified mechanism involves the stimulation of Insulin-like Growth Factor 1 (IGF-I) production in vivo, a potent signaling molecule known to be a critical regulator of bone formation and skeletal development.[21]

2.3. Anti-Resorptive Effects: Inhibition of Bone Resorption

Concurrently with its anabolic effects, strontium ranelate exerts an inhibitory influence on bone resorption by targeting osteoclasts.

• Osteoclast Differentiation and Activity: The drug has been shown to decrease the differentiation of osteoclast precursors into mature, multinucleated osteoclasts. It also directly impairs the function of existing osteoclasts by disrupting their actin cytoskeleton, a structure that is essential for forming the "sealing zone" required for bone resorption.[4]
• Increased Osteoclast Apoptosis: Strontium ranelate induces apoptosis in osteoclasts, which reduces the total number of resorptive cells within the bone remodeling unit.[8]
• The OPG/RANKL Signaling Axis: A principal mechanism for its anti-resorptive effect is not a direct action on osteoclasts, but rather an indirect effect mediated by osteoblasts. This highlights a sophisticated level of control over the bone remodeling process. Strontium ranelate stimulates osteoblasts to increase their secretion of osteoprotegerin (OPG) while simultaneously reducing their expression of Receptor Activator of Nuclear Factor κB Ligand (RANKL).[4] The OPG/RANKL/RANK system is the final common pathway regulating osteoclast formation, function, and survival. RANKL, expressed by osteoblasts, binds to its receptor, RANK, on the surface of osteoclast precursors, which is the critical signal that drives their differentiation and activation. OPG, also produced by osteoblasts, acts as a soluble decoy receptor that binds to RANKL and prevents it from interacting with RANK. The ratio of OPG to RANKL is therefore a key determinant of bone resorption activity. By increasing this ratio, strontium ranelate effectively applies a molecular brake to osteoclastogenesis, reducing the formation of new bone-resorbing cells.[4] This demonstrates that the drug leverages the natural cross-talk between bone cells, turning the osteoblast into an anti-resorptive signaling center, providing an elegant explanation for its "rebalancing" effect.

2.4. Molecular Targets and Other Mechanisms

The pleiotropic effects of strontium ranelate are initiated through its interaction with specific cellular receptors and pathways.

• Calcium-Sensing Receptor (CaSR): Strontium is an alkaline earth metal, located directly below calcium in the periodic table, and thus shares chemical similarities. It is widely believed that strontium acts as an agonist at the extracellular Calcium-Sensing Receptor (CaSR), which is expressed on osteoblasts, osteoclasts, and other cell types.[5] The activation of CaSR on osteoblasts is thought to be a key initial step that triggers downstream signaling cascades leading to the anabolic effects and the modulation of the OPG/RANKL axis.[5]
• Other Potential Receptors: While CaSR is a primary candidate, research has also suggested the potential involvement of other receptors, such as the G protein-coupled receptor class C group 6 member A (GPRC6A), and intracellular signaling pathways involving calcineurin/nuclear factor of activated T-cells (Cn/NFATc).[10]
• Inhibition of Adipogenesis: A particularly insightful discovery has been the effect of strontium ranelate on mesenchymal stem cell lineage selection within the bone marrow. Studies have shown that strontium can inhibit the differentiation of bone marrow stromal cells into adipocytes (fat cells) while simultaneously enhancing their differentiation into osteoblasts.[4] In aging and osteoporosis, there is a well-documented shift in the bone marrow environment that favors adipogenesis at the expense of osteogenesis, leading to increased marrow fat and reduced bone formation.[4] By intervening at this fundamental stage of cell fate determination, strontium ranelate may not just be modulating the activity of existing bone cells but actively "reprogramming" the bone marrow microenvironment to be more pro-osteogenic. This profound mechanism could contribute significantly to the drug's sustained, long-term efficacy in preventing fractures, representing a more durable effect than that of many other osteoporosis therapies.

Section 3: Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The clinical use and effectiveness of strontium ranelate are heavily influenced by its pharmacokinetic profile. Its absorption, distribution, metabolism, and excretion (ADME) characteristics dictate a strict dosing regimen and have important implications for both efficacy and safety.

3.1. Absorption and Bioavailability

The absorption of strontium from the gastrointestinal tract is incomplete and subject to significant interactions.

