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PubMed1995

The effects of clodronate on increased bone turnover and bone loss due to ovariectomy in rats.

The present study was carried out to investigate the ability of clodronate to inhibit ovariectomy-induced bone loss and increased bone turnover in rats. Estradiol was administered as a reference compound. Seventy Sprague-Dawley rats were ovariectomized (OVX) or sham-operated (Sham) at the age of 90 days and divided into seven groups. Two Sham and two OVX groups received subcutaneously either the vehicle of clodronate or the vehicle of estradiol. Other OVX groups were given s.c. either disodium clodronate at two dose levels (5 mg/kg or 12.5 mg/kg twice a week) or 17 beta-estradiol (10 micrograms/kg five times a week) for 8 weeks. Femur length, volume, dry weight, and ash weight were determined, and proximal ends of tibiae were used for bone histomorphometry. Markers of bone metabolism were measured from urine and serum. A significant loss of 54% of trabecular bone area of proximal tibial metaphysis was found at 8 weeks after ovariectomy. Clodronate and estradiol inhibited (p < 0.001) this osteopenia. Both drugs prevented the decrease in ash weight/volume of the femur. The inhibitory effect of clodronate and estradiol on bone resorption in OVX rats could be detected also in decreased urinary excretion of hydroxyproline and lysylpyridinoline (p < 0.001). Clodronate and estradiol decreased (p < 0.001) the ovariectomy-induced enhanced tibial endocortical mineral apposition rate (Ec.MAR) on the lateral cortex to the level of the Sham group. In contrast, periosteal MAR analyzed on the medial side of tibial cortical bone did not change significantly in the OVX/Veh group. Estradiol decreased periosteal MAR to below the level in the Sham group (p < 0.01). These results suggest that ovariectomy of growing rats resulted in tibial and femoral osteopenia two months later. Clodronate as well as estradiol can suppress bone resorption and turnover in ovariectomized rats, inhibiting the development of osteopenia. Both clodronate doses (5 and 12.5 mg/kg) had beneficial effects in ovariectomized animals.

Analgesics, Non-Narcotic↗
PubMed1996

Time responses of cancellous and cortical bones to sciatic neurectomy in growing female rats.

Effects of unilateral sciatic neurectomy on the responses of both cancellous and cortical bones were studied in growing female rats at 0, 1, 4, 8, and 12 weeks after operation. Using double-fluorescent labeling techniques, histomorphometric analyses were performed on longitudinal sections of proximal tibial metaphyseal secondary spongiosa (PTM) and on cross sections of tibial shaft (TX). In PTM, sciatic neurectomy not only inhibited the age-related bone gain, but also reduced the trabecular bone mass by 46%, which was accompanied by decreases in trabecular number, thickness, and node to node density, and an increase in trabecular separation and free end to free end density. The bone loss occurred mainly between 1 and 4 weeks after operation. A sharp increase in bone formation indices was observed during the first week after nerve section. However, these endpoints quickly dropped to levels lower than those of sham-operated controls at 4 weeks, and were not different from the control levels at 8 weeks after operation. Eroded surface increased progressively after sciatic neurectomy during the 12 weeks experimental period. In TX, sciatic neurectomy inhibited the age-related increase in total tissue area that maintained it at the basal control level. However, the cortical bone area in neurectomized legs was lower than that in sham-operated controls. Sciatic neurectomy also stimulated the bone formation indices on both periosteal and endocortical surfaces during the first week after operation. These endpoints declined sharply between 1 and 4 weeks and then maintained at control levels between 8 and 12 weeks post surgery. Endocortical eroded surface increased 1 week after neurectomy, reached the peak at 8 weeks, and then decreased thereafter. These findings suggest that (1) sciatic neurectomy not only inhibited age-related bone gain but also induced marked bone loss in cancellous bone site and inhibited age-related bone gain in cortical bone site, which mainly resulted from the decrease in bone formation and the increase in bone resorption; (2) the changes in both cancellous and cortical bones responded to sciatic neurectomy occurred mostly within the first 4 weeks and stabilized between 8 and 12 weeks after surgical intervention. In conclusion, the unilateral sciatic neurectomized rat is a complex model in which to study osteopenia. Despite sciatic neurectomy being a simple operation, the interactions of skeletal responses to postsurgical regional acceleratory phenomenon (RAP) and disuse and adaptation changes cannot be clearly differentiated. Furthermore, the complications from growth and aging should be avoided.

