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R R Recker

Publications and source records attributed to R R Recker.

At least 19 recordsLinked to original sources
PubMed2004

Histomorphometric evaluation of daily and intermittent oral ibandronate in women with postmenopausal osteoporosis: results from the BONE study.

The bisphosphonate ibandronate, administered either daily or intermittently with an extended between-dose interval of >2 months, has been shown to reduce significantly the incidence of vertebral fractures, to increase bone mineral density and to reduce levels of biochemical markers of bone turnover in a phase III randomized study in women with postmenopausal osteoporosis (PMO). Bone histomorphometry was performed on a subgroup of women participating in this study in order to assess bone quality and architecture. The patients were randomized to receive one of the following: placebo, continuous oral daily ibandronate (2.5 mg/day) or intermittent oral ibandronate (20 mg every other day for 12 doses every 3 months). Out of the overall study population of 2,946 patients, 110 were randomly assigned to undergo transiliac bone biopsy at either month 22 or month 34 of treatment. The primary safety endpoint was osteoid thickness in trabecular bone, which was measured to exclude treatment-induced bone mineralization defects. Secondary safety endpoints assessed bone volume, bone turnover and micro-architecture. The primary efficacy endpoint was bone mineralizing surface. In all bone biopsy cores, newly formed trabecular bone retained its structure without any signs of woven bone. Marrow fibrosis and signs of cellular toxicity were not observed. Quantitative assessment demonstrated no impairment in mineralization of bone matrix: osteoid thickness tended to be similar or slightly lower in the ibandronate groups versus the placebo group. All secondary safety variables and the bone efficacy parameter were consistent with the production of normal-quality, newly formed bone and a modest reduction in bone turnover with both ibandronate regimens relative to placebo. Long-term treatment with oral ibandronate, even when administered with an extended between-dose interval of >2 months, produces normal-quality, newly formed bone in women with PMO.

Aged↗
PubMed2003

Gene expression studies of osteoporosis: implications for microarray research.

Osteoporosis is one of the most common bone-related disorders in the elderly. It is a complex disease, and largely determined genetically. Traditional gene expression studies have shown that osteoporosis has complex regulating mechanisms which are controlled by multiple inherent factors, such as hormones, cytokines, various receptors, etc. The complex nature of osteoporosis, and the large number of genes involved in its onset and development, suggest the use of the state of the art microarray technique as a powerful tool to unravel mechanisms underlying etiology of osteoporosis.

Aged↗
PubMed2003

Effects of nicotine on bone mass and strength in aged female rats.

This study investigated the effects of nicotine on bone mass and biomechanical properties in aged, estrogen-replete (sham-operated) and estrogen-deplete (ovariectomized) female rats. Eight month old, retired breeder, sham-operated and ovariectomized Sprague-Dawley rats were left untreated for 12 weeks to establish cancellous osteopenia in the ovariectomized group. The animals were then administered saline, low dose nicotine (6.0 mg/kg/day) or high dose nicotine (9.0 mg/kg/day) via osmotic minipumps for 12 weeks. Vertebrae and femora were collected at necropsy for determination of bone mass and strength. As expected, ovariectomy had a negative effect on most endpoints evaluated. Vertebral body bone mineral content (BMC) and density (BMD) and the structural (ultimate load and yield load) and material (ultimate stress, yield stress, and flexural modulus of elasticity) strength properties were lower in the OVX rats than in the sham-operated rats. Femoral diaphysis BMC, BMD, ultimate load, and flexural modulus were also lower in the OVX rats than in the sham-operated rats. The nicotine doses administered resulted in serum nicotine levels that averaged 1.5-4.5-fold greater than those observed in heavy smokers. Despite the high doses used, nicotine had no effect on vertebral BMC, BMD, or any of the structural and material strength properties in either the OVX or the Sham rats. In addition, nicotine had no effect on femoral diaphysis BMC, BMD, ultimate load, stiffness, ultimate stress, or flexural modulus. Femoral yield load and stress were lower in low dose nicotine-treated rats than in vehicle-treated rats. However, differences were not detected between the high dose nicotine- and vehicle-treated rats for either femoral yield load or stress. The results suggest that tobacco agents other than nicotine are responsible for the decreased bone density and increased fracture risk as observed in smokers.