• Bioavailability: Following a standard oral dose of 2 g of strontium ranelate, the absolute bioavailability of the elemental strontium component is relatively low, averaging approximately 25%, with a reported range of 19% to 27%.[5]
• Time to Peak Concentration (Tmax​): Maximum plasma concentrations of strontium are typically achieved between 3 and 5 hours after a single oral dose.[5] With daily dosing, a steady state in plasma is reached after approximately two weeks of continuous treatment.[5]
• Critical Food and Mineral Interactions: The absorption of strontium is highly sensitive to the presence of food and, in particular, calcium. Co-administration of strontium ranelate with food, milk, milk derivatives, or calcium-containing supplements can drastically reduce its bioavailability by 60% to 70%.[5] This interaction is a critical consideration for clinical practice.
• Administration Recommendations: To overcome these interactions and ensure optimal absorption, a strict administration protocol is required. Patients are instructed to take the 2 g dose on an empty stomach, preferably at bedtime. This should be at least two hours after consuming any food, milk, or calcium-containing products.[5] Consequently, any required calcium and vitamin D supplements, which are standard for osteoporosis patients, must be taken at a different time of day, such as with a morning or midday meal.[12] This complex dosing regimen can pose a challenge to patient adherence, particularly in an elderly population often managing multiple medications.

3.2. Distribution and Protein Binding

Once absorbed, strontium distributes widely, with a pronounced affinity for bone tissue.

• Volume of Distribution: The apparent volume of distribution for strontium is approximately 1 L/kg, indicating distribution into tissues beyond the plasma volume.[5]
• Protein Binding: Strontium exhibits low binding to human plasma proteins, with only about 25% of the circulating element being protein-bound.[5] This leaves a large fraction free to distribute into tissues.
• High Affinity for Bone: The defining characteristic of strontium's distribution is its high affinity for bone tissue, which acts as its primary reservoir.[5] Strontium is incorporated into the skeleton through two main processes: a rapid adsorption onto the surface of existing hydroxyapatite crystals and a slower substitution for calcium within the apatite crystal lattice of newly formed bone.[5] Over long-term treatment, strontium accumulates in the bone, reaching a stable molar fraction of approximately 1% relative to calcium.[12] This accumulation is responsible for a significant measurement artifact in dual-energy X-ray absorptiometry (DXA) scans. Because strontium has a higher atomic number than calcium, it absorbs more X-rays, leading to an artificial inflation of the measured bone mineral density (BMD).[5] It has been estimated that approximately half of the observed increase in BMD during treatment is attributable to this physical artifact rather than a true increase in bone mass. This complicates the monitoring of treatment efficacy, requiring clinicians to interpret follow-up DXA results with caution and focus on the ultimate clinical outcome of fracture prevention.[10]

3.3. Metabolism and Elimination

Strontium itself is not metabolized, and its elimination is a slow process.

• Metabolism: As a divalent cation, elemental strontium is not subject to metabolic transformation in the body.[5] The ranelic acid moiety is metabolized and cleared rapidly and does not accumulate.
• Route of Elimination: The elimination of absorbed strontium is independent of dose and time and occurs via two primary pathways: renal excretion through the kidneys into urine and gastrointestinal excretion of unabsorbed and re-secreted strontium into feces.[5]
• Half-Life and Clearance: Strontium has a long effective elimination half-life of approximately 60 hours.[5] This long half-life, combined with its accumulation in bone, means that the element persists in the body for an extended period even after treatment is discontinued. Total plasma clearance is approximately 12 mL/min, with renal clearance accounting for about 7 mL/min.[5] The persistence of strontium in the skeleton has dual implications: it may provide a sustained therapeutic effect, but it also means that in the event of an adverse reaction, the causative agent cannot be rapidly cleared from the body.

3.4. Pharmacokinetics in Special Populations

• Renal Impairment: The kidneys are a major route of strontium elimination. In patients with mild-to-moderate renal impairment (creatinine clearance of 30-70 mL/min), strontium clearance is reduced, leading to an increase in plasma strontium levels. However, this increase is not considered clinically significant enough to warrant a dose adjustment.[5] In contrast, there is no pharmacokinetic data available for patients with severe renal impairment (creatinine clearance <30 mL/min). Due to the risk of accumulation, the use of strontium ranelate is not recommended in this patient group.[12]

Section 4: Clinical Efficacy and Pivotal Trials

The clinical evidence supporting the anti-fracture efficacy of strontium ranelate is primarily derived from a comprehensive Phase III clinical trial program, most notably the SOTI and TROPOS studies. These large, multinational, randomized, double-blind, placebo-controlled trials were rigorously designed to assess the drug's ability to reduce the risk of osteoporotic fractures in postmenopausal women.[4] The findings from these studies established strontium ranelate as an effective treatment and formed the basis of its initial regulatory approvals.

4.1. Overview of Clinical Evidence

The SOTI (Spinal Osteoporosis Therapeutic Intervention) and TROPOS (Treatment Of Peripheral Osteoporosis) trials were the cornerstones of the clinical development program.[12] They were designed to evaluate the efficacy of a 2 g/day oral dose of strontium ranelate versus placebo in preventing vertebral and non-vertebral fractures, respectively. All participants in both the treatment and placebo arms also received daily calcium and vitamin D supplements to ensure nutritional adequacy.[12] The results demonstrated a statistically significant and sustained reduction in fracture risk over a multi-year period, validating the drug's therapeutic potential.[9]

4.2. The SOTI (Spinal Osteoporosis Therapeutic Intervention) Study

The SOTI study was specifically designed to assess the efficacy of strontium ranelate in preventing vertebral fractures in a population with established disease.

