Urinary pentosidine and plasma homocysteine levels at baseline predict future fractures in osteoporosis patients under bisphosphonate treatment.

To clarify what kind of risk factors predict incident fractures in patients treated with bisphosphonates, the authors investigated the relationship between baseline characteristics and incident vertebral fracture in Japanese osteoporosis patients undergoing bisphosphonate treatment. This was a multi-center follow-up study conducted at three centers, in which a total of 251 Japanese patients with osteoporosis (mean age 70.5 years) from the three centers were followed for 3.2 ± 2.0 years. Baseline data, including pre-existing fractures, bone mineral density in the lumbar spine (LBMD), bone metabolic markers, urinary pentosidine, and plasma homocysteine, were evaluated. Changes in LBMD, bone turnover markers, and incident fractures after the treatment were followed. Sixty-one patients developed incident vertebral fractures; this group of patients was older and had lower LBMD, a higher prevalent vertebral fracture number, and higher homocysteine and pentosidine levels than patients who did not develop incident vertebral fractures. Changes in LBMD, urinary N-terminal telopeptides of type I collagen (NTX), and bone-derived alkaline phosphatase showed no significant association with the occurrence of vertebral fractures. Cox's proportional hazard model demonstrated that age, prevalent fracture, pentosidine, and homocysteine were independent predictors of the incident vertebral fracture rate under bisphosphonate treatment. Higher baseline levels of pentosidine and homocysteine in osteoporosis patients are potential risk factors for incident vertebral fractures when these patients are treated with bisphosphonates. Further clarification is needed to explain why such patients have higher fracture susceptibility.

Low urine pH and acid excretion do not predict bone fractures or the loss of bone mineral density: a prospective cohort study.

BACKGROUND: The acid-ash hypothesis, the alkaline diet, and related products are marketed to the general public. Websites, lay literature, and direct mail marketing encourage people to measure their urine pH to assess their health status and their risk of osteoporosis.The objectives of this study were to determine whether 1) low urine pH, or 2) acid excretion in urine [sulfate + chloride + 1.8x phosphate + organic acids] minus [sodium + potassium + 2x calcium + 2x magnesium mEq] in fasting morning urine predict: a) fragility fractures; and b) five-year change of bone mineral density (BMD) in adults. DESIGN: Cohort study: the prospective population-based Canadian Multicentre Osteoporosis Study. Multiple logistic regression was used to examine associations between acid excretion (urine pH and urine acid excretion) in fasting morning with the incidence of fractures (6804 person years). Multiple linear regression was used to examine associations between acid excretion with changes in BMD over 5-years at three sites: lumbar spine, femoral neck, and total hip (n = 651). Potential confounders controlled included: age, gender, family history of osteoporosis, physical activity, smoking, calcium intake, vitamin D status, estrogen status, medications, renal function, urine creatinine, body mass index, and change of body mass index. RESULTS: There were no associations between either urine pH or acid excretion and either the incidence of fractures or change of BMD after adjustment for confounders. CONCLUSION: Urine pH and urine acid excretion do not predict osteoporosis risk.

Effect of changes in serum levels of endogenous hydrogen sulfide on fracture healing: Study protocol clinical trial (SPIRIT compliant).

BACKGROUND: Fracture is a common disease; many factors affect fracture healing. Recent studies have confirmed that hydrogen sulfide (H2S) plays an essential role in bone formation, but most of these studies are drawing conclusions based on animal experiment; whether H2S could promote fracture healing in patients is still unclear. We aim to investigate the change of serum H2S in fracture patients, and analyze its effort on fracture healing. METHODS: This is a single-center, prospective cohort study. Patients with spinal or limb fracture will be recruited. Patient's serum and urine will be collected at baseline for examination (serum H2S, ß-CTX, OC, PINP, 25-OH-VitD3, S-CTX, urinary calcium, and urinary creatinine). All patients will be followed-up for 24 months in outpatients settings, the image of X-ray or CT will be reviewed and fracture healing will be judged by 2 experienced orthopedic physicians. The difference in serum parameters especially H2S will be compared between patients with fracture healed within 9 months and those with fracture unhealed at 9 months. DISCUSSION: Results of the trial could provide insight into influence of H2S on fracture healing. ETHICS AND DISSEMINATION: The study was approved by the ethics committee of School of Medicine UESTC & Sichuan Provincial People's Hospital Ethics Committee. All the participants will be asked to provide written informed consent before data collection. The findings of the study will be published in peer-reviewed journals and will be presented at national or international conferences.

