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Biomedical subjects

M A Hansen

Publications and source records attributed to M A Hansen.

At least 37 records · Page 2Linked to original sources

Ligand recognition sites on P2X receptors studied by quantitative autoradiography of [3H]alpha,beta-methylene-ATP binding in rat brain.

The specificity of alpha, beta-methylene-ATP for P2X receptor binding sites in the CNS has been examined by testing the effects of several ATP analogues and other ATP-related substances on the binding of 10 nM [3H]alpha,beta-methylene-ATP to 20 microns thick sections of fresh-frozen rat brain. The labelling of the putative P2X receptor binding sites by [3H]alpha,beta-methylene-ATP was evaluated by quantitative densitometry. [3H]alpha,beta-methylene-ATP binding was strongly inhibited by two close ATP analogues, 3'-O-(trinitrophenyl)-adenosine-5'-triphosphate and beta,gamma-imido-ATP (IC50 2.5 microM). beta,gamma-Methylene-ATP was, however, less potent (< 50% inhibition at 25 microM). Inosine-5'-triphosphate, guanosine-5'-triphosphate, uridine-5'-triphosphate, and cytidine-5'-triphosphate were practically inactive up to concentrations of 100 microM. Periodate oxidised ATP and 1, N6-etheno-ATP produced < 50% inhibition at 100 and 500 microM concentrations, respectively. Cations (K+, Rb+, Cs+, and Mg2+ at 5 mM and Na+ at 150 mM) reduced [3H]alpha,beta-methylene-ATP binding by no more than 50%. Several agents known to interact with Ca2+- and/or ATP-related cationic channels (Cd2+, glibenclamide, dantrolene, nifedipine, and thapsigargin) had no effect. We conclude that [3H]alpha,beta-methylene-ATP at low nanomolar concentrations binds to a site that has very strict structural requirements and is pharmacologically similar to ATP P2X receptors.

Adenosine Triphosphate↗

Alterations in the expression of P2X1 receptors in failing and nondiseased human atria.

This is the first report of the analysis of the ATP-specific P2X1 receptor subunit in human hearts. We have examined homogenate samples of human left atria for the presence of P2X1 receptors using Western blots. Anti-P2X1 immunoreactivity was detected in populations of nondiseased atria as well as in atria from explanted hearts from patients with terminally failing heart conditions such as dilated cardiomyopathy. At least three groups of P2X1 immunoreactive proteins were detected in the Western blots with approximate molecular mass values of 50, 70, and 160 kDa. We report changes in expression of their 50 and 70 kDa components. These changes may be related to the type of deficit in these hearts since the changes have been observed in hearts with decreased ejection fractions characteristic of dilated cardiomyopathy.

Animals↗

The distribution of single P2x1-receptor clusters on smooth muscle cells in relation to nerve varicosities in the rat urinary bladder.

The distribution of purinergic (P2x1) receptors on smooth muscle cells in relation to autonomic nerve varicosities in the rat urinary bladder has been determined using immunofluorescence and confocal microscopy. P2x1 receptors were visualized using rabbit polyclonal antibodies against the extracellular domain of the P2x1 receptor, and varicosities were visualized using a mouse monoclonal antibody against the ubiquitous synaptic vesicle proteoglycan SV2. Two size classes of P2x1 receptor clusters were observed on the smooth muscle cells of the detrusor, namely, a large ellipse of mean long axis 1.23+/-0.21 microm and short axis 0.92+/-0.17 microm and a smaller spherical cluster with a mean diameter of 0.40+/-0.04 microm. The latter occured in much greater numbers than the former in selected areas, with a density as high as 0.8 per microm2 or two orders of magnitude more than the larger-sized clusters. The large clusters are in general located beneath varicosities, with only 4.5% of P2x1 clusters not possessing an overlying varicosity. None of the small clusters was associated with varicosities. Three-dimensional reconstruction of the P2x1 and SV2 labelling at individual varicosities showed that the varicosities were immediately apposed to the P2x1 receptor clusters. On occasions, two or more small SV2-labelled varicosities about 0.7 microm in diameter each with a receptor patch were found juxtaposed to each other; these might represent the splitting up of a single large varicosity. These observations are discussed in relation to the identity of the autonomic neuromuscular junction.

Animals↗

Youth risk behavior survey: the Alaskan perspective.

