Urinary Cross-linked N-telopeptides Of Type Research Articles

Phosphaturia in HIV-exposed Uninfected Neonates Associated with Maternal Use of Tenofovir Disoproxil Fumarate in Late Pregnancy.

Tenofovir disoproxil fumarate (TDF) is often used in treating pregnant women living with HIV. Third trimester TDF exposure is associated with a 12% reduction in bone mineral content in HIV-exposed uninfected (HEU) neonates. Potential mechanisms underlying this observation are unknown. The TDF study enrolled newborns of gestational age ≥36 weeks from the Surveillance Monitoring for Antiretroviral Therapy and Toxicities study based on in utero TDF exposure (TDF use ≥8 weeks in third trimester versus none). Blood and urine samples were collected cross-sectionally within 30 days of birth to assess renal function (serum creatinine, serum phosphate, eGFR, percent tubular reabsorption of phosphate [PTRP]), and bone turnover (serum parathyroid hormone, 25-OH vitamin D [25(OH)D], and urinary cross-linked N-telopeptide of type 1 collagen). For each biomarker, a LOESS plot was fit using values at age at specimen collection; regression lines over age were fit among samples collected from 4-30 days, to compare slopes by TDF exposure. Among 141 neonates, 77 were TDF-exposed and 64 TDF-unexposed. Between age 4 and 30 days, PTRP decreased more rapidly in the TDF-exposed compared to the unexposed group with slopes of -0.58 versus -0.08/day (difference -0.50/day [95%CI -0.88, -0.11]). Slopes for 25(OH)D were similar in both groups, but serum levels lower in TDF-exposed neonates (median [IQR]: 22 [19, 29] versus 26 [22,37] ng/mL). No differences were observed for other biomarkers. Third trimester in utero exposure to TDF is associated with increased urinary loss of phosphate and lower serum concentrations of 25(OH)D in HEU neonates.

An analysis of osteoporosis in patients with hereditary multiple exostoses.

There are few reports of osteoporosis in hereditary multiple exostoses (HME) patients. Therefore, the purpose of this study was to analyze osteoporosis in HME patients. This retrospective cohort study included 20 patients diagnosed with HME. Patients underwent bone mineral density (BMD) measurement of the lumbar spine (n= 20) and femoral neck (n= 40). Bone metabolic parameters, including serum osteocalcin and urinary cross-linked N-telopeptide of type 1 collagen (NTx), were analyzed in all subjects. EXT1 and EXT2 genes were sequenced using genomic DNA. We also examined the correlation between genotype and BMD Z-score and T-score. The mean BMD values of the lumbar spine were 1.085 ± 0.116g/cm2 (n= 11) in male and 1.108 ± 0.088g/cm2 (n= 9) in female. The mean BMD values of the femoral neck area were 0.759 ± 0.125g/cm2 (n= 22) in male and 0.749 ± 0.115g/cm2 (n= 18) in female. Z-score of most HME patients show < 0, indicating that these patients tend to have low bone mass compared with the age-matched population. According to the T-score of BMD, 30% (6 of 20) and 67.5% (27 of 40) of the patients fell in the range of osteopenia in the lumbar spine and femoral neck areas, respectively. Serum osteocalcin and urinary NTx were in the normal range in most patients. There was no significant correlation between genotypes and Z-score. HME patients have low bone mass, especially in the femoral neck area. They do not have abnormal bone metabolism, and there was no correlation between genotypes and Z-score.

Retraction Note: Urinary Cross-linked N-telopeptides of Type I Collagen Levels in Patients with Rheumatoid Arthritis.

The Editors-in-Chief have retracted this article [1]. Serious concerns have been raised about the data presented [2], and after careful consideration and additional investigation the Editors-in-Chief no longer have confidence in this article. All authors were contacted and did not respond to correspondence about this retraction.