Aging↗
PubMed2003

Intermittent intravenous administration of the bisphosphonate ibandronate prevents bone loss and maintains bone strength and quality in ovariectomized cynomolgus monkeys.

Using a clinically relevant regimen, this study investigated the effects of treatment with ibandronate, a highly potent nitrogen-containing bisphosphonate, on bone loss, biochemical markers of bone turnover, densitometry, histomorphometry, biomechanical properties, and bone concentration in aged ovariectomized monkeys. Sixty-six female cynomolgus monkeys, aged 9 years and older, were ovariectomized (OVX) or sham operated. Intravenous (iv) bolus injections of ibandronate at 10, 30, or 150 microg/kg or placebo were administered at 30-day intervals (corresponding to intervals of 3 months in humans), starting at OVX, for 16 months. OVX significantly decreased bone mass at the lumbar spine, proximal femur, femoral neck, and radius and increased bone turnover in a time-dependent manner, as assessed by dual energy X-ray absorptiometry, peripheral quantitative computed tomography, or histomorphometry. Ibandronate iv bolus injections administered at 30 microg/kg every 30 days prevented osteopenia induced by estrogen depletion. OVX-induced increases in bone turnover (as determined by activation frequency, bone formation rate, and biochemical markers of bone turnover, including urinary N-telopeptide and deoxypyridinoline excretion and serum values for osteocalcin and bone-specific alkaline phosphatase) were suppressed on treatment, and bone mass, architecture, and strength were preserved at clinically relevant sites. Treatment with high-dose (150 microg/kg/dose) iv bolus injections of ibandronate further increased bone mass and improved bone strength at both the spine and femoral neck, without adversely affecting bone quality. In contrast, treatment with a 10 microg/kg/dose only partially prevented the OVX-induced effects. These data support the potential for the long-term administration of ibandronate by intermittent iv bolus injections in humans to prevent osteoporosis and improve bone quality at clinically relevant sites.

Animals↗
PubMed2003

Differentiation of Caucasians and Chinese at bone mass candidate genes: implication for ethnic difference of bone mass.

Bone mineral density (BMD) is an important risk factor for osteoporosis and has strong genetic determination. While average BMD differs among major ethnic groups, several important candidate genes have been shown to underlie BMD variation within populations of the same ethnicity. To investigate whether important candidate genes may contribute to ethnic differences in BMD, we studied the degree of genetic differentiation among several important candidate genes between two major ethnic groups: Caucasians and Chinese. The genetic variability of these two populations (1131 randomly selected individuals) was studied at six restriction sites exhibiting polymorphisms of five important candidate genes for BMD: the BsaHI polymorphism of the calcium-sensing receptor (CASR) gene, the SacI polymorphism of the alpha2HS-glycoprotein (AHSG) gene, the PvuII and XbaI polymorphisms of the estrogen receptor alpha (ESR1) gene, the ApaI polymorphism of the vitamin D receptor (VDR) gene, and the BstBI polymorphism of the parathyroid hormone (PTH) gene. The two ethnic groups showed significant allelic and genotypic differentiation of all the polymorphisms studied. The mean FST was 0.103, which significantly differed from zero (P < 0.01). The Chinese population had lower mean heterozygosity (0.331) than the Caucasian one (0.444); the CASR-BsaHI and PTH-BstBI polymorphisms contributed most significantly to this difference. Analysis of the intra- and inter-population variability suggests that various types of natural selection may affect the observed patterns of variation at some loci. If some of the candidate genes we studied indeed underlie variation in BMD, their population differentiation revealed here between ethnic groups may contribute to understanding ethnic difference in BMD.

Asian People↗
PubMed2003

Molecular and genetic mechanisms of osteoporosis: implication for treatment.

