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PubMed2006

Biochemical markers of bone turnover in the clinical development of drugs for osteoporosis and metastatic bone disease: potential uses and pitfalls.

Biochemical markers of bone turnover are used increasingly during the clinical development of drugs for the treatment of metabolic bone diseases such as Paget's disease, osteoporosis and cancer that has metastasised to the bone. However, assessing the optimal value of these markers is often complicated, and such an assessment is an obvious prerequisite for rational use of the markers and, consequently, potential improvement of clinical drug development. Biochemical markers of bone turnover are substances in the blood or urine that are produced or released during bone remodelling. They provide semiquantitative information on bone remodelling, and are often the most adequate tool to describe the pharmacodynamics of the drug. Their use has increased considerably because of dose-effect relationships that have been seen with certain drugs, but also because they have proven relationships with clinical outcomes in several metabolic bone diseases. However, there is a lack of information on the kinetics of these markers, and the immunoassays that are frequently used in their monitoring often measure a mixture of fragments rather than a single molecular entity. For drug development it should also be realised that different markers, but also different assays for the same marker, may provide different results, considerably limiting the ability to compare results. In postmenopausal osteoporosis, relationships have been shown between several biochemical markers of bone turnover, and either fracture risk and/or the antifracture efficacy of drugs. Such relationships can be used for the development of drugs with similar mechanisms of action, but also for the development of these drugs for closely related indications, such as corticosteroid-induced osteoporosis. In both of these instances, data on effects on biochemical markers of bone turnover are usually employed in combination with information about effects on bone mineral density. However, the relationships of these parameters with clinical outcomes may be remarkably different for drugs with alternative mechanisms of action, challenging the use of the markers for the development of new drugs for the treatment of patients with osteoporosis. At present, the pharmacological treatment of cancer that has metastasised to the bone is limited to several bisphosphonates. Recent studies have shown relationships between the normalisation of levels of biochemical markers of bone turnover and clinical outcomes, and prospective studies investigating the application of such relationships are ongoing. The markers may play an important role in the optimisation of registered bisphosphonate treatments. However, their role in the development of new drugs is still limited to dose selection, and potential relationships with clinical outcomes remain to be investigated in instances of new mechanisms of action. Biochemical markers of bone turnover are a valuable asset for drug development, but their rational use is determined by a number of variables. Correctly manipulating these may improve clinical development of drugs for the treatment of patients with metabolic bone diseases such as osteoporosis and cancer metastatic to the bone.

Adrenal Cortex Hormones↗
PubMedDate not supplied

[Bone mineral density: correlation with body weight, height, bone age and insulin-like growth factor].

OBJECTIVE: To evaluate bone mineral density and bone mineral content of skeleton and lumbar spine of pre-pubertal children and to correlate results thus found with sex, bone age, body weight, height and insulin-like growth factor 1 serum level. METHODS: 26 boys and 12 girls aged between 7 and 8 years old, students from a São Paulo public school, were studied. They all presented weight and height between 2.5 and 97.5 percentiles of the Brazilian childreńs curve, lack of secondary sex characteristics, no reports on chronic diseases and normal physical examination. Bone age was determined from radiograms of the left hand and wrist. Serum levels of insulin-like growth factor 1 were measured by radioimmunoassay. Bone mineral density and bone mineral content were measured in skeleton and lumbar spine using a dual X-ray absorptiometry equipment. RESULTS: The mean values of skeleton bone mineral density found were 0.812 -/+ 0.057 g/cm(2) in the girls and 0.839 -/+0.053 g/cm(2) in the boys, while the respective mean lumbar values were 0.649 -/+ 0.092 g/cm(2) and 0.657 -/+ 0.062 g/cm(2). The mean values of skeleton bone mineral content found were 840 -/+ 181g in the girls and 919 -/+ 133 g in the boys, while the respective lumbar values were 13.3 -/+ 3,0g and 14.5 -/+ 2,4. It was found that the bone mass of children at this age corresponds to about 50% of the bone mass pick found in the young adult. No significant bone mass differences between sexes were found. No correlation was found between bone mass and insulin-like growth factor 1 serum levels. Positive correlations between bone mass and body weight and bone age were found. CONCLUSIONS: In pre-pubertal children (1) the analysis of bone mass should be interpreted mainly as a function of body weight and (2) bone mineral density of the lumbar spine and skeleton correlate with bone age and may represent an additional parameter of skeleton maturation.

