Bone Marker Levels Research Articles

Clinical value of the biochemical markers of bone remodeling in the assessment of bone metabolic diseases

Bone markers have been useful research tools, with their clinical utility limited by their specific technical and analytical aspects and pre-analytical variability. Bone markers reflect different aspects of the quality of bone than BMD and, therefore, may add an independent, predictive value to the assessment of changes in bone mineral density and reductions in the risk of fracture. The decrease in bone marker levels is strongly related to the reduction in vertebral fracture risk through raloxifene, risedronate and alendronate. After anabolic therapy with teriparatide, early increases in bone formation markers are strong predictors of BMD responses. There are potential advantages of using markers for monitoring anti-osteoporosis treatment in the short term, in addition to the bone mineral measurements, to identify non-responders or non-compliance. The transition of biochemical bone markers into everyday clinical practice requires standardization of assays and quality control programs to reduce large inter-laboratory variations of data, defining criteria of a high bone turnover in terms of reference values, either young adult or age-matched, and better characterization of the markers across geographic areas and races and under various clinical conditions.

Loop Diuretics Increase Bone Turnover and Decrease BMD in Osteopenic Postmenopausal Women: Results From a Randomized Controlled Study With Bumetanide

To study effects of loop diuretics on bone, 87 women were randomized to 1 year of treatment with bumetanide or placebo. Compared with placebo, bumetanide decreased BMD by 2% at the total hip and by 1.4% at the whole body. Levels of biochemical bone markers were lower in the placebo than in the bumetanide group. Thus, treatment with loop diuretics affects bone metabolism. Loop diuretics may affect bone because they increase the renal calcium excretion and alters the diurnal rhythm of plasma PTH levels. We studied the effects of 1 year of treatment with the loop diuretic bumetanide on bone metabolism. In a double-blinded design, 87 healthy postmenopausal women with osteopenia were randomized to 1-year bumetanide treatment 2 mg/day or placebo. BMD, plasma levels of calcitropic hormones, and biochemical bone markers were measured at baseline, after 1 year of treatment (week 52), and 6 months after withdrawal of treatment (week 78). Calcium (800 mg/day) and vitamin D (10 microg/day) were administered to all participants during the entire 1.5-year study period. Compared with placebo, urinary calcium (+17%) and plasma PTH levels (+9%) increased significantly in response to bumetanide. After 1 year of treatment, BMD in the bumetanide compared with the placebo group was significantly decreased by 2% at the total hip and ultradistal forearm and by 1.4% at the whole body. In addition, levels of biochemical markers of bone turnover differed significantly (approximately 20%) between groups, with lower levels in the placebo than in the bumetanide group. Six months after the end of treatment, the effects of bumetanide were weakening. Treatment with loop diuretics affects bone turnover and decreases BMD. Further studies may reveal whether loop diuretics should be considered as a risk factor for fracture.

Relations between interleukin-1, its receptor antagonist gene polymorphism, and bone mineral density in postmenopausal Korean women

We investigated the relation between polymorphisms in the interleukin-1(IL-1) and IL-1 receptor antagonist (IL-1ra) gene, and bone mineral density (BMD) in postmenopausal Korean women. The IL-1alpha C(-889)T polymorphism, and IL-1beta C(-511)T polymorphism were examined by restriction fragment length polymorphism, and 86-bp variable number tandem repeat polymorphism in the IL-1ra gene was analyzed by the polymerase chain reaction and electrophoresis in 202 postmenopausal Korean women. Serum osteocalcin, and C-telopeptide of type I collagen were measured using a radioimmunoassay and enzyme-linked immunosorbent assay, respectively. BMD at the lumbar spine and proximal femur was measured by dual-energy X-ray absorptiometer. No significant differences in BMD or in serum bone markers levels were noted across the IL-1alpha or IL-1beta genotype. There were no significant differences in the distribution of IL-1alpha or IL-1beta genotype according to the status of bone mass. BMD in women carrying the A2 allele of the IL-1ra gene was significantly lower than those without this allele, and the A2 allele was more frequent in osteoporotic women than in normal women. These data suggest that IL-1ra gene VNTR polymorphism is a genetic factor that may affect BMD in Korean women.

