Osteocalcin gene polymorphisms influence concentration of serum osteocalcin and enhance fracture identification.

Osteoporosis is a major health problem affecting more than 75 million people throughout Europe, the United States, and Japan. Epidemiologic studies have determined that both genetic and environmental factors contribute to the pathogenesis of osteoporosis. We have investigated the association between polymorphisms at the osteocalcin locus and variables linked to bone health. Osteocalcin provides a link between bone and energy metabolism, hence its potential importance as an osteoporosis candidate gene. In this study, we included a total of 996 women (all aged 75 years) from the Osteoporosis Prospective Risk Assessment (OPRA) cohort. We sequenced the osteocalcin gene along with flanking regions to search for novel coding polymorphisms. We also analyzed four polymorphisms selected from within and flanking regions of the osteocalcin gene to study their association with serum total osteocalcin levels (S-TotalOC), total-body (TB) bone mineral density (BMD), fracture, TB fat mass, and body mass index (BMI). The promoter polymorphism rs1800247 was significantly associated with S-TotalOC (p = .012) after controlling for BMI and TB BMD. The polymorphism rs1543297 was significantly associated with prospectively occurring fractures (p = .008). In a model taking into account rs1543297 and rs1800247, along with TB BMD, BMI, smoking, and S-TotalOC, the polymorphisms together were able to identify an additional 6% of women who sustained a fracture (p = .02). We found no association between the polymorphisms and TB BMD, BMI, or TB fat mass. In conclusion, polymorphisms in and around the osteocalcin locus are significantly associated with S-TotalOC and fracture. Genotyping at the osteocalcin locus could add valuable information in the identification of women at risk of osteoporosis.

Bone turnover markers and prediction of fracture: a prospective follow-up study of 1040 elderly women for a mean of 9 years.

Osteoporosis is characterized by compromised bone mass and strength, predisposing to an increased risk of fracture. Increased bone metabolism has been suggested to be a risk factor for fracture. The aim of this study was to evaluate whether baseline bone turnover markers are associated with long-term incidence of fracture in a population-based sample of 1040 women who were 75 years old (Malmö OPRA study). Seven bone markers (S-TRACP5b, S-CTX-I, S-OC[1-49], S-TotalOC, S-cOC, S-boneALP, and urinary osteocalcin) were measured at baseline and 1-year follow-up visit. During the mean follow-up of 9.0 years (range 7.4-10.9), 363 women sustained at least one fracture of any type, including 116 hip fractures and 103 clinical vertebral fractures. High S-TRACP5b and S-CTX-I levels were associated with increased risk of any fracture with hazard ratios [HRs (95% confidence interval)] of 1.16 (1.04-1.29) and 1.13 (1.01-1.27) per SD increase, respectively. They also were associated with increased risk of clinical vertebral fracture with HRs of 1.22 (1.01-1.48) and 1.32 (1.05-1.67), respectively. Markers were not associated with risk for hip fracture. Results were similar when we used resorption markers, including urinary osteocalcin, measured at the 1-year visit or an average of the two measurements. The HRs were highest for any fracture in the beginning of the follow-up period, 2.5 years from baseline. For vertebral fractures, the association was more pronounced and lasted for a longer period of time, at least for 5 years. In conclusion, elevated levels of S-TRACP5b, S-CTX-I, and urinary osteocalcin are associated with increased fracture risk for up to a decade in elderly women.

Different skeletal effects of the peroxisome proliferator activated receptor (PPAR)alpha agonist fenofibrate and the PPARgamma agonist pioglitazone.

