Genetic influences on type I collagen synthesis and degradation: further evidence for genetic regulation of bone turnover.

Tokita, Akifumi; Kelly, Paul; Nguyen, Tuan V.; Qi, Jian-Cheng; Morrison, Nigel Alexander; Risteli, Leila; Risteli, Juha; Sambrook, Philip N.; Eisman, John A.

doi:10.1210/jcem.78.6.8200950

Cited by 49 publications

(28 citation statements)

References 35 publications

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“…Thus, the changes observed in these markers during bed rest are more clearly related to bed rest itself and/or the LBNP exercise. The heritability of these markers of bone resorption also provides a biochemical explanation for previously documented heritability of bone health [1,7,16,24,40]. The relatively high between-subject variability in bone markers is frequently criticized as limiting their utility, but our data suggest that the variability is likely related to genetics, and that studies to determine the causes of variability may reveal more about bone metabolism than expected.…”

Section: Discussionsupporting

confidence: 57%

Lower body negative pressure treadmill exercise as a countermeasure for bed rest-induced bone loss in female identical twins

Zwart

Hargens

Lee

et al. 2007

Bone

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Supine weight-bearing exercise within lower body negative pressure (LBNP) alleviates some of the skeletal deconditioning induced by simulated weightlessness in men. We examined the potential beneficial effect in women. Because dietary acid load affected the degree of bone resorption in men during bed rest, we also investigated this variable in women. Subjects were 7 pairs of female identical twins assigned at random to 2 groups, sedentary bed rest (control) or bed rest with supine treadmill exercise within LBNP. Dietary intake was controlled and monitored. Urinary calcium and markers of bone resorption were measured before bed rest (BR) and on BR days 5/6, 12/13, 19/20, and 26/27. Bone mineral content was assessed by dual-energy X-ray absorptiometry before and after bed rest. Data were analyzed by repeated measures two-way analysis of variance. Pearson correlation coefficients were used to define the relationships between diet and markers of bone metabolism, and to estimate heritability of markers. During bed rest, all markers of bone resorption and urinary calcium and phosphorus increased (P < 0.001); parathyroid hormone (P = 0.06), bone-specific alkaline phosphatase (P = 0.06), and 1,25-dihydroxyvitamin D (P = 0.09) tended to decrease. LBNP exercise tended to mitigate bone density loss. The ratio of dietary animal protein to potassium was positively correlated with urinary calcium excretion for all weeks of bed rest in the control group, but only during weeks 1 and 3 for the exercise group. Pre-bed rest data suggested that many markers of bone metabolism have strong genetic determinants. Treadmill exercise within LBNP had less of a protective effect on bone resorption during bed rest in women than previously-published results had Sources of support: This study was funded by NASA through grant NAG 9-1425 and by NIH through grant GCRC M01-RR00827 to UCSD.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. shown for its effect in men, but the same trends were observed for both sexes. Dietary acid load of these female subjects was significantly correlated with calcium excretion but not with other bone resorption markers. NIH Public Access

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Section: Discussionsupporting

confidence: 57%

Lower body negative pressure treadmill exercise as a countermeasure for bed rest-induced bone loss in female identical twins

Zwart

Hargens

Lee

et al. 2007

Bone

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“…Family-based studies have also yielded strong heritability estimates for BMD (Gueguen et al 1995), with effects that are maximal in young adults and persist even after adjusting for lifestyle factors that are known to regulate BMD (Krall & Dawson-Hughes 1993). Other determinants of osteoporotic fracture risk also have a heritable component, including: femoral neck geometry and hip axis length (Arden et al 1996, Flicker et al 1996, Slemenda et al 1996, ultrasound properties of bone (Arden et al 1996), biochemical markers of bone turnover (Morrison et al 1992, Tokita et al 1994, Garnero et al 1996, Harris et al 1998, body mass index (Carmichael & McGue 1995, Kaprio et al 1995, Arden & Spector 1997, muscle strength (Arden & Spector 1997), age at menarche (Kaprio et al 1995) and age at menopause (Snieder et al 1998). The data are conflicting with regard to the influence of genetic factors on bone loss; Christian et al (1989) found no evidence for a genetic effect on bone loss at the wrist in ageing male twins, whereas Kelly et al (1993) concluded that there were strong genetic effects on axial bone loss in female twins.…”