The Youth Risk Behavior Survey (YRBS) is a national school-based survey used to monitor health risk behaviors that contribute to the leading causes of mortality, morbidity, and social problems among youth and adults in the United States. Both high school and middle school surveys were administered to a representative group of Alaska high school and middle school students for the first time in 1995. Surveys were administered in a confidential and anonymous manner, taking care to assure student privacy. A total of 1,634 high school students and 1,265 middle school students completed surveys. The survey revealed that, for the most part, Alaska students are similar to U.S. students. Among high school students, 23.2% of boys and 15.4% of girls seldom or never used seat belts; 36.4% of boys and 36.5% of girls had smoked cigarettes in the previous 30 days; 23.5% of boys and 6.7% of girls had used smokeless tobacco in the previous 30 days; 48.7% of boys and 48.0% of girls reported having had sexual intercourse at least once; 23.7% of boys and 59.5% of girls were trying to lose weight; and 77.9% of boys and 65.6% of girls had exercised vigorously on three of the previous seven days. The middle school survey was somewhat different than the high school survey, so that results are not directly comparable. Nonetheless, the data indicate that high-risk behaviors, such as tobacco use, drug use, and early sexual intercourse, do occur at the middle school level. The survey also showed that Alaska teens have desirable health behaviors as well, such as frequent exercise and eating fruits and vegetables. The 1995 Alaska YRBS was the first time that representative data on Alaska students were collected on a statewide basis. The YRBS provides Alaska with baseline data that can be compared to national data.

Adolescent↗

P2 purinoceptor blocker suramin antagonises NMDA receptors and protects against excitatory behaviour caused by NMDA receptor agonist (RS)-(tetrazol-5-yl)-glycine in rats.

It has been reported that suramin, an anthelminthic, trypanocidal agent and an inhibitor of P2 receptors, may antagonise N-methyl-D-aspartate (NMDA) subtype of the excitatory amino acid receptors. Both NMDA receptors and P2X subclass of P2 receptors are ligand-gated Ca2+-selective channels and, since the increased influx of Ca2+ into neurons has been linked to neurotoxicity, simultaneous inhibition of P2X and NMDA receptors in vivo by suramin could represent an effective neuroprotective treatment. We have found that suramin inhibited the binding of [3H]CGP 39653 to NMDA receptor binding sites in vitro and reduced the frequency of NMDA channel openings in patch-clamp studies. Suramin (1 mM) had no effect on [3H]kainate binding in vitro. In vivo, intracerebroventricular (I.C.V.) injections of suramin (70 nmol/brain) antagonised convulsive effects of the NMDA agonist (RS)-(tetrazol-5-yl)-glycine (TZG, LY 285265). Suramin, however, did not prevent neurotoxic lesions in the hippocampus caused by I.C.V. administration of TZG. Increasing the dose of suramin resulted in death from severe respiratory depression.

Animals↗

Structural motif and characteristics of the extracellular domain of P2X receptors.

Seven sequences of the proteins recently cloned from rat tissues and identified as P2X receptors are examined. Their putative transmembrane and extracellular domains and the most probable locations of disulphide bridges are discussed. Some surface accessible regions are identified and the structure of the putative ATP binding domain is discussed in the light of known selectivities and physiological characteristics of individual P2X subunits. The summarised information and the theoretical considerations regarding the protein structure of P2X receptors have been used to select amino acid sequences for raising antibodies against the P2X1 receptor subunit. Initial results suggest that, in rat brainstem, P2X1 receptor subunits are found on a distinct subpopulation of neuronal perikarya in distributions consistent with distributions of known alpha,beta-methylene-ATP autoradiography and physiological effects of purinoceptor activation.

Adenosine Triphosphate↗

Autoradiography of [3H]alpha,beta-methylene-ATP binding sites in medulla oblongata and spinal cord of the rat.

