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1.
Reduction of instability-induced bone resorption using bisphosphonates: High doses are needed in rats 总被引:2,自引:0,他引:2
Bone resorption associated with prosthetic loosening can be reduced by giving bisphosphonates since they bind to bone surfaces and inactivate osteoclasts when bisphosphonate-containing bone is resorbed. During loosening, an increase in osteoclastic activity can be triggered by mechanical instability, fluid pressure or wear particles. We used a rat model in which a titanium surface can be made to slide over a bone surface and cause instability-induced bone resorption. 111 rats were operated on with a plate implant and treated with alendronate or clodronate injections in different doses or saline controls. After 4 weeks of osseointegration, the plate was moved during 2 weeks and the findings evaluated with histomorphometry. The percentage of persisting bonemetal contact and the soft tissue area at the interface were measured to estimate bone loss. Low or intermediate doses of the bisphosphonates increased the ash weight of untraumatized bone, but did not inhibit resorption at the unstable interface. Only rats treated with the highest doses of alendronate or clodronate had more bone-metal contact than controls. Instability-induced bone resorption therefore seems to be reduced by bisphosphonates, but higher doses are needed to obtain this effect than to reduce bone resorption associated with normal remodeling of untraumatized bone. 相似文献
2.
Bone resorption associated with prosthetic loosening can be reduced by giving bisphosphonates since they bind to bone surfaces and inactivate osteoclasts when bisphosphonate-containing bone is resorbed. During loosening, an increase in osteoclastic activity can be triggered by mechanical instability, fluid pressure or wear particles. We used a rat model in which a titanium surface can be made to slide over a bone surface and cause instability-induced bone resorption. 111 rats were operated on with a plate implant and treated with alendronate or clodronate injections in different doses or saline controls. After 4 weeks of osseointegration, the plate was moved during 2 weeks and the findings evaluated with histomorphometry. The percentage of persisting bone-metal contact and the soft tissue area at the interface were measured to estimate bone loss. Low or intermediate doses of the bisphosphonates increased the ash weight of untraumatized bone, but did not inhibit resorption at the unstable interface. Only rats treated with the highest doses of alendronate or clodronate had more bone-metal contact than controls. Instability-induced bone resorption therefore seems to be reduced by bisphosphonates, but higher doses are needed to obtain this effect than to reduce bone resorption associated with normal remodeling of untraumatized bone. 相似文献
3.
N. Morabito A. Lasco A. Gaudio A. Crisafulli C. Di Pietro A. Meo N. Frisina 《Osteoporosis international》2002,13(8):644-649
The aim of our randomized, placebo-controlled study was to investigate the effects of 2 years’ daily oral administration
of alendronate or intramuscular administration of clodronate every 10 days, on bone remodeling parameters and bone mineral
density (BMD), safety and tolerability in a group of osteoporotic thalassemic patients. Twenty-five young patients (mean age
26.6 ± 7.1 years) with beta-thalassemia major were randomly divided to receive placebo or 100 mg of clodronate intramuscularly
every 10 days or 10 mg of alendronate per os daily. All patients took 500 mg of elemental calcium and 400 IU cholecalciferol
in the evening at meal time. After 2 years, pyridinium crosslinks, which are bone resorption markers, did not differ significantly
from baseline values in the placebo group, whereas they had decreased significantly in the clodronate and alendronate groups.
Osteocalcin, a bone formation marker, did not change significantly in the placebo group, whereas it decreased slightly, but
not significantly, in the clodronate and alendronate groups after 12 and 24 months. At the end of the study, the lumbar spine
BMD had decreased significantly in the placebo group; it did not change significantly in the clodronate group; in the alendronate
group it had increased but not significantly, whereas the increase was significant with respect to the placebo group. Femoral
neck BMD decreased significantly in the placebo group; it did not change significantly in the clodronate group, but increased
significantly in the alendronate group. No relevant side effects were recorded during our study. In conclusion, in patients
with thalassemia-induced osteoporosis, the daily administration of alendronate significantly increases BMD, the most important
predictor of the risk of fracture at several sites. Clodronate treatment at our dosage is ineffective in this pathology in
spite of the good compliance of patients.
Received: 13 August 2001 / Accepted: 19 February 2002 相似文献
4.