• Objective and Population: The trial enrolled 1,649 postmenopausal women (mean age 69 years) with established osteoporosis, defined by the presence of at least one prevalent vertebral fracture and low lumbar spine bone mineral density.[12] This population represented a group at high risk for subsequent fractures.
• Key Findings: The results showed a rapid and sustained reduction in the risk of new vertebral fractures.
• After just one year of treatment, the risk of a new radiographic vertebral fracture was reduced by 49% compared to the placebo group.[12]
• Over the primary three-year study period, strontium ranelate significantly reduced the risk of a new radiographic (morphometric) vertebral fracture by 41% (relative risk = 0.59; 95% confidence interval [CI]: 0.48–0.73; p<0.001).[12]
• Crucially, the risk of new clinical vertebral fractures (those causing symptoms such as back pain) was also reduced by 38% (RR = 0.62; 95% CI: 0.47–0.83; p<0.001).[12]
• This efficacy was maintained in long-term follow-up, with a 33% risk reduction still evident after four years of treatment.[12]

4.3. The TROPOS (Treatment Of Peripheral Osteoporosis) Study

The TROPOS study was a larger trial designed to evaluate the drug's efficacy against non-vertebral fractures in an older, more frail population.

• Objective and Population: The trial enrolled 5,091 postmenopausal women with osteoporosis, who were notably older (mean age 77 years) and had low femoral neck BMD.[12]
• Key Findings: The TROPOS study demonstrated the drug's efficacy extended beyond the spine.
• Over three years, treatment with strontium ranelate led to a 16% reduction in the risk of any non-vertebral fracture compared to placebo (RR = 0.84; 95% CI: 0.702–0.995; p=0.04).[12]
• The risk of major non-vertebral fragility fractures (at sites including the hip, wrist, pelvis, sacrum, ribs, clavicle, and humerus) was reduced by 19% (RR = 0.81; 95% CI: 0.66–0.98; p=0.031).[26]
• Hip Fracture Efficacy: A critical endpoint for any osteoporosis therapy is the prevention of hip fractures, which are associated with the highest rates of morbidity, mortality, and healthcare costs. While the overall TROPOS study was not statistically powered to detect a reduction in hip fractures as a primary endpoint, a pre-specified post-hoc analysis was conducted on a high-risk subgroup. This subgroup consisted of women aged 74 years or older with very low femoral neck BMD (T-score ≤ -2.4). In this vulnerable population, strontium ranelate demonstrated a significant 36% reduction in the risk of hip fracture (RR = 0.64; 95% CI: 0.412–0.997; p=0.046).[12] While post-hoc analyses are considered hypothesis-generating rather than definitive proof, this finding was clinically important. However, the lack of a statistically significant primary endpoint for hip fracture in the overall study population represented a relative weakness compared to some competitor drugs, like certain bisphosphonates, which had demonstrated such efficacy in their pivotal trials.[28] This ambiguity likely influenced its clinical positioning even before major safety issues came to light.
• Efficacy in the Very Elderly: The large number of older participants in TROPOS allowed for a robust analysis of efficacy in the very elderly. Pooled data from SOTI and TROPOS showed that strontium ranelate was effective in women aged 80 years and older, a group often underrepresented in clinical trials. In this population, the drug reduced the risk of vertebral fractures by 32% and non-vertebral fractures by 31%.[9] This suggested that its mechanism was particularly beneficial in settings of advanced age and established bone fragility.

4.4. Impact on Bone Mineral Density (BMD) and Microarchitecture

Beyond fracture reduction, the clinical trials also demonstrated favorable effects on surrogate markers of bone health.

• Bone Mineral Density (BMD): Treatment with strontium ranelate resulted in a significant, continuous, and progressive increase in BMD at both the lumbar spine and the femoral neck. Over three years, BMD increased by 14.4% at the lumbar spine and 8.3% at the femoral neck compared to placebo.[10] A notable finding was the absence of a plateau effect, with BMD continuing to increase even after eight years of treatment, suggesting a sustained anabolic effect.[10] As previously noted, these values are amplified by the measurement artifact caused by strontium's incorporation into bone.[5]
• Bone Quality and Microarchitecture: Histomorphometric and three-dimensional micro-computed tomography (μCT) analyses of bone biopsies taken from trial participants provided direct evidence that strontium ranelate improves bone quality. The results confirmed that the quality of bone mineralization was preserved and that the underlying bone microarchitecture was significantly ameliorated.[4] Specific improvements included an increase in the number of trabeculae (+14%), a reduction in the separation between them, and an increase in cortical bone thickness.[10] This enhancement of the bone's structural integrity is a key mechanistic contributor to the observed increase in bone strength and the ultimate reduction in fracture risk.[4]

