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PubMed1995

Efficacy of simultaneous determination of bone alkaline phosphatase mass concentration in serum and urinary excretion of pyridinium cross-links for detection of bone metastases.

OBJECTIVES: To examine the diagnostic validity of bone alkaline phosphatase (BAP) in serum (a marker of bone formation) and of urinary excretion of pyridinium cross-links (PYR) (a marker of bone resorption) for detection of bone metastases. DESIGN AND METHODS: Two heterogeneous immunoassays were employed for determination of BAP mass concentrations (Tandem-R Ostase) in serum and the urinary excretion of PYR (Collagen Crosslinks) in a consecutive series of 89 tumor patients examined by bone scintigraphy (with 99mTc-methylene diphosphonate). RESULTS: The discrimination power (as determined by Z score analysis) and the accuracy (as assessed by the area under the receiver-operating characteristic curve) was higher for BAP (0.84) than for PYR (0.76). Combination of both markers yielded a further increase of accuracy (0.89). There was a correlation (r = +0.422; p < 0.001) between the urinary excretion of pyridinium cross-links and bone alkaline phosphatase mass concentrations in the whole of 89 patients examined. In 14 (16%) of 89 patients bone alkaline phosphatase values were within the reference interval in spite of total alkaline phosphatase activity being increased; this indicates a higher diagnostic specificity of bone alkaline phosphatase (compared with total alkaline phosphatase) with respect to detection of bone metastases. CONCLUSION: Simultaneous assessment of bone formation by BAP and of bone resorption by PYR provides a suitable tool for detection of bone metastases.

Adult↗
PubMed1991

The induction of bone in osteogenic composites of bone matrix and porous hydroxyapatite replicas: an experimental study on the baboon (Papio ursinus).

This study evaluated the morphogenetic properties of osteogenic composites of bone matrix and porous coralline hydroxyapatite (HA) replicas after intramuscular implantation in adult baboons (Papio ursinus). Composite implants were prepared by inserting rods of nonresorbable HA replicas, 20 mm in length, and 5 or 7 mm in diameter, into the medullary canals of 90 diaphyseal baboon bone cylinders, 20 mm in height, sequentially extracted and chemosterilized to obtain autolysed antigen-extracted allogeneic (AAA) bone matrix, preserving the bone morphogenetic protein (BMP) activity. Composites were implanted in the rectus abdominis and in the dorsal musculature of 24 adult male baboons. Before implantation, 45 composites were coated with an allogeneic fibrin-fibronectin protein concentrate (AFFP) prepared from fresh-frozen baboon plasma. Histologic analysis of undecalcified and decalcified specimens procured at 3, 6, and 9 months showed bone differentiation by induction along the endosteal surfaces of the chemosterilized matrix and within the porous spaces of the HA substratum. Bone formation was often extensive, culminating in complete penetration of the porous spaces. Histomorphometry showed that bone in the HA substratum increased at each time period. The biochemical treatment of the composite implants with AFFP did increase significantly the amount of induced bone, although only in the HA substratum. Bone differentiation was confirmed by fluorescence microscopy of the mineralization fronts after intravital double tetracycline labeling. The differentiation of bone in composites of bone matrix and porous HA replicas in extraskeletal sites of adult baboons may help to design appropriate delivery systems for the controlled therapeutic initiation of bone formation for craniofacial and orthopedic applications in man.

Animals↗
PubMed1991

Differential activity of granulocyte-macrophage and macrophage colony stimulating factors on bone resorption in fetal rat long bone organ cultures.

In this study, the ability of recombinant human macrophage (M) and murine granulocyte-macrophage (GM) colony stimulating factor (CSF) to affect both basal and stimulated bone resorption in fetal rat long-bone organ cultures was assessed. It was found that M-CSF does not affect basal bone resorption or bone resorption stimulated by parathyroid hormone, recombinant human interleukin 1 beta, prostaglandin E2 (PGE2), and 1,25 dihydroxy vitamin D3. Specifically, M-CSF at concentrations as high as 30 nM (1 microgram/mL) did not modulate 45Ca release from fetal rat long bones stimulated by these agents. The addition of recombinant murine GM-CSF (at equal molar concentration to M-CSF) also did not affect bone resorption stimulated by parathyroid hormone and interleukin 1 beta. On the other hand, GM-CSF stimulated basal bone resorption over a 120-h period and augmented the resorption mediated by exogenous PGE2 over a 48-h incubation. In addition, GM-CSF was shown to stimulate production of endogenous PGE2 in cultures of bone rudiments. These effects on bone resorption were blocked by the addition of prostaglandin synthesis inhibitors and specific antibodies to murine GM-CSF. These data indicate that M-CSF does not act as a regulator of bone turnover, but GM-CSF may cause bone resorption by stimulating the synthesis of PGE2 in bone.