Effects of Clodronate on Cortical and Trabecular Bone in Ovariectomized Rats on a Low Calcium Diet 总被引:5,自引:0,他引:5
T. S. Kaastad O. Reikerås J. E. Madsen S. Narum J. H. Strømme K. J. Obrant L. Nordsletten 《Calcified tissue international》1997,61(2):158-164
The aim of this study was to evaluate the contribution of a low calcium diet to the cortical and trabecular osteoporosis
seen in ovariectomized rats after 7 weeks on a low calcium diet and to investigate the effects of the bisphosphonate clodronate
on this development of osteoporosis. Thirty-six mature, female Wistar rats were randomized into four groups: Ovx−B (bisphosphonate)
and Ovx−C (control) were ovariectomized, and Sham−Ca (low calcium) and Sham+Ca (normal calcium) were sham operated. The first
three groups were fed a low calcium diet (0.01%) and Sham+Ca normal rat chow (Ca 1.1%). The Ovx−B received 10 mg/kg s.c. clodronate
daily for nine weeks, and Ovx−C, Sham−Ca, and Sham+Ca received the same volumes of saline. Bone mineral turnover measured
as 85Sr-uptake was increased in all low calcium groups compared to Sham+Ca. The Sham+Ca femora had higher dry weight and ash weight
than the other groups, and Ovx−C had higher dry weight compared with Ovx−B and Sham−Ca. Calcium content was lower in both
Ovx groups compared to both Sham groups. Magnesium was lower in all groups compared to Sham+Ca and higher in Ovx−B compared
with Ovx−C. In the femoral shaft, Sham+Ca had significantly higher ultimate bending moment, energy absorption, and deflection
compared to the other three groups. Ultimate bending moment was higher in Sham−Ca than in Ovx−C. Stiffness was increased in
both Sham+Ca and Ovx−B compared to Ovx−C. The maximum stress in the femoral midshaft was higher in Sham+Ca than in the other
groups, and higher in Ovx−B than in Ovx−C. Histomorphometry showed increased medullary area in all low calcium groups compared
to Sham+Ca and larger cortical area in Sham+Ca and Ovx−B compared to Ovx−C. Compared to Sham+Ca the trabecular bone volume
was decreased to 30% in Sham−Ca and to 9% in Ovx−C, but was unchanged in Ovx−B. The low calcium diet generally increased bone
mineral turnover and reduced the tibial bone volume. Femoral changes led to a reduction of cortical fracture strength and
maximal stress. Ovariectomy in addition to a low calcium diet reduced femoral strength even more. Daily injections of clodronate
to ovariectomized rats on a low calcium diet increased femoral shaft stiffness and maximum stress, and clodronate preserved
both trabecular and cortical tibial bone volume completely.
Received: 11 June 1996 / Accepted: 5 March 1997 相似文献
5.
Inhibition of bone resorption by alendronate and risedronate does not require osteoclast apoptosis 总被引:8,自引:0,他引:8
Bisphosphonate inhibition of bone resorption was proposed to be due to osteoclast apoptosis. We tested this hypothesis for both the N-containing bisphosphonates alendronate and risedronate, which inhibit farnesyldiphosphate synthase and thus protein isoprenylation, and for clodronate and etidronate, which are metabolized to adenosine triphosphate (ATP) analogs. We found, in dose-response studies, that alendronate and risedronate inhibit bone resorption (in pit assays) at doses tenfold lower than those reducing osteoclast number. At an N-bisphosphonate dose that inhibited resorption and induced apoptosis, the antiapoptotic caspase inhibitor, Z-VAD-FMK, maintained osteoclast (Oc) number but did not prevent inhibition of resorption. Furthermore, when cells were treated with either alendronate alone or in combination with Z-VAD-FMK for 24 or 48 h, subsequent addition of geranylgeraniol, which restores geranylgeranylation, returned bone resorption to control levels. On the other hand, Z-VAD-FMK did block etidronate and clodronate inhibition of resorption. Moreover, in cells treated with etidronate, but not alendronate or risedronate, Z-VAD-FMK also prevented actin disruption, an early sign of osteoclast inhibition by bisphosphonates. These observations indicate that, whereas induction of apoptosis plays a major role in etidronate and clodronate inhibition of resorption, alendronate and risedronate suppression of bone resorption is independent of their effects on apoptosis. 相似文献
6.
