Long-term calcitonin therapy in postmenopausal osteoporosis

Results are presented from a 2-year controlled study evaluating the efficacy of 100 units synthetic salmon calcitonin/d in the treatment of postmenopausal osteoporosis. All patients received 400 units D₂ po qd and 1200 mg CaCO₃ po qd. The 21 control and 24 treated patients (mean age 65) were not statistically different at baseline. Although mean total body calcium (TBCa) was not significantly different between treated and control patients throughout the study, mean differences in the change in TBCa from baseline (treated minus control) were significant at 12, 18, and 26 months. The mean slope of TBCa for treated patients, but not for controls, was significantly positive through 18 months. Iliac crest bone biopsies showed (1) a significantly greater percent total bone area in treated compared to control patients at 2 years, and (2) a significantly decreased percent resorbing surface in treated patients when evaluated by paired difference from baseline. At 4 months, serum calcium values were significantly lower in treated patients than in controls (mean difference, treated minus controls), but were not statistically different from controls at study completion. Urine calcium increased significantly for the first 4 months in treated subjects and then declined to baseline levels. Since urinary calcium increased, the increase in TBCa was probably associated with an increase in net intestinal calcium absorption.     

Basal plasma immunoreactive calcitonin in postmenopausal osteoporosis

Calcitonin (CT) deficiency has been suggested as an etiologic factor in postmenopausal osteoporosis (PM-OP). Basal immunoreactive calcitonin (iCT) was measured with a sensitive radioimmunoassay (RIA) in 62 PM-OP women with compressin fractures (CF) and in 28 normal age-matched women. Mean iCT values in the two groups were not significantly different (43.5 and 45.1 pg/ml, p > 0.10). In the 62 PM-OP females, no significant correlation was noted between basal plasma iCT levels and (1) age; (2) severity of disease as assessed by number of CF; (3) serum calcium, phosphorus, alkaline phosphatase, and immunoreactive parathyroid hormone; and (4) total bone mass as assessed by neutron activation analysis determinations of total body calcium (TBC). In 20 PM-OP patients treated for 24 mo with 100 Medical Research Council (MRC) units daily of synthetic salmon CT, no correlation was observed between basal plasma iCT and response of bone mass (TBC) to therapy. These data suggest that basal CT is not decreased in women with PM-OP, and that the level of circulating CT does not influence therapeutic changes in bone mass during CT therapy. CT is probably not a major etiologic or pathogenetic factor in PM-OP.     

鲑鱼降钙素对绝经后骨质疏松症的影响

目的观察鲑鱼降钙素对绝经后骨质疏松症的作用。方法鲑鱼降钙素治疗组９２例,隔日肌注５０Ｕ,每日加服元素钙３００ｍｇ,单用钙剂治疗的对照组２３例,每日服元素钙３００ｍｇ。疗程６个月。结果用药组腰２～４椎骨密度分别升高９．３％,１０．６％和８．９％,髋部骨密度无改变,与此同时,血骨钙素明显升高,尿羟脯氨酸／肌酐比值明显降低。对照组用药前后无明显改变。结论鲑鱼降钙素有改善绝经后骨质疏松病人腰椎骨密度作用,其机理与增加骨合成和降低骨吸收有关。     

氟加钙对实验大鼠骨质疏松疗效的形态计量学观察

目的探讨氟加钙联合疗法对实验大鼠骨质疏松疗效,找出一种治疗老年性骨质疏松的规范方法。方法采用3月龄雌性大鼠去卵巢,建立女性增龄型骨质疏松模型,并分别单纯给氟或钙,联合应用氟加钙口服,6个月后取大鼠左侧胫骨近端进行松质骨形态计量学分析,对比3种方法对该骨质疏松模型的治疗作用。结果大鼠去卵巢6个月后可出现松质骨骨量丢失(P<0.05),微细结构破坏(P<0.05),骨转换加快(P<0.05),模型建立成功。单纯应用小剂量氟和单纯补钙对改善模型的骨量、微结构及骨转换方面有一定作用,但不如联合应用氟加钙作用明显。高剂量氟加钙的方法、疗效更加显著。结论氟加钙疗法比单纯应用氟或钙疗效更好。     

Lactose and calcium absorption in postmenopausal osteoporosis

The prevalence of lactase deficiency and the relationship between lactose and calcium malabsorption in postmenopausal osteoporosis has been assessed in 46 subjects. Malabsorption of lactose occurred in 25 (54%) of the subjects and was associated with a significantly lower milk intake. Malabsorption of calcium occurred in 11 (44%) of the lactase-deficient subjects and in 11 (52%) of normal lactose absorbers. There was no relationship between lactose and calcium malabsorption. Vertebral and forearm mineral densities were not significantly different between normal lactose absorbers and lactase-deficient subjects.     

