Bone turnover markers are correlated with quantitative ultrasound of the calcaneus: 5-year longitudinal data

Summary  Associations between bone turnover markers and calcaneal ultrasound (quantitative ultrasound, QUS) were studied in a population-based sample of 810 elderly women. Baseline bone turnover markers correlated with baseline QUS as well as with 5-year prospective changes in QUS. Introduction  Bone turnover markers are associated with areal bone mineral density, but the knowledge on the association with QUS is limited. Methods  Eight hundred ten women, all 75 years old, were investigated at baseline. Five hundred six completed a 5-year follow-up. Bone turnover markers and calcaneal QUS [speed of sound (SoS), broadband ultrasound attenuation (BUA), stiffness] were investigated at baseline. QUS was investigated at follow-up. Results  All bone turnover markers were correlated with baseline QUS [standardized regression (Beta_std) values from −0.07, p < 0.05 to −0.23, p < 0.001], with the exception of bone-specific alkaline phosphatase (S-Bone ALP) which was not correlated with BUA and stiffness index. When the correlations between baseline bone turnover markers and 5-year changes in QUS were analyzed, three serum osteocalcins were correlated with changes of SoS and stiffness index (Beta_std = −0.11, p < 0.05 to −0.17, p < 0.001). Also S-CTX-I correlated with changes of SoS and stiffness index (Beta_std = −0.10 and −0.09, respectively, p < 0.05). S-TRACP5b, urinary deoxypyridinoline/crea, and U-MidOC/crea correlated with changes of SoS (Beta_std = −0.10 and p < 0.05 for all). S-Bone ALP did not correlate with change of QUS. None of the bone turnover markers correlated with changes of BUA. Conclusions  Bone turnover markers correlate with concomitantly assessed QUS as well as with longitudinal change in QUS.     

Quantitative Ultrasound of the Calcaneus and Falls Risk in the Institutionalized Elderly: Sex Differences and Relationship to Vitamin D Status

Very frail older people constitute an increasing proportion of aging populations and are likely to contribute substantially to costs due to osteoporosis. Quantitative ultrasound (QUS) of the calcaneus is potentially a simple method for assessing fracture risk in frail elderly, but there have been few studies of male/female differences in QUS or its relationship to falls risk or vitamin D status, which is often subnormal in this population. We studied QUS, falls risk and serum 25(OH)-vitamin D in subjects living in institutional aged care facilities (hostels or nursing homes). The study sample comprised 294 men (mean age 81.2 years, range 65–102 years) and 899 women (mean age 86.7 years, range 65–104 years). Broadband ultrasound attenuation (BUA) and velocity of sound (VOS) were higher in men than women by approximately 30% and 2% respectively (p<0.0001) and this difference was maintained at all ages. Serum 25(OH)D levels were higher in men than women (p<0.001) but vitamin D deficiency was very common in both sexes and serum 25(OH)D was not associated with QUS in either sex. There was no significant decline in BUA or VOS with age in men; however, for women BUA declined by 2.8–4.7% per decade and VOS by 1% per decade (both p<0.001). Mean BUA T-scores were −1.55 and −2.48 at age 90 years in men and women. Quadriceps strength and weight but not serum 25(OH)D were significantly associated with BUA. These data suggest only minor loss occurs at the calcaneal site in BUA and VOS with very old age in either sex. Received: 7 March 2002 / Accepted: 5 June 2002 Correspondence and offprint requests to: Professor Philip Sambrook, Royal North Shore Hospital, St Leonards, NSW 2065, Australia. Tel: +61 2 9926 7281. Fax: +61 2 9906 1859. e-mail: sambrook@med.usyd.edu.au     

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.     

Influence of fall related factors and bone strength on fracture risk in the frail elderly

Introduction When subjects are selected on the basis of fall risk alone, therapies for osteoporosis have not been effective. In a prospective study of elderly subjects at high risk of falls, we investigated the influence of bone strength and fall risk on fracture. Methods At baseline we assessed calcaneal bone ultrasound attenuation (BUA) as well as quantitative measures of fall risk in 2005 subjects in residential care. Incident falls and fractures were recorded (median follow-up 705 days). Results A total of 6646 fall events and 375 low trauma fracture events occurred. The fall rate was 214 per 100 person years and the fracture rate 12.1 per 100 person years. 82% of the fractures could be attributed to falls. Although fracture rates increased with decreasing BUA (incidence rate ratio 1.94 for lowest vs. highest BUA tertile, p<0.002), incident falls also affected fracture incidence. Subjects who fell frequently (>3.15 falls/per person year) were 3.35 times more likely to suffer a fracture than those who did not fall. Some fall risk factors such as balance were associated with the lowest fracture risk lowest in the worst performing group. Multivariate analysis revealed higher fall rate, history of previous fracture, lower BUA, lower body weight, cognitive impairment and better balance as significant independent risk factors for fracture. Conclusions In the frail elderly, both skeletal fragility and fall risk including the frequency of exposure to falls are important determinants of fracture risk.     