L. Miravet J. Redel M. Carre M. L. Queillé P. Bordier 《Calcified tissue international》1976,21(12):145-152
The biological activity of synthetic 24,25 and 25,26 diOHD3 was studied in vitamin D-deficient rats. The purpose of this study
was to investigate the influence of small doses of both metabolites (0.125–0.250 μg) upon intestinal calcium transport and
bone calcium mobilization. Both metabolites were able to increase calcium absorption in rats maintained on a calcium-deficient
diet, but failed to do it in rats on a normal calcium diet. Bilateral nephrectomy suppressed this effect. The “bone calcium
mobilization” of both derivatives was measured in vitamin D and calcium- or phosphorus-deprived rats after one intravenous
dose. When serum calcium was initially low, 24,25 and 25,26 diOHD3 increased serum calcium moderately, but the increment was
only significant with 24,25 diOHD3. When serum calcium was normal before the injection, both metabolites decreased serum calcium
significantly, and the decrease was greater with 24,25 diOHD3.
Intraperitoneal administration of the metabolites for 5 consecutive days produced a significant increase of calcium in serum
and bone ash. 相似文献
7.
BM 21.0955, a potent new bisphosphonate to inhibit bone resorption. 总被引:12,自引:0,他引:12
R C Mühlbauer F Bauss R Schenk M Janner E Bosies K Strein H Fleisch 《Journal of bone and mineral research》1991,6(9):1003-1011
A total of 300 new bisphosphonates were screened for their effect on bone resorption in the rat. Among these, 1-hydroxy-3-(methylpentylamino)propylidenebisphosphonate (BM 21.0955) was selected for detailed investigation. It inhibited arotinoid-stimulated bone resorption as assessed by calcemia in thyroparathyroidectomized rats at a SC dose as low as 0.001 mg P (0.016 mumol) per kg body weight per day. The compound was thus about 2, 10, 50, and 500 times more potent than risedronate, alendronate, pamidronate, and clodronate, respectively. Intravenous administration was as effective as subcutaneous, and oral administration was 100 times less effective. The effect after one administration decreased with time but was still measurable after 2 weeks. Nonstimulated bone resorption assayed by the urinary excretion of radiolabeled tetracycline from lifelong prelabeled animals was also inhibited. This effect started 3 days after a single dose and was still maximal after 7 days. Histomorphometric analysis of the tibial metaphysis in growing intact rats also showed an inhibition of bone resorption along with an increase in bone mass. The number of osteoclasts increased in animals treated with 0.01 and 0.1 mg P per kg (0.16 and 1.6 mumol/kg) body weight SC but decreased in animals given 1 mg P per kg (16.1 mumol/kg), showing that the inhibition of bone resorption was not due to an inhibition of osteoclast recruitment. No inhibition of mineralization occurred. This new bisphosphonate appears to have great potential for use in human bone disease. 相似文献
8.
Tabuchi M Miyazawa K Kimura M Maeda H Kawai T Kameyama Y Goto S 《Calcified tissue international》2005,77(4):239-249
Osteoprotegerin (OPG) is a novel secreted member of the tumor necrosis factor receptor family which plays a crucial role in
negative regulation of osteoclastic bone resorption. We investigated both the quantity and quality of heterotopic new bone
induced by crude bone morphogenetic protein (BMP) as a means of examining bone metabolism by bisphosphonate administration
in OPG−/− mice. Four weeks after implantation of crude BMP, the volume of heterotopic new bone in OPG−/− mice without alendronate was significantly less than in wild-type (WT) mice. Alendronate treatment of OPG−/− mice resulted in enhancement of the volume of heterotopic new bone. Histological findings revealed that WT mice showed normal
bone formation with persistent cartilage that was interspersed with islands of bone. In contrast, the cartilage was replaced
by trabecular bone and bone marrow adipocytes in OPG−/− mice without alendronate. However, some cartilage was still present in OPG−/− mice with alendronate compared to those without alendronate. All bone formation-related parameters and bone resorption-related
parameters were significantly lower in OPG−/− mice with alendronate than in those without alendronate. These findings suggest that in stimulated osteoclastogenesis without
OPG, osteoinductive activity induced by crude BMP is inhibited and endochondral ossification induced by crude BMP is accelerated.
