Urinary NTX Research Articles

Ghrelin and Bone: Is There an Association in Older Adults?: The Rancho Bernardo Study

Laboratory studies suggest that ghrelin is involved in bone metabolism, but studies of ghrelin and bone in humans are limited. We studied sex-specific associations of ghrelin with BMD, NTX, and bone loss. Ghrelin was not associated with BMD or bone loss in either sex. There was a significant inverse association with NTX in men but not in women. Ghrelin is a gastric hormone recently shown to be associated with bone metabolism in animal and in vitro studies. Studies in humans are limited. We investigated the association of ghrelin with BMD, the bone resorption marker N-telopeptide (NTX), and bone loss in older men and women. Participants were 977 community-dwelling men and non-estrogen-using postmenopausal women, 50-91 years of age. Plasma ghrelin was measured by radioimmunoassay from blood obtained between 1984 and 1987. Between 1988 and 1991, BMD was measured at the midshaft radius by single photon absorptiometry and at the femoral neck, total hip, and lumbar spine by DXA. Axial BMD measurements were repeated an average of 4 years later in 544 participants. Bone turnover was assessed by NTX in urine obtained at the same time as the initial BMD. Multiple regression analyses were used to test sex-specific associations of ghrelin with BMD, NTX, and bone loss in both sexes. No significant ghrelin-BMD or ghrelin-bone loss associations were observed in either sex, after adjusting for age and body mass index (BMI). Ghrelin was inversely associated with NTX in men and positively associated with NTX in women, independent of age. After adjusting for both age and BMI, this association reached statistical significance in men and was weakened in women. Ghrelin may be associated with bone turnover, but there is no evidence for an association with BMD or short-term change in BMD in older adults.

Calcium Supplementation Increases Bone Mass in GH-Deficient Prepubertal Children during GH Replacement

Background/aims: Since GH plays an important role in bone mineralization, and several studies demonstrated the positive influence of a higher calcium intake on bone mass, we studied the effect of calcium supplementation in GHD children during GH therapy. Methods: 28 prepubertal GHD children, 5.0–9.9 years old, were assigned to two groups: group A (n = 14; 7 females) treated with GH, and group B (n = 14; 7 females) treated with GH + calcium gluconolactate and carbonate (1 g calcium/day per os). Auxological parameters, total bone mineral content (TBMC) and density (TBMD), leg BMC and BMD, lumbar BMD, fat mass (FM) and lean tissue mass (LTM), blood 25-hydroxyvitamin D (25-OHD), parathyroid hormone (PTH), osteocalcin (OC) and urinary N-terminal telopeptide of type I collagen (NTx) were determined at the start of therapy and after 1 and 2 years of treatment. Results: During the 2 years of the study, TBMC, TBMD, leg BMC and BMD (but not lumbar BMD) increased in both groups of patients, however after 2 years of treatment they were significantly higher in the calcium-supplemented group B than in group A (p < 0.05, for all parameters). At the start of therapy, in both groups of patients percentage FM was higher and total and leg LTM lower than in controls (p < 0.05 for each parameter). Thereafter, FM decreased and LTM increased and after 2 years they were both different from baseline (p < 0.05). After 2 years of treatment, leg BMC and BMD were more positively correlated with regional leg LTM in patients of group B (r = 0.834 and r = 0.827, respectively; p < 0.001) than in patients of group A (r = 0.617 and r = 0.637, respectively; p < 0.05). 25-OHD and PTH levels were in the normal range in all patients at the start and during treatment. OC levels were lower and urinary NTx levels higher in patients than in controls (p < 0.05 for both parameters), either at the start and after 1 year of treatment. After 2 years of treatment, OC levels were significantly higher than at the start of the study (p < 0.05) in both groups of patients, but they were higher in group B than in group A (p < 0.05); on the contrary, urinary Ntx levels were lower in group B than in group A (p < 0.05). Conclusion: In GHD children, treated with GH, calcium supplementation improved bone mass; it may aid in reaching better peak bone mass and in protecting weight-bearing bones, usually completed in childhood to maximum levels, from risk of osteoporosis and fractures later in life.