Biochemical Bone Markers Are Useful to Monitor Fracture Repair

Biochemical bone markers reflect bone metabolism but little is known regarding their usefulness during fracture repair. Reduced bone mineral density may influence fracture healing. We hypothesized that low bone mineral density results in decreased levels of bone markers during the acute phase of fracture healing, especially in women who are postmenopausal. We also addressed the question of different fracture types and locations resulting in different levels of bone markers. Urinary levels of N-terminal cross-linked telopeptide, deoxypyridinoline, and pyridinoline were measured preoperatively and postoperatively in patients with hip fractures, distal forearm fractures, and in 25 control subjects. Bone mineral density was determined using quantitative computed tomography of the spine. Patients with low bone mineral density, especially women who were postmenopausal, had greater concentrations of N-terminal cross-linked telopeptide when compared with patients with normal bone mineral density or men. Patients with pertrochanteric fractures had greater concentrations than patients with femoral neck fractures, as did patients with hip fractures compared with patients with fractures of the distal forearm. These results suggest that levels of bone markers increase during fracture healing despite low bone mineral density and that different fracture types and locations result in different levels of bone markers. Prognostic study, Level I (high quality prospective study-all patients were enrolled at the same time with > or = 80% of followup of enrolled patients). See the Guidelines for Authors for a complete description of levels of evidence.

Amelioration of rat adjuvant‐induced arthritis by Met‐RANTES

CC chemokines and their receptors play a fundamental role in trafficking and activation of leukocytes at sites of inflammation, contributing to joint damage in rheumatoid arthritis. Met-RANTES, an amino-terminal-modified methionylated form of RANTES (CCL5), antagonizes the binding of the chemokines RANTES and macrophage inflammatory protein 1alpha (MIP-1alpha; CCL3) to their receptors CCR1 and CCR5, respectively. The aim of this study was to investigate whether Met-RANTES could ameliorate adjuvant-induced arthritis (AIA) in the rat. Using immunohistochemistry, enzyme-linked immunosorbent assay, real-time reverse transcription-polymerase chain reaction, Western blot analysis, adoptive transfer, and chemotaxis, we defined joint inflammation, bony destruction, neutrophil and macrophage migration, Met-RANTES binding affinity to rat receptors, proinflammatory cytokine and bone marker levels, CCR1 and CCR5 expression and activation, and macrophage homing into joints with AIA. Administration of Met-RANTES as a preventative reduced the severity of joint inflammation. Administration of Met-RANTES to ankles with AIA showed decreases in inflammation, radiographic soft tissue swelling, and bone erosion. Met-RANTES significantly reduced the number of neutrophils and macrophages at the peak of arthritis compared with saline-injected controls. Competitive chemotaxis in peripheral blood mononuclear cells demonstrated that Met-RANTES inhibited MIP-1alpha and MIP-1beta at 50% inhibition concentrations of 5 nM and 2 nM, respectively. Furthermore, levels of tumor necrosis factor alpha, interleukin-1beta, macrophage colony-stimulating factor, and RANKL were decreased in joints with AIA in the Met-RANTES group compared with the control group. Interestingly, the expression and activation of CCR1 and CCR5 in the joint were down-regulated in the Met-RANTES group compared with the control group. Functionally, Met-RANTES administration decreased adoptively transferred peritoneal macrophage homing into the joint. The data suggest that the targeting of Th1-associated chemokine receptors reduce joint inflammation, bone destruction, and cell recruitment into joints with AIA.

Interrelationships of serum estradiol, estrone, and estrone sulfate, adiposity, biochemical bone markers, and leptin in post-menopausal women

Objective The aim of this study was to examine the relationships between endogenous estrogens and adiposity, bone markers, and leptin in post-menopausal (PM) women. Design Seventy-three post-menopausal (PM) women participated in a clinical correlational study. Weight, height, waist–hip ratio, fasted morning serum and first morning voided urine samples were obtained to compare body mass index (BMI), waist–hip ratio, endogenous estrogens, leptin, and bone markers. Serum estradiol, estrone (E1), estrone sulfate (E1S), leptin, osteocalcin, and urinary deoxypyridinoline (Dpd) were determined. Results Significant positive relationships were found between BMI and estradiol, E1, and E1S ( r = 0.52, 0.38, and 0.29; P ≤ 0.001, 0.001, and 0.013 respectively). Significant relationships between leptin and estrogens were revealed, but were not significant when BMI was used as a covariate. Although many subjects revealed elevated bone marker levels, no correlation between estrogens or BMI and bone markers (Dpd and osteocalcin) was found. Conclusions There are significant positive correlations between estrogens and BMI in PM women. Increasing levels of estradiol, E1, and E1S with increasing BMI may be an indicator of adiposity, but are without effect as a stimulatory factor on leptin production. Waist–hip ratio did not significantly affect leptin concentrations when accounting for BMI. Due to assay sensitivity in the present study, data represent a more precise representation of these relationships. The lack of correlation between estrogens and bone marker levels may have been due to low estrogen levels in PM women.