Osteoporosis is a leading public health problem in our rapidly growing, aging population. It is characterized by reduced bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture risk. Osteoporosis is a complex multifactorial disease, determined by genetic and environmental factors as well as their interactions. A large number of molecular, genetic and environmental factors underlying osteoporosis have been identified in past decades. In this article, we review 1) the molecular mechanisms of several principal systemic and local factors regulating bone metabolism; and 2) the current status of genetic studies searching for genes underlying osteoporosis. Further, we attempt to integrate knowledge from those two fields, and their potential implications for osteoporosis treatment.

Bone Density↗
PubMed2002

Evidence for a major gene for bone mineral density/content in human pedigrees identified via probands with extreme bone mineral density.

Bone mineral content (BMC) and/or bone mineral density (BMD, i.e. BMC scaled by bone size) are major determinants for osteoporosis, which is a serious health problem. The major determinant of variation in BMD/BMC is genetic. The few studies now available are inconsistent in the identification and/or even in the existence of major gene(s) for BMD/BMC. In 51 human pedigrees with 941 individuals (526 measured for phenotypes) identified via probands with extreme BMD values, we performed complex segregation analyses to test the existence of a genetic locus with a major effect on BMD/BMC variation. We analyzed BMD and BMC at the spine, hip and wrist jointly by employing, as the study phenotype, factor scores (FS) of the principle component that explains approximately 75% of the total BMD/BMC variation at the three sites. The results indicate that a major gene exists with a codominant effect that is responsible for approximately 16% of the FS variation when adjusted for significant effects of sex, body weight and age. A significant genotype-x-sex-x-age interaction was found, which may explain approximately 14% of the FS variation after adjusting for body weight. Testing of various models did not provide support for shared familial environmental effects but suggested the existence of residual polygenic effects, which may explain approximately 50% of the FS variation when adjusting for sex, body weight and age. This study indicates a promising aspect of studies to identify a major gene for BMD/BMC variation in our pedigrees identified via extreme probands.

Bone Density↗
PubMed2002

Bone adaptation response to sham and bending stimuli in mice.

This study presents inbred-strain-related differences in tibial bone adaptation response to low-force loading in four-point bending and sham (pad pressure) arrangements in mice. Our previous work in mice has shown that at relatively high but equal bending forces (9 N or a bending moment of 16.88 N-mm), C57BL/6J mice respond with significantly greater bone formation than C3H/HeJ mice. Because of high tibial strains, the majority of the bone response in our previous study was woven bone. In this, study, we reduced the loading forces to 5 N or a bending moment of 9.38 N-mm (to decrease the woven-bone formation response) and investigated inbred-strain-related bone adaptation differences resulting from bending and sham loading (reported here for the first time in C57BL/6J) in these mice. Twenty-four female mice within each inbred mouse strain (C3H/HeJ [C3H] and C57BL/6J [B6]) were randomly divided into the two loading groups (12 per group sham and bending, total of 48 mice). All of the external loading was done for 36 cycles at 2 Hz, 3 d/wk for 3 wk. The bone adaptation response at lower forces exhibited a pattern similar to that seen for the higher forces in the previous study, suggesting that the patterns of bone adaptation were inbred strain related and independent of bending force magnitude. The bending-related periosteal mineral apposition surface (pMS) and mineral apposition rate (MAR) were respectively 40% and 45% greater in B6 than in C3H. The cortical bone adaptation response to bending was greater when compared to sham or pad pressure for each inbred strain of mice, suggesting that the majority of the bone adaptation response was the result of bending stimulus and not local pressure from pad contact. In addition, regardless of loading arrangement (sham or bending), the bone adaptation response in C57BL/6J mice was greater than C3H/HeJ.

Adaptation, Physiological↗
PubMed2001

Effect of polygenes on Xiong's transmission disequilibrium test of a QTL in nuclear families with multiple children.