Friday, September 28, 2018 10:30 AM–12:00 PM abstracts: complications of cervical spine surgery: 162. Urinary N-telopeptide can predict pseudarthrosis after anterior cervical decompression and fusion (ACDF): a prospective study

BACKGROUND CONTEXT Anterior cervical decompression and fusion (ACDF) is one of the most successful and widely performed spine surgeries. Although high rates of fusion have been reported, there is a risk for pseudarthrosis. Urinary cross-linked n-telopeptide of type I collagen (uNTx), is an important marker of bone turnover and may prove useful as a predictor of fusion in pts undergoing ACDF. PURPOSE The purpose of present study was to examine the association of preop uNTx level and successful fusion after ACDF. STUDY DESIGN/SETTING Prospective cohort study. PATIENT SAMPLE Adult patients who underwent ACDF with allograft and plating technique. OUTCOME MEASURES Fusion status was assessed using radiographic criteria published by Song et al. METHODS Patients undergoing primary ACDF with allograft and plating technique from 2015 to 2017 by a single surgeon were consecutively enrolled and preop uNTx was measured. Revision cases, improperly timed uNTx collection, pts with a Cr>1.2 were excluded. Demographics, operative, laboratory and fusion data was assessed at 6 months, 1 year and 2 years. NDI and VAS outcome scores were compared between fusion and nonfusion groups. Regression analysis was performed to assess the association of preop uNTx and successful fusion. RESULTS Of the 97 patients enrolled, 67 met inclusion criteria and were studied. 41%, 33%, 18% and 8% underwent one, two, three and four level ACDFs, respectively. Fusion rates were 37.3% at 6 months (n=67), 70.9% at 1 year (n=55) and 95.3% at 2 years (n=43). The preop uNTx was higher in the fusion group at 6mo (31 vs. 22, p CONCLUSIONS Urinary NTx was higher in patients with successful ACDF fusion compared to patients with radiographic pseudarthrosis at 6 months and 1 year. A linear relationship between uNTx levels and Fusion was observed. Surgeons should consider measuring uNTx prior to cervical fusion procedures to identify patients at risk for pseudarthrosis.

Gender-Specific Impact of Cadmium Exposure on Bone Metabolism in Older People Living in a Cadmium-Polluted Area in Thailand.

To elucidate the influence of cadmium exposure on bone metabolism, associations between urinary/blood cadmium and bone resorption/formation markers were investigated in older cadmium exposed men and women. Increased urinary cross-linked N-telopeptide of type I collagen (NTx), a bone resorption marker, was found to be associated with increased levels of parathyroid hormone, fractional excretion of calcium, and urinary/blood cadmium after adjusting for confounding factors in men. In women, urinary NTx was significantly associated with only urinary cadmium and a strong relationship with increased fractional excretion of calcium. Risk for bone metabolic disorders, indicated by high urinary NTx, significantly increased in men with blood cadmium ≥ 10 μg/L or urinary cadmium ≥ 10 μg/g creatinine. Increased osteocalcin level was significantly associated with increased blood cadmium in men. In conclusion, cadmium exposure appeared to have an influence on bone remodeling both bone resorption and formation in this population of older Thai men, and blood cadmium was more closely associated with bone metabolism than urinary cadmium.

Protease inhibitor-associated bone mineral density loss is related to hypothyroidism and related bone turnover acceleration.

Clinical and experiments evidence indicate that protease inhibitors (PI) can cause bone mineral density (BMD) loss. However, the mechanism of such loss remains obscure. This single-center, cross-sectional study included 184 HIV-infected patients treated with PI who underwent dual-energy X-ray absorptiometry scan. Serum phosphorus, percentage of tubular reabsorption of phosphate (%TRP), thyroid and parathyroid function (iPTH), vitamin D, osteocalcin (OC), urinary deoxypyridinoline (DPD), and urinary cross-linked N-telopeptide of type I collagen (u-NTx) were measured. The rate of hypothyroidism in PI-users [32/117 (27%)] was double that in non-PI users [8/67 (12%), p=0.016] and was significantly associated with PI use in multivariate analysis [odds ratio (OR) 11.37, 95% confidence interval (CI) 1.358-95.17, p=0.025]. Spine BMD was significantly lower in hypothyroid patients than euthyroid, for both total population (-1.37 vs.-1.00, p=0.041) and PI users (-1.56 vs.-1.13, p=0.029). Multivariate regression analysis identified inverse correlation between hypothyroidism and spine BMD [estimate-0.437, 95% CI -0.858 to-0.024, p=0.042]. OC, DPD and u-NTx were significantly higher in PI users than in non-PI users (p=0.01, 0.05, and 0.01, respectively). PI use is associated with hypothyroidism as well as bone turnover acceleration, which worsens PI-associated BMD loss. In PI-treated patients, thyroid function tests are warranted to prevent further progression of PI-associated BMD loss.

