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PubMed2006

Normal bone density obtained in the absence of insulin receptor expression in bone.

Type I diabetes is characterized by little or no insulin production and hyperglycemic conditions. It is also associated with significant bone loss and increased bone marrow adiposity. To examine the role of reduced insulin signaling in type I diabetic bone loss without inducing hyperglycemia, we used genetically reconstituted insulin receptor knockout mice (IRKO-L1) that are euglycemic as a result of human insulin receptor transgene expression in the pancreas, liver, and brain. RT-PCR analyses demonstrated undetectable levels of insulin receptor expression in IRKO-L1 bone, yet IRKO-L1 bones exhibit similar (and trend toward greater) bone density compared with wild-type animals as determined by microcomputed tomography. More detailed bone analyses indicated that cortical bone area was increased in tibias of IRKO-L1 mice. Osteoblast markers (osteocalcin and runx2 mRNA levels) and resorption markers (serum pyridinoline levels) were similar in wild-type and IRKO-L1 bones. When marrow adiposity was examined, we noticed a decrease in adipocyte number and fatty-acid-binding protein 2 expression in IRKO-L1 mice compared with wild-type mice. Bone marrow stromal cell cultures obtained from wild-type and IRKO-L1 mice demonstrated similar adipogenic and osteogenic potentials, indicating that systemic factors likely contribute to differences in marrow adiposity in vivo. Interestingly, IGF-I receptor mRNA levels were elevated in IRKO-L1 bones, suggesting (in combination with hyperinsulinemic conditions) that increased IGF-I receptor signaling may represent a compensatory response and contribute to the changes in cortical bone. Taken together, these results suggest that reduced insulin receptor signaling in bone is not a major factor contributing to bone loss in type I diabetes.

Adipocytes, White↗
PubMed2001

Genetic control of bone density and turnover: role of the collagen 1alpha1, estrogen receptor, and vitamin D receptor genes.

Genetic factors are known to influence both the peak bone mass and probably the rate of change in bone density. A range of regulatory and structural genes has been proposed to be involved including collagen 1alpha (COL1A1), the estrogen receptor (ER), and the vitamin D receptor (VDR), but the actual genes involved are uncertain. We therefore studied the role of the COL1A1 and VDR loci in control of bone density by linkage in 45 dizygotic twin pairs and 29 nuclear families comprising 120 individuals. The influences on bone density of polymorphisms of COL1A1, VDR, and ER were studied by association both cross-sectionally and longitudinally in 193 elderly postmenopausal women (average age, 69 years) over a mean follow-up time of 6.3 years. Weak linkage of the COL1A1 locus with bone density was observed in both twins and families (p = 0.02 in both data sets), confirming previous observations of linkage of this locus with bone density. Association between the MscI polymorphism of COL1A1 and rate of lumbar spine bone loss was observed with significant gene-environment interaction related to dietary calcium intake (p = 0.0006). In the lowest tertile of dietary calcium intake, carriers of "s" alleles lost more bone than "SS" homozygotes (p = 0.01), whereas the opposite was observed in the highest dietary calcium intake (p = 0.003). Association also was observed between rate of bone loss at both the femoral neck and the lumbar spine and the TaqI VDR polymorphism (p = 0.03). This association was strongest in those in the lowest tertile of calcium intake, also suggesting the presence of gene-environment interaction involving dietary calcium and VDR, influencing bone turnover. No significant association was observed between the PvuII ER polymorphism alone or in combination with VDR or COL1A1 genotypes, with either bone density or its rate of change. These data support the involvement of COL1A1 in determination of bone density and the interaction of both COL1A1 and VDR with calcium intake in regulation of change of bone density over time.

Absorptiometry, Photon↗
PubMed1995

Ipriflavone improves bone density and biomechanical properties of adult male rat bones.

