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PubMed2005

Nano-mechanics of bone and bioactive bone cement interfaces in a load-bearing model.

Many bioactive bone cements were developed for total hip replacement and found to bond with bone directly. However, the mechanical properties at the bone/bone cement interface under load bearing are not fully understood. In this study, a bioactive bone cement, which consists of strontium-containing hydroxyapatite (Sr-HA) powder and bisphenol-alpha-glycidyl dimethacrylate (Bis-GMA)-based resin, was evaluated in rabbit hip replacement for 6 months, and the mechanical properties of interfaces of cancellous bone/Sr-HA cement and cortical bone/Sr-HA cement were investigated by nanoindentation. The results showed that Young's modulus (17.6+/-4.2 GPa) and hardness (987.6+/-329.2 MPa) at interface between cancellous bone and Sr-HA cement were significantly higher than those at the cancellous bone (12.7+/-1.7 GPa; 632.7+/-108.4 MPa) and Sr-HA cement (5.2+/-0.5 GPa; 265.5+/-39.2 MPa); whereas Young's modulus (6.3+/-2.8 GPa) and hardness (417.4+/-164.5 MPa) at interface between cortical bone and Sr-HA cement were significantly lower than those at cortical bone (12.9+/-2.2 GPa; 887.9+/-162.0 MPa), but significantly higher than Sr-HA cement (3.6+/-0.3 GPa; 239.1+/-30.4 MPa). The results of the mechanical properties of the interfaces were supported by the histological observation and chemical composition. Osseointegration of Sr-HA cement with cancellous bone was observed. An apatite layer with high content of calcium and phosphorus was found between cancellous bone and Sr-HA cement. However, no such apatite layer was observed at the interface between cortical bone and Sr-HA cement. And the contents of calcium and phosphorus of the interface were lower than those of cortical bone. The mechanical properties indicated that these two interfaces were diffused interfaces, and cancellous bone or cortical bone was grown into Sr-HA cement 6 months after the implantation.

Animals↗
PubMed2005

Local application of rhTGF-beta2 enhances peri-implant bone volume and bone-implant contact in a rat model.

Orthopedic and dental implant fixation depends upon bone regeneration. Growth factors such as transforming growth factor-beta (TGF-beta) have been shown to enhance bone repair and strengthen the mechanical connection between implant and host skeleton in canine models. To provide a platform for studying molecular mechanisms of growth factor stimulated bone regeneration and implant fixation, the present study examined peri-implant bone volume as a response to TGF-beta treatment in a rodent model. The rat femoral ablation model in which an implant is placed in the medullary cavity of the femur was used to examine the dose response to TGF-beta2 applied to the implant (0, 0.1, 1.0, or 10 microg). The study included a total of 40 rats (10 per dose) examined at 28 days. Peri-implant bone volume and bone-implant contact were assessed through microcomputed tomography and implant fixation strength was determined by a mechanical pullout test. Treatment of the implant with 10 microg TGF-beta2 led to a 2-fold increase in bone volume (P<0.001) and a 1.5-fold increase in bone-implant contact (P<0.01) with a trend of increasing fixation strength (non-significant increase of 1.4-fold). TGF-beta2 treatment with 10 microg led to uniform peri-implant bone volume and bone-implant contact along the length of the implant, whereas the other groups had less bone at the mid-point compared to the proximal and distal aspects of the implant. About 50% of the variance in implant fixation strength was explained by a regression model involving both bone-implant contact and peri-implant bone volume.

Animals↗
PubMed2005

Proliferation and osteogenic differentiation of cells from cortical bone cylinders, bone particles from mill, and drilling dust.

