Biomedical subjects

P Garnero

Publications and source records attributed to P Garnero.

At least 91 records · Page 5Linked to original sources

PubMed1998

The collagenolytic activity of cathepsin K is unique among mammalian proteinases.

Type I collagen fibers account for 90% of the organic matrix of bone. The degradation of this collagen is a major event during bone resorption, but its mechanism is unknown. A series of data obtained in biological models strongly suggests that the recently discovered cysteine proteinase cathepsin K plays a key role in bone resorption. Little is known, however, about the actual action of cathepsin K on type I collagen. Here, we show that the activity of cathepsin K alone is sufficient to dissolve completely insoluble collagen of adult human cortical bone. We found that the collagenolytic activity of cathepsin K is directed both outside the helical region of the molecule, i.e. the typical activity of cysteine proteinases, and at various sites inside the helical region, hitherto believed to resist all mammalian proteinases but the collagenases of the matrix metalloproteinase family and the neutrophil elastase. This property of cathepsin K is unique among mammalian proteinases and is reminiscent of bacterial collagenases. It is likely to be responsible for the key role of cathepsin K in bone resorption.

Adult↗

PubMed1998

Measurement of urinary excretion of nonisomerized and beta-isomerized forms of type I collagen breakdown products to monitor the effects of the bisphosphonate zoledronate in Paget's disease.

OBJECTIVE: We have previously shown that the woven pagetic bone in patients with Paget's disease is characterized by an impaired degree of beta-isomerization of C-telopeptides of type I collagen molecules, which results in a preferential urinary excretion of nonisomerized type I collagen C-telopeptide breakdown products (CTX). The aim of this study was to measure the urinary excretion of nonisomerized (alpha) and beta-isomerized (beta) CTX in patients with Paget's disease treated with a bisphosphonate. METHODS: We studied 28 patients with active Paget's disease of bone who were a part of a randomized, double-blind, placebo-controlled study comparing the effects of several doses of a single injection of zoledronate, a new potent bisphosphonate. Serum bone alkaline phosphatase (BAP) and type I collagen C-terminal extension propeptide (PICP) and urinary excretion of free deoxypyridinoline (free D-Pyr), N-telopeptide breakdown products (NTX), alphaCTX, and betaCTX were measured at baseline and 5, 10, 30, and 60 days after injection. RESULTS: At baseline, all markers were significantly increased in the patients compared with a group of 97 sex- and age-matched controls, with a greater increase in BAP (12-fold), NTX (19-fold), and alphaCTX (10-fold) compared with PICP (2.2-fold), free D-Pyr (2.5-fold), and betaCTX (3-fold). The ratio of alphaCTX to betaCTX was about 3-fold higher than in controls (2.1 versus 0.76; P < 0.001). After a single intravenous injection of zoledronate (200 or 400 microg), all markers decreased within 5 days, except for BAP and free D-Pyr, which decreased on day 10. The maximum decrease was greater and occurred faster for NTX, alphaCTX (-55% after 10 days), and betaCTX (-42% after 10 days) than for free D-Pyr (-25% after 30 days). After the initial decrease, the urinary excretion of betaCTX increased between days 10 and 30 and returned to pretreatment levels after 2 months, in contrast to the sustained decrease in alphaCTX and NTX that was maintained up to 60 days. The urinary ratio of alphaCTX to betaCTX decreased significantly between days 10 and 60, and returned to within the normal range in most patients after 2 months of treatment, probably reflecting the progressive replacement of woven bone by a lamellar bone with a higher and normal degree of beta-isomerization of type I collagen, as previously documented by histology. CONCLUSION: The determination of the urinary ratio of alphaCTX to betaCTX could be useful for monitoring the effect of bisphosphonate treatment in restoring bone quality in patients with Paget's disease.

Aged↗

PubMed1998

Do markers of bone resorption add to bone mineral density and ultrasonographic heel measurement for the prediction of hip fracture in elderly women? The EPIDOS prospective study.