On the other hand, alendronate treatment of OPG−/− mice caused osteoinductive activity induced by crude BMP to increase and endochondral ossification induced by crude BMP to
be decelerated. In conclusion, inhibition of stimulated osteoclastogenesis results in the enhancement of new bone formation
and normalization of endochondral ossification. 相似文献
9.
Clodronate Prevents Bone Loss in Aged Ovariectomized Rats 总被引:1,自引:1,他引:0
K. Kippo R. Hannuniemi L. Laurén Z. Peng P. Isaksson T. Virtamo T. Österman I. Pasanen R. Sellman H. K. Väänänen 《Calcified tissue international》1997,61(2):151-157
The purpose of this study was to investigate the ability of clodronate to prevent ovariectomy (OVX)-induced osteopenia in
aged rats. Fourteen-month-old female Sprague-Dawley rats (n = 166) were randomized into six groups. One group was sacrificed
at the start of the study, four groups were ovariectomized, and one group was sham-operated (Sham). The OVX rats were given
subcutaneously either vehicle (veh) or clodronate at doses of 3, 7, or 25 mg/kg once a week for 3 months, and the Sham rats
were given the vehicle. At all dose levels clodronate inhibited trabecular bone loss in the distal femur and in the fourth
lumbar vertebral body (L4), and decreased bone resorption as evidenced by urinary deoxypyridinoline excretion. The lowest
dose of clodronate preserved serum osteocalcin and endosteal bone formation of secondary spongiosa in L4 at the level of the
Sham/veh group. The OVX-induced increase in periosteal bone formation of femoral diaphysis was unaffected by two smaller doses
of clodronate, but was decreased to the level of Sham rats after the highest dose. After 3 mg/kg clodronate, the percentage
of femoral cortical bone area and the mean relative cortical thickness were higher compared with the OVX/veh group. There
was a good positive correlation between the maximum load in three-point bending of the tibia and tibial ash weight. Normal
lamellar pattern of newly formed cancellous and cortical bone was found after clodronate treatment. No signs of adverse accumulation
of osteoid or any deleterious effect on mechanical strength of long bones and lumbar vertebrae were found.
Received: 28 August 1996 / Accepted: 5 March 1997 相似文献
10.
Antagonistic effects of different classes of bisphosphonates in osteoclasts and macrophages in vitro. 总被引:6,自引:0,他引:6
Nitrogen-containing bisphosphonates, such as alendronate and ibandronate, inhibit bone resorption by preventing protein prenylation in osteoclasts, whereas non-nitrogen-containing bisphosphonates, such as clodronate, are metabolized to nonhydrolyzable analogs of ATP, resulting in osteoclast apoptosis. Because these two classes of bisphosphonates have different molecular mechanisms of action, we examined in vitro whether combined treatment with clodronate and alendronate would alter antiresorptive effectiveness. Although, in cultures of rabbit osteoclasts, the antiresorptive effect of 10 microM alendronate was increased by the addition of clodronate, the effect of higher concentrations of alendronate was not altered by addition of clodronate. Furthermore, the inhibition of protein prenylation in osteoclasts caused by higher alendronate concentrations was partially prevented by cotreatment with clodronate. As in osteoclasts, the inhibition of protein prenylation in J774 cells caused by alendronate or ibandronate treatment was dose-dependently prevented by cotreatment with clodronate. Furthermore, alendronate-induced J774 apoptosis was significantly inhibited in the presence of clodronate. The presence of clodronate also decreased the short-term cellular uptake of [14C]ibandronate. These observations suggest that combined treatment with clodronate could enhance the antiresorptive effect of a low concentration of nitrogen-containing bisphosphonate, but clodronate can also antagonize some of the molecular actions and effects of higher concentrations of nitrogen-containing bisphosphonates. The exact molecular basis for the antagonistic effects between bisphosphonates remain to be determined, but could involve competition for cellular uptake by a membrane-bound transport protein. 相似文献
11.