Animals↗
PubMed1974

Osseous malrepair in calcium-deficient states.

A primary body tissue involved in metabolic change under the influence of gravity is bone. Osseous integrity is obviously essential for normal musculoskeletal activity; this is of particular importance in long manned space flights where some evidence suggesting calcium loss from bone exists. Studies in our laboratory, utilizing an avian model, have been on the effects of chronic calcium deficiency (or "nutritional secondary hyperparathyroidism"), particularly on bone repair. Quantitative methods to determine both the rate and quality of osseous defects have been developed. A calcium-deficient synthetic diet (0.002% calcium by weight, but otherwise nutritionally complete) has been formulated to permit the induction of true calcium deficiency states in adult, skeletally mature, male domestic fowl. This report is concerned with the effects of long-term calcium depletion on bone repair. It has been classically taught that bone injury repair is always preferentially treated by the body, despite skeletal calcium depletion. For the first time, we have been able to demonstrate that this is incorrect; in the chronic calcium-deficient state, an osseous defect will not be preferentially calcified at the expense of an already-decalcifying skeleton. Quantitative data demonstrate that healing patterns in bone vary in response to the duration of the calcium deficiency. In adult male fowl, calcium-deficient for ten months, bone repair is almost completely absent; in those calcium-deficient for six months, bone repair is both retarded and imperfect; repair is absent even when supplemental calcium is administered at the time of osseous injury induction and thereafter. The conclusions to be drawn from this study are that (i) bone repair is adversely affected in the calcium-deficient state, (ii) the rate and quality of bone repair are directly related to the duration of the calcium-deficient state, and (iii) supplemental calcium administration in chronic calcium-deficient states initially retards, rather than enhances, bone repair. These conclusions have direct relevance to long-term manned space flight.

Animals↗
PubMedDate not supplied

Quantification of spatial structure of human proximal tibial bone biopsies using 3D measures of complexity.

Changes in trabecular bone composition during development of osteoporosis are used as a model for bone loss in microgravity conditions during a space flight. Symbolic dynamics and measures of complexity are proposed and applied to assess quantitatively the structural composition of bone tissue from 3D data sets of human tibia bone biopsies acquired by a micro-CT scanner. In order to justify the newly proposed approach, the measures of complexity of the bone architecture were compared with the results of traditional 2D bone histomorphometry. The proposed technique is able to quantify the structural loss of the bone tissue and may help to diagnose and to monitor changes in bone structure of patients on Earth as well as of the space-flying personnel.

Aged↗
PubMedDate not supplied

Neutral buoyancy and sleep-deprived serum factors alter expression of cytokines regulating osteogenesis.

We examined expression of genes associated with cytokine production, and genes implicated in regulating bone metabolism, in bone stromal and osteoblast cells incubated under standard ground conditions and under conditions of neutral buoyancy, and in the presence/absence of serum from normal or sleep-deprived mice. We observed a clear interaction between these two conditions (exposure to neutral buoyancy and serum stimulation) in promoting enhanced osteoclastogenesis. Both conditions independently altered expression of a number of cytokines implicated in the regulation of bone metabolism. However, using stromal cells from IL-1 and TNFx cytokine(r) KO mice, we concluded that the increased bone loss under microgravity conditions was not primarily cytokine mediated.

3T3 Cells↗
PubMed2005

Muscle strength is a determinant of bone mineral content in the hemiparetic upper extremity: implications for stroke rehabilitation.