Changes in Bone Mass and Bone Turnover Following Ankle Fracture

Bone loss and increased bone turnover are recognized local changes after a fracture, but the exact patterns of these changes after different fractures are unclear. We aimed to investigate the changes in bone density and biochemical markers following ankle fracture. Fourteen subjects (7 postmenopausal women and 7 men, mean age 63 years) were recruited following fracture of the distal tibia and fibula. Bone mineral density (BMD) of the ankle and proximal femur were measured by dual-energy X-ray absorptiometry (DXA) and quantitative ultrasound (QUS) of the calcaneus at 0, 6, 12, 26 and 52 weeks after fracture. Serum and urine samples were collected at 0, 3 and 7 days and at 2, 4, 6, 12, 26 and 52 weeks after fracture to measure markers of bone turnover. For bone formation we measured: bone alkaline phosphatase (iBAP), osteocalcin (Oc), procollagen type I N-terminal propeptide (PINP); and for bone resorption: tartrate-resistant acid phosphatase (TRAcP), deoxypyridinoline (iFDpd), N-telopeptides of type I collagen (NTx). We used the nonfractured limb to calculate values for baseline BMD and QUS. There was a significant decrease in BMD at the ultradistal ankle (p<0.001), the trochanteric region of the hip (p<0.01) and QUS of the heel after ankle fracture. This bone loss was maximal for ultradistal ankle BMD by 6 weeks at 13% (p<0.001) and for the trochanter by 26 weeks at 3% (p<0.01). The ankle BMD returned to baseline at 52 weeks but the trochanter BMD did not. Velocity of sound (VOS) decreased at 6 weeks by 2% (p<0.01) and broadband ultrasound attenuation (BUA) by 15% (p<0.01). VOS recovered completely by 52 weeks, but BUA did not return to baseline. Bone formation markers increased significantly between 1 and 4 weeks by 11–78% (p<0.01), and iBAP returned to baseline at 52 weeks but PINP and Oc remained elevated. Bone resorption markers did not increase and NTx was decreased at 52 weeks. We conclude that BMD decreased distal and immediately proximal to the fracture line when measured with DXA and QUS. Ankle BMD and heel VOS recovered at 52 weeks (trochanteric BMD and heel BUA did not) and the bone turnover markers returned toward baseline. Received: 27 January 1999 / Accepted: 19 April 1999     

Changes in bone mass and bone turnover following tibial shaft fracture

Introduction: Bone loss occurs in the regional bone following tibial shaft fracture. An earlier cross-sectional study showed that measurements made at the metaphyseal region of the tibia using peripheral quantitative computed tomography (pQCT) and the ultradistal region of the tibia using dual-energy X-ray absorptiometry (DXA) were the most responsive at monitoring this bone loss. Biochemical markers of bone turnover enable us to assess the activity of bone formation and resorption during fracture healing. The aim of this longitudinal study was to determine the pattern and distribution of bone loss and bone turnover following a tibial shaft fracture treated with either plaster cast or intramedullary nail. Methods: Eighteen subjects underwent bone mass measurements using DXA at the tibia and hip and quantitative ultrasound (QUS) at the tibia and calcaneus of both limbs at 2 weeks, 8 weeks, 12 weeks and 24 weeks following fracture, with hip and tibia DXA measurements also performed at 52 weeks. Nine of the patients treated with plaster cast had pQCT measurements at the tibia at 24 weeks. We measured three bone formation markers, bone alkaline phosphatase (bone ALP), osteocalcin (OC) and procollagen type 1 N-terminal peptide (PINP), a marker of bone resorption, serum C-telopeptides of type 1 collagen (β-CTX) and a marker of collagen III turnover, procollagen type III N-terminal peptide (PIIINP) at 1 day, 3 days and 7 days and at 2, 4, 8, 12, 16 and 24 weeks following fracture. The greatest bone losses were observed at the ultradistal region of the tibia using DXA (28%, p <0.001) and the metaphyseal region of the tibia using pQCT (26–31%, p <0.001) at 24 weeks. In the hip, the greatest loss was in the trochanter region at 24 weeks (10%, p <0.001). The greatest loss at the calcaneus measured using QUS was for broadband ultrasound attenuation (BUA) measured using CUBA Clinical at 24 weeks (13%, p =0.01). Results: At 1 year, there was a small recovery in bone loss (ultradistal tibia DXA, 20%, p <0.01; trochanter DXA 9%, p <0.001). Bone turnover increased following fracture (PINP +72±21%, p <0.0001, bone ALP +199±22%, p =0.004, β-CTX +105±23%, p <0.0001, all at 24 weeks). There was a smaller +33±10% increase in osteocalcin at 24 weeks. PIIINP concentration peaked at week 8 (+57±9%, p <0.0001). The bone resorption marker β-CTX showed an earlier rise (week 2, 139±33%) than the bone formation markers. Conclusions: We conclude that: (1) bone loss following tibial shaft fracture occurs both proximal and distal to the fracture; (2) the decreased BMD is largest for trabecular bone in the tibia with similar measurements using DXA and pQCT; (3) there is limited recovery of bone lost at the hip and tibia at 1 year; (4) tibial speed of sound (SOS) demonstrated a greater decrease than calcaneal SOS when comparing z -scores; (5) BUA is the QUS variable that shows the biggest decrease of bone mass at the calcaneus; (6) increase in bone turnover occurs following fracture with an earlier increase in bone resorption markers and a later rise in bone formation markers.     