Short-term bisphosphonate treatment reduces serum 25(OH) vitamin D3 and alters values of parathyroid hormone, pentosidine, and bone metabolic markers.

This study aimed to clarify the effects of short-term bisphosphonate (BP) administration in Japanese osteoporotic patients retrospectively. Daily minodronate (MIN) at 1 mg/day (MIN group) or weekly risedronate (RIS) at 17.5 mg/week (RIS group) was primarily prescribed for each patient. We analyzed the laboratory data of 35 cases (18 of MIN and 17 of RIS) before the start of treatment and at 4 months afterward. The changes in 25(OH)D3, whole parathyroid hormone (PTH), serum pentosidine, and the bone turnover markers urinary cross-linked N-telopeptide of type I collagen (NTX), serum tartrate-resistant acid phosphatase (TRACP)-5b, bone-specific alkaline phosphatase (BAP), and undercarboxylated osteocalcin were evaluated. Overall, serum 25(OH)D3 was significantly decreased from 21.8 to 18.4 ng/mL at 4 months, with a percent change of −14.7%. Whole PTH increased significantly from 23.4 to 30.0 pg/mL, with a percent change of 32.1%. Serum pentosidine rose from 0.0306 to 0.0337 μg/mL, with a percent change of 15.2%. In group comparisons, 25(OH)D3 and pentosidine showed comparable changes in both groups after 4 months of treatment, whereas whole PTH became significantly more increased in the MIN group. All bone turnover markers were significantly decreased at 4 months in both groups. Compared with the RIS group, the MIN group exhibited significantly larger value changes for urinary NTX, serum TRACP-5b, and BAP at the study end point. This study demonstrated that serum 25(OH)D3 became significantly decreased after only 4 months of BP treatment in Japanese osteoporotic patients and confirmed that MIN more strongly inhibited bone turnover as compared with RIS.

High bone turnover elevates the risk of denosumab-induced hypocalcemia in women with postmenopausal osteoporosis.

Hypocalcemia is the most common major adverse event in patients with osteoporosis receiving the bone resorption inhibitor denosumab; however, limited information is available regarding risk factors of hypocalcemia. Therefore, this study aimed to identify the risk factors of hypocalcemia induced by denosumab treatment for osteoporosis. We retrospectively reviewed the records of patients who had received initial denosumab supplemented with activated vitamin D for osteoporosis. Serum levels of the following bone turnover markers (BTMs) were measured at baseline: bone-specific alkaline phosphatase (BAP), total N-terminal propeptide of type 1 procollagen (P1NP), tartrate-resistant acid phosphatase 5b (TRACP-5b), and urinary cross-linked N-telopeptide of type 1 collagen (NTX). Of the 85 denosumab-treated patients with osteoporosis studied, 22 (25.9%) developed hypocalcemia. Baseline serum total P1NP, TRACP-5b, and urinary NTX were significantly higher in patients with hypocalcemia than in those with normocalcemia following denosumab administration (all P<0.01). Multivariate logistic regression analysis revealed that patients with total P1NP >76.5 μg/L, TRACP-5b >474 mU/dL, or urinary NTX >49.5 nmol bone collagen equivalent/mmol creatinine had a higher risk of hypocalcemia (P<0.01). Our study suggests that denosumab may have a greater impact on serum calcium levels in patients with postmenopausal osteoporosis with higher baseline bone turnover than in patients with postmenopausal osteoporosis with normal baseline bone turnover, because maintenance of normal serum calcium in this subgroup is more dependent on bone resorption. Close monitoring of serum calcium levels is strongly recommended for denosumab-treated patients with high bone turnover, despite supplementation with activated vitamin D and oral calcium.