The transmission disequilibrium test (TDT), originally developed for mapping disease genes, has recently been extended to identify quantitative trait loci (QTL). For quantitative traits important for human health, generally multiple QTLs are involved. In the investigation of the statistical properties of the TDT, background polygenes (QTLs other than the QTL under test) generally have not been explicitly considered. The effects of background polygenes on the statistical properties of the TDT are thus largely unknown. Investigation of these effects will provide more realistic analyses of the statistical properties of the TDT under biologically plausible situations, and thus provide more accurate guidelines on the application of the TDT in practice. A general TDT (TDT(G)) has been developed to test linkage of a QTL in nuclear families that may be composed of more than one heterozygous parent and multiple children. Using the TDT(G) as an example, we develop an analytical method to investigate the effects of background polygenes on the power of the TDT. The accuracy of our analytical method is validated by computation simulations. We found that the power of the TDT(G) is increased with background polygenes when more than one child is employed in nuclear families, and the effect is stronger with more children per family recruited for study. The power of the TDT(G) increases dramatically when the number of children recruited from each nuclear family increases from one to two or from two to three. The type one error rate is not affected by the presence of background polygenes. The results of this study should be of theoretical significance in generalizing the investigation of the TDT to biologically plausible situations with background polygenes. They should also be of practical values in providing guidance on the recruitment of nuclear families with multiple children with the TDT(G).

Computer Simulation↗
PubMed2001

The impact of lifestyle factors on stress fractures in female Army recruits.

Estimates are that stress fractures during basic training (BT) occur in as many as 14% of US female military recruits. Injuries of this type lead to morbidity ranging from minor pain to serious lifetime disability. Since women are assuming an increasing role in the military, this high risk of stress fracture is of concern. The purpose of this prospective study was to determine factors that predict stress fracture during BT in US Army female recruits. The analysis was part of an investigation using quantitative ultrasound (QUS) to determine risk of stress fracture during BT. Prior to the start of BT, we obtained QUS measurements and asked each subject to complete a risk factor questionnaire. We completed assessments for 3758 recruits who then proceeded to 8 weeks of BT, during which time any diagnosed stress fractures were reported to us by Army clinicians. Stress fractures were confirmed with radiographs. The incidence of stress fracture was 8.5% per 8 weeks. Factors associated with stress fracture include: QUS, age, race, alcohol and tobacco use, weight-bearing exercise, lowest adult weight, corticosteroid use, and, in white women only, use of depo-medroxyprogesterone acetate (DMPA). Women who fractured were older than women who remained fracture-free, and black women were less likely to sustain a fracture than whites and other races. Compared with their non-stress-fracture counterparts, recruits who developed stress fractures were more likely to report current or past smoking, alcoholic drinking of > 10 drinks/week, corticosteroid use and lower adult weight. A history of regular exercise was protective against stress fracture, and a longer history of exercise further decreased the relative risk of fracture. Although current weight was not associated with stress fracture, lowest adult weight was inversely related to the risk of fracture. We conclude that prevention of stress fractures in female military recruits should include a thorough assessment of lifestyle factors such as exercise patterns, alcohol and tobacco habits, and corticosteroid and DMPA use. Assessment of risk factors may be helpful in pinpointing female recruits who should have further evaluation of their bone health or additional preparation, such as gradual increases in physical activity, prior to being exposed to the rigor of BT.

Adult↗
PubMed2001

Maintenance of cortical bone in human parathyroid hormone(1-84)-treated ovariectomized rats.