Dr. L. Miravet J. Redel M. Carre M. L. Queillé P. Bordier 《Calcified tissue international》1976,21(1):145-152
The biological activity of synthetic 24,25 and 25,26 diOHD3 was studied in vitamin D-deficient rats. The purpose of this study was to investigate the influence of small doses of both metabolites (0.125–0.250 μg) upon intestinal calcium transport and bone calcium mobilization. Both metabolites were able to increase calcium absorption in rats maintained on a calcium-deficient diet, but failed to do it in rats on a normal calcium diet. Bilateral nephrectomy suppressed this effect. The “bone calcium mobilization” of both derivatives was measured in vitamin D and calcium- or phosphorus-deprived rats after one intravenous dose. When serum calcium was initially low, 24,25 and 25,26 diOHD3 increased serum calcium moderately, but the increment was only significant with 24,25 diOHD3. When serum calcium was normal before the injection, both metabolites decreased serum calcium significantly, and the decrease was greater with 24,25 diOHD3. Intraperitoneal administration of the metabolites for 5 consecutive days produced a significant increase of calcium in serum and bone ash. 相似文献
12.
Bisphosphonates have been used effectively to treat established osteoporosis and prevent postmenopausal bone loss. However,
the optimal manner of its administration—whether cyclic or continuous—has not been well established. This study investigated
the efficacy of cyclic and continuous oral administration of clodronate in 54 newly identified osteopenic postmenopausal women
in a randomized, double-blind, crossover fashion. The participants were randomly separated into two groups. The cyclic group
(n = 29) received 800 mg twice daily of oral clodronate for 2 weeks every 3 months for the first 12 months followed by placebo
for the second 12 months. The continuous group (n = 25) received placebo in the first 12 months and ingested 400 mg of clodronate
once daily for the second 12 months. The urinary amino-terminal (NTX™) and carboxy-terminal (CrossLaps™) cross-linked fragments
of type I collagen, both markers of bone resorption, showed a marked decrease (25–50%) with both regimens during the period
of active treatment. In the cyclic group, the levels of these two markers increased in the second 12 months with placebo,
but did not return to the baseline completely. However, bone mineral density (BMD), determined by dual-energy X-ray absorptiometry
(DXA), showed no significant change of BMD at various sites after 1 year of active treatment in both groups. Thoracic and
lumbar spine X-ray showed no new vertebral fracture in either group after 2 years of treatment. With the two treatment protocols
in this study, oral clodronate was effective in decreasing postmenopausal bone resorption, causing no significant changes
in BMD at various sites.
Received: 16 April 1997 / Accepted: 1 October 1998 相似文献
13.
Tsukasa Izumisawa Tomio Morohashi Hitoshi Amano Shoji Yamada 《Journal of bone and mineral metabolism》1994,12(1):43-49
It has been postulated that the effect of strontium on bone metabolism due to the reduced plasma 1,25-dihydroxyvitamin D3 level following the inhibition of 1α-hydroxylation by strontium. The effects of strontium were examined on intestinal calcium
absorption when rats were received synthetic 1α-hydroxyvitamin D3. Four groups of rats at the age of 36 days were fed a semi-synthetic vitamin D-deficient diet for 4 weeks containing 1% strontium
and vitamin D3 (Sr-D group), 1% strontium and 1α-hydroxyvitamin D3 (Sr-α group), vitamin D3 (Co-D group), or 1α-hydroxyvitamin D3 (Co- α group), respectively. At the age of 60 days, calcium and strontium balance studies were conducted to determine intestinal
calcium absorption over a 3-day period, and 1,25-dihydroxyvitamin D level was then measured. Serum 1,25-dihydroxyvitamin D
in Sr-D group was undetectable, and intestinal calcium absorption significantly decreased. Replacement of vitamin D3 with 1α-hydroxyvitamin D3 recovered serum 1,25-dihydroxyvitamin D to the level in Co-D group. However, this substitution in Sr-α group failed to increase
intestinal calcium absorption. We also examined the direct of strontium on bone resorption using45Ca pre-labeled mouse calvaria. Strontium was injected every day until sacrifice, and percent45Ca release from cultured calvariae was measured. Bone resorption was inhibited by strontium dose-dependently in groups which
had and had not received parathyroid hormone in culture. These results suggest that strontium inhibits intestinal calcium
absorption and has a direct inhibitory effect on bone resorption. 相似文献
14.