Quantitative ultrasound of bone in institutionalized elderly women: A cross-sectional and longitudinal study

Quantitative ultrasound of bone is a promising method for bone assessment: radiation-free, portable and predictive of hip fracture. Its portability allowed us to study the relationships between ultrasonic parameters of bone with age and with non-vertebral fractures in elderly women living in 19 nursing homes. Broadband ultrasound attenuation (BUA) and speed of sound (SOS) of the calcaneus were measured (and the stiffness index calculated) in a sample of 270 institutionalized women, aged 85±7 years, using an Achilles bone densitometer (Lunar). The effects of age, history of non-vertebral and non-traumatic fractures, body mass index, triceps skinfold and arm circumference were assessed on BUA, SOS and stiffness index. Furthermore, to evaluate longitudinally the influence of aging on the ultrasound parameters of bone, 60 subjects from the same group had a second ultrasound measurement after 1 year. The cross-sectional analysis of the data on all 270 women showed a significant decrease (p<0.001) with age in BUA, SOS and stiffness index (–0.47%, –0.06%, and –1.01% respectively per year). In the 94 women (35%) with a history of previous non-vertebral fractures, ultrasound parameters were significantly lower (p<0.0001) than in the 176 women with no history of fracture (–8.3% for BUA, –1.3% for SOS, –18.9% for stiffness index). In contrast, there was no significant difference in anthropometric measurements between the groups with and without previous non-vertebral fractures, although the measurements decreased significantly with age. In the longitudinal study, repeated quantitative ultrasound after 11.4±0.8 months showed no significant decrease in BUA (–1%) but a significant decrease in SOS (–0.3%,p<0.0001) and in stiffness index (–3.6%,p<0.0002). In conclusion, quantitative ultrasound of the calcaneus measures properties of bone which continue to decline in institutionalized elderly women, and is able to discriminate women with previous non-vertebral fractures.     

Quantitative ultrasound variables of the heel in Finnish men aged 18–20 yr: predictors, relationship to bone mineral content, and changes during military service

Introduction Determinants of BUA and SOS and their changes during military service-associated physical training were studied in 196 army recruits and 50 control men, aged 18–20 years.Methods Heel ultrasound measurement, DXA, muscle strength test, Cooper’s running test and genetic analyses were performed. Lifestyle factors were recorded. Sex steroids and bone turnover markers were determined. Heel ultrasound was repeated after six months.Results Exercise was the most significant determinant of both BUA (p<0.0001) and SOS (p<0.0001). There were 10% and 1.3% differences in BUA (p=0.006) and SOS (p=0.0001), respectively, between men belonging to the lowest and highest quartiles of exercise index. Weight associated with BUA (p=0.005) and height with SOS (p=0.03). BUA and SOS correlated with BMC and BMD (p<0.0001) but explained only up to 21% of their variance. Over six months SOS increased more in recruits than in control men (p=0.0043), the increase being higher, the lower muscle strength at baseline (r =−0.27, p=0.0028).Conclusion Exercise is the most important determinant of ultrasonographic variables in men, aged 18–20 years. Physical loading during military training increases SOS.     