English Abstract↗
PubMed1998

Morphological examination of bone synthesis via direct administration of basic fibroblast growth factor into rat bone marrow.

Woven bone induced by direct injection of basic fibroblast growth factor (bFGF) into rat bone marrow was examined. On the first day after injection, fibrous tissues formed in the treated region of the bone marrow. Tissue-nonspecific alkaline phosphatase (TNAPase)-immunopositive osteoblastic cells and osteopontin immunopositive-extracellular matrices were observed in the fibrous tissues, indicating bone induction. On the fifth day, the bFGF-induced bone was found broadly in the bone marrow. In the originally existing bone, osteopontin-immunoreactivity was observed at cement lines, but not in the fully calcified matrix, whereas the woven bone displayed immunoreactivity throughout the matrix. Numerous TRAPase-positive osteoclasts were present on the surfaces of the woven bone, but no obvious cement line was observed. Therefore, both bone formation and resorption appeared highly active, without normal cellular coupling equilibrated between bone formation and resorption performed by osteoblasts and osteoclasts. On the tenth day, the bFGF-induced bone was almost replaced by bone marrow. Thus, bone formation actively occurred in the first half of the experimental period, whereas bone resorption came to be predominant thereafter. This study demonstrated that bFGF stimulates bone formation, which, however, is subject to subsequent resorption, probably due in part to the absence of coordinated cellular coupling between osteoclasts and osteoblasts.

Acid Phosphatase↗
PubMed2002

The clinical use of bone resorption markers in patients with malignant bone disease.

BACKGROUND: Advanced tumors often metastasize to bone, resulting in a variety of skeletal complications. Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption that reduce the incidence and delay the onset of skeletal complications and reduce the need for radiation and surgery. Biochemical markers of bone resorption have been identified that can augment the imaging techniques used to diagnose bone metastases and assess response to bisphosphonate therapy. METHODS: In the current study, the available literature regarding bone resorption markers is reviewed and the clinical relevance of these data with respect to the treatment of bone metastases discussed. RESULTS: Urinary calcium and hydroxyproline have been widely used to assess bone metabolism, but do not appear to be well correlated with clinical outcome in patients with bone metastases. Several unique breakdown products of Type I collagen (including pyridinium crosslinks, pyridinoline, and deoxypyridinoline) and peptide-bound crosslinks (N-telopeptide and C-telopeptide) are more specific and sensitive markers of bone resorption. N-telopeptide and C-telopeptide have been identified as the most sensitive biochemical markers currently available for detecting bone metastases and for assessing response to therapy or disease progression. CONCLUSIONS: To the author's knowledge markers of bone resorption have not yet been recommended for routine clinical use. However, further research is needed to define their potential role in the diagnosis of bone metastases, the assessment of disease progression and response to bisphosphonate therapy, and predict the rate of bone loss and the potential for fracture. Suppression of bone resorption markers in response to bisphosphonate therapy appears to correlate with clinical outcome in patients with both osteolytic and blastic bone lesions; therefore, the goal of bisphosphonate therapy should be to suppress markers of bone resorption.

Biomarkers↗
PubMed1998

Reduced bone mineral density and unbalanced bone metabolism in patients with inflammatory bowel disease.

Patients with chronic inflammatory bowel diseases (IBD) are at increased risk to develop osteopenia and osteoporosis. New parameters for the assessment of bone formation and especially bone resorption have significantly improved the diagnostic procedures to characterize bone metabolism. Biochemical characterization of bone turnover in IBD patients may provide important information about the pathogenesis of osteoporosis in this patient population. A cross-sectional study was performed. One hundred forty-nine patients (77 men, 52 premenopausal, and 20 postmenopausal women) with IBD (104 with Crohn's disease [CD] and 45 with ulcerative colitis [UC]) underwent clinical, osteodensitometric, and metabolic bone assessment. Bone mineral density was determined by dual energy X-ray absorptiometry. Bone formation (bone alkaline phosphatase), bone resorption (N-terminal telopeptide of type-I collagen, free desoxypyridinoline, total pyridinoline, and desoxypyridinoline), vitamin D, and parathyroid hormone were assessed. Thirty-six percent of patients with CD and 32% with UC showed osteopenia, 15% with CD and 7% with UC showed osteoporosis. Bone resorption was significantly increased in IBD patients compared to normal controls, whereas bone formation did not show a compensatory increase. Bone formation was even more suppressed in the subset of patients currently treated with corticosteroids. Our data confirm the high prevalence of osteopenia and osteoporosis reported in IBD patients. Furthermore, we provide evidence for an increased bone resorption accompanied by low bone formation in IBD patients. This imbalance of bone metabolism is likely to be one of the reasons for increased bone loss in IBD patients.