Excitatory purinoceptors of P2x-type have long been known to exist on smooth muscle cells, but recently it has been shown that they are also involved in synaptic transmission in the CNS. We have used a P2x-specific agonist, alpha,beta-methylene-ATP, as a 3H-labelled radioligand, to study the distribution and characteristics of P2x receptor-binding sites in the spinal cord and medulla oblongata. Using auto-radiographic techniques, [3H]alpha,beta-methylene-ATP binding was found throughout the grey matter of the spinal cord with small areas of above-average density of binding sites in the marginal zone and substantia gelatinosa at all spinal levels and in the central grey matter of the thoracic spinal cord. In the medulla, [3H]alpha,beta-methylene-ATP binding was found to be strong in all cranial nerve nuclei, particularly those known to receive primary sensory fibres. We have found that the binding of [3H]alpha,beta-methylene-ATP in the spinal cord and medulla was inhibited by a broad-spectrum P2-receptor antagonist suramin (IC50 approximately 27 microM). This is in accordance with the data obtained previously in the forebrain and cerebellum. There was, however, no inhibition of [3H]alpha,beta-methylene-ATP binding by another close analogue of alpha,beta-methylene-ATP and P2x ligand beta,gamma-methylene-ATP (10 microM). The latter result is discussed in terms of possible involvement of Ca2+ in the binding of [3H]alpha,beta-methylene-ATP to P2x receptors in the CNS.

Adenosine Triphosphate↗

The impact of degenerative conditions in the spine on bone mineral density and fracture risk prediction.

We examined the impact of degenerative conditions in the spine (osteophytosis and endplate sclerosis) and aortic calcification in the lumbar region on bone mineral content/density (BMC/BMD) measured in the spine and forearm by absorptiometry and on fracture risk prediction. The radiographs of 387 healthy postmenopausal women, aged 68-72 years, were assessed in masked fashion for the presence of osteophytosis, endplate sclerosis and aortic calcification in the region from L2 to L4. Vertebral deformities/fractures were assessed by different definitions. Osteophytes larger than 3 mm and in numbers of 3 or more resulted in a significantly (12%) higher spinal bone mass (p < 0.001). Endplate sclerosis had a similar effect (p < 0.001). In subjects with both degenerative conditions the BMC/BMD in the spine and forearm were significantly higher than in unaffected women (19% in the spine, 10% in the forearm; p < 0.001). The spinal BMD values were significantly lower in fractured women if both degenerative conditions were absent (p < 0.001), whereas fractured and unfractured women had similar values if degenerative conditions were present. Degenerative conditions did not alter the ability of forearm BMC to discriminate vertebral or peripheral fractures. Receiver operating characteristic (ROC) curves (true positive fraction versus false positive fraction) were generated for BMD of the lumbar spine and BMC of the forearm with regard to the discrimination between women with vertebral and peripheral fractures and healthy premenopausal women. The ROC curves for women without degenerative conditions were consistently above the curves for women affected by osteophytosis and endplate sclerosis in the lumbar spine (p < 0.001). In conclusion, osteophytes and endplate sclerosis have a considerable influence on spinal bone mass measurements in elderly postmenopausal women and affect the diagnostic ability of spinal scans to discriminate osteoporotic women. Our data suggest that in elderly women, unless the spine is radiologically clear of degenerative conditions, a peripheral measurement procedure should be considered an alternative for assessment of bone mineral content/density.

Aged↗

Low bone mass and fast rate of bone loss at menopause: equal risk factors for future fracture: a 15-year follow-up study.

The aim of the study was to examine the role of peak bone mass and rate of postmenopausal bone loss for the subsequent risk of osteoporotic fracture. 182 women within 3 years of menopause were followed longitudinally for 15 years. Over the first 2 years, forearm bone mass (single photon absorptiometry) was measured nine times, the rate of bone loss was calculated, and the women were stratified into a group of "fast bone losers" (n = 49) and a group of "normal bone losers" (n = 133). Later, bone mass was also measured in the lumbar spine and hip with dual energy X-ray absorptiometry. At 15 years, the fast losers had significantly lower body weight (4.4 kG; p < 0.05) than the normal losers. Furthermore, the fast losers had significantly increased values of bone turnover (osteocalcin and C-terminal type I collagen breakdown products). In both the forearm, spine, and hip, the fast bone losers had at all sites significantly less bone mass than the normal bone losers (p < 0.001). 23 women had experienced a peripheral (Colles') fracture and 25 a spinal fracture. The fracture groups had generally significantly (p < 0.05) less bone mass than the group without fracture, both in the forearm, spine, and hip and they also had the highest rate of bone loss after menopause (p < 0.05). Baseline bone mass and rate of loss predisposed to the same extent to fractures with ODD's ratios of about 2. If both low bone mass and rate of loss were present, the ODD's ratio increased to about 3. We conclude that fast rate of bone loss and low bone mass are equally important for the risk of fracture. The identification of women at risk of osteoporosis should therefore consider both a measurement of bone mass status, and a determination of the postmenopausal rate of loss.