The Effects of 10 Weeks Military Training on Heel Ultrasound and Bone Turnover

To measure the physiological changes in bone in response to strenuous exercise we performed a prospective study of male army recruits over 10 weeks of basic training. Measurements performed at the start and completion of training consisted of ultrasound (US) measurements of the heel: velocity of sound (VOS in m/seconds) and broadband ultrasound attenuation (BUA in dB/MHz) and bone turnover markers; osteocalcin (OC), bone-specific alkaline phosphatase (BALP), and tartrate-resistant acid phosphatase (TRAP). Forty subjects were recruited for the study and 26 completed training. Over the 10-week study period there was a significant 1.7% fall in mean VOS [mean paired difference (mpd) 27.2 m/second, SEM 9.5 (95% CI 7.5–46.8) P= 0.009] and a nonsignificant 3.4% increase in BUA (P= 0.159). There were significant falls in markers of bone formation OC [11.6%, mpd 0.11 μg/liter (95% CI 0.07–0.14) P < 0.001] and BALP [13.3%, mpd 3.49 U/liter (CI 0.80–6.18) P= 0.013] and a nonsignificant 9.5% fall in TRAP a marker of bone resorption. The 10 recruits subsequently injured had a significantly lower VOS on entry [mean difference 24.2 m/seconds (95% CI 4.6–43.7) P= 0.017] and nonsignificantly raised BUA and baseline levels of all bone markers. The ultrasound changes may be accounted for by increase in trabecular separation and a fall in trabecular connectivity due to microfracture. The decrease in bone markers implies a fall in bone turnover. Received: 26 June 1997 / Accepted: 26 August 1998     

Low serum levels of intact osteocalcin in patients with congestive heart failure

 Impaired bone metabolism is a frequent complication following heart transplantation. Little is known, however, about possible alterations in bone turnover of pretransplant patients with congestive heart failure (CHF). We therefore studied biomarkers of bone turnover in 21 male patients with CHF (New York Heart Association [NYHA] classification > II) compared with 21 controls (NYHA classification < II). Biomarkers of bone formation (intact osteocalcin and carboxy-terminal propeptide of type I collagen), markers of bone resorption (N-telopeptide and C-telopeptide of type I collagen), undercarboxylated osteocalcin (an indicator of fracture risk), and concentrations of calcium, parathyroid hormone, and vitamin D metabolites (25-hydroxyvitamin D and calcitriol) were measured in fasting blood samples. Serum levels of intact osteocalcin were 44.5% lower (P < 0.01), and the ratio of undercarboxylated-to-intact osteocalcin was 113% higher (P < 0.01) in the patients in comparison with the controls. Moreover, patients had 34% lower 25-hydroxyvitamin D levels (P < 0.01) and 22% lower calcitriol levels (P < 0.05) than the controls. The bone resorption markers, N-telopeptide and C-telopeptide; the bone formation marker, carboxy-terminal propeptide of type I collagen; parathyroid hormone levels; and albumin-adjusted serum calcium concentrations did not differ between patients and controls (all P values > 0.05). In summary, there were no biochemical signs of enhanced bone collagen resorption in pretransplant CHF patients. However, the low serum levels of intact osteocalcin and the high ratio of undercarboxylated-to-intact osteocalcin deserve further consideration. Received: September 13, 2002 / Accepted: January 27, 2003 RID="*" ID="*" Offprint requests to: A. Zittermann Acknowledgments. This study was supported by the Pinguin Foundation, Düsseldorf, Germany.     

Biochemical Markers of Bone Turnover Reflect Femoral Bone Loss in Elderly Women

Although over 90% of hip fractures occur in patients over age 70, few data are available on femoral bone loss in this age group. To examine the relationship between biochemical markers of bone turnover and femoral bone loss in the elderly, 36 female and 17 male, healthy, community-dwelling elderly over age 65 (mean ± SD age: women 71 ± 4 years, men 75 ± 5 years) were followed for 3 years. Annual bone mineral density measurements of the hip and lumbar spine by dual-energy x-ray absorptiometry (DXA) were obtained and biochemical markers of bone resorption (urinary N-telopeptide crosslinks, free pyridinoline, total pyridinoline, total deoxypyridinoline, and hydroxyproline) and bone formation (serum osteocalcin, bone-specific alkaline phosphatase) were obtained at the end of year 3. In elderly women, longitudinal bone loss at the total hip was negatively correlated with markers of bone resorption (r =−0.39 to −0.52, P < 0.05), bone formation (r =−0.38, P < 0.05), and age (r =−0.39, P < 0.05). Markers of bone resorption were correlated with markers of bone formation (r = 0.63 to 0.74, P < 0.01). In multiple regression analysis, urinary N-telopeptide crosslinks (marker of resorption), serum osteocalcin (marker of formation), and serum parathyroid hormone explained 43% of the variability of bone loss at the total hip in women. These parameters were not related to bone loss in men. We conclude that femoral bone loss increases with age in women over 65. Measurements of specific biochemical markers of bone turnover are correlated with longitudinal bone loss in elderly women. These markers may help identify women at greatest risk for bone loss who would benefit most from therapeutic interventions. Received: 28 January 1996 / Accepted: 3 May 1996     

Which bone mass measures discriminate adolescents who have fractured from those who have not?

