Specific Marker Of Bone Resorption Research Articles

Serum bone resorption markers and 25-hydroxyvitamin D level in women of the Trans-Baikal region of the Russian and Buryat nationalities

Osteoporosis (OP) is a metabolic bone disease , characterized by a decrease of bone mineral density , leading to the development of low-energy fractures . Serum pyridinoline (PYD) and C- terminal cross-linking telopeptide type I (β- CrossLaps ) are among the specific markers of bone resorption . Vitamin D is involved in the metabolism of bone tissue , its deficiency accelerates the processes of bone tissue breakdown . Material and methods . 60 women with osteoporosis were studied (30 Russian and 30 Buryat nationalities ) aged 50 to 80 years ; the control group included 20 women (10 Russian and 10 Buryat nationalities ). Serum bone resorption markers , namely pyridinoline a nd β- C rossLaps , 25-hydroxyvitamin D (25(OH)D) w ere m easured u sing i mmunoassays . R esults a nd d iscussion . The l evel o f β- C rossLaps w as h igher a nd t he c ontent o f 25(OH)D w as l ower i n w omen w ith o steoporosis c ompared t o t he c ontrol g roup . T here w as a p ositive r elationship b etween β- C rossLaps c oncentration a nd b ody m ass i ndex < 20 k g / cm 2 , f requent f alls , a nd a h ip f racture , b etween t he l evel o f 25(OH)D a nd h ereditary h istory o f o steoporosis i n Russian w omen . T here w as a p ositive r elationship b etween S erum p yridinoline a nd s moking , b etween 25(OH)D a nd l ow p hysical a ctivity , β- C rossLaps a nd t he m ajor o steoporotic f ractures i n B uryat w omen . It w as f ound t hat t he β- C rossLaps i s a n i ndependent p redictor o f t he d evelopment o f f ractures i n Russian w omen (β = 0.678, p = 0.04). In B uryat w omen , i ndependent p redictors o f f ractures a re p yridinoline (β = –0.38, p = 0.04) a nd β- C rossLaps (β = 0.671, p = 0.01). C onclusions . The s ystemic m arkers o f b one r esorption ( p yridinoline , β- C rossLaps ) a nd 25(OH)D c an b e u sed i n t he d iagnosis o f o steoporosis a nd f ractures i n r esidents o f t he Trans- B aikal R egion i n a ddition t o r isk f actor a ssessment a nd b one m ineral d ensity m easurement .

Effects of strawberries on bone biomarkers in pre- and stage 1-hypertensive postmenopausal women: a secondary analysis.

Postmenopausal women experience an increase in bone remodeling with the rate of bone resorption superseding the rate of bone formation. This results in a net bone loss with a subsequent increased risk for osteoporosis and fractures. High blood pressure (BP) has been associated with loss of bone mineral density and increased propensity to fractures. Strawberries are rich in polyphenols, which have been shown to have anti-hypertensive and bone-protective properties. Thus, we examined whether daily intake of strawberries would positively affect biomarkers of bone metabolism in postmenopausal women with pre- and stage 1-hypertension. Participants (age: 59 ± 6 years; body mass index: 31.5 ± 4.1 kg m-2; systolic BP: 140 ± 13 mmHg) were randomly assigned to consume (1) 50 g of freeze-dried strawberry powder (FDSP), (2) 25 g FDSP + 25 g of placebo powder, or (3) 50 g placebo powder for eight weeks. Results indicate a significant time-by-treatment interaction (P = 0.04) for serum insulin-like growth factor (IGF)-1, a hormone that plays a major role in bone formation. Serum concentrations of bone-specific alkaline phosphatase, a marker of bone formation, and tartrate-resistant acid phosphatase-5b, a specific marker of bone resorption, were not affected by FDSP compared to placebo. Although not statistically significant, after eight weeks, osteocalcin increased in the 50 g FDSP group with a large effect size (d = 0.6) when compared to the placebo-control group. Adiponectin increased by 5% and 6% in the 25 g and 50 g FDSP groups, respectively, while it declined in the placebo-control group by 25% (P = 0.03 for time-by-treatment interaction). Our findings suggest that consumption of 25 g FDSP increases IGF-1 in postmenopausal women with pre- and stage 1-hypertension. However, further studies are needed to assert the effectiveness of a strawberry intervention for bone health.

Effect of calcium supplementation on bone resorption in pregnancy and the early postpartum: a randomized controlled trial in Mexican women.