Monthly minodronate inhibits bone resorption to a greater extent than does monthly risedronate

As a bisphosphonate, minodronate (MIN) is one of the strongest inhibitors of bone resorption. However, there have been no reports directly comparing the antiresorptive effects of monthly MIN with those of monthly risedronate (RIS). We enrolled 30 cases of osteoporosis (OP; 16 in the MIN group [mean age: 68.2 years] and 14 in the RIS group [mean age: 68.1 years]) to investigate the early effects of treatment by monthly MIN or RIS over a 4-month period using bone turnover marker values. Only female patients were enrolled to avoid gender bias. Urinary cross-linked N-telopeptide of type I collagen (NTX) before treatment and at 1, 2, and 4 months of therapy, as well as serum bone alkaline phosphatase and alkaline phosphatase before treatment and at 4 months afterwards, were evaluated. All bone turnover marker values were significantly decreased at 4 months in both groups. The changes in urinary NTX at the study end point for RIS and MIN were −30.1% and −63.1%, respectively. From 2 months of treatment, the antiresorptive effects on urinary NTX by MIN were significantly higher than those by RIS, indicating that MIN more immediately and strongly inhibited bone absorption. Thus, monthly MIN seems to suppress bone resorption faster and more strongly than RIS in OP treatment.

Bone turnover and mineral density in adult thalassemic patients: relationships with growth hormone secretory status and circulating somatomedins.

Previous evidence supports a role for growth hormone (GH)-insulin-like growth factor (IGF)-I deficiency in the pathophysiology of osteopenia/osteoporosis in adult thalassemia. Moreover, serum IGF-II has never been studied in this clinical condition. Thus, we elected to study the GH secretory status and the levels of circulating somatomedins, correlating these parameters with bone mineral density (BMD) and biochemical markers of bone turnover. A hundred and thirty-nine normal weight adult thalassemic patients (72 men and 67 women) were studied. Lumbar and femoral neck BMD were measured in 106/139 patients. Sixty-eight patients underwent growth hormone releasing hormone plus arginine testing. Measurement of baseline IGF-I and IGF-II was performed in all patients, while osteocalcin, C-terminal telopeptide of type I collagen (CTx), and urinary cross-linked N-telopeptides of type I collagen (NTx) were assayed in 95 of them. Femoral and lumbar osteoporosis/Z score below the expected range for age were documented in 61.3 and in 56.6% of patients, respectively. Severe GH deficiency (GHD) was demonstrated in 27.9% of cases, whereas IGF-I SDS was low in 86.3%. No thalassemic patients displayed circulating levels of IGF-II below the reference range. GH peaks were positively correlated with femoral, but not lumbar, Z score. No correlations were found between GH peaks and osteocalcin, CTx and NTx. GH peaks were positively correlated with IGF-I values, which in their turn displayed a positive correlation with osteocalcin, CTx, and NTx. No correlations emerged between IGF-I values and either femoral or lumbar Z scores. No correlations were found between IGF-II and any of the following parameters: GH peaks, osteocalcin, CTx, NTx, femoral Z score, and lumbar Z score. Our study, besides providing for the first time evidence of a normal IGF-II production in thalassemia, contributes to a better understanding of the involvement of the somatotropin-somatomedin axis in the pathophysiology of bone demineralization in this disease. In particular, the contribution of GHD to femoral osteoporosis appears to be likely mediated by locally produced rather than circulating IGF-I.

Profile of changes in bone turnover markers during once-weekly teriparatide administration for 24 weeks in postmenopausal women with osteoporosis

SummaryChanges in bone turnover markers with weekly 56.5 μg teriparatide injections for 24 weeks were investigated in women with osteoporosis. Changes in bone turnover markers 24 h after each injection of teriparatide were constant. During the 24 week period, bone formation markers increased and baseline bone resorption marker levels were maintained.IntroductionThis study aimed to clarify the changes in bone turnover markers during 24 weeks of once-weekly teriparatide injections in postmenopausal women with osteoporosis.MethodsThe 24 h changes in pharmacokinetics (PK), calcium metabolism, and bone turnover markers (serum osteocalcin, procollagen type I N-terminal propeptide (P1NP), urinary cross-linked N-telopeptide of type I collagen (NTX), deoxypiridinoline (DPD)) after each injection of 56.5 μg teriparatide at the data collection weeks (0, 4, 12, and 24 weeks) were investigated. The changes were evaluated by comparison with the data at 0 h in each data collection week.ResultsSimilar 24 h changes in each parameter after injection of teriparatide were observed in each data collection week. Serum calcium increased transiently, and intact PTH decreased 4–8 h after injection; serum calcium subsequently returned to baseline levels. Calcium and intact PTH levels decreased for 24 weeks. Although serum osteocalcin decreased at 24 h, it was significantly increased at 4 weeks. P1NP decreased transiently and then increased significantly at 24 h. P1NP was significantly increased at 4 weeks. Urinary NTX and DPD were significantly increased transiently and then decreased at 24 h. The urinary DPD level decreased significantly at 4 weeks.ConclusionsTwenty-four hour changes in PK, calcium metabolism, and bone turnover markers showed the same direction and level after once-weekly teriparatide injections for 24 weeks, with no attenuation of the effect over time. After 24 weeks, the bone formation marker, serum osteocalcin, increased significantly, but the serum P1NP, did not. Bone resorption markers decreased or remained the same.