PURPOSE: The osteogenic potential of a graft is based on the parallel lines ability of cells to survive transplantation and to respond to local factors that stimulate new bone formation. Here we investigated the potential of cells that had grown out of porcine cortical bone grafts obtained by 3 preparation techniques to respond to mitogenic and osteogenic stimuli. MATERIALS AND METHODS: Bone grafts were harvested from 2 pigs. Cortical bone was taken in cylindrical form and ground in a bone mill or harvested via drilling and aspiration. RESULTS: Cell outgrowth was observed in all cortical bone cylinders, bone cylinders homogenized by mill, and 5 of 10 explants of bone dust collected upon drilling. After a 2-week culture period, the number of outgrown cells did not significantly differ among the 3 preparations. Bone cells showed increased proliferation in response to platelet-released supernatants as determined by 3 [H]-thymidine incorporation assay. When cultured under conditions that favor the expression of an osteogenic phenotype, the outgrown cells expressed alkaline phosphatase activity and transcripts of the osteoblast-specific marker osteocalcin. Individual cell preparations showed accumulation of mineral salts in their extracellular matrix. Bone cells also increased alkaline phosphatase activity in response to bone morphogenetic protein (BMP)-2, BMP-6, and BMP-7. The mitogenic and osteogenic response was obtained with cells from the mandible as well as from the maxilla, irrespective of the preparation technique. CONCLUSION: These data show that cortical bone grafts contain cells that have the ability to proliferate and differentiate into the osteogenic lineage, suggesting that these cells can contribute to bone regeneration following transplantation.

Alkaline Phosphatase↗
PubMed1999

A variation in Bone Alkaline Phosphatase levels that correlates positively with bone loss and normal levels of aminoterminal propeptide of collagen I in girls with anorexia nervosa.

Anorexia nervosa (AN) is a very extended pathology among adolescent girls nowadays. These patients show a high degree of osteopenia; hence, study of their bone remodelling is of great interest. Serum bone alkaline phosphatase (bAP) and aminoterminal propeptide of procollagen I (PINP) provide good sensitivity in the analysis of bone alterations in postmenopausal osteoporosis. The aim of this study was to compare the usefulness of bAP and PINP in the study of bone remodelling in AN, and their possible correlation with the degree of osteopenia in this pathology. In order to help in the interpretation of the results, levels of the beta-isomer of urinary carboxyterminal propeptide of collagen I (beta-CTX) have also been included. Serum bAP (IRMA) Tandem R-Ostase, Hybritech), PINP (RIA, Orion Diagnostica) and CTX (CrossLaps ELISA, Osteometer) were determined in 41 girls with AN, aged 18.5+/-2.2 years (mean+/-SD) and in 31 healthy control women, aged 19+/-2.3 years. Bone mineral density (BMD) in lumbar spine was measured by DEXA in the AN group. We found that 41 of the 43 patients had BMD z-scores under -2. No significant differences were found in the levels of serum bAP nor in PINP and beta-CTX levels between controls and patients, although values in the AN group were highly variable. All the BMD z-score values were negative, and their absolute value correlates positively with bAP (P = 0.0279) and almost with beta-CTX (P = 0.0921) but not with PINP (P = 0.4627). Bone AP correlates with PINP in control girls (P = 0.017), but not in the AN group (P = 0.3573). Patients with AN were divided into three groups according to their levels of bAP: low (I), normal (II) or high (III). Patients with the highest bAP levels also presented the highest increase in bone resorption, according to their beta-CTX levels, and the highest degree of osteopenia. However, values of PINP were similar in the three groups of patients. The bAP/beta-CTX ratios in subgroups I, II and III of AN patients were 0.035, 0.065 and 0.073, a finding that suggests that bAP is not indicating the real degree of bone mineralization in these patients, because it is a contradiction that the formation/resorption ratio should be higher in the patients who have the highest bone loss. These results could suggest that bone loss in AN is produced by an increase in bone resorption (beta-CTX), without variations in bone matrix formation (PINP); bAP levels are a good marker in the follow-up of osteopenia degree, but not a real indicator of bone mineralization, a similar situation to that of osteomalacia.

Adolescent↗
PubMed1996

Excretion of urinary N-telopeptides reflects changes in bone turnover during ovarian suppression and indicates individually variable estradiol threshold for bone loss.