BACKGROUND: All the peroxisome proliferator activated receptors (PPARs) are found to be expressed in bone cells. The PPARgamma agonist rosiglitazone has been shown to decrease bone mass in mice and thiazolidinediones (TZDs) have recently been found to increase bone loss and fracture risk in humans treated for type 2 diabetes mellitus. The aim of the study was to examine the effect of the PPARalpha agonist fenofibrate (FENO) and the PPARgamma agonist pioglitazone (PIO) on bone in intact female rats. METHODS: Rats were given methylcellulose (vehicle), fenofibrate or pioglitazone (35 mg/kg body weight/day) by gavage for 4 months. BMC, BMD, and body composition were measured by DXA. Histomorphometry and biomechanical testing of excised femurs were performed. Effects of the compounds on bone cells were studied. RESULTS: The FENO group had higher femoral BMD and smaller medullary area at the distal femur; while trabecular bone volume was similar to controls. Whole body BMD, BMC, and trabecular bone volume were lower, while medullary area was increased in PIO rats compared to controls. Ultimate bending moment and energy absorption of the femoral shafts were reduced in the PIO group, while similar to controls in the FENO group. Plasma osteocalcin was higher in the FENO group than in the other groups. FENO stimulated proliferation and differentiation of, and OPG release from, the preosteoblast cell line MC3T3-E1. CONCLUSION: We show opposite skeletal effects of PPARalpha and gamma agonists in intact female rats. FENO resulted in significantly higher femoral BMD and lower medullary area, while PIO induced bone loss and impairment of the mechanical strength. This represents a novel effect of PPARalpha activation.

Bone turnover markers are correlated with total skeletal uptake of 99mTc-methylene diphosphonate (99mTc-MDP).

BACKGROUND: Skeletal uptake of 99mTc labelled methylene diphosphonate (99mTc-MDP) is used for producing images of pathological bone uptake due to its incorporation to the sites of active bone turnover. This study was done to validate bone turnover markers using total skeletal uptake (TSU) of 99mTc-MDP. METHODS: 22 postmenopausal women (52-80 years) volunteered to participate. Scintigraphy was performed by injecting 520 MBq of 99mTc-MDP and taking whole body images after 3 minutes, and 5 hours. TSU was calculated from these two images by taking into account the urinary loss and soft tissue uptake. Bone turnover markers used were bone specific alkaline phosphatase (S-Bone ALP), three different assays for serum osteocalcin (OC), tartrate resistant acid phosphatase 5b (S-TRACP5b), serum C-terminal cross-linked telopeptides of type I collagen (S-CTX-I) and three assays for urinary osteocalcin (U-OC). RESULTS: The median TSU of 99mTc-MDP was 23% of the administered activity. All bone turnover markers were significantly correlated with TSU with r-values from 0.52 (p = 0.013) to 0.90 (p < 0.001). The two resorption markers had numerically higher correlations (S-TRACP5b r = 0.90, S-CTX-I r = 0.80) than the formation markers (S-Total OC r = 0.72, S-Bone ALP r = 0.66), but the difference was not statistically significant. TSU did not correlate with age, weight, body mass index or bone mineral density. CONCLUSION: In conclusion, bone turnover markers are strongly correlated with total skeletal uptake of 99mTc-MDP. There were no significant differences in correlations for bone formation and resorption markers. This should be due to the coupling between formation and resorption.

Serial assessment of serum bone metabolism markers identifies women with the highest rate of bone loss and osteoporosis risk.

CONTEXT: One of the important challenges in the management of osteoporosis is to identify women who are at high risk of developing osteoporosis and fragility fractures. OBJECTIVE: Our objective was to evaluate whether assessment of bone metabolism at multiple occasions can identify women with the highest risk for bone loss. DESIGN: The Malmö Osteoporosis Prospective Risk Assessment study is an ongoing longitudinal study. Participants have been evaluated at baseline and after 1, 3, and 5 yr. SETTING: We conducted a population-based study. PARTICIPANTS: Participants included 1044 women, all 75 yr old at baseline. MAIN OUTCOME MEASURES: Seven bone turnover markers were assessed at baseline and at 1, 3, and 5 yr (n = 573). The 5-yr change in areal bone mineral density (aBMD) was also determined. RESULTS: Baseline markers correlated weakly to change in total body aBMD. The associations were more pronounced when the average of the baseline and 1-yr measurements was used (standardized regression coefficients -0.12 to -0.23, P < 0.01). Adding the 3-yr and 5-yr measurement further strengthened the correlation (regression coefficients up to -0.30, P < 0.001). Women with constantly high turnover lost significantly more bone at total body assessment (-2.6%) than women with intermediate (-1.6%) or low turnover (-0.2%, P for trend < 0.001). They also had a greater decrease in hip BMD (-8.3, -6.0, and -5.1%, respectively, P = 0.010). Results were similar also in the subgroup of women with osteopenia. CONCLUSIONS: Our results suggest that serial assessment of bone turnover improves the identification of women with the highest rate of bone loss and osteoporosis risk.

