Cardiovascular safety of calcium, magnesium and strontium: what does the evidence say?

Calcium, magnesium and strontium have all been implicated in both musculoskeletal and cardiovascular health and disease. However, despite these three elements being closely chemically related, there is marked heterogeneity of their characteristics in relation to cardiovascular outcomes. In this narrative review, we describe the relevant evidential landscape, focusing on clinical trials where possible and incorporating findings from observational and causal analyses, to discern the relative roles of these elements in musculoskeletal and cardiovascular health. We conclude that calcium supplementation (for bone health) is most appropriately used in combination with vitamin D supplementation and targeted to those who are deficient in these nutrients, or in combination with antiosteoporosis medications. Whilst calcium supplementation is associated with gastrointestinal side effects and a small increased risk of renal stones, purported links with cardiovascular outcomes remain unconvincing. In normal physiology, no mechanism for an association has been elucidated and other considerations such as dose response and temporal relationships do not support a causal relationship. There is little evidence to support routine magnesium supplementation for musculoskeletal outcomes; greater dietary intake and serum concentrations appear protective against cardiovascular events. Strontium ranelate, which is now available again as a generic medication, has clear anti-fracture efficacy but is associated with an increased risk of thromboembolic disease. Whilst a signal for increased risk of myocardial infarction has been detected in some studies, this is not supported by wider analyses. Strontium ranelate, under its current licence, thus provides a useful therapeutic option for severe osteoporosis in those who do not have cardiovascular risk factors.

Safety of Strontium Chloride as a Skeletal Marking Agent for Pacific Salmon.

The purpose of this study was to evaluate the biological effects associated with administering strontium chloride as a marking agent to age-0 Chinook Salmon Oncorhynchus tshawytscha fry. Fish were held in a 0× (0 mg/L), 1× (3,000 mg/L; current standard dosage), 3× (9,000 mg/L), or 5× (15,000 mg/L) solution of strontium chloride for 72 h (three times the standard duration of 24 h). The mortality among fish in the 5× strontium chloride exposure group was significantly higher than that observed in the other groups. A dose-related effect on general fish behavior and on feeding behavior was observed. Fish in all test tanks appeared to feed to satiation, except for fish in the 5× tanks during days 2 and 3. Fish in all other test tanks behaved normally. No dose-related effect on fish growth was detected. Histopathological evaluations showed that fish in the 5× exposure group had a significantly higher number of gill lesions than the 0× group. Our mortality, behavioral, and histological assessments suggested that juvenile Chinook Salmon could be safely immersed for three consecutive days in a 9,000-mg/L solution of strontium chloride. This finding potentially expands the present 1,000-3,000-mg/L dosage and 24-h holding period that can be used to mark juvenile fish with strontium chloride solutions. The research also provides necessary target animal safety data for U.S. Food and Drug Administration approval of strontium chloride as an alternative marking method that is suitable for fish with a short holding time. Received February 19, 2017; accepted July 16, 2017.

Interactive effects of vitamin D3 and strontium on performance, nutrient retention and bone mineral composition in laying hens.

BACKGROUND: Strontium is currently prescribed for patients with osteoporosis to increase bone density and reduce bone fractures but its relevance in animal nutrition is obscure. In order to investigate the effect of supplemental strontium and vitamin D3 on performance, egg quality and skeletal integrity in poultry a total of 108 laying hens, 99 weeks of age, were fed three levels of strontium (0, 500, 1000 mg kg(-1) ) and two levels of vitamin D3 (2500, 5,000 iu kg(-1)) over a 12-week period. RESULTS: There was an improvement (P < 0.05) in egg production and feed conversion efficiency with strontium at 500 mg kg(-1) and a significant increase in egg weight in those hens fed additional vitamin D3 . Supplemental strontium increased phosphorus, sodium and strontium retention in birds fed 2500 iu D3 kg(-1) but reduced phosphorus, sodium and strontium retention in birds fed 5000 iu D3 kg(-1), resulting in an interaction (P < 0.01) between strontium and vitamin D3 . Addition of 5000 iu D3 kg(-1) increased egg weight (P < 0.05); predominantly by increased albumen content (P < 0.05), whereas strontium supplementation reduced egg weight (P < 0.001). Similarly, 5000 iu kg(-1) D3 increased apparent metabolizable energy (P < 0.05); in contrast, strontium supplementation reduced (P < 0.05) apparent metabolizable energy. CONCLUSION: The addition of 500 mg kg(-1) strontium significantly improved egg production and feed efficiency; however, further investigation needs to be undertaken to refine the optimum level of strontium required to maximize hen performance. The interrelationship between strontium and vitamin D3 requires further exploratory study.