Prospective Study of Urinary and Serum Cross-Linked N-Telopeptide of Type I Collagen (NTx) for Diagnosis of Bone Metastasis in Patients With Lung Cancer

BackgroundMany cancers metastasize to bone, which may cause an increase in bone resorption because of the direct effects of the tumor itself or osteoclastic activation. Patients and MethodsLevels of urinary cross-linked N-telopeptide of type I collagen (uNTx) and serum cross-linked N-telopeptide of type I collagen (sNTx) were measured in 100 patients with lung cancer and 50 patients with benign respiratory disease using the Osteomark NTx urine and serum assays (Osteomark, Princeton, NJ). Bone metastasis was diagnosed by bone scintigraphy. Receiver operating characteristic (ROC) analysis was used to evaluate the detection of bone metastasis. Sensitivity and specificity to detect bone metastasis were calculated when cutoff points were set to 64 nmol bone collagen equivalents (BCE)/mmol Cr for uNTx and 22 nmol BCE/L for sNTx. ResultsPatients with lung cancer and bone metastasis had significantly higher levels of both uNTx and sNTx (uNTx median [range], 61.3 [22.7-593.1] nmol BCE/mmol creatinine [Cr]; sNTx median [range], 19.7 [10.7-97.1] nmol BCE/L) than did patients with lung cancer without bone metastasis (uNTx median [range], 45.2 [19.8-153.0] nmol BCE/mmol Cr; sNTx median [range], 16.7 [11.0-28.4] nmol BCE/L), or patients with benign respiratory diseases (uNTx median [range], 40.6 [15.2-155.9] nmol BCE/mmol Cr; sNTx median [range], 14.8 [9.5-55.5] nmol BCE/L.). There was good correlation between uNTx and sNTx (R = 0.807). Area under the curve (AUC) for ROC was 0.743 for uNTx and 0.712 for sNTx. The sensitivity and specificity for the diagnosis of bone metastasis were 48.0% and 86.0%, respectively, using uNTx, and 40.0% and 87.0%, respectively, using sNTx. ConclusionThis prospective study indicates equivalency between sNTx and uNTx in sensitivity and specificity to detect bone metastasis, and both uNTx and sNTx may have value as aids in the diagnosis of bone metastasis in patients with lung cancer.

Bone resorption and fracture across the menopausal transition: the Study of Women's Health Across the Nation.

Bone turnover markers (BTMs) predict fracture in older women, whereas data on younger women are lacking. To test the hypothesis that BTMs measured before and after menopause predict fracture risk, we performed a cohort study of 2,305 women. Women attended up to nine clinic visits for an average of 7.6 ± 1.6 years; all were aged 42 to 52 years and were premenopausal or early perimenopausal at baseline. Incident fractures were self-reported. Serum osteocalcin and urinary cross-linked N-telopeptide of type I collagen (NTX) were measured at baseline. NTX was measured at each annual follow-up. Interval-censored survival models or generalized estimating equations were used to test whether baseline BTMs and changes in NTX, respectively, were associated with fracture risk. Hazard ratios (HRs) or odds ratios were calculated with 95% CIs. Women who experienced fractures (n = 184) had about a 10% higher baseline median NTX (34.4 vs 31.5 nanomoles of bone collagen equivalents per liter per nanomole of creatinine per liter; P = 0.001), but there was no difference in osteocalcin. A 1-SD decrease in lumbar spine bone mineral density (BMD) measured premenopausally was associated with a higher fracture risk during menopause (HR, 1.50; 95% CI, 1.28-1.68). Women with a baseline NTX greater than the median had a 45% higher risk of fracture, multivariable-adjusted (HR, 1.46; 95% CI, 1.05-2.26). The HR of fracture among women with both the lowest spine BMD (quartile 1) and the highest NTX (quartile 4) at baseline was 2.87 (95% CI, 1.61-6.01), compared with women with lower NTX and higher BMD. Women whose NTX increased more than the median had a higher risk of fracture (odds ratio, 1.51; 95% CI, 1.08-2.10). Women who had baseline NTX greater than the median experienced greater loss of spine and hip BMD. A higher urinary NTX excretion measured before menopause and across menopause is associated with a higher risk of fracture. Our results are consistent with the pathophysiology of transmenopausal changes in bone strength.