Bone Density↗

Spontaneous postmenopausal bone loss in different skeletal areas--followed up for 15 years.

We examined the spontaneous bone loss in two populations of healthy postmenopausal women, who were followed for 9.5 and 14.5 years without any treatment influencing the calcium metabolism. The bone mass was measured in different skeletal areas: the distal forearm, the lumbar spine, the proximal femur, and the total skeleton. The spontaneous bone loss in the distal forearm, the lumbar spine, and the total skeleton was fitted to an exponential model as a function of years since menopause. The overall bone loss averaged 20-25% of premenopausal bone mass 16 years after menopause. The patterns of bone loss were, however, different for the axial and the peripheral skeleton. Thus, the bone loss in the distal forearm approached a more linear model with a more consistent bone loss throughout the observation period. In contrast, the lumbar spine showed no significant loss 8 years after menopause. This arrest in bone loss could not be explained by the presence of degenerative changes in the lumbar spine and/or aortic calcifications, although these changes significantly contributed to 14% increased bone mineral density (p < 0.001). We conclude that bone loss averages 20-25% over the initial 16 years of menopause regardless of skeletal site and that patterns of bone loss are different in the axial and peripheral skeleton.

Absorptiometry, Photon↗

Estimation of the effect of salmon calcitonin in established osteoporosis by biochemical bone markers.

We reviewed data on 42 postmenopausal women with established osteoporosis (forearm fracture or a low bone mass) who had been randomly treated for 1 year with either rectal salmon calcitonin (sCT), 100 IU daily (n = 25) or nasal sCT, 200 IU daily (n = 17) applying an estimation algorithm for bone loss rates. Both groups received a daily calcium supplement of 500 mg. A group of 18 age-matched women who received no treatment served as controls. The bone mineral content of the distal forearm (BMCarm) was measured every 3 months by single photon absorptiometry. The individual rates of change during the 1-year period were calculated by linear regression analysis (alpha BMCarm). Bone loss rates were estimated initially and after 1 year of therapy by measurements of serum alkaline phosphatase, plasma bone Gla protein, and fasting urinary hydroxyproline and calcium (both corrected for creatinine excretion) according to the estimation algorithm. Both administration forms revealed significant control group-corrected decreases in serum and urine markers of bone turnover of 15-40% (P < 0.05-0.01) and positive outcomes of 2% in alpha BMCarm (P < 0.01). The estimated effect on bone mass was expressed as the difference between the bone loss estimated after 1 year and initially (delta ESTBIO). A significant correlation was seen between alpha BMCarm and delta ESTBIO (r = 0.5, P < 0.0001). We conclude that the effect of sCT on bone can be followed up by biochemical markers for bone turnover, i.e., by an annual blood and fasting urine sample, applying an estimation algorithm for the rate of bone loss.

Absorptiometry, Photon↗

Assessment of age and risk factors on bone density and bone turnover in healthy premenopausal women.

The influence of age and risk factors on bone density and bone turnover was evaluated in 249 healthy premenopausal women. Risk factors were assessed by standardized questionnaires and included reproductive history and lifestyle factors (intake of calcium and vitamin D supplements, consumption of caffeine, smoking habits and physical activity). Bone mineral density (BMD) measurements were obtained in the distal forearm, the lumbar spine and the proximal femur. Bone turnover were assessed by plasma bone Gla proteins (pBGP) and fasting urinary hydroxyproline corrected for creatinine (fUHPr/Cr). Peak bone density seems to be achieved before the age of 30 years, whereafter we found no appreciable bone loss at any skeletal site. Accordingly, the levels of pBGP and fUHPr/Cr were increased before the age of 30, whereafter the values stabilized at a lower level. A dairy calcium intake above 660 mg/day significantly increased BMD in the spine and proximal femur by 3%-5%. Physical activity alone had no influence on BMD, but in combination with calcium intake an additive effect was observed. Women who had an active lifestyle (corresponding to at least 1 h of daily walking) and a dairy calcium intake above 660 mg/day had a 3%-7% increase in BMD compared with more sedentary women with a calcium intake below this limit. Vitamin D supplements, caffeine, smoking and reproductive history did not consistently influence BMD or bone turnover. Only pBGP was selectively reduced by smoking and current use of oral contraceptives, respectively. We conclude that there is no appreciable change in BMD before the menopause once skeletal maturity has been reached.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorptiometry, Photon↗

[Salmon calcitonin in osteoporosis. The effect of intranasal application on bone mineral content and fracture frequency in postmenopausal women with manifest osteoporotic changes].

