tetracycline and Osteoporosis--Postmenopausal

In a substudy of the HORIZON pivotal fracture trial, in which yearly intravenous zoledronic acid 5 mg was found to significantly reduce risk of various fracture types in patients with postmenopausal osteoporosis, 152 patients underwent bone biopsy. Zoledronic acid reduced bone turnover by 63% and preserved bone structure and volume, with evidence of ongoing bone remodeling in 99% of biopsies obtained.. In the HORIZON pivotal fracture trial (PFT), enrolling 7,736 women with postmenopausal osteoporosis, three annual intravenous infusions of the bisphosphonate zoledronic acid (5 mg) significantly reduced morphometric vertebral, clinical vertebral, hip, and nonvertebral fractures by 70%, 77%, 41%, and 25%, respectively. Whereas 79% of patients received zoledronic acid/placebo only (stratum I, n = 6,113), 21% received concomitant treatment with other antiresorptive drugs, excluding other bisphosphonates, PTH, and strontium (stratum II, n = 1,652).. To determine effects on bone remodeling and bone architecture, iliac crest bone biopsies were obtained in 152 patients on active treatment or placebo at 3 yr after double tetracycline labeling. In five patients, only qualitative histology was performed, leaving 147 biopsy cores (79 on active treatment and 68 on placebo) for microCT analysis and histomorphometry.. Analysis of bone structure by microCT revealed higher trabecular bone volume (BV/TV) in the zoledronic acid group (median, 16.6% versus 12.8%; p = 0.020). In addition, patients treated with zoledronic acid exhibited higher trabecular numbers (p = 0.008), decreased trabecular separation (p = 0.011), and a trend toward improvement in connectivity density (p = 0.062), all indicating better preservation of trabecular structure after treatment with zoledronic acid. Qualitative analysis revealed presence of tetracycline label in 81 of 82 biopsies from patients on zoledronic acid and all 70 biopsies from placebo patients, indicative of continued bone remodeling. No bone pathology was observed. Zoledronic acid induced a 63% median (71% mean) reduction of the activation frequency (Ac.f; p < 0.0001) and reduced mineralizing surface (MS/BS; p < 0.0001) and volume referent bone formation rate (BFR/BV) versus placebo, indicating reduced bone turnover. Mineral appositional rate was higher in the zoledronic acid group (p = 0.0002), suggesting improved osteoblast function compared with placebo. Mineralization lag time was similar in the two groups, whereas osteoid volume (OV/BV; p < 0.0001) and osteoid thickness (O.Th; p = 0.0094) were lower in zoledronic acid-treated patients, indicating normal osteoid formation and mineralization of newly formed bone. Concomitant administration of other antiresorptive osteoporosis therapies (e.g., raloxifene, tamoxifen, tibolone, ipriflavone) did not significantly alter the tissue level response to zoledronic acid.. Annual dosing for 3 yr with zoledronic acid 5 mg intravenously resulted in a median 63% (mean, 71%) reduction of bone turnover and preservation of bone structure and mass without any signs of adynamic bone. Concomitant treatment with other osteoporosis therapies did not significantly affect the bone response to zoledronic acid.

Topics: Aged; Biopsy; Bone and Bones; Bone Remodeling; Diphosphonates; Female; Humans; Imidazoles; Infusions, Intravenous; Osteoporosis, Postmenopausal; Tetracycline; Zoledronic Acid

Estrogen replacement is currently the preferred therapy for postmenopausal osteoporosis, although its mechanism of action remains poorly understood. Its primary action on bone is generally considered to be antiresorptive, but there is evidence in animals to suggest a stimulatory effect on bone formation. We have now attempted to detect a similar effect in humans by administering hormone replacement therapy (estradiol valerate 2 mg/day and dydrogesterone 5 mg/day given in a continuous, combined manner) to ten postmenopausal women. We carried out histomorphometric analyses of transiliac bone biopsies after quadruple tetracycline labeling, which was commenced before and continued during the first 4 weeks of hormone replacement therapy. Biochemical markers of bone turnover suggested that bone resorption decreased, but no significant effects on histomorphometric parameters of bone formation were detected. We conclude that hormone replacement therapy at the dose given does not stimulate bone formation in the iliac crest as assessed by histomorphometry.