To assess the potential impact of ipriflavone on the biomechanical properties and mineral composition of bone, we administered two doses (200 or 400 mg/kg bw) of the drug orally to adult male rats for 1 month. Bone biomechanics were evaluated by vibration damping, an index of strain energy loss, and impact strength (the amount of energy required to fracture after a single impact). At the higher dose, ipriflavone significantly decreased vibration damping of rat femurs by 23.0 +/- 9.8% compared with control, vehicle-treated animals, suggesting a higher capacity to withstand dynamic stress. This result was confirmed by the impact strength studies showing that a higher energy (49.6 +/- 21.3% above control) was required to fracture femurs of rat treated with 400 mg/kg bw ipriflavone. The high dose of ipriflavone increased bone mineral density, assessed by both volume displacement and ash analysis (4.2% and 2.5% above controls, respectively). The relative content of calcium, phosphorus, and magnesium in the ashes was not different among the treated and untreated groups, indicating that no gross abnormalities in mineral composition of bone occurred after ipriflavone administration. Similarly, there were no differences in serum calcium and magnesium levels between treated and control animals at the end of the study, whereas lower circulating phosphorus levels were detected in the latter. Ipriflavone treatment was not associated with significant changes in serum alkaline phosphatase nor type I collagen telopeptide levels, two markers of bone turnover. In summary, 1-month treatment with ipriflavone increased bone density and improved the biomechanical properties of adult rat male bones without altering mineral composition.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1998

Development and validation of a simple questionnaire to facilitate identification of women likely to have low bone density.

The relationship between low bone mass and risk of fracture is well documented. Although bone densitometry is the method of choice for detecting low bone mass, its use may be limited by the availability of equipment, cost, and reimbursement issues. Improved patient selection for bone densitometry might increase the cost-effectiveness of screening for osteoporosis, a goal we sought to achieve by developing and validating a questionnaire based solely on patient-derived data. Responses to the questionnaire were used to assign postmenopausal women to one of two groups: (1) those unlikely to have low bone mineral density (defined as 2 standard deviations or more below the mean bone mass at the femoral neck in young, healthy white women) and therefore probably not currently candidates for bone densitometry; and (2) those likely to have low bone mineral density and therefore probably candidates for bone densitometry. We asked community-dwelling perimenopausal and postmenopausal women attending one of 106 participating multispecialty centers (both academic and community based) to complete a self-administered questionnaire and undergo bone density measurement using dual x-ray absorptiometry. We used regression modeling to identify factors most predictive of low bone density at the femoral neck in the postmenopausal group. A simple additive scoring system was developed based on the regression model. Results were validated in a separate cohort of postmenopausal women. Data were collected from 1279 postmenopausal women in the development cohort. Using only six questions (age, weight, race, fracture history, rheumatoid arthritis history, and estrogen use), we achieved a target of 89% sensitivity and 50% specificity. The likelihood ratio was 1.78. Validation in a separate group of 207 postmenopausal women yielded 91% sensitivity and 40% specificity. Assuming population characteristics similar to those of our development cohort, use of our questionnaire could decrease the use of bone densitometry by approximately 30%. Sensitivity and specificity can be varied by changing the level for referral for densitometry to provide the most cost-effective use within a particular healthcare setting. Thus use of our questionnaire, an inexpensive prescreening tool, in conjunction with physician assessment can optimize the use of bone densitometry and may lead to substantial savings in many healthcare settings where large numbers of women require evaluation for low bone mass.

Bone Density↗
PubMed2002

[Prediction of changes in bone density during alendronate treatment in postmenopausal women].

Alendronate is an aminobisphosphonate, a selective inhibitor of osteoclast-mediated bone resorption. Due to its influence a decline of markers of bone turnover occurs. The latter react much sooner than it is possible to detect significant changes of bone density. In the submitted trial the authors investigated changes of selected markers: total alkaline phosphatase (ALP), osteocalcin (OC), N-terminal telopeptide fragment of collagen type I (NTx) after 3 months' treatment with alendronate, the influence on bone density after one year's treatment in 50 postmenopausal women with densitometrically verified osteoporosis. After one-year treatment in the whole group a significant increase of bone density occurred in the area L2-L4 by 4.52% (SD = 3.9), neck of the femur by 2.24% (SD = 3.6), trochanter by 2.81% (SD = 3.0) and total by 1.89% (SD = 2.7). Total ALP and OC in serum, similarly as NTx in urine declined significantly already after 3 months treatment and the decline persisted also after one year of treatment. With the change of bone density after one year correlated significantly only NTx. A decline of NTx after 3 months by more than 30% as compared with the baseline value was recorded in 81% patients and this change predicted a significant rise of the bone density in the area of the neck of the femur, on average by 30. Urinary NTx is a promising predictor of the effect of alendronate treatment. Its drop by more than 30% after 3 months justifies the assumption that bone density increased after one year's treatment.