BackgroundCalcium needs are physiologically upregulated during pregnancy and lactation to meet demands of the developing fetus and breastfeeding infant. Maternal calcium homeostasis is maintained by hormonal adaptive mechanisms, thus, the role of dietary calcium supplementation in altering maternal responses to fetal-infant demand for calcium is thought to be limited. However, increased calcium absorption is directly related to maternal calcium intake and dietary supplementation has been suggested to prevent transient bone loss associated with childbearing.MethodsIn a double-blind, randomized placebo-controlled trial, we randomly assigned 670 women in their first trimester of pregnancy to 1,200 mg/day calcium (N = 334) or placebo (N = 336). Subjects were followed through 1-month postpartum and the effect on urinary cross-linked N-telopeptides (NTx) of type I collagen, a specific marker of bone resorption, was evaluated using an intent-to-treat analysis. Women with a baseline and at least one follow-up measurement (N = 563; 84%) were included. Subsequent analyses were conducted stratifying subjects by compliance assessed using pill counts. In random subsets of participants, bone-specific alkaline phosphatase (BAP) (N = 100) and quantitative ultrasound (QUS) (N = 290) were also measured.ResultsCalcium was associated with an overall reduction of 15.8% in urinary NTx relative to placebo (p < 0.001). Among those who consumed ≥50%, ≥67%, and ≥75% of pills, respectively, the effect was associated with 17.3%, 21.3%, and 22.1% reductions in bone resorption (all p < 0.001). There was no significant effect of calcium on bone formation measured by BAP. However, by 1-month postpartum, those in the calcium group had significantly lower NTx/BAP ratios than those in the placebo group (p = 0.04) indicating a net reduction in bone loss in the supplement group by the end of follow-up. Among subjects who consumed ≥50% and ≥75% of pills, respectively, calcium was also associated with an increase of 26.3 m/s (p = 0.03) and 59.0 m/s (p = 0.009) in radial SOS relative to placebo by 1-month postpartum.ConclusionsCalcium administered during pregnancy and the early postpartum period, to women with intakes around adequacy, was associated with reduced bone resorption and, thus, may constitute a practical intervention to prevent transient skeletal loss associated with childbearing.Trial registrationClinicalTrials.gov Identifier NCT00558623

PO-0079 Urinary N-telopeptide Levels Are Not Associated With Vitamin D Status In Healthy Children

Background and aims Urinary levels of N-telopeptide (NTx) have been reported to be a sensitive and specific marker of bone resorption. This cross-sectional study determined the urinary levels of NTx among healthy children living in Calgary and explored their relationship with age, sex and vitamin D status. Methods We included healthy children 2 to 13 years of age who presented to the Alberta Children’s Hospital for elective surgery during a 12-month period. Data including the child’s weight, height, age, gender, ethnicity, dietary intake, vitamin intake, and physical activity were collected. Urinary NTx levels were measured with a commercially (Wampole Laboratories, Princeton) available competitive-inhibition enzyme-linked immunosorbent assay. Results Urinary NTx levels were available for 968 out of 1862 participants, of whom 605 (62.5%) were boys. The mean urinary NTx/Creatinine ratio was 605.4 nmol/mmol (SD 264.8, range 200–2985.1). We found that mean urinary NTx/creatinine excretion was higher in the younger children (2–5 years) compared to subsequent ages. There was no significant difference in urinary NTx levels between children with suboptimal vitamin D status (serum 25-hydroxyvitamin D Conclusions Higher urinary NTx levels were measured in our healthy paediatric participants compared to what has been reported in healthy adults. In healthy children, urinary NTx levels may not be a useful marker of increased bone turnover in face of suboptimal vitamin D status. Future research is needed to determine the effect of suboptimal vitamin D status on bone health in children.