Summary This study of 415 adolescent children examined the association between four different measures of bone mass and prevalent fracture (N = 160 children). DXA measures and calcaneal ultrasound (but not radial ultrasound or metacarpal index) were associated with upper limb fracture, suggesting heel ultrasound is also a discriminator of fractures in children. Introduction The aim of the study was to describe the association between different measures of bone mass and prevalent fracture in adolescents. Methods A total of 415 adolescents (150 girls and 265 boys), mean age 16.3 years were examined. Dual energy X-ray absorptiometry (DXA) measures were performed at hip, spine, radius and total body. Calcaneal bone ultrasound attenuation (BUA), speed of sound (SOS), and stiffness were assessed by a Sahara densitometer. Radial ultrasound SOS was assessed by a Sunlight 8000P machine. Metacarpal index was calculated from a left hand X-ray. Prevalent fractures were assessed by questionnaire. Results A total of 160 adolescents (39%) reported at least one previous fracture (106 upper limb, 53 lower limb, one other for first fracture). Significantly lower DXA measures, heel BUA, and heel stiffness was observed in those with a history of upper limb fracture (all P < 0.05). Despite significant correlations between all the bone mass measures, radial ultrasound and metacarpal index did not discriminate those with fracture from those without. Similar associations were present for number of fractures. No bone measure was able to discriminate lower limb fracture. Conclusions Both calcaneal quantitative ultrasound and DXA are able to discriminate adolescents with a history of upper limb fracture from those without. Source of support: National Health and Medical Research Council.     

Quantitative Ultrasound of Bone and Markers of Bone Turnover in Cushing’s Syndrome

Quantitative ultrasound (QUS) of bone is a valuable tool in the assessment of postmenopausal osteoporosis. QUS and new markers of bone turnover have been poorly assessed in Cushing’s syndrome, however. Twenty-five patients with Cushing’s syndrome (20 women, 3 men; mean age ± SEM: 38 ± 2 years) were studied and compared with 35 age- and sex-matched control patients (mean age ± SEM: 38 ± 2 years). The following variables were measured in both groups: QUS parameters at the heel (BUA; SOS; Stiffness Index, SI); bone mineral density (BMD) at both the lumbar spine (LS) and femoral neck (FN) by dual-energy X-ray absorptiometry; and serum markers of bone turnover (osteocalcin, procollagen type I N- and C-terminal propeptides (PINP and PICP), bone alkaline phosphatase (BAP), procollagen type I C-terminal telopeptide (ICTP) and urinary type I collagen C-telopepetide breakdown products (CTX)). Both BUA and SI were decreased in patients with Cushing’s syndrome (p<0.01) but not SOS (p=0.08). BMD was also strongly decreased in Cushing’s syndrome, at both the LS and FN (p<0.005). The two markers of bone turnover statistically significantly different between the two groups were osteocalcin (mean ± SEM: 3.5 ± 0.7 ng/ml (Cushing’s syndrome) vs 6.4 ± 0.5 ng/ml (controls, p<0.01)) and CTX (mean ± SEM: 148.7 ± 17.1 μg/mmol Cr (Cushing’s syndrome) vs 220.8 ± 22.9 μg/mmol Cr (controls), p<0.05). The areas under the receiver operating characteristic curve (AUC) were 0.72 (BUA), 0.73 (SI), 0.90 (BMD_LS), 0.81 (BMD_FN), 0.83 (osteocalcin) and 0.64 (CTX) respectively. AUC was significantly higher for BMD_LS than for both BUA and SI (p<0.05). Conversely AUC was not statistically significantly different for BMD_FN as compared with either BUA or SI. AUC was also higher for osteocalcin than for other markers of bone turnover. In conclusion, QUS of bone seems to be a relevant tool for assessing bone involvement in Cushing’s syndrome. QUS does have a lower sensitivity compared with DXA, however, and the relevance of QUS cannot be ascertained until some longitudinal data are forthcoming. Except for CTX, the other new markers of bone turnover assessed in this study (PINP, PICP, BAP and ICTP) do not seem of interest in Cushing’s syndrome. Received: February 2000 / Accepted: 24 August 2000     