We have previously shown that hip bone mineral density (BMD), heel broadband ultrasound attenuation (BUA) and bone resorption markers are independent predictors of hip fracture in elderly women. We investigated whether a combination of these three parameters could improve the predictive value of a single test in a nested case-control analysis (75 hip fractures and 228 age-matched controls) of the EPIDOS prospective study comprising 7598 healthy women 75 years of age and older followed prospectively for a mean 22 months. At baseline, prior fracture, femoral neck BMD by dual-energy X-ray absorptiometry (DXA), heel BUA and urinary type I collagen C-telopeptide breakdown products (CTX) were assessed. The area under the receiver operating characteristic curve was significant for the three diagnostic tests, heel BUA being the best single predictor. The added value of urinary CTX to either BMD or BUA depends on the cutoff point chosen to define patients at risk and on the therapeutic strategy that is considered. Defining patients at risk as those with low BMD (or low BUA) or high CTX resulted in a significant increase in the sensitivity compared with BMD or BUA alone--a strategy that could be applied when a broad treatment is considered. However, this increased sensitivity was also obtained simply by increasing the BMD and BUA cutoffs, suggesting that a combination of CTX with BMD/BUA is not useful for that type of treatment strategy. Conversely, defining patients at risk as those with both low BMD and high CTX increases the specificity (88% vs 78%) with a similar number of hip fracture patients being identified (30% vs 32%)--a combination that could be useful when the strategy is to target treatment to a subset of high-risk patients. This strategy appears to be more cost-effective than bone mass measurement alone as indicated by the 37% fewer patients who need to be treated to avoid one fracture per year. If DXA or ultrasound is not available, the combination of a bone resorption marker with a history of any type of fracture after the age of 50 years gave a predictive value similar to that obtained with femoral neck BMD or heel BUA alone, for both types of treatment strategy. We conclude that the combination of urinary CTX with hip BMD could be useful for the identification of elderly women at high risk for hip fracture, resulting in higher specificity for a given sensitivity threshold than BMD measurement alone. If DXA is not available, the combination of history of fracture and urinary CTX performs as well as hip BMD to assess hip fracture risk in elderly women.

Aged↗

PubMed1998

Biochemical markers of bone turnover. Applications for osteoporosis.

The recent discovery of specific and sensitive biochemical markers reflecting the overall rate of bone formation and bone resorption has markedly improved the noninvasive assessment of bone turnover in various metabolic bone diseases, especially in osteoporosis. The immunoassay of human osteocalcin, recognizing the intact molecule and its major proteolytic fragment, and assays for bone alkaline phosphatase and the intact form of the N-terminal extension propeptide of type I collagen are currently the most sensitive markers for assessing bone formation. The best indices of bone resorption are the new immunoassays for pyridinoline cross-links and type I collagen-related peptides in urine and, recently, in serum. Several studies indicate that screening for these bone markers may be useful for improving the prognostic assessment of postmenopausal women in combination with bone mass measurement, that is, their risk for osteoporosis and, ultimately, for fractures and to monitor rapidly the efficacy of antiresorptive drugs.

Alkaline Phosphatase↗

PubMed1998

Lack of correlation between start codon polymorphism of the vitamin D receptor gene and bone mineral density in premenopausal French women: the OFELY study.

Previous studies have demonstrated an association between bone mineral density (BMD) and a start codon polymorphism (SCP) of the vitamin D receptor (VDR) gene in pre- and postmenopausal Caucasian and Japanese women. The SCP can be determined by a restriction fragment length polymorphism defined by the FokI restriction endonuclease. VDR alleles containing the FokI site are denoted by f and alleles lacking the site by F. In this study, the association between BMD and the SCP was examined in a group of 174 premenopausal French women who previously had been studied for a relationship between BMD and the VDR BsmI polymorphism. The SCP genotypes of the French women were FF 40%, Ff 44%, and ff 16% and they were independent of the BsmI genotype. BMD was measured by dual-energy X-ray absorptiometry at the lumbar spine, proximal femur, forearm, and total body. In contrast to previous reports, there was no association of BMD with SCP genotype in this group of Caucasian women at any site. We also measured several biochemical indices of calcium homeostasis and bone turnover. We found no statistically significant associations between SCP genotype and calcium, parathyroid hormone, or vitamin D levels. There was a 33.5% higher level of the skeletal resorption marker N-telopeptides of type I collagen in the women with the ff genotype when compared with women with the FF genotype (p = 0.004). Other bone turnover markers failed to show an association with SCP genotype. In summary, the SCP genotype may not be associated with reduced BMD in all geographical or ethnic populations.