Early effect of nasal salmon calcitonin on the bone marker Crosslaps

The aim of this study was to investigate the early effect of nasal salmon calcitonin on a bone-resorption marker, "Crosslaps", in postmenopausal osteoporotic women. In this randomized, single-blind and placebo-controlled study we included 78 postmenopausal women with osteoporosis, between 45 and 65 years of age, with at least 5 years duration of menopause. Patients were randomly divided into two groups, the treatment and the placebo groups. Patients in the treatment group were given 100 IU day(-1) nasal salmon calcitonin, 1,000 mg day(-1) elemental calcium, and 400 IU day(-1) vitamin D. Patients in the placebo group took only 1,000 mg day(-1) elemental calcium, and 400 IU day(-1) vitamin D. The outcome measurements were urinary deoxypyridinoline, serum alkaline phosphatase, osteocalcin, and Crosslaps. The treatment group consisted of 39 patients whose mean age was 60.4 +/- 6 years and the placebo group included 39 patients with a mean age of 60.5 +/- 4.9 years. There was no significant difference between two groups in terms of demographic characteristics. The results of bone marker measurements were analyzed statistically. Crosslaps levels in the treatment group were significantly lower (P < 0.05) than in the placebo group. Other bone marker levels at the end of the study were not significantly lower (P > 0.05) than those at baseline in both treatment and placebo groups, however. Salmon calcitonin affects bone turnover within a few months and bone-resorption markers such as Crosslaps can be used to monitor the effect of nasal salmon calcitonin in the early phase of treatment for postmenopausal osteoporosis.

The Effect of Increasing Zoledronic Acid Dose and Infusion Rate on Pharmacokinetics, Pharmacodynamics, and Renal Function in Patients with Multiple Myeloma.

Background: Zoledronic acid is a new-generation bisphosphonate with demonstrated efficacy and safety in the treatment of bone lesions in patients with multiple myeloma and solid tumors using a monthly regimen of 4 mg infused over 15 minutes. This phase I open-label study investigated the pharmacokinetics (PK), pharmacodynamics (PD), and safety of a monthly regimen of zoledronic acid, at doses of 4, 8, and 12 mg, using an infusion rates model predicted to yield a Cmax similar to that for 4 mg infused over 15 minutes.Methods: Patients received a total of 6 doses of zoledronic acid administered every 28 days: 4 mg via 15-minute infusion on day 1, 8 mg via 60-minute infusion on days 29 and 57, 12 mg via 120-minute infusion on days 85 and 113, and 4 mg via 15-minute infusion on day 141. Assessments of PK, PD (bone and tumor marker levels), and safety (biochemistry, hematology, and renal function) were completed after each dose.Results: A total of 10 patients (6 male, 4 female) with multiple myeloma were enrolled and 7 completed the 6-month study (1 patient withdrew consent, 2 patients had abnormal lab values). Median age was 57.5 years (range, 42 to 75 years). ECOG performance status was 0 or 1 in 9 patients and 2 in 1 patient. Eight of 10 patients had received prior antineoplastic therapy and all patients had received prior radiation and surgery. Zoledronic acid was generally well tolerated; the most commonly reported adverse events involved the known acute-phase reactions, namely fatigue (60%), myalgia (50%), and arthralgia/nausea/bone pain (40% each), associated with IV bisphosphonates. Transient serum creatinine elevations from baseline were observed in 3 patients and resulted in either dose delay/decrease (n = 1) or discontinuation after Infusion 5 (n = 2). A single serious adverse event was reported in 1 patient (secondary malignancy to the left lung). Clinically significant (grade 3/4) nonrenal-related adverse events occurred in 5 patients. No patient discontinued due to clinically significant adverse events nor died while on study. Mean Cmax (± SD) was 329 (± 84) mg/L after the first 4-mg dose (Infusion 1), 407 (± 99) mg/L after the second 8-mg dose (Infusion 3), and 411 (± 75) mg/L after the second 12-mg dose (Infusion 5). These values were nearly identical to the model-extrapolated values. Mean observed AUC0–6h (± SD) was 403 (± 135), 877 (± 177), and 1,233 (± 259) after Infusions 1, 3, and 5, respectively. Mean modeled AUC0–24h (± SD) was 603 (± 189), 1,489 (± 451), and 1,662 (± 325) for the same infusion schedule. Decreases from baseline were observed in serum markers of bone metabolism (CTX, NTX, and osteocalcin) after zoledronic acid treatment. There were no relevant changes from baseline in serum interleukin-6, quantitative immunoglobulins, C-reactive protein, or albumin.Conclusions: Zoledronic acid was safe and well tolerated when infused at doses of 8 and 12 mg over 60 and 120 minutes, respectively, and the model-predicted Cmax of zoledronic acid was achieved in patients with multiple myeloma at all doses and infusion rates tested. This study provides a rationale for investigating doses ≥ 4 mg infused over > 15 minutes in a broader clinical trial. Updated analyses will be presented.

