Administration Of Strontium Research Articles

A retrospective cohort study of the effect of zolendronic acid on mandibular bone optical density in cancer patients

To analyze the density of the mandible in cancer patients during treatment with zoledronic acid. A retrospective cohort study included 45 patients with cancer aged 26-81 years (average age 55±12.88 years), of whom 14 patients had bone metastases (n=14) and took 4 mg of zolendronic acid once every 28 days. The patients underwent standard PET-CT examinations in the «whole body» mode, and the density of the mandible was examined on CT. Radiation therapy was performed by intracavitary administration of strontium 89 chloride; remote radiation therapy with cisplatin radiomodification. In the presence of bone metastases, patients received complex supportive therapy with zolendronic acid. The effect of zolendronic acid on the density of the mandible in the frontal and lateral sections was studied by multidimensional dispersion analysis. Statistically significant differences (p=0.002) were revealed for density indicators according to CT scans of the mandible in the frontal region against the background of zolendronic acid therapy. We attribute the absence of statistically significant differences for the density of the mandible in the lateral sections (p=0.101 and p=0.082) against the background of zolendronic acid therapy to a measurement bias. We attribute the absence of statistically significant differences in density indices against the background of hormonal, radiation, targeted and chemotherapy to the design of the study. Density measurement based on CT examination data can be recommended for use as an additional tool in assessing the effect of zolendronic acid on the density of the mandible. However, the method of measuring the density of the mandible in the lateral sections requires improvement to prevent measurement bias.

Systemic administration of strontium or NBD peptide ameliorates early stage cartilage degradation of mouse mandibular condyles

To determine whether mandibular condylar cartilage degradation induced by experimentally abnormal occlusion could be ameliorated via systemic administration of strontium or NBD peptide. Six-week-old female C57BL/6J mice were used. From the seventh day after mock operation or unilateral anterior crossbite (UAC) treatment, the control and UAC mice were further respectively pharmacologically treated for 2 weeks or 4 weeks of saline (CON + Saline and UAC + Saline groups), SrCl2 (CON + SrCl2 and UAC + SrCl2 groups) or NBD peptide (CON + NBD peptide and UAC + NBD peptide groups). Changes in condylar cartilage and subchondral bone were assessed 21 and 35 days after mock operation or UAC procedure by histology and micro-CT. Real-time PCR and/or immunohistochemistry (IHC) were performed to evaluate changes in expression levels of col2a1, aggrecan, ADAMTS-5, tnf-α, il-1β, nfkbia, nuclear factor-kappaB phospho-p65 in condylar cartilage, and rankl/rank/opg in both condylar cartilage and subchondral bone. Cartilage degradation with decreased col2a1 and aggrecan expression, and increased ADAMTS-5, tnf-α/il1-β, nfkbia and NF-κB phospho-p65 was observed in UAC + Saline groups. Subchondral bone loss with increased osteoclast numbers and decreased opg/rankl ratio was found in UAC + Saline groups compared to age-match CON + Saline groups. Cartilage degradation and subchondral bone loss were reversed by treatment of SrCl2 or NBD peptide while the same dosage in control mice induced few changes in condylar cartilage and subchondral bone. The results demonstrate reverse effect of systemic administration of strontium or NBD peptide on UAC-induced condylar cartilage degradation and subchondral bone loss.

A novel method for local administration of strontium from implant surfaces

This study proves that a film of Strontianite (SrCO(3)) successfully can be formed on a bioactive surface of sodium titanate when exposed to a strontium acetate solution. This Strontianite film is believed to enable local release of strontium ions from implant surfaces and thus stimulate bone formation in vivo. Depending on the method, different types of films were achieved with different release rates of strontium ions, and the results points at the possibility to tailor the rate and amount of strontium that is to be released from the surface. Strontium has earlier been shown to be highly involved in the formation of new bone as it stimulates the replication of osteoblasts and decreases the activity of osteoclasts. The benefit of strontium has for example been proved in studies where the number of vertebral compression fractures in osteoporotic persons was drastically reduced in patients receiving therapeutical doses of strontium. Therefore, it is here suggested that the bone healing process around an implant may be improved if strontium is administered locally at the site of the implant. The films described in this paper were produced by a simple immersion process where alkali treated titanium was exposed to an aqueous solution containing strontium acetate. By heating the samples at different times during the process, different release rates of strontium ions were achieved when the samples were exposed to simulated body fluid. The strontium containing films also promoted precipitation of bone like apatite when exposed to a simulated body fluid.