Animals↗
PubMed1986

Bone particles from osteopetrotic mice not cured by bone marrow transplants are resorbed in normal littermates.

Osteosclerotic (oc/oc) and osteopetrotic (op/op) mice are not cured by bone marrow transplantation from normal littermates. The possibility that this is due to production of poorly resorbable bone was examined by comparing the fate of mutant and normal bone particles implanted subcutaneously in normal hosts. Bone, removed aseptically from calvarial and tibial sites of normal littermates and mutants, was cleaned of adherent soft tissue, ground and sieved to a particle size of 70-300 micron. Aliquots (17-20 mg) of bone from each phenotype of each stock were pelleted and implanted beneath the anterior thoracic skin of normal littermates for two weeks. Particle density in tissue sections was determined as percent of field by a point-counting method. Giant cell response was recorded as number per high-power field. Percent bone present initially was determined in pellets implanted for less than 24 hr. Bone particles were reduced in each pellet with time, about 25% of the original volume being removed in two weeks. No statistically significant differences were noted in the rates of disappearance of mutant and normal bone or in the percentage or number of giant cells in implants of mutant and normal bone in either stock. Furthermore, these values were not different from identical studies in microphthalmic mice, an osteopetrotic stock cured by bone marrow transplantation. These data suggest that the failure of osteopetrotic and osteosclerotic mice to be cured by bone marrow transplants from normal littermates is not due to the presence of unresorbable bone.

Animals↗
PubMed2005

De novo bone induction by recombinant human bone morphogenetic protein-2 (rhBMP-2) in maxillary sinus floor augmentation.

PURPOSE: This phase II study was designed to evaluate 2 concentrations of recombinant human bone morphogenetic protein-2 (rhBMP-2) for safety and efficacy in inducing adequate bone for endosseous dental implant in patients requiring staged maxillary sinus floor augmentation. MATERIALS AND METHODS: Patients were treated with rhBMP-2 (via an absorbable collagen sponge [ACS]), at concentrations of 0.75 mg/mL (n = 18), 1.50 mg/mL (n = 17), or with bone graft (n = 13). Bone induction was assessed by alveolar ridge height, width, and density measurements from computed tomography scans obtained before and 4 months after treatment and 6 months post-functional loading of dental implants (density only). RESULTS: Mean increases in alveolar ridge height at 4 months after treatment were similar among the groups; 11.3 mm, 9.5 mm, and 10.2 mm, respectively, in the bone graft, 0.75 mg/mL, and 1.50 mg/mL rhBMP-2/ACS treatment groups. Mean increases in alveolar ridge width (buccal to lingual) at the crest of the ridge were statistically different among the treatment groups; 4.7 mm, 2.0 mm, and 2.0 mm, respectively, in the bone graft, 0.75 mg/mL, and 1.50 mg/mL treatment groups (P <or= .01 vs 0.75 mg/mL; P < .01 vs 1.50 mg/mL). At 4 months postoperative new bone density was statistically different among the treatment groups; 350 mg/cc, 84 mg/cc, and 134 mg/cc for the bone graft, 0.75 mg/mL, and 1.50 mg/mL rhBMP-2/ACS treatment groups, respectively (P = .003 vs 0.75 mg/mL, P = .0137 vs 1.50 mg/mL, P = .0188; 1.50 mg/mL vs 0.75 mg/mL). Core bone biopsies obtained at the time of dental implant placement confirmed normal bone formation. The proportion of patients who received dental implants that were functionally loaded and remained functional at 36 months post-functional loading was 62%, 67%, and 76% in the bone graft, 0.75 mg/mL, and 1.50 mg/mL rhBMP-2/ACS treatment groups, respectively. CONCLUSION: This study is the first randomized controlled trial demonstrating de novo organ tissue growth in humans from a recombinant human protein. rhBMP-2/ACS safely induced adequate bone for the placement and functional loading of endosseous dental implants in patients requiring staged maxillary sinus floor augmentation.