Effect of fracture on bone turnover markers: a longitudinal study comparing marker levels before and after injury in 113 elderly women.

UNLABELLED: In this longitudinal, prospective, and population-based study (n = 1044), seven BTMs were assessed before and after trauma in 113 elderly women (85 with fractures). Markers were not altered in the immediate postfracture period but were clearly elevated during fracture repair. Recent fracture should thus be taken into account when markers are used in clinical practice. INTRODUCTION: Fracture may influence the levels of bone turnover markers (BTM) and have implications for their use in clinical practice. In this longitudinal, prospective, and population-based study, we assessed prefracture levels of BTMs and compared them with postfracture levels of the same individuals immediately after fracture and during fracture repair. This is the first study in which the effect of fracture on bone markers has been evaluated with prefracture samples available. MATERIALS AND METHODS: Serum and urine were collected at the emergency unit from 85 women (77.9 +/- 1.8 yr) who sustained a fracture after low-energy trauma and 28 controls (77.8 +/- 2.0 yr) with similar trauma but no fracture. All were participants of the Malmö OPRA study (n = 1044), and pretrauma samples were collected 1.05 +/- 0.85 yr before. Bone turnover was assessed by seven different BTMs reflecting different stages of bone metabolism {C-terminal cross-linked telopeptides of type I collagen [S-CTX], S-TRACP5b, N-terminal propeptides of type I collagen [S-PINP], serum osteocalcin (S-OC[1-49] and S-TotalOC), urinary deoxypyridinoline [U-DPD], and urinary osteocalcin [U-OC]}. RESULTS: BTMs sampled within a few hours after fracture were not altered from preinjury levels. Both bone formation and bone resorption markers were, however, significantly increased 4 mo after fracture. The elevation was most pronounced after hip fracture. Bone turnover remained elevated up to 12 mo after fracture. CONCLUSIONS: We believe this study extends our knowledge on the skeletal postfracture metabolic processes. In addition, it may provide a basis for future means to monitor pharmacological intervention promoting fracture healing.

Associations between homocysteine, bone turnover, BMD, mortality, and fracture risk in elderly women.

UNLABELLED: Homocysteine has been suggested to be a risk factor for fracture, but the causal relationship is not clear. In 996 women from the OPRA study, high homocysteine level was associated with high bone marker levels and low BMD at baseline. During a mean 7-year follow-up, high homocysteine level was associated with mortality, but no clear association to fracture risk existed. INTRODUCTION: Recently, the association between high serum homocysteine (Hcy) levels and an increased risk of fracture has been described. MATERIALS AND METHODS: Hcy levels were measured at baseline in 996 women, all 75 years old. Vitamin B(12), folate, serum cross-linking telopeptide of type I collagen (CTX), serum TRACP5b, serum osteocalcin, urine deoxypyridinoline, PTH, areal BMD (aBMD), calcaneal quantitative ultrasound (QUS), and physical performance were assessed at baseline. Fractures and mortality were recorded during a mean follow-up of 7.0 years. RESULTS: Bone marker levels were higher in women with Hcy in the highest quartile compared with all other women (p < 0.05). The most evident correlation between Hcy and a bone marker was seen with CTX (r = 0.19, p < 0.001). aBMD (hip) was 4% lower, QUS was up to 2% lower, and gait speed was 11% slower among women with Hcy in the highest quartile compared with the other women (p < 0.05). During the follow-up, 267 women sustained at least one low-energy fracture (including 69 hip fractures). When women in the highest Hcy quartile were compared with all other women, the hazard ratios (HRs) for sustaining any type of fracture was 1.18 (95% CI, 0.89-1.36) and for hip fracture was 1.50 (95% CI, 0.91-1.94). For the same group of women, the mortality risk was 2.16 (95% CI, 1.58-2.55). Adjustments for confounders did not substantially change these associations. Adjustment for PTH increased the HR for hip fracture to 1.67 (95% CI, 1.01-2.17). Low vitamin B(12) or folate was not associated with increased fracture risk or mortality. CONCLUSIONS: High Hcy levels were associated with higher bone turnover, poor physical performance, and lower BMD. There was no clear association to fracture risk. The increased mortality among women with high Hcy levels indicates that a high Hcy level may be a marker of frailty.