OBJECTIVE: To evaluate the effectiveness of N-telopeptides and E2 in monitoring bone turnover during GnRH agonist- (GnRH-a) or danazol-induced hypoestrogenism. DESIGN: Comparative, nonrandomized prospective study. SETTING: Institute for the Study and Treatment of Endometriosis. PATIENT(S): Premenopausal women undergoing ovarian suppression with GnRH-a (n = 16) or danazol (n = 9). INTERVENTION(S): Serum and urine samples were collected and bone mineral density was measured before, during, and after treatment. MAIN OUTCOME MEASURE(S): N-telopeptide excretion, serum E2, and bone mineral density at L1 to L4 and femoral neck. RESULT(S): During treatment in the GnRH-a group, mean E2 levels were 53% below and N-telopeptides were 38% above the mean baseline. At 1 month post-treatment, L1 to L4 bone mineral density decreased by 3.85%. In the danazol group, E2, N-telopeptides and L1 to L4 bone mineral density changed nonsignificantly in the opposite direction with the mean 1.25% increase in L1 to L4 at 1 month post-treatment. In combined groups, L1 to L4 bone mineral density better correlated with other measures than femoral neck bone mineral density. N-telopeptide excretion was more predictive of L1 to L4 change, with correlation the highest between N-telopeptides at month 4 and bone mineral density at month 1 afterward, while E2 appeared more predictive of the less reliable femoral neck bone mineral density. Individual exceptions to the model of an E2 threshold for bone loss were observed. Also noted were high correlation between on-therapy levels of E2 and N-telopeptides, as well as the presence of a 1-month time lag between E2 and N-telopeptide changes. CONCLUSION(S): Bone density decreases during GnRH-a and may slightly increase during danazol treatment. However, E2 threshold for bone loss varies individually. N-telopeptides predict changes in bone mineral density at L1 to L4 better than E2.

Adult↗
PubMed2003

Inhibition of alpha(v)beta3 integrin reduces angiogenesis, bone turnover, and tumor cell proliferation in experimental prostate cancer bone metastases.

The growth of metastatic prostate cancer cells in the bone involves an intimate interaction between the tumor cells and various elements of the bone microenvironment, resulting in increased rate of bone turnover and rapid tumor growth. The alpha(v)beta3 integrin has been shown to play an important role in tumor growth and angiogenesis, and is known to be critical to osteoclast formation and activity. This study was designed to examine the role of alpha(v)beta3 expressed by cells native to the bone in the growth and pathogenesis of prostate cancer bone metastases. Human prostate cancer cells which do not express alpha(v)beta3 or alpha(IIb)beta3 integrins were injected directly into human bone fragments previously implanted subcutaneously in SCID mice (SCID-human-bone model). At the same time treatment with anti-beta3 antibody fragment (m7E3 F(ab')2) i.p. at 300 microg/dose 3 x per week was initiated and continued for 2 weeks. In this system, m7E3 F(ab')2 only recognizes human bone-derived alpha(v)beta3. Antibody inhibition of alpha(v)beta3 integrin in vivo resulted in a specific reduction in the proportion of antigenically-human blood vessels within tumor-bearing bone implants (from 73.5% +/- 3.93 in controls to 17.74% +/- 5.64 in treated animals). Proliferation of the alpha(v)beta3-negative tumor cells was also reduced, although the overall vessel density was maintained by compensating mouse vasculature. Blockage of human bone-derived alpha(v)beta3 also significantly reduced the recruitment of osteoclasts in response to tumor cells, as well as degradation of calcified bone tissue. Together these observations confirm the importance of alpha(v)beta3 in bone metabolism and angiogenesis, and point to the role of these processes in controlling growth of metastatic prostate cancer cells in the bone.

Animals↗
PubMed1988

1987 Douglas Lea memorial lecture. Particle dosimetry in bone and the toxicity of bone-seeking radionuclides.

Consideration is given to the tissues at risk in bone and a Monte Carlo method is described which determines the absorbed dose to endosteal tissues and marrow in trabecular bone. The method synthesizes random tracks through the trabecular structures that deposit energy along a path through any given trabecular cavity. The path lengths through the trabeculae and marrow cavities are measured with a bone-scanning microscope and other bone data, such as trabecular surface areas, can also be derived. Results are given for human bones and for bones of the beagle, miniature pig and rhesus monkey. They show that, for the same radionuclide concentration, the doses to endosteal tissues and bone marrow are several times greater in animal than in human bone, and that higher doses in human bone from the Ca and Sr radionuclides are obtained if the initial deposition on bone surfaces is allowed for. Other studies show that the occurrence of osteosarcoma in the human long bones correlates well with trabecular surface area and also that, unlike the case of beta-particles from 90Sr+90Y, leukaemia is not a significant consequence of the alpha-particle doses from 226Ra in human bone or from 226Ra, 239Pu and other alpha emitters in beagle bone.