BIOCHEMICAL MARKERS OF BONE RESORPTION, REGULATION OF OSTEOCLASTOGENESIS AND BONE LOSS FOLLOWING LIVER TRANSPLANTATION

Methods and results: bone densitometry of L2-L4 and neck of femur, the level in serum of blood some hormones (PTH, vitamin D3, estradiol, testosterone) and cytokines (OPG, IL-6, FNO-a) regulating osteoclastogenesis as well as comparative analyses of two bone resorption markers β-crosslaps and tartrate-resistant acid phosphatase type 5b (TRAP-5b) were fulfilled at different periods following orthotopic liver transplantation. At the early date after operation there were the bone density decrease of L2-L4, the lowering of vitamin D3, estradiol in women, testosterone in men and the elevation of cytokines and of resorption markers. In 1 and 2 years following liver transplantation there were revealed the rise of bone density, the level of PTH, estradiol, testosterone, which were associated with the lowering of IL-6, FNO-a and β-crosslaps while the level of vitamin D3 and TRAP-5b remained stable. Conclusion: at the early date TRAP-5b was more specific marker of bone resorption which did not depend on collagen metabolism in liver. In 1 and 2 years following liver transplantation bone resorbtion was association with level of PTH, FNO-a and OPG.

A Novel Bruton′s Tyrosine Kinase Inhibitor CC-292 In Combination With The Proteasome Inhibitor Carfilzomib Iimpacts Multiple Myeloma Bone Microenviroment With Resultant Anti-Myeloma Activity

A member of the Tec family kinases, Bruton's tyrosine kinase (Btk) modulates B-cell development and activation, and plays an important role in antibody production. Interestingly, Btk and Tec (the other Tec kinase family) regulate osteoclast (OC) differentiation via Receptor Activator of Nuclear Factor κ B (RANK) signaling. Moreover, OCs derived from X-linked agammaglobulinemia (XLA) patients who harbor Btk null mutations have impaired function.Here we show that a potent and specific Btk inhibitor, CC-292 inhibits OC function in multiple myeloma (MM) patients. CC-292 is a highly selective, covalent Btk inhibitor. OC derived from MM patient monocytes were assayed with or without CC-292. Interestingly, OC function was significantly inhibited in the presence of CC-292 (100 nM and 1000 nM) as demonstrated by pit formation assay. However, mRNA expression for TRAP and Cathepsin K, two OC differentiation markers were increased in the presence of CC-292 suggesting that CC-292 inhibits OC function without inhibiting OC differentiation.OC sealing zone contributes to OC bone resorption function. Given the role of c-Src and Proline-rich tyrosine Kinase 2 (Pyk2) signaling in sealing zone formation and OC function we next evaluated CC-292's effect on Pyk2 and c-Src. Pyk2 plays a role in OC activation and localizes to the sealing zone in OC. RANK signaling activates c-Src, which phosphorylates Pyk2. Moreover c-Src controls OC bone resorption by regulating actin organization via cortactin. Interestingly, CC-292 (100 nM) inhibited c-Src total protein, c-Src phosphorylation and Pyk2 phosphorylation. Furthermore, CC-292 (100 nM) inhibited cortactin protein and mRNA expression, and upregulated c-Cbl protein (E3 ubiquitin ligase for c-Src) expression in OC derived from MM patient monocytes with resultant inhibition of OC sealing zone formation. However, at the same low doses (100 nM) CC-292 did not show any direct in vitro effect against MM cell viability.Because carfilzomib, a proteasome inhibitor that binds irreversibly to its target, has potent anti-MM activity and also inhibits OC resorptive activity, we studied CC-292 in combination with carfilzomib. Our data suggests that carfilzomib (1.25 nM) has no impact on OC sealing zone formation but inhibits OC differentiation. CC-292 (100 nM) in combination with carfilzomib (1.25 nM) inhibited not only sealing zone formation but also OC differentiation, resulting in stronger suppression of OC function than carfilzomib alone.The combination of CC-292 (30mg/kg p.o. for 5 days per week for 6 weeks) and carfilzomib (3 mg/kg i.v. x 2 days per week for 4 weeks and 2 mg/kg i.v. x 2 days per week for 2 weeks) significantly inhibited tumor burden and myeloma cell numbers in a diffuse NOD-SCID MM model. The calvarial cells derived from these mice treated with CC-292 alone, carfilzomib alone or the combination showed higher osteocalcin mRNA (osteoblast differentiation marker) expression. A specific bone resorption marker, carboxy-terminal telopeptide collagen crosslinks (CTX) in mouse serum was significantly inhibited in CC-292 and CC-292 in combination with carfilzomib treatment groups in comparison with control mice. Furthermore, 3D microCT reconstructions showed increase in cancellous bone volume in lumbar vertebrae in mice treated with CC-292 or carfilzomib, while the combination treatment resulted in an increase in cancellous bone volume in an additive manner.These data demonstrate that the novel BTK inhibitor CC-292 inhibits OC function through inhibition of OC sealing zone formation. Moreover, CC-292 in combination with carfilzomib augments effects against the bone microenvironment with resultant anti-MM activity. Disclosures:Arastu-Kapur:Onyx Pharmaceuticals, Inc.: Employment. Evans:Celgene Avilomics Research: Employment, Equity Ownership. Singh:Celgene Avilomics Research: Employment, Equity Ownership. Kirk:Onyx Pharmaceuticals, Inc.: Employment. Westlin:Celgene Avilomics Research: Employment, Equity Ownership. Raje:Celgene: Consultancy; Millenium: Consultancy; Onyx: Consultancy; Amgen: Consultancy; Acetylon: Research Funding; Eli Lilly: Research Funding.