Vertebroplasty and kyphoplasty: New treatment strategies for fractures in the osteoporotic spine.

During the last decade, two new treatment modalities for osteoporotic vertebral fractures have gained more interest: percutaneous vertebroplasty and kyphoplasty. The techniques and the short-term clinical results and complications have been presented but there is no scientific evidence-based information regarding the efficacy of the procedures, such as randomized controlled trials (RCT). Instead, we have to rely on prospective and retrospective uncontrolled short-term observational studies and case-control studies. These studies have shown consistently that the short-term results after the procedures are favorable as regards both pain relief and functional status. It is currently unknown, however, whether a vertebroplasty or a kyphoplasty gives a better outcome than nonoperative treatment, and whether the long-term results are as favorable as the short-term results.

[Treatment of osteoporotic vertebral compression. Explosive interest for vertebroplasty and kyphoplasty]. / Behandling av osteoporotisk kotkompression. Explosionsartat intresse för vertebroplastik och kyfoplastik.

During the last 15 years, two new treatment strategies have gained worldwide attention in the treatment of osteoporotic vertebral fractures. The exponential increase in the use of percutaneous vertebro- or kyphoplasty has up to now not been supported by scientific sound evidence-based data. There exist no prospective randomised controlled trials (RCT) that support the efficacy of the treatments, not even adequate controlled studies. Instead we have to rely on prospective and retrospective uncontrolled short-term observational studies and case-control studies. These studies consistently indicate that the short-term results after the procedures in the treatment of osteoporotic vertebral fractures are favourable, regarding both pain relief and functional status. However, if a vertebro- or a kyphoplasty produces a better outcome than conservative treatment, and if the long-term results are as favourable as the short-term results in the treatment of osteoporotic vertebral fractures, is currently unknown.

Biochemical markers of bone turnover are influenced by recently sustained fracture.

In striving to refine the clinical utility of different markers of bone metabolism, we should take into account numerous confounders, many of which are well known, such as sampling time, fasting status, and bone density. One further confounder may be ongoing fracture healing and/or post-fracture immobilization, which at least theoretically should impose an increased bone formation and resorption. Since both recent fracture and high bone turnover are independent predictors for new fracture, we thought it of importance to define the potential influence of such fracture on markers of bone turnover. From a population-based cohort of 1604 women, all 75 years old (the OPRA-study), 1024 women attended a clinical examination. The bone metabolism was assessed in serum, by three markers of bone formation [bone-specific alkaline phosphatase (S-Bone ALP), intact and N-Mid osteocalcin (S-Total OC), and total carboxylated osteocalcin (S-cOC)], two markers of bone resorption [C-terminal cross-linked telopeptides of type I collagen (S-CTX) and tartrate-resistant acid phosphatase type 5b (S-TRACP5b)], and in urine by one marker of bone resorption [deoxypyridinoline/creatinine (U-DPD/crea)] and two putative markers of bone resorption [urinary osteocalcins (U-OC/crea)]. Current physical activity and retrospective fracture data were recorded by questionnaires. The fracture data, for the entire cohort of 1604 women, were validated with radiographic referrals and reports, saved since the beginning of the last century. All data provided, except date of occurrence of retrospectively sustained fracture, were thus obtained cross-sectionally and in all women at the age of 75. Fracture had ever been sustained by 727 of the entire cohort (n = 1604), and by 523 of the attending women (n = 1024). All markers were marginally higher (significant only for U-DPD/crea, P = 0.027) in women who had ever sustained fracture, compared to women without fracture. In women with recent retrospective fracture (since 2 years) (n = 100), the levels of all markers, except the two S-OCs, were significantly higher (r = 0.20-0.33, P = 0.049-0.001) the more recently the fracture had been sustained. Women with low current physical activity had elevated levels of U-DPD/crea (P < 0.001) and one U-OC (P = 0.014), while the other markers were unaffected.