The duration of exercise as a regulator of bone turnover

The relationship between duration of exercise and serum remodeling markers of bone turnover was evaluated by osteocalcin (OC), carboxy-terminal propeptide of type I collagen (PICP), total and bone-specific alkaline phosphatase (ALP) and carboxyterminal cross-linked telopeptide of type I collagen (ICTP) in 24 male premier league soccer players exercising 12 hours/week (range 8–18), 19 third league players exercising 8 hours/week (range 3–18) and 20 sixth league players exercising 6 hours/week (range 2–10). Twenty-seven volunteers served as controls. Forty-six former male soccer players (mean age 38 years, range 19–47), mean 15 years older than the current players, were compared with 41 matched controls. Data is presented as mean ± SEM. Active male players had 18 ± 4% higher OC, 37 ± 9% higher bone ALP and 36 ± 7% higher ICTP than controls (all P < 0.01). There were no differences in remodeling markers within the three groups of active players but each group had higher OC and ICTP than controls (both P < 0.05). Former players had no difference in bone remodeling markers compared to matched controls, but 39 ± 4% lower OC and 69 ± 8% lower ICTP than active players (both P < 0.001). Duration of activity was correlated with bone ALP and ICTP (both r = 0.3, P < 0.05) in individuals exercising 6 hours/week or less. No correlation was found in those exercising above this level. It seems as if the bone turnover, evaluated by serum bone remodeling markers, adapts to the current activity needed to maintain bone strength, and a duration of exercise above that level seems to confer no additional benefits.     

Linkage and Association for Bone Mineral Density and Heel Ultrasound Measurements with a Simple Tandem Repeat Polymorphism near the Osteocalcin Gene in Female Dizygotic Twins

In this confirmatory candidate gene study, we investigated possible linkage and association for bone density, heel ultrasound and bone turnover with the osteocalcin gene using the nearby (50–180kb) microsatellite marker D1S3737. Non-identical twin sisters aged 18–75 years at first interview were recruited for the study from the St Thomas’ UK Adult Twin Registry with 1366 women being genotyped for marker D1S3737. Linkage, allelic association and joint linkage and association tests were carried out using quantitative transmission disequilibrium tests (QTDT), along with post-hoc multivariate tests of linkage and association. Phenotypes tested were bone mineral density (BMD) at the spine, left forearm and left total hip; quantitative ultrasound measurements of the heel including velocity of ultrasound (VOS) and broadband ultrasound attenuation (BUA); and bone turnover markers, urine deoxypyridinoline (DPD), serum osteocalcin, bone specific and total alkaline phosphatase (ALP). BMD and ultrasound variables showed evidence of pleiotropic linkage (p= 0.05) and association (p= 0.02) with the marker in postmenopausal women. Bone markers showed little or no evidence of linkage and association for any age group. Evidence for pleiotropic linkage appeared to be strongest for BUA and spine BMD in postmenopausal women. The univariate test statistic for BUA was χ² ₁=12.8 (p= 0.0003), equivalent to a LOD score of 2.8. DPD showed borderline evidence of linkage to the marker for women of all ages. Multivariate model-fitting showed allele 10 to be negatively associated with BMD, VOS and BUA via a common pathway, suggesting the putative functional polymorphism affects both bone content and structure through shared underlying metabolic pathways. It is likely that the alleles are in linkage disequilibrium with functional polymorphism(s) in or nearby the osteocalcin gene, which may contribute to the onset of osteoporosis. Received: 24 January 2002 / Accepted: 25 April 2002     

Stiffness in Discrimination of Patients with Vertebral Fractures

We measured the ultrasound parameters of the heels of 49 women with vertebral fractures and 87 age-matched controls using an Achilles ultrasound device. Average broadband ultrasound attenuation (BUA), speed of sound (SOS) and Stiffness were significantly lower in fracture patients (p<0.0001). We also estimated the ultrasound parameters of patients compared with age-matched non-fracture controls and found the mean BUA to be −1.02 SD below control values. The mean SOS was −0.97 SD and the mean Stiffness was −1.12 SD below control values.  Femoral bone mineral density (BMD) at the neck, Ward’s triangle and the trochanter, the total-body BMD and L2–4 BMD were measured with dual-energy X-ray absorptiometry (DXA) and found to be significantly lower in fracture patients (p<0.0001). All correlation coefficients between ultrasound parameters and DXA measurements were >0.5 and statistically significant (p<0.0001). A stepwise logistic regression with presence or absence of vertebral fracture as the response variable and all ultrasound – DXA parameters as the explanatory variables indicated that the best predictor of fracture was Stiffness, with additional predictive ability provided by spine BMD. Sensitivity and specificity of all measures were determined by the areas under the receiver operating characteristic (ROC) curve, which were 0.76 ± 0.04 for BUA, 0.77 ± 0.04 for SOS, 0.78 ± 0.04 for Stiffness and 0.78 ± 0.03 for spine BMD. The areas under the ROC curves of BUA, SOS, Stiffness and spine BMD were compared and it was found that Stiffness and spine BMD were significantly better predictors of fracture than BUA and SOS. These results support many recent studies showing that ultrasound measurements of the os-calcis have diagnostic sensitivity comparable to DXA, and also demonstrated that Stiffness was a better predictor of fracture than spine BMD. Received: 23 September 1997 / Accepted: 10 April 1998     