RETRACTED ARTICLE: Comparison of the effect of alendronate on lumbar bone mineral density and bone turnover in men and postmenopausal women with osteoporosis

The purpose of the present study was to compare the effect of alendronate treatment on lumbar bone mineral density (BMD) and bone turnover in men and postmenopausal women with osteoporosis. Sixty men with primary or secondary osteoporosis and 318 women with postmenopausal osteoporosis were treated with alendronate. The primary end points were lumbar BMD and urinary cross-linked N-terminal telopeptides of type I collagen (NTX) and serum alkaline phosphatase (ALP) levels. The secondary end point was the incidence of vertebral and nonvertebral fractures. Forty-seven (78.3%) men and 254 (79.9%) women who could complete the 12-month trial were analyzed. The mean ages of men and postmenopausal women were 69.1 and 70.4 years, respectively. Both men and postmenopausal women showed higher levels of urinary NTX as compared with normal range of premenopausal women. Alendronate treatment decreased urinary NTX level by 39.2% in men and 45.4% in postmenopausal women at 3 months and serum ALP level by 17.8 and 21.0%, respectively, at 12 months. Following reduction in bone turnover markers, lumbar BMD increased 5.8 and 7.6% in men and postmenopausal women, respectively, at 12 months. Reduction in urinary NTX level and increase in lumbar BMD were smaller in men than in postmenopausal women. The incidence of vertebral and nonvertebral fractures was 10.6 and 8.5%, respectively, in men and 8.3 and 7.5%, respectively, in postmenopausal women, with no significant difference in these incidences between them. These results suggested that alendronate treatment effectively increased lumbar BMD from baseline in men with primary or secondary osteoporosis following reduction in bone turnover, although its efficacy did not appear to be greater than in postmenopausal women with osteoporosis.

Effects of acid base balance on bone metabolism in bed rest subjects as an analog for space flight

As mission durations increase, the long-term effects of weightlessness on the deterioration of the skeleton are inevitable, and countermeasures must be developed. Previous studies show that diet and acid-base balance can affect bone loss during simulated weightlessness (bed rest)(AJCN, 80:1058). The present study was to evaluate effects of acid-base balance on bone after 60–90 days of −6° head-down tilt bed rest. A total of 11 subjects participated (8 M, 3 F; age 26–55 y) in the study. Blood and urine were collected twice before and once per month of bed rest. Urine samples were analyzed for n-telopeptide (NTX), pyridinium crosslinks (PYD), deoxypridinoline (DPD), sulfate, and pH. Data were analyzed using repeated measures ANOVA and Pearson correlation coefficients determined. Similar to space flight, markers of bone resorption increased during bed rest. Significant correlations were recorded between urinary sulfate and NTX (r=0.72), PYD (r=0.78), DPD (r=0.72) (p<0.01 for all). Urine pH (both 2nd void and 24 hr pool) was negatively correlated with the percent change in NTX from pre-bed rest (p<0.01). These data suggest that factors such as diet, urinary pH, and sulfur metabolism are related to bone metabolism during bed rest. The effects of acid-base balance on bone metabolism during bed rest may have significant implications for bone health in space flight and on Earth. This project was supported by the NASA Flight Analogs/Bed Rest Research Project.

Risk factors for vertebral fracture in menopausal or postmenopausal Japanese women with rheumatoid arthritis: a cross-sectional and longitudinal study

The occurrence of vertebral fracture was examined cross-sectionally and longitudinally over a 4-year interval in 117 menopausal and postmenopausal Japanese women with rheumatoid arthritis (RA), whose ages ranged from 50 to 64 years. Patients treated with bisphosphonate were excluded. Vertebral fracture was diagnosed by lateral thoracic and lumbar spine radiography at the start and end of a 4-year period. Bone mineral density (BMD) at L2-L4 according to dual-energy X-ray absorptiometry (DXA), the administration of corticosteroids or methotrexate, and urinary excretion of N-telopeptide of type I collagen (NTx) were also recorded. In the cross-sectional study, the prevalence of vertebral fracture in the initial radiographs of RA patients was 21%, while it was 5% in healthy age-matched controls. Among RA patients treated with corticosteroids, 33% had vertebral fracture, which was a significantly higher prevalence than that in RA patients without steroid administration. In the longitudinal study, vertebral fracture prevalence was also increased in patients more than 60 years old. RA patients having steroid treatment and a BMD/YAM (young adult mean) ratio below 70% had higher risk of vertebral fracture than patients with a BMD/YAM ratio of 70%-80%, which in turn exceeded the risk with a BMD of 80% or more. No adverse effect of low-dose methotrexate on vertebral fracture was found. Urinary NTx was high in RA patients, as reported previously, and did not differ between patients with or without new fracture after 4 years. In conclusion, Japanese RA patients more than 60 years old who were treated with corticosteroid or had a BMD below 80% had high risk of vertebral fracture.