Table 1: Summary of Key Efficacy Endpoints from SOTI and TROPOS Trials (3-Year Data)

Study	Fracture Type	Strontium Ranelate Incidence (%)	Placebo Incidence (%)	Relative Risk (RR) [95% CI]	p-value	Number Needed to Treat (NNT)
SOTI	New Vertebral (Radiographic)	20.9	32.8	0.59 [0.48–0.73]	<0.001	9
SOTI	New Vertebral (Clinical)	11.3	17.4	0.62 [0.47–0.83]	<0.001	16
TROPOS	All Non-Vertebral	11.2	12.9	0.84 [0.70–1.00]	0.04	59
TROPOS	Major Non-Vertebral	8.7	10.4	0.81 [0.66–0.98]	0.031	59
TROPOS	Hip Fracture (High-Risk Subgroup)	4.3	6.4	0.64 [0.41–1.00]	0.046	48
Data compiled from sources.12

Section 5: Safety Profile and Adverse Events

While the efficacy of strontium ranelate in reducing fractures was well-established, its clinical utility and market longevity were ultimately determined by its safety profile. Although initial trials suggested good tolerability, the accumulation of data from pooled analyses and extensive post-marketing surveillance revealed several rare but serious safety signals. These findings prompted a fundamental reassessment of the drug's risk-benefit balance and led to significant regulatory actions globally.[6] The most critical safety concerns revolve around an increased risk of cardiovascular events, venous thromboembolism, and the severe hypersensitivity reaction known as DRESS syndrome.

5.1. Overview of Safety Concerns

The unraveling of strontium ranelate's safety profile is a quintessential example of the importance of pharmacovigilance. While common side effects like gastrointestinal upset were identified in Phase III trials, the most severe risks only became fully apparent after the drug was used by millions of patients in real-world settings. This highlights the limitations of pre-market clinical trials, which, despite their size, may not be sufficient to detect rare adverse events or risks that are concentrated in specific patient subpopulations. The three pivotal safety issues that defined the drug's later history are cardiovascular risk (specifically myocardial infarction), venous thromboembolism (VTE), and DRESS syndrome.[13]

5.2. Cardiovascular Risk: The Central Controversy

The association between strontium ranelate and an increased risk of myocardial infarction (MI) became the most significant and debated safety issue, leading to the most stringent regulatory restrictions.

5.2.1. Evidence from Randomized Controlled Trials (RCTs)

The primary evidence for cardiovascular risk emerged from a pooled analysis of data from multiple randomized controlled trials involving approximately 7,500 patients, which was submitted to and reviewed by the European Medicines Agency (EMA).[6]

• The analysis revealed a statistically significant increase in the risk of non-adjudicated MI in patients treated with strontium ranelate compared to those receiving placebo.[6]
• The incidence of MI was 1.7% in the strontium ranelate group versus 1.1% in the placebo group, which translated to an odds ratio (OR) of 1.6 (95% CI: 1.07–2.38).[14] This indicated a 60% increase in the odds of experiencing an MI for patients taking the drug.
• It is critical to note that this increased risk of MI was not accompanied by an increase in cardiovascular-related mortality.[14]
• Further analysis suggested that the risk was concentrated in patients who had pre-existing cardiovascular risk factors. When patients with known cardiovascular contraindications were excluded from the analysis, the increased risk was mitigated and no longer statistically significant.[14]

5.2.2. The Discrepancy: RCTs vs. Observational Studies

A major point of scientific and clinical debate arose from the fact that the clear cardiovascular risk signal observed in the controlled environment of RCTs was not replicated in several large-scale, "real-world" observational studies and analyses of healthcare registries in the United Kingdom and Denmark.[10] This discrepancy highlights a fundamental challenge in pharmacoepidemiology.

Potential explanations for this divergence are complex. One of the most significant factors is likely channelling bias. Observational studies revealed that, in routine clinical practice, strontium ranelate was often prescribed to older, more frail patients with more severe osteoporosis. Crucially, these patients also had a higher burden of comorbidities, including pre-existing cardiovascular diseases.[33] This means that the patients receiving strontium ranelate in the real world had a much higher baseline risk of MI than the general population or the healthier, more selected populations in the RCTs. This high baseline risk may have masked or confounded the specific pharmacological effect of the drug, making the signal disappear into the statistical "noise" of pre-existing conditions.