Alveolar Process↗
PubMed1980

A comparison of bone scanning and radiology in the evaluation of patients with metabolic bone disease.

Bone scans and radiographs were evaluated in 80 patients with metabolic bone disease (27 with osteoporosis, 14 with primary hyperparathyroidism, 24 with renal osteodystrophy and 15 with osteomalacia). The bone scan did not suggest a metabolic bone disorder in any of 27 patients with histologically proven osteoporosis. In 22 (81%) patients radiographs were reported as showing osteoporosis. In 10 (70%) vertebral fractures were seen on X-ray while these were noted in 11 (41%) patients on the bone scan. Vertebral fractures were usually visualised on the bone scan when these had occurred less than one year previously. In primary hyperparathyroidism the bone scan was suggestive of a metabolic bone disorder in 7 of 14 (50%) patients, while radiographs were reported as showing evidence of hyperparathyroidism in three (21%) cases. The bone scan suggested the presence of a metabolic bone disorder in all 24 patients with renal osteodystrophy and 15 patients with osteomalacia while the correct diagnosis was obtained in 14 (58%) and nine (60%) of these patients on X-ray. It is concluded that the bone scan is the more sensitive investigation in patients with osteomalacia, primary hyperparathyroidism and renal osteodystrophy. For osteoporosis radiology is the investigation of choice but the bone scan may be of value in assessing the duration of vertebral collapse.

Animals↗
PubMed1999

Primary hyperparathyroidism: short-term changes in bone remodeling and bone mineral density following parathyroidectomy.

Changes in bone remodeling and bone mineral density were observed during a period of 6 months after surgery in 24 patients with primary hyperparathyroidism (20 women and 4 men; age 54+/-12 years, range 26-69 years). All bone markers declined significantly within the 6 month follow-up period, but the time course for changes in renal N-terminal telopeptide of type 1 collagen (NTx) excretion differed from those of the other markers by a steep and significant reduction (p < 0.05) after less than 1 month. During the 6 month period, bone mineral density (BMD) increased significantly at all sites measured (p < 0.05) apart from the femoral neck and the proximal and midforearm. The greatest increase of 4.2% was observed in the trochanteric region (p < 0.001). The increase in BMD in spine, trochanteric, and intertrochanteric regions of the hip correlated inversely with baseline forearm BMD values (p < 0.05). Baseline bone markers (serum alkaline phosphatase [AP], serum bone AP, serum pyridinoline crosslinked telopeptide of type 1 collagen, urinary hydroxyproline, urinary osteocalcin), as well as baseline histomorphometric indices of bone turnover (eroded and labeled surface, bone formation rate, activation frequency, and cortical porosity) were positively correlated with changes in spinal BMD over 6 months (p < 0.05). It was concluded that, within 6 months after parathyroidectomy, patients with primary hyperparathyroidism obtain normalization of bone remodeling and a substantial increase in bone mineral density in regions rich in cancellous bone but no significant changes in regions with predominantly cortical bone.

Aged↗
PubMed1997

The biological effect of natural bone mineral on bone neoformation on the rabbit skull.

The aim of this study was to evaluate the effect of deproteinized bovine bone graft material on new bone formation in a guided bone regeneration model system. In 20 rabbits, a periosteal skin flap was raised uncovering the calvaria. A form stable hemispherical dome made of poly-lactic acid (PLA) was placed onto the roughened calvaria. Prior to placement, the dome was either filled with peripheral blood alone (control group, 8 rabbits), or with blood and OsteoGraf/N-300 (test group, 12 rabbits). The wound was closed for primary healing. Morphometric assessment of 1- and 2-month undecalcified histologic specimens revealed better tissue fill in the test domes at 1 month (test 99%, control 55%) (P < 0.05) and 2 months (t, 100%; c, 82%). The fraction of the new bone within the regenerated tissue was higher in the test specimens at 1 month (t, 22%; c, 12%) (P < 0.05) and 2 months (t, 34%; c, 24%). The fraction of the entire space underneath the domes occupied by bone was higher in the test at 1 month, but higher in the controls at 2 months. The fraction of the bone substitute material in contact with bone increased from 1 month (34% +/- 14) to 2 months (45% +/- 5). The surface fraction of osteoblast layers was tendentially higher in the test at 1 month but higher in the control specimens at 2 months. In both test and control, initially woven bone was formed which underwent subsequent remodeling. Cellular degradation of the deproteinized bone graft was frequently detected. It is concluded that deproteinized bovine bone mineral has osteoconductive properties and can initially accelerate new bone formation during guided bone regeneration by increased recruitment of osteoblasts.