First‐line therapy with thalidomide, dexamethasone and zoledronic acid decreases bone resorption markers in patients with multiple myeloma

Bone involvement is frequently observed in multiple myeloma (MM) patients both at diagnosis and during the course of the disease. The evaluation of biochemical markers of bone turnover could allow a dynamic evaluation of the effects of a given therapy on bone metabolism. In the present study, markers of bone resorption [urinary free pyridinoline (PYD), deoxypyridinoline (DPYD), N-terminal telopeptide of collagen I (NTX) and C-terminal telopeptide (serum crosslaps)] and of bone formation [bone alkaline phosphatase (BAP) and osteocalcin] were evaluated at diagnosis and after induction therapy in 40 patients (23M, 17F, median age = 53.5 yr) enrolled in the 'Bologna 2002' clinical trial. By study design, all patients received 4 months of combined thalidomide (100 mg/d for 2 wk then 200 mg/d), dexamethasone (40 mg/d on days 1-4, 9-12, 17-20/28 on odd cycles and on days 1-4 on even cycles) and zoledronic acid (4 mg/28 d). At diagnosis, although bone resorption markers were increased in more than 40% of the patients, only NTX (P = 0.029) and crosslaps (P = 0.000) were significantly related to the extent of skeletal lesions, as assessed by X-ray. After 4 months of therapy, a significant decrease in mean (+/-SE) urinary NTX (52.7 +/-6.9 nmol/mmol creatinine +/-6.9 vs. 14 +/- 1.42 nmol/mmol creatinine, P = 0.000) and serum crosslaps (6242.4 +/-945 pmol/L vs. 1414.9 +/- 173.8 pmol/L, P = 0.000) was observed in patients obtaining > or =partial response, at variance to what has been detected in patients showing <partial response. Among all bone resorption markers, urinary NTX and serum crosslaps seem to be strictly related to the extent of bone involvement in MM. Combined thalidomide + dexamethasone and zoledronic acid seem to be highly effective in reducing bone resorption in sensitive patients, although the relative contribution of each drug cannot yet be determined.

Positive effect of alendronate on bone mineral density and markers of bone turnover in patients with rheumatoid arthritis on chronic treatment with low-dose prednisone: a randomized, double-blind, placebo-controlled trial

Alendronate has been described to have a bone-sparing effect in patients treated with moderate and high dosages of prednisone for heterogeneous diseases, however no data are available on groups of patients with the same underlying diseases who receive chronic low-dose prednisone treatment. The objective of the investigation reported here was, therefore, to study the effect of alendronate on bone mineral density (BMD) of the lumbar spine and hips in patients with rheumatoid arthritis (RA) who are on chronic low-dose prednisone treatment. A total of 163 patients with RA, according to the ACR-criteria, were enrolled in a double-blind, placebo-controlled trial. The patients were treated with low-dose prednisone (<or=10 mg/day) for at least 3 months. The patients were randomized to receive daily doses of alendronate or placebo: men and premenopausal women received 5 mg alendronate (or placebo) daily; postmenopausal women received 10 mg alendronate (or placebo) daily. All patients received daily calcium (500 mg, or 1000 mg, depending on baseline dietary calcium intake) and vitamin D3 (400 IU) supplementation. BMD of the lumbar spine (L1-L4) and the (total) hip was measured at baseline and after 6 and 12 months. The primary endpoint was change in BMD of the lumbar spine after 12 months (ITT). At baseline and after 3 and 12 months, serum bone-specific alkaline phosphatase (BAP) and urinary excretion of N-telopeptide (NTX) were measured. Radiographs of the thoracic and lumbar spine were made at baseline and after 12 months and subsequently scored for vertebral deformities. The groups were comparable at baseline in age, gender, daily dosage of prednisone, BMD at the spine and the hip and markers of bone turnover, while the number of patients with prevalent vertebral deformities was slightly higher in the alendronate-treated patients (54% versus 39%, not significant). After 12 months, BMD at the lumbar spine had increased by 3.7% in the alendronate-treated patients and decreased by -1.0% in the placebo-treated patients (p<0.0001); at the hip, the changes were +1.0% and -0.1%, respectively (not significant). After 3 months, serum BAP had decreased by 16.9% in the alendronate group versus 3.3% in the placebo group (p=0.0005), while urinary NTX had decreased by 46.4% in the alendronate group versus 12.1% in the placebo group (p<0.0001). After 12 months, no statistically significant difference was found between the groups with respect to number of patients with incident vertebral or non-vertebral fractures. Adverse effects were relatively common in these patients with severe RA: adverse effects were observed in 68% of the alendronate-treated patients and in 73% of the placebo patients (not significant), while serious adverse events were observed in 13% and 17%, respectively (not significant). We observed a favourable effect of alendronate on the BMD of the lumbar spine and on the markers of bone turnover in patients with RA treated with low-dose prednisone. These data support the conclusion that the prescribing of alendronate is not only beneficial in patients treated with high-dose prednisone but also in RA patients chronically treated with low-dose prednisone.