The purpose of this cross-sectional study was to evaluate the effects of human parathyroid hormone(1-84) (hPTH) followed by maintenance treatment with 17beta-estradiol (E(2)), risedronate (Ris), or a reduced dose of hPTH (LowPTH) on cortical bone in the ovariectomized (ovx) rat. Eight groups of ovx and one group of intact female rats (3.5 months) were left untreated for 11 weeks. For the following 12 weeks, four groups received subcutaneous injections of hPTH (75 microg/kg per day on 3 days/week) and four groups received vehicle. Treatments were then changed to E(2) (10 microg/kg per day on 2 days/week), Ris (3 microg/kg per day on 3 days/week), LowPTH (25 microg/kg per day on 3 days/week), or vehicle. Bone tissue was collected at weeks -11 (baseline), 0 (ovx effect), 12 (hPTH effect), 24, 36, and 48 (maintenance effect). Bone mineral density (BMD) and bone mineral content (BMC) of the diaphyseal femur and total cross-sectional area (Tt.Ar), marrow area (Ma.Ar), cortical area (Ct.Ar), and periosteal and endocortical bone formation of the tibia were measured. Ovariectomy resulted in lower BMD (weeks 0-48), unaffected BMC, and greater Tt.Ar (weeks 12 and 36), Ma.Ar (week 48), and Ct.Ar (weeks 0 and 12) compared with intact rats. Endocortical and periosteal bone formation were greater in the ovx than in the intact rats up to 23 weeks postovariectomy. Treatment of ovx rats with hPTH for 12 weeks resulted in greater cortical BMD, BMC, and endocortical bone formation than in intact or ovx controls. In ovx rats pretreated with hPTH and then treated with Ris for 36 weeks, BMD and BMC were greater and Ma.Ar was smaller than in ovx controls. In ovx rats pretreated with hPTH and then treated with LowPTH, BMD, BMC, Ct.Ar, and endocortical bone formation were greater and Ma.Ar was smaller than in ovx controls. Treatment of hPTH-pretreated rats with E(2) for 36 weeks did not affect cortical BMD, BMC, and Ct.Ar, although periosteal bone formation was lower in the E(2) group compared with the ovx group. Thus, in ovariectomized rats, cortical bone gained by 12 weeks of hPTH treatment was maintained for up to 36 weeks by treatment with risedronate or low-dose hPTH, but not with 17beta-estradiol.

Animals↗
PubMed2001

Maintenance of vertebral body bone mass and strength created by human parathyroid hormone treatment in ovariectomized rats.

The purpose of this cross-sectional study was to evaluate the effects of human parathyroid hormone (1-84) (hPTH) followed by maintenance administration of 17beta-estradiol (E2), risedronate (Ris), or a reduced dose of hPTH (LowPTH) on vertebral body bone mineral density (BMD) and bone strength in ovariectomized (ovx) rats. Eight groups of ovx (219 rats) and one group of intact female rats (48 rats) were left untreated for 11 weeks (age 3.5 months at the beginning). For the following 12 weeks, four ovx groups received subcutaneous injections of hPTH (75 microg/kg per day, 3 days/week) and four groups received vehicle. Treatments were then changed to: E2 (10 microg/kg per day, 2 days/week); Ris (3 microg/kg per day, 3 days/week); LowPTH (25 microg/kg per day, 3 days/week); or vehicle for 36 weeks. Bone tissue was collected at weeks -11 (baseline), 0 (ovx effect), 12 (hPTH effect), 24, 36, and 48 (maintenance effect). The endpoints were vertebral body BMD, ultimate stress (Ultstr), and moduli of elasticity from compression tests (ModM), and from ultrasound tests (ModUS). Ovariectomy resulted in lower BMD (p < 0.001). The hPTH treatment for 12 weeks restored BMD to the level of intact rats. Ultstr and ModUS followed a similar pattern, but the ovx-induced Ultstr was not significant (p = 0.073, ModUS: p = 0.003), nor was the hPTH-induced increase in ModUS (p = 0.131, Ultstr: p = 0.02). After hPTH withdrawal, BMD, Ultstr, and ModUS levels were not different from levels in ovx animals. In Ris-treated rats pretreated with hPTH, BMD (weeks 24 and 48, p < 0.002) and ModUS (week 24, p = 0.018) values were greater than in ovx animals. In LowPTH-treated rats pretreated with hPTH, BMD (weeks 24 and 48, p < 0.001) and Ultstr (week 48, p = 0.005) were greater than in ovx animals. In E(2)-treated rats pretreated with hPTH, BMD was greater than in ovx rats at week 24 (p = 0.009), but did not differ at weeks 36-48. Neither Ultstr nor ModUS in E(2)-treated rats differed significantly from ovx rats at any timepoint. Of the agents and dosing regimens used, we conclude that the hPTH-related vertebral bone mass gain in ovx rats can be maintained for up to 36 weeks with risedronate and low-dose hPTH treatment. Bone strength is maintained by treatment with low-dose hPTH, but only partially maintained with risedronate.