Animals↗
PubMed2001

Reconstruction of the primate mandible with a combination graft of recombinant human bone morphogenetic protein-2 and bone marrow.

PURPOSE: This study evaluated whether recombinant human bone morphogenetic protein-2 (rhBMP-2) can be used to regenerate a resected part of the mandible in a primate model. MATERIALS AND METHODS: Segmental bone defects were created surgically in the mandible of Japanese monkeys. rhBMP-2 was suspended in a solution of polyglycolic co-lactic acid (PGLA) and lyophilized to make a BMP/PGLA complex. The rhBMP-2/PGLA complex and autogenous bone marrow in ratios of 3:0, 2.5:0.5, or 2:1 (vol:vol) were each implanted into the bone defects in 3 monkeys. Bone marrow or P(GLA alone were each implanted in 1 monkey as a control. The animals were killed 16 weeks after surgery, followed by radiologic and histologic evaluation. RESULTS: The implantation of bone marrow alone succeeded in reconstruction of the mandible, but the implantation of the rhBMP-2/PGLA complex showed only a small amount of bone formation. The combination graft of rhBMP-2/PGLA and bone marrow resulted in a greater degree of bone formation; especially the 2:1 combination showed the same result as only bone marrow implantation. CONCLUSION: The combination graft of rhBMP-2 and bone marrow, which requires only a small amount of bone marrow, was a reliable method for reconstruction of mandibular segmental defects in this animal model.

Animals↗
PubMedDate not supplied

[Bone density in children and adolescents with rheumatic diseases. Preliminary results of selective measurement of trabecular and cortical bone using peripheral computerized tomography].

UNLABELLED: Selective measurements of bone mineral density (BMD) of trabecular and cortical bone at the ultradistal radius were made in 27 children with rheumatic diseases and in age- and sex-matched healthy controls using peripheral quantitative computed tomography (pQCT). RESULTS: Mineral density of trabecular bone (-34,5%) and total bone mineral density (-18,9%) differed significantly between patients and controls (p < 0.01). BMD of the cortical bone (-13,6%) did not differ significantly between the groups. There was no difference in BMD in patients with systemic or non-systemic diseases. BMD did not correlate with duration of disease or steroid medication. CONCLUSIONS: Total bone mineral density and trabecular bone density are decreased in children and adolescents with sytemic and non-systemic rheumatic diseases. Age of onset of disease and steroid medication did not correlate with bone mineral density. PQCT has the advantages of low local and no total body radiation, high sensitivity, high reproducibility and selective measurement of different bone compartements. Because selective measurement can be made in metabolically active trabecular bone changes of BMD can be detected at an early stage before the whole bone is affected. With this method therapy for chronic diseases affecting bone density can be initiated and the course of the disease can be followed.

Adolescent↗
PubMed2002

Gastrectomy has no effect on bone regeneration in rats despite a decrease in bone mass.