Topics: Absorptiometry, Photon; Amino Acids; Biomarkers; Bone Density; Bone Development; Drug Therapy, Combination; Dydrogesterone; Estradiol; Estrogen Replacement Therapy; Female; Femur Neck; Follicle Stimulating Hormone; Humans; Ilium; Lumbar Vertebrae; Luteinizing Hormone; Middle Aged; Osteoporosis, Postmenopausal; Tetracycline

Osteonecrosis of the jaws (ONJ) associated with bisphosphonate therapy is being reported with increasing frequency all over the world. Pain may be the presenting symptom commonly associated with intra-oral bone exposure. The aetiology of this therapeutic complication is still not well understood. Three cases are presented and the management of the condition is discussed.

Topics: Aged; Anti-Bacterial Agents; Anti-Infective Agents, Local; Bone Density Conservation Agents; Chlorhexidine; Diphosphonates; Facial Pain; Female; Humans; Imidazoles; Jaw Diseases; Male; Middle Aged; Osteonecrosis; Osteoporosis, Postmenopausal; Tetracycline; Zoledronic Acid

We describe a quadruple tetracycline labeling method that allows longitudinal assessment of short-term changes in bone formation in a single biopsy. We show that 1 month of hPTH(1-34) treatment extends the bone-forming surface, increases mineral apposition rate, and initiates modeling-based formation.. Iliac crest biopsy, with histomorphometric evaluation, provides important information about cellular activity in bone. However, to obtain longitudinal information, repeat biopsies must be performed. In this study, we show the capability to obtain short-term longitudinal information on bone formation in a single biopsy using a novel, quadruple labeling technique.. Two tetracycline labels were administered using a standard 3 days on, 12 days off, 3 days on format. Four weeks later, the tetracycline labeling was repeated using the same schedule but with a different tetracycline that can be distinguished from the first by its color under fluorescent light. Iliac crest biopsies were performed 1 week later and prepared undecalcified for histomorphometry. Indices of bone formation 1 month apart were measured and calculated using the two sets of labels. We used this method to investigate the early effects of teriparatide [hPTH(1-34)] treatment on bone formation. The results were compared with those from a group of control subjects who were quadruple-labeled, but did not receive hPTH(1-34).. Treatment with hPTH(1-34) dramatically stimulated bone formation on cancellous and endocortical surfaces. This was achieved by both an increase in the linear rate of matrix apposition and extension of the bone-forming surface. New bone was deposited on previously quiescent surfaces (i.e., modeling-based formation), but a proportion of this could occur by encroachment from adjacent resorption cavities.. A single transiliac crest bone biopsy, after sequential administration of two sets of tetracycline labels is a useful approach to study the short-term effects of anabolic agents on human bone. One month of hPTH(1-34) treatment extends the bone-forming surface, increases mineral apposition rate, and initiates modeling-based formation.

Topics: Anabolic Agents; Biopsy; Bone Density Conservation Agents; Female; Humans; Ilium; Longitudinal Studies; Middle Aged; Osteogenesis; Osteoporosis, Postmenopausal; Teriparatide; Tetracycline

To study the effects of 2-[3-estrone-N-ethyl-piperazine-methyl]tetracycline (XW630) on experimental osteoporosis in ovariectomized (OVX) rats.. Serum estradiol (E2) content and bone 1-carboxyglutamic acid-containing protein (BGP) content were measured by radioimmunoassay. With undecalcified bone section and tetracycline intraperitoneal labeling, the bone static and dynamic data were studied in right femur samples.. After treatment with XW630 2.5 mg.kg-1, serum BGP content increased by 75.7% but there was no change in serum E2 content and uterus weight compared with OVX rats. Compared with OVX rats, the static data of trabecular bone volume/total tissue volume, trabecular bone volume/sponge bone volume, and mean trabecular plate density were enhanced after treatment with XW630 for 13 wk. The dynamic data of single-labeled surface, double-labeled surface, trabecular osteoid surface, and bone formation rate in tissue level in XW630 group were increased and osteoid maturation period was shortened.. XW630 enhanced bone activation frequency and increased trabecular connectivity, stability, and strength. XW630 stimulated bone formation and inhibited bone resorption with no effect on reproductive system.