Absorptiometry, Photon↗
PubMed1989

[Increase of vertebral bone density in heavy drinkers of mineral water with a high fluoride content].

The mineral density of bone (MDB) was measured by dualphoton absorptiometry in the lumbar vertebrae of 23 healthy volunteers who consumed large amounts of a mineral water with high fluoride content (8.5 mg/l). The subjects studied had ingested a minimum of 0.75 litre of this water each day for 5 years or more. None of them had a history of pain in the bones or spontaneous fracture. MDB was found to be significantly higher in these subjects than in age - and sex-matched controls, and particularly high in those who were older than 60 years. There was positive correlation (r = 0.61, p less than 0.02) between MDB and mineral water consumption index. Serum levels of osteocalcin - a marker of bone formation - and urinary fluoride levels were significantly higher in drinkers of St-Yorre water than in controls. These data suggest that prolonged consumption of this mineral water by subjects without renal impairment might protect against the risk, increasing with age, of vertebral osteoporosis.

Adult↗
PubMed1993

Predicting vertebral fracture incidence from prevalent fractures and bone density among non-black, osteoporotic women.

We evaluated the ability of bone density and vertebral fractures at baseline to predict vertebral fracture incidence in a cohort of postmenopausal women with osteoporosis. The study population was 380 postmenopausal women (mean age 65 years) treated for osteoporosis in a randomized, placebo-controlled, clinical trial of the bisphosphonate etidronate at seven geographic centers in the United States. Baseline measurements of bone mineral density were obtained in 1986 by quantitative computed tomography at the spine and dual-photon absorptiometry at the lumbar spine and hip. Vertebral fractures were documented on serial spine radiographs. Proportional hazards models were used to evaluate the ability to predict the risk of subsequent fractures during an average of 2.9 years of follow-up. Presence of one or two fractures increased the rate of new vertebral fractures 7.4-fold (95% confidence interval = 1.0 to 55.9). Additional fractures at baseline further increased the fracture rate. A decrease of 2 standard deviations in spinal bone density by absorptiometry was associated with a 5.8-fold increase in fracture rate (95% confidence interval = 2.9 to 11.6). The lowest and highest quintiles of bone density had absolute fracture rates of 120 and 6 cases per 1000 patient-years, respectively. In general, the simultaneous use of two predictors (bone density and prevalent fractures or two bone density measurements) improved fracture prediction, compared with the use of a single predictor. We conclude that both bone density and prevalent vertebral fractures are strong, complementary predictors of vertebral fracture risk. The results suggest that physicians can use bone density and prevalent vertebral fractures, individually or in combination, as risk factors to identify patients at greatest risk of new fractures.

Aged↗
PubMed1997

Vitamin D receptor genotypes and changes of bone density in physically active German women with high calcium intake.