Absorptiometry, Photon↗
PubMed1992

Stimulative effects of cadmium on bone resorption in neonatal parietal bone resorption.

Effects of cadmium on bone resorption were investigated using neonatal mouse parietal bone culture system. Cadmium at 0.5 microM and above stimulated hydroxyproline release as well as 45Ca release. As cadmium-stimulated bone resorption was inhibited by calcitonin, bone resorption induced by cadmium is osteoclast-mediated bone resorption. CI-1, collagenase inhibitor, depressed cadmium-stimulated bone resorption in a dose-dependent manner. Osteoblasts are also involved in cadmium-induced bone resorption. Indomethacin-inhibited cadmium-stimulated bone resorption and cadmium-treated bones released prostaglandin E2 to a greater extent than untreated bones. Cadmium-stimulated bone resorption was shown to be dependent on the production of prostaglandin E2. 3-Isobutyl-1-methylxanthine potentiated cadmium-stimulated bone resorption and verapamil depressed it. It is possible that an increase in levels of cAMP and calcium ion in bone cells is involved in cadmium-induced bone resorption. From these results, cadmium was found to stimulate osteoclast-mediated bone resorption which is dependent on prostaglandin E2. Second messengers in cadmium-induced bone resorption may be cAMP and calcium ion.

Animals↗
PubMed2005

Common biochemical markers of bone turnover predict future bone loss: a 5-year follow-up study.

BACKGROUND: Bone mineral density (BMD) is used to follow gain or loss of bone mass but cannot detect changes within a short period of time. Biochemical markers of bone turnover may be of value for prediction of individual bone loss. METHODS: We studied the relation between common inexpensive markers of bone turnover (serum alkaline phosphatase (ALP), osteocalcin (OC), urinary hydroxyproline (OHPr), and calcium (Ca)), BMD, age, and menopause in a combined cross-sectional and longitudinal design comprising 429 pre- and postmenopausal randomly selected women aged 21-79 years (mean 50 years). A follow-up was initiated after 5 years (including 192 of these women), which focused on changes in bone mass and the ability of these four common markers of bone turnover (sampled at baseline) to predict future bone loss. RESULTS: A marked increase was observed for all markers at the beginning of menopause. During the postmenopausal period ALP and Ca decreased to near premenopausal levels, while OC and OHPr remained high even 15 years after menopause. We also found inverse correlations at baseline between the bone markers and BMD, independent of the selected marker or skeletal site, r=-0.14 to -0.46, P<0.05. The correlations between ALP, OC, OHPr, and subsequent bone loss over 5 years, was significant for arm, r=-0.23 to -0.36, P<0.01. Baseline levels of all bone markers correlated significantly at group level with the 5-year follow-up of BMD for all sites. The ability of markers to predict individual bone loss was estimated by a multivariate regression model, which included baseline BMD, age, and body mass index as independent variables. ROC analysis showed a validity of approximately 76% for the forearm model, but was lower for the hip (55%) and lumbar spine (65%). CONCLUSIONS: These data show that the common inexpensive biochemical markers of bone turnover ALP, OC, OHPr, and Ca were related to the current bone mass and, moreover, provides information about future bone loss at the individual level. Future investigations should include an evaluation of the clinical relevance of markers of bone turnover in relation to fracture risk.

Adult↗
PubMed2003

Effect of withdrawal of hormone replacement therapy on bone mass and bone turnover: the OFELY study.

