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Microgravity inhibits intestinal calcium absorption as shown by a stable strontium test.

BACKGROUND: Little is known about the onset and degree of biochemical and functional alterations in calcium metabolism during microgravity. OBJECTIVE: To evaluate the effect of microgravity on intestinal calcium absorption and calcium-regulating hormones under metabolic ward conditions. MATERIALS AND METHODS: Fractional calcium absorption (Fc240 in percentage of dose administered) was determined pre-flight, in-flight and post-flight, by use of a stable strontium test in one cosmonaut who spent 20 days in space. Moreover, a sequence of blood samples was collected for the determination of serum parathyroid hormone (PTH), 25-hydroxyvitamin D, calcitriol and serum C-telopeptide (CTx, biomarker of bone resorption) levels. During all periods of data collection, calcium intake was held constant at a minimum level of 1.000 mg day(-1) and a daily supplement of 16.6 microg vitamin D2 was given. Personal ultraviolet (UV) light exposure was measured during the whole mission using a biologically weighting UV dosimeter. RESULTS: Fc240 was markedly reduced on flight day 19 (4.4%) as compared to pre-flight and post-flight data (13.4% and 17.2%, respectively). Serum calcitriol levels fell from 40.6 pg mL(-1) (mean pre-flight level) to 1.3 pg mL(-1) on flight day 18 and returned into the normal range after recovery. Serum CTx increased during the flight, while serum PTH and 25-hydroxyvitamin D levels did not change significantly. CONCLUSIONS: Intestinal calcium absorption can be diminished after only three weeks of microgravity. Changes are associated with a severe suppression of circulating calcitriol levels, but are independent of exogenous vitamin D supply and serum PTH levels.

Adult↗

Strontium causes osteomalacia in chronic renal failure rats.

BACKGROUND: We recently reported an association between increased bone strontium (Sr) levels and osteomalacia in dialysis patients. METHODS: To delineate whether or not Sr acts as a causal factor in the development of osteomalacia, we devised the following study: four groups of chronic renal failure (CRF) rats were given Sr, aluminum (Al), both of these compounds or none of the elements (controls). RESULTS: Administration of Sr and/or A1 resulted in increased bone levels of the respective elements. Histological examination revealed impairment of mineralization in the Sr group and to a lesser extent in the Al group as compared to the control group. There was also a significant increase in osteoid area in the Sr group, but not in the Al group. No differences in bone surface or erodic perimeter were noted between the various study groups. Histochemically, Sr could be localized in calcified bone, mainly in new bone close to the osteoid/calcification front, a critical site of bone mineralization. Histochemical findings were confirmed by electron probe X-ray microanalysis. CONCLUSIONS: These findings indicate that Sr accumulation in chronic renal failure rats resulted in the development of osteomalacic lesions, in contrast to the Al group where adynamic bone disease was induced in the present set-up. Further studies are required to define the mechanism by which way Sr causes osteomalacia in chronic renal failure rats.

Aluminum↗

No difference in intestinal strontium absorption after oral or IV calcitriol in children with secondary hyperparathyroidism. The European Study Group on Vitamin D in Children with Renal Failure.