Hyperparathyroidism in patients over 75: Clinical characteristics and outcome. Is conservative treatment a safe alternative?

OBJECTIVE: With the current aging of the world's population, primary hyperparathyroidism (PHPT) is increasingly detected in the elderly. Yet data on the presentation and outcome of PHPT in this group are scarce. The objective was to describe a cohort of patients aged 75 years or more with PHPT observed in our endocrine clinic. STUDY DESIGN: A retrospective analysis of medical records in an endocrine clinic at a tertiary hospital. We evaluated 182 patients with PHPT, aged 75 years or more at their last follow-up, all diagnosed at age 65 or more. Laboratory data were compared at diagnosis and last follow-up. RESULTS: Mean age at diagnosis was 73 ± 4 years, last follow-up was at 83 ± 4 years, and mean follow-up was 11.3 ± 5.5 years. Osteoporosis, fractures, and nephrolithiasis were diagnosed in 114(63 %), 84(46 %), and 43(24 %) patients, respectively. Overall, 150 patients had an indication for surgery; of them, the 29 who underwent parathyroidectomy were younger than the non-operated patients and had higher rates of hypercalciuria. During the follow-up of the 141 patients who did not undergo operation, serum and urinary calcium levels significantly had decreased, and vitamin D level had increased at last visit (10.4 ± 0.5 mg/dl, 161 ± 70 mg/24 h, 69 ± 17 nmol/l, p < 0.01 respectively) compared with levels at diagnosis (10.6 ± 0.2 mg/dl, 223 ± 95 mg/24 h, 53 ± 15 nmol/l, respectively, p = 0.001). Overall, 38 of the 182 patients (20 %) died during follow-up; these patients were significantly older at diagnosis (76 ± 5 vs. 72 ± 4 years) but there were no differences in laboratory variables. CONCLUSIONS: While most patients had a formal indication for surgery, few underwent parathyroidectomy. Serum and urinary calcium significantly decreased during follow-up in patients who did not undergo surgery. Our data are reassuring and support at least the consideration of conservative treatment for these patients.

Proteinuria Is Associated With Increased Risk of Fragility Fracture in Men With or at Risk of HIV Infection.

BACKGROUND: Proteinuria has been associated with bone loss and fractures in general population, but data in HIV-infected population are lacking. SETTING: Prospective, multicenter cohort study of men with or at risk of HIV infection. METHODS: Between 2006 and 2015, urine protein measurements and bone fracture histories were ascertained semiannually in 947 HIV-infected (HIV+) and 969 HIV-uninfected (HIV-) men aged 40 years or older. Proteinuria was defined as protein-to-creatinine ratio ≥200 mg/g at ≥2 consecutive visits. Outcome measures (1) all fractures (excluding fractures of skull, face, and digits) and (2) fragility fractures (fractures of vertebral column, femur, wrist, and humerus). Multivariable Cox proportional hazards models assessed the association between proteinuria and fracture after adjusting for additional risk factors. RESULTS: The overall period prevalence of proteinuria was higher among HIV+ than HIV- (29% vs 6%, P < 0.001). Men with proteinuria had a significantly higher risk of fragility fracture compared with men without proteinuria [adjusted hazard ratio (aHR) = 2.29 (1.12-4.66)] and did not differ by HIV serostatus (p-interaction = 0.83). The risk of all fractures was not statistically different between men with or without proteinuria [aHR = 1.31 (0.84-2.05)]. Among HIV+ men, the association between confirmed proteinuria and fragility fracture was attenuated [aHR = 2.12 (0.95-4.73)] after additional adjustment for CD4 T-cell count/mm, history of AIDS, the presence of detectable plasma HIV-1 RNA, and cumulative exposure to tenofovir disoproxil fumarate. CONCLUSIONS: Proteinuria was more common in HIV+ than in HIV- men and was a strong independent risk factor for fragility fracture regardless of HIV serostatus. Proteinuria should prompt consideration of a thorough evaluation for bone disease among HIV+ persons.