The beneficial effects of hormone replacement therapy (HRT) on bone mineral density (BMD) and bone turnover are well documented but whether HRT withdrawal is followed by an accelerated rate of bone loss is still controversial. We analyzed 26 women who have withdrawn HRT during a 6-year follow-up of the OFELY cohort. They were compared with three groups of women from the same cohort: one hundred four healthy postmenopausal women who continued HRT during the 6-year follow-up, 78 untreated postmenopausal women matched for age, and 31 untreated women within 5 years of menopause. Bone markers [serum osteocalcin (Intact OC), bone alkaline phosphatase (Bone ALP), and serum CTX] were performed annually during 4 years and bone mineral density (BMD) was measured at the forearm (DXA) during 6 years. Withdrawal of HRT was followed by a significant bone loss with an annual rate ranged from -0.7 to -1.6% at the radius according to the skeletal site and by a marked increase of bone markers after 6 months: +36 % for osteocalcin, +23% for bone alkaline phosphatase, and +120% for serum CTX (P < 0.05 to P < 0.001). In contrast, in the HRT continuing group, there was no bone loss and no substantial change of bone markers over 4 years. The rate of bone loss after withdrawal of HRT was significantly greater than in postmenopausal women matched for age who never received HRT (2.2 to 2.8 times higher according to the radius area) and not different as compared to the accelerated bone loss observed in untreated women within 5 years of menopause. We conclude that in postmenopausal women who have been on HRT for 6 years, cessation of treatment results in a rapid increase of bone turnover and a rate of bone loss similar to early postmenopausal women during the subsequent 4 years and greater than untreated women of the same age.

Adult↗
PubMed1996

Minocycline prevents the decrease in bone mineral density and trabecular bone in ovariectomized aged rats.

In the current study, we examined the effects of minocycline, on the osteopenia of ovariectomized aged rats. Old female rats were randomly divided into five groups: sham, ovariectomized control and ovariectomized treated with minocycline, 17beta-estradiol, or both agents. Bone samples were collected 8 wk after the treatment. Ovariectomy reduced bone mineral density of the whole femur and at the condylar, distal metaphyseal and head-neck-trochanter regions 10%-19% and the loss of bone density was prevented by treatment with minocycline or 17beta-estradiol. Histomorphometric analysis of distal femur showed ovariectomy reduced the trabecular bone area, the trabecular bone number, trabecular bone thickness and increased the trabecular bone separation. The microanatomic structure of trabecular bone also showed that the number of nodes, node to node, cortical to node, node to free end was reduced by ovariectomy. Treatment with minocycline attenuated the effect of ovariectomy on trabecular bone in aged animals. In contrast, cortical bone was not affected by ovariectomy or minocycline treatment. The effect of minocycline on bone turnover was also examined. Minocycline increased osteoid surface, mineralizing surface, mineral apposition rate, bone formation rate and reduced eroded surface. We have therefore concluded that the modest increase in bone mineral density and the improvement in the trabecular bone status noted in minocycline treated ovariectomized aged rats is likely due to an increase in bone formation coupled with a decrease in bone resorption.

Absorptiometry, Photon↗
PubMed1997

Bone mass and bone turnover in power athletes, endurance athletes, and controls: a 12-month longitudinal study.

Strain magnitude may be more important than the number of loading cycles in controlling bone adaptation to loading. To test this hypothesis, we performed a 12 month longitudinal cohort study comparing bone mass and bone turnover in elite and subelite track and field athletes and less active controls. The cohort comprised 50 power athletes (sprinters, jumpers, hurdlers, multievent athletes; 23 women, 27 men), 61 endurance athletes (middle-distance runners, distance runners; 30 women, 31 men), and 55 nonathlete controls (28 women, 27 men) aged 17-26 years. Total bone mineral content (BMC), regional bone mineral density (BMD), and soft tissue composition were measured by dual-energy X-ray absorptiometry. Bone turnover was assessed by serum osteocalcin (human immunoradiometric assay) indicative of bone formation, and urinary pyridinium crosslinks (high-performance liquid chromatography) indicative of bone resorption. Questionnaires quantified menstrual, dietary and physical activity characteristics. Baseline results showed that power athletes had higher regional BMD at lower limb, lumbar spine, and upper limb sites compared with controls (p < 0.05). Endurance athletes had higher BMD than controls in lower limb sites only (p < 0.05). Maximal differences in BMD between athletes and controls were noted at sites loaded by exercise. Male and female power athletes had greater bone density at the lumbar spine than endurance athletes. Over the 12 months, both athletes and controls showed modest but significant increases in total body BMC and femur BMD (p < 0.001). Changes in bone density were independent of exercise status except at the lumbar spine. At this site, power athletes gained significantly more bone density than the other groups. Levels of bone formation were not elevated in athletes and levels of bone turnover were not predictive of subsequent changes in bone mass. Our results provide further support for the concept that bone response to mechanical loading depends upon the bone site and the mode of exercise.