Bone Neoplasms↗
PubMed2003

A hyperboliod representation of the bone-marrow interface within 3D NMR images of trabecular bone: applications to skeletal dosimetry.

Recent advances in physical models of skeletal dosimetry utilize high-resolution NMR microscopy images of trabecular bone. These images are coupled to radiation transport codes to assess energy deposition within active bone marrow irradiated by bone- or marrow-incorporated radionuclides. Recent studies have demonstrated that the rectangular shape of image voxels is responsible for cross-region (bone-to-marrow) absorbed fraction errors of up to 50% for very low-energy electrons (<50 keV). In this study, a new hyperboloid adaptation of the marching cube (MC) image-visualization algorithm is implemented within 3D digital images of trabecular bone to better define the bone-marrow interface, and thus reduce voxel effects in the assessment of cross-region absorbed fractions. To test the method, a mathematical sample of trabecular bone was constructed, composed of a random distribution of spherical marrow cavities, and subsequently coupled to the EGSnrc radiation code to generate reference values for the energy deposition in marrow or bone. Next, digital images of the bone model were constructed over a range of simulated image resolutions, and coupled to EGSnrc using the hyperboloid MC (HMC) algorithm. For the radionuclides 33P, 117mSn, 131I and 153Sm, values of S(marrow<--bone) estimated using voxel models of trabecular bone were shown to have relative errors of 10%, 9%, <1% and <1% at a voxel size of 150 microm. At a voxel size of 60 microm, these errors were 6%, 5%, <1% and <1%, respectively. When the HMC model was applied during particle transport, the relative errors on S(marrow<--bone) for these same radionuclides were reduced to 7%, 6%, <1% and <1% at a voxel size of 150 microm, and to 2%, 2%, <1% and <1% at a voxel size of 60 microm. The technique was also applied to a real NMR image of human trabecular bone with a similar demonstration of reductions in dosimetry errors.

Algorithms↗
PubMed2002

Effects of enamel matrix derivative on mineralized tissue formation during bone wound healing in rat parietal bone defects.

Enamel matrix derivative (EMD: Emdogain) has been reported to stimulate the biosynthesis and regeneration of trabecular bone. To address whether the biological action of EMD is dependent on the local environment of osseous tissue, circular perforations were made in parietal bones and immediately filled with either EMD or its carrier, propylene glycol alginate (PGA), as control. On post-operative days 4-60, the dissected bones were examined by various histological techniques. New bone matrix, which was immunoreactive for bone sialoprotein (BSP), was formed from the periosteum at the peripheral area of perforations. Different from the findings reported in injured long bones, mineralized tissue was produced in the regenerating connective tissue within bone defects. This mineralized tissue was hardly immunostained for BSP, contained few collagen fibres, and lacked osteocytic lacunae and layers of osteoblasts and osteoid. Energy-dispersive X-ray analysis showed that Ca and P weight % and Ca/P molar ratio of this mineralized tissue were similar to or slightly higher than those in the pre-existing parietal bones. In addition, most multinucleated cells located in mineralized tissue lacked a ruffled border structure and showed weak immunoreaction for the lysosomal cysteine proteinase, cathepsin K, whereas those located in the bone matrix exhibited ruffled borders and strong cathepsin K expression. However, multinucleated cells located in both tissues were strongly stained for tartrate-resistant acid phosphatase. The volume fraction of such mineralized tissue appeared to be higher in EMD-applied bones than in PGA-applied controls. The mineralized tissue-forming stromal cells within bone defects appeared to show greater accumulation in EMD-applied bones than in PGA-applied controls. Our results suggest that the bioactive effects of EMD on bone wound healing and mineralized tissue formation depend, at least in part, on the local osseous environment where EMD has been applied.