The clinical utility of bone marker measurements in osteoporosis

Osteoporosis is characterised by low bone mass and structural deterioration of bone tissue, resulting in increased fragility and susceptibility to fracture. Osteoporotic fractures are a significant cause of morbidity and mortality. Direct medical costs from such fractures in the UK are currently estimated at over two billion pounds per year, resulting in a substantial healthcare burden that is expected to rise exponentially due to increasing life expectancy. Currently bone mineral density is the WHO standard for diagnosis of osteoporosis, but poor sensitivity means that potential fractures will be missed if it is used alone. During the past decade considerable progress has been made in the identification and characterisation of specific biomarkers to aid the management of metabolic bone disease. Technological developments have greatly enhanced assay performance producing reliable, rapid, non-invasive cost effective assays with improved sensitivity and specificity. We now have a greater understanding of the need to regulate pre-analytical sample collection to minimise the effects of biological variation. However, bone turnover markers (BTMs) still have limited clinical utility. It is not routinely recommended to use BTMs to select those at risk of fractures, but baseline measurements of resorption markers are useful before commencement of anti-resorptive treatment and can be checked 3–6 months later to monitor response and adherence to treatment. Similarly, formation markers can be used to monitor bone forming agents. BTMs may also be useful when monitoring patients during treatment holidays and aid in the decision as to when therapy should be recommenced. Recent recommendations by the Bone Marker Standards Working Group propose to standardise research and include a specific marker of bone resorption (CTX) and bone formation (P1NP) in all future studies. It is hoped that improved research in turn will lead to optimised markers for the clinical management of osteoporosis and other bone diseases.

What is the value of bone remodeling markers in patients with calcium stones?

The association between recurrent calcium stones and bone mineral density has been studied over years. Patients with recurrent calcium stones shown a decrease in bone mineral density, which is higher in patients with hypercalciuria [1]. Bone mineral density loss produces osteopenia or osteoporosis that can be assessed by bone densitometry or serum values of biochemical markers of bone turnover (bone formation and bone resorption) [2]. In addition to different metabolic and mineral alterations, which are present in patients with calcium stones, such as hypercalciuria, hyperoxaluria or hypocitraturia, patients with recurrent calcium lithogenic activity have shown abnormal values of bone remodeling markers, that in most cases are independent of iPTH activity [3]. Now a days, one of the markers that indicates the activity of bone formation more reliably is osteocalcin, which can be determined in serum and usually shows higher values in patients with recurrent calcium stones [3]. Also, patients with recurrent calcium stones and severe bone resorption present significantly higher serum values b-crosslaps, a specific marker of bone resorption according to recent studies [3, 4]. This marker indicates a higher osteoclastic activity in patients with calcium stones, and may serve as a follow-up parameter and for medical treatment control (potassium citrate, thiazides or bisphosphonates). Our studies on recurrent calcium stones and loss of bone mineral density [3, 4] demonstrate the importance of bone metabolism and bone turnover markers in these patients; so, we believe that osteocalcin and b-crosslaps should be included routinely in the mineral and metabolic tests performed to patients with recurrent calcium stones as they provide useful information on bone metabolic activity. Moreover, the ratio b-crosslaps/osteocalcin has been evaluated and is higher in patients with recurrent calcium stones [4]. This demonstrates that bone resorption is higher than bone formation, which is the most important reason for bone density loss in these patients.