Adult↗

PubMed1998

Collagen Ialpha1 Sp1 polymorphism, bone mass, and bone turnover in healthy French premenopausal women: the OFELY study.

Bone mineral density (BMD) is under strong genetic control. Recent work has suggested that a polymorphism affecting an Sp1 binding site in the collagen I (COLI) A1 gene is associated with BMD and vertebral fracture in postmenopausal women. We analyzed this polymorphism in relation to BMD and bone turnover in 220 healthy premenopausal women aged 31-57 years. There were 61% SS homozygotes, 35% Ss heterozygotes, and 4% ss homozygotes, genotype frequencies similar to those previously reported in other Caucasian populations. Women in the three genotype groups were matched for age, body weight, physical activity, smoking habits, and oral contraceptive use, but height was greatest in the SS group and lowest in the ss group (p = 0.03). Between-group comparisons by analysis of variance (ANOVA) showed that COLI A1 genotype was significantly associated with spine BMD (p = 0.05), total body BMD (p = 0.046), and total body bone mineral content (BMC) (p = 0.02), but the differences between extreme genotypes were small (4, 5, and 10%, for spine BMD, total body BMD, and total body BMC, respectively). After adjustment for height, the differences between genotypes decreased and were no longer significant by ANOVA (p = 0.08, 0.17, and 0.33 for spine BMD, total body BMD, and total body BMC). Furthermore, no significant difference between genotypes was observed for femoral neck, trochanter, Ward's triangle, or forearm BMD. COLI A1 genotype was associated with serum C-terminal extension propeptide of type I collagen (p = 0.04), with lowest levels in ss individuals, but not with any other marker of bone formation (osteocalcin, alkaline phosphatase, and type I collagen N-terminal extension propeptide) or bone resorption (urinary excretion of type I collagen C and N telopeptide breakdown products). The COLI A1 Sp1 polymorphism is associated with height, peak total body BMD and BMC, and spine BMD. The genotype-specific differences account for only a small proportion of variance in BMD at these sites and are not significant after adjustment for height, suggesting that part of the effect on bone mass may be due to differences in body size. Our data support the view that COLI A1 may be a candidate gene for regulation of bone mass, but our results must be treated with caution, in view of the small number of ss individuals, and will require confirmation in larger studies.

Adult↗

PubMed1997

Osteoporosis.

Osteoporosis, one of the most prevalent diseases associated with aging, is characterized by a low bone mass and microarchitectural deterioration of bone tissue leading to increased susceptibility of fracture. The management of osteoporotic patients relies especially on the static measurement of bone mass as bone mineral and dynamic changes of bone turn over. New developments of bone mineral density measurement techniques and biochemical markers of bone turnover are reviewed. Their clinical uses for the management of patients with osteoporosis are discussed.

Biomarkers↗

PubMed1997

Bone markers.

The recent development of specific and sensitive biochemical markers reflecting the overall rate of bone formation and bone resorption, has markedly improved the non-invasive assessment of bone turnover in various metabolic bone diseases, especially osteoporosis. The immunoassay of human osteocalcin recognizing the intact molecule and its major proteolytic fragment, along with that of bone alkaline phosphatase, are currently the most sensitive markers to assess bone formation. For bone resorption, the total urinary excretion of pyridinoline crosslinks measured by high pressure liquid chromatography has shown its superiority over all other markers for the clinical assessment of osteoporosis. The recent development of immunoassays recognizing either the free pyridinoline crosslinks or pyridinoline crosslinked-type I collagen peptides in urine and serum should allow a broad use of this sensitive resorption marker. Recent studies, some of them still in progress, define the clinical use of these markers: first, to improve the prognostic assessment of post-menopausal women in combination with bone mass measurement, i.e. their risk of developing osteoporosis and, ultimately, fractures and, second, to monitor the efficacy of anti-resorption drugs.