Individuals with stroke have a high incidence of bone fractures and approximately 30% of these fractures occur in the upper extremity. The high risk of falls and the decline in bone and muscle health make the chronic stroke population particularly prone to upper extremity fractures. This was the first study to investigate the bone mineral content (BMC), bone mineral density (BMD), and soft tissue composition of the upper extremities and their relationship to stroke-related impairments in ambulatory individuals with chronic stroke (onset >1 year). Dual-energy X-ray absorptiometry (DXA) was used to acquire total body scans on 56 (22 women) community-dwelling individuals (>or=50 years of age) with chronic stroke. BMC (g) and BMD (g/cm2), lean mass (g), and fat mass (g) for each arm were derived from the total body scans. The paretic upper extremity was evaluated for muscle strength (hand-held dynamometry), impairment of motor function (Fugl-Meyer motor assessment), spasticity (Modified Ashworth Scale), and amount of use of the paretic arm in daily activities (Motor Activity Log). Results showed that the paretic arm had significantly lower BMC (13.8%, P<0.001), BMD (4.5%, P<0.001), and lean mass (9.0%, P<0.001) but higher fat mass (6.3%, P=0.028) than the non-paretic arm. Multiple regression analysis showed that lean mass in the paretic arm, height, and muscle strength were significant predictors (R2=0.810, P<0.001) of the paretic arm BMC. Height, muscle strength, and gender were significant predictors (R2=0.822, P<0.001) of lean mass in the paretic arm. These results highlight the potential of muscle strengthening to promote bone health of the paretic arm in individuals with chronic stroke.

Adipose Tissue↗
PubMed2006

Treatment with leuprolide acetate and hormonal add-back for up to 10 years in stage IV endometriosis patients with chronic pelvic pain.

This pilot study examined the effect of a low-dose E and pulsed progestogen hormone therapy (HT) regimen for add-back during long-term GnRH-agonist therapy on bone mineral density (BMD) in five patients with stage IV endometriosis. Bone mineral density was stable after initiation of HT for the entire follow-up period (up to 10 years). One patient stopped her treatment on two occasions to conceive and was successful each time with delivery of a normal baby. No patient had return of pelvic pain after HT add-back.

Adult↗
PubMed2004

Depot medroxyprogesterone acetate, oral contraceptives and bone mineral density in a cohort of adolescent girls.

PURPOSE: To conduct a longitudinal comparison of bone mineral density (BMD) in 370 adolescent girls, aged 12-18, who self-selected depot medroxyprogesterone acetate (DMPA) or an oral contraceptive (OC) containing 20 microg ethinyl estradiol/100 microg levonorgestrel with that in girls who received no hormonal treatment (control group). METHODS: Lumbar spine and femoral neck BMD measurements were obtained by dual energy x-ray absorptiometry at baseline and 12 months. Data were analyzed with repeated measures analysis of covariance methods. RESULTS: Over 12 months, lumbar spine BMD decreased in the DMPA group (n = 29), with a mean percent change of -1.4% (95% confidence interval [CI] -2.73, -0.10), and increased by a mean of 3.8% (95% CI 3.11, 4.57) in the control group [n = 107 (p < .001)]. The increase in mean percent change in lumbar spine BMD in the OC group (n = 79), 2.3% (95% CI 1.49, 3.18), was significantly smaller than in the control group (p = .03). Over 12 months, the mean percent change in femoral neck BMD was -2.2% (95% CI -3.95, -0.39) in the DMPA group, but increased 2.3% (95% CI 1.29, 3.27) in the control group (p < .001). The increase in mean percent change at the femoral neck in the OC group, 0.3% (95% CI -0.87, 1.41), was significantly lower than in the control group (p = .03). CONCLUSIONS: Our study contributes to an increasing body of knowledge indicating a negative impact of DMPA on bone health in young women. Additional findings suggest a potential adverse effect of an OC containing 20 microg ethinyl estradiol/100 microg levonorgestrel on bone health in adolescents.

Absorptiometry, Photon↗
PubMed1995

Bone mineralization, hypothalamic amenorrhea, and sex steroid therapy in female adolescents and young adults.

