Bone turnover in neonates: Changes of urinary excretion rate of collagen type I cross-linked peptides during the first days of life and influence of gestational age

New markers have been used to monitor the changes of bone turnover occurring during growth. Data on bone turnover rate during the perinatal period are, however, very scarce. In the present study we evaluated bone turnover rate, assessed by the measurement of urinary N-terminal telopeptide of type I collagen (NTx) concentrations, at different gestational ages, and we documented the trend of bone turnover rate occurring in the first days after birth. Urine samples were obtained from 83 healthy full term newborn infants, 16 preterm, and 17 infants of diabetic mothers (IDMs). The first miction after birth was collected. Urine samples were also collected 24 and 48 h after birth. NTx was measured by an enzyme-linked immunosorbent assay (Osteomark®, Ostex International, Inc. Seattle, WA). The relationship between NTx at birth and all the other variables has been evaluated using multiple regression analysis. The changes of NTx excretion over time and the effect of the groups were studied by multivariate analysis of variance (MANOVA) for repeated measures. We found a remarkable association between gestational age and NTx concentrations at birth (R = 0.56; p < 0.00001). NTx concentrations showed a progressive decrement, reaching a nadir between the 38th and the 42nd week of gestation. The NTx concentrations changed significantly during the first 48 h of life in the three groups. Moreover, preterm infants had NTx excretion values at birth significantly higher than full term infants (p < 0.001), whereas NTx excretion rates of IDMs were not different from those of the other two groups of subjects. In conclusion, gestational age seems to be the major determinant of bone turnover in neonates; NTx excretion rate is higher before term, it slows in proximity of delivery, and it increases significantly during the first 48 h of life. Preterm infants have higher bone turnover rate than full term infants. NTx excretion rate of IDMs was comparable with those of the control subjects.     

Effect of pamidronate administration on markers of bone turnover and disease activity in multiple myeloma

AIM: Bisphosphonates are potent inhibitors of osteoclastic activity and are used in the treatment of multiple myeloma (MM) in combination with chemotherapy. The effect of pamidronate on markers of bone resorption [cross-linked N-telopeptides of type I collagen (NTx)], markers of bone formation [serum alkaline phosphatase (BAP) and osteocalcin (OSC)], interleukin-6 (IL-6), beta2-microglobulin, CRP, paraprotein and disease-related pain and skeletal events has been evaluated in 62 newly diagnosed patients with MM. PATIENTS AND METHODS: The patients were randomly assigned to two groups: the first included 32 patients under chemotherapy and pamidronate (group I) and the second 30 patients on chemotherapy only (group II). Pamidronate was administered at a monthly dose of 90 mg iv, and the above parameters were evaluated at the beginning of this study and after 1, 3, 6, 9, 12 and 14 months of treatment. RESULTS: The addition of pamidronate to chemotherapy resulted in a significant reduction of NTx, IL-6 and paraprotein from the 3rd month and of beta2-microglobulin, CRP and pain from the 6th month of treatment. No changes of NTx, IL-6, beta2-microglobulin, CRP or skeletal events were observed in patients of group II, while paraprotein was significantly reduced after 6 months of treatment. The differences in NTx, IL-6, paraprotein and beta2-microglobulin were statistically significant between the two groups. Multivariate analysis revealed a significant correlation between changes of NTx, changes of IL-6 in both groups and reduction of pain and paraprotein in group I. CONCLUSIONS: These results suggest that pamidronate may have a synergistic action with chemotherapy in decreasing osteoclastic activity, in reducing markers of myeloma activity and myeloma related pain and in improving the quality of life in patients with MM.     

Vitamin K supplementation does not significantly impact bone mineral density and biochemical markers of bone in pre- and perimenopausal women

Because of its role in osteoblastic metabolism, vitamin K has been studied with respect to bone. However, there has been limited research examining the influence of long-term vitamin K supplementation on bone mineral density (BMD). Therefore, the purpose of this study was to assess the impact of 6 months of vitamin K supplementation on BMD and biomarkers of bone in pre- and perimenopausal women. Based on previous work, we hypothesized that vitamin K would improve BMD and biochemical markers of bone formation. A double-blind, placebo-controlled, randomized trial is an effective way to study the impact of long-term supplementation. Thus, 14 pre- and perimenopausal women, 25 to 50 years of age, were randomly assigned to an experimental group (E) that received 600 μg/d of vitamin K in the form of phylloquinone (K₁) or a control group (C) that received identical-looking placebo tablets. Regional BMD and percent body fat, measured by dual-energy x-ray absorptiometry, and serum osteocalcin and urinary N-telopeptide levels were all assessed at 0, 3, and 6 months. When BMD was measured across time, C had a significant increase (P = .011) in greater trochanter BMD compared to E. The E group had a nonsignificant increase (P = .067) in shaft BMD compared to the C group. There was no significant difference between E and C in serum osteocalcin concentrations over time. Urinary N-telopeptide levels increased significantly over time in E compared to C (P = .008). Six months of 600 μg/d vitamin K₁ supplementation did not improve regional BMD in this group of pre- and perimenopausal women.     