Urinary NTX results rarely alter the clinical management of patients with osteoporosis in the tertiary hospital

Urinary levels of cross-linked N-terminal telopeptide of type I collagen (NTX) are used as a marker of bone resorption and are useful for monitoring response of patients treated with anti-resorptive agents. We aimed to determine how urinary NTX results alter clinical decision making by physicians treating patients with osteoporosis in a tertiary hospital setting. We reviewed patient notes of all new NTX requests in 2002 and 2003 with at least one subsequent repeat measurement. Patients with a diagnosis of osteoporosis and both pre- and post-treatment measurements of bone mineral density (BMD) and NTX were included. Urinary NTX was measured with the Osteomark enzyme-linked immunosorbent assay. BMD of the hip and lumbar spine was measured using dual energy X-ray absorptiometry (DEXA). A total of 357 patients had serial NTX requests during the time period. Sixty-five of these patients had a diagnosis of osteoporosis. Out of 37 patients treated for osteoporosis who had complete data available, 29 patients had concordant results between BMD and NTX and eight patients had discordant results. Only one patient had treatment changed as a result of a lack of reduction in NTX following treatment. Thirteen patients had therapy altered. Common reasons for altering therapy were patient non-compliance, side effects and failure of BMD to increase. Alteration to therapy in this patient population is mainly dictated by issues such as patient compliance, medication side effects and bone mineral density results rather than urinary NTX values.

The effect of infliximab on bone metabolism markers in patients with rheumatoid arthritis

The aim of this study was to evaluate urinary excretion of N-telopeptide of type I collagen (NTX) and deoxypyridinoline (DPD), markers of bone resorption, and serum bone alkaline phosphatase (BAP) level, a marker of bone formation and an early marker of osteoblast differentiation, in patients with rheumatoid arthritis (RA) treated with infliximab. Seventeen male and female patients (age 60.7+/-2.53 yr; mean disease duration 12.9+/-3.01 yr; Steinbrocker's class II-IV) with RA, diagnosed according to the criteria of the American College of Rheumatology (ACR), took part in the study between March 2003 and January 2005. None of the patients had a history of oestrogen replacement therapy. All patients were treated with infliximab combined with methotrexate. Infliximab was infused intravenously at 3 mg/kg at baseline, 2 and 6 weeks, then every 8 weeks. To evaluate disease activity, ESR, CRP, the numbers of swollen and tender joints, modified Stanford Health Assessment Questionnaire (mHAQ) score and ACR score were measured. Levels of NTX and DPD in urine and BAP in serum were measured in all patients. ESR, CRP, the number of swollen joints and tender joints, and mHAQ score had decreased significantly 6 weeks after initial treatment and were still low 6 months after initial treatment. NTX levels had decreased significantly 6 weeks after the initial treatment and were still low 6 months after initial treatment. DPD levels had decreased 6 months after initial infusion. Mean serum BAP level did not differ significantly among the three time points. NTX levels were statistically corresponding with the number of swollen joints and mHAQ scores. DPD levels were statistically lower corresponding with ESR. Infliximab therapy may inhibit generalized bone loss in patients with RA. NTX is a more sensitive marker than DPD.

超高齢者骨粗鬆症はビスフォスフォネートで治療すべきである（Ｐｒｏ）

Although alendronate treatment for the prevention of osteoporotic fracture has been considered to be first line treatment, there is little knowledge whether very old osteoporosis should be treated with alendronate or not. To elucidate this question, we investigated the effectiveness of osteoporotic drugs in terms of effects of treatment on bone mineral density (BMD), bone resorption markers and fracture prevention in osteoporosis aged over 75 years old or less. A total of 1,041 postmenopausal osteoporosis cases were classified into 4 categories, Young controls (n = 165) and Old controls (n = 95) (Control group), Young (n = 309) and Old osteoporosis (n = 110) treated with alendronate (ALN group), and Young (n = 238) and Old osteoporosis (n = 124) treated with vitamins D3 or K2 (VDK group). We followed their lumbar BMD, urinary excretion of NTX and incident vertebral fracture rate for three years. The effects of the ALN treatment on lumbar BMD and on urinary NTX were not different between the two age-categorized osteoporosis groups, namely, the lumbar BMD increased by around 6-7% after ALN treatment in both Old and Young groups. The urinary excretion of NTX was decreased by 50% from baseline in both Old and Young ALN treated groups. Those effects of ALN were significantly superior to those in the controls and VDK-treated groups of both age categories. Therefore, ALN biological effects on bone were not age-dependent and the effects of ALN were strongest than the other treatments. The effects on fracture prevention in the Old ALN-treated group showed a 66.7% risk reduction rate (RRR) (p< 0.05) when the fracture incidence rate in the control group (50%) was taken as 100%, while it was 18.8% RRR (ns) in VDK-treated Old group. The Young group treated with ALN showed a 35.6% RRR from the Young control group (25% as 100%) (p<0.05). The VDK treated group did not show a significant RRR of incident fracture (24.4%). Thus, alendronate was the only effective modality to prevent fractures in both young and old osteoporosis. These results clearly indicated that very old osteoporotics should be treated with alendronate at this moment.