Is the calcium receptor a molecular target for the actions of strontium on bone?

The extracellular calcium-sensing receptor (CaR) plays key roles in maintaining extracellular calcium homeostasis by enabling several of the cells and tissues involved in this process to sense small changes in Ca(2+)(o) and to respond with changes in cellular function that will restore Ca(2+)(o) to its normal level. The chief cells of the parathyroid gland and the thyroidal C-cells, for example, respond to decreases in Ca(2+)(o) with increased secretion of the Ca(2+)(o)-elevating hormone, parathyroid hormone (PTH), and decreased secretion of the Ca(2+)(o)-lowering hormone, calcitonin, respectively. The cells of the renal distal tubule are likewise capable of sensing Ca(2+)(o) and respond to decreases in Ca(2+)(o) with increased tubular reabsorption of Ca(2+) and vice versa, alterations in tubular function that will contribute to normalization of Ca(2+)(o). The skeleton also plays key roles in maintaining Ca(2+)(o) homeostasis and both osteoblasts and osteoclasts can sense Ca(2+)(o), with elevations in Ca(2+)(o) promoting bone formation and inhibiting bone resorption. It has been suggested that Sr(2+) could act on bone via the CaR; however, the molecular mechanisms through which Ca(2+)(o) and Sr(2+)(o) exert these actions on bone cells remain controversial. Therefore, identifying their molecular target(s) would have significant implications for the treatment of bone loss. Ideally, therapies should simultaneously inhibit bone resorption while stimulating bone formation. Administration of strontium produces exactly those effects. Previous studies with dispersed bovine parathyroid cells as well as a preliminary study using CaR-transfected Chinese hamster ovary (CHO) cells indicate that Sr(2+)(o) is an agonist of the CaR, albeit with slightly lower efficacies and potencies than Ca(2+)(o). Given that Sr(2+)(o) is distributed preferentially in bone, therefore, an action of this divalent cation on the CaR in bone cells represents one possible mechanism by which strontium ranelate, a new antiosteoporotic drug, exerts it skeletal actions in vivo.

Incorporation and distribution of strontium in bone

The distribution and incorporation of strontium into bone has been examined in rats, monkeys, and humans after oral administration of strontium (either strontium chloride or strontium ranelate). After repeated administration for a sufficient period of time (at least 4 weeks in rats), strontium incorporation into bone reaches a plateau level. This plateau appears to be lower in females than in males due to a difference in the absorption process. Steady-state plasma strontium levels are reached more rapidly than in bones, and within 10 days in the rat. The strontium levels in bone vary according to the anatomical site. However, strontium levels at different skeletal sites are strongly correlated, and the strontium content of the lumbar vertebra may be estimated from iliac crest bone biopsies in monkeys. The strontium levels in bone also vary according to the bone structure and higher amounts of strontium are found in cancellous bone than in cortical bone. Furthermore, at the crystal level, higher concentrations of strontium are observed in newly formed bone than in old bone. After withdrawal of treatment, the bone strontium content rapidly decreases in monkeys. The relatively high clearance rate of strontium from bone can be explained by the mechanisms of its incorporation. Strontium is mainly incorporated by exchange onto the crystal surface. In new bone, only a few strontium atoms may be incorporated into the crystal by ionic substitution of calcium. After treatment withdrawal, strontium exchanged onto the crystal is rapidly eliminated, which leads to a rapid decrease in total bone strontium levels. In summary, incorporation of strontium into bone, mainly by exchange onto the crystal surface, is dependent on the duration of treatment, dose, gender, and skeletal site. Nevertheless, bone strontium content is highly correlated with plasma strontium levels and, in bone, between the different skeletal sites.

Removal of strontium by the chelating agent acetylamino propylidene diphosphonic acid in rats.

Studies of the effects of the chelating agent, calcium acetylamino propylidene diphosphonic acid (Ca-APDA), on the removal of radioactive strontium with two administration modalities were carried out in rats. The parenteral (intraperitoneal) administration of 150, 300, or 600 mg kg(-1) Ca-APDA was carried out for 3 d, 10 min after exposure of the animals to the strontium injection. On the first day post-treatment, the retention of strontium in the whole body decreased to 90.1%, 83.9%, and 35.1% that of the control level, respectively. The strontium deposited in femur of 600 mg kg(-1) Ca-APDA group was lowered to 28.4% of the control value. A single oral dose of 600 mg kg(-1) Ca-APDA administered simultaneously with, or 10 min after, oral administration of strontium, radionuclide retention in the whole body was reduced after 1 d to 42.9% and 31.9% of the control, respectively; meanwhile the strontium deposited in the femur was reduced to 16.9% and 29.3% of the control. In conclusion, the results indicate the efficacy of the new agent, Ca-APDA, to remove radioactive strontium from the body, or to inhibit the strontium intestinal absorption, in radio-strontium contaminated individuals.