Geographic Differences in Bone Turnover: Data from a Multinational Study in Healthy Postmenopausal Women

Biochemical markers of bone metabolism (bone markers) are used increasingly to monitor response to therapy and may be predictors of bone loss and fractures. The relationship between fracture rates, which differ between countries, and the rate of bone turnover has not been examined. Therefore, we explored the geographic variability of bone turnover in a selected, healthy study population of 619 postmenopausal women, ages 40–61, participating in a clinical trial of raloxifene hydrochloride for osteoporosis prevention. The subjects were distributed among 38 investigative sites in 10 countries (9–211 subjects/country) on four continents (North America, n = 277, Europe, n = 168, Australia, n = 125, and Africa, n = 49). Specimens for serum osteocalcin (OC), bone-specific alkaline phosphatase (BSAP), and urine type I collagen fragment/urinary creatinine ratio (CTX) were handled in a uniform fashion and assayed in a central laboratory. Mean levels of OC (P < 0.001), BSAP (P= 0.006), and CTX (P < 0.001) varied significantly by country (ANOVA), with the lowest values typically in German and Spanish subjects and the highest in American and Canadian subjects. The consistent pattern and wide ranges of mean bone marker values (OC 1.6-fold, BSAP 1.7-fold, CTX 3.1-fold) between countries suggest clinically significant differences in bone turnover. Geographic differences in bone markers were not explained by the determined potential confounders of age, years posthysterectomy, total serum cholesterol, and serum follicle stimulating hormone (FSH). We conclude that bone marker values vary substantially by country in this selected study population, suggesting systematic geographic differences in bone metabolism that potentially relate to osteoporotic fracture rates. Received: 28 November 1997 / Accepted: 23 March 1998     

Acute Effects of Calcitonin Nasal Spray on Serum C-telopeptide of Type 1 Collagen (CTx) Levels in Elderly Osteopenic Women with Increased Bone Turnover

Salmon calcitonin is a potent inhibitor of osteoclastic activity. The effect of calcitonin in elderly women with high bone turnover at higher risk of developing osteoporosis has not been studied. To investigate acute effects of calcitonin treatment on bone resorption markers in elderly women, we conducted a randomized trial in women >65 years of age with high bone turnover assessed as urinary N-telopeptide of type-I collagen (NTx) levels 1 SD higher than mean premenopausal levels, which was irrespective of bone density. A total of 98 elderly women were randomly assigned to receive either 200 IU calcitonin nasal spray (n = 75) with calcium (500 mg) and vitamin D (200 IU) or calcium and vitamin D (n = 23) alone for 6 months. Blood and urine samples were collected at 0, 2, 4, and 6 months and analyzed for urinary NTx and serum C-telopeptide of type-1 collagen (CTx). At baseline, mean age was 72.1 ± 4.7 (mean ± SD) in the calcitonin group and 72.2 ± 6 years in the control group. The spine and total hip BMD, serum PTH levels and urinary calcium/creatinine ratios were similar in both groups. Mean BMD was in the osteopenic range in both groups. Calcitonin treatment resulted in significant decreases in serum CTx levels, 2, 4 and 6 months after treatment as compared to baseline, and after 4 and 6 months as compared to controls. A maximum decrease from baseline of 33% was seen at 6 months. The urinary resorption marker, urine NTx, showed a significant decrease in the calcitonin group when compared to baseline only at the 6-month time point. Analysis of least significance change (LSC) showed that 70% of calcitonin patients were categorized as responders using serum CTx after 6 months of treatment. We conclude that 200 IU calcitonin effectively decreases bone resorption within 60 days of therapy, thus preventing further bone loss in elderly women who are at a high risk of developing osteoporosis.     

Homocysteine and vitamin B12 status relate to bone turnover markers, broadband ultrasound attenuation, and fractures in healthy elderly people.