This does not invalidate the RCT finding. Rather, it suggests that a drug's safety profile is not an absolute property but is highly context-dependent. The RCTs, through randomization, isolated the "pure" pharmacological risk of the drug. The observational studies reflected its use in a complex clinical reality. The EMA's ultimate decision to trust the robust RCT data and restrict the drug's use to patients without these confounding cardiovascular risk factors was a direct application of this understanding, effectively attempting to recreate the safer conditions of the clinical trial population in real-world practice.[6]

5.3. Venous Thromboembolism (VTE)

An increased risk of VTE, which includes deep vein thrombosis and pulmonary embolism, was identified early in the drug's clinical evaluation and has remained a consistent safety signal.[3]

• Pooled data from the pivotal trials showed an annual incidence of VTE of approximately 0.7% in the strontium ranelate group.
• This corresponded to a 42% increase in relative risk compared to placebo (RR = 1.42; 95% CI: 1.02–1.98).[12]
• As a result, strontium ranelate is contraindicated in patients with a current or past history of VTE and in those who are temporarily or permanently immobilized, as immobility is itself a major risk factor for VTE.[16]

5.4. DRESS Syndrome (Drug Rash with Eosinophilia and Systemic Symptoms)

DRESS syndrome is a rare but life-threatening adverse drug reaction that has been definitively linked to strontium ranelate.

• Description: DRESS is a severe, delayed-type hypersensitivity reaction. It is characterized by a long latency period, typically developing 2 to 6 weeks after initiation of the offending drug.[35] The clinical presentation is dramatic and involves a constellation of symptoms: high fever, an extensive maculopapular skin rash, prominent facial edema, lymphadenopathy, and characteristic hematological abnormalities, most notably hypereosinophilia (a high count of eosinophils) and atypical lymphocytes.[30] The most dangerous feature is multi-organ involvement, with the liver, kidneys, heart, and lungs being commonly affected. The mortality rate is estimated to be around 10%, often due to fulminant hepatitis.[35]
• Association and Incidence: Numerous case reports and pharmacovigilance database analyses have established a causal link between strontium ranelate and DRESS syndrome.[30] A review of cases reported to the manufacturer up to March 2011 confirmed 47 cases. The highest estimated incidence was calculated from French data, at approximately 1 case per 24,112 newly treated patients.[43]
• Pathophysiology: The underlying mechanism is believed to be a complex, T-cell mediated immune response. A key feature in many DRESS cases is the reactivation of latent herpesviruses, such as human herpesvirus 6 (HHV-6), HHV-7, or Epstein-Barr virus (EBV). This viral reactivation is thought to play a role in the severity and protracted course of the illness.[30]

5.5. Common and Other Adverse Effects

• Gastrointestinal Effects: The most frequently reported adverse events in clinical trials were nausea and diarrhea. These were generally mild, transient, and occurred more commonly than with placebo, particularly during the first three months of treatment, after which their incidence did not differ significantly.[12]
• Nervous System and Musculoskeletal Effects: Other less common side effects reported include headache, transient and asymptomatic increases in muscle creatine kinase (CK) levels, and rare instances of disturbances in consciousness or memory loss.[30]

Table 2: Comprehensive Safety Profile of Strontium Ranelate

Adverse Event	Reported Incidence / Frequency	Key Clinical Context & Management
Myocardial Infarction (MI)	OR 1.6 (95% CI: 1.07–2.38) vs. placebo in RCTs	Signal identified in pooled RCT data but not consistently in observational studies. Risk is concentrated in patients with pre-existing CV risk factors. Contraindicated in patients with any history of ischemic heart disease, peripheral arterial disease, cerebrovascular disease, or uncontrolled hypertension. Regular CV risk monitoring is mandatory.
Venous Thromboembolism (VTE)	RR 1.42 (95% CI: 1.02–1.98) vs. placebo	An early and consistent safety signal. Contraindicated in patients with a current or past history of VTE and in those who are temporarily or permanently immobilized.
DRESS Syndrome	Rare (~1 in 24,000 newly treated patients)	A severe, potentially fatal, delayed hypersensitivity reaction (latency 2-6 weeks). Characterized by rash, fever, eosinophilia, and multi-organ involvement. Treatment must be stopped immediately and permanently at the first sign of a rash.
Nausea and Diarrhea	Common (<1 in 10 patients)	Typically mild and transient, occurring most frequently in the first few months of therapy. Usually improves as the body adapts to the medication.
Severe Skin Reactions (other)	Rare (<1 in 1,000 patients)	Includes other serious reactions like Stevens-Johnson syndrome and toxic epidermal necrolysis. The emergence of any rash should prompt immediate and permanent discontinuation of the drug.
Data compiled from sources.12

Section 6: Regulatory History and Current Status

The regulatory journey of strontium ranelate is a compelling narrative of a drug's life cycle, marked by initial optimism, escalating safety concerns, progressively severe restrictions, and eventual commercial withdrawal in many regions. The actions taken by the European Medicines Agency (EMA) were pivotal, creating a global ripple effect that influenced regulators worldwide.

6.1. European Medicines Agency (EMA)

As the drug was developed and first launched in Europe, the EMA's oversight was central to its history.