Meta-analyses of therapies for postmenopausal osteoporosis. VI. Meta-analysis of calcitonin for the treatment of postmenopausal osteoporosis

OBJECTIVE: To review the effect of calcitonin on bone density and fractures in postmenopausal women. DATA SOURCE: We searched MEDLINE and EMBASE from 1966 to 2000 and examined citations of relevant articles and the proceedings of international osteoporosis meetings. We contacted osteoporosis investigators to identify additional studies and primary authors for unpublished data. STUDY SELECTION: We included 30 studies that randomized women to calcitonin or an alternative (placebo or calcium and/or vitamin D) and measured bone density or fracture incidence for at least 1 yr. DATA EXTRACTION: For each trial, three independent reviewers assessed the methodological quality and abstracted data. DATA SYNTHESIS: Calcitonin reduced the incidence of vertebral fractures, with a pooled relative risk (RR) of 0.46 [95% confidence interval (CI) 0.25-0.87, P = 0.02, n = 1404, 4 trials]. However, the RR from the one relatively large randomized controlled trial (RCT) was 0.79 (95% CI 0.62-1.00, P = 0.05, n = 1108). For nonvertebral fractures, the pooled RR was 0.52 (95% CI 0.22-1.23, P = 0.14, n = 1481, 3 trials). Once again, the single large trial showed a less impressive effect than the smaller trials (RR 0.80, 95% CI 0.59-1.09, P = 0.16, n = 1245). For bone density of the lumbar spine, the pooled weekly dose of 250 to 2800 IU per week resulted in significant increase in the weighted mean difference (WMD) of 3.74 (2.04-5.43, P < 0.01, n = 2260, 24 trials). The combined forearm showed a similar effect, with a WMD of 3.02 (95% CI 0.98-5.07, P < 0.01, n = 468, 9 trials). At the femoral neck, the pooled weighted mean difference showed a nonsignificant trend toward benefit, WMD 3.80 (95% CI -0.32-7.91, P = 0.07, 9 trials, n = 513). Methodologically weaker studies tended to show greater effects on bone density, and the lumbar spine results suggested the possibility of publication bias. CONCLUSIONS: Calcitonin likely increases bone density in postmenopausal women predominantly at the lumbar spine and forearm for weekly doses of greater than 250 IU, although the true effect may be smaller than the pooled estimate would suggest. Calcitonin likely reduces the risk of vertebral fracture; its effect on nonvertebral fracture remains uncertain.     

Superiority of alfacalcidol compared to vitamin D plus calcium in lumbar bone mineral density in postmenopausal osteoporosis

In a randomized multicenter, double-blind, double-dummy, parallel group study a comparison of the efficacy and safety of 1 μg alfacalcidol to 880 IU vitamin D plus calcium carbonate (1 g calcium) once daily per os was performed on 148 postmenopausal osteoporotic Caucasian patients with normal vitamin D serum levels for 18 months. Bone mineral density (BMD) was measured at baseline, 12 and 18 months. Safety parameters were followed during the entire study period. Sixty-nine (90.8%) in the alfacalcidol group and 67 (93.1%) in the vitamin D group were included in the ITT analysis. Lumbar BMD in the alfacalcidol group increased by 0.017 g/cm² (2.33%) and 0.021 g/cm² (2.87%) from baseline (P<0.001) at 12 and 18 months, respectively, whereas in the vitamin D plus calcium group the increase was 0.005 g/cm² (0.70%) from baseline (N.S.) at both 12 and 18 months. The higher changes from baseline in the alfacalcidol group, as compared to the changes in the vitamin D plus calcium group at both 12 and 18 months, were found to be statistically significant (P=0.018, 0.005). A small increase of mean femoral BMD was achieved in both groups (N.S.). Adverse events were similar in both groups. No significant differences were noted between the groups in serum calcium. In conclusion, alfacalcidol was found to be superior in significantly increasing lumbar BMD as compared to vitamin D plus calcium while safety characteristics were found to be similar in both treatments.     