Osteocalcin and specific markers of bone resorption in sickle cell disease

Sickle cell disease commonly causes avascular necrosis of bone. Plain radiographs are not useful if obtained early in the disease. Radionuclide scans do not appear to increase the sensitivity of the diagnosis. Magnetic resonance imaging can detect disease but this is expensive and hard to employ on a routine or regular basis. The determination of the following new biochemical markers of bone metabolism has not been previously performed in sickle cell disease: serum osteocalcin (S-BGP), urinary cross-linked aminoterminal telopeptide of type I collagen (INTP or NTx) and urinary deoxypyridinoline (U∼DPD). As a first step or preliminary study we evaluate the usefulness of these biochemical markers of bone metabolism, by measuring the plasma or serum and urine levels of these markers in 20 adult patients with sickle cell disease. There was no change in S-BGP (p<0.9) a biochemical marker of bone formation. The two markers of bone resorption, urinary NTx (p<0.002) and U-DPD (p<0.001) increased highly significantly. Although the mean values of urinary NTx and U-DPD were significantly elevated in five patients with clinical evidence of bone complications, only two of these subjects had values above mean +2 SD of normal (control) mean values. Hence the sensitivity and specificity of these measures need to be further investigated with a larger sample size. There was significant correlation (P < 0.001) between NTx and U-DPD. These preliminary findings indicate that urinary NTx and U-DPD should be further investigated as possible biochemical markers of skeletal changes in SCD.

Bone Metabolic Abnormalities Associated with Well-Controlled Type 1 Diabetes (IDDM) in Young Adult Women: A Disease Complication Often Ignored or Neglected

Objectives: This investigation on a homogenous cohort of young adult Caucasian type 1 diabetic (IDDM) patients (1) aimed at studying the occurrence of low bone mineral density (BMD) at an early stage prior to menopause (i.e., during the first decade after peak bone mass) and (2) elucidating the possible mechanisms underlying IDDM-induced bone complication.Methods: Twenty-seven female patients with insulin-treated and well-controlled diabetes, without renal complications, and 32 well-matched healthy controls, aged between 30 and 40 years and fulfilling rigorous inclusion criteria to minimize bone-confounding factors, were enrolled. Areal BMD was evaluated by dual energy X-ray absorptiometry at axial (lumbar spine) and appendicular (femur) sites, using diagnostic WHO reference (T-scores). Osteoblast functions, bone metabolism, related key minerals, and 2 osteoclast-stimulating calciotropic hormones regulating their serum levels were assessed biochemically.Results: The number of cases with low BMD (T-score below −1.1 SD) was almost 2-fold greater (p < 0.01) in the IDDM group. BMD was significantly lower in this group for 3 lumbar sites (p < 0.01) and femur Ward's triangle (p < 0.05). Bone formation was reduced, as evidenced by the suppressions of osteocalcin (OC; p < 0.01) and IGF-I (p < 0.001). However, bone alkaline phosphatase (bALP) was induced (p < 0.01), in contrast to what is usually observed in cases of reduced bone formation. Correlated total ALP activity was also significantly increased. There was no change in the specific marker of bone resorption (urinary deoxypyridinoline). Serum calcium was significantly elevated, particularly after adjustment for albumin (p < 0.001), despite lower 1,25(OH)2D3 (p < 0.001) and no elevation of PTH. All significant bone-related biochemical changes were significantly correlated with glycosylated hemoglobin, a clinical indicator of long-term glycemic control, indicating a direct effect of the disease.Conclusions: Bone loss in the IDDM group results from a decrease in bone formation rather than an increase of bone resorption. The induction of bALP is indicative of impaired osteoblast differentiation and maturation, which delayed (down-regulated) later stages of matrix mineralization, as evidenced by lower OC and BMD.

Urinary N‐telopeptides of type I collagen in healthy children

Urinary N-telopeptides of type I collagen (NTx) is a specific marker of bone resorption. The NTx levels of children have been reported to be higher than in adults, but such reports are limited. The aim of the present study was to measure the urine NTx of healthy children to define reference values, and study the circadian rhythm of urine NTx excretion between the first and second voided urines. Three hundred and sixty-two healthy Japanese children (209 boys and 153 girls; age range, 6-11 years) served as subjects to study age-related changes in NTx. Urine samples were collected as the first voided specimen of the day. To evaluate the circadian variation, we measured the excretion of urinary NTx of the first and second voided urine specimens in 30 healthy Japanese children (15 boys and 15 girls), 6-12 years of age. Urine NTx was measured on enzyme-linked immunosorbent assay (ELISA). Urinary NTx levels were higher in children of both genders than in healthy adults. In boys, the urinary NTx levels decreased with age. In girls, the urinary NTx levels decreased with age between 6 and 9 years of age, but increased between 9 and 10 years of age. NTx of the first voided urine specimen was significantly higher than the second voided urine specimen. Moreover, a significant linear relationship between the first voided urine and the second void urine existed in both genders. Urinary NTx levels in children are higher than in adults. The urine NTx of the first voided urine specimen may be a good marker of bone resorption for children.