1. The vast majority of bone mineralization in girls occurs by the middle of the second decade. 2. Premature bone demineralization occurs in women with hypothalamic dysfunction manifest as amenorrhea and oligomenorrhea, associated with athletics, dancing, and eating disorders. 3. In young women with amenorrhea associated with weight loss, BMD loss will be occurring soon after the amenorrhea develops. Treatment to prevent BMD loss or promote BMD accretion should begin soon, probably within 6 months after amenorrhea occurs. 4. Women who recover from anorexia nervosa at a young age (< 15 years of age) can have normal total body BMD, but regional (lumbar spine and femoral neck) BMD may remain low. The longer the anorexia nervosa persists, the less likely it is that the BMD will return to normal. Girls and women with anorexia nervosa need to be rehabilitated early in the disease to maximize BMD accretion. 5. Conjugated estrogen, in doses that improve bone mineralization in postmenopausal women and in combination with medroxyprogesterone, has not been shown to improve BMD in young women with hypothalamic amenorrhea. The role of orally administered medroxyprogesterone at a dose of 10 mg per day, 10 days per month, in improving BMD in teenage girls with hypothalamic amenorrhea or oligomenorrhea remains to be established. 6. Treatment with OCP may have a beneficial effect on BMD in young women with hypothalamic amenorrhea, but this has not been established in a double-masked, randomized, controlled trial. Doing a double-masked trial using OCP will be difficult because estrogen-deficient subjects treated with OCP will be likely to have menstrual bleeding, whereas those treated with placebo will not. In addition, the risk of pregnancy in a sexually active subject, who does not know whether she is receiving OCP, is too great for some subjects. 7. Osteoporosis is a major cause of morbidity and death. Peak bone mass is a major determinant of the risk of osteoporosis, and the second decade is the critical period of peak bone mass acquisition; thus providers of health care for adolescents need to understand the factors that affect bone mineralization during this period, and advise patients accordingly.

Adolescent↗
PubMedDate not supplied

Osteopenia in anorexia nervosa: specific mechanisms of bone loss.

Osteopenia is a well recognized medical complication of anorexia nervosa (AN). The mechanism of bone loss is not fully understood and there is uncertainty about its management. New markers of bone turnover have been developed. C-terminal type 1 propeptide (PICP) is a measure of bone formation and urinary pyridinolines such as deoxypyridinoline (DPYRX) and serum carboxyterminal crosslinked telopeptide (ICTP) are markers of bone resorption. The aim of this study was to examine these bone markers in patients with AN. Twenty female patients with AN and 12 healthy controls were included in the study. Bone mineral density (BMD) of AN patients was measured by dual energy X-ray absorptiometry (DEXA). Lumbar bone density was significantly reduced in the AN group compared to standardised values of thirty year old adults (t-score 83.2%, S.D. 12.1). Femoral neck bone density showed an even greater reduction (t-score 79.4%, S.D. 13.5). We found a significant negative correlation between femoral BMD and the duration of the illness. Femoral BMD correlated significantly with minimal body weight (r(16) = 0.504, p = 0.033). The markers of bone resorption were significantly higher in the patients with AN compared to the values of the control group (ICTP t(30) = -2.15, p = 0.04, DPYRX t(25) = -2.26, p = 0.033), whereas the markers of bone formation did not differ significantly between the groups. AN appears to be a low turn over state associated with increased bone resorption without concomitant bone formation. This pattern differs from osteopenia in menopausal women and should, therefore, lead to the development of specific therapeutic strategies in AN associated osteopenia. Hormone replacement therapy as well as calcium and vitamine D-supplementation are so far discussed controversially. Long-term treatment studies are warranted.

Adult↗
PubMed2000

Electrolytes in femur and plasma of rats during prolonged restriction of motor activity.

Hypokinesia (decreased motor activity) induces insignificant bone mineral changes. The aim of this study was to measure mineralization, density, and also electrolyte content in the femur of rats during prolonged hypokinesia (HK). Studies were done on 144 male Wistar rats (370-390 g) during 15 days period of pre-HK and 90 days period of HK. Rats were equally divided into two groups: hypokinetic rats (HKR) and vivarium control (VCR). The HKR group of rats was kept in small individual cages. Femur mineralization density, ash mineral content, calcium (Ca) and phosphate (P) content, and plasma Ca and P concentration were measured. In the HKR group body weight, femur mineralization, density, ash mineral content, Ca and P concentration decreased significantly (p < or = 0.01) while plasma Ca and P concentration increased significantly (p < or = 0.01) when compared with the VCR group. The measured parameters did not change significantly in the VCR group when compared with the baseline control values. It was concluded that prolonged HK induces a significant reduction in electrolyte concentration accompanied by decreased mineralization, density, and ash mineral content of the femur of rats.