Physical training and hormone replacement therapy reduce the decrease in bone mineral density in perimenopausal women: a pilot study

The effects of physical training and hormone replacement therapy (HRT) on bone mineral density in perimenopausal women were studied. Sixty perimenopausal women were randomized to either physical training (n = 20), HRT (n = 20), or control group (n = 20). The study period was 18 months. Bone mineral density (BMD) in the femoral neck and lumbar spine was measured using dual-energy X-ray absorptiometry (DXA). DXA was performed before treatment and after 6 and 18 months. Blood samples for analysis of the bone markers U-deoxypyridinoline and osteocalcin were collected at the same time points. After 18 months, BMD in the spine had not decreased in either the training group or in the HRT group. In the control group, spine BMD had significantly decreased (p = 0.0014). U-Deoxypyridinoline and osteocalcin were increased significantly in the control group (p = 0.0198, p = 0.0295, respectively). No significant changes in bone marker levels were found in the training group or the HRT group. We found that both HRT and physical training can prevent loss of spine BMD in perimenopausal women over a period of 18 months. HRT remains a cornerstone in the treatment of vasomotor symptoms and preservation of BMD. However, HRT can only be used for limited periods of time due to the potential serious adverse effects. This study indicates a beneficial effect of physical activity on spine BMD in the perimenopausal period, and highlights its potential as an alternative to HRT during this period.

Additive protective effects of estrogen and androgen treatment on trabecular bone in ovariectomized rats.

Both ER and AR activation regulates trabecular bone mass. We show that combined estrogen and androgen treatment results in additive protection of trabecular bone in OVX rats. This may in part be attributable to the effect of AR activation to attenuate the inhibitory effect of ER activation on bone formation. Sex steroids are important regulators of trabecular bone mass. Both estrogen receptor (ER) and androgen receptor (AR) activation results in increased trabecular bone mass. The aim of this study was to investigate if combined estrogen and androgen treatment might be beneficial in the treatment of trabecular bone loss. Twelve-week-old female rats were ovariectomized (OVX) and treated with vehicle (V), 17beta-estradiol (E2; ER activation), dihydrotestosterone (DHT; AR activation), or the combination (E2 + DHT) for 6 weeks. The skeletal phenotype was analyzed by pQCT, microCT, histomorphometry of growth plates, and serum levels of biochemical bone markers. Both E2 (+121% over V) and DHT (+34%) preserved the trabecular volumetric BMD (tvBMD) in OVX rats. The effect of E2 and DHT on tvBMD was additive, resulting in a 182% increase over V in the rats given E2 + DHT. MicroCT analyses of the trabecular bone microstructure revealed that the effect of E2 and DHT was additive on the number of trabeculae. E2 treatment reduced serum markers of both bone resorption (collagen C-terminal telopeptide) and bone formation (osteocalcin), indicating reduced bone turnover. Addition of DHT to E2 treatment did not modulate the effects of E2 on the marker of bone resorption, whereas it attenuated the inhibitory effect of E2 on the bone formation marker, which might explain the additive protective effect of E2 and DHT on trabecular bone mass. In contrast, DHT partially counteracted the suppressive effect of E2 on longitudinal bone growth and the E2-induced alterations in growth plate morphology. These findings show that combined estrogen and androgen treatment results in additive protective effects on trabecular bone in OVX rats. Our data suggest that a combined treatment with selective ER and AR modulators might be beneficial in the treatment of osteoporosis.

Molecularly defined lactose malabsorption, peak bone mass and bone turnover rate in young finnish men.