Adult↗

PubMed1997

Short-term effects of corticosteroids on trabecular bone remodeling in old ewes.

This study was an attempt to develop an animal model of steroid-induced low bone formation, potentially suitable for testing bone forming agents. The short-term effects of corticosteroids on bone remodeling were analyzed in ewes. One group of 16 animals (mean age: 9 +/- 1 years) received a daily intramuscular injection of 16 mg of methylprednisone (MP group) for 3 months. The other group of 16 animals was considered the control group. At the end of treatment, significant decreases of osteoblastic (-50%) and mineralizing (-64%) perimeters and wall width (-5%) were noted in the MP group. The bone formation rate at the tissue level was significantly decreased by 91%. In contrast, at the cell level, there was no reduction in the daily production of matrix by the osteoblasts: Aj.AR was 40% lower than in controls, but the difference was not significant. At the end of the treatment, a significant increase in eroded perimeter (+97%) was associated with a significant decrease of osteoclast number. Biochemical markers of bone formation (osteocalcin and bone-specific alkaline phosphatase) and urinary cAMP were unchanged. Due to the short duration of the treatment, neither bone volume nor microarchitecture parameters were modified. The decreases of both the activation frequency and osteoclast number associated with the increase in eroded surfaces suggest a prolongation of the reversal phase due to an inhibition of osteoblast differentiation. Changes of bone formation in ewes induced by short-term administration of MP were similar to those reported after 3 months of treatment in humans. Thus, corticosteroid-treated ewes may represent a suitable animal model of low bone formation.

Alkaline Phosphatase↗

PubMed1997

Undercarboxylated osteocalcin measured with a specific immunoassay predicts hip fracture in elderly women: the EPIDOS Study.

Increased levels of circulating undercarboxylated osteocalcin (ucOC), measured indirectly with the hydroxyapatite (HAP) binding assay, have been shown to predict hip fracture risk in a small group of elderly institutionalized women. The aim of this study was to confirm these findings in a prospective cohort study (EPIDOS prospective study) of 7598 healthy, independently living women over 75 yr of age. One hundred and four women who sustained a hip fracture during a 22-month follow-up period were age matched with 255 controls who did not fracture. Baseline samples were collected before hip fracture for measurement of total OC and ucOC, assessed either with the HAP binding assay or directly with a new enzyme-linked immunosorbent assay (ELISA). This direct ELISA uses human recombinant noncarboxylated OC as a standard and two monoclonal antibodies, one of which was raised against the 14-30 Glu synthetic peptide. We found that the intra- and interassay variations are less than 11%, and this assay exhibits a 5% cross-reactivity with purified human bone OC, used as a source of carboxylated OC. ucOC levels measured with this ELISA correlated well with the HAP binding assay in the population of 359 elderly women (r = 0.82; P < 0.0001). We estimated the risk of hip fracture for women with levels of ucOC in the highest quartile of values for the 255 controls. We found that increased levels of ucOC measured by ELISA were associated with increased hip fracture risk with an odds ratio (OR) of 1.9 (95% confidence interval, 1.2-3.0), and the ELISA had a greater sensitivity than the HAP assay. In contrast, total OC was not associated with hip fracture risk. After adjustment for femoral neck bone mineral density (BMD) and mobility status assessed by gait speed, ucOC still predicted hip fracture with an OR of 1.8 (1.0-3.0). Women with both femoral neck BMD in the lowest quartile and ucOC in the highest quartile were at higher risk of hip fracture, with an OR of 5.5 (2.7-11.2), than those with only low BMD or high ucOC levels. In conclusion, we have developed a new specific ELISA for serum ucOC, with low cross-reactivity with carboxylated OC and increased specificity and sensitivity over the HAP assay. Using this new ELISA, we found that ucOC, but not total OC, predicts hip fracture risk independently of femoral neck BMD in elderly women drawn from the general population. Thus, ucOC measurement could be combined with bone mass determination to improve the assessment of hip fracture risk in elderly women.