High bone turnover is associated with accelerated bone loss but not with increased fracture risk in men aged 50 and over: the prospective MINOS study.

OBJECTIVES: The association of bone turnover markers (BTM) with bone loss and fracture risk in men is poorly studied. The morphological basis of such a relationship is unknown. The objective of this study was to evaluate the association between baseline BTM levels and subsequent bone loss and fracture risk in men. METHODS: This study is a prospective 7.5-year follow-up of the cohort composed of 723 men aged 50-85 years. Serum concentrations of osteocalcin, bone alkaline phosphatase (BAP), procollagen type I N-terminal propeptide, C-terminal telopeptide of type I collagen (beta-CTX-I) and urinary excretion of deoxypyridinoline and beta-CTX-I were measured at baseline. Every 18 months, incident fractures were recorded and bone mineral density (BMD) was measured by dual energy x ray absorptiometry DXA (spine, hip, distal forearm, whole body). RESULTS: Increase in BTM levels was associated with faster bone loss at the level of the trochanter, whole body and distal forearm. At the level of the distal radius and the ulna, increase in the serum BAP and beta-CTX-I levels were associated with faster apparent, net and estimated endosteal bone mineral loss. BTM levels did not correlate with the periosteal expansion rate. BTMs were significantly associated with bone mineral loss but their predictive power was poor. BTMs did not predict incident fractures. CONCLUSIONS: In men aged 50 and over, accelerated bone turnover is associated with greater endosteal bone mineral loss. From a practical point of view, BTMs cannot be used for the prediction of accelerated bone loss or fractures in the clinical management of osteoporosis in men.

Effect of fracture on bone turnover markers: a longitudinal study comparing marker levels before and after injury in 113 elderly women.

UNLABELLED: In this longitudinal, prospective, and population-based study (n = 1044), seven BTMs were assessed before and after trauma in 113 elderly women (85 with fractures). Markers were not altered in the immediate postfracture period but were clearly elevated during fracture repair. Recent fracture should thus be taken into account when markers are used in clinical practice. INTRODUCTION: Fracture may influence the levels of bone turnover markers (BTM) and have implications for their use in clinical practice. In this longitudinal, prospective, and population-based study, we assessed prefracture levels of BTMs and compared them with postfracture levels of the same individuals immediately after fracture and during fracture repair. This is the first study in which the effect of fracture on bone markers has been evaluated with prefracture samples available. MATERIALS AND METHODS: Serum and urine were collected at the emergency unit from 85 women (77.9 +/- 1.8 yr) who sustained a fracture after low-energy trauma and 28 controls (77.8 +/- 2.0 yr) with similar trauma but no fracture. All were participants of the Malmö OPRA study (n = 1044), and pretrauma samples were collected 1.05 +/- 0.85 yr before. Bone turnover was assessed by seven different BTMs reflecting different stages of bone metabolism {C-terminal cross-linked telopeptides of type I collagen [S-CTX], S-TRACP5b, N-terminal propeptides of type I collagen [S-PINP], serum osteocalcin (S-OC[1-49] and S-TotalOC), urinary deoxypyridinoline [U-DPD], and urinary osteocalcin [U-OC]}. RESULTS: BTMs sampled within a few hours after fracture were not altered from preinjury levels. Both bone formation and bone resorption markers were, however, significantly increased 4 mo after fracture. The elevation was most pronounced after hip fracture. Bone turnover remained elevated up to 12 mo after fracture. CONCLUSIONS: We believe this study extends our knowledge on the skeletal postfracture metabolic processes. In addition, it may provide a basis for future means to monitor pharmacological intervention promoting fracture healing.

Vitamin K deficiency from long-term warfarin anticoagulation does not alter skeletal status in male rhesus monkeys.