Lactose malabsorption (LM; adult-type hypolactasia), an autosomal recessive condition, results from the down-regulation of the activity of lactase enzyme in the intestinal wall. In previous studies the effect of LM on bone mass, bone turnover rate, development of osteoporosis and osteoporotic fractures has remained controversial. We have recently identified a single nucleotide polymorphism (SNP), a C to T change residing 13910 base pairs upstream of the lactase (LCT) gene at chromosome 2q21-22, which shows complete association with lactase persistence, with the C/C-13910 genotype defining LM and the genotypes C/T-13910 and T/T-13910 lactase persistence. The present study was undertaken to examine the relationship of the C/T-13910 polymorphism to peak bone mass, bone turnover rate, and stress fractures among young Finnish men. The study population comprised 234 young men, aged 18.3 to 20.6 years, 184 men were recruits of the Finnish Army, and 50 were men of similar age who had postponed their military service for reasons not related to health. Bone mineral content (BMC), density (BMD), and scan area were measured in the lumbar spine and upper femur by dual-energy X-ray absorptiometry (DXA). Blood was sampled for genotyping of the C/T-13910 polymorphism and determination of serum 25-hydroxyvitamin D (25OHD), intact parathyroid hormone (iPTH), type I procollagen aminoterminal propeptide (PINP), and tartrate-resistant acid phosphatase 5b (TRACP5b). Second-void urine samples were collected for the determination of type I collagen aminoterminal telopeptide (NTX). The prevalence of the C/C-13910-genotype of these young adults did not differ significantly from the corresponding population prevalence of C/C-13910 (17.1% vs 18.1%) among Finnish blood donors. Fifteen recruits of the army experienced a stress fracture; 3 of them (20%) had the C/C-13910-genotype. Calcium intake was similar for the three genotypes as were the unadjusted BMCs, scan areas, and BMDs at different measurement sites. The adjustments for age, height, weight, smoking, alcohol consumption, and physical exercise in the multiple regression analysis did not reveal any significant relationships between the lactase genotypes and BMDs at lumbar (P = 0.16), femoral neck (P = 0.99) or total hip (P = 0.96) sites. Serum 25OHD, iPTH, and bone marker levels were similar for the C/C-13910 C/T-13910 and T/T-13910 genotypes. In summary, in young Finnish men, molecularly defined lactose malabsorption does not alter bone turnover rate and impair the acquisition of peak bone mass. Moreover, the C/C-13910 genotype does not seem to be a risk factor for stress fractures in army recruits.

Assessment of the role of 17beta-oestradiol in bone metabolism in men: does the assay technique matter? The MINOS study.

17Beta-oestradiol (17beta-E2), mainly its bioavailable fraction (bio-17beta-E2), is a determinant of bone mineral density (BMD) and bone remodelling in men. As direct measurement of bio-17beta-E2 is time-consuming, we compared the value of directly measured bio-17beta-E2 and of calculated bio-17beta-E2 and free 17beta-E2 by studying their association with BMD and markers of bone turnover in a cohort of men (MINOS). A cross-sectional study in which the association between BMD and bone markers, on the one hand, and serum levels of 17beta-E2, on the other, was analysed according to the levels of measured and calculated bio-17beta-E2 and free 17beta-E2 in a cohort of men. Men from the MINOS cohort including 87 men aged 19-45 to establish the reference control normal range of hormones and 637 men aged 50-85 (studied group). Total 17beta-E2, testosterone, SHBG and albumin were measured by standard methods. bio-17beta-E2 was directly measured after the precipitation of SHBG by ammonium sulfate. bio-17beta-E2 and free 17beta-E2 were calculated using serum SHBG and albumin levels as described by Sodegard et al. (J. Steroid Biochem., 16 (1982) 801). Calculated bio-17beta-E2 and free 17beta-E2 were correlated with measured bio-17beta-E2 and between themselves (r = 0.90-1.00, P < 0.0001). Calculated bio-17beta-E2 and free 17beta-E2 disclosed a similar association with BMD (difference between lowest and highest quartiles of 17beta-E2: 2.6-6.8%, P < 0.05-0.005) to that of measured bio-17beta-E2 (3.6-6.1%, P < 0.005-0.001). The association between bone markers levels and measured vs. calculated 17beta-E2 were also similar. Predictive accuracy for lowered BMD and elevated levels of biochemical bone markers (evaluated using receiver operating characteristics) was relatively low (area under curve -0.582 to 0.709) but similar for different forms of bioavailable and free 17beta-E2. In elderly men, the concentrations of bioavailable and free 17beta-E2, calculated using equations including either the measured albumin concentration or the constant albumin concentration of 43 g/l, can be used, at least in clinical studies, instead of the bio-17beta-E2 concentrations measured after ammonium sulfate precipitation.

Elite volunteer athletes of different sport disciplines may have elevated baseline GH levels divorced from unaltered levels of both IGF-I and GH-dependent bone and collagen markers: a study on-the-field.