Bone Mineral Density and Alterations of Bone Metabolism in Children and Adolescents with Type 1 Diabetes Mellitus

To analysis bone mineral density (BMD) and bone turnover markers in children and adolescents with type 1 diabetes mellitus (DM1) and to establish possible correlations with duration of the disease and degree of metabolic control. Fifty-eight (26 prepubertal, 32 pubertal) children (29 boys) with DM1 (age: 11.7 +/- 3.1 years) and 44 (20 prepubertal, 24 pubertal) healthy children (21 boys) as controls (age: 10.8 +/- 3.2 years) were included in the study. BMD was measured by dual energy X-ray absorptiometry (DEXA). Scans of the lumbar spine (LS2-4) and femoral neck (FN) were carried out. Serum levels of osteocalcin, amino-terminal propeptide of type I procollagen (PINP), and alkaline phosphatase, as markers of bone formation, and urinary calcium/creatinine (Ca/Cr) ratio and levels of N-telopeptide (Ntx), as markers of bone resorption, were assessed. Anthropometrics, duration of DM1, presence of complications, insulin dose, and degree of metabolic control were obtained from the patients' records. In children with DM1 and controls, the mean measurements of LS2-4 BMD were 0.698 +/- 0.178 g/cm2 and 0.669 +/- 0.192 g/cm2, respectively (p >0.05), and FN-BMD measurements were 0.743 +/- 0.147 g/cm2 and 0.744 +/- 0.170 g/cm2, respectively (p >0.05). Children with DM1 had lower serum levels of calcium, intact parathyroid hormone, osteocalcin and PINP, and higher serum levels of 25-hydroxyvitamin D and urinary Ca/Cr (p <0.05). BMD was not related to any of the markers of bone resorption or formation, duration of the disease, or degree of metabolic control. Although we did not establish decreased LS2-4 and FN-BMD measurements in patients with DM1, we found reduced bone formation and increased bone resorption markers in children with DM1. Measurements of serum osteocalcin, PINP, urinary Ntx and Ca/Cr might be useful for long-term follow-up in children and adolescents with DM1.

Urine N-Telopeptide Excretion in Dogs with Appendicular Osteosarcoma

Canine appendicular osteosarcoma (OSA) is a commonly diagnosed cancer that is capable of inducing pathologic bone remodeling. Investigating surrogate indices of bone metabolism may contribute to the diagnostic and therapeutic management of bone malignancies in companion animals. This study evaluated the excretion of N-terminal telopeptide (NTx), a marker of bone resorption that is detected in urine. Sixty-three dogs with appendicular OSA were compared with 29 age-matched healthy dogs. Dogs with appendicular OSA had significantly higher baseline urine NTx excretion than healthy controls (P < .0001). In 17 dogs with OSA treated with either amputation or standardized palliative therapies, significant reductions in urine NTx excretion were observed, suggesting that excessive bone resorption in dogs with OSA may be linked with focal skeletal osteolysis or its consequences. To identify any relationship between indicators of pathologic bone turnover, baseline urine NTx excretion was correlated with serum bone alkaline phosphatase (bALP) or radiographic tumor lengths at diagnosis. No significant correlations were identified between baseline urine NTx excretion and either bALP or tumor length. The findings from this study suggest that high urinary NTx excretion may support the diagnosis of focal skeletal osteolysis in dogs, and reductions in urine NTx excretion after treatment may reflect elimination or minimization of pathologic bone resorption.

A Single-Dose Placebo-Controlled Study of AMG 162, a Fully Human Monoclonal Antibody to RANKL, in Postmenopausal Women