Animals↗
PubMed2004

Bone morphogenetic protein 7: a novel treatment for chronic renal and bone disease.

PURPOSE OF REVIEW: When last reviewed, bone morphogenetic protein 7 was presented as a potential new renal therapeutic agent, with multiple efficacies in chronic kidney disease. The object of this review is to describe progress from many sources since then in support or denial of the hypothesis. RECENT FINDINGS: Bone morphogenetic protein 7 has been shown to be an effective defence in several forms of chronic kidney disease in animal models, and its mechanisms of action have begun to be elucidated. Bone morphogenetic protein 7 inhibits tubular epithelial cell de-differentiation, mesenchymal transformation and apoptosis stimulated by various renal injuries. Bone morphogenetic protein 7 preserves glomerular integrity and inhibits injury-mediated mesangial matrix accumulation. In renal osteodystrophy, bone morphogenetic protein 7 affects osteoblast morphology and number, eliminates peritrabecular fibrosis, decreases bone resorption, and increases bone formation in secondary hyperparathyroidism. Bone morphogenetic protein 7 restores normal rates of bone formation in the adynamic bone disorder. Bone morphogenetic protein 7 is broadly efficacious in renal osteodystrophy, and importantly increases the skeletal deposition of ingested phosphorus and calcium, improving ion homeostasis in chronic kidney disease. Bone morphogenetic protein 7 was shown to prevent vascular calcification in a model of chronic kidney disease associated with the restoration of osteocalcin expression to normal tissue-restricted sites. SUMMARY: Bone morphogenetic protein 7 may be a powerful new therapeutic agent for chronic kidney disease, with the novel attribute of not only treating the kidney disease itself, but also directly inhibiting some of the most important complications of the disease state.

Bone Morphogenetic Protein 7↗
PubMed2006

Commercially available demineralized bone matrix compositions to regenerate calvarial critical-sized bone defects.

BACKGROUND: Demineralized bone matrix products are often used by surgeons to regenerate bone. Several different types of carriers have been combined with demineralized bone matrix to improve clinical handling and surgical outcome. The aim of the study was to quantitate bone regeneration in standard-sized calvarial defects (a critical-sized defect) in response to commercially available demineralized bone matrix formulations. METHODS: The commercial demineralized bone matrix formulations were tested as received in 8-mm-diameter calvarial critical-sized defects in an athymic rat model. The demineralized bone matrix treatment groups included the following: (1) Allomatrix; (2) demineralized bone matrix plus sodium hyaluronate (DBX); (3) DBX with poly(DL-lactide) mesh; 4) Dynagraft; (5) Grafton; (6) Regenafil; and (7) human demineralized bone matrix without a carrier. An eighth treatment was a poly(DL-lactide) mesh. At designated times of 2, 4, and 8 weeks, the critical-sized defects were recovered and processed for undecalcified histology and histomorphometry. Histomorphometric data were subjected to an analysis of variance and Fisher's protected least significant difference multiple comparison test. Significance was established at p <or= 0.05. RESULTS: Allomatrix, Dynagraft, Regenafil, and poly(DL-lactide) mesh alone had less bone formation than DBX, Grafton, DBX plus mesh, and demineralized bone matrix. CONCLUSIONS: DBX, DBX plus mesh, demineralized bone matrix, and Grafton produced more bone formation than Allomatrix, Dynagraft, mesh alone, and Regenafil.

Animals↗
PubMed2001

Effect of statins on bone mineral density and bone histomorphometry in rodents.