Of the many compounds belonging to the diphosphonate family, clodronate has been widely used in hypercalcemia and osteolysis
of malignancy. All published reports indicate that clodronate can normalize plasma calcium in the majority of hypercalcemic,
rehydrated cancer patients in whom increased bone resorption is the prevailing disturbed calcium flux. In these patients,
clodronate, given intravenously either as a single infusion or as repeated daily administrations, can normalize serum calcium,
usually 3–5 days after the onset of therapy. In these good responders, long-term maintenance treatment should be individually
adjusted since relapse appears to depend upon the type of tumor, the extent of malignancy and the administration of anticancer
therapy. In a subset of well-rehydrated hypercalcemic patients in whom increased tubular calcium reabsorption represents the
prevailing disturbed calcium flux, the acute effect of clodronate on plasma calcium is incomplete, despite the normalization
of bone resorption. This type of therapeutic response can be experimentally reproduced in diphosphonate-treated animals receiving
a constant infusion of parathyroid hormone-related peptide, a peptide isolated from lung, kidney and breast carcinomas. This
indicates that, in addition to antiosteolytic drugs, such as clodronate, patients with hypercalcemia of malignancy would benefit
from the development of agents that can selectively reduce the renal tubular reabsorption of calcium. In patients displaying
a good response to clodronate, the fall in plasma calcium is accompanied by an increase in the calcium-regulating hormones,
parathyroid hormone and 1,25-dihydroxyvitamin D3. This homeostatic reaction probably explains why hypocalcemia rarely occurs in clodronate-treated patients. No serious side
effects have been reported in cancer patients receiving oral clodronate, except for the occasional occurrence of mild and
transient gastrointestinal upset. A large number of clinical studies indicate that clodronate is a safe and efficacious drug
in the treatment of hypercalcemia of malignancy, particularly in cases in which increased bone resorption is the major mechanism
disturbing the homeostasis of extracellular calcium. 相似文献
15.
Preclinical pharmacology of alendronate 总被引:1,自引:0,他引:1
This brief review summarizes some of the preclinical findings of studies aimed at assessing the efficacy and safety of the aminobisphosphonate alendronate (ALN) in preventing or restoring the bone loss caused by calcium or estrogen deficiency. Mode of action studies show that ALN localizes at sites of bone resorption and inhibits osteoclastic activity. In secondary hyperparathyroidism caused by calcium-deficient diets in the rat, ALN reduced the bone loss. For low doses, daily administration proved most efficient. In ovariectomized rats, ALN both prevented and reversed the bone changes produced by estrogen deficiency at oral doses equivalent to 0.1 mg/kg per day or higher, and also maintained the mechanical strength of vertebrae. In ovariectomized baboons, which show bone changes similar to those seen in ovariectomized women, ALN also prevented the increase in bone turnover and increased both bone volume and bone strength in vertebrae. In a comparative study between ALN and etidronate, we found that ALN was 1000-fold more potent in inhibiting bone resorption and had at least a 1000-fold higher safety margin with respect to inhibition of mineralization and osteomalacia. 相似文献
16.
Brown JE McCloskey EV Dewar JA Body JJ Cameron DA Harnett AN Ruutu M Purohit OP Tähtelä R Coleman RE 《Calcified tissue international》2007,81(5):341-351
Biochemical markers of bone metabolism are strongly associated with skeletal complications in metastatic bone disease. The
bisphosphonate clodronate reduces skeletal morbidity by inhibiting bone resorption. This study investigated the use of bone
markers to assess the efficacy of oral clodronate across a range of clinically relevant doses. There were 125 patients with
metastatic bone disease randomized to daily oral clodronate (800, 1,600, 2,400 and 3,200 mg) or placebo in a double-blind,
multicenter study. Urinary N-terminal telopeptide of type I collagen (U-NTX), serum C-terminal telopeptide of type I collagen
(S-CTX), urinary calcium (U-Ca), and bone alkaline phosphatase were measured weekly for a 6-week treatment period. Doses of
≥1,600 mg clodronate produced mean reductions of >40% in U-NTX, S-CTX and U-Ca, all significantly different from placebo (P = 0.0015, 0.001, 0.0036, respectively), after 6 weeks. Evaluation of least significant changes in markers suggested that
the commonly used 1,600 mg dose was most appropriate for breast cancer patients. However, this dose was suboptimal for other
(mainly prostate cancer) patients, who showed better response to 2,400 mg. The number of adverse events in the treatment arms
was not significantly different from that in placebo, but a higher number of patients had diarrhea in the 3,200 mg arm and
withdrew from the study. This trial is the first to explore the dose-response relationship of clodronate in oncology using
specific markers of bone turnover. It has confirmed that the 1,600 mg dose is safe and effective for breast cancer patients
but may be suboptimal for the other tumors studied. 相似文献
17.