Pyridinium cross-links in the urine. Specific markers of bone resorption in metabolic bone diseases

Drug Prescribing for Patients with Chronic Kidney Disease in General Practice: a Cross-Sectional Study

Bone Resorption and Environmental Exposure to Cadmium in Women: A Population Study

BackgroundEnvironmental exposure to cadmium decreases bone density indirectly through hypercalciuria resulting from renal tubular dysfunction.ObjectiveWe sought evidence for a direct osteotoxic effect of cadmium in women.MethodsWe randomly recruited 294 women (mean age, 49.2 years) from a Flemish population with environmental cadmium exposure. We measured 24-hr urinary cadmium and blood cadmium as indexes of lifetime and recent exposure, respectively. We assessed the multivariate-adjusted association of exposure with specific markers of bone resorption, urinary hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP), as well as with calcium excretion, various calciotropic hormones, and forearm bone density.ResultsIn all women, the effect sizes associated with a doubling of lifetime exposure were 8.4% (p = 0.009) for HP, 6.9% (p = 0.10) for LP, 0.77 mmol/day (p = 0.003) for urinary calcium, –0.009 g/cm2 (p = 0.055) for proximal forearm bone density, and –16.8% (p = 0.065) for serum parathyroid hormone. In 144 postmenopausal women, the corresponding effect sizes were –0.01223 g/cm2 (p = 0.008) for distal forearm bone density, 4.7% (p = 0.064) for serum calcitonin, and 10.2% for bone-specific alkaline phosphatase. In all women, the effect sizes associated with a doubling of recent exposure were 7.2% (p = 0.001) for urinary HP, 7.2% (p = 0.021) for urinary LP, –9.0% (p = 0.097) for serum parathyroid hormone, and 5.5% (p = 0.008) for serum calcitonin. Only one woman had renal tubular dysfunction (urinary retinol-binding protein > 338 μg/day).ConclusionsIn the absence of renal tubular dysfunction, environmental exposure to cadmium increases bone resorption in women, suggesting a direct osteotoxic effect with increased calciuria and reactive changes in calciotropic hormones.

Calcium metabolism and vitamin D in the extreme longevity

Skeletal remodelling is a continuous process during life and is still active also in extreme senescence. In the elderly, bone resorption often prevails over bone formation, causing bone loss and fragility. Elderly subjects are exposed to the risk of fractures, and loss of self-sufficiency, if considering that the proximal femur is the most frequently involved site. Bone remodelling can maintain circulating calcium within physiological ranges, at the expense of a substantial loss of this ion from the skeleton, particularly during senescence. Calcium metabolism is regulated at cellular/molecular level by a network of cytokines, growth factors, systemic hormones that act on bone in paracrine/autocrine/systemic fashion. Among the molecules involved in bone metabolism, parathyroid hormone (PTH) and vitamin D present some peculiar aspects during senescence. The osteometabolic features in a consistent group of centenarians have been evaluated. It results that a severe hypovitaminosis D was present in 99 out of 104 centenarians (25-OH vitamin D below 5 nmol/L), and that it plays an important role as a factor inducing a vicious circle involving hypocalcemia, secondary hyperparathyroidism, together with biochemical features indicating a consistent bone loss. Serum C-terminal cross-linking telopeptide, a specific marker of bone resorption was elevated in 92% of these subjects. Moreover, it has been found that several femoral fractures had occurred after 90 years of age. These data offer a rational for the possible prevention of elevated bone turnover, bone loss and consequently the reduction of osteoporotic fractures and fractures-induced disability, in the oldest olds, through the simple supplementation with calcium and vitamin D.