Radiotherapy for palliation of symptoms in incurable cancer

Approximately one half of prescribed radiotherapy is given for palliation of symptoms due to incurable cancer. Distressing symptoms including pain, bleeding, and obstruction can often be relieved with minimal toxic effects. Painful osseous metastasis is common in oncologic practice. Ninety percent of patients with symptomatic bone metastases obtain some pain relief with a lowdose, brief course of palliative radiotherapy. One half of the responding patients may experience complete pain relief. A single dose of 800 cGy in the setting of painful bone metastasis may provide pain control comparable to more protracted treatment at a higher dose of radiation. Patients with lytic disease in weight-bearing bones, particularly in the presence of cortical destruction, should be considered for prophylactic surgical stabilization of their condition. Routinely a brief, fractionated course of radiotherapy is given postoperatively. Pain due to multiple bone metastases uncontrolled by analgesics can be managed with single doses of halfbody irradiation. Doses of 600 cGy delivered to the upper half-body (above the umbilicus) and 800 cGy to the lower half-body (from the umbilicus to the middle of the femur) will provide some pain relief in 73% of patients. Half-body techniques have been investigated as prophylactic treatment, as a complement to local-field irradiation, and as fractionated rather than singledose therapy. Although intravenous administration of strontium 89 has been associated with myelosuppression, this treatment has been shown (a) to relieve pain due to bone metastasis and (b) to delay development of new painful sites. Recent data from phase III trials demonstrated that bisphosphonates have a role in reducing skeletal morbidity due to bone metastasis. Bone pain was reduced, and the incidence of pathologic fracture and the need for future radiotherapy was decreased. Radiotherapy relieves clinical symptoms in 70% to 90% of patients with brain metastases. Brief treatment schedules (e.g., 2000 cGy in five fractions over 1 week) are as effective as more prolonged therapy. Patients with solitary brain metastasis and no extracranial disease or controlled extracranial disease should be considered for surgical resection, because phase III data indicate enhanced survival with such an approach. Whole-brain radiotherapy is routinely administered postoperatively. A phase III study is examining the impact of accelerated fractionated doses of radiotherapy (two treatments per day) on survival of patients with brain metastases. Stereotaxic radiosurgical treatment is becoming increasingly available and permits delivery of radiation to metastatic intracranial tumor with minimal exposure of normal surrounding brain This treatment is most commonly used at the time of a solitary recurrence of disease in patients who previously received whole-brain radiotherapy. A role for this modality in newly diagnosed brain metastases remains to be defined. Chest symptoms are common in patients with locally advanced lung cancer and are effectively palliated with one 1000 cGy or two 850 cGy one fraction doses of radiation to the thoracic inlet and mediastinum. Chest pain and hemoptysis are more effectively palliated than cough and dyspnea. In patients with stage III cancer there is no compelling evidence that radiotherapy confers a survival advantage, and it may be reasonable to administer thoracic radiotherapy only when the patient has significant symptoms and the goal is to achieve control of these symptoms. Approximately 75% of the cases of superior vena cava syndrome are due to lung cancer, and small-cell lung cancer is the most common histologic type. A histologic diagnosis should be obtained before treatment is started, because detection of lymphoma or small-cell carcinoma would necessitate systemic therapy. Eighty percent of the patients with vena cava syndrome due to malignant disease achieve symptom relief with a brief, fractionated, palliative course of rad

Miscellaneous and experimental agents.