[The double DNA content is detected in hemocytes of snail Lymnaea stagnalis from a population with high radiation load].

The research of hemocytes of laboratory cultivated pond snails Lymnaea stagnalis originating from two areas near Chernobyl with different radiation load has been carried out by means of comet assay. Significant interpopulation distinctions in parameters of DNA-comets have been revealed by means of the software analysis of hemocyte DNA-comet images: hemocytes of mollusks from radiationally unfavourable "Perstok" population have contained a twice DNA quantity in comparison with "Pripyat" population, and also have been statistically more resistant to the influence of strontium. Strontium reduces the amount of DNA in hemocytes, at that strontium dose of 0.5 MPC is already substantial (i.e., causes a negative impact).for snail Lymnaea stagnalis. According to a RAPD-analysis previously conducted, the snails of two populations are characterized by high genetic similarity, on the basis of which a hypothesis is suggested that the observed differences in the DNA content of hemocytes and resistance to strontium are inherited as prolonged adaptive modification (epigenetic change) in response to the intensive damaging impact of environment. Comet assay can be its indicator while carrying out the environmental monitoring.

Reduced burning and stinging associated with topical application of lactic acid 10% with strontium versus ammonium lactate 12%.

Burning and/or stinging is one of the most common concerns expressed by patients using topical therapies for treatment of dermatologic disorders. Topical lactic acid preparations often are used to treat dry scaly skin. In this study, we compared the level of burning/stinging reported by participants with application of lactic acid cream 10% containing strontium versus ammonium lactate lotion 12% and cetearyl alcohol lotion. The mean rating of burning/stinging reported for lactic acid cream 10% with strontium and cetearyl alcohol lotion was lower than ammonium lactate lotion 12% (P<.0001). Based on the study results, lactic acid cream 10% with strontium causes less burning/stinging than ammonium lactate lotion 12%.

A pilot risk assessment study of strontium chromate among painters in the aeronautical industry.

OBJECTIVE: A method for risk assessment of occupational exposure to strontium chromate (SrCrO4) in painters employed in the aeronautical industry is described. METHODS: Assessment was made of 21 male workers of the painting division, potentially exposed to SrCrO4 (exposed), and 20 male workers of the tests and warehouse divisions (controls). All participants completed a questionnaire about work tasks, lifestyle habits, hobbies and diet. Personal active sampling for the determination of Cr and Sr was performed both during paint-spraying and during other operations in the painting division area. On the same day as environmental sampling, urine samples were collected at the beginning and end of the work shift in exposed workers to determine urinary chromium (CrU), and only at the end of the shift in controls. In the second half of the shift, a blood sample was taken in 10 exposed workers and 10 controls, to determine Cr in plasma (CrP) and in red blood cells (CrRBC). RESULTS: During paint-spraying, Cr concentrations ranged between 1.38 and 17.10 microg/m3, versus 0.02 to 0.07 microg/mi in the painting division area, while the Sr concentration was 22.90 microg/m3 in the paint-spray booth versus 0.07 microg/m3 in the painting division area. CrU at the end of the work shift, CrP and CrRBC, did not show significant differences between exposed workers and controls. Moreover, in exposed workers there were no differences between CrU measured at the beginning and at the end of the work shift. CONCLUSIONS: This approach, consisting of simultaneous environmental and biological monitoring, suggested no absorption of chromium in the painters thanks to the efficacy of the technical, organizational and personal protection measures adopted. However, the evident exposure to high levels of SrCrO4 during paint-spraying highlights how absolutely essential it is to ensure strict compliance with all the preventive measures foreseen by the EU and national regulations for occupational exposure to carcinogens.