Statins have been postulated to affect bone metabolism. We investigated the effects of different doses of simvastatin (1, 5, 10, and 20 mg. kg(-1). d(-1)), atorvastatin (2.5 mg. kg(-1). d(-1)), and pravastatin (10 mg. kg(-1). d(-1)) administered orally for 12 weeks to intact female Sprague-Dawley rats and the effect of 20 mg. kg(-1). d(-1) simvastatin in sham-operated and ovariectomized rats on femoral bone mineral density (BMD) and quantitative bone histomorphometry (QBH) and compared them with controls. BMD was decreased by 1 mg. kg(-1). d(-1) simvastatin (P=0.042), atorvastatin (P=0.0002), and pravastatin (P=0.002). The effect on QBH parameters differed with different doses of simvastatin (ANOVA, P=0.00012). QBH parameters of both bone formation and resorption were equivalently and markedly increased by 20 mg. kg(-1). d(-1) simvastatin in 2 separate groups of intact rats and were reflected by a relatively unchanged BMD. At lower doses, 1 mg. kg(-1). d(-1) simvastatin decreased bone formation while increasing bone resorption, as reflected by a marked decrease in BMD. Ovariectomized animals receiving 20 mg. kg(-1). d(-1) simvastatin showed no change in BMD relative to the untreated, ovariectomized controls; their increase in bone formation was smaller than in sham-operated rats receiving simvastatin, and there was no change in bone resorption. Dose-response curves of simvastatin for bone formation and resorption differed. These studies indicate that (1) statins decrease BMD in rodents, (2) high-dose simvastatin increases bone formation and resorption, (3) low-dose simvastatin decreases bone formation and increases bone resorption, (4) the effects of simvastatin on QBH differ at different dosages, (5) the effects of simvastatin seen in intact rats are not observed in ovariectomized rats, and (6) simvastatin is unable to prevent bone loss caused by ovariectomy.

Animals↗
PubMed2002

Synergistic enhancement of bone formation and healing by stem cell-expressed VEGF and bone morphogenetic protein-4.

We investigated the interaction between angiogenic and osteogenic factors in bone formation and bone healing with ex vivo gene therapy using muscle-derived stem cells genetically engineered to express human bone morphogenetic protein-4 (BMP4), VEGF, or VEGF-specific antagonist (soluble Flt1). Our results show that although VEGF alone did not improve bone regeneration, it acted synergistically with BMP4 to increase recruitment of mesenchymal stem cells, to enhance cell survival, and to augment cartilage formation in the early stages of endochondral bone formation. These early effects, coupled with accelerated cartilage resorption, eventually led to a significant enhancement of bone formation and bone healing. The beneficial effect of VEGF on bone healing elicited by BMP4 depends critically on the ratio of VEGF to BMP4, with an improper ratio leading to detrimental effects on bone healing. Finally, we show that soluble Flt1 inhibits bone formation elicited by BMP4. Thus, VEGF plays an important role in bone formation elicited by BMP4, and it can significantly enhance BMP4-elicited bone formation and regeneration through multiple mechanisms. This study has important implications for the formulation of new strategies to improve bone healing through increasing mesenchymal stem cell recruitment and survival, in combination with muscle-derived stem cell-based gene therapy.

Animals↗
PubMed2002

Clinical and biochemical determinants of bone metabolism and bone mass in adolescent female patients with anorexia nervosa.