Topics: Animals; Estradiol; Estrogens, Conjugated (USP); Estrone; Female; Femur; Humans; Osteoporosis, Postmenopausal; Ovariectomy; Piperazines; Rats; Rats, Wistar; Tetracycline; Tetracyclines; Uterus

Changes in cancellous bone of the rat mandibular condyle following estrogen deficiency were histomorphometrically examined with 120-day-old female Fischer rats. Sixty-four animals were either ovariectomized bilaterally (ovx) or subjected to sham surgery (sham), and eight from each group were killed at 7, 14, 30, and 60 days after surgery. Seven intact animals were killed on day 0. Before killing, tetracycline and calcein were administered to all animals. Following histological observation, bone histomorphometry of the mandibular condyle was done using a confocal laser scanning microscope and an image analyzer. The sampling site was divided into two regions for analysis: (1) a "subchondral region," formed by the region connected to cartilage; and (2) a "central region," formed by the region beneath the former. The changes in these two regions were analyzed separately. In the sham group's condyle, the bone volume of the subchondral and central regions increased with the passage of time, although the bone turnover became low. This bone gain could be due to the effects of growth and the mechanical stimulus by occlusal load. In the subchondral region of the ovx group's condyle, the bone volume decreased significantly at 7 days, but recovered to reach approximately the same value as the sham group from 14 days onward. In the central region of the ovx group's condyle, the bone volume was unchanged, but revealed a significantly lower value than that of the sham group at 60 days (p < 0.01). Thus, ovariectomy inhibited bone gain, which was observed in the sham group's condyle even though there was no bone loss. On the other hand, the trabecular separation in the ovx's condyle of both the subchondral and central regions increased considerably and small marrow cavities interconnected to form a large bone marrow. Therefore, the ovx rat mandibular condyles dynamically altered their structures under the effects of estrogen deficiency and occlusal loads. Consequently, estrogen deficiency induced transient subchondral bone loss and recovery, whereas, in the central region, it inhibited bone gain. This suggests that mechanical loading modulates the normal ovx-induced bone loss found in other parts of the skeleton.

Topics: Animals; Bone Density; Bone Marrow; Cell Count; Estrogens; Female; Fluoresceins; Humans; Mandibular Condyle; Microscopy, Confocal; Osteoclasts; Osteoporosis, Postmenopausal; Ovariectomy; Radiography; Rats; Rats, Inbred F344; Tetracycline

To compare the effects of tetracycline-estrone (TE) and estrone (E) on bone histomorphometric parameters of femoral distal diaphysis in ovariectomized (OVX) rats.. Twenty female rats were randomly allocated into four groups, 5 rats in each: tetracycline-estrone (TE), estrone (E), OVX and sham operation (S). The OVX rats were used as a model for osteoporosis. After being fed with TE or E for 13 weeks, all rats were sacrificed. The effects of TE and E on bone microarchitecture and dynamics were studied by bone histomorphometry.. The histomorphometric data showed that the connectivity of trabecular bone in TE and E groups was significantly improved in comparision with that in S group (P < 0.05). The dynamic data indicated that in TE and E group, the tetracycline labelled and osteoid surfaces were remarkably increased in comparision with those in OVX group, especially the data in TE group were significantly higher than those in E group and other two groups (P < 0.05).. The connectivity of trabecular bone could be significantly improved by both TE and E. The activation frequency seemed to be higher in TE group than that in E group.

Topics: Animals; Bone Density; Estrone; Female; Femur; Humans; Osteoporosis, Postmenopausal; Ovariectomy; Random Allocation; Rats; Rats, Wistar; Tetracycline