BACKGROUND: Gastrectomy, specifically the removal of the acid-producing part of the stomach (fundectomy), is known to cause osteopenia. This effect has been ascribed to the elimination of a hypothetical osteotropic peptide hormone, presumably produced in the oxyntic mucosa. Since osteopenia is due to a disturbed balance between bone formation and resorption, we assessed the effect of gastrectomy on osteogenesis, more specifically mandibular orthotopic bone regeneration. METHODS: Adult rats were either gastrectomized or sham-operated. Two weeks later, unilateral 5-mm transosseous defects were made in the mandibles and covered with microporous barrier membranes (GORE-TEX Membrane). After 6 weeks of healing. bone-bridging of the defects was analyzed by computerized light microscopic image analysis. Furthermore, bone mass was analyzed in the contralateral untreated mandibular side, in calvarial bone, and in femora by morphometry and dry/ash weights. RESULTS: While gastrectomy resulted in a clearly decreased bone mass, manifested as increased marrow spaces in all bones and as decreased dry and ash weights in femora, no difference in mandibular bone healing rate was found between the groups. CONCLUSIONS: Since secluding of the defect space by membrane barriers implies that osteogenic cells have to be recruited primarily from intra-osseous stem cells by their proliferation and differentiation into actively bone-forming osteoblasts, the results indicate that gastrectomy has no effect on these processes. The findings thus imply that the disturbed balance in bone remodeling caused by gastrectomy, resulting in osteopenia, may be due to stimulated bone resorption rather than to reduced bone formation.

Animals↗
PubMed2004

Vitamin K, bone turnover, and bone mass in girls.

BACKGROUND: Vitamin K has been suggested to have a role in bone metabolism, and low vitamin K intake has been related to low bone density and increased risk of osteoporotic fracture. OBJECTIVE: The objective of this study was to determine whether phylloquinone (vitamin K(1)) intake and biochemical indicators of vitamin K status are related to bone mineral content (BMC) and markers of bone formation and bone resorption in girls. DESIGN: Vitamin K status [plasma phylloquinone concentration and percentage of undercarboxylated osteocalcin (%ucOC)] was measured at baseline in a study of 245 healthy girls aged 3-16 y. Cross-linked N-telopeptide of type 1 collagen (NTx) breakdown, osteocalcin, and bone-specific alkaline phosphatase were measured to reflect bone resorption and formation. BMC of the total body, lumbar spine, and hip and dietary phylloquinone intake were measured annually for 4 y. RESULTS: Phylloquinone intake (median: 45 microg/d) was not consistently associated with bone turnover markers or BMC. Better vitamin K status (high plasma phylloquinone and low %ucOC) was associated with lower bone resorption and formation. Plasma phylloquinone was inversely associated with NTx and osteocalcin concentrations (P < 0.05), and %ucOC was positively associated with NTx and bone-specific alkaline phosphatase concentrations (P < 0.05). Indicators of vitamin K status were not consistently associated with current BMC or gain in BMC over the 4-y study period. CONCLUSIONS: Better vitamin K status was associated with decreased bone turnover in healthy girls consuming a typical US diet. Randomized phylloquinone supplementation trials are needed to further understand the potential benefits of phylloquinone on bone acquisition in growing children.

Adolescent↗
PubMedDate not supplied

The effects of screw removal on bone strain in an idealized plated bone model.

An idealized plated bone model was used to test the hypothesis that selected screw removal could alter the bone strain field and be a viable treatment for stress protection osteoporosis. Eighteen bone screw modifications were evaluated for their effects on bone strain. The three variables studied were number, position, and length of screws. Removal of two or four bone screws from an eight hole plate significantly increased the strain per load on the bone model over the values with eight screws in the plate (p less than 0.05). The four screw configurations increased bone strain more than the six screw configurations. It also was shown that the position of screws in the plate could significantly alter the bone strain per load results. Removal of six bone screws from an eight hole plate also increased the bone strain per load, but to excess in some tests. In those configurations, the results were not statistically different from the unplated configuration. Replacement of the full length screws with eight half length screws that engaged only the near cortex significantly reduced bone strain per load as compared with eight bicortical bone screws.

Animals↗
PubMed2004

Effects of cortical bone perforation on experimental guided bone regeneration.