Abstract The safety and bone antiresorptive effect of a single subcutaneous dose of AMG 162, a human monoclonal antibody to RANKL, was investigated in 49 postmenopausal women. AMG 162 is a potent antiresorptive agent for diseases such as osteoporosis. Introduction: RANKL is an essential osteoclastic differentiation and activation factor. Materials and Methods: The bone antiresorptive activity and safety of AMG 162, a fully human monoclonal antibody to RANKL, were evaluated in postmenopausal women in this randomized, double-blind, placebo-controlled, single-dose, dose escalation study. Six cohorts of eight to nine women were randomly assigned to receive a single subcutaneous injection of either AMG 162 or placebo (3:1 ratio). AMG 162 doses were 0.01, 0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg. Subjects were followed up to 6 months in all cohorts and 9 months in the three highest dose cohorts. Second morning void urinary N-telopeptide/creatinine (NTX; Osteomark), serum NTX, and serum bone-specific alkaline phosphatase (BALP, Ostase) were assessed as bone turnover markers. Results and Conclusions: Forty-nine women were enrolled. A single subcutaneous dose of AMG 162 resulted in a dose-dependent, rapid (within 12 h), profound (up to 84%), and sustained (up to 6 months) decrease in urinary NTX. At 6 months, there was a mean change from baseline of −81% in the 3.0 mg/kg AMG 162 group compared with −10% in the placebo group; serum NTX changes were −56% and 2%, respectively. BALP levels did not decrease remarkably until after 1 month, indicating that the effect of AMG 162 is primarily antiresorptive. Intact parathyroid hormone (PTH) levels increased up to ∼3-fold after 4 days in the 3.0 mg/kg dose group, but returned toward baseline with follow-up. Albumin-adjusted serum calcium did not decrease &amp;gt;10% on average in any group, and no subject had values beiow 2 mmol/liter. AMG 162 was well tolerated. No related serious adverse events occurred. No clinically meaningful laboratory changes, other than those described above, were observed. In summary, a single subcutaneous dose of AMG 162 resulted in a dose-dependent rapid and sustained decrease from baseline in bone turnover and could be an effective and convenient treatment for osteoporosis.

Once Weekly Bortezomib (Velcade) Preserves Bone Health by a Direct Effect on Osteoclast Function Independent of Its Effect on the Malignant Plasma Cells.

Bone resorption is increased in multiple myeloma (MM) due to increased osteoclast activity leading to osteoporosis and osteolytic bone lesions. Assays of urinary excretion of N-telopeptide (NTX), a highly specific marker of bone resorption, decrease by 20–70% following treatment with bisphosphonates. Receptor activator of NF-kB (RANK) ligand increases osteoclast mediated bone resorption in part through activation of nuclear factor kappa-B(NF-kB). Preclinical studies have shown bortezomib to decrease osteoclast function through inhibition of NF-kB. However, no clinical data exists on the effect of bortezomib on markers of bone resorption. We designed a prospective clinical trial aimed at measuring the effect of bortezomib on urinary NTX excretion and serum osteocalcin levels in patients with MM. Patients received six cycles of consolidation bortezomib 1.3mg/m2 given once weekly (for ease of administration) for 4 of every 5 weeks, 90–120 days post transplant. Urinary NTX excretion and serum osteocalcin were measured on day 1 of cycles 1, 2 and 3 of therapy. Treatment with bisphosphonates was prohibited from 42 days prior to stem cell collection and until cycle 3 of post transplant bortezomib therapy. To date, 31 of 40 enrolled patients have proceeded to receive bortezomib consolidation therapy and are evaluable for markers of bone metabolism. Characteristics of the patient population and disease include (no. of patients): male (21), female (10), median age 56 years (range 39–70), Stage II (8), Stage III (23), IgG (20), IgA (9), free light chain (2). The median duration between discontinuation of prior bisphosphonate therapy and initiation of post transplantation weekly bortezomib was 158 days (Range 132–196). Of the 19 patients who have completed all 6 prescribed cycles of consolidation bortezomib, only one patient has had a 50% or greater reduction in paraprotein, 16 had stable disease and 2 had disease progression. Nevertheless, excretion of NTX decreased by a mean of 7.4 nmol/mmol creatinine over each 5 week treatment cycle (p=0.007) with a mean decline of 33% over baseline values after 2 cycles of consolidation, once weekly bortezomib therapy (see table). Only one patient displayed an increase in urinary NTX of greater than 30%. This was the only patient with evidence of disease progression during this period of consolidation. Contrary to preclinical and clinical reports of proteasome inhibition resulting in increased osteoblastic bone formation, a decrease was seen in serum osteocalcin. This data suggests that bortezomib, given just once weekly, has a substantial inhibitory effect on osteoclastic bone resorption in MM even in the absence of effects on the malignant plasma cells. The magnitude of effect appears comparable to that achieved with bisphosphonates. Given concerns regarding long term toxicities of bisphosphonate therapy, including nephrotoxicity and osteonecrosis of the jaw, bortezomib may represent an alternative agent effective in controlling both the myeloma and bone disease in this patient population.Cycle 1 Day 1Cycle 2 Day 1Cycle 3 Day 1Mean Changep valueMean Osteocalcin (Range)(ng/ml)28.16 (9.30 – 81.90) (n = 28)26.69 (9.50 – 57.40) (n = 25)26.12 (11.60 – 73.00) (n = 21)−4.6 (16%)0.02Mean NTX excretion (Range)(nmol/mmol Cr)44.87 (10 – 121) (n = 23)36.00 (7 – 65) (n = 24)30.43 (9 – 87) (n = 21)−14.8 (33%)0.007