Aged↗

PubMed1997

Apparent pre- and postmenopausal bone loss evaluated by DXA at different skeletal sites in women: the OFELY cohort.

We measured the bone mineral density (BMD) at various skeletal sites (total body, hip, anteroposterior [AP] and lateral [lat] spine, and forearm) in a large population-based cohort of women aged 31-89 years (the OFELY cohort), and results were analyzed according to age and postmenopausal years. A significant apparent bone loss was found before the menopause in cancellous bone, i.e., at the lat spine and Ward's triangle (-10%; p < 0.05-0.001). Cross-sectional analysis indicated that, after the menopause, apparent bone loss was accelerated within the 10 years following menopause, continued thereafter at all sites except the AP spine, and was again accelerated in elderly menopausal for more than 25 years. Between 30 and 80 years, BMD decreased by 15 to 44% (T score -1.6 to -3.4) according to the site. The amount of apparent bone loss was highest at the Ward's triangle when expressed in percentage (44%) and at the mid- and distal radius when expressed in number of standard deviations from the peak bone mass (-3.4). As a result, the percentage of women classified as osteoporotic according to the World Heath Organization, i.e., with a T score < or = -2.5, varied substantially from site to site and was highest at the radius (37% and 46%) and lateral spine (25-31%), intermediate at the Ward's triangle, AP spine, and whole body BMD, and lowest at the whole body bone mineral content, femoral neck, and trochanter (10-12%). In conclusion, this cross-sectional but large study suggests that there is a moderate apparent premenopausal bone loss that occurs only at cancellous bone sites and that apparent bone loss is accelerated at most skeletal sites after the age of 75 years. Because of the highly variable coefficient of variation of the peak bone mass at various skeletal sites, the percentage of postmenopausal women identified as being osteoporotic varies widely according to the site of measurement.

Absorptiometry, Photon↗

PubMed1997

Measurement of bone degradation products in serum using antibodies reactive with an isomerized form of an 8 amino acid sequence of the C-telopeptide of type I collagen.

An enzyme-linked immunosorbent assay for measuring type I collagen degradation products in serum (S-ELISA) was developed. The assay uses a high affinity polyclonal antibody which reacts with an isomerized form of an 8 amino acid sequence of the C-telopeptides of type I collagen (EKAHD-beta-GGR). Cross-reactivity to a nonisomerized synthetic peptide form of the 8 amino acid sequence is less than 0.2%. Values obtained in a group of premenopausal women (age, 33.3 +/- 3.11 years) were 69 +/- 24 ng/ml(n = 22). In a group of early postmenopausal women (age, 51.8 +/- 1.88 years) values obtained were 125 +/- 43 ng/ml (n = 46), which represents an increase of 81% (p < 0.001). Values found in untreated patients with Paget's disease were 234 +/- 95 ng/ml (n = 15), and for primary hyperparathyroidism we found 335 +/- 82 ng/ml (n = 10). Intravenous administration of a bisphosphonate (Pamidronate) to Paget's disease patients for 3 days was reflected in the S-ELISA by a decrease in the values of 55% when compared with values before treatment (n = 15). Following treatment with another bisphosphonate (Alendronate) for 6 months, values were decreased to 48 +/- 19 ng/ml (n = 12), which corresponds to a 62% decrease. Clinical results presented in this context support that the assay is a sensitive and specific index of bone resorption. It may, therefore, prove useful in the follow up of treatment of patients with metabolic bone diseases and in the clinical investigation of osteoporosis.

Adult↗

PubMed1997

Decreased beta-isomerization of the C-terminal telopeptide of type I collagen alpha 1 chain in Paget's disease of bone.