Seventy-seven Italian eliteathletes(42 M, 35 F, mean age +/- SE: 24.4-0.7 yr, age range: 17-47 yr) of different sport disciplines (sprinters, triathletes, middle-distance runners, road-walkers, cyclists, rowing athletes, skiers, roller hockey players, swimmers) were sampled on-the-field (before a training session) for the determination of basal GH, IGF-I, C-terminal cross-linked telopeptide of type I collagen (ICTP) and amino-terminal propeptide of type III procollagen (PIIINP) levels, two GH-dependent peripheral markers of bone and collagen turnover, respectively. Basal GH concentrations were significantly higher (p<0.001) in female (5.8 +/- 1.0 ng/ml) vs male athletes (1.8 +/- 0.5 ng/ml), with a large spread of values in either gender. Mean GH levels of athletes were significantly higher than those recorded in age-matched sedentary controls (females: 2.5 +/- 0.5 ng/ml, p<0.001; males: 0.5 +/- 0.2 ng/ml, p<0.05). Among female athletes, 7/35 had basal GH values higher than the upper limit of control values (>9.5 ng/ml), while among males 7/42 had values higher than the upper limit of male sedentary controls (>3.6 ng/ml). No significant differences in basal GH concentrations were found between females taking oral contraceptives (OC) and those who did not receive this treatment (5.0 +/- 2.1 vs 6.0 +/- 1.2 ng/ml). IGF-I levels (236.4 +/- 7.8 ng/ml) were in the normal range for age in all athletes (except for 1 athlete with slightly increased levels), no significant correlation being found between GH and IGF-I levels (R2=0.0393). Mean ICTP (4.6 +/- 0.2 ng/ml) and PIIINP (4.4-0.1 ng/ml) concentrations of elite athletes were not significantly different from those recorded in age and matched healthy sedentary subjects; 4 athletes showed increased PIIINP levels and 2 had increased ICTP levels. ICTP and PIIINP levels were positively correlated with chronological age (p<0.001), a positive correlation being also found between the two markers (p<0.001). On the contrary, no significant correlation was found between basal GH/IGF-I levels and ICTP/PIIINP levels. In conclusion, the present study demonstrates that: 1) elite athletes (particularly females), which have frequently increased basal GH on-the-field, have actually normal IGF-I levels; 2) ICTP and PIIINP levels of athletes are similar to those recorded in healthy sedentary, being significantly higher in younger subjects of both groups; 3) the presence of increased basal GH levels, being associated with normal IGF-I, ICTP and PIIINP levels, is probably the result of a transient GH peak in this study group. Further additional studies are requested to verify the possible use of these peripheral GH-dependent markers for detecting exogenous chronic administration of recombinant GH in athletes.

Ability of myeloma cells to secrete macrophage inflammatory protein (MIP)-1alpha and MIP-1beta correlates with lytic bone lesions in patients with multiple myeloma.

Macrophage inflammatory protein (MIP)-1alpha and MIP-1beta have been identified as candidates for multiple myeloma (MM)-derived bone-resorbing factors. To validate the clinical relevance of these observations, we investigated correlations between the ability of MM cells to secrete these chemokines and the extent of MM bone lesions as well as levels of biochemical bone markers in patients with MM. Patients with multiple bone lesions exhibited higher MIP-1alpha and MIP-1beta secretion from MM cells along with elevated urinary deoxypyridinoline (Dpd), without significant elevation of serum bone-specific alkaline phosphatase (BALP) or osteocalcin compared with those with minimal bone lesions. MIP-1alpha and MIP-1beta levels correlated positively with urinary Dpd and serum BALP but not with serum osteocalcin. These results provide further evidence for a causal role of MIP-1alpha and MIP-1beta in the development of lytic bone lesions, and suggest that MM cells suppress osteoblastic bone formation to cause an imbalance of bone turnover and development of destructive bone lesions.

Bone turnover markers and bone strength during the first weeks of life in very low birth weight premature infants.