BACKGROUND: Oral and intravenous calcitriol bolus therapy are both recommended for the treatment of secondary hyperparathyroidism, but it has been claimed that the latter is less likely to induce absorptive hypercalcemia. The present study was undertaken to verify whether intravenous calcitriol actually stimulates intestinal calcium absorption less than oral calcitriol and whether it is superior in suppressing parathyroid hormone (PTH) secretion. METHODS: Twenty children (16 males, age range of 5.1 to 16.9 years, mean creatinine clearance 21.9 +/- 11.5 mL/min/1.73 m2, range of 7.4 to 52.7) with chronic renal failure (CRF) and secondary hyperparathyroidism [median intact PTH (iPTH), 327 pg/mL; range 143 to 1323] received two single calcitriol boli (1.5 mg/m2 body surface area) orally and intravenously using a randomized crossover design. iPTH and 1,25(OH)2D3 levels were measured over 72 hours, and intestinal calcium absorption was measured 24 hours after the calcitriol bolus using stable strontium (Sr) as a surrogate marker. Baseline control values for Sr absorption were obtained in a separate group of children with CRF of similar severity. RESULTS: The peak serum level of 1,25(OH)2D3 and area under the curve baseline to 72 hours (AUC0-72h) were significantly higher after intravenous (IV) calcitriol (AUC0-72h oral, 1399 +/- 979 pg/mL. hour vs. IV 2793 +/- 1102 pg/mL. hour, P < 0.01), but the mean intestinal Sr absorption was not different [SrAUC0-240min during the 4 hours after Sr administration 2867 +/- 1101 FAD% (fraction of the absorbed dose) vs. 3117 +/- 1581 FAD% with oral and IV calcitriol, respectively]. The calcitriol-stimulated Sr absorption was more then 30% higher compared with control values (2165 +/- 176 FAD%). A significant decrease in plasma iPTH was noted 12 hours after the administration of the calcitriol bolus, which was maintained for up to 72 hours without any differences regarding the two routes of administration. CONCLUSIONS: These results demonstrate that under acute conditions, intravenous and oral calcitriol boli equally stimulate calcium absorption and had a similar efficacy in suppressing PTH secretion.

Administration, Oral↗

Strontium-89 for symptomatic metastatic prostate cancer to bone: recommendations for hospice patients.

In our institution, 4 mCi doses of the radiopharmaceutical strontium-89 (Sr89) have been given to 101 prostate cancer patients suffering from symptomatic bone metastases. Patients were prospectively analyzed for pain response, treatment-related hematologic toxicity, and survival. Pre-treatment clinical factors were correlated with outcome. Karnofsky Performance Scores (KPS) predicted for survival and pain response. Myelosuppression from the Sr89 treatment was minimal. Twenty-eight of the treated patients had a KPS of 60 or less. This group of patients had a median actuarial survival of 17.5 weeks, and collectively, met Hospice admission survival criteria. In a subset analysis of this group, patients with a KPS of 50 or less demonstrated a low pain response (40%) and average survival (12.5 weeks), both of which did not appear to justify the significant cost and risk of toxicity associated with Sr89 treatment. In these patients, opioids appeared to offer more cost-effective pain control. Patients with a pre-treatment KPS score of 60 had a mean survival of 20.5 weeks following Sr89 therapy, with 42 percent of patients experiencing a reduction in pain. We conclude that patients with a pretreatment KPS of 50 or less should not be treated with Sr89 and patients with a pretreatment KPS of 60 should be evaluated on a case-by-case basis to determine whether or not Sr89 represents the most reasonable treatment option for palliation of their bone pain.

Bone Neoplasms↗

Mobilization of radioactive strontium from mouse and rat using dicarboxylic acid derivatives of cryptand (2.2).

To date, there has been no effective therapy to counter incorporated radionuclides of strontium. In an endeavour to solve this problem, we have synthesized and evaluated various N,N'-disubstituted derivatives of 1,4,10,13-tetraoxa-7,16-diaza-cyclooctadecane(crypt and 2.2) for their ability to mobilize 85Sr2+. These ligands are water soluble and have a relatively low acute i.v. toxicity, as demonstrated by their evaluation in rat and mouse. The di-sodium-calcium complex and tetra-sodium salt of the cryptand (2.2) dimalonate have exerted a remarkable decorporation effectiveness for 85Sr2+ in extracellular space. The tetra-potassium salt of the cryptand (2.2) dimalonate has a moderate effect, while no mobilization activity can be detected with the cryptand (2.2) that does not have a side chain substituent. Animals were initially given 85SrCl2 either i.p. or into the lung, then the compounds were administered 30-60 min later using an alternative route. The degree of decorporation achieved a 80-95% of the initial body burden (ibb) compared with the control values of 20-30%. The agents are resorbed easily from the lung, and the radiostrontium deposition in bone was inhibited strongly by a decorporation agent. The success of the treatment, however, is dependent upon the speed with which decorporation therapy commences.

Animals↗

Project Sunshine and the slippery slope: the ethics of tissue sampling for strontium-90.