• Initial Approval: Strontium ranelate, under the brand name Protelos®, was granted a centralized marketing authorization in the European Union on September 21, 2004. The initial indication was for the treatment of postmenopausal osteoporosis to reduce the risk of vertebral and hip fractures.[7] This indication was subsequently expanded in 2012 to include the treatment of osteoporosis in men at increased risk of fracture.[3]
• Escalating Safety Reviews (2012-2014): A series of safety reviews conducted by the EMA's pharmacovigilance committees dramatically altered the drug's approved use.
• March 2012: An initial review acknowledged the drug's positive benefit-risk balance but led to new warnings being added to the product information regarding the risks of VTE and severe skin reactions, including DRESS syndrome.[48]
• April 2013: A routine benefit-risk assessment of pooled trial data uncovered the increased risk of myocardial infarction. This prompted the EMA's Pharmacovigilance Risk Assessment Committee (PRAC) and the Committee for Medicinal Products for Human Use (CHMP) to recommend significant restrictions. The indication was narrowed to the treatment of severe osteoporosis only. Furthermore, the drug was now contraindicated in patients with any current or past history of ischemic heart disease (e.g., angina, MI), peripheral arterial disease, cerebrovascular disease, or uncontrolled hypertension.[6]
• January-February 2014: The safety review culminated in the PRAC recommending a full suspension of the medicine. However, after further deliberation, the CHMP opted for a different course. It recommended that the drug should remain available but under even tighter restrictions, positioning it as a last-resort option. The final recommendation was that strontium ranelate should only be used to treat patients with severe osteoporosis who cannot be treated with any other approved osteoporosis medicine, and who have no history of cardiovascular disease. The CHMP also mandated regular cardiovascular risk monitoring for all patients on the drug.[34]
• Withdrawal: The severe restrictions placed on its use dramatically narrowed the eligible patient population. This rendered the drug commercially unviable for the original manufacturer, Servier, who ceased marketing and distributing Protelos® and Osseor® in August 2017, citing "commercial reasons".[48] The formal withdrawal of the EU marketing authorization, at the company's request, was finalized on April 14, 2020.[48] In some markets, such as the UK, a generic version manufactured by Aristo later became available for the small, highly-restricted patient population.[53] This sequence illustrates how regulatory action, driven by safety science, can directly lead to a market withdrawal when a drug's clinical niche becomes too small to be profitable.

6.2. U.S. Food and Drug Administration (FDA)

The regulatory status of strontium ranelate in the United States is straightforward: it has never been approved for any indication by the FDA.[6] While the FDA has not formally reviewed strontium ranelate for osteoporosis, it has been aware of the safety concerns from Europe. In its review of other strontium-containing products, such as esomeprazole strontium, the agency has explicitly noted the high dose of elemental strontium in the European Protelos® formulation and the associated adverse events.[56] Strontium, in the form of strontium chloride, is an ingredient in some FDA-approved over-the-counter toothpastes for dentin hypersensitivity.[55]

6.3. Health Canada

Similar to the US, strontium ranelate is not approved as a prescription drug in Canada.[13] However, various other strontium salts, such as strontium citrate, lactate, and gluconate, are available as licensed Natural Health Products (NHPs), often marketed to support bone health.[13]

The EMA's actions prompted a safety review by Health Canada in 2015. The review acknowledged the lack of specific adverse event data for the non-ranelate salts sold in Canada and for lower doses. Nevertheless, exercising a "precautionary approach," Health Canada concluded that a risk could not be ruled out. The agency requested that the labels of all NHP products containing strontium be updated with new warnings, advising against their use in individuals with, or at high risk for, heart disease, circulatory problems, or blood clots.[13] This action demonstrates the interconnectedness of global pharmacovigilance, where a finding in one major jurisdiction prompts precautionary measures in others to protect public health.

6.4. Therapeutic Goods Administration (TGA) - Australia

Strontium ranelate (marketed as Protos®) was approved for the treatment of osteoporosis by the TGA in Australia.[61] Following the EMA's regulatory cascade, the TGA initiated its own safety review. In April 2014, the TGA issued a safety alert and mandated that the Australian Product Information be updated to incorporate the same stringent contraindications and warnings regarding cardiovascular and VTE risk that had been implemented in Europe.[36]

The TGA's actions effectively repositioned the drug as a second-line or last-resort treatment for severe osteoporosis in patients who were intolerant of or had contraindications to other therapies. Reflecting the need for careful patient selection and monitoring, the TGA also restricted prescribing authority to medical practitioners, removing the ability for nurse practitioners to prescribe the medication.[36]

Section 7: Comparative Analysis and Clinical Context

To fully understand the clinical role and legacy of strontium ranelate, it must be placed within the context of the broader therapeutic landscape for osteoporosis. Its unique profile of efficacy and safety is best appreciated when compared directly with the primary alternative treatments. This comparison, combined with an understanding of current clinical guidelines, explains why its use has become so highly restricted.