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

Effects of Salmon Calcitonin on Trabecular Microarchitecture as Determined by Magnetic Resonance Imaging: Results From the QUEST Study

The unique noninvasive MRI technique was used to assess trabecular microarchitecture at multiple skeletal sites in 91 postmenopausal osteoporotic women receiving nasal spray salmon calcitonin (CT-NS) or placebo over 2 years. In the distal radius and lower trochanter of the hip, individuals treated with CT-NS exhibited significant preservation of trabecular bone microarchitecture compared with placebo, where significant deterioration was shown. MRI analyses of os calcis or microCT/histomorphometric analyses of bone biopsies did not reveal consistent differences in architecture between CT-NS and placebo. It is postulated that the reduction in osteoporotic fracture risk in response to certain antiresorptive osteoporosis therapies is caused less by effects on bone quantity than on bone quality (specifically trabecular microarchitecture). To test this hypothesis, the QUEST study was conducted to assess the effects of nasal spray salmon calcitonin (CT-NS) or placebo on parameters of trabecular microarchitecture at multiple skeletal sites using noninvasive MRI technology and iliac crest bone biopsies by microCT/histomorphometry. Ninety-one postmenopausal osteoporotic women were followed for 2 years (n = 46 for CT-NS, n = 45 for placebo); all women received 500 mg calcium daily. MRI measurements at distal radius, hip (T2 relaxation time [T2*]), and os calcis (obtained yearly), iliac crest bone biopsies with 2D histomorphometry and 3D microCT (obtained at study onset and conclusion), DXA-BMD at spine/hip/wrist/os calcis (obtained yearly), and markers of bone turnover (obtained at 2-week to 12-month intervals) were analyzed, with an analysis of covariance model used to assess treatment effect for parameters of interest. MRI assessment of trabecular microarchitecture at individual regions of the distal radius revealed significant improvement, or preservation (no significant loss), in the CT-NS-treated group compared with significant deterioration in the placebo control group, as reflected in apparent BV/TV (p < 0.03), apparent trabecular number (p < 0.01), and apparent trabecular spacing (p < 0.01). Also, at the hip, the CT-NS group exhibited preservation of trabecular microarchitecture at the lower trochanter (p < 0.05) as determined by T2* MRI technology. Significant deterioration of trabecular bone architecture was noted in the placebo group at the femoral neck, Ward's triangle, and lower trochanteric sites. Apart from a significant increase in apparent trabecular number in the CT-NS group, significant changes within or between groups were not noted at the os calcis. Combined microCT/histomorphometric analysis of iliac crest bone biopsies did not reveal significant differences between treated and placebo groups. In the CT-NS group, regardless of the change in BMD (gain or loss) at the spine, hip, or distal radius, preservation of parameters of trabecular microarchitecture was noted, whereas in the placebo group, regardless of the change in BMD (gain or loss) at the spine, hip, or distal radius, loss or preservation was noted; however, changes in DXA/BMD (of the spine, hip, wrist, os calcis) between CT-NS and placebo groups were not significant. Serum C-telopeptide (S-CTx), a specific bone resorption marker, was reduced by 22.5% at 24 months (p = 0.056). The results of the QUEST study suggest therapeutic benefit of CT-NS compared with placebo in maintaining trabecular microarchitecture at multiple skeletal sites and support the use of MRI technology for assessment of trabecular microarchitecture in clinical research trials. However, the results also highlight site specific differences in response to antiresorptive therapies and the importance of sufficiently large sampling volumes (areas) to obtain reliable assessment of bone architecture.

The effect on cartilage of different forms of application of postmenopausal estrogen therapy: comparison of oral and transdermal therapy

The effect on urine C-telopeptides of type II collagen (uCTX-II) of oral and transdermal estradiol treatment was compared using samples from two randomized, double-blind, placebo-controlled trials. A total of 171 healthy, Danish postmenopausal women, 45–65 years of age completed the 2-year study periods. The uCTX-II marker assessed cartilage degradation, and this response was compared with the effect on urine C-telopeptides of type I collagen (uCTX-I), considered a specific marker of bone resorption. Doses in the oral estradiol treatment groups (continuous combined therapy) were 1 mg 17-β-estradiol + 1 mg drosperinone or 1 mg 17-β-estradiol + 2 mg drosperinone or 1 mg 17-β-estradiol + 3 mg drosperinone or placebo. Doses in the transdermal estradiol treatment groups (continuous combined therapy) were 45 μg 17-β-estradiol + 30 levonorgestrel or 45 μg 17-β-estradiol + 40 μg levonorgestrel or placebo. The effect of oral and transdermal estradiol therapy on cartilage degradation was reflected as a decrease of 19–30% in uCTX-II ( P = 0.02 and P = 0.003 vs. placebo) after 1 year of treatment. uCTX-I decreased 70% ( P < 0.0001 vs. placebo) reflecting a pronounced effect on bone resorption that was consistent with a 2-year increase in spine and hip BMD of 7–8% and 4–6%, respectively. The results indicate that different regimens of postmenopausal HRT both have an effect on cartilage and bone thus protecting against osteoporosis and osteoarthritis (OA). However, long-term clinical trials are needed to further investigate this issue.