When citizens of Atlantic alliance countries are being asked by their elected leaders to suspend many of the fundamental rights of democracy in order to defend them, it is timely to consider the perils of the slippery slope that was opened up by the harvesting of human bones and tissue for studies of strontium-90 fallout during the height of the cold war. In particular, the need to collect samples from recently deceased infants and children seems to have overridden the rights of parents to determine what became of their loved ones after death. Forty years later, parents and others question whether the fact that this research contributed significantly to the partial moratorium on atmospheric tests justified the overriding of their rights. It also reminds us that the testing of nuclear devices, even in the defence of democracy, presents global health hazards.

Global Health↗

Mineralogical and hydrochemical effects on adsorption removal of cesium-137 and strontium-90 by kaolinite.

Adsorption characteristics of the nuclides onto kaolinite were investigated by batch experiment under various pH conditions and concentrations of groundwater cations (Ca2+, Mg2+, K+ and Na+) and anions (HCO3-, CO3(2-) and SO4(2-). Adsorption removal of 137Cs and 90Sr by kaolinite greatly increased as the concentration of groundwater cations increased from 10(-5) to 10(-1) M. In contrast, the pH exerted a small effect on the adsorption of 137Cs and 90Sr onto kaolinite. The zeta potential of kaolinite particles showed a negative increase of amphoteric surface charge with increasing pH. The adsorption behavior of 90Sr was also highly dependent on the concentration of bicarbonate. The thermodynamic saturation index indicated that bicarbonate exerts great effect on strontium adsorption by the precipitation of a strontianite (SrCO3) and a change in pH.

Adsorption↗

Surface Charges of K channels. Effects of strontium on five cloned channels expressed in Xenopus oocytes.

The effects of strontium (Sr2+; 7-50 mM) on five different cloned rat K channels (Kv1.1, Kv1.5, Kv1.6, Kv2.1, and Kv3.4), expressed in oocytes of Xenopus laevis, were investigated with a two-electrode voltage clamp technique. The main effect was a shift of the Gk(V) curve along the potential axis, different in size for the different channels. Kv1.1 was shifted most and Kv3.4 least, 21 and 8 mV, respectively, at 50 mM. The effect was interpreted in terms of screening of fixed surface charges. The estimated charge densities ranged from -0.37 (Kv1.1) to -0.11 (Kv3.4) e nm-2 and showed good correlation with the total net charge of the extracellularly located amino acid residues of the channel as well as with the charge of a specific region (the loop between the S5 segment and the pore forming segment). The estimated surface potentials were found to be linearly related to the activation midpoint potential, suggesting a functional role for the surface charges.

Amino Acid Sequence↗

Effect of stable strontium on the tissue alkaline and acid phosphatase activities of rat: feeding studies.

The effect of feeding stable strontium (Sr) on the tissue alkaline and acid phosphatase activities was studied in young rats. These activities were reduced in liver and small intestine by 10% to 15% at 2 weeks, 20% to 30% at 4 weeks and in kidney by 20% at 6 weeks only in rats fed 2% Sr diet; bone alkaliine phosphatase activity was, however, increased by 80% to 100% (2-6 weeks) in these rats. Gross lesions like paralysis, hemorrhage, rickets and high mortality were observed after 4 to 6 weeks. Although no such lesions were seen, appreciable changes in enzyme activities as mentioned above were discernible in rats fed 1% Sr diet for 6 weeks. Feeding of a 0.5% Sr diet for a period up to 6 weeks had no deleterious effect. Recovery following consumption of a normal diet for 2 weeks was almost complete in liver and small intestine but not in kidney. The elevated tissue Sr levels do not explain the pronounced losses seen in this investigation as compared to those in the earlier in vitro experiments. This study depicts the possible damage due to prolonged therapeutic use of large amounts of stable Sr for the removal of radiostrontium.

Acid Phosphatase↗

Strontium transfer from maternal skeleton to the fetus estimated on the basis of the Techa river data.