Celecoxib Does Not Affect Osteointegration of Cementless Total Hip Stems

Celecoxib's effect on prosthetic osteointegration in patients undergoing total hip arthroplasty was studied. In a prospective, placebo-controlled, double-blind study of 49 patients, 24 were randomized to celecoxib (200 mg/d) and 25 to placebo over 6 weeks. Bone markers, N-teleopeptide, and bone-specific alkaline phosphatase were obtained postoperatively, and at 6 and 12 weeks. No radiographic prosthetic subsidence occurred. There were no significant differences from baseline in periprosthetic bone mineral density between the celecoxib and placebo groups at 3 and 6 months. There were no significant differences in baseline BSAlkP values between the 2 groups. At 6 and 12 weeks, average BSAlkP values increased. Urinary NTx concentrations followed a skewed distribution. Normalized NTx concentrations were statistically significantly greater in the celecoxib group than the placebo group at 6 weeks but not at 12 weeks.

Estrogen receptor alpha gene polymorphisms are associated with changes in bone remodeling markers and treatment response to estrogen

Objectives Association studies between estrogen receptor α (ERα) gene polymorphisms and bone mineral density (BMD) have yielded inconsistent results. In the present study we evaluated the influence of XbaI and PvuII ERα gene polymorphisms on BMD, biochemical markers, rates of bone loss and the response to estrogen/hormone therapy (ET/HT) in elderly postmenopausal women. Methods At baseline, we measured the association between ERα genotypes and BMD and biochemical markers in 489 elderly women, mean age 71 ± 3 years. In the longitudinal study, the changes in the same measures were determined in 96 women on placebo and in 79 women receiving the ET/HT for 3 years. The XbaI and PvuII ERα polymorphisms were determined by polymerase chain reaction (PCR). BMD measurements for spine, femoral neck and total body were performed by DEXA, and biochemical indices were measured by standard methods. Results Neither the PvuII nor the XbaI ERα gene polymorphisms were associated with baseline BMD and biochemical indices. In the longitudinal study, there were trends for higher bone loss in the placebo group in the genotypes pp or xx compared to PP or XX genotypes, but the changes were not significant. However, the changes in the bone markers were significantly ( p < 0.05) higher in genotype group pp compared to PP (serum osteocalcin, 4.9 ± 7.0% versus −13.4 ± 6.7%; urine NTx:Cr ratio, 32.3 ± 10.3% versus −2.5 ± 10.3%) or xx compared to XX (serum osteocalcin, 7.5 ± 6.4% versus −15.6 ± 7.3%; urine NTx:Cr ratio, 39.4 ± 9.2% versus −8.84 ± 10.7%). At the end of 3 years, the mean urine NTx:Cr ratio was 78.7 ± 9.0 versus 44.6 ± 4.9 in pp versus PP ( p < 0.05) and 75.5 ± 10.7 versus 48.7 ± 5.4 in xx versus XX ( p < 0.05) genotypes. The response in total body BMD to ET/HT treatment was significantly higher in women with the PP genotype compared to pp genotype (2.48 ± 0.55% versus 0.66 ± 0.46%). Similar trends were seen at other skeletal sites for both XX and PP compared to pp and xx genotypes. Conclusion Women with ERα, PP and XX genotypes have lower bone remodeling, lower rates of bone loss and benefit more from hormone therapy.

A controlled trial of the effect of milk basic protein (MBP) supplementation on bone metabolism in healthy menopausal women

Milk has more beneficial effects on bone health than other food sources. Recent in vitro and in vivo studies have shown that milk whey protein, especially its basic protein fraction (milk basic protein, MBP), contains several components capable of promoting bone formation and inhibiting bone resorption. The object of this study was to examine the effect of MBP on the bone metabolism of healthy menopausal women. Thirty-two healthy menopausal women were randomly assigned to treatment with either placebo or MBP (40 mg per day) for 6 months. The bone mineral density (BMD) of the lumbar vertebrae L2-L4 of each subject was measured by dual-energy X-ray absorptiometry (DXA) at 0 and 6 months of treatment. Serum and urine indices of bone metabolism were measured at 0, 3 and 6 months. Twenty-seven subjects who completed the study in accordance with the protocol were included in the analysis. The mean rate of gain of lumbar BMD in the MBP group (1.21%) was significantly higher than in the placebo group (-0.66%, P=0.046). When compared with the placebo group, urinary cross-linked N-telopeptides of type-I collagen (NTx) were significantly decreased in the MBP group at 6 months, but no significant difference in serum osteocalcin was observed between the two groups. The urinary NTx excretion was found to be related to serum osteocalcin in the MBP group at 3 and 6 months, indicating that MBP maintained the balance of bone remodeling. These results suggested that MBP supplementation was effective in preventing bone loss in menopausal women and that this improvement in BMD may be primarily mediated through the inhibition of bone resorption while maintaining the balance of bone remodeling by MBP supplementation.