Among pathologies prevalent in western societies, anorexia nervosa has increased over the last decade. Its effects on bone mass need to be defined, and prognostic factors, either clinical or biochemical, could aid clinicians in individual patient management. To determine which clinical and/or biochemical parameters could be related to bone mass status in adolescent female anorexia nervosa patients, 73 female patients were classified according to different stages of their illness and studied in terms of clinical and biochemical parameters and bone densitometric mineral content at lumbar spine. Patients (age 17.2 +/- 1.7 y, mean +/- SD) with Tanner pubertal stage 5, regular menstruation for more than 3 mo before the onset of secondary amenorrhea, and diagnosed with anorexia nervosa were consecutively studied and classified in three clinical situations: I) active phase (34 patients): undernourished and amenorrheic; II) weight recovered but still amenorrheic (20 patients); III) fully recovered (19 patients). Clinical data were recorded at the time of bone density measurement, concomitant with blood sample extraction for study of IGF-I, IGF-binding protein 3 (IGFBP-3), IGFBP-1, estradiol, sex hormone-binding globulin, dehydroepiandrosterone sulfate, prealbumin, amino-terminal propeptide of procollagen III, osteocalcin, bone alkaline phosphatase, carboxy-terminal propeptide of procollagen I, amino-terminal propeptide of procollagen I, carboxy-terminal telopeptide of collagen I, 25-OH-vitamin D, 1,25(OH)(2)-vitamin D, and parathormone. In addition, a 24-h urine collection was made for cortisol, GH, deoxypyridinoline, amino-terminal telopeptide of collagen I, and calcium and creatinine content analysis. IGF-I, estradiol, and biochemical bone formation markers were higher and IGFBP-1, sex hormone-binding globulin, and biochemical bone resorption markers were lower in the weight-recovered stages (stages II and III) compared with the active phase (stage I). Bone formation markers correlated positively with body mass index SD score and IGF-I, whereas bone resorption markers correlated negatively with body mass index SD score and estradiol. Although no statistically significant differences regarding lumbar spine bone mineral density SD score values were recorded among the three stages of the illness, the proportion of osteopenic patients was clearly lower among stage III patients. The actual bone mineral density was inversely related to the duration of amenorrhea and directly related to duration of postmenarcheal menses before amenorrhea. In addition, a subset of osteopenic patients (five of 19) in the fully clinically recovered group with accelerated bone turnover was identified. Normal circulating estrogen level exposure time predicts actual bone mineral density at lumbar spine in young adolescent anorexia nervosa patients. In addition to psychiatric and nutritional interventions, estrogen-deprivation periods must be shortened to less than 20 mo. Patients remaining osteopenic at full clinical recovery require additional follow-up studies.

Adolescent↗
PubMed2003

Diabetes causes decreased osteoclastogenesis, reduced bone formation, and enhanced apoptosis of osteoblastic cells in bacteria stimulated bone loss.

The most common cause of inflammatory bone loss is periodontal disease. After bacterial insult, inflammation induces bone resorption, which is followed by new reparative bone formation. Because diabetics have a higher incidence and more severe periodontitis, we examined mechanisms by which diabetes alters the response of bone to bacterial challenge. This was accomplished with db/db mice, which naturally develop type 2 diabetes. After inoculation of bacteria osteoclastogenesis and bone resorption was measured. Both parameters were decreased in the diabetic group. Diabetes also suppressed reparative bone formation measured histologically and by the expression of osteocalcin. The impact of diabetes on new bone formation coincided with the effect of diabetes on apoptosis of bone-lining cells. Within 5 d of bacterial challenge, apoptosis declined in the wild-type animals yet remained significantly higher in the diabetic group. Thus, diabetes may cause a net loss of bone because the suppression of bone formation is greater than the suppression of bone resorption. The uncoupling of bone formation and resorption may be due in part to prolonged apoptosis of bone lining cells.

Animals↗
PubMed1990

Transforming growth factor-beta stimulates bone matrix apposition and bone cell replication in cultured fetal rat calvariae.

Transforming growth factor-beta (TGF beta) stimulates the expression of extracellular matrix proteins and may be a local regulator of bone growth. The aims of this research were to localize the effect of TGF beta on bone matrix formation and to determine if this effect was dependent on increased cell replication, using histomorphometry and autoradiography of bone organ cultures. Half-calvariae of 21-day-old fetal rats were cultured with native or recombinant TGF beta 1 for 24 h and labeled either with [3H]proline for 0-24 or 24-48 h or with [3H]thymidine for the last 6 h of culture. Bones were fixed in glutaraldehyde, embedded in glycol methacrylate, and processed for autoradiography. Bone matrix formation was assessed as the matrix apposition rate per day and the percentage of [3H]proline-labeled bone surface. Cell replication was evaluated based on the number and percentage of [3H]thymidine labeled cells in the osteoblast cell zone, the osteoprogenitor cell zone, and the pericranial fibroblastic periosteum. Both native and recombinant TGF beta at 1-30 ng/ml increased bone matrix formation by 25-40% (P less than 0.05). At 30 ng/ml, TGF beta had a generalized mitogenic effect as cell replication increased by approximately 2-fold in all cell zones of the pericranial periosteum. TGF beta had specific effects on bone cell differentiation. The number of unlabeled cells lining the bone surface increased, and the number of osteoclasts on bone decreased. Inhibition of cell replication by hydroxyurea only partially blocked the stimulatory effect of TGF beta on bone matrix formation, suggesting that TGF beta may have independent effects on cell replication and differentiated bone cell function. In summary, TGF beta had a generalized mitogenic effect on the pericranial periosteum and specific stimulatory and inhibitory effects on bone cell differentiation and function.