[Initial report of strontium-89 chloride treatment for painful osseous metastases at Sakai Municipal Hospital].

Strontium-89 chloride has been available at our hospital for painful osseous metastases since October 2008. Of the 17 patients(22 treatments)seen until September 2010, response to initial treatment of 13 patients was analyzed. These included cancers of the lung(5 patients, 6 treatments), breast(4 patients), thyroid(2 patients, 5 treatments), liver, 1, and prostate, 1. Other treatments patients received within 1 month of Sr-89 injection were; chemotherapy, 5 patients; radiotherapy, 3 patients; and bisphosphonate, 9 patients. The treatment effects were assessed 1 month after injection, and for 11 of the 13 patients, pain-relief was obtained in a mild and gradual manner. Transient flare was frequently observed, some of which made assessment of pain-relief in 6 patients difficult. We recognized that the bone marrow function before treatment was well above the 'Optimal Treatment Manual Japan ' criteria. After treatment, bone marrow functions kept above the value of grade 2(CTCAE), and even in 5 patients with recent or concomitant chemotherapy, it remained above grade 3 of the CTCAE criteria. These results led us to the conclusion that the indication and inclusion criteria for strontium-89 chloride treatment should be patients with an earlier bone metastasis burden that is currently manifested, without too much attention to bone marrow function criteria.

[Zeolite Produced from Fly Ash by Thermal Treatment in Alkaline Solution and Its Capability to Adsorb Cs(I) and Sr(II) in Aqueous Solution].

In this study, we evaluated the efficiency of fly ash (FA) recycling technology, produced from a coal-fired power plant, with the capability to adsorb cesium ion[Cs(I)] and strontium ion [Sr(II)] from aqueous phase. Zeolite was produced from FA by hydrothermal treatment in an alkaline solution. Zeolite 12, 24, and 48 have a Garronite structure. Moreover, the specific surface area of Zeolite was greater than that of FA. Zeolite 12 demonstrated the adsorption capability of Cs(I) and Sr(II) from aqueous phase. Adsorption isotherms data fitted both the Langmuir equation (correlation coefficient: >0.895) and the Freundlich equation (correlation coefficient: >0.881). In addition, the kinetic data fitted the pseudo-second-order model when compared to the pseudo-first-order model. Cs(I) and Sr(II) were selectively adsorbed by Zeolite 12 in complex solution system. Our findings indicate that Zeolite can be produced from FA by hydrothermal treatment in an alkaline solution and shows the capability to adsorb Cs(I) and Sr(II) from aqueous phase. Therefore, Zeolite can be useful adsorbent for purification in water environments.

Forensic tracers of exposure to produced water in freshwater mussels: a preliminary assessment of Ba, Sr, and cyclic hydrocarbons.

Hydraulic fracturing is often criticized due in part to the potential degradation of ground and surface water quality by high-salinity produced water generated during well stimulation and production. This preliminary study evaluated the response of the freshwater mussel, Elliptio complanata, after exposure to produced water. A limited number of adult mussels were grown over an 8-week period in tanks dosed with produced water collected from a hydraulically fractured well. The fatty tissue and carbonate shells were assessed for accumulation of both inorganic and organic pollutants. Ba, Sr, and cyclic hydrocarbons indicated the potential to accumulate in the soft tissue of freshwater mussels following exposure to diluted oil and gas produced water. Exposed mussels showed accumulation of Ba in the soft tissue several hundred times above background water concentrations and increased concentrations of Sr. Cyclic hydrocarbons were detected in dosed mussels and principle component analysis of gas chromatograph time-of-flight mass spectrometer results could be a novel tool to help identify areas where aquatic organisms are impacted by oil and gas produced water, but larger studies with greater replication are necessary to confirm these results.

Structural phase formation and in vitro bioactivity evaluations of strontium phosphosilicate for orthopedic applications.