When administered intermittently, parathyroid hormone (PTH) is a potent anabolic agent in both human and animal bone. To improve our understanding of this anabolic effect, we have examined the time course of PTH action in an established animal model of estrogen deficiency-induced bone loss: the ovariectomized rat. Animals were ovariectomized (Ovx) and allowed to lose bone for 6 weeks. A dose of 20 micrograms/kg/d of rat PTH (1-34) was administered s.c., 6 days each week for periods of 1, 2, 3, 4, 6 and 8 weeks. Animals were sacrificed for evaluation of skeletal histomorphometry of the proximal tibia and mechanical strength of the cancellous bone in the marrow cavity of the distal femur. Cancellous bone volume (Cn-BV/TV) increased gradually over 8 weeks of treatment (16.8 +/- 1.6 to 24.1 +/- 2.7%) as did the bone formation rate (0.308 +/- 0.054 to 1.659 +/- 0.293 microns3/micron2/d), as determined by an increase in both total mineralization surface (15.5 +/- 2.1 to 42.7 +/- 5.0%) and mineral apposition rate (1.88 +/- 0.20 to 3.55 +/- 0.39 microns/d). The largest increments in these variables reflecting bone formation occurred over the first week of treatment. This bone formation was accompanied by an increase in trabecular thickness (Tb.Th) (55.3 +/- 3.4 to 80.5 +/- 5.0 microns) without a corresponding increment in trabecular number (Tb.N) (3.65 +/- 0.17 to 3.55 +/- 0.26). Extensive tetracycline labels were visualized on the surface of trabecular rod-like and plate-like structures. A small transient, though not statistically significant, increase occurred in both eroded surface and urinary pyridinoline concentration immediately after the onset of PTH administration. Osteocalcin showed a small decrement in the first two weeks after PTH administration, but the levels were elevated when compared with the Ovx control in later weeks. Mechanical strength of the cancellous bone also increased significantly with PTH treatment (20.5 +/- 2.4 to 46.1 +/- 10.0 Newtons). Our results showed that: 1) intermittent PTH treatment of Ovx rats elicited an immediate increase of bone formation activity by the existing osteoblasts, 2) the increase of Cn-BV/TV after PTH administration resulted primarily from an increase in Tb.Th, and 3) improved mechanical strength after PTH treatment can be achieved by increases in Tb.Th without an increase in Tb.N.

Topics: Amino Acids; Analysis of Variance; Animals; Biomechanical Phenomena; Bone Density; Bone Development; Disease Models, Animal; Estrogens; Female; Femur; Humans; Injections, Subcutaneous; Microscopy, Electron, Scanning; Microscopy, Fluorescence; Osteocalcin; Osteoporosis, Postmenopausal; Ovariectomy; Parathyroid Hormone; Rats; Rats, Sprague-Dawley; Tetracycline; Tibia

Estrogen deficiency in rats is responsible for increased osteoclastic resorption and a subsequent rapid bone loss. TGF-beta, which is known to have acute effects on bone resorption in several in vitro models, has been shown to be secreted by osteoblastic cells in vitro in response to 17 beta-estradiol, but little is known about its in vivo effects on bone resorption. We therefore decided to investigate the short-term effect of TGF-beta 1 on bone resorption in ovariectomized rats. TGF-beta 1 (0.04-20 ng/injection), or vehicle, was injected daily directly into the bone marrow space, through a thin catheter implanted in the distal end of the right femur, during 4 consecutive days, starting 14 days after the ovariectomy. Bone histomorphometry was performed in the secondary spongiosa of the metaphysis of injected femurs and compared with vehicle-injected femurs of sham ovariectomized rats. Ovariectomy was associated with a marked increase in the resorption surface, a 2-fold increase in the number of osteoclasts, and no change in the number of TRAP-positive marrow cells distant from bone surfaces. Bone resorption was significantly lower in the TGF-beta 1-injected bones of ovariectomized rats, as compared with vehicle injected bones: the osteoclast surface and the number of osteoclasts were, respectively, 11.0 +/- 5.1% versus 20.8 +/- 1.3% and 287 +/- 41 versus 505 +/- 53, in bones injected with 0.2 ng of TGF-beta 1 as compared with vehicle-injected bones (mean +/- SE, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Analysis of Variance; Animals; Bone Development; Bone Marrow; Bone Resorption; Catheterization; Disease Models, Animal; Dose-Response Relationship, Drug; Estrogens; Female; Femur; Humans; Osteoclasts; Osteoporosis, Postmenopausal; Ovariectomy; Rats; Rats, Sprague-Dawley; Tetracycline; Transforming Growth Factor beta