7.1. Strontium Ranelate vs. Other Osteoporosis Therapies

The primary pharmacological treatments for osteoporosis fall into distinct classes, against which strontium ranelate was compared and ultimately judged.[25]

• Efficacy Comparison:
• In terms of overall anti-fracture efficacy, strontium ranelate is generally considered less efficacious than the most potent bisphosphonates (alendronate, risedronate, zoledronic acid) and the RANKL inhibitor denosumab. These agents have all demonstrated robust efficacy in reducing the risk of vertebral, non-vertebral, and, crucially, hip fractures in the primary analyses of their respective pivotal trials.[28] Strontium ranelate's hip fracture data, derived from a subgroup analysis, is considered less robust.[12]
• Conversely, strontium ranelate is considered more efficacious than agents like the SERM raloxifene or the older bisphosphonate etidronate. These drugs have demonstrated efficacy primarily against vertebral fractures only, with limited or no proven effect on non-vertebral or hip fractures.[28]
• While head-to-head fracture outcome trials are lacking, one study comparing effects on bone structure found that strontium ranelate led to a greater increase in cortical thickness and bone volume than alendronate after one year of treatment, suggesting a potential qualitative advantage in bone architecture.[21]
• Safety Profile Comparison: The safety profile is where the most critical distinctions lie.
• Cardiovascular and VTE Risk: The increased risk of MI, stroke, and VTE is the key negative differentiator for strontium ranelate. While raloxifene is also associated with an increased risk of VTE and fatal stroke, and some concerns have been raised about atrial fibrillation with bisphosphonates, the specific MI signal for strontium ranelate was unique and severe enough to warrant its specific contraindications.[28] Denosumab appeared to have a more favorable cardiovascular profile in its main clinical trial.[28]
• Gastrointestinal Tolerability: Strontium ranelate was often perceived as having an advantage over oral bisphosphonates, which are known to cause upper gastrointestinal issues like esophagitis and gastritis. For patients unable to tolerate oral bisphosphonates, strontium ranelate was once considered a viable alternative.[9]
• Rare but Serious Side Effects: The risk-benefit balance is also shaped by rare but severe class-specific adverse events. Bisphosphonates and denosumab carry a rare risk of osteonecrosis of the jaw (ONJ) and atypical femur fractures (AFF). While long-term data for strontium ranelate did not show a signal for ONJ or AFF [11], its unique and potentially fatal risk of DRESS syndrome is a major liability not shared by the other major drug classes.

Table 3: Comparative Profile of Key Osteoporosis Treatments

Drug Class	Example(s)	Mechanism of Action	Efficacy (Vertebral / Non-Vert. / Hip)	Key Safety Concerns
Dual-Action Agent	Strontium Ranelate	Dual: Anabolic & Anti-resorptive	Yes / Yes / Yes (High-Risk Subgroup)	Cardiovascular Risk (MI, Stroke), VTE, DRESS Syndrome, GI upset
Oral Bisphosphonates	Alendronate, Risedronate	Anti-resorptive	Yes / Yes / Yes	GI intolerance (esophagitis), ONJ, AFF, renal toxicity
IV Bisphosphonates	Zoledronic Acid	Anti-resorptive	Yes / Yes / Yes	Acute phase reaction, ONJ, AFF, renal toxicity
RANKL Inhibitor	Denosumab	Anti-resorptive	Yes / Yes / Yes	Hypocalcemia, ONJ, AFF, rebound fractures upon cessation, skin infections
Anabolic Agent	Teriparatide	Anabolic (PTH analog)	Yes / Yes / No	Hypercalcemia, nausea, dizziness, limited treatment duration (2 years)
Data compiled from sources.9

7.2. Current Clinical Guidelines and Patient Management

The accumulation of safety data has led to the development of extremely strict clinical guidelines that define a very narrow therapeutic niche for strontium ranelate.

• Patient Selection: Strontium ranelate is now universally considered a second-line or last-resort therapy.[10] Its use is restricted to patients with severe osteoporosis who are at a high risk of fracture and for whom all other approved treatments are considered unsuitable, either due to contraindications or intolerance.[5] The practical challenge is that the patient profile required for strontium ranelate is exceedingly rare. A patient must be sick enough (severe osteoporosis) to warrant aggressive treatment, have failed or be intolerant to multiple other drug classes (oral bisphosphonates, IV bisphosphonates, denosumab), and yet be healthy enough to have a completely clean cardiovascular and thromboembolic risk profile. This combination is uncommon in the elderly osteoporotic population, where cardiovascular comorbidities are prevalent.[65]
• Absolute Contraindications: Treatment with strontium ranelate is absolutely contraindicated in any patient with an established, current, or past history of the following conditions [6]:
• Ischemic heart disease (including angina pectoris and myocardial infarction)
• Peripheral arterial disease
• Cerebrovascular disease (including stroke and transient ischemic attack)
• Uncontrolled hypertension
• Venous thromboembolism (deep vein thrombosis or pulmonary embolism)
• Conditions requiring temporary or permanent immobilization
• Mandatory Monitoring:
• Cardiovascular Assessment: A thorough assessment of the patient's cardiovascular risk must be performed before initiating therapy. This assessment must be repeated at regular intervals, typically every 6 to 12 months, for the duration of treatment.[6] If a patient develops any of the contraindicated cardiovascular conditions or if their hypertension becomes uncontrolled, treatment must be stopped immediately.[16]
• Dermatological Monitoring: Patients must be educated about the risk of severe skin reactions, particularly DRESS syndrome. They should be instructed to report any new skin rash immediately, especially within the first few weeks of treatment. The drug must be promptly and permanently discontinued at the first sign of a rash.[43]
• Patient Education on Administration: Due to its pharmacokinetic profile, strict adherence to administration guidelines is essential. Patients must be counselled to take the single 2 g sachet, mixed in water, once daily at bedtime, and at least two hours after consuming any food, milk, or calcium-containing products to ensure adequate absorption.[15]