Effects of gonadotropin-releasing hormone agonists on bone metabolism markers and bone mineral density in patients with prostate cancer

Objectives To better understand bone metabolism and predict bone loss in treatment using gonadotropin-releasing hormone agonist for patients with prostate cancer. Methods The changes in bone mineral density and blood levels of bone metabolism markers and the level of pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen, a specific marker of bone resorption, and carboxy-terminal pro-peptide of human type I procollagen, a specific marker of bone formation, were examined in 27 consecutive patients with prostate cancer without bone metastasis. Results After 2 years of gonadotropin-releasing hormone treatment, the bone mineral density was significantly lower (median 0.937 g/cm 2) than before treatment. Pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen began to increase significantly 6 months after the start of treatment (3.0 to 8.3 ng/mL, median 4.6, at baseline versus 3.4 to 8.2 ng/mL, median 5.2, after 6 months). Carboxy-terminal pro-peptide of human type I procollagen began to show a significant rise 1 year after the start of treatment (from 72.8 to 221.5 ng/mL, median 102.0, at baseline to 82.7 to 293.4 ng/mL, median 132.0, at 1 year). Conclusions Functional coupling between bone resorption and formation was noted, and a decrease in bone mass, even in men, owing to androgen deficiency, was biochemically demonstrated. Fluctuations in these two bone metabolism markers preceded the decrease of bone mineral density. Therefore, these markers might be a predictor of bone loss.

Urinary N-telopeptide levels in multiple myeloma patients, correlation with Tc-99m-sestaMIBI scintigraphy and other biochemical markers of disease activity.

Urinary cross-linked N-telopeptide of type I collagen (NTx) has been reported to be a sensitive and specific marker of bone resorption in multiple myeloma (MM). In this study, we measured the levels of NTx in 30 newly diagnosed MM patients and 25 controls. We examined its association with the overall score of skeletal involvement measured by Tc-99m-MIBI scintigraphy and other biochemical markers of bone disease (tumour necrosis factor a (TNF-a), serum calcium and creatinine). We further studied the correlation of NTx with the stage of disease (according to Durie-Salmon criteria) and bone marrow infiltration by plasma cells. High levels of NTx, bone marrow infiltration, TNF-alpha, calcium and creatinine were noted at advanced stages of disease (p < 0.05). NTx and TNF-a were found at significantly higher concentrations in patients with a high overall score (3 and 4) in Tc-99m-sestaMIBI in comparison to a low score (0, 1 and 2; p < 0.05). Positive correlations were found between NTx and TNF-a, as well as between bone infiltration and TNF-a or calcium. In conclusion, NTx is a useful marker for the monitoring of bone resorption in MM and correlates with imaging findings on Tc-99m-sestaMIBI and other biochemical markers of disease activity.

Soy Protein Supplementation Increases Serum Insulin-Like Growth Factor-I in Young and Old Men but Does Not Affect Markers of Bone Metabolism

Recent studies suggest that soy protein (SP) protects bone in women; however, its effects on bone metabolism in men have not been investigated. Healthy men (59.2 +/- 17.6 y) were assigned to consume 40 g of either SP or milk-based protein (MP) daily for 3 mo in a double-blind, randomized, controlled, parallel design. Serum insulin-like growth factor-I (IGF-I), which is associated with higher rates of bone formation, was greater (P < 0.01) in men supplemented with SP than in those consuming MP. Serum alkaline phosphatase and bone-specific alkaline phosphatase activities, markers of bone formation, and urinary deoxypyridinoline excretion, a specific marker of bone resorption, were not different between the SP and MP groups. Furthermore, because substantial reductions in bone density occur in men at approximately 65 y of age, data were analyzed separately for men >/=65 y and those <65 y of age. The response to protein supplementation was consistent in the two age groups. The effects of SP on serum IGF-I levels suggest that SP may positively influence bone in men. Longer-duration studies examining the effects of SP or its isoflavones on bone turnover and bone mineral density and content in men are warranted.