Effects of estrogens and calcium on calcitonin secretion in postmenopausal women

The protective action of estrogens on bone mass may be mediated by an increase in calcitonin (CT) secretion. We reevaluated this hypothesis using a method for measuring CT in extracts of serum that allows sensitive specific measurement of CT monomer. We studied seven healthy postmenopausal women before and on the 7th and 28th days of each of three 4-week treatment periods: estrogen (estradiol valerate; 2 mg/day), calcium supplement (1500 mg/day), and estrogen plus calcium; the three cycles were separated by intervals of 4 weeks. Serum extractable CT (exCT) levels were measured before and after a short calcium stimulation test (2 mg Ca/kg in 5 min) to assess the C-cell secretory response on each day. Estrogen had the expected biological effects, decreasing (P less than 0.05) serum gonadotropin concentrations and fasting or 24-h urinary calcium excretion. The calcium supplement caused a significant increase in 24-h urinary calcium excretion. However, there was no increase in basal or stimulated serum exCT levels during any of the three cycles. On the contrary, basal serum exCT concentrations decreased slightly but significantly during estrogen treatment from 1.9 +/- 0.5 (+/- SE) to 1.5 +/- 0.4 ng/L on day 7 and 1.2 +/- 0.2 ng/L on day 28 (P less than 0.05). This decrease in basal exCT levels did not occur during the combined estrogen and calcium administration period, probably because the slight decrease in serum calcium induced by estrogen did not occur during combined estrogen and calcium administration. In summary, estrogens do not stimulate CT secretion; variations in serum exCT levels appear to be related to the changes in bone metabolism induced by estrogens.     

Comparison of alendronate and intranasal calcitonin for treatment of osteoporosis in postmenopausal women

This study compared the effects of oral alendronate and intranasal calcitonin for treatment of osteoporosis in postmenopausal women. Women at least 5 yr postmenopause (n = 299) were randomized to either 10 mg alendronate, matching alendronate placebo, or open-label intranasal calcitonin 200 IU daily for 12 months. Hip and spine bone mineral density (BMD) and markers of bone turnover were measured, and safety and tolerability were assessed. Alendronate produced greater increases in BMD than calcitonin at 12 months at the lumbar spine (5.16% vs. 1.18%; P < 0.001), trochanter (4.73% vs. 0.47%; P < 0.001), and femoral neck (2.78% vs. 0.58%; P < 0.001). Changes in BMD with calcitonin were greater than with placebo at the femoral neck, but were not different from placebo at either the trochanter or lumbar spine. Greater decreases in bone turnover were seen with alendronate than with calcitonin (serum bone-specific alkaline phosphatase, 43% vs. 9%, P < 0.001; urinary N-telopeptide, 62% vs. 11%, P < 0.001). Similar percentages of patients in each group reported an adverse experience during the study. We conclude that, in postmenopausal women with osteoporosis, 12 months of therapy with alendronate produced significantly greater increases in BMD of the hip and spine and greater decreases in bone turnover than intranasal calcitonin.     

Comparison of cyclic and continuous calcitonin regimens in the treatment of postmenopausal osteoporosis

We aimed to compare and evaluate the efficacies of a continuous regimen of intranasal salmon calcitonin (SCT) and two cyclic regimens (different cyclic regimens from previous studies) based on alternating 15 days or on 10 days consecutively per month for 1 year in the treatment of postmenopausal osteoporosis. We performed an open-label, prospective, randomized clinical trial. A total of 120 postmenopausal osteoporotic participants between 50 and 65 years old were randomly assigned to one of three treatment groups. Patients in group 1 (n=40) received continuously SCT nasal spray at a dose of 200 IU/day, plus continuously 500 mg/day elementary calcium and 0.25 g/day 1- hydroxyvitamin D3, for 1 year. Patients in group 2 (n=40) received cyclically SCT nasal spray at a dose of 200 IU/day on alternating 15 days per month, plus continuously 500 mg/day elementary calcium and 0.25 g/day 1- hydroxyvitamin D3, for 1 year. Patients in group 3 (n=40) received cyclically SCT nasal spray on 10 days consecutively per month (20 days/month rest), plus continuously 500 mg/day elementary calcium and 0.25 g/day 1- hydroxyvitamin D3, for 1 year. Data was evaluated by repeated analysis of variance (ANOVA). In addition, statistical differences between groups were assessed by the two-tailed Students t test. After 1 year of the study, seven patients from group 1, eight patients from group 2 and five patients from group 3 withdrew from the study. No patient discontinued the study because of adverse drug effects. There was a statistically-significant improvement in pain intensity VAS scores at the end of the year to baseline scores in all three groups (p<0.001). There was no significant difference in pain intensity VAS scores between groups at the end of the year (p>0.05). Lumbar and femur neck BMD scores improved significantly at the end of treatment in all three groups (p<0.05). There was no statistically-significant difference in BMD scores between groups at final (p>0.05). Urinary DPD/Cre levels decreased significantly in all three groups by the end of the year (p<0.05). There was no statistically-significant difference in urinary DPD/Cre final levels between groups (p>0.05). According to the results of the present study, consecutive 10 days therapy with SCT, which is the first in the literature to our knowledge, is as effective as the other two regimens in the treatmnent of osteoporosis. Both cyclic regimens in our study (alternating 15 days and 10 consecutive days each month for 1 year) do appear to offer some advantages, especially economically and clinically, as compared to continuous treatment.     