The present study investigated the prophylactic effects of vitamin D metabolites and vitamin D metabolite combinations on static and dynamic, tetracycline-based, histomorphometric parameters in the axial skeleton of ovariectomized rats. Forty-three Fischer-344 rats (10 weeks old, 130 g each body weight, BW) were either bilaterally ovariectomized (OVX) or sham-operated (SHAM). The rats were allocated into the following groups: SHAM; OVX; OVX + 7.5 ng 1 alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3]/rat/day; OVX + 15 ng 1 alpha,24R,25-trihydroxyvitamin D3 [1,24,25-(OH)3D3]/rat/day; OVX + 75 ng 24R,25-dihydroxyvitamin D3 [24,25(OH)2D3]/rat/day; OVX + 7.5 ng 1,25(OH)2D3/rat/day + 15 ng 1,24,25(OH)3D3/rat/day; OVX + 7.5 ng 1,25(OH)2D3/rat/day + 75 ng 24,25(OH)2D3/rat/day. The vitamin D metabolites were fed orally starting 4 weeks after surgery. Urine and blood samples were collected 12 and 16 weeks postovariectomy, respectively. Sixteen weeks after surgery, all rats were sacrificed, and the first lumbar vertebrae were processed undecalcified for histomorphometric analysis. Ovariectomy induced a highly significant reduction (P less than 0.001) of cancellous bone mass in the secondary spongiosa of the lumbar vertebral body. The bone loss in OVX rats was accompanied by a distinct elevation of all histomorphometric parameters of bone formation and resorption. 1,25(OH)2D3 and both vitamin D metabolite combinations significantly raised serum calcium levels and prevented the bone loss by inhibiting the increased bone resorption in OVX rats. In the applied dosage, 1,24,25(OH)3D3 and 24,25(OH)2D3 alone were ineffective in preserving the cancellous bone of the lumbar vertebra in OVX rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Body Weight; Bone Diseases, Metabolic; Bone Resorption; Calcitriol; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Humans; Hydroxycholecalciferols; Lumbar Vertebrae; Osteoporosis, Postmenopausal; Ovariectomy; Rats; Rats, Inbred F344; Tetracycline

In 28 patients with idiopathic or postmenopausal type 1 (spinal crush fracture) osteoporosis, resorption indices and dynamic measurements of trabecular bone formation based on in vivo tetracycline labeling in 7.5 mm transiliac biopsies have been compared with trends in radial cortical and trabecular bone density measured with computed tomography. Positive correlations were observed between trabecular bone density trends in the radius and indices of bone formation in the ilium. These were improved when one of the two resorption indices was included with a formation index in bivariate regressions. Marked interindividual variations in radial bone density trends were also seen in cortical bone. These correlated poorly with trends in trabecular bone. Weak negative relationships between cortical bone trends and indices relating to bone formation and resorption were observed, but a positive association was seen with single-labeled surfaces on iliac trabeculae. If, as has been suggested, there are periodic variations in bone formation, the results suggest that axial and peripheral trabecular bone density trends are synchronized in osteoporosis, perhaps in response to systemic factors, such as circulating hormones.

Topics: Aged; Bone and Bones; Bone Density; Bone Development; Bone Resorption; Female; Humans; Ilium; Male; Middle Aged; Osteoporosis; Osteoporosis, Postmenopausal; Regression Analysis; Tetracycline

The frequency distributions of mineral apposition rate (MAR) and mineralizing surface (MS), measured separately on the intracortical, endocortical, and cancellous surfaces in 46 normal subjects and 79 patients with postmenopausal osteoporosis, indicated that MAR has a finite lower limit of 0.3 mu/day (uncorrected for section obliquity) but that MS has no finite lower limit. We conclude that in the absence of labels MAR, and indices derived from it, must be treated as missing values, but that MS and indices with MS in the numerator should be allowed to take values of zero. To avoid infinite values for indices with MS in the denominator, we propose that osteoid mineralization rate (the reciprocal of mineralization lag time) and osteoblast vigor (the reciprocal of formation period) be used instead. For surfaces with genuine single labels (SL) but no double labels, we propose that MS is calculated as SL/2 and that for MAR either the lower limit of 0.3 or the mean measured value from other surfaces be used for calculating derived indices.

Topics: Adult; Aged; Bone Density; Bone Development; Female; Humans; Middle Aged; Osteoporosis, Postmenopausal; Surface Properties; Tetracycline