UNLABELLED: Vitamin K (K) inadequacy may cause bone loss. Thus, K deficiency induced by anticoagulants (e.g., warfarin) may be an osteoporosis risk factor. The skeletal impact of long-term warfarin anticoagulation was evaluated in male monkeys. No effect on BMD or bone markers of skeletal turnover was observed. This study suggests that warfarin-induced K deficiency does not have skeletal effects. INTRODUCTION: The skeletal role of vitamin K (K) remains unclear. It is reasonable that a potential role of vitamin K in bone health could be elucidated by study of patients receiving oral anticoagulants that act to produce vitamin K deficiency. However, some, but not all, reports find K deficiency induced by warfarin (W) anticoagulation to be associated with low bone mass. Additionally, epidemiologic studies have found W use to be associated with either increased or no change in fracture risk. Such divergent results may imply that human studies are compromised by the physical illnesses for which W was prescribed. MATERIALS AND METHODS: To remove this potential confounder, we prospectively assessed skeletal status during long-term W anticoagulation of healthy nonhuman primates. Twenty adult (age, 7.4-17.9 yr, mean, 11.7 yr) male rhesus monkeys (Macaca mulatta) were randomized to daily W treatment or control groups. Bone mass of the total body, lumbar spine, and distal and central radius was determined by DXA at baseline and after 3, 6, 9, 12, 18, 24, and 30 mo of W treatment. Serum chemistries, urinary calcium excretion, bone-specific alkaline phosphatase, and total and percent unbound osteocalcin were measured at the same time-points. Prothrombin time and international normalized ratio (INR) were monitored monthly. Serum 25-hydroxyvitamin D was measured at the time of study conclusion. RESULTS: W treatment produced skeletal K deficiency documented by elevation of circulating undercarboxylated osteocalcin (8.3% W versus 0.4% control, p<0.0001) but did not alter serum markers of skeletal turnover, urinary calcium excretion, or BMD. CONCLUSIONS: In male rhesus monkeys, long-term W anticoagulation does not alter serum markers of bone turnover or BMD. Long-term W therapy does not have adverse skeletal consequences in primates with high intakes of calcium and vitamin D.

Association of Increased Urinary Albumin With Risk of Incident Clinical Fracture and Rate of Hip Bone Loss: the Osteoporotic Fractures in Men Study.

Prior studies suggest that increased urine albumin is associated with a heightened fracture risk in women, but results in men are unclear. We used data from Osteoporotic Fractures in Men (MrOS), a prospective cohort study of community-dwelling men aged ≥65 years, to evaluate the association of increased urine albumin with subsequent fractures and annualized rate of hip bone loss. We calculated albumin/creatinine ratio (ACR) from urine collected at the 2003-2005 visit. Subsequent clinical fractures were ascertained from triannual questionnaires and centrally adjudicated by review of radiographic reports. Total hip BMD was measured by DXA at the 2003-2005 visit and again an average of 3.5 years later. We estimated risk of incident clinical fracture using Cox proportional hazards models, and annualized BMD change using ANCOVA. Of 2982 men with calculable ACR, 9.4% had ACR ≥30 mg/g (albuminuria) and 1.0% had ACR ≥300 mg/g (macroalbuminuria). During a mean of 8.7 years of follow-up, 20.0% of men had an incident clinical fracture. In multivariate-adjusted models, neither higher ACR quintile (p for trend 0.75) nor albuminuria (HR versus no albuminuria, 0.89; 95% CI, 0.65 to 1.20) was associated with increased risk of incident clinical fracture. Increased urine albumin had a borderline significant, multivariate-adjusted, positive association with rate of total hip bone loss when modeled in ACR quintiles (p = 0.06), but not when modeled as albuminuria versus no albuminuria. Macroalbuminuria was associated with a higher rate of annualized hip bone loss compared to no albuminuria (-1.8% more annualized loss than in men with ACR <30 mg/g; p < 0.001), but the limited prevalence of macroalbuminuria precluded reliable estimates of its fracture associations. In these community-dwelling older men, we found no association between urine albumin levels and risk of incident clinical fracture, but found a borderline significant, positive association with rate of hip bone loss. © 2016 American Society for Bone and Mineral Research.