Corrigenda

Vitamin D therapy for hypoparathyroidism does not restore PTH-dependent renal calcium reabsorption, which can lead to renal damage. An alternative approach, PTH 1-34 administered twice daily, provides acceptable long-term treatment but is associated with nonphysiological serum calcium fluctuation. Our objective was to compare continuous PTH 1-34 delivery, by insulin pump, with twice-daily delivery. In a 6-month, open-label, randomized, crossover trial, PTH 1-34 was delivered by pump or twice-daily sc injection. After each 3-month study period, serum and 24-h urine mineral levels and bone turnover markers were measured daily for 3 d, and 24-h biochemical profiles were determined for serum minerals and 1,25-dihydroxyvitamin D(3) and for urine minerals and cAMP. STUDY PARTICIPANTS AND SETTING: Eight patients with postsurgical hypoparathyroidism (mean ± sd age 46 ± 5.6 yr) participated at a tertiary care referral center. Pump vs. twice-daily delivery of PTH 1-34 produced less fluctuation in serum calcium, a more than 50% reduction in urine calcium (P = 0.002), and a 65% reduction in the PTH dose to maintain eucalcemia (P < 0.001). Pump delivery also produced higher serum magnesium level (P = 0.02), normal urine magnesium, and reduced need for magnesium supplements. Finally, pump delivery normalized bone turnover markers and significantly lowered urinary cross-linked N-telopeptide of type 1 collagen and pyridinium crosslinks compared with twice-daily injections (P < 0.05). Pump delivery of PTH 1-34 provides the closest approach to date to physiological replacement therapy for hypoparathyroidism.

Predictors and Correlates of Vitamin D Status in Children and Adolescents with Osteogenesis Imperfecta

The prevalence of vitamin D deficiency and its consequences on bone in pediatric bone fragility disorders is not well characterized. In the present study, we evaluated determinants of vitamin D status in children and adolescents with osteogenesis imperfecta (OI) and assessed the relationship between 25-hydroxyvitamin D (25OH D) serum concentrations and lumbar spine areal bone mineral density (LS-aBMD). This retrospective cross-sectional study comprised 315 patients with a diagnosis of OI type I, III, or IV (aged 1.1-17.9 yr; 161 girls) who had not received bisphosphonate treatment at the time of 25OH D analysis. In 282 patients (90%), LS-aBMD measurements were available at the same time. Serum concentrations of 25OH D ranged from 14 to 133 nmol/liter and were less than 50 nmol/liter in 86 patients (27%). Regression analysis revealed that age (P < 0.001), season (P < 0.001), and OI severity (P = 0.048), but not gender, were significant independent predictive factors of 25OH D levels. Serum 25OH D concentrations were negatively correlated with serum PTH levels (P = 0.003) and urinary cross-linked N-telopeptides of type I collagen to creatinine ratios (P = 0.005). Serum 25OH D levels were positively associated (P = 0.02) with LS-aBMD z-scores after accounting for OI severity, age, and gender. Serum 25OH D levels are positively associated with LS-aBMD z-scores in children and adolescents with OI types I, III, and IV.