Section 8: Conclusion and Expert Synthesis

Strontium ranelate occupies a unique and cautionary position in the pharmacopeia for metabolic bone disease. Its journey from a promising, mechanistically novel agent to a highly restricted, commercially withdrawn therapy offers profound lessons for drug development, regulatory science, and clinical practice. It is, in essence, a drug of stark dichotomies: proven efficacy overshadowed by significant risk.

8.1. A Drug of Dichotomies

At its core, strontium ranelate was defined by its innovative "dual-action" pharmacology. By simultaneously stimulating bone formation and inhibiting bone resorption, it promised a more holistic and physiological approach to reversing the bone loss characteristic of osteoporosis. This promise was substantiated by robust clinical evidence from the landmark SOTI and TROPOS trials, which unequivocally demonstrated its ability to reduce the risk of both vertebral and non-vertebral fractures. Its efficacy was particularly notable in the populations most in need: postmenopausal women with established, severe osteoporosis and the very elderly, a group often difficult to treat effectively. For a time, it appeared to be a valuable addition to the therapeutic armamentarium.

8.2. The Unraveling of the Risk-Benefit Profile

This initial promise, however, was systematically dismantled by findings that emerged from post-marketing pharmacovigilance. The accumulation of real-world data from millions of patient-years of use revealed a safety profile far more complex and concerning than was apparent in the initial clinical trials. Three critical, albeit rare, adverse events came to define the drug's liability:

1. Cardiovascular Risk: A statistically significant increase in the risk of myocardial infarction, identified in pooled analyses of randomized controlled trials.
2. Venous Thromboembolism: A consistent, low-level increase in the risk of deep vein thrombosis and pulmonary embolism.
3. DRESS Syndrome: A rare but potentially fatal drug hypersensitivity reaction.

The emergence of these risks fundamentally altered the drug's benefit-risk equation. The benefits of fracture reduction, while real, had to be weighed against the new risks of life-threatening cardiovascular and immunological events. This led to a cascade of regulatory actions, spearheaded by the European Medicines Agency, which saw the drug's indications progressively narrowed, its contraindications expanded, and its monitoring requirements intensified. This regulatory pressure ultimately culminated in the manufacturer's decision to withdraw the product from most major markets for commercial reasons, a direct market consequence of a drug's therapeutic niche becoming too small and too fraught with liability to sustain.

8.3. Lessons Learned and Lasting Legacy

The story of strontium ranelate is more than a history of a single drug; it is a powerful case study with enduring lessons for the field of medicine.

First, it underscores the indispensable role of post-marketing pharmacovigilance. It demonstrates that even large, well-conducted Phase III trials may not be sufficient to uncover the full spectrum of a drug's risks, particularly those that are rare or concentrated in patient subpopulations excluded from trials. A drug's true safety profile is only revealed over time and across a vast and heterogeneous patient population.

Second, the discrepancy between the cardiovascular risk signal in RCTs and the lack thereof in observational studies provides a critical lesson in pharmacoepidemiology. It highlights the profound impact of study design, confounding variables like channelling bias, and the fact that drug safety is not an absolute, but a context-dependent, property. The decision by regulators to trust the causal evidence from RCTs and restrict the drug's use accordingly was a testament to a rigorous, precautionary approach to patient safety.

Finally, the fate of strontium ranelate illustrates a fundamental principle of modern therapeutics: in a crowded field with multiple effective options, a drug's unique or severe safety risks can render it clinically obsolete, even if it possesses proven efficacy. The risk-benefit calculation for strontium ranelate became untenable when compared against alternatives that offered similar or greater anti-fracture efficacy without the same profile of cardiovascular and hypersensitivity risks. Its legacy, therefore, is not merely that of a discontinued therapy, but that of a vital lesson that has sharpened the tools of regulatory science and reinforced the primacy of patient safety in clinical decision-making.

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