Alendronate administration and skeletal response during chronic alcohol intake in the adolescent male rat. 总被引:3,自引:0,他引:3
F H Wezeman M A Emanuele S F Moskal J Steiner N Lapaglia 《Journal of bone and mineral research》2000,15(10):2033-2041
Alendronate is an aminobisphosphonate that inhibits bone resorption in osteoporotic humans and rats but does not induce osteomalacia. Several bisphosphonates, including alendronate, also have direct positive actions on osteoblasts, bone formation, and mineralization. We studied the effects of alendronate on skeletal development in adolescent male rats during chronic alcohol intake. Four groups of age- and weight-matched male Sprague-Dawley rats (35 days of age) were fed the Lieber-DeCarli diet containing 36% of calories as EtOH (E), the EtOH diet plus 60 mg/kg alendronate (EA) every other day intraperitoneally (ip), an isocaloric diet (I), or the isocaloric diet plus 60 mg/kg alendronate (IA) every other day ip. Body weight, femur length, serum levels of osteocalcin (OC), insulin-like growth factor 1 (IGF-1), testosterone, and luteinizing hormone (LH); femur distal metaphyseal and middiaphyseal bone mineral density (BMD) and tibial metaphyseal gene expression for alpha-1-type I collagen (Col I), OC, and bone alkaline phosphatase (AP); and femur strength by four-point bending to failure were measured after 28 days of feeding and alendronate injections. Serum alcohol levels at death were 156 +/- 13 mg/dl (E) and 203 +/- 40 mg/dl (EA). Alendronate given to alcohol-fed rats increased metaphyseal BMD by more than 3-fold over rats fed alcohol alone. Alendronate given to isocaloric pair-fed rats increased metaphyseal BMD by more than 2.5-fold over rats fed the isocaloric diet alone. Cortical BMD was reduced by alcohol but was increased by alendronate. Alcohol consumption reduced serum IGF-1 levels, and alendronate increased IGF-1 levels in alcohol-fed rats. Serum OC, testosterone, and LH were unaffected by alcohol and alendronate. Quantitative dot blot hybridization using rat complementary DNA (cDNA) probes and normalization against 18S subunit ribosomal RNA (rRNA) levels revealed no changes in tibial metaphyseal gene expression for type I collagen, osteocalcin, or alkaline phosphatase. Alcohol significantly reduced the biomechanical properties of the femurs that were partially compensated by alendronate. Chronic alcohol consumption uncouples formation from ongoing resorption, and resorption is inhibited by alendronate. However, alendronate's positive effects on osteoblast-mediated mineralization during chronic alcohol consumption point to the potential use of bisphosphonates in the treatment of decreased bone formation secondary to alcohol-induced diminished osteoblast function. 相似文献
18.
Absorptive hypercalciuria (AH), a common stone-forming condition characterized biochemically by intestinal hyperabsorption of calcium and hypercalciuria may be associated with bone loss. In AH type I (AH-1), hypercalciuria persists despite restriction in dietary calcium intake. We therefore hypothesized that the skeleton may contribute to the hypercalciuria in this subgroup of patients. Histomorphometric analysis of iliac crest biopsies were performed on nine stone-formers with AH-1 and on nine matched normal subjects. After stabilization on a stone-prevention diet, calcium homeostasis in the stone formers was then evaluated on inpatient constant metabolic diet before and after short-term blockade of bone resorption by alendronate (10 mg daily, 17 days total). Compared with controls, the stone-formers had lower indices of bone formation (osteoblast surface/bone surface 1.8+/-2.1 vs 3.0+/-1.5%, P=0.04; wall thickness 35.8+/-6.9 vs 47.2+/-7.6%, P=0.001) and relatively higher bone resorption (osteoclast surface/bone surface 0.4+/-0.2 vs 0.2+/-0.2%, P=0.05). In the stone-formers, a short-term course of alendronate treatment corrected fasting urinary calcium (0.14+/-0.06 to 0.06+/-0.04 mg Ca/mg Cr, P=0.001) and marginally reduced 24-h urinary calcium by 48 mg/day (P=0.06). Increased intestinal calcium absorption and hypercalciuria persisted, but estimated calcium balance improved (P=0.007). Our results suggest that the hypercalciuria of AH-1 originates primarily from intestinal hyperabsorption of calcium, but bone resorption in excess of bone formation may contribute. 相似文献
19.