Hyperhomocysteinemia may contribute to the development of osteoporosis. The relationship of Hcy and vitamin B12 with bone turnover markers, BUA, and fracture incidence was studied in 1267 subjects of the Longitudinal Aging Study Amsterdam. High Hcy and low vitamin B12 concentrations were significantly associated with low BUA, high markers of bone turnover, and increased fracture risk. INTRODUCTION: Hyperhomocysteinemia may contribute to the development of osteoporosis. Vitamin B12 is closely correlated to homocysteine (Hcy). The main objective of our study was to examine the association of Hcy and vitamin B12 status and the combined effect of these two with broadband ultrasound attenuation (BUA), bone turnover markers, and fracture. MATERIALS AND METHODS: Subjects were 615 men and 652 women with a mean age of 76 +/- 6.6 (SD) years of the Longitudinal Aging Study Amsterdam (LASA). At baseline (1995/1996), blood samples were taken after an overnight fast for dairy products. Plasma Hcy was measured with IMx, serum vitamin B12 with competitive immunoassay (IA) luminescence, serum osteocalcin (OC) with immunoradiometric assay (IRMA), and urinary excretion of deoxypyridinoline (DPD) with competitive IA and corrected for creatinine (Cr) concentration. CVs were 4%, 5%, 8%, and 5%, respectively. BUA was assessed in the heel bone twice in both the right and left calcaneus. Mean BUA value was calculated from these four measurements. CV was 3.4%. After baseline measurements in 1995, a 3-year prospective follow-up of fractures was carried out until 1998/1999. Subjects were grouped by using two different approaches on the basis of their vitamin B12 concentration, normal versus low (<200 pM) or lowest quartile (Q1) versus normal quartiles (Q2-Q4), and Hcy concentration, normal versus high (>15 microM) or highest quartile (Q4) versus normal quartiles (Q1-Q3). Analysis of covariance was performed to calculate mean values of BUA, OC, and DPD/Cr(urine) based on the specified categories of Hcy and vitamin B12 and adjusted for several confounders (potential confounders were age, sex, body weight, body height, current smoking [yes/no], mobility, cognition). The relative risk (RR) of any fracture was assessed with Cox regression analysis. Quartiles were used when Hcy and vitamin B12 were separately studied in their relationship with fracture incidence. RESULTS: Fourteen percent of the men and 9% of the women had high Hcy (>15 microM) and low vitamin B12 (<200 pM) concentrations. Women with vitamin B12 levels <200 pM and Hcy concentrations >15 microM had lower BUA, higher DPD/Cr, and higher OC concentrations than their counterparts. In men, no differences were found between the different Hcy and vitamin B12 categories in adjusted means of BUA, OC, or DPD/Cr(urine). Twenty-eight men and 43 women sustained a fracture during the 3-year follow-up period. The adjusted RR for fractures (95% CI) for men with high Hcy and/or low vitamin B12 concentrations was 3.8 (1.2-11.6) compared with men with normal Hcy and vitamin B12 concentrations. Women with high Hcy and/or low vitamin B12 concentrations had an adjusted RR for fractures of 2.8 (1.3-5.7). CONCLUSIONS: High Hcy and low vitamin B12 concentrations were significantly associated with low BUA, high markers of bone turnover, and increased fracture risk.     

Effect of alendronate in elderly patients after low trauma hip fracture repair

Summary

One year of once weekly alendronate, when given shortly after the surgical repair of a hip fracture, produces reductions in bone markers and increases proximal femoral bone density. The therapy was well tolerated.

Introduction

Hip fracture is the most devastating type of osteoporotic fracture and increases notably the risk of subsequent fractures. The aim of this paper was to evaluate the effects of 1 year therapy with a weekly dose of alendronate in the bone mineral density and bone markers in elderly patients after low trauma hip fracture repair.

Methods

Two hundred thirty-nine patients (81?±?7 years; 79.8% women) were randomized to be treated either with calcium (500 mg/daily) and vitamin D₃ (400 IU/daily; Ca–Vit D group) or with alendronate (ALN, 70 mg/week) plus calcium and vitamin D₃ (500 mg/daily and 400 IU/daily, respectively; ALN + Ca–Vit D group).

Results

One hundred forty-seven (61.5%) patients completed the trial. Alendronate increased proximal femoral bone mineral density (BMD) in the intention-to-treat analysis (mean difference (95% confidence interval); total hip 2.57% (0.67; 4.47); trochanteric 2.96% (0.71; 5.20), intertrochanteric 2.32% (0.36; 4.29)), but the differences were not significant in the BMD of the femoral neck (0.47%; (?2.03; 2.96) and the lumbar spine (0.69%; (?0.86; 2.23)). Bone turnover markers decreased during alendronate treatment.

Conclusion

The present study demonstrates for the first time the anti-resorptive efficacy of alendronate given immediately after surgical repair in an elderly population with recent hip fracture. This effect should positively affect the rate of subsequent fractures.