Structural features of apatites make them one of the most promising candidates for bone tissue regenerative applications. The unique structure and availability of mobile Metal ion as well as other components help interaction with biological fluids and can promote as well as stimulate bone regeneration with correct components. The present study focusses on Strontium phosphosilicate, an apatite analogue to Calcium phosphate-based HAP only loaded with better composition replacing Calcium with stimulatory Strontium and co-existent Silicate alongside phosphate both known to stimulate osteogenesis. Bulk particles were synthesized as powders with Acidic medium as well as the Basic medium of reaction mixture via Sol-Gel and Co-precipitation techniques respectively and phase formation was studied with respect to temperature further detailed by TGA-DSC studies. Secondary phases were also indexed based on which Acidic medium samples sintered at 800°C were comparatively better from the Basic medium on account of the presence of silicate phase forming agglomerated Strontium phosphosilicate. Hemolysis assay and MG-63 based cytotoxicity assay were carried out to study biocompatibility and antibacterial properties were also elucidated in Gram-positive and Gram-negative bacteria. Apatite seeding and bone mineralization studies were carried out with Simulated body fluid and characterized structurally and morphologically.

Strontium induced rickets: metabolic basis.

Dietary strontium inhibits both the synthesis of 1,25-dihydroxycholecalciferol and intestinal calcium absorption in vitamin D(3)-repleted chicks. 1,25-Dihydroxycholecalciferol restores calcium absorption to normal, while 25-hydroxycholecalciferol is without effect in the strontium-fed chick. It is suggested that strontium induces rickets by blocking the biosynthesis of 1,25-dihydroxycholecalciferol, the metabolically active form of vitamin D in the intestine.

Radiation safety considerations for the bone seeking radiopharmaceuticals. 89SrCl2, 186Re-HEDP and 153Sm-EDTMP.

UNLABELLED: The radiation exposure to bystanders from 89SrCl2, 186Re-HEDP and 153Sm-EDTMP, is generally thought to be caused by "bremsstrahlung" and gamma-radiation, with negligible contribution from beta-radiation. The latter assumption may be erroneous. The aim of this prospective study was the investigation of radiation safety after treatment with these radiopharmaceuticals. The radiation field around treated patients was characterized and the magnitude estimated. PATIENTS, METHODS: 33 patients (30 prostate carcinoma, 3 breast carcinoma) were treated with 150 MBq 89SrCl2 (9 patients), 1295 MBq 186Re-HEDP (12 patients) or 37 MBq/kg 153Sm-EDTMP (12 patients). External exposure rates at 30 cm from the patient were measured at times 0 to 72 h post-injection. To evaluate the respective contribution of Bremsstrahlung, beta- and gamma-radiation, a calibrated survey meter was used, equipped with a shutter. For each patient, the measured exposure rate-versus-time data were fit to a curve and the curve integrated (area under the curve) to estimate the total exposure. RESULTS: For 29/33 patients the total ambient equivalent doses (mean+/-1 standard deviation [SD]) based on the integral of the fitted curve were 2.1+/-1.2 mSv for 89SrCl2, 3.3+/-0.6 mSv for 186Re-HEDP and 2.8+/-0.6 mSv for 153Sm-EDTMP. Beta-radiation contributes significantly to these doses (>99% for 89SrCl2, 87% for 186Re-HEDP and 27% for 153Sm-EDTMP). The effective doses (at 30 cm) are <0.1 mSv for 89SrCl2, 0.3 mSv for 186Re-HEDP and 1.6 mSv for 153Sm-EDTMP. CONCLUSION: Patients treated with 89SrCl2, 186Re-HEDP or 153Sm-EDTMP emit a spectrum of radiation, including non-negligible beta-radiation. With specific instructions effective doses to bystanders are acceptable.

Development of a novel method for quantitative evaluation of sensory skin irritation inhibitors.