To determine the association between changes in bone turnover markers and bone strength of very low birth weight infants during the first eight postnatal weeks. Twelve very low birth weight premature infants [mean gestational age: 28.4 +/- 0.6 weeks, mean birth weight: 1131 +/- 62 grams] participated in the study. Bone strength was evaluated weekly by quantitative ultrasound measurements of tibial bone speed of sound (SOS, Sunlight Omnisense). Bone specific alkaline phosphatase (BSAP), a marker of bone formation, and carboxy terminal cross-links telopeptide of type-I collagen (ICTP), a marker of bone resorption, were collected at the ages of one, four and eight weeks. BSAP increased significantly (from 119.9 +/- 16.2 U/L to 132.1 +/- 11.9 U/L and 152.1 +/- 15.7 U/L at one, four and eight weeks of life, respectively, p<0.05). ICTP decreased significantly during the study period (from 122.3 +/- 8.7 ng/ml to 96.0 +/- 4.8 ng/ml and 92.3 +/- 5.4 ng/ml at one, four and eight weeks of life, respectively; p<0.05). There was a significant decrease in bone SOS (from 2886 +/- 29 m/sec to 2792 +/- 30 m/sec and 2753 +/- 30 m/sec at birth, four weeks and eight weeks of life, respectively; p<0.02). There was no correlation between the levels of bone markers and bone SOS. In VLBW premature infants, there is a significant decrease in bone strength concomitant with biochemical evidence for new bone formation (increase in BSAP and a decrease in ICTP) during the first eight postnatal weeks. Changes in the biochemical markers could not predict the changes in bone strength.

Effects of treadmill exercise on bone mass, bone metabolism, and calciotropic hormones in young growing rats.

The aim of the present study was to examine the effects of exercise on bone mass, bone metabolism, and calciotropic hormones in young growing rats. Twenty 6-week-old female Wistar rats were randomized into the following four groups with 5 animals each: 7 weeks of exercise, 7 weeks of sedentary control, 11 weeks of exercise, and 11 weeks of sedentary control. The exercise regimen consisted of running on a treadmill at 25 m/min for 1 h each day on 5 days a week. After each period of exercise, the bone mineral content (BMC) of the tibia and fifth lumbar spine was measured by dual-energy X-ray absorptiometry, using a Lunar DPX-L instrument. The femoral length and levels of bone markers and calciotropic hormones were also assessed. Seven and 11 weeks of exercise increased the serum osteocalcin and 1,25-dihydroxyvitamin D(3) levels, and decreased the serum parathyroid level. Seven weeks of exercise decreased the urinary deoxypyridinoline level, and 11 weeks of exercise increased the serum alkaline phosphatase level and decreased the serum tartrate-resistant acid phosphatase level. As a result, 7 and 11 weeks of exercise increased the femoral length and tibial BMC, but did not alter the lumbar BMC. The present study demonstrates that treadmill exercise stimulates bone formation and suppresses bone resorption, increases the serum 1,25-dihydroxyvitamin D(3) level, and decreases the serum parathyroid hormone level, resulting in an increase in bone mass with stimulation of longitudinal bone growth, especially at weight-bearing sites, in young growing rats. Further studies with long-term exercise may be needed to obtain a positive effect on the lumbar BMC.

Association between vitamin D receptor gene haplotypes and bone mass in postmenopausal Korean women

Objectives The objective of the study was to evaluate the effect of vitamin D receptor (VDR) gene haplotypes on bone mineral density (BMD). Study design The VDR Bsm I, Apa I, Taq I, and poly(A) polymorphisms were analyzed in 417 postmenopausal Korean women. Serum 1,25(OH) 2 vitamin D 3, osteocalcin, bone alkaline phosphatase, and CrossLaps were measured by immunoradiometric assay and enzyme-linked immunosorbent assay. BMD at the lumbar spine and proximal femur was determined by dual-energy x-ray absorptiometry. Results At all skeletal sites, genotypes not carrying the baTL haplotype allele (uppercase letters signifying the absence, lowercase letters the presence, of the restriction site, and L a repeat length of more than 17) had significantly lower BMD than baTL homozygotes. The former genotypes were more prevalent in women with low bone mass than in healthy women. No significant differences in vitamin D 3 or bone markers levels were noted among the baTL haplotype genotypes. Conclusion The VDR baTL haplotype allele is related to bone mass in Korean women.

Long-term variability of markers of bone turnover in postmenopausal women and implications for their clinical use: the OFELY study.