Secondary hyperparathyroidism is associated with vitamin D receptor polymorphism and bone density after renal transplantation

Immunosuppresive treatment and secondary hyperparathyroidism (SHPT) are considered among the most important pathogenetic factors for post-renal transplant bone disease. The aim of this study was to investigate the relationships among vitamin D receptor (VDR) gene polymorphism, parathyroid hormone (PTH) levels and bone density in renal transplant recipients. We enrolled 75 patients (50 male and 25 female, mean age 47 ± 11 years) who had undergone kidney transplantation 53 ± 4 months before. All patients underwent an evaluation of the main biochemical parameters of bone metabolism as well bone densitometry. VDR alleles were typed by a PCR assay based on a polymorphic BsmI restriction site. When patients were categorized according to the VDR genotype (BB, Bb, bb), serum creatinine and the cumulative doses of immunosuppressive drugs were similar across the groups. PTH levels higher than 80 pg/ml were found in 53.6% of the patients, with the highest values being detected in the bb VDR genotype ( P < 0.05). PTH was significantly correlated to urinary NTx values. Bone density was low in the whole population; however, spinal bone density was lower in the bb subgroup ( P < 0.02). In the whole population, only PTH ( P < 0.05) and body mass index ( P < 0.01) were independent predictors of spinal bone density. Grouping patients by the VDR gene polymorphism, only PTH continued to be an independent predictor of spinal bone density in the bb allele subgroup ( R 2 Adj. = 0.17). We can conclude that the VDR genotype polymorphism affects bone density of renal transplant recipients via its effects on the severity of SHPT.

Feto-maternal Bone Remodeling in Normal Pregnancy and Preeclampsia

To investigate feto-maternal bone turnover in normal pregnancy and preeclampsia and to test the hypothesis whether the reported low bone mass at birth in small-for-gestational age infants is associated with decreased bone formation or increased bone resorption. Thirty-two patients with preeclampsia (17 mild and 15 severe) and 20 normotensive women (controls) with singleton gestations in the third trimester participated in this study. Furthermore, 25 nonpregnant healthy women were chosen as nonpregnant controls. Maternal 24-hour urine specimens and venous blood samples were collected. In addition, fetal cord blood and the first voided neonatal urine were also collected. The freshly separated sera were assayed for osteocalcin (OC) and carboxy-terminal propeptide of type 1 collagen (PICP) by radioimmunoassay. Urine samples were assayed for N-telopeptide of type 1 collagen (NTx) by enzyme-linked immunosorbent assay. Maternal and cord serum OC and PICP levels were significantly decreased in severe preeclampsia, whereas maternal and first-voided neonatal urinary NTx level were significantly increased compared to the corresponding levels of controls. In both mother and fetus, the coupling index of markers of bone turnover in normal pregnancy or mild preeclampsia was in favor of bone formation, whereas in severe preeclampsia the markers suggested marked bone resorption. Increased bone resorption and decreased bone formation occur in preeclampsia in both mother and fetus, being more pronounced in the latter. The increased osteoclastic activity in preeclampsia may be attributed to increased RANKL induced by increased interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and transforming growth factor beta2 (TGF-beta2) production.

Bone resorption in infants of diabetic mothers

Abstract Aim: Previous studies, using different techniques, have yielded contradictory findings concerning whether bone remodelling is altered in infants of diabetic mothers (IDM). The objective of the study was to assess the bone resorption of IDM during the first 3 mo of age. Methods: We conducted a longitudinal study using a specific index of bone resorption, urinary excretion of collagen type I cross‐linked N‐telopeptide (NTX), to compare bone resorption of a cohort of IDM and that of age‐matched controls throughout the first 3 mo of life. Results: NTX/Cr ratio in IDM followed the same pattern over time as observed in control infants, i.e., a rapid increase during the first 10 d of life, a peak at 1 mo of life, and then a progressive decrease at 3 mo of life. There was no statistically significant difference between urinary NTX excretion observed in IDM and that observed in controls at any age studied. Conclusion: By using urinary NTX excretion, normal bone resorption was found in IDM throughout the first 3 mo of life.