Current therapeutic approaches to postmenopausal bone loss or established osteoporosis vary widely among the different regions of the world. Because no treatment of osteoporosis has unequivocally demonstrated full prevention of the appearance or the recurrence of axial or peripheral fractures so far, many investigational compounds are being developed. Anabolic steroids act mainly as inhibitors of bone resorption with very few, if any, effects on bone formation. Because of the high occurrence of signs of virilization and the weak effects on bone structure, the risk/benefit ratio in osteoporosis should be considered at least problematic. If ongoing large-scale trials confirm the expected benefits of estrogen antagonist/agonists on the skeleton and confirm no cardiovascular risk to postmenopausal women with optimal uterine safety, these substances are likely to become the most prominent alternative to hormonal replacement therapy after the menopause. Additional studies are requested to evaluate the potential benefit of growth hormone or insulin-like growth factors in treatment of osteoporosis. Ipriflavone acts predominantly as an inhibitor of bone resorption. To confirm the efficacy of ipriflavone on the prevention of vertebral fractures and its effects on bone mineral density in women with postmenopausal established osteoporosis, a large multicentric European study is being conducted. Treatment with parathyroid peptides induces a significant gain in bone mass, mainly in the axial skeleton. Long-term studies that compare peptides, doses, and regimes are needed to better understand the exact position of parathyroid peptides as treatment of osteoporosis. Prolonged administration of strontium to postmenopausal osteoporotic women resulted in a decoupling between bone resorption and formation that yielded a significant increase in the lumbar spine bone mineral density of treated subjects. In the view of these promising results and of the excellent tolerance of strontium during preliminary trials, additional investigations of this compound in prevention and treatment of osteoporosis should be promptly initiated. Several other compounds have been punctually suggested for treatment of osteoporosis or are at very early stages of development. Finally, besides pharmacologic approaches to the treatment of osteoporosis, hip fractures may also be reduced by the use of hip protectors.

Miscellaneous and Experimental Agents

AbstractCurrent therapeutic approaches to postmenopausal bone loss or established osteoporosis vary widely among the different regions of the world. Because no treatment of osteoporosis has unequivocally demonstrated full prevention of the appearance or the recurrence of axial or peripheral fractures so far, many investigational compounds are being developed. Anabolic steroids act mainly as inhibitors of bone resorption with very few, if any, effects on bone formation. Because of the high occurrence of signs of virilization and the weak effects on bone structure, the risklbenefit ratio in osteoporosis should be considered at least problematic. If ongoing large-scale trials confirm the expected benefits of estrogen antagonist/ agonists on the skeleton and confirm no cardiovascular risk to postmenopausal women with optimal uterine safety, these substances are likely to become the most prominent alternative to hormonal replacement therapy after the menopause. Additional studies are requested to evaluate the potential benefit of growth hormone or insulin-like growth factors in treatment of osteoporosis. Ipriflavone acts predominantly as an inhibitor of bone resorption. To confirm the efficacy of ipriflavone on the prevention of vertebral fractures and its effects on bone mineral density in women with postmenopausal established osteoporosis, a large multicentric European study is being conducted. Treatment with parathyroid peptides induces a significant gain in bone mass, mainly in the axial skeleton. Long-term studies that compare peptides, doses, and regimes are needed to better understand the exact position of parathyroid peptides as treatment of osteoporosis. Prolonged administration of strontium to postmenopausal osteoporotic women resulted in a decoupling between bone resorption and forma-tion that yielded a significant increase in the lumbar spine bone mineral density of treated subjects. In the view of these promising results and of the excellent tolerance of strontium during preliminary trials, additional investigations of this compound in prevention and treatment of osteoporosis should be promptly initiated. Several other compounds have been punctually suggested for treatment of osteoporosis or are at very early stages of development. Finally, besides pharmacologic approaches to the treatment of osteoporosis, hip fractures may also be reduced by the use of hip protectors.

Intestinal strontium absorption: from bioavailability to validation of a simple test representative for intestinal calcium absorption

Calcium absorption tests have rarely been validated for being representative for absolute bioavailability (true absorption) or for intraindividual variation. Therefore, we investigated the reproducibility of the absolute bioavailability of strontium chloride, a marker for intestinal calcium absorption, in healthy male volunteers (n = 8) by measuring the area under the plasma strontium concentration-time curve after oral and intravenous administration of strontium. Subsequently, we selected a simple test variable as being representative of absolute bioavailability. The mean absolute bioavailability (+/- SD) was 25% +/- 7%. The best test variable appeared to be the fractional absorption at 240 min (Fc240) after oral intake, which demonstrated the highest correlation with absolute bioavailability (r = 0.66). The intraindividual variations of the data for this variable and for the absolute bioavailability are similar to those described for various absorption tests based on the use of calcium isotopes. Thus, the Fc240 of strontium offers the potential of a simple clinical test for use as a measure of intestinal calcium absorption and its modulation.