BACKGROUND/AIMS: Sensory skin irritation is regarded as one of the most serious side effects of cosmetic use. Thus, it is desirable to develop good inhibitors of sensory skin irritation. However, it is difficult to quantify the effect of sensory skin irritation inhibitors. METHODS: We investigated the possibility of using an electrical current perception threshold (CPT) measurement for the quantitative evaluation of these inhibitors. We divided study populations into stinger and non-stinger groups based on their response to 5% lactic acid and assessed CPT values at 2000, 250, and 5 Hz on the cheek. Stingers showed significantly lower CPT values than non-stingers did at 250 and 5 Hz. We also measured CPT values before and after the application of nine materials with inhibitory effects on sensory skin irritation. To investigate the relationship between the change in CPT values and the effect of each material in the clinical stinging test, we conducted the stinging test with the test materials in a 5% lactic acid solution and with a 5% lactic acid solution (positive control). RESULTS: There was a positive correlation between the change in CPT values and the inhibitory effect that each material had on the stinging test. CONCLUSION: The change in CPT values can be used for the quantitative evaluation of sensory skin irritation inhibitors .

Comparison of the efficacy of strontium-89 chloride in treating bone metastasis of lung, breast, and prostate cancers.

OBJECTIVE: The aim of this study was to comparatively evaluate the efficacy of strontium-89 chloride (89 SrCl2) in treating bone metastasis-associated pain in patients with lung, breast, or prostate cancer. MATERIALS AND METHODS: The 126 patients with lung cancer included 88, 16, 15, 4, and 3 patients with adenocarcinoma, squamous cell carcinoma, nonsmall cell carcinoma, mixed carcinoma, and small cell carcinoma, respectively, and the control group consisted of patients with breast (71 patients) or prostate cancer (49 patients) who underwent 89 SrCl2 treatment during the same period. The treatment dose of 89 SrCl2 was 2.22 MBq/kg. RESULTS: The efficacy rate of treatment in the lung cancer group was 75.4%, compared to 95.0% in the control group. Approximately 67% of patients with lung cancer and bone metastases and 47% of control patients exhibited mild-to-moderate reductions of leukocyte and platelet counts 4 weeks after 89 SrCl2 treatment. CONCLUSIONS: 89 SrCl2 can safely and effectively relieve bone pain caused by bone metastasis from lung cancer. However, its efficacy was lower in patients with lung cancer with bone metastasis than in those with breast or prostate cancer with bone metastasis, and its effects on the peripheral hemogram were also significantly stronger in the lung cancer group.

Multifunctional effects of a modification of SLA titanium implant surface with strontium-containing nanostructures on immunoinflammatory and osteogenic cell function.

This study investigated the effects of surface modification of clinically available sandblasted/acid-etched (SLA) titanium oral implants with strontium (Sr)-containing nanostructures on both early immunoinflammatory macrophage cell functions and osteogenic stem cell functions. The goal was to provide insight for future surface engineering of titanium implants with multifunctional effects, that is, tissue healing capacity at both the nonosteogenic cell centered initial stage and the subsequent osteogenic cell-governed later stage-osseointegration process. The Sr-containing nanostructure was prepared in on the SLA-type implant surface by wet chemical treatment. The results showed that Sr modification is favorable for early macrophage cell functions and increases osteogenic capacity of the SLA surface. Surface Sr modification notably upregulated regenerative macrophage phenotype expression and anti-inflammatory cytokine IL10 production while suppressing inflammatory cytokine TNFα. Sr incorporation enhanced certain early cellular events of ST2 stem cells such as early cellular spreading and critical integrin gene expression, which in turn notably increased osteogenic differentiation (osteogenesis-related phenotype gene expression and osteocalcin production) when combined with the microstructured SLA implant surface. Surface modification of SLA-type implants with Sr-containing nanostructures demonstrated the ability to favorably influence early immunoinflammatory macrophage cell functions and the functionality of osteogenesis cells, resulting in an enhanced osseointegration outcome. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 3009-3020, 2018.

Increased serum cadmium and strontium levels in young smokers: effects on arterial endothelial cell gene transcription.