Animals↗
PubMedDate not supplied

Bone loss during long term space flight is prevented by the application of a short term impulsive mechanical stimulus

In long term space flight, the mechanical forces applied to the skeleton are substantially reduced and are altered in character. This reduced skeletal loading results in a reduction in bone mass. Exercise techniques currently used in space can maintain muscle mass but the mechanical stimulus provided by this exercise does not prevent bone loss. By applying an external impulsive load for a short period each day, which is intended to mimic the heel strike transient, to the lower limb of an astronaut during a long term space flight (5 months), this study tests the hypothesis that the bone cells can be activated by an appropriate external mechanical stimulus to maintain bone mass throughout prolonged periods of weightlessness. A mechanical loading device was developed to produce a loading of the os-calcis similar to that observed during the heel strike transient. The device is activated by the astronaut to provide a transient load to the heel of one leg whilst providing an equivalent exercising load to the other leg. During the EUROMIR95 mission on the MIR space station, an astronaut used this device for a short period daily throughout the duration of the mission. Pre- and post-flight measurements of bone mineral density (BMD) of the os-calcis and femoral neck of the astronaut were made to determine the efficacy of the device in preventing loss of bone mineral during the mission. On the os-calcis which received the mechanical stimulus, BMD was maintained throughout the period of the flight, while it was reduced by up to 7% on the os-calcis which received no stimulus. Post-flight, BMD in both the stimulated and non-stimulated os-calcis reduces, the extent of this reduction however is less in the stimulated os-calcis. For the femoral neck, the mechanical stimulation does not produce a positive effect.

Aerospace Medicine↗
PubMed2001

Long-term impact of chemotherapy-induced ovarian failure on bone mineral density (BMD) in premenopausal breast cancer patients. The effect of adjuvant clodronate treatment.

We present the 5-year results of the effect of adjuvant chemotherapy on bone mineral density (BMD) and the efficacy of clodronate in the prevention of bone loss in 73 premenopausal women with primary breast cancer. All patients were treated with cyclophosphamide, methotrexate, 5-fluorouracil (CMF) chemotherapy. The patients were randomised to oral clodronate 1600 mg daily for 3 years or to a control group. At 5 years, patients were divided into those with preserved menstruation and those with amenorrhoea. Changes in BMD correlated significantly with the menstrual function after chemotherapy. The change in the lumbar spine BMD at 3 and 5 years were +0.6 and -1.3% in the menstruating group and -7.5 and -10.4% in the amenorrhoeic group (P=0.0001 and 0.0001, respectively), and in femoral neck +1.7 and -0.3%, and -3.5 and -5.8% (P=0.002 and P=0.001, respectively). Three-year clodronate treatment significantly reduced the bone loss in the lumbar spine -3.0% compared with controls -7.4% at three years (P=0.003), but no significant difference was found in the femoral neck: -1.7% versus -2.8%, respectively (P=0.86). These differences between the study groups were still seen at 5 years: in the lumbar spine -5.8% versus -9.7% (P=0.008) and femoral neck -3.5% versus -5.1% (P=0.91). In conclusion, chemotherapy-induced ovarian failure in premenopausal women caused a temporary accelerated bone loss of the lumbar spine. Adjuvant clodronate treatment significantly reduced this bone loss. Two years after the termination of treatment, the bone loss was still significantly less in the clodronate group compared with the control group.

Absorptiometry, Photon↗
PubMed1999

Long-term consequences of fracture of the lower leg: cross-sectional study and long-term longitudinal follow-up of bone mineral density in the hip after fracture of lower leg.