The effect of adding PTH(1–84) to conventional treatment of hypoparathyroidism: A randomized, placebo-controlled study

In hypoparathyroidism, plasma parathyroid hormone (PTH) levels are inadequate to maintain plasma calcium concentration within the reference range. On conventional treatment with calcium supplements and active vitamin D analogues, bone turnover is abnormally low, and BMD is markedly increased. We aimed to study the effects of PTH-replacement therapy (PTH-RT) on calcium-phosphate homeostasis and BMD. In a double-blind design, we randomized 62 patients with hypoparathyroidism to daily treatment with PTH(1-84) 100 µg or similar placebo for 24 weeks as add-on therapy to conventional treatment. Compared with placebo, patients on PTH(1-84) reduced their daily dose of calcium and active vitamin D significantly by 75% and 73%, respectively, without developing hypocalcemia. However, hypercalcemia occurred frequently during the downtitration of calcium and active vitamin D. Plasma phosphate and renal calcium and phosphate excretion did not change. Compared with placebo, PTH(1-84) treatment significantly increased plasma levels of bone-specific alkaline phosphatase (+226% ± 36%), osteocalcin (+807% ± 186%), N-terminal propeptide of procollagen 1 (P1NP; +1315% ± 330%), cross-linked C-telopeptide of type 1 collagen (CTX; +1209% ± 459%), and urinary cross-linked N-telopeptide of type 1 collagen (NTX; (+830% ± 165%), whereas BMD decreased at the hip (-1.59% ± 0.57%), lumbar spine (-1.76% ± 1.03%), and whole body (-1.26% ± 0.49%) but not at the forearm. In conclusion, the need for calcium and active vitamin D is reduced significantly during PTH-RT, whereas plasma calcium and phosphate levels are maintained within the physiologic range. In contrast to the effect of PTH(1-84) treatment in patients with osteoporosis, PTH-RT in hypoparathyroidism causes a decrease in BMD. This is most likely due to the marked increased bone turnover. Accordingly, PTH-RT counteracts the state of overmineralized bone and, during long-term treatment, may cause a more physiologic bone metabolism.

Relationships among bone turnover, renal function and periodontal disease in elderly Japanese

We hypothesized that renal function is associated with the relationship between periodontal disease and bone metabolism. The present study evaluated the relationship of bone formation and resorption markers to periodontal disease, taking renal function into consideration, in elderly Japanese subjects. We selected 148 subjects aged 77 years. The periodontal examination included the assessment of clinical attachment level (CAL). We measured two bone formation markers (serum bone-specific alkaline phosphatase and serum osteocalcin) and two bone resorption markers (urinary deoxypyridinoline and urinary cross-linked N-telopeptide of type I collagen). Creatinine clearance per 24 h, as a measure of renal function, was also determined. The correlations between mean CAL or percentage of sites with ≥6mm CAL (6+mm CAL) and bone turnover markers, and between bone turnover markers and creatinine clearance levels, were performed by multiple linear regression analysis. There were significant negative relationships between mean CAL or 6+mm CAL and serum osteocalcin levels adjusted for gender, smoking habits and oral care habits (β=-0.25, p=0.014 and β=-0.35, p=0.001, respectively). In addition, there was a negative relationship between serum osteocalcin and creatinine clearance levels adjusted for gender and smoking habits (β=-0.45, p<0.0001). Results from the present study suggest that serum osteocalcin was significantly associated with renal function and periodontal disease. The low systemic bone metabolism, which might be caused by low renal function, is associated with periodontal disease.

Relationship between environmental exposure to cadmium and bone metabolism in a non-polluted area of Japan.

The purpose of this study was to investigate the effects of environmental low-grade cadmium exposure on bone in the population of a non-polluted area. We investigated the relationship between environmental cadmium exposure (via rice intake) and bone metabolism in middle-aged and elderly women living in a non-polluted area in Japan. Four hundred and twenty-nine women over the age of 39years (54.6±9.1years; arithmetic mean±SD) participated in this study in 2003. We investigated blood and urine, and rice intake, and performed ultrasonic bone evaluation, and obtained individual information about the subjects' health. Multiple regression analysis was performed in the statistical analysis. The arithmetic mean of cadmium content in rice was 70.8±44.7μg/kg (AM±SD). The geometric mean of daily cadmium intake (Cd intake) from rice calculated based on food consumption data was 9.12μg/day (GSD 2.33). The geometric means of serum and urine cadmium concentrations were 1.57μg/l (GSD 2.11) and 1.93μg/g creatinine (cr.) (GSD 2.05), respectively. Multiple regression analysis showed positive correlations between (1) urinary free deoxypyridinoline (FDPD-U) and Cd intake (p<0.05), (2) urinary cross-linked N-telopeptides of type I collagen (NTx-U) and Cd intake (p<0.05), and (3) FDPD-U or NTx-U and cadmium concentration in urine (p<0.01). No significant correlation between the parameters of ultrasonic bone evaluation and cadmium associated biomarkers was observed. The results of the present study suggest the possibility of bone metabolic disorder induced by environmental low-grade cadmium exposure. With respect to osteoporosis, a long-term follow-up survey is required to assess the tolerable intake of cadmium in environmental exposure.