Summary The object of this study was to investigate whether a calcium-deficient diet increases the bone loss produced by mechanical
hypofunction (disuse) in the rat. Male Sprague-Dawley rats of approximately 150 g were placed on either a normal diet or a
calcium-deficient diet. After 7 days, all rats underwent unilateral hind-limb immobilization by sciatic neurectomy and were
sacrificed 30 hours, 72 hours, or 10 days postsurgery. Femora were ashed and the total mineral content (ash weight) was determined.
Tibiae were embedded, sectioned, and stained. The metaphyseal secondary spongiosa and the diaphyseal cortical bone were subjected
to histomorphometric analysis. Femoral length and serum calcium were not affected by calcium intake or immobilization. Serum
parathyroid hormone levels were elevated in rats on the calcium-deficient diet compared to those on the normal diet. Calcium
deficiency caused a significant reduction in femoral ash weight (20–35%), tibial cortical thickness (16–20%), and trabecular
bone volume (TBV) (33–39%) at 72 hours and 10 days postsurgery. Additional loss of bone mass occurred in the immobilized limb
compared to the contralateral intact limb of both dietary groups. This loss occurred earlier (30 hours postsurgery versus
72 hours) in the animals on a calcium-deficient diet and was larger compared to animals on a normal diet (10.6% versus 4.8%
at 72 hours and 17.9% versus 12.45% at 10 days). The total bone loss induced by the combination of a calcium-deficient diet
and immobilization in this experiment was estimated to equal 46% of femoral ash weight and 79% of tibial TBV. Calcium deficiency
increased the number of osteoclasts/mm bone surface in the secondary spongiosa by 25–45%. Immobilization caused a further
increase of 50–60% by 72 hours postsurgery. Endosteal mineral apposition rate was significantly decreased (27–44%) by immobilization
but was not altered by the low-calcium diet. These data suggest that dietary calcium deficiency augments immobilization-related
osteopenia by increasing bone resorption. 相似文献
20.
Koivukangas A Tuukkanen J Lehenkari P Peura R Hannuniemi R Kippo K Jämsä T Jalovaara P 《Journal of bone and mineral metabolism》2002,20(4):223-227
Bisphosphonates (BPs) are known to increase bone mineral density, but it is not known how this increase manifests at low
hierarchic levels of the bone structure. The present study aimed to clarify the effects of the long-term use of clodronate
on the microstructure and chemical composition of bone. The second lumbar vertebral body (L2) in growing rats, subjected to
32 weeks' treatment with clodronate at either a therapeutic dose of 2 mg/kg, or a high dose of 10 mg/kg, or physiological
saline (control group), was studied by scanning electron microscopy for morphology, by backscattered electron image (BSE)
for density, and by energy dispersive spectrometry for material analysis. BSE images showed that the degree of mineralization
in the different areas of trabecular bone of the vertebral body varied in both the control and the study groups, but this
variation seemed to be different in the control and study groups. BSE analysis showed that there was more high-density bone
(white area) in the low-dose clodronate group than in the controls, but the difference between the high-dose clodronate group
and the control group was not significant. The density of the white area (high-density bone) was slightly increased in the
low-dose clodronate group. There were no differences in the density of the gray area (low-density bone) between the groups.
Neither the distribution of Ca, P, or Mg, nor the total mineral content, was affected by the clodronate treatment. Our results
indicate that long-term clodronate treatment at the therapeutic level increases the proportion of high-density bone in the
vertebral body in non-osteoporotic rats.
Received: October 29, 2001 / Accepted: January 25, 2002 相似文献