OBJECTIVE: Metal constituents of tobacco have long been suspected to contribute to cardiovascular diseases. In this study, we determined the serum concentrations of aluminum, cadmium (Cd), cobalt, copper, iron, manganese, nickel, lead, strontium (Sr), and zinc of young nonsmokers, passive smokers, and smokers. METHODS AND RESULTS: Cd and Sr were found to be significantly increased in smokers compared with nonsmokers. The effects of these metals on primary arterial endothelial cells were then assessed using microarray technology and real-time polymerase chain reaction (RT-PCR). The data showed that Sr does not interfere with endothelial cell transcription. In contrast, the effects of Cd in amounts delivered to the human body by smoking were dramatic. CONCLUSIONS: Arterial endothelial cells responded to Cd exposure by massively upregulating metal and oxidant defense genes (metallothioneins) and by downregulating a number of transcription factors. In addition, the mRNA of the intermediate filament protein vimentin, crucial for the maintenance of cellular shape, was reduced. Surprisingly, a number of pro-inflammatory genes were downregulated in response to Cd. The present data suggest that by delivering Cd to the human body, smoking deregulates transcription, exerts stress, and damages the structure of the vascular endothelium; furthermore, in contrast to the effects of cigarette smoke as a whole, Cd seems to possess anti-inflammatory properties.

Serum concentrations of IL-2 and TNF-alpha in patients with painful bone metastases: correlation with responses to 89SrCl2 therapy.

UNLABELLED: We have used 89SrCl2 for the palliative treatment of painful bone metastases from various malignant diseases. We studied the correlation between serum interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF-alpha) levels and the response to 89SrCl2 therapy. METHODS: Forty-two patients (24 men and 18 women) were treated intravenously with 89SrCl2 at a dose of 148 MBq (4 mCi). RESULTS: The response rate was 33 of 42 (79%). In the control subjects, serum IL-2 concentrations were higher but TNF-alpha concentrations lower (P < 0.05) than in the patients with bone metastases. After treatment with 89SrCl2, IL-2 levels increased and TNF-alpha levels decreased, with maximal changes at the fourth month after therapy. After comparing the serum levels of IL-2 and TNF-alpha between responders and nonresponders, we found that these variables did not differ before 89SrCl2 therapy but differed significantly (P < 0.05) after therapy. Responders had higher IL-2 and lower TNF-alpha concentrations than nonresponders. A good correlation was found between IL-2 and TNF-alpha levels and the number of metastases and pain score. CONCLUSION: 89SrCl2 is effective for palliation of bone pain in patients with disseminated bone metastases. In addition to managing pain, 89SrCl2 can improve immunity and the quality of life for most patients. Further studies are needed to elucidate the roles of IL-2 and TNF-alpha in the response to 89SrCl2 therapy and to evaluate their usefulness as indicators of 89SrCl2 efficacy.

Single inhalation exposure to 90SrCl2 in the beagle dog: late biological effects.

Late-occurring biologic effects were studied in beagle dogs that were given graded levels of 90SrCl2 via single brief inhalation exposures and were subsequently observed for their life-span. Due to the soluble chemical form of the aerosol, 90Sr was rapidly translocated from lung and deposited in bone where it was subsequently retained for a long period of time. Radiation-induced lesions were confined to the bone, bone marrow, and adjacent soft tissue. Forty-five primary bone tumors occurred in 31 of 66 exposed dogs. Metastasis occurred from 21 tumors, with the lung being the most frequent site of metastasis (76%). Twenty-seven tumors were classified as different subtypes of osteosarcoma, 14 as hemangiosarcomas, 3 as fibrosarcomas, and 1 as a myxosarcoma. Four carcinomas arising from soft tissues adjacent to bone were also considered to be 90Sr induced. In contrast to bone tumors arising in beagles chronically exposed to 90Sr through ingestion, histologic lesions of radiation osteodystrophy were minimal in this study, indicating that these lesions are not a necessary precursor of osteosarcoma development. The incidences of hemangiosarcomas (31%) and telangiectatic osteosarcomas (11%) in addition to osteosarcomas suggest that the cell of origin for all of these neoplasms is a multipotent mesenchymal cell with the potential for various morphologic expressions dependent on local environmental factors.