Increased bone density and decreased bone turnover, but no evident alteration of fracture susceptibility in elderly women with diabetes mellitus.

Bone density, bone turnover and fracture susceptibility were evaluated in 1,132 randomly recruited women, all 75 years old. Seventy-four of the women had diabetes, while 1,058 women did not. Areal bone mineral density (aBMD) of the hip and lumbar spine was investigated by dual energy X-ray absorptiometry (DXA), and bone mass of the calcaneus was measured by ultrasound. Urinary deoxypyridinoline/creatinine (U-DPD/Crea) and serum C-terminal cross-linked telopeptide of type 1 collagen (S-CTX) were assessed as markers of bone resorption. Serum bone-specific alkaline phosphatase (S-bone ALP) and serum osteocalcin (S-OC) were assessed as markers of bone formation. Also, serum 25(OH) vitamin D and serum parathyroid hormone (S-PTH) were assessed. Fracture susceptibility was evaluated retrospectively and prospectively for up to 6.5 years. In diabetic women, the aBMD of the femoral neck was 11% higher (p<0.001), and BMD of the lumbar spine was 8% higher (p=0.002) than in non-diabetic women. There was no difference in bone mass by ultrasound of the calcaneus. Women with diabetes had higher BMD of the femoral neck (p<0.001) and lumbar spine (p=0.03) also after correction for differences in body weight. In diabetic women, U-DPD/Crea, S-CTX, and S-OC were decreased when compared with non-diabetic women (p=0.001 or less). After correction for covariance of body weight and plasma creatinine, S-CTX (p<0.001) and S-OC (p<0.001) were still lower in the diabetic women. Diabetic patients had hypovitaminosis D (p=0.008), a difference explained by differences in time spent outdoors and body weight. S-PTH did not differ between the groups. Women with diabetes had no more lifetime fractures (52%) than women without diabetic disease (57%), (p=0.31). This study shows that elderly women with diabetes and without severe renal insufficiency have high bone mass and low bone turnover. The high bone mass and low bone turnover is not likely to have a strong influence on fracture susceptibility.

Clinical history and biologic age predicted falls better than objective functional tests.

OBJECTIVE: Fall risk assessment is important because the consequences, such as a fracture, may be devastating. The objective of this study was to find the test or tests that best predicted falls in a population-based sample of elderly women. STUDY DESIGN AND SETTING: The fall-predictive ability of a questionnaire, a subjective estimate of biologic age and objective functional tests (gait, balance [Romberg and sway test], thigh muscle strength, and visual acuity) were compared in 984 randomly selected women, all 75 years of age. RESULTS: A recalled fall was the most important predictor for future falls. Only recalled falls and intake of psycho-active drugs independently predicted future falls. Women with at least five of the most important fall predictors (previous falls, conditions affecting the balance, tendency to fall, intake of psychoactive medication, inability to stand on one leg, high biologic age) had an odds ratio of 11.27 (95% confidence interval 4.61-27.60) for a fall (sensitivity 70%, specificity 79%). CONCLUSION: The more time-consuming objective functional tests were of limited importance for fall prediction. A simple clinical history, the inability to stand on one leg, and a subjective estimate of biologic age were more important as part of the fall risk assessment.

Urinary osteocalcin as a marker of bone metabolism.

BACKGROUND: Osteocalcin (OC) is produced by osteoblasts during bone formation, and circulating OC has been used in clinical investigations as a marker of bone metabolism. OC is excreted into urine by glomerular filtration and can be found in urine as midmolecule fragments. METHODS: We developed and evaluated three immunoassays (U-MidOC, U-LongOC, and U-TotalOC) for the detection of various molecular forms of urine OC (U-OC). We evaluated the association of U-OC with other markers of bone turnover and with bone mass in 1044 elderly women and studied seasonal and circadian variation of U-OC. RESULTS: U-OC correlated with other bone turnover markers [Spearman correlation (r), 0.30-0.57; P <0.0001], demonstrating the association between U-OC and skeletal metabolism. There was also a significant association between bone metabolism assessed by U-OC quartiles and bone mass assessed by total body bone mineral content (P <0.0001). The seasonal effects appeared to be rather small, but we observed a significant circadian rhythm similar to the one reported for serum OC with high values in the morning and low values in the afternoon. CONCLUSIONS: The three immunoassays had unique specificities toward different naturally occurring U-OC fragments. U-OC concentrations measured with any of these assays correlated with bone turnover rates assessed by conventional serum markers of bone metabolism. The measurement of OC in urine samples could be used as an index of bone turnover in monitoring bone metabolism.