Polymorphisms at the vitamin D receptor (VDR) gene have been reported to mediate important differences in bone mineral density (BMD) and bone metabolism. In this longitudinal study we examined the relationships between VDR genotypes and bone metabolism, changes in BMD and changes in ultrasound transmission velocity in a population of healthy unrelated German women. The study population comprised 50 physically active women (aged 43.3 to 62.8 years, 14 premenopausal, 36 postmenopausal) with a daily calcium intake of (mean +/- SD) 1045 +/- 338 mg, who had earlier participated in a longitudinal study on the association of physical activity and bone density and bone turnover. Each participant was genotyped for the BsmI polymorphism at the VDR gene locus. Markers of bone turnover (alkaline phosphatase, osteocalcin, procollagen type I C-terminal propeptide, collagen type I C-terminal telopeptide, tartrate-resistant acid phosphatase) were measured at baseline. BMD (determined by peripheral quantitative computed tomography at the distal radius) and ultrasound transmission velocity through bone (at calcaneus, patella and thumb) were analysed at baseline and 15 months later. The genotypic groups did not differ significantly (p > 0.05) in any of the parameters determined at baseline. Neither were there any differences between these groups in the changes of BMD or ultrasound transmission velocity during the study period. Thus, we conclude that in physically active German women with a relatively high calcium intake the impact of VDR genotypic polymorphisms on bone density, bone metabolism and changes in bone density may be of limited importance.

Alleles↗
PubMed2000

A fracture risk profile using single-site bone density assessment and clinical risk factors.

The Risk Factor Profile combines single-site bone density assessment and selected clinical risk factors to help estimate the risk of osteoporotic fracture for Caucasian postmenopausal women over the next 5 years. The bone density assessment uses T score cut-off values equivalent to the WHO definitions of osteoporosis and osteopenia at the hip that would identify 16-17% of women over 50 years of age as "high" risk. The clinical risk factors are defined as "major" producing about a doubling of fracture risk independent of bone density, and "minor" where the predictive power is less certain. The indications for a risk factor assessment using the Profile are the same as for any bone density assessment with the exception of monitoring response to treatment. In practice the clinical risk factors can be measured at the time of the bone density estimation taking only a few minutes. The decision to treat, or not to treat, a postmenopausal woman at high or medium risk will ultimately depend on the overall assessment of risks and benefits, costs of treatment and the desires of the patient. The Risk Factor Profile aims to supply the clinician with a simple tool to aid treatment decision-making.

Absorptiometry, Photon↗
PubMed2003

Bone density: its influence on implant stability after uncovering.

Primary implant stability and bone density are variables that have long been considered to be essential to achieving predictable osseointegration and long-term clinical survival. Although the dentist can control most factors associated with implant survival, bone density is the one factor that cannot be controlled. Measuring implant stability would assist in determining if an implant has integrated and is ready for the fabrication of the final prosthesis. Changes in implant stability in each type of Bone Quality (BQ-1, -2, -3, and -4), which may occur with time, have not been studied. Such information could help identify well-integrated implants and identify changes associated with impending implant failure. Several studies have used the Periotest instrument to study implant stability. Use of the Periotest implant stability will be studied during each phase of implant treatment for each bone density, and a range for clinically satisfactory integration will be suggested. Implant stability changes over time, and the changes are different for each bone density as the bone surrounding the nonhydroxyapatite implant becomes denser. This is clearly demonstrated in a postmortem histological specimen. The changes in implant stability (Periotest Values [PTVs]) are more apparent in BQ-1 and BQ-2 bone and less apparent in BQ-3 and BQ-4 bone. The Periotest is capable of providing valuable information concerning favorable or unfavorable changes in the bone-implant interface after uncovering. In addition, it can help identify when an implant is ready to be loaded. A new range of PTVs (-5 to -2) is suggested for monitoring the status of implants. Implants with PTVs more positive than -2 would indicate a bone-implant complex that may be marginal.

Bone Density↗
PubMed1999

Gamma-ray scattering for mandibular bone density measurement.

There has been considerable interest in the measurement of bone density in the mandible, either to study bone resorption following tooth loss or to determine the relationship between mandibular and skeletal bone mineral density. Measurements mostly have been made on dental radiographs but more significant correlations between mandibular and skeletal bone density have been obtained when more sophisticated techniques have been used, such as quantitative CT and dual energy X-ray absorptiometry. The present work investigates the feasibility of using gamma-ray scattering measurements to estimate mandibular bone density. Using a phantom to simulate the jaw, an 241Am source and a hyperpure germanium detector it is shown that bone density may be measured with a precision of about 1%.

Absorptiometry, Photon↗
PubMed2005

Prospective bone density changes after periacetabular osteotomy: a methodological study.