The objective was to study the dose-related response of intranasal salmon calcitonin (Salcatonin) on bone mass and bone turnover and the effect of salcatonin on rates of fracture in elderly women with moderate osteoporosis. A total of 208 healthy women aged 68-72 years, who had a bone mineral content (BMC) of the distal forearm 30% below the mean value for healthy premenopausal women, were examined in a double-blind, placebo-controlled, randomized group comparison study. They were randomized to a two-year daily treatment of either 50 IU, 100 IU, 200 IU Salcatonin or placebo. All received 500 mg calcium daily. In the calcium-(placebo)-treated group the BMC of the spine increased 1%, whereas an increase of 3% was seen in the 200 IU Salcatonin treated group. There was a dose-related response to Salcatonin manifested by an increase in BMC of 1.0%/100 IU. The incidence of new fractures was significantly lower in the women treated with Salcatonin (about one third of that in the non-Salcatonin treated women). In conclusion the results suggest that, compared with calcium alone, Salcatonin given intranasally reduces the rate of fracture by two thirds in elderly women with moderate osteoporosis. Furthermore, it increases spinal bone mass in a dose dependent manner.

Administration, Intranasal↗

[No increase in the prevalence of vertebral fractures among postmenopausal women over a 10-year period].

We examined whether the prevalence of vertebral fracture in otherwise healthy, 70-year-old Danish women had increased over a period of ten years. The population-based, epidemiological study included two age-matched, representative samples of postmenopausal women. Group 1 (1979) consisted of 173 healthy women without secondary causes of osteoporosis, Group 2 (1989) of 387 women. X-rays of the thoraco-lumbar spine were assessed for vertebral fracture by five radiological methods. There was no significant difference between the two groups in the prevalence of vertebral fracture and the 95% confidence intervals overlapped completely in all methods. The prevalence rates varied by method from 35% to 80% but the distribution of fracture types was similar in the two groups. We conclude that the prevalence of vertebral fractures due to postmenopausal osteoporosis has not increased since 1979 in suburban Copenhagen, and that comparison of prevalences requires the same method of radiological assessment.

Aged↗

Effect of salcatonin given intranasally on bone mass and fracture rates in established osteoporosis: a dose-response study.

OBJECTIVE: To study the dose related response of salmon calcitonin (salcatonin) given intranasally on bone mass and bone turnover and the effect of salcatonin on rates of fracture in elderly women with moderate osteoporosis. DESIGN: Double blind, placebo controlled, randomised group comparison. SETTING: Outpatient clinic for research into osteoporosis. SUBJECTS: 208 healthy women aged 68-72 years who had a bone mineral content of the distal forearm on average 30% below the mean value for healthy premenopausal women. INTERVENTIONS: The 208 women were allocated randomly in blocks of four to two years of treatment with either salcatonin 50 IU, 100 IU, or 200 IU given intranasally or placebo. All groups received a calcium supplement of 500 mg. 32 of the women left the study before its end and 164 women complied with the study criteria throughout. MAIN OUTCOME MEASURES: Bone mineral content of the distal forearm and lumbar spine and rates of vertebral and peripheral fractures after two years of treatment. RESULTS: The average changes in bone mineral content of the spine showed positive outcomes of 1% (95% confidence interval -0.1% to 1.5%) in the group treated with calcium (placebo) and 3% (1.8% to 4.2%) in the group treated with salcatonin 200 IU. There was a significant dose related response to salcatonin, manifested by an increase of 1.0%/100 IU (0.2% to 1.7%, p = 0.008). The rate of patients with new fractures was reduced significantly in the women treated with salcatonin to about one third of that in the non-salcatonin treated women (relative risk 0.23 (0.07 to 0.77)). CONCLUSION: The results suggest that, compared with calcium alone, salcatonin given intranasally reduces the rates of fracture by two thirds in elderly women with moderate osteoporosis. Furthermore, it increases spinal bone mass in a dose dependent manner.