This study was designed to evaluate the effects of cortical bone perforation histologically and histomorphometrically on guided bone regeneration (GBR) in rabbits. After elimination of the periosteum, cortical bone defects of two sizes were made in the external cortical plate of the frontal bone (Group A: 1 x 15 mm; Group B: 3 x 15 mm). A non-resorbable membrane filled with autogenous blood was placed in the experimental area and secured with titanium pins. After 1 and 2 weeks, vascularized connective tissue and new bone were generated in the space surrounding the defects in both the groups. The amount of vascularized connective tissue generated in Group B was greater than that in Group A at 1 week. Alkaline phosphatase (ALP) was expressed on the bone surrounding the perforation. The expression of ALP was more extensive in Group B than in Group A and was proportional to the breadth of perforation. At 2 weeks, the perforated region was almost covered with new bone in Group A. ALP was expressed at the periphery of newly formed bone. The expression of ALP was proportional to the breadth and height of perforation. At 6 weeks, semicircular outgrowth of bone towards the periphery of the perforated region was observed in both the groups. Newly formed bone volume and ALP expression in Group B were more extensive than those in Group A. At 12 weeks, the space was filled with bone and connective tissue in both the groups. There was no difference in ALP expression between Groups A and B. Histomorphometric analysis showed significant differences between both the groups (two-way ANOVA, P<0.01). We conclude that a larger perforation is associated with prompter bone formation in the secluded space during GBR.

Alkaline Phosphatase↗
PubMed1999

Long-term influence of inhaled corticosteroids on bone metabolism and density. Are biological markers predictors of bone loss?

Long-term effects of high doses of inhaled corticosteroids (ICS) on bone density and metabolism are still uncertain. Fifty-one patients (37 male, 14 female) using beclomethasone or budesonide at a daily dose > 800 microgram/d (high-dose group [Group HD] mean: 983 microgram/d [prescribed dose x estimated compliance]) or no or < 500 microgram/d (control group [Group C] mean: 309 microgram/d) for more than 5 yr were enrolled in this study. Each had, 3 yr ago and at this last evaluation, a clinical evaluation and measurements of expiratory flows and of bone density and bone metabolism markers. Lumbar spine bone density (last visit) was similar in the two groups with respective values of 0.94 +/- 0.03 (HD) and 0.96 +/- 0.03 g/cm2 (C) (p > 0.05). T and Z scores were -1.21 +/- 0.19 and -0.70 +/- 0.18 (HD), -0.95 +/- 0.25 and -0.47 +/- 0.21 (C) respectively (p > 0.05). A correlation was found between the decrease in bone density and the mean daily dose of corticosteroid in Group HD although these changes were quite small, mean bone density being unchanged over the 3-yr period. Serum and urinary parameters were similar in the two groups. Furthermore, neither initial bone density nor any of the biological parameters could predict changes in bone density over a period of 3 yr. In conclusion, bone density was similar in both study groups and not significantly different over a 3-yr period. Neither initial bone density nor biological markers of bone metabolism helped to predict changes in bone mass.

Administration, Inhalation↗
PubMed1996

Bone sialoprotein stimulates in vitro bone resorption.

Bone sialoprotein (BSP) is a protein highly specific for bone, which contains an arginine-glycine-aspartic acid (RGD) cell attachment sequence involved in osteoclast adhesion to bone matrix via the vitronectin receptor. We have investigated its role in in vitro bone resorption using the well described isolated osteoclast resorption pit assay. BSP significantly stimulates bone resorption in a dose-dependent manner, increasing the overall resorbed area on ivory slices and the number of lacunae at concentrations as low as 50 nM. Neither recombinant osteopontin nor intact vitronectin has any effect on bone resorption, suggesting a specific effect of BSP. The stimulation of bone resorption induced by BSP could be partially explained by an increase in osteoclast adhesion to bone via its RGD sequence, and our results suggest another mechanism of action of BSP that might involve another region of the molecule, such as its acidic sequences. Although BSP stimulates bone resorption in a coculture system of bone marrow cells and osteoblastic cells, it dose dependently inhibits the formation of osteoclast-like cells at equivalent concentrations in this culture model. In conclusion, we provide evidence that BSP plays an important role in the bone resorption process and may regulate bone resorption as well as osteoclast formation.

Animals↗
PubMed1997

The effects of orbital spaceflight on bone histomorphometry and messenger ribonucleic acid levels for bone matrix proteins and skeletal signaling peptides in ovariectomized growing rats.