Fracture-induced changes in bone turnover: a potential confounder in the use of biochemical markers in osteoporosis.

To examine the short- and long-term bone metabolic effects of fracture assessed by biochemical markers, we utilized a clinical fracture model-proximal tibial osteotomy-and prospectively followed 14 patients. This model of an induced fracture of a major bone gives the advantage of assessing baseline levels prior to fracture. Follow-up occurred at 6-9 weeks, 4-7 months, 9-13 months, and 14-17 months after fracture. Serum was assayed for type 1 procollagen peptide (PICP), total alkaline phosphatase (ALP), and carboxy-terminal-telopeptide of type I collagen (ICTP), while deoxypyridinoline (Dpyr) was measured in urine. Serum osteocalcin (OC) was measured using two recently developed two-site immunofluorometric assays, which both measure full-length and fragmented forms of OC (OCtot), with one of the assays specifically detecting only the carboxylated form of OC (OCcxy). In addition, OC was measured in urine using the same assays as those used for serum. Serum OCtot increased to a peak at 4-7 months after fracture (P < 0.001) and a similar increase was seen for OCcxy (P < 0.05) and ALP (P < 0.01). Bone formation had returned to baseline after a year. Dpyr increased significantly, with a doubling at 6 weeks, while serum (S)-ICTP increased by 73% (P < 0.01 and P < 0.001). Urine OC increased to a maximum of 84% at 6 weeks. The initial percentage increase of bone resorption was greater than that of bone formation. We conclude that: (1) bone turnover as measured by biochemical markers is altered soon after fracture, (2) the major changes occur within 6 weeks to 6 months, but may persist for up to a year. (3) The initial increase in bone resorption exceeds the increase in bone formation, which may contribute to the enhanced bone loss after fracture. (4) The two novel urine OC assays show a similar pattern of change as established marks of bone resorption, which may indicate that they measure bone resorption. (5) Fracture-induced effects on bone turnover are significant and, thus, are potential confounders in the assessment of osteoporosis.

Just one look, and fractures and death can be predicted in elderly ambulatory women.

BACKGROUND: The chronological age is clearly the strongest risk factor for fractures or death. Age as a concept can be described exactly as chronological age. Age in relative terms can be described as biological age. OBJECTIVE: We postulated that, even without taking into account known or unknown comorbidity, an immediate and totally subjective evaluation of an individual's biological age is predictive of forthcoming fractures and death. METHODS: At baseline the biological age was estimated in 1,004 randomly recruited ambulatory 75-year-old women. All women were of the same ethnic background. Two independent observers estimated the biological age within 15 s of first sight of each woman. Based on this estimation of the biological age, the women were divided into tertiles. The women were then followed prospectively for a mean of 4.6 (range 3.0-6.5) years. All retrospective fractures and prospective fractures and deaths were registered. RESULTS: When the tertile of the biologically oldest women was compared with all other women, their odds ratio for sustaining any type of prospective fracture was 1.71 (95% confidence interval 1.22-2.39), for hip fractures 2.69 (1.42-5.11), for clinical vertebral fractures 2.83 (1.57-5.11), and for multiple fractures 3.17 (1.64-6.10). Also, when retrospectively sustained fractures were included, the predictive ability for biological age remained. The death rate amongst the tertile of biologically oldest women was increased when compared with the rest of the women (odds ratio 4.33, CI 3.62-5.17). CONCLUSIONS: In ambulatory elderly women, without specific consideration of comorbidity, a subjective estimate of the biological age is predictive of future fractures and death. Subjective estimation of the biological age, in relation to the chronological age, is a valuable indicator of health, conveying additional information that merits its use in clinical practice.