Adolescent↗
PubMed2005

Clinical use of markers of bone turnover in metastatic bone disease.

Bone metastases profoundly perturb normal bone remodeling. Biochemical markers of bone turnover have been shown to reflect these tumor-induced changes in bone remodeling and might therefore be useful in the diagnosis and follow-up of patients with malignant bone disease. Most markers of bone turnover, particularly those of bone resorption, are elevated in patients with established bone metastases. While this might indicate a role for bone markers as diagnostic tools in cancer patients, the available evidence does not provide any final conclusions as to the accuracy and validity of the markers presently used in the early diagnosis of bone metastases. Markers of bone resorption respond promptly and profoundly to bisphosphonate and antineoplastic therapy, and this response is associated with a favorable clinical outcome. Most markers, however, have been more useful in groups of patients monitored in clinical studies than in studies of individuals. While this makes them a good tool for drug development, it remains unknown whether the use of bone markers in a routine clinical setting has any defined beneficial effects on overall outcome in cancer patients. In particular, no study has addressed the question of whether patients with bone metastases should be treated according to their rate of bone turnover and what the treatment goals are in this respect. While it is unlikely that bone-turnover markers have sufficient diagnostic or prognostic value when used in isolation, the combination of these markers with other diagnostic techniques might be the way forward to improve the clinical assessment of patients with cancers of the bone.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

Experimental study of vascularized bone grafts: hypertrophy of the grafted bone.

The mechanism underlying hypertrophy of experimentally vascularized bone grafts was studied in 15-week-old rats. The segmental ulna was grafted to the tibial defect with an external fixator. In experiment 1, 24 rats were classified into four groups to evaluate conventional (non-vascularized), cuff (periosteum-encased, non-vascularized), and vascularized bone grafts, and vascularized segmental grafts with fracture. In experiment 2, 12 rats were classified into two groups according to the presence of mechanical loading. This involved vascularized bone grafts with external fixators, and vascularized bone grafts with external fixators removed after bone union. The bone dynamics of the grafts were investigated by several methods, including roentgenographic analysis, histologic studies, and fluorochrome labeling. In experiment 1, a slight bone formation was recognized in the conventional bone graft, while irregular bone formation with creeping substitution was observed in the cuff graft. The vascularized bone graft showed significant hypertrophy; hypertrophy of the vascularized bone with fracture was greater than that without fracture. In experiment 2, markedly circumferential bone formation was observed after removal of the external fixator, while slight new bone formation was observed during the late postoperative period in bone with an external fixator. These results suggest that hypertrophy can be promoted by artificial fracture of the grafted bone, and that mechanical loading is an important factor for remodeling of grafted bone.

Animals↗
PubMed1994

Antigranulocyte antibody bone marrow scans in cancer patients with metastatic bone superscan appearance.

In clinical practice, it may be difficult to distinguish a metastatic bone superscan appearance from a normal bone scan. To determine if assessment of bone marrow is helpful in the diagnosis of bone invasion in patients with suspected bone superscans, the authors performed antigranulocyte antibody bone marrow scans in 10 consecutive cancer patients who had a conventional bone scan interpreted as metastatic superscan appearance. All patients presented with bone marrow scans showing marked absence of tracer uptake in the central skeleton suggesting tumour replacement. Laboratory tests showed decreased peripheral blood cells in 9 patients. Bone radiographs showed metastatic involvement with diffuse osteoblastic lesions in 9 patients. Antigranulocyte bone marrow scans show extensive bone marrow invasion in cancer patients with suspected bone superscans. This result reinforces the concept of these patients having extensive bone invasion despite mild abnormalities in the bone scan. Confirmation of extensive bone invasion on patients with suspected bone superscans may contribute to a proper staging of these patients.

Adult↗
PubMed2005

Bone quality and healing in a swine vascularized bone allotransplantation model using cyclosporine-based immunosuppression therapy.