Comparison of the bone protective effects of an isoflavone-rich diet with dietary and subcutaneous administrations of genistein in ovariectomized rats

Administration of the isoflavone genistein (GEN) has been described to result in bone protection but also to induce uterotrophic responses. To compare bone protective effects of GEN with an isoflavone-rich diet (IRD) and to further elucidate molecular mechanisms involved in bone-protection, ovariectomized rats (OVX) received either a diet low in isoflavone content (IDD) enriched with GEN (42 mg kg⁻¹ b.wt d⁻¹) (GEN^d), an IRD (14 mg kg⁻¹ b.wt d⁻¹ GEN, 14 mg kg⁻¹ b.wt d⁻¹ daidzein) or were treated subcutaneously (s.c.) with GEN (10 mg kg⁻¹ b.wt d⁻¹) (GEN^sc) for 12 weeks. Intact (SHAM), vehicle treated OVX animals and those substituted with 17β-estradiol (2 μg kg⁻¹ b.wt d⁻¹) (E₂), served as controls.     

Reduced bone mineral density in Japanese premenopausal women with systemic lupus erythematosus treated with glucocorticoids

We evaluated bone mineral density (BMD) in Japanese female patients with systemic lupus erythematosus (SLE) and assessed the influence of the use of glucocorticoids. Lumbar BMD was measured by dual x-ray absorptiometry (DXA) in 60 premenopausal females who previously had been receiving glucocorticoid therapy. Therapeutic- and disease-related variables for SLE were analyzed and bone resorption or formation markers were measured. Osteoporosis was defined as a T-score below 2.5 SD by DXA; 12 patients (20%) showed osteoporosis, and 30 (50%) had osteopenia. Compared with the nonosteoporotic group (n = 48), the osteoporotic group (n = 12) had a significantly longer duration of glucocorticoid treatment (P = 0.01), a cumulative prednisolone dose (P = 0.002), and an SLE damage index (SLICC/ACR). There was no difference in the incidence of osteoporosis either with or without the previous use of methyl-prednisolone pulse or immunosuppressive drugs. There was a significant positive correlation between urinary type I collagen cross-linked N-telopeptides (NTx) and serum bone-specific alkaline phosphatase (BAP) (r = 0.404, P = 0.002), but these bone metabolic markers showed no difference between the osteoporotic and nonosteoporotic groups. A good significant negative correlation was shown between BMD and the cumulative glucocorticoid dose (r = −0.351, P = 0.007). Stepwise logistic regression analysis showed that the cumulative glucocorticoid intake was independently associated with osteoporosis. Glucocorticoid-induced osteoporosis was frequently observed in Japanese SLE patients, as in Caucasian populations. The cumulative glucocorticoid dose was associated with an increased risk for osteoporosis. Bone metabolic markers such as NTx and BAP were not influenced by glucocorticoid treatment and could not predict current osteoporosis in SLE patients. Received: October 18, 2001 / Accepted: April 8, 2002 Correspondence to:S. Banno     

骨转换生物标记物在乳腺癌骨转移瘤疗效评价与监测中的作用

骨转换生物标记物是近年来探索用于骨转移瘤疗效评价及监测的新方法.这些存在于骨转移患者血液及尿液中的生物标记物让我们更深入了解骨破坏的过程及骨骼与肿瘤之间的相互作用.本文旨在通过回顾常用骨生物标记物在骨转移瘤治疗与监测的相关研究,探讨其潜在的临床价值.     

NTx在小细胞肺癌骨转移裸鼠模型中疗效的预测作用

目的探讨溶骨性骨代谢生化指标血Ⅰ型胶原交联氨基末端肽（cross-linked N-telopeptide of typeⅠcollagen,NTx）的定量测定对肺癌骨转移治疗的意义。方法将18只Balb/c-nu/nu雄性裸鼠随机分成正常组、实验组和对照组。将人肺小细胞肺癌细胞株H446种植于实验组和对照组裸鼠右后肢胫骨,制成小细胞肺癌骨转移裸鼠动物模型,第一次服氯磷酸二钠前及处死前半小时各留血样1次,每1周测体重,观察存活情况,给药6周后处死裸鼠, 所有裸鼠行放射学检查并取各裸鼠的右后肢行病理分析,用ELISA方法测定血清NTx水平。结果放射学及病理检查显示裸鼠接种H446细胞后引起明显的肿瘤性骨损伤。实验组、对照组裸鼠血清NTx高于正常组裸鼠血清NTx (P< 0. 01),实验组裸鼠经氯膦酸二钠治疗前后血清NTx水平差异有统计学意义(P< 0. 01)。结论定量测定NTx水平变化可用于预测氯膦酸二钠治疗小细胞肺癌骨转移的疗效。血清NTx对小细胞肺癌骨转移的诊断有重要参考意义,可协助及时诊断恶性肿瘤骨转移,且氯膦酸二钠可明显减轻小细胞肺癌骨转移程度。     