A 14-day orbital spaceflight was performed using ovariectomized Fisher 344 rats to determine the combined effects of estrogen deficiency and near weightlessness on tibia radial bone growth and cancellous bone turnover. Twelve ovariectomized rats with established cancellous osteopenia were flown aboard the space shuttle Columbia (STS-62). Thirty ovariectomized rats were housed on earth as ground controls: 12 in animal enclosure modules, 12 in vivarium cages, and 6 killed the day of launch for baseline measurements. An additional 18 ovary-intact rats were housed in vivarium cages as ground controls: 8 rats were killed as baseline controls and the remaining 10 rats were killed 14 days later. Ovariectomy increased periosteal bone formation at the tibia-fibula synostosis; cancellous bone resorption and formation in the secondary spongiosa of the proximal tibial metaphysis; and messenger RNA (mRNA) levels for the prepro-alpha2(1) subunit of type 1 collagen, osteocalcin, transforming growth factor-beta, and insulin-like growth factor I in the contralateral proximal tibial metaphysis and for the collagen subunit in periosteum pooled from tibiae and femora and decreased cancellous bone area. Compared to ovariectomized weight-bearing rats, the flight group experienced decreases in periosteal bone formation, collagen subunit mRNA levels, and cancellous bone area. The flight rats had a small decrease in the cancellous mineral apposition rate, but no change in the calculated bone formation rate. Also, spaceflight had no effect on cancellous osteoblast and osteoclast perimeters or on mRNA levels for bone matrix proteins and signaling peptides. On the other hand, spaceflight resulted in an increase in bone resorption, as ascertained from the diminished retention of a preflight fluorochrome label. This latter finding suggests that osteoclast activity was increased. In a follow-up ground-based experiment, unilateral sciatic neurotomy of ovariectomized rats resulted in cancellous bone loss in the unloaded limb in excess of that induced by gonadal hormone deficiency. This additional bone loss was arrested by estrogen replacement. We conclude from these studies that estrogen alters the expression of signaling peptides believed to mediate skeletal adaptation to changes in mechanical usage and likewise modifies the skeletal response to mechanical unloading.

Animals↗
PubMed2003

Effects of suppression of estrogen action by the p450 aromatase inhibitor letrozole on bone mineral density and bone turnover in pubertal boys.

The essential role of estrogen (E) in regulation of developing peak bone mass in males was confirmed when young adult men were described who cannot respond to or produce E because of defective E receptor alpha or P-450 aromatase enzyme, respectively. These men had significantly reduced bone mineral density (BMD) despite normal or supranormal androgen concentrations, and E administration improved BMD in the men with aromatase deficiency, whereas testosterone (T) was ineffective. Because new P450 aromatase inhibitors may prove to be potential drugs in various growth disorders, the effect of suppression of E action on developing peak bone mass has to be closely evaluated. In this study, we explored the effects of suppression of E synthesis on bone metabolism in pubertal boys. A total of 23 boys with constitutional delay of puberty were randomized to receive T and placebo or T and a specific and potent P450 aromatase inhibitor, letrozole. We determined BMD in the lumbar spine and the femoral neck. Bone resorption was studied by measuring the serum concentration of cross-linked carboxyterminal telopeptide of type I collagen by two different methods (CTx and ICTP), and bone formation by determining the serum concentrations of carboxyterminal propeptide of type I procollagen (PICP), osteocalcin, and alkaline phosphatase. We demonstrated previously that, during treatment with T and placebo, the concentrations of androgens and E increased. During treatment with T and letrozole, the E concentrations remained at the pretreatment level, but the androgen concentrations increased; the increase in the T concentration was more than 5-fold higher than during treatment with T and placebo. We did not observe any significant differences in the changes in bone mineral content, BMD, or bone mineral apparent density, an estimate of true volumetric BMD, between the treated groups. Lumbar spine bone mineral apparent density increased in both treated groups; but in the T- plus letrozole-treated group, the increase was statistically significant only 6 months after discontinuation of letrozole treatment. All bone resorption and formation markers increased during treatment with T and placebo. During treatment with T plus letrozole, CTx, PICP, and osteocalcin remained unchanged, whereas ICTP and alkaline phosphatase increased. Thus, 1-yr treatment with this new P450 aromatase inhibitor in pubertal boys is unlikely to be associated with any major harmful effect on developing peak bone mass. However, to convincingly exclude such effects, particularly rare or minor ones, will require a study with a larger sample size; and thus, close follow-up of bone metabolism during treatment with P450 aromatase inhibitors is still warranted.

Adolescent↗