We used computed tomography (CT) and 3D design-based sampling principles (stereology) to estimate changes in acetabular bone density after periacetabular osteotomy. We included six consecutive patients with hip dysplasia in the study. Baseline density was measured within the first 7 days following periacetabular osteotomy and compared with bone density 2 years later. Double measurements were performed on three patients, and the coefficient of error of the mean was estimated to 0.05. Bone density in zone 1 increased significantly in the anteromedial quadrant as well as in the posteromedial quadrant of the acetabulum. In the anterolateral and the posterolateral quadrant, bone density was unchanged. In zone 2 and 3, bone density was unchanged 2 years postoperatively. We suggest that the observed increase in bone density medially represents a remodelling response to an altered load distribution after osteotomy. The method used is a precise tool to estimate changes in acetabular bone density.

Acetabulum↗
PubMed1998

Spinal bone density in women using depot medroxyprogesterone contraception.

OBJECTIVE: To determine factors possibly associated with reduced bone density in women using the injectable contraceptive depot medroxyprogesterone acetate. METHODS: In a cross-sectional study, bone mineral density of the lumbar spine was measured by dual energy x-ray absorptiometry in 200 current users of depot medroxyprogesterone acetate who had used this method of contraception for 2-26 years and compared with 350 control subjects. Bone density results are expressed as standard deviation scores (z score). RESULTS: The bone density was significantly lower in depot medroxyprogesterone acetate users (mean z score: -0.65, 95% confidence intervals [CI] -0.80, -0.49, P < .001). Bone density was significantly reduced in nonsmokers and smokers, and there was no significant difference in mean z score between smokers and nonsmokers (mean -0.75 versus -0.58, P=.30). Women who had started depot medroxyprogesterone acetate after the age of 20 years and who had used it for 15 or fewer years had a significantly higher bone density than the remainder of the cohort (mean -0.45 [95% CI -0.62, -0.27] versus -1.02 [95% CI -1.32, -0.73], P < .005). Bone density in depot medroxyprogesterone acetate users was not related to current age, parity, body mass index, calcium intake, or exercise. CONCLUSION: Depot medroxyprogesterone acetate use is associated with a significant reduction in bone density, and although a high proportion of depot medroxyprogesterone users do smoke, the reduction in bone density cannot be explained by smoking. Women who use it for a long time and those who start it before peak bone mass is attained may be at highest risk.

Adolescent↗
PubMed2002

The effects of vitamin D receptor polymorphism on secondary hyperparathyroidism and bone density after renal transplantation.

Immunosuppresive treatment and secondary hyperparathyroidism (SHPT) are considered among the most important pathogenetic factors for postrenal transplant bone disease. The aim of this study was to investigate the relationships among vitamin D receptor (VDR) gene polymorphism, parathyroid hormone (PTH) levels, and bone density in renal transplant recipients. We enrolled 69 patients (47 men and 22 women; mean age, 47 +/- 11 years) who had undergone kidney transplantation 51 +/- 5 months before. All patients underwent an evaluation of the main biochemical parameters of bone metabolism as well as bone densitometry. VDR alleles were typed by a polymerase chain reaction (PCR) assay based on a polymorphic BsmI restriction site. When the patients were categorized according to the VDR genotype (BB, Bb, and bb), serum creatinine, and the cumulative doses of immunosuppressive drugs were similar across the groups. PTH levels higher than 80 pg/ml were found in 53.6% of the patients, with the highest values being detected in the bb VDR genotype (p < 0.05). PTH was significantly correlated to urinary type I collagen cross-linked N-telopeptide (NTx) values. Bone density was low in the whole population; however, spinal bone density was lower in the bb subgroup (p < 0.02). In the whole population, only PTH (p < 0.05) and body mass index (BMI; p < 0.01) were independent predictors of spinal bone density. When grouping the patients by the VDR gene polymorphism, only PTH continued to be an independent predictor of spinal bone density in the bb allele subgroup (R2 adj. = 0.17). We can conclude that the VDR genotype polymorphism affects bone density of renal transplant recipients via its effects on the severity of SHPT.