Maxillary bone mineral density and its relationship to the bone mineral density of the lumbar spine and hip.

OBJECTIVE: We sought to measure the bone mineral density (BMD) of various regions in the maxilla before implant treatment and to investigate correlations between these values and the BMDs of the spine and hip. STUDY DESIGN: Eighteen patients were examined by means of quantitative computed tomography, and the BMD of the maxillary alveolar ridge was calculated. The same patients also underwent dual-energy x-ray absorptiometry of the lumbar spine and the total hip. Analysis of variance was used to compare BMD values between and within individuals. The Pearson correlation coefficient was used to correct for sex and body mass and to calculate the correlation between the BMD of the maxillary alveolar ridge and the BMD of the spine and hip. RESULTS: The maxillary BMD varied significantly between individuals (P <.001) and within individuals (P <.001). The BMD of the anterior region of the maxilla was correlated significantly with the BMD of the lumbar spine (r=0.6; P <.05). CONCLUSION: A site-specific evaluation of maxillary bone tissue could be of value before implant treatment.

Bone mineral density in old age: the influence of age at menarche and menopause.

Being aware that age at menarche, age at menopause, and length of fertile period influence bone mineral density (BMD) in the early postmenopausal period, we have failed to find any earlier studies where such an influence on the axial skeleton has been studied in old age when the incidence of hip fracture starts to increase. A large cohort of women, all 75 years old (n = 1044) participated in the Malmö Osteoporosis Prospective Risk Assessment (OPRA) Study. The BMD of the lumbar spine and femoral neck was assessed by a dual-energy X-ray absorptiometry (DXA) technique. Age at menarche and at menopause was recalled with a questionnaire. Also, data on estrogen medication was collected. We found that, after excluding ever-users of potent estrogens (n = 49), there was a small but significant correlation of early menarcheal age with high BMD of the lumbar spine (r = -0.08; P = 0.017) and femoral neck (r = -0.10; P = 0.002) at age 75. Excluding the extremes (5% of the women) with very early or very late menarche, age at menarche no longer influenced the BMD in old age (r = -0.06; P = 0.113). Age at menopause had no influence on the BMD of the lumbar spine (r = 0.04; P = 0.246) or femoral neck (r = 0.00; P = 0.985), at age 75. The length of the fertile period did not influence BMD in old age. The influence of menarcheal or menopausal age on BMD at age 75 was not substantially altered after including body mass index (BMI) in a multiple regression model. Age at menarche or menopause seems to be of limited or no importance as a risk factor for osteoporosis when subjects are age 75 or older.

Biochemical markers of bone metabolism and prediction of fracture in elderly women.

UNLABELLED: We studied the ability of various markers of bone turnover to predict fracture in 1040 randomly recruited 75-year-old women. A total of 178 of the women sustained at least one fracture during follow-up (mean, 4.6 years). In elderly women, TRACP5b and urinary fragments of osteocalcin are promising new markers for prediction of fracture, in particular, vertebral fracture. INTRODUCTION: Biochemical markers reflecting bone turnover may improve the prediction of fractures. MATERIALS AND METHODS: The ability of 10 markers of bone turnover to predict fracture in 1040 elderly women in the Malmö OPRA study was studied. Serum bone-specific alkaline phosphatase and four different forms of serum osteocalcin (S-OC) were analyzed as markers of bone formation and serum C-terminal cross-linking telopeptides of type I collagen (S-CTX), serum TRACP isoform 5b (S-TRACP5b) and urinary free deoxypyridinoline (U-DPD) as markers of bone resorption. Two novel assays for osteocalcin fragments in urine (U-OC) were analyzed. Areal BMD (aBMD) was measured by DXA in the femoral neck and lumbar spine. RESULTS: In total, 231 fractures were sustained by 178 of the women during a 3- to 6.5-year (mean, 4.6 years) follow-up period. When women with prospective fractures were compared with women without fractures, S-TRACP5b, S-CTX, one S-OC, and one U-OC were higher in women with a fracture of any type (all p < 0.05), and all bone markers were higher in women with clinical vertebral fracture (all p < 0.05). Markers were not significantly elevated in women with hip fracture. When women within the highest quartile of a bone marker were compared with all others, S-TRACP5b and one U-OC predicted the occurrence of a fracture of any type (odds ratio [OR]), 1.55 and 1.53; p < 0.05). S-TRACP5b, the two U-OCs, and S-CTX predicted vertebral fracture (OR, 2.28, 2.75, 2.71, and 1.94, respectively; all p < 0.05), and the predictive value remained significant for S-TRACP5b and the two U-OCs after adjusting for aBMD (OR, 2.02-2.25; p < 0.05). Bone markers were not able to predict hip fracture. CONCLUSION: These results show that biochemical markers of bone turnover can predict fracture, and in particular, fractures that engage trabecular bone. S-TRACP5b and U-OC are promising new markers for prediction of fracture.