The purpose of this study was to investigate whether bone loss in the hip, occurring after a fracture of the lower leg, persists many years after the fracture. In a long-term follow-up we measured bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) of both hips and the lumbar spine in a group of 11 patients, 5 years after a fracture of the lower leg. These patients were part of an earlier study, evaluating bone loss in the hip, up to 1 year after fracture of the lower leg. In this follow-up study, 5 years after fracture, loss from baseline BMD in the trochanteric region of the ipsilateral hip was 4.7% (p=0.04), whereas after a year in this group there was a decrease of 12.5% from baseline. On the contralateral side, hardly any change occurred. In the ipsilateral femoral neck, 5 years after fracture, BMD decreased by 2.9% (p=0.10), after 1 year loss from baseline was 5.1%. In a cross-sectional study we examined the differences in BMD of both hips, measured by DXA, in a group of 19 elderly patients reporting a fracture of the lower leg, with a mean time of 9.3 years after fracture. In this study, we found a 4.7% lower BMD in the trochanteric region of the hip on the fractured side compared with the nonfractured side (p=0.006), and a 2.9% lower BMD in the femoral neck (p=0.25). We conclude that, after fracture of the lower leg, BMD in the ipsilateral hip decreases significantly, with maximal bone loss after 1 year. After 5 years recovery has occurred, but not to baseline. Thereafter, significant excess bone loss is still observed in the trochanteric region. This persisting lower BMD may lead to an increased risk of another fracture in later years.

Aged↗
PubMed1999

Cortical tibial bone volume in two strains of mice: effects of sciatic neurectomy and genetic regulation of bone response to mechanical loading.

Although C3H/HeJ (C3H) and C57BL/6J (B6) mice are similar in body size (and adult weight), and have bones of similar external size, C3H mice have higher peak bone densities than B6 mice (e.g., 53% higher peak bone density in the femora). The current studies were intended to assess the role of mechanical loading/unloading as a possible determinant of the bone density difference between these inbred strains of mice and, specifically, to assess the effect of sciatic neurectomy on histomorphometric indices of bone formation and resorption in the tibiae of female C3H and B6 mice. Groups of 10 mice of each strain were subjected to left-side sciatic neurectomy (left hindlimb immobilization) or a sham procedure. The contralateral (right) legs of each mouse were used as controls. Four weeks of immobilization produced no systemic changes in bone formation indices in either strain of mice (i.e., no change in serum alkaline phosphatase or serum osteocalcin). However, histomorphometric assessments at the tibiofibular junction showed that 4 weeks of immobilization caused a time-dependent decrease in the length of the endosteal bone forming perimeter (e.g., 14% of control single-labeled, noneroded surface at 4 weeks, p < 0.005) with a concomitant increase in the length of the endosteal bone resorbing perimeter (i.e., 424% of control eroded surface at 4 weeks, p < 0.005), in the B6 mice. These effects were associated with an increase in medullary area (132% of control, p < 0.05) at this site, in the B6 mice. The pattern of response was different in the tibiae of the C3 mice-a much smaller decrease in bone forming perimeter (88% of control at 4 weeks, p < 0.05), with no associated increase in bone resorbing perimeter, and no change in medullary area. Similar effects were seen at a second cross-sectional sampling site, in the proximal tibia. Together, these findings indicate that B6 mice are more sensitive to endosteal bone loss from hindlimb immobilization than C3H mice.

Alkaline Phosphatase↗
PubMed2001

Bone mineral content and bone mineral density in adolescent girls with anorexia nervosa--a longitudinal study.

OBJECTIVE: Total body and lumbar spine bone mineral density (BMD-TB, BMD-L) and total body bone mineral content (BMC-TB) were measured to establish the course of bone demineralization in anorexia nervosa and the clinical factors influencing BMC-TB and BMD changes during treatment. METHOD: Forty-two girls with DSM III-R anorexia nervosa, age 14.7+/-2.4 years. BMC-TB, BMD-TB and BMD-L were measured in approximately 7-month intervals for 27.8+/-4.1 months using DXA. RESULTS: Despite nutritional improvement, there was an initial decrease of BMD-L, and no change in BMC-TB and BMD-TB. an increase in BMC-TB and BMD was observed after approx. 21 months from the beginning of the study. CONCLUSION: The improvement in BMC-TB and BMD was related to changes in nutritional status and was significantly marked in younger patients, with earlier anorexia onset and before menarche.

Adolescent↗