Course of NTX changes under continuous bisphosphonate treatment in cases of NTX over-reduction due to long-term treatment with bisphosphonates

BackgroundIt has recently been suggested that long-term continuous treatment with bisphosphonates can eventually result in skeletal harm. We reported that the level of urinary cross-linked N-telopeptide of type I collagen (NTX) was over-reduced in 11 of 87 (12.7%) patients receiving long-term therapy with bisphosphonates. In this case, it is inconclusive whether treatment with bisphosphonates should be continued or not after over-reduction of bone resorption markers. In this study, we demonstrated changes in NTX levels in 13 patients who consented to continue treatment with bisphosphonates even after the over-reduction of NTX levels. Materials and methodsWe investigated 13 osteoporosis patients who wanted to continue taking bisphosphonates even after an over-reduction of their NTX levels (less than 9.3 nmolBCE/mmol Cr) caused by the long-term treatment had been recognized. We measured NTX and serum alkaline phosphatase (ALP) levels, and lumbar bone mineral density (BMD). Measurements were made at 12, 24 and 36 months before and after the recognition of NTX over-reduction. ResultsMean NTX levels at 42, 36, 24 and 12 months prior to recognition of NTX over-reduction (42.6 ± 38.5, 31.9 ± 16.4, 25.0 ± 10.2 and 20.4 ± 9.5 nmolBCE/mmol Cr, respectively) decreased incrementally. In contrast, mean NTX levels at 6, 12, 24 and 36 months (16.0 ± 4.6, 19.6 ± 11.9, 16.8 ± 6.4 and 18.2 ± 5.9 nmolBCE/mmol Cr, respectively) after NTX over-reduction (8.7 ± 0.9 nmolBCE/mmol Cr) returned to within the reference range. Mean ALP levels did not reveal significant change and stayed within the reference range (110–370 IU/l) during the total course of bisphosphonate treatment. Mean BMD values had a tendency to increase throughout the entire period of bisphosphonate treatment. ConclusionThe NTX levels in all 13 cases returned to within the reference range even when bisphosphonate treatment was continued after the over-reduction of NTX levels because of long-term bisphosphonate treatment, and continued treatment was not observed to cause atypical fractures of the femur in any of the patients.

Evaluation of the safety, pharmacokinetics and treatment effects of an ανβ3 integrin inhibitor on bone turnover and disease activity in men with hormone‐refractory prostate cancer and bone metastases

This study aimed to evaluate the safety, pharmacokinetics and treatment effects of an alpha(nu)beta(3) integrin inhibitor on bone turnover and disease activity in men with hormone-refractory prostate cancer (HRPC) and bone metastases. A total of 21 patients with bone metastases and HRPC were randomized to receive MK-0429 200 mg b.i.d. or 1600 mg b.i.d. for 4 weeks. Toxicity, pharmacokinetics and markers of bone turnover and tumor activity were examined. Nausea was the most common adverse event: one (200-mg group) and 11 (1600-mg group) patients. At 4 weeks, mean AUC(0-12 h) was 210 mmol*h (200-mg group) and 673 mmol*h (1600-mg group); mean C(max) values were 42 mmol/L (200-mg group) and 154 mmol/L (1600-mg group). Urinary cross-linked N-telopeptides of type I collagen to creatinine ratio (uNTx), a bone turnover biomarker, showed a change from baseline of -43.4 percent (200-mg group) and -34.1 percent (1600-mg group). There was an increase in serum prostate specific antigen (PSA), a marker for disease activity, of 54.1 percent (200-mg group) and 44.5 percent (1600-mg group). MK-0429 was generally well tolerated, with the most common side-effect being nausea. There was some evidence of an early reduction of bone turnover, indicating a potential for clinical use in the treatment of MBD although serum PSA was unexpectedly increased during the study.