Measurements of 90Sr in human bone of inhabitants of the Techa river region were started in 1951, and since 1974 the Techa river population has been studied with a whole-body counter. One of the dosimetric tasks that could be decided using data on 90Sr measurements is direct evaluation of strontium transfer to the fetus from the maternal skeleton. Six cases were selected for which 90Sr measurements were available both for stillborn infants and their mothers. The ratio of 90Sr concentrations in fetal bone to maternal bone for the year of pregnancy has been evaluated. Two clusters of values were found and the difference between clusters could be explained by age-dependent features of maternal bone formation and remodelling. When the mother's 90Sr intake occurred in the period of intensive compact bone growth, the transfer coefficient was very low (0.012-0.032). If 90Sr ingestion occurred during the woman's reproductive age, the transfer to fetus was equal to 0.21-0.26.

Adult↗

Strontium supports human sperm capacitation but not follicular fluid-induced acrosome reaction.

The ability of strontium (Sr(2+)) to replace calcium (Ca(2+)) in maintaining human sperm function has still not been completely characterized. In the present study, acrosome reaction (AR) inducibility in response to human follicular fluid (hFF) was compared in spermatozoa incubated in either Ca(2+)- or Sr(2+)-containing media. Other events related to sperm capacitation, such as protein tyrosine phosphorylation and hyperactivation as well as zona pellucida (ZP) recognition under both conditions, were also analyzed. Spermatozoa incubated overnight in the presence of Sr(2+) were unable to undergo the AR when exposed to hFF. Nevertheless, when spermatozoa were incubated under this condition and then transferred to medium with Ca(2+), sperm response to hFF was similar to that of cells incubated throughout in the presence of Ca(2+). The sperm protein tyrosine phosphorylation patterns and the percentages of sperm motility and hyperactivation were similar after incubation in Ca(2+)- or Sr(2+)-containing media. Under both conditions, the same binding capacity to homologous ZP was observed. Similar results were obtained when EGTA was added in order to chelate traces of Ca(2+) present in Sr(2+) medium. From these results, it can be concluded that Sr(2+) can replace Ca(2+) in supporting capacitation-related events and ZP binding, but not hFF-induced AR of human spermatozoa.

Acrosome Reaction↗

Strontium 89 therapy and relief of pain in patients with prostatic carcinoma metastatic to bone: a dose response relationship?

Reports published in the English literature of clinical trials utilizing intravenous strontium 89 (89Sr) in the treatment of patients with prostatic adenocarcinoma metastatic to bone were reviewed. Correlation coefficients were calculated for increasing dose of 89Sr and complete pain relief and complete and partial pain relief. Statistically significant positive correlations were obtained for complete relief of pain. Positive correlations were also found between those patients who had at least partial pain relief (defined as at least a 50% reduction in analgesia requirement), but these did not reach significance. This analysis suggests that a dose response relationship may exist between the dosage of 89Sr administered, and complete relief of pain due to skeletal metastases. The optimal dosage of 89Sr in this clinical situation has not been established, and prospective, carefully executed and analyzed randomized trials will be required to test whether and to what extent dose intensity of 89Sr determines outcome independently of other factors.

Adenocarcinoma↗

Strontium-89 (89Sr) analgesia for rare thymic carcinoid tumor with bony metastases.

The authors report the cases of two patients in whom strontium-89 (89Sr) was used to relieve diffuse metastatic bone pain. The type of cancer involved, thymic carcinoid tumor, is itself rare and the risk of its metastasizing to the bone is very low. Both patients showed a measure of response to treatment, suggesting that this analgesic method has value for some patients. The marked benefit of one patient for a total of 9 months was attributable to two 89Sr injections, whereas the other patient improved for only 5 weeks after one injection.

Adult↗

Bone marrow suppression after strontium-89 therapy and local radiation therapy in patients with diffuse marrow involvement.