Bone marker variability has raised concern for its use in individual patients. Serum osteocalcin (formation) and CTX (resorption) were measured every year for 4 years in 268 postmenopausal women. Seventy percent to 80% of women classified as having high bone turnover at baseline were similarly classified by the same methods 4 years later. High bone marker levels are a risk factor for osteoporosis in postmenopausal women, but variability of measurements has raised doubts about their clinical use in an individual patient. We studied 268 untreated postmenopausal women (50-81 years of age) belonging to a population-based prospective cohort. We collected fasting morning blood samples every year for 4 years to measure serum intact osteocalcin (OC) and serum C-terminal cross-linked telopeptide of type I collagen (CTX) as bone formation and resorption markers, respectively. Serum OC and CTX remained stable during follow-up (+ 1.2%/year, p = 0.003 and -0.13%/year, p = 0.70 for OC and S-CTX, respectively). At baseline, women were classified as having low (tertile 1), intermediate (tertile 2), or high (tertile 3) bone turnover. Agreement of classification between baseline and 4-year measurements was moderate (kappa [95% CI]: 0.51 [0.43-0.59] and 0.52 [0.44-0.60] for OC and S-CTX, respectively). Less than 10% of women in tertile 1 or 3 of either marker at baseline were found in the opposite tertile 4 years later. When the two markers were combined, only 2% of women at high turnover at baseline--defined as OC and/or S-CTX in tertile 3--were classified at low turnover 4 years later. Among women classified at high bone turnover at baseline (tertile 3), 70-80% were also found at high turnover 4 years later. Among women in tertile 2, only 51% and 43% for OC and CTX, respectively, remained in the same tertile at the second measurement. Serum levels of bone formation and resorption markers are stable over 4 years in postmenopausal women, on average. The majority of women classified as having high bone turnover were similarly classified by the same methods 4 years later. However, 20-30% of these women at risk for fracture would be incorrectly classified, suggesting that further investigation would be required to reduce the number of patients who would be treated unnecessarily if the decision was made on bone marker measurement. For women with intermediate levels, classification may be improved by a second measurement or by combining two markers.

Percutaneous maxacalcitol injection therapy regresses hyperplasia of parathyroid and induces apoptosis in uremia

A high level of parathyroid hormone (PTH) is considered to be an indicator of poor prognosis and a poor quality of life of dialysis patients; therefore, an effective and safe therapy for secondary hyperparathyroidism (SHPT) has been developed. In 20 patients with SHPT resistant to maxacalcitol (OCT) intravenously administered, all detectably enlarged parathyroid glands were treated by percutaneous maxacalcitol injection therapy (PMIT) under ultrasonographic guidance consecutively 6 times, which was followed by OCT that was intravenously administered. The clinical effects of PMIT were evaluated based on the changes in the serum intact-PTH, adjusted Ca, phosphorus, and bone marker levels, and the parathyroid gland volume determined by ultrasonography. Morphologic examination, apoptosis analysis, and PTH mRNA expression level determination by reverse transcription-polymerase chain reaction (RT-PCR) using parathyroid tissues obtained by a biopsy technique were performed. PMIT and subsequent intravenous OCT administrations significantly decreased the serum intact-PTH level and parathyroid gland volume for at least 12 weeks after PMIT without major complications. Parathyroid tissues obtained after PMIT exhibited some partial defects of parathyroid cells, a marked increase in the number of the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL)-positive cells, the ladder formation determined by DNA electrophoresis, and the decrease in the PTH mRNA expression level. PMIT is effective and safe for the treatment of refractory SHPT, and a locally high level of OCT suppresses PTH secretion and regresses parathyroid hyperplasia, which is involved in the induction of apoptosis of parathyroid cells.

Do markers of bone metabolism reflect the presence of a high- or low-turnover state of bone metabolism?

A pathophysiological concept of osteoporosis therapy - antiresorptive treatment of high-turnover osteoporosis (e. g. bisphosphonates, raloxifen) and osteoanabolic treatment of low-turnover osteoporosis (e. g. parathyroid hormone) - is clinically and economically reasonable to enable physicians to decide who will benefit most from which drug. Biochemical bone markers in serum and urine are frequently used for the diagnosis of high- or low-turnover osteoporosis. We investigated whether bone marker levels reflect the histologically diagnosed high- or low-turnover state of osteoporosis. 175 bone biopsies of male and female osteoporotic patients (WHO criteria) were histologically classified in high- and low-turnover osteoporosis and associated with bone marker levels in serum and urine. Patients with any osteotropic therapy and with fractures were excluded. There were no significant differences between patients with high- and low-turnover osteoporosis with regards to osteocalcin, DPD crosslinks, alkaline phosphatase, 25-OH vitamin D(3), parathyroid hormone and bone mass (spine and hip). Single measurements of biochemical bone markers in serum and urine do not allow a valid differentiation between histologically diagnosed high- and low-turnover states of osteoporosis. The therapeutic concept of treating with osteoanabolic drugs requires valid diagnostic criteria for the differentiation between high- and low-turnover state of bone metabolism which can be provided by a bone biopsy but not by single measurements of bone markers.