Although vascularized bone and joint allotransplantation is a promising new treatment option for reconstructing large bone defects, the need for immunosuppressive agents to prevent rejection in these procedures poses a major problem. This problem stems from the fact that several of these agents can cause harmful side effects, such as alterations in bone quality and healing. Therefore, the purpose of this study was to determine what effect the commonly used immunosuppressant regimen cyclosporine A-based combination therapy has on bone quality and healing. In 10 pigs, vascularized bone allografts with skin and muscle components (osteomyocutaneous free flaps) were transplanted from size-matched donor animals. Recipient animals received oral cyclosporine A/mycophenolate mofetil/prednisone therapy for 90 days. Bone quality was studied before and after transplantation by measuring the bone's acoustic velocity and density and calculating the bone's elastic coefficient. Bone healing was assessed using radiographic analysis. Four animals were lost as a result of graft rejection or immunosuppression-related complications before the 90-day endpoint of the study. Although bone specimens taken from the six animals that completed the 90-day protocol had histological signs of rejection, they all seemed to have normal bone healing. Posttransplant bone density values were significantly decreased (p < 0.05) (1544.7 +/- 47.5 kg/m3) as compared with pretransplant values (1722.7 +/- 44.1 kg/m3). Results of the acoustic velocity and elastic coefficients measurements showed a significant decrease (p < 0.05) in posttransplant values (from 3503.0 +/- 165.1 meters/sec to 2963.0 +/- 54.6 meters/sec and from 21.6 +/- 2.2 GPa to 13.6 +/- 0.5 GPa, respectively), indicating diminished bone quality. The findings indicate that cyclosporine A/mycophenolate mofetil/prednisone combination therapy is ineffective in preventing bone rejection, that it decreases bone quality, and that it is associated with systemic toxicity, suggesting that this immunosuppressive regimen at the doses used in this study is not ideal for vascularized bone allotransplantation procedures.

Animals↗
PubMed1999

Early changes in the distal intertarsal joint of Dutch Warmblood foals and the influence of exercise on bone density in the third tarsal bone.

It was hypothesised that imposition of different exercise levels at a young age would lead to differences in bone density in the third tarsal bone and to difference in the prevalence of pathological lesions that might contribute to the development of bone spavin later in life. Furthermore, based on earlier literature, it was hypothesised that such lesions could be classified as a manifestation of osteochondrosis. Changes in bone density in the third tarsal bone and early pathological changes in the articular cartilage of the distal intertarsal joint were studied in the offspring of sires with radiographic evidence of osteochondrosis in either stifle or hock. Twenty-four foals were studied at age 5 months after having been subjected to different exercise programmes (box-rest, box-rest with sprint training, pasture exercise) from age one week. Nineteen other foals that originally belonged to the same exercise groups were studied at age 11 months, after they had been weaned, housed together and subjected to an identical low level exercise regimen for an additional 6 months. Bone density was quantified using a microscopic technique. Histomorphological analysis was performed semiquantitatively and using high detail radiography techniques. At age 5 months, mean +/- s.d. bone density in the compact bone of the third tarsal bone was significantly lower in the box-rested foals (37 +/- 4%) than in both the trained and pastured foals (48 +/- 7% and 52 +/- 11%, respectively). After 6 months of identical exercise the previously box-rested foals showed an increase in bone density (53 +/- 12%) which became similar to the value found in the formerly pastured foals (52 +/- 8%). Major pathological lesions (chondrocyte necrosis, fragmentation and chondrone formation) of the articular cartilage of the third and central tarsal bones were already present at age 5 months, but were significantly more numerous at 11 months. There was no relation between the number of cartilage lesions and the osteochondrosis status of the foals. Only 2 lesions in 11-month-old foals had histological characteristics compatible with osteochondrosis, all other lesions were degenerative in nature. It is concluded that bone density of the compact bone of the subchondral bone plate in the third tarsal bone reacts strongly to variations in exercise at a very young age. Low bone density, caused by lack of exercise, can be compensated for when exercise is later increased. Pathological changes in the distal intertarsal joint are common at 5 months and increase to 11 months. These lesions are degenerative in nature and seem not to be related to osteochondrosis. Although the clinical relevance of these abnormalities is uncertain, they may be relevant for the development of osteoarthritic processes in this region later in life.

Animals↗
PubMed2000

Retardation in bone resorption after bone marrow ablation in klotho mutant mice.