Section: What Is the Evidence For A Genetic Contribution To Osteoporomentioning

confidence: 99%

Role of genetic factors in the pathogenesis of osteoporosis

Stewart¹,

Ralston²

2000

Journal of Endocrinology

192

125

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Osteoporosis is a common disease with a strong genetic component characterised by low bone mass, microarchitectural deterioration of bone tissue and an increased risk of fracture. Twin and family studies have shown that genetic factors play an important role in regulating bone mineral density and other determinants of osteoporotic fracture risk, such as ultrasound properties of bone, skeletal geometry and bone turnover. Osteoporosis is a polygenic disorder, determined by the effects of several genes, each with relatively modest effects on bone mass and other determinants of fracture risk. It is only on rare occasions that osteoporosis occurs as the result of mutations in a single gene. Linkage studies in man and experimental animals have defined multiple loci which regulate bone mass but the genes responsible for these effects remain to be defined. Population-based studies and case-control studies have similarly identified polymorphisms in several candidate genes that have been associated with bone mass or osteoporotic fracture, including the vitamin D receptor, oestrogen receptor and collagen type I I gene. The individual contribution of these genes to the pathogenesis of osteoporosis is small however, reflected by the fact that the relationship between individual candidate genes and osteoporosis has been inconsistent in different studies. An important aim of future work will be to define how the genes which regulate bone mass, bone turnover and other aspects of bone metabolism interact with each other and with environmental variables to cause osteoporosis in individual patients. If that aim can be achieved then there is every prospect that preventative therapy could be targeted to those at greatest risk of the osteoporosis, before fractures have occurred.

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“…(10,11) Moreover, genetic factors also account for a large proportion of variance in risk factors for fracture, such as bone mineral density (BMD), (12) bone loss, (13) quantitative ultrasound, (14) and bone turnover markers. (15) Thus genetic factors may be useful in the prognosis of fracture. However, studies in the fields of diabetes (16) and cancer (17) suggested that genetic profiling contributed minimally to the prognosis of these diseases.…”

Section: Introductionmentioning

confidence: 99%

Genetic profiling and individualized prognosis of fracture

Tran

Nguyen

et al. 2010

Journal of Bone and Mineral Research

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Fragility fracture is a serious public health problem in the world. The risk of fracture is determined by genetic and nongenetic clinical risk factors. This study sought to quantify the contribution of genetic profiling to fracture prognosis. The study was built on the ongoing Dubbo Osteoporosis Epidemiology Study, in which fracture and risk factors of 858 men and 1358 women had been monitored continuously from 1989 and 2008. Fragility fracture was ascertained by radiologic reports. Bone mineral density at the femoral neck was measured by dual-energy X-ray absorptiometry (DXA). Fifty independent genes with allele frequencies ranging from 0.01 to 0.60 and relative risks (RRs) ranging from 1.01 to 3.0 were simulated. Three predictive models were fitted to the data in which fracture was a function of (1) clinical risk factors only, (2) genes only, and (3) clinical risk factors and 50 genes. The area under the curve (AUC) for model 1 was 0.77, which was lower than that of model II (AUC ¼ 0.82). Adding genes into the clinical risk factors model (model 3) increased the AUC to 0.88 and improved the accuracy of fracture classification by 45%, with most (41%) improvement in specificity. In the presence of clinical risk factors, the number of genes required to achieve an AUC of 0.85 was around 25. These results suggest that genetic profiling could enhance the predictive accuracy of fracture prognosis and help to identify high-risk individuals for appropriate management of osteoporosis or intervention. ß

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Genetic influences on type I collagen synthesis and degradation: further evidence for genetic regulation of bone turnover.

Cited by 49 publications

References 35 publications

Lower body negative pressure treadmill exercise as a countermeasure for bed rest-induced bone loss in female identical twins

Lower body negative pressure treadmill exercise as a countermeasure for bed rest-induced bone loss in female identical twins

Role of genetic factors in the pathogenesis of osteoporosis

Genetic profiling and individualized prognosis of fracture

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