Animals↗
PubMed1999

Monofluorophosphate combined with hormone replacement therapy induces a synergistic effect on bone mass by dissociating bone formation and resorption in postmenopausal women: a randomized study.

Sodium fluoride stimulates bone formation and has been used to treat osteoporosis for decades despite debate about the antifracture efficacy. Hormone replacement therapy (HRT) results in only modest increases in bone mineral density (BMD). However, for women with low bone mass, the ideal therapy should not only inhibit bone resorption but simultaneously stimulate bone formation to increase bone mass above the fracture threshold. We thus performed a randomized, double-blind, placebo-controlled intervention study to prospectively investigate the effect of a low dose of fluoride, in combination with HRT, on BMD and biochemical markers of bone turnover. One hundred healthy postmenopausal women (60-70 yr old) were thus randomly assigned to: 1) HRT [transdermal 17beta-estradiol, releasing 50 microg/day; plus oral norethisterone acetate (NETA), 1 mg/day]; or 2) oral monofluorophosphate (MFP; equivalent to fluoride, 20 mg/day); or 3) HRT+MFP; or 4) placebo, for 96 weeks. All participants received a calcium supplement of 1000 mg/day. Sixty-eight women completed the study. We found a pronounced, linear increase in spinal BMD during treatment with HRT+MFP [11.8% (1.7% SEM)], which was significantly greater than the increase in the HRT group [4.0% (0.5% per yr); P < 0.05]. MFP produced a smaller increase [2.4% (0.6% per yr)], whereas there was no change in the placebo group [0.0% (0.5% SEM)]. Similar changes were found at the other skeletal sites (distal forearm, hip, and total body). Markers of bone formation showed a fall in the HRT group, which was significantly more pronounced than in the combined HRT+MFP group. A nonsignificant increase was found in the MFP group, whereas the placebo group showed a decrease caused by calcium treatment. The marker of bone resorption decreased significantly more in the HRT and the HRT+MFP groups than in the placebo group but tended to increase in the MFP group. In conclusion, this study shows, by use of biochemical markers of bone turnover, that bone resorption and formation may be dissociated, as a result of actions of two compounds with diverging effects on bone turnover. Furthermore, the synergistic effects of relatively low doses of the compounds suggested statistically and clinically significant increases in trabecular and probably also cortical bone. Adverse effects were relatively rare and mild.

Aged↗
PubMed1999

Biochemical markers of bone turnover and prediction of hip bone loss in older women: the study of osteoporotic fractures.

To examine the ability of commercially available biochemical markers of bone formation and resorption to predict hip bone loss, we prospectively obtained serum and timed 2-h urine specimens from 295 women age 67 years or older who were not receiving estrogen replacement therapy. Serum was assayed for two markers of bone formation: osteocalcin (OC) and bone-specific alkaline phosphatase (BALP). Urine specimens were assayed for four markers of bone resorption: N-telopeptides (NTX), free pyridinolines (Pyr), free deoxypyridinoline (Dpyr), and C-telopeptides (CTX). Measurements of hip bone mineral density were made at the time the samples were collected and then repeated an average of 3.8 years later. Higher levels of all four resorption markers were, on average, significantly associated with faster rates of bone loss at the total hip, but not at the femoral neck. Women with OC levels above the median had a significantly faster rate of bone loss than women with levels below the median, but there was no significant association between levels of BALP and hip bone loss. The sensitivity and specificity of higher marker levels for predicting rapid hip bone loss was limited, and there was considerable overlap in bone loss rates between women with high and low marker levels. We conclude that higher levels of urine NTX, CTX, Pyr, Dpyr, and serum OC are associated with faster bone loss at the hip in this population of elderly women not receiving estrogen replacement therapy, but these biochemical markers have limited value for predicting rapid hip bone loss in individuals.

Aged↗