In Paget's disease of bone, the normal lamellar bone is replaced by a woven structure with an irregular arrangement of collagen fibers. In this study, we investigated whether the degree of beta-isomerization within C-telopeptide of alpha 1 chain of type I collagen was altered in Paget's disease compared with other bone diseases with no alteration of bone structure. In Paget's disease (n = 26), but not in patients with primary hyperparathyroidism (n = 6) or hyperthyroidism (n = 17), the urinary excretion of nonisomerized (alpha) fragments derived from degradation of type I collagen C-telopeptide (CTX) was markedly increased compared with beta-isomerized CTX (+ 13-fold vs. + 3.5-fold over controls) resulting in an urinary alpha CTX/beta CTX ratio 3-fold higher than in controls (2.6 +/- 1.0 vs. 0.8 +/- 0.3, p < 0.001). In five pagetic patients in complete remission, as demonstrated by normal total alkaline phosphatase activity, the alpha CTX/beta CTX ratio was normal. The immunohistochemistry of normal and pagetic human bone sections showed a preferential distribution of alpha CTX within woven structure, while lamellar bone was intensely stained with an anti-beta CTX antibody, suggesting a lower degree of beta-isomerization of type I collagen in the woven pagetic bone. In collagenase digest of human bone specimens, we found a lower proportion of beta-isomerized type I collagen molecules in pagetic bone (40% of beta CTX) than in normal bone taken from trabecular (68%) and cortical compartments (71%). In conclusion, we found that in Paget's disease the alpha CTX/beta CTX ratio in bone and in urine is markedly increased. This altered beta isomerization can be accurately detected in vivo by measuring urinary degradation products arising from bone resorption.

Adult↗

PubMed1996

Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis.

Changes of bone turnover with aging are responsible for bone loss and play a major role in osteoporosis. Although an increase of bone turnover has been documented at the time of menopause, the subsequent abnormalities of bone resorption and formation and their potential role in determining bone mass in the elderly have not been investigated. To address this issue, we have measured a battery of new sensitive and specific markers of bone turnover in a population-based study of 653 healthy women analyzed cross-sectionally, including 432 women postmenopausal from 1 to 40 years, and the data were correlated with bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) at different skeletal sites. Bone formation was assessed by serum osteocalcin (OC), serum bone-specific alkaline phosphatase (B-ALP), serum C-propeptide of type I collagen (PICP), and bone resorption by the urinary excretion of two pyridinoline cross-linked peptides (NTX and CTX). Bone turnover increased in perimenopausal women with both irregular menses and elevated serum follicle stimulating hormone (FSH). Menopause induced a 37-52% and 79-97% increase in the bone formation and bone resorption marker levels, respectively (p < 0.0001 except for PICP). In postmenopausal women, bone formation markers did not decrease with age. When resorption markers were corrected by whole body bone mineral content (BMC), the fraction of bone resorbed per day was not correlated with age in postmenopausal women and remained elevated for up to 40 years after menopause. In premenopausal women, the bone turnover rate accounted for only 0-10% of the variation in whole body BMC, total hip, distal radius, and lumbar spine BMD. With increasing time after menopause, the importance of the bone turnover rate as a determinant of bone mass increased at all sites and accounted for up to 52% of the BMD variance in elderly women. Thus, in women 20 years or more postmenopause, bone turnover was higher in those in the lowest quartile than in those in the highest quartile of BMD. In elderly women, 20 years since menopause and over, but not in younger ones, serum PTH was negatively correlated with serum 25-hydroxyvitamin D (r = -0.22, p < 0.05) and explained only 5-8% of the bone turnover variance (p < 0.01-0.001). These data indicate that the overall rates of both bone formation and bone resorption remain high in elderly women. The rate of bone turnover appears to play an increasing role as a determinant of bone mass with increasing time since menopause with a high bone turnover rate being associated with a low bone mass. Thus assessing bone marker levels may be useful in the evaluation of osteoporosis risk. In elderly women, secondary hyperparathyroidism caused in part by reduced serum 25-hydroxyvitamin D appears to be a marginal determinant of an increased bone turnover rate.

Absorptiometry, Photon↗

PubMed1996

Vitamin D receptor gene polymorphisms are not related to bone turnover, rate of bone loss, and bone mass in postmenopausal women: the OFELY Study.