Absorptiometry, Photon↗
PubMed1993

[Ultrasound attenuation in calcaneus and bone density].

Broadband ultrasound attenuation (BUA) is a new technique for investigating bone status. We evaluated its use in osteoporosis. To assess in vivo reproducibility, we determined the coefficient of variation (cv) on the basis of five measurements (with repositioning) of the same foot in 50 women. The cv was 2.8 +/- 1.7%. BUA values were similar in the right feet and left foot and were correlated with bone density in the calcaneal area investigated (r = 0.8, p < 10(-4). BUA of the calcaneus was correlated with bone density in the lumbar spine, femur, and forearm in 240 healthy postmenopausal women (correlation coefficients 0.36 to 0.55; p < 10(-4)). BUA decreased with age, with a sharper drop during the first years following menopause. Mean broadband ultrasonic attenuation in 37 females with osteoporosis (58.92 +/- 11.59 dB/MHz) is lower than controls (66.10 +/- 15.29 dB/MHz, p = 0.04). Areas under receiver operating characteristic curves, used to evaluate the discriminating value of BUA in osteoporosis and osteopenia, were 0.79 and 0.72, respectively. The kappa coefficient of concordance between BUA and spinal density was 0.59. These data demonstrate that BUA cannot replace bone density measurements. Prospective studies are needed to investigate the potential role of this technique for identifying women at high risk for osteoporotic fractures.

Adult↗
PubMed1999

Strain differences in bone density and calcium metabolism between C3H/HeJ and C57BL/6J mice.

Previous reports indicate that peak bone density is significantly higher in C3H/HeJ (C3H) than in C57BL/6J (C57BL) mice, making these two inbred strains useful models for studying the genetic basis for peak bone density. The following study was undertaken to examine whether strain differences in the bone density of C3H and C57BL mice are associated with differences in intestinal calcium (Ca) absorption. Calcium absorption was measured by the balance technique and animals received two injections of fluorochromes 5 days apart before killing. Subsequently, the femurs were removed and, following measurement of volumetric density, the left femur was divided into three equal parts and the middle third served as the femoral cortical diaphysis. Femur diaphyseal volumetric bone density, ash, and Ca content were 10%, 29%, and 29% higher in C3H than in C57BL mice (p < 0.001), respectively. Bone length, periosteal mineral apposition rate, and periosteal bone formation rate of femoral diaphyseal cortical bone were not significantly different between the two strains of mice, but the marrow area of C57BL mice was almost twofold that of C3H mice (p < 0.0001). Intestinal Ca absorption and 1,25-dihydroxyvitamin D [1,25(OH)2D]-stimulated Ca2+ uptake by intestinal mucosal cells were 38% and 51% higher in C3H than in C57BL mice p < 0.001), respectively. Serum Ca and 1,25(OH)2D levels were 6% and 32% higher in C3H than in C57BL mice (p < 0.001), respectively, and the number of intestinal-occupied vitamin D receptors was 51% higher in C3H than in C57BL mice (p < 0.01). In a second experiment, three groups of C3H mice and three groups of C57BL mice were fed diets that contained 0.4%, 0.1%, or 0.02% Ca, and serum Ca, 1,25(OH)2D, parathyroid hormone (PTH), and intestinal Ca absorption measured. At all dietary Ca levels, C3H mice maintained positive Ca absorption and absorbed significantly more Ca than C57BL mice. In contrast, at low dietary Ca levels (0.1% and 0.02% Ca), C57BL mice maintained negative Ca absorption. Low dietary Ca increased serum PTH significantly in C57BL but not in C3H mice, and decreased serum 1,25(OH)2D and Ca levels in both strains of mice. Our findings indicate that the C57BL mice relied more on the mobilization of Ca from bone to maintain extracellular Ca homeostasis than the C3H mice. We conclude that strain differences in bone mass and density between C3H and C57BL mice is expressed, in part, through the vitamin D and PTH endocrine systems and their effects on the maintenance of extracellular Ca homeostasis.

Animals↗