The role of calcitonin in the development and treatment of osteoporosis

CT is a peptide hormone produced predominantly by thyroid C cells and probably to a lesser extent by extrathyroidal tissues. Although its physiological function has not yet been established, it is a pharmacological inhibitor of osteoclastic bone resorption. There is currently no convincing evidence that naturally occurring or iatrogenic CT deficiency is involved in the pathogenesis of osteoporosis; however, a selective examination of patients with various rates of bone turnover would help to resolve this issue. As a pharmacological inhibitor of bone resorption, CT has potential usefulness in the therapy of osteoporosis. CT has been shown to stabilize or modestly increase indices of cortical and trabecular bone mass and total body calcium when administered to patients with established osteoporosis for periods of 1-2 yr. The increments in bone mass seen in some studies appear to be transient and are likely due to reductions in bone resorption with bone formation remaining unaffected until remodeling spaces are filled. The duration and magnitude of these increases are probably limited by the eventual decline in bone formation as remodeling equilibrium is reestablished. Therefore, reduction in the rate of bone loss with maintenance of the existing skeletal mass, rather than significant sustained increases in bone mass, should be considered the most realistic therapeutic goal with this agent. Whether or not a reduction in the rate of bone loss persists for longer periods needs further evaluation as does the important issue of subsequent fracture rates. The identification of patients with increased bone resorption rates (high turnover osteoporosis) should help provide a basis for more selective treatment of those patients who would be most likely to respond to this form of therapy. Whether there is additional benefit to using intermittent CT concurrently or sequentially with bone formation stimulating agents (coherence therapy) also needs to be explored. CT may also be of benefit in the prevention of osteoporosis, particularly in postmenopausal women who are unable or unwilling to take estrogen replacement. These potential benefits must be weighed carefully against the current cost of CT and the inconvenience of it having to be given by injection, problems which should be solved by future research.     

Effects of calcium infusions in patients with postmenopausal osteoporosis.

From earlier studies, it appeared that postmenopausal women with osteoporosis may not be so responsive to therapeutic calcium infusions as younger men. A study of seven women with postmenopausal osteoporosis revealed that only one had a good therapeutic response as judged by sustained decrease in bone pain and improvement in calcium balance. It is concluded that a series of calcium infusions is unlikely to be therapeutically useful in postmenopausal osteoporosis.     

Estrogen replacement therapy for osteoporosis in postmenopausal women

At perimenopausal stage, women start losing their bone mineral density. The bone loss results from accelerated bone absorption due to lower estrogen level which often caused climacteric disorders. Then it is possible to treat both osteoporosis and climacteric disorders with estrogen replacement therapy. However, it is necessary that we properly explain the hormone-related disorders (breast cancer, endometrial cancer and heart disease) and get the informed consent at beginning of this therapy.     

Reduction in intestinal calcium absorption by hydrochlorothiazide in postmenopausal osteoporosis

In six women with postmenopausal osteoporosis, most of whom responded to 50 micrograms/day 25-hydroxyvitamin D (25-OHD) therapy with a rise in intestinal calcium (Ca) absorption, 50 mg/day hydrochlorothiazide (TZ) were added to determine whether the resulting decline in urinary Ca would cause Ca retention in the skeleton. Urinary Ca decreased from 183 +/- 48 (SD) mg/day to 142 +/- 67 mg/day (P less than 0.05) when TZ was added. However, fractional Ca absorption also declined from 0.532 +/- 0.077 during 25-OHD treatment to 0.401 +/- 0.064 during combined 25-OHD and TZ therapy (P less than 0.0025). The above changes were accompanied by a significant decline in urinary cAMP from 4.29 +/- 1.64 to 3.19 +/- 1.44 mumol/g creatinine (P less than 0.05) and in serum 1,25-dihydroxyvitamin D from 41 +/- 14 to 22 +/- 11 pg/ml (P less than 0.01). The results suggest that TZ lowers urinary Ca, suppresses parathyroid function, inhibits 1,25-dihydroxyvitamin D synthesis, and thereby reduces intestinal Ca absorption. Thus, combined 25-OHD and TZ therapy probably does not improve Ca balance.     

The Budd-Chiari syndrome. Possible pathogenetic role of anti-phospholipid antibodies

The case of a young woman with the Budd-Chiari syndrome is reported. She first noticed abdominal symptoms following a late spontaneous abortion. Antiphospholipid antibodies were detected in her serum. We suggest that these may have been causally related to the development of her hepatic disease.