Vitamin D receptor (VDR) gene polymorphisms have been reported to account for most of the well established genetic influence on bone mineral density (BMD). However, discordant studies have been published and it is still not clear whether VDR genotypes influence bone mass accretion and/or postmenopausal bone loss. In this study, we analyzed VDR gene polymorphisms, i.e., that of BsmI, ApaI, and TaqI restriction enzymes in 268 untreated postmenopausal women 1-26 years postmenopausal. There were 37 BBAA homozygote (absence of BsmI and ApaI restriction sites on both alleles), 55 bbaa homozygote (presence of restriction sites on both alleles), and 176 heterozygotes. At baseline, women between the three genotypes did not differ significantly in age, years since menopause, body mass index (BMI), nor dietary calcium intake. We found no relationship between VDR genotypes and bone turnover assessed by three serum markers of bone formation and three urinary bone resorption markers, nor with BMD measured at the spine, hip, forearm, and whole body by dual-energy X-ray absorptiometry (DXA). Rates of bone loss assessed by repeated DXA measurements over 2 years were highly significant (p = 0.02-0.0001) at all skeletal sites except for the lumbar spine but did not differ between genotypes at any sites either before or after adjustment for potential confounding factors such as years since menopause, BMI, calcium intake, serum 25 hydroxyvitamin D levels, and baseline BMD. When we restricted the analysis to early postmenopausal women, within 10 years of menopause (n = 128), lumbar spine bone loss became significant, but no significant difference between VDR genotypes in the rate of bone loss measured at any site was found. We conclude that VDR genotypes are not predictive of bone turnover, rate of postmenopausal bone loss, and bone mass in either early or late postmenopausal women. In a subgroup of women with a low calcium intake (below 600 mg/day), we also found no significant differences between genotypes in BMD and the rate of bone loss measured at any site, although the sample size (n = 64) may be too small to detect small differences. In conclusion, these data, along with the absence of relationships between VDR gene polymorphisms and peak bone mass that we recently reported, suggest that the determination of VDR genotypes is probably not a useful clinical test for the risk assessment of osteoporosis.

Absorptiometry, Photon↗

PubMed1996

Markers of bone resorption predict hip fracture in elderly women: the EPIDOS Prospective Study.

Increased bone turnover has been suggested as a potential risk factor for osteoporotic fractures. We investigated this hypothesis in a prospective cohort study performed on 7598 healthy women more than 75 years of age. One hundred and twenty-six women (mean years 82.5) who sustained a hip fracture during a mean 22-month follow-up were age-matched with three controls who did not fracture. Baseline samples were collected prior to fracture for the measurement of two markers of bone formation and three urinary markers of bone resorption: type I collagen cross-linked N- (NTX) or C-telopeptide (CTX) and free deoxypyridinoline (free D-Pyr). Elderly women had increased bone formation and resorption compared with healthy premenopausal women. Urinary excretion of CTX and free D-Pyr, but not other markers, was higher in patients with hip fracture than in age-matched controls (p = 0.02 and 0.005, respectively). CTX and free D-Pyr excretion above the upper limit of the premenopausal range was associated with an increased hip fracture risk with an odds ratio (95% confidence interval) of 2.2 (1.3-3.6) and 1.9 (1.1-3.2), respectively, while markers of formation were not. Increased bone resorption predicted hip fracture independently of bone mass, i.e., after adjustment for femoral neck bone mineral density (BMD) and independently of mobility status assessed by the gait speed. Women with both a femoral BMD value of 2.5 SD or more below the mean of young adults and either high CTX or high free D-Pyr levels were at greater risk of hip fracture, with an odds ratio of 4.8 and 4.1, respectively, than those with only low BMD or high bone resorption. Elderly women are characterized by increased bone turnover, and some markers of bone resorption predict the subsequent risk of hip fracture independently of hip BMD. Combining the measurement of BMD and bone resorption may be useful to improve the assessment of the risk of hip fracture in elderly women.

Absorptiometry, Photon↗

PubMed1996

New developments in biochemical markers for osteoporosis.