Interleukin-6 promoter polymorphism is associated with bone quality assessed by calcaneus ultrasound and previous fractures in a cohort of 75-year-old women.

Interleukin 6 (IL-6) is a multifunctional cytokine and a potent stimulator of bone resorption and has been implicated in the pathogenesis of osteoporosis in postmenopausal women. The aim of this study was to investigate if a functional IL-6 promoter polymorphism (-174) was related to bone mass and fractures in a cohort consisting of 964 postmenopausal Caucasian women aged 75 years. Bone mineral density (BMD; g/cm2) of the femoral neck, lumbar spine and total body was measured using dual energy X-ray absorptiometry (DXA). Quantitative ultrasound (QUS) was also measured in the calcaneus and quantified as speed of sound (SOS; m/s), broadband ultrasound attenuation (BUA; dB/MHz), and stiffness index (SI). IL-6 genotypes was determined by restriction fragment length polymorphism (RFLP) using the restriction enzyme NlaIII. The frequencies of the different IL-6 genotypes were 27.5% (GG), 47.9% (GC), 24.6% (CC). The IL-6 polymorphism (presence of G) was independently related to a lower stiffness (beta=-0.07; P=0.03) and BUA (beta=-0.08; P=0.02), but not to BMD at any site measured by DXA. In the cohort, 420 subjects (44%) reported at least one fracture during their lifetime, and 349 (36%) reported at least one fracture after the age of 50. Using binary logistic regression, the IL-6 polymorphism (presence of G) was significantly related to an increased risk of a previous fracture during life (odds ratio 1.46, 95% CI 1.08-1.97) and to an increased risk of a fracture occurring after 50 years of age (odds ratio 1.37, 95% CI 1.004-1.88). The risk was further increased for fractures grouped as osteoporotic fractures (odds ratio 1.67, 95% CI 1.14-2.45), including forearm fractures (odds ratio 1.59, 95% CI 1.05-2.40). In conclusion, presence of G allele in the IL-6 promoter polymorphism at position -174 is independently related to previous fractures in postmenopausal women. This association may be related primarily to an altered bone quality identified by QUS and not a lower bone mass. This is also the first demonstration of association of IL-6 gene polymorphism to calcaneal QUS.

Seasonal variation in bone density in postmenopausal women.

We investigated seasonal variation in bone density by cross-sectional designs in two large cohorts of women (N = 2337) in Sweden. One cohort was strictly population-based (all 75 yr old, N = 1044), and one cohort was patient-based (age > or = 55 yr, mean age 68, N = 1293). Each woman was assessed once and the inclusion was continuous throughout almost all days of the year. Bone mineral density (BMD) of the total body, hip, and lumbar spine was determined by means of dual X-ray absorptiometry (DXA). For both cohorts, the BMD was similar in those assessed during the period April-September compared to those assessed during the period October-March. On the other hand, when women who had been assessed during July-December were compared with women assessed during January-June, we found the BMD to be up to 5% lower during July-December in all skeletal regions in the population-based sample, and 4% lower at the Ward's triangle and trochanter in the patient-based sample. After correction for small differences in age and weight, women of both cohorts who had been assessed during July-December still had lower BMD at the hip compared with women assessed during January-June. In conclusion, we found no variation in bone density during the period April-September compared to the period October-March in these two cohorts of postmenopausal women. In elderly women living at a northern latitude, BMD may be a few percent lower during the period July-December compared to the period January-June.