Aging↗
PubMed2001

Bone biomechanical properties in prostaglandin EP1 and EP2 knockout mice.

Prostaglandins play an important role in regulating the bone adaptation response to mechanical stimuli. Prostaglandin E2 (PGE2) is an effective modulator of bone metabolism. Administration of PGE2 to rodents results in increased cancellous and cortical bone mass translating into enhanced mechanical strength. The PGE2 influence on bone is mediated through four well-characterized receptors (EP1, EP2, EP3, and EP4). Although the PGE2 pathways and mechanisms of action on cells involved in bone adaptation are still under investigation, it is now known that each receptor plays a unique role in regulating PGE2-related bone cell function. The EP1 subtype is coupled with Ca2+ mobilization. The EP2 subtype stimulates cyclic adenosine monophosphate (cAMP) formation. cAMP in turn is responsible for the early cellular signal that stimulates bone formation. This study compared physical and biomechanical properties of bone in EP1 and EP2 knockout mice to their corresponding wild-type controls. Ash weight was measured in the ulnae, and femurs and vertebral bodies were tested in three-point bending and compression, respectively. The results suggest: (a) EP1 receptors have a minimal influence on skeletal strength or size in mice; and (b) EP2 receptors have a major influence on the biomechanical properties of bone in mice. The absence of EP2 receptors resulted in weak bone biomechanical strength properties in the EP2 knockout model as compared with the corresponding wild-type control mice.

Animals↗
PubMed2001

LOD score exclusion analyses for candidate genes using random population samples.

While extensive analyses have been conducted to test for, no formal analyses have been conducted to test against, the importance of candidate genes with random population samples. We develop a LOD score approach for exclusion analyses of candidate genes with random population samples. Under this approach, specific genetic effects and inheritance models at candidate genes can be analysed and if a LOD score is < or = - 2.0, the locus can be excluded from having an effect larger than that specified. Computer simulations show that, with sample sizes often employed in association studies, this approach has high power to exclude a gene from having moderate genetic effects. In contrast to regular association analyses, population admixture will not affect the robustness of our analyses; in fact, it renders our analyses more conservative and thus any significant exclusion result is robust. Our exclusion analysis complements association analysis for candidate genes in random population samples and is parallel to the exclusion mapping analyses that may be conducted in linkage analyses with pedigrees or relative pairs. The usefulness of the approach is demonstrated by an application to test the importance of vitamin D receptor and estrogen receptor genes underlying the differential risk to osteoporotic fractures.

Alleles↗
PubMed2001

Hormones, weight change and menopause.

OBJECTIVE: To determine total body weight change occurring in women at mid-life, specifically with respect to occurrence of menopause and use of estrogen. DESIGN: Retrospective analysis of body weight measurements accumulated in two cohorts of healthy women participating in studies of skeletal metabolism. SUBJECTS: Cohort 1: 191 healthy nuns enrolled in a prospective study of osteoporosis risk, aged 35-45 in 1967; cohort 2: 75 women aged 46 or older and still menstruating, enrolled in 1988 in a study of bone cell dynamics across menopause. Roughly one-third of each group received hormone replacement after menopause. MEASUREMENTS: Body weight and height, age, menstrual status and use of estrogen replacement. Cohort 1: 608 measurements at 5 y intervals spanning a period from 17 y before to 22 y after menopause; cohort 2: 1180 measurements at 6-month intervals spanning a period from 5 y prior to 5 y after menopause. RESULTS: In cohort 1 weight rose as a linear function of age (both chronological and menopausal), both before and after cessation of ovarian function, at a rate of approximately 0.43% y(-1). Neither the menopausal transition nor the use of estrogen had an appreciable effect on this rate of gain. In cohort 2 the rate of gain seemed to diminish slightly at menopause. As with cohort 1, hormone replacement (or its absence) had no appreciable effect on weight. CONCLUSIONS: The long-term, total body weight trajectory at mid-life is not influenced appreciably by either cessation of ovarian function or by hormone replacement.

Adult↗