The noninvasive assessment of bone turnover has markedly improved in the past few years with the development of sensitive and specific markers of bone formation and bone resorption. Markers of bone formation in serum include total and bone-specific alkaline phosphatase, osteocalcin, and type I collagen carboxyterminal extension peptide. Assessment of bone resorption can be achieved by measuring plasma tartrate-resistant acid phosphate and the urinary excretion (and possibly serum levels) of bone type I collagen degradation products: hydroxyproline, hydroxylysine glycosides, and, more recently, the pyridinium crosslinks (pyridinoline and deoxypyridinoline) and associated peptides. The immunoassay of human osteocalcin and bone alkaline phosphatase for formation and the pyridinoline crosslinks measured by high-pressure liquid chromatography or by immunoassay for bone resorption are currently the most sensitive and specific markers of bone turnover for the clinical assessment of osteoporosis. Using these new markers, several studies have shown that bone turnover increases after the menopause and remains elevated in late postmenopausal and elderly women. An increased bone turnover rate is related to a high rate of bone loss in postmenopausal women and to a decreased bone mass in elderly women. Recent data suggest that some of the new immunoassays for pyridinoline crosslinks could predict the subsequent risk of hip fracture in elderly women. Thus, bone markers might be used in combination with bone mass measurement to improve the prognostic assessment of postmenopausal women, i.e., their risk of developing osteoporosis and ultimately fractures. Treatment of postmenopausal women with antiresorptive drugs such as estrogens, bisphosphonates, and calcitonin induces a rapid decrease in the levels of bone markers that is correlated with the long-term effect of such treatments on bone mass. Thus, bone markers should be very useful in monitoring treatment efficacy in patients with osteoporosis.

Age Factors↗

PubMed1996

Genetic influence on bone turnover in postmenopausal twins.

Postmenopausal bone mass is determined by both peak bone mass and subsequent bone loss. Previous studies have shown that peak bone mass is under genetic influence mediated partly by factors affecting bone formation. The rate of bone loss increases markedly after the menopause, but is highly variable from subject to subject. The aims of this study were to determine whether postmenopausal bone turnover was under genetic control, which should be linked to the genetic influence on the rate of postmenopausal bone loss. A classical twin study was performed that compared the intraclass correlations in monozygotic (MZ) twins with those in dizygotic (DZ) twins, with any difference assumed to be due to genetic factors. Markers of bone formation and resorption were measured in 240 untreated postmenopausal twins, aged 45-69 yr, on the average 12.3 yr (SD, 6.0) postmenopause, including 61 MZ pairs and 59 DZ pairs. The intraclass correlation coefficient of MZ twin pairs, rMZ (95% confidence interval), for 2 specific markers of bone formation, serum osteocalcin and bone-specific alkaline phosphatase, were higher than the corresponding rDZ [0.67 (range, 0.59-0.75) vs. 0.48 (range, 0.35-0.61; P = 0.06) for osteocalcin and 0.53 (range, 0.41-0.65) vs. 0.21 (range, 0.01-0.41; P = 0.02) for bone-specific alkaline phosphatase]. For serum propeptide of type I collagen, a type I collagen synthesis marker that exhibits only a slight increase after menopause, a high proportion of its variance was explained by genetic factors [rMZ = 0.82 (0.77-0.87), rDZ = 0.33 (0.16-0.50); P < 0.001]. The correlations for bone resorption measured by three distinct urinary markers, total deoxypyridinoline and two cross-linked type I collagen peptides (CrossLaps and NTX), that increase markedly after menopause were higher in MZ than in DZ pairs, but the difference reached significance only for NTX (P = 0.03). For urinary free dexoypyridinoline, a marker reflecting bone collagen degradation that increases moderately after menopause, the proportion of the variance explained by genetic factors was highly significant (P = 0.002). In conclusion, our data indicate that a proportion of the variance in postmenopausal levels of both bone formation and resorption markers are explained by genetic factors, but this contribution was clearly significant only for markers that do not change markedly at the menopause. These data suggest that the contribution of genetic factors to overall postmenopausal bone turnover and possibly bone loss is likely to be small.

Aged↗