Route-Dependent and Non-Synergistic Induction of Hepatic Metallothionein after Administration of Strontium and Calcium to Mice.

To investigate the induction of hepatic metallothionein (MT) after administration of strontium (Sr) and calcium (Ca), male mice of the ICR strain were injected subcutaneously with Sr and/or Ca at a dose of 2 mmol/kg body weight, respectively. Both metals induced hepatic MT, though Ca was twice as effective as Sr when observed at 24 h. When Sr and Ca were co-administered, hepatic MT induction was essentially additive and hence no synergism was observed in the induction. When intraperitoneal (i.p.) and subcutaneous (s.c.) injections were compared, the induction by s.c. injection was higher in spite of the lower hepatic concentration of Sr at 24 h. When hepatic Sr concentration was also followed during an initial period, the i.p. injection always showed a higher level than the s.c. injection. Our results showed that the higher level of MT induction observed with s.c. injection of Sr relative to i.p. injection is not due to the higher Sr level.

The parathyroid gland in metal rickets. A stereological study.

Rickets can be induced by oral administration of metals. A depressive effect exerted by metal ions on the parathyroid gland has previously been suggested to be a pathogenetic factor in strontium-induced rickets. In the present investigation, rickets was induced in young rats by oral administration of strontium and manganese, respectively. The parathyroids were fixed by perfusion and the total volume of the parathyroid glands was determined by serial sectioning. Conventional stereological techniques were applied on the ultrastructural level and the densities obtained could be related to the total mass of parathyroid tissue. In both rachitic groups the volume of the parathyroid glands as well as the absolute amounts of all cellular components studied, were reduced. All these changes were, however, correlated to the decreased body weight of the experimental animals. This is well in line with the finding of unaltered serum concentrations of calcium and immunoreactive parathyroid hormone. Therefore, it is concluded that the parathyroids do not play an important role in the pathogenesis of metal rickets.

The in situ measurement of strontium content in bone using X-ray fluorescence analysis

A technique is described which uses X-ray fluorescence to determine in situ the strontium content of bone. Measurements were made of the skulls of seven rabbits both before and after a single bolus injection of strontium was administered intravenously. The retention of strontium was followed for up to eight months and could be represented either by a three-exponential model or, for data obtained between 12 and 252 d following injection, the power function At-b, where t is the time in days following injection. The three-exponential terms had linear coefficients of similar magnitude and half lives of 3-4 h, 10-40 d and 200-300 d. The exponent of the power function was 0.25-0.57. Measurements were also made of the skull and medial surface of the tibial crest of an adult dog for four months following subcutaneous administration of strontium. The results obtained using X-ray fluorescence are found to be similar to those reported by others for radiostrontium studies. The precision and errors associated with the fluorescence technique are discussed. Estimates of radiation dose are given. It is concluded that the technique may serve to determine in situ the strontium content of bone near the surface of the body.

Kidney mitochondrial metabolism of 25-hydroxyvitamin D 3, : Evaluation of in vitro cation modulation

Oxidative phosphorylation and 1 α,25-dihydroxyvitamin D 3 [lα,25-(OH) 2D 3]synthesis in isolated mitochondria were decreased by the addition of strontium. Calcium effected a similar inhibition of 1α,25-(OH) 2D 3 synthesis which correlated with cation-induced mitochondrial swelling. The ultrastructural changes were found to be a consequence of experimental conditions and not a prerequisite for suppressed 1α,25-(OH) 2D 3 synthesis. Dietary administration of strontium or calcium also resulted in a decreased rate of 1α,25-(OH) 2D 3 synthesis; however, the decrease in 1-hydroxylase activity was accompanied by an induction of mitochondrial 25-hydroxyvitamin D 3 24-hydroxylase activity. Such an in vivo-prompted mitochondrial response occurred in the absenee of morphological changes or extensive loss of oxidative phosphorylation activity. In contrast, no induction of 24-hydroxylase activity could be observed in acute studies using isolated mitochondria. Therefore, the in vitro action of calcium and strontium does not appear to reflect the in vivo mechanism whereby the cations act to change renal 25-hydroxyvitamin D 3 (25-OHD 3) hydroxylation. Results from in vitro studies corcerning the action of calcium to alter renal 25-OHD 3 metabolism should be interpreted in light of the cation's capacity to decrease oxidative phosphorylation and the subsequent intramitochondrial generation of NADPH.