Administration, Intranasal↗

Is heritability a risk factor for postmenopausal osteoporosis?

We investigated heritability as a risk factor for the development of osteoporosis in two randomly selected populations of postmenopausal women and their premenopausal daughters. We determined the familial resemblance in bone mass at three sites; the distal forearm, lumbar spine, and proximal femur, premenopausally and with increasing maternal postmenopausal age. We also examined the bone mass of daughters in relation to mothers with and without osteoporotic fractures. Peak bone mass among premenopausal siblings was significantly correlated at all sites (r = 0.30-0.42, p less than 0.001). The same levels of resemblance were found between early postmenopausal mothers and premenopausal daughters. There was no significant difference in bone mass at any skeletal site between daughters of women with either peripheral or spinal fractures and daughters of women without fractures. We also examined familial resemblance with four biochemical markers of bone turnover (fasting urinary calcium and hydroxyproline, both corrected for creatinine, serum alkaline phosphatase, and plasma bone Gla protein). A generally significant resemblance were seen in premenopausal siblings (r = 0.25-0.39, hydroxyproline NS), but not between premenopausal daughters and postmenopausal mothers. We conclude that peak bone mass is hereditary in the distal forearm, lumbar spine, and proximal femur, but the mother-daughter resemblance explains only about 16% of the variability in daughters' bone mass. Furthermore, daughters of women with a moderate state of osteoporotic fractures are not substantially at an increased risk of having a low peak bone mass compared to the daughters of women without fractures.

Absorptiometry, Photon↗

Discriminatory ability of bone mass measurements (SPA and DEXA) for fractures in elderly postmenopausal women.

We investigated the discriminatory ability of forearm bone mineral content (BMCarm) measured by single photon absorptiometry (SPA) and spinal bone mineral density (BMDspine) measured by dual-energy X-ray absorptiometry (DEXA) in 387 elderly postmenopausal women. Of these, 22 had never sustained a fracture (normal), 91 had had less than three vertebral wedge fractures (mild), 51 had experienced a peripheral fracture (moderate), and 24 had had more than three vertebral wedge or compression fractures (severe). BMCarm exceeded BMDspine slightly in the ability to discriminate the mild and moderate groups (P less than 0.01-0.001), whether calculations were performed on raw values or the Z-scores compared with premenopausal women. Receiver operating (ROC) analysis showed that at every cutoff level BMCarm had a similar ability as BMDspine to discriminate between the vertebral fracture (mild and severe) groups and healthy premenopausal and nonfractured postmenopausal women (normal), whereas BMCarm had a significantly higher discriminatory ability of peripheral fractures (P less than 0.05) (moderate) group compared with premenopausal women. We conclude that SPA and DEXA are equally capable as diagnostic procedures in women with established osteoporosis.

Absorptiometry, Photon↗

Rectal salmon calcitonin for the treatment of postmenopausal osteoporosis.

In a 2-year study, we examined bone mass and calcium metabolism in 36 elderly women with moderate osteoporosis. The study period comprised 1 year of observation, during which the women received no treatment affecting calcium metabolism, and 1 year of treatment, during which all participants received daily salmon calcitonin (sCT) 100 IU rectally and calcium 500 mg. During the observational period a significant bone loss of 1.5% was seen in the forearm (P less than 0.01), whereas the spinal bone mass was virtually unchanged. After institution of treatment, the bone loss was arrested in the forearm and a significant increase of about 2% was seen in the spine (P less than 0.01). The net effect of treatment revealed a positive outcome in both bone compartments (1.9% and 2.9%, P less than 0.05-0.01). Correspondingly, the parameters of bone turnover (serum alkaline phosphatase, plasma bone Gla protein, and fasting urinary hydroxy-proline/creatinine) did not change during the observational period, but significantly declined, 10-30%, during sCT treatment (P less than 0.01-0.001). Tolerance was generally good, although in one woman, anoscopy revealed irritative changes in the rectal mucosa. We conclude that, given rectally, sCT is well absorbed and well tolerated and that it has a beneficial effect on calcium metabolism in moderately osteoporotic women.

Administration, Rectal↗