Three-month changes in bone turnover markers and bone mineral density response to raloxifene in Japanese postmenopausal women with osteoporosis

It has been well established that raloxifene (RLX) improves bone turnover, increases bone mineral density (BMD), and reduces the risk of fractures. However, it remains obscure how to monitor the therapeutic effects of RLX, while numerous clinical trials for other antiresorptive agents have suggested that greater short-term reductions of bone turnover markers (BTMs) can predict greater increases in BMD and greater reduction in risk of future fractures. The purpose of this study was to investigate associations between short-term reductions of BTMs and subsequent changes of BMD after 1-year treatment with RLX. Seventy-three Japanese postmenopausal women with untreated osteoporosis were selected for this study. Reductions in BTMs [bone-specific alkaline phosphatase (BAP) or serum N-terminal telopeptide of type I collagen (NTx)] after 3 months did not correlate with increases of BMD at any major sites (lumbar spine, femoral neck, total neck, and distal 1/3 radius) either after 6 months or after 12 months. Our results suggest that short-term reductions or 3-month reductions of BTMs with RLX treatment cannot be used to predict increases of BMD. However, this does not directly mean that short-term reductions or 3-month reductions of BTMs with RLX treatment cannot be used to predict risk reduction of future fractures or the ultimate effects of RLX on bone. Further studies with fracture endpoints in longer observation and larger number of patients are warranted to establish how to monitor the therapeutic effects of RLX or early identification of responders or nonresponders to RLX treatment.     

Cross-linked N-telopeptide of type I collagen (NTx) in urine as a predictor of periprosthetic osteolysis.

Periprosthetic osteolysis is often nonsymptomatic and hard to visualize by conventional radiography. Cross-linked N-telopeptide of type I collagen (NTx), a marker of osteoclast mediated bone resorption, has been suggested to evaluate local particulate-induced osteolysis in patients operated on with a total hip prosthesis. Urine specimens were sampled after hip joint replacement in 160 patients. NTx was analyzed by a commercially available ELISA kit. Osteolysis was identified in the acetabulum and confirmed at operation. Using analysis of covariance to correct for differences in age, gender, and time after operation, NTx (mean SD) was 36+/-12 BCE/nM creatinine in patients with osteolysis (n=33) and 27+/-13 BCE/nM creatinine in patients without osteolysis (n=127) (p=0.003). Eighteen hips of 38 (47%), demonstrating an annual wear of more than 0.2 mm and an NTx value above 29 BCE/nM creatinine, had been revised due to osteolysis. The osteolysis prevalence in this group was increased 10 times (CI 4-23, p<0.05). Indeed, NTx release and annual wear were both associated with increased prevalence of osteolysis, however, independently of each other. NTx seems a feasible marker of periprosthetic osteolysis. A preoperative baseline NTx level is likely needed for its use as a predictor of periprosthetic osteolysis in individual cases.     

Trochanteric hip fracture in an elderly patient with leprosy during osteoporosis treatment with risedronate and alfacalcidol

There is no well-established treatment for osteoporosis in male patients with leprosy, because no clinical trials have examined the efficacy of treatment on bone mineral density (BMD) or fracture incidence in patients with leprosy. In this study, we report a case of osteoporosis in a man with leprosy, treated by oral administration of risedronate and alfacalcidol. An 82-year-old man with leprosy presented to our hospital with chronic back pain, due to osteoporosis, in July 2002. To prevent the progession of osteoporosis, oral administration of risedronate and alfacalcidol was started for this patient. An increase in forearm BMD and a decrease in the level of urinary crosslinked N-telopeptides of type I collagen (NTx) were observed in January 2003. The patient suffered a trochanteric fracture of the proximal femur at the end of March 2003. Surgical treatment with a sliding-screw plate was performed 5 days after the injury. Complete bony union of the right proximal femur was confirmed by radiography in July 2003. The above findings suggested that the treatment with risedronate and alfacalcidol contributed to the increase in BMD; however, the treatment did not prevent fracture due to osteoporosis in this male patient with leprosy.