Strontium-89 is routinely used for pain control in advanced skeletal metastatic disease. A common side effect of Sr-89 therapy is a mild to moderate bone marrow suppression. To avoid complications from marrow suppression, a pretreatment platelet count of > 60,000/mm3 and a WBC count of > 2,400/mm3 are suggested. The authors present two patients who, despite satisfying these criteria, developed profound and prolonged bone marrow suppression after therapy. The severity of this response was most likely caused by pre-existing extensive bone marrow replacement with tumor. The contribution of local radiation therapy to bone marrow suppression is presumed to be minimal. The authors recommend that pretreatment criteria for determination of eligibility for Sr-89 therapy in selected patients be expanded to include steadily decreasing blood counts, and evaluation of extent of marrow involvement by biopsy or MR imaging.

Bone Marrow↗

Reduction in the absorption and retention of strontium in rats.

Rats were fed a stock diet supplemented with calcium phosphate and sodium alginate, both separately and simultaneously, over a period of 4-5 months. Observations were made at intervals on the growth rate and on visual and histological abnormalities in some body tissues. No toxic effects were observed. The absorption and skeletal retention of calcium for rats on the combined supplements remained almost unchanged but the absorption and retention of strontium was reduced 7-fold.

Alginates↗

Dynamic modeling of the cesium, strontium and ruthenium transfer to grass and vegetables.

From 1988 to 1993, the Nuclear Safety and Protection Institute (Institut de Protection et de Sûreté Nucléaire--IPSN) conducted experimental programs focused on transfers to vegetation following accidental localized deposits of radioactive aerosols. In relation to vegetable crops (fruit, leaves, and root vegetables) and meadow grass these experiments have enabled a determination of the factors involved in the transfer of cesium, strontium, and ruthenium at successive harvests, or cuttings, in respect of various time lags after contamination. The dynamic modeling given by these results allows an evaluation of changes in the mass activity of vegetables and grass during the months following deposit. It constitutes part of the ASTRAL post-accident radioecology model.

Cesium Radioisotopes↗

Radiosensitization with low-dose carboplatin enhances pain palliation in radioisotope therapy with strontium-89.

Strontium-89 (89Sr) is currently used for the treatment of painful bone metastases. This study reports the use of low-dose carboplatin as a radiosensitizer in 89Sr radioisotope therapy. The study design comprised two groups: 15 patients treated with 89Sr (148 MBq) followed by carboplatin (100 mg m-2 at 7 and 21 days) and 15 patients treated with 89Sr alone. Their pain response was assessed 8 weeks post-injection. Follow-up was continued for up to 1 year in the survivors. Twenty-seven patients were evaluable. A pain response was observed in 20 of 27 (74%) patients. The pain response in the patients treated with 89Sr and carboplatin was clearly superior to that seen in the patients treated with 89Sr alone (P = 0.025), whereas survival was only marginally better in the combined treatment group (8.1 vs 5.7 months, P = 0.19). No clinically significant adverse effects or myelosuppression by carboplatin were observed. Low-dose carboplatin enhances the effects of 89Sr radioisotope therapy on pain from bone metastases.

Adult↗

Usefulness of strontium-89 for bone pain palliation in metastatic breast cancer patients.

Most studies of prostate cancer have shown that strontium-89 chloride (89Sr) is effective in the palliation of metastatic bone pain, refractory to conventional analgesia. The aim of this study was to evaluate the usefulness of 89Sr for bone pain palliation in breast cancer patients. Forty women were treated with 148 MBq of 89Sr. Six patients were retreated, receiving two or more doses. The Karnofsky performance status was assessed and pain and analgesia were scored on scales of 9 and 5 points, respectively. The efficacy of 89Sr was evaluated at 3 months of treatment. The response was good in 60% of the patients and partial in 32%; there was no response in the remaining 8% (pre-treatment Karnofsky < or = 60). The duration of the response was 120+/-143 days. In the patients retreated, the response was good in 83% and partial in 17%, without significant differences compared with the first dose, but the pre-treatment Karnofsky and the duration of the efficacy were lower (P < 0.05). A transient and slight decrease of leukocyte and platelet counts after the first month of treatment with 59Sr was observed. In conclusion, breast cancer patients with metastatic bone pain can benefit from therapy with 89Sr. If necessary, the treatment may be repeated safely and with the same efficacy as is achieved after the first dose. A low functional performance status could be a cause of the lower effectiveness of 89Sr.

Aged↗