The klotho gene mutant mice exhibit both osteopetrotic phenotype, including elongation of trabeculae in the epiphyses of long bones and vertebral bodies, and osteopenic phenotype, such as thin cortical bones in the diaphyses of these bones. These diverse features raise the question of whether the klotho gene defect results in alteration in bone resorption in vivo. Therefore, we examined the effect of the klotho gene defect on bone resorption by using bone marrow ablation model. At 1 week after bone marrow ablation, trabecular bones were formed in the ablated marrow cavity to levels higher than those in unablated bones in both klotho mutant and wild-type mice. At 2 weeks postsurgery, newly formed trabecular bones were resorbed in wild-type mice to resume normal bone marrow and trabecular bone volume fraction as reported previously. In contrast, the newly formed trabecular bones in the ablated marrow in klotho mutant mice remained at levels similar to those at 1 week. The defect in the bone resorption phase in klotho mutant mice is associated with site-specific reduction of the number and size of osteoclasts in klotho mutant mice. Moreover, the expression levels of osteoprotegerin messenger RNA in the ablated femora of klotho mutant mice were higher than those in wild-type mice. These results indicate that lack of klotho gene expression suppressed bone resorption that should normally take place 2 weeks after bone marrow ablation.

Animals↗
PubMed2005

Platelet-derived growth factor inhibits demineralized bone matrix-induced intramuscular cartilage and bone formation. A study of immunocompromised mice.

BACKGROUND: Platelet-derived growth factor (PDGF) has been proposed as a therapeutic agent to promote bone-healing. The purpose of this study was to examine the effect of PDGF on the ability of human demineralized bone matrix to induce bone formation in a nude-mouse muscle-implantation model. We also examined whether platelet-rich plasma, which contains PDGF, also modulates osteoinduction in this model. METHODS: Human demineralized bone matrix, previously shown to be osteoinductive in the calf muscles of nude mice, was mixed with PDGF-BB (0, 0.1, 1, and 10 microg/10 mg of demineralized bone matrix) and was implanted bilaterally in the calf muscles of immunocompromised (nu/nu) mice (six mice in each group). Heat-inactivated demineralized bone matrix was used as a control. Tissue was harvested at fourteen, twenty-eight, and fifty-six days after implantation. Platelet-rich plasma was prepared from the blood of a healthy donor with use of the Harvest PRP preparation device, activated with thrombin, and mixed with active and inactive demineralized bone matrix. Fifty-six days post-implantation, tissues were harvested. Osteoinduction was assessed with use of a qualitative scoring system and with quantitative histomorphometry. RESULTS: Cartilage was present at fourteen days in all tissues that had received an implant, but the amount decreased as the PDGF concentration increased. PDGF reduced bone formation at twenty-eight days in a dose-dependent manner. This inhibitory effect was resolved by fifty-six days, except in tissues in which demineralized bone matrix and 10 microg of PDGF had been implanted. In sites treated with 10 microg of PDGF, the area of new bone was decreased and the area of bone marrow was reduced at twenty-eight and fifty-six days. PDGF also appeared to retard resorption of demineralized bone matrix in a dose-dependent manner. Platelet-rich plasma reduced osteoinduction by human demineralized bone matrix that had high osteoinductive activity and had no effect on osteoinduction by demineralized bone matrix with low activity. CONCLUSIONS: PDGF inhibits, in a dose-dependent manner, intramuscular osteoinduction and chondrogenesis by demineralized bone matrix in immunocompromised mice. Platelet-rich plasma also reduces the osteoinductivity of active demineralized bone matrix.

Analysis of Variance↗
PubMed1987

Phosphorus availability bioassay using bone ash and bone densitometry as response criteria.

Two experiments were conducted to examine the relative precision of bone densitometry and bone ash methodologies as response criteria in measurement of bioavailability of phosphorus from various supplements for turkeys. Multivariate analyses of variance were used to analyze data collected. Coefficients of correlation and variation and F ratios were used for evaluation. Bone densitometry with one scan at each of 3 points on the bone was faster than bone ash and as precise as bone ash analysis in measuring phosphorus availability in turkeys. The coefficient of correlation between percentage ash (of dry bone) and scan density (milligrams per centimeter length of bone) measurements for treatment effects was .986. The coefficient of variation was about the same for the bone ash (5.8) and the three-point bone scan (6.9) methods. As indicated by the F ratio for testing treatment effects, bone densitometry was better able to detect differences among phosphorus sources. A technician may scan 50 cleaned bones in 3 hr, but with the bone ash method, drying, ashing, and weighing may require 3 working days. Bone sampling technique, multiple operators, different bone sizes, and decay of iodine source were the major factors affecting precision of the bone densitometry technique. Relative biological availabilities of phosphorus from various supplements were about the same by the two methods.

Animals↗