The variation in urinary calcium levels in adult patients with fracture and surgical intervention.

BACKGROUND: Generally, a higher calcium diet is fed to fracture patients after surgery. However, recent studies have indicated that higher dietary calcium intakes increase the risk of urinary stones for fracture patients. Therefore, this study aimed to observe the variation in urinary calcium levels among fracture patients who underwent surgery, based on fracture type, fracture location, age and gender. METHODS: A total of 768 subjects were enrolled in this study from 2012 to 2015 and were divided into 2 groups: group A (fracture patients who underwent surgery) and group B (normal patients without fracture). Urine samples were collected for a 24-h period (24-h urine), at multiple specific time points before and after surgery for group A, or after hospitalisation for group B. Subsequently, urine calcium was detected and the changes were evaluated according to fracture location, fracture type, age and gender, as well as the distribution of hypercalciuria. RESULTS: Compared with group B, the level of urine calcium in group A significantly increased at different time points during the study period (P < 0.05). There were significant differences in the changes in urine calcium levels according to fracture location, fracture type and age, but not gender. Further, there were more patients with hypercalciuria in group A at the different time points, compared with group B. CONCLUSION: Variation in urinary calcium among fracture patients that underwent surgery was of a regular pattern and hypercalciuria was also found in these patients. Therefore, a high-calcium diet and calcium supplements should be used with caution in this patient population.

Urinary Citrate, an Index of Acid-Base Status, Predicts Bone Strength in Youths and Fracture Risk in Adult Females.

CONTEXT: Diet can impact on bone strength via metabolic shifts in acid-base status. In contrast to the strongly diet-dependent biomarker urinary potential renal acid load (uPRAL), the amount of renally excreted citrate integrates nutritional and systemic influences on acid-base homeostasis with high citrate indicating prevailing alkalization. OBJECTIVE: To examine the association between urinary citrate excretion and bone strength as well as long-term fracture risk. DESIGN AND PARTICIPANTS: Prospective cross-sectional analysis; 231 healthy children (6-18 y) of the Dortmund Nutritional and Anthropometric Longitudinally Designed Study were included, with at least 2 urine collections available during the 4 years preceding peripheral quantitative computed tomography (pQCT) of the nondominant proximal forearm. uPRAL, urinary citrate, and urinary nitrogen excretion were quantified in 857 24-hour urine samples. Data on overall fracture incidence were collected within a 15-year follow-up after pQCT measurement. MAIN OUTCOME MEASURES: Parameters of bone quality and geometry (pQCT) as well as long-term fracture incidence. RESULTS: After controlling for confounders, especially forearm length, muscle area, and urinary nitrogen (biomarker of protein intake), urinary citrate excretion was positively associated with various parameters of bone quality and geometry (P < .05). Fracture risk in adult females, but not in males, was inversely associated with urinary citrate and positively with uPRAL (P < .05). CONCLUSIONS: Although urinary citrate has to be confirmed as an integrated noninvasive biomarker of systemic acid-base status in further studies, our results substantiate dietary and metabolic acidity as potentially adverse for bone health in the long run from childhood onward.

Low-Level Cadmium Exposure Is Associated With Decreased Bone Mineral Density and Increased Risk of Incident Fractures in Elderly Men: The MrOS Sweden Study.

One risk factor for osteoporosis that has attracted increasing attention in recent years is exposure to cadmium. The aim of this study was to examine the associations between low-level cadmium exposure, from diet and smoking, and bone mineral density (BMD) and incident fractures in elderly men. The study population consisted of 936 men from the Swedish cohort of the Osteoporotic Fractures in Men (MrOS) study, aged 70 to 81 years at inclusion (years 2002 to 2004), with reliable data on cadmium in urine (U-Cd) analyzed using inductively coupled plasma mass spectrometry in baseline samples. The participants also answered a questionnaire on lifestyle factors and medical history. BMD was measured at baseline using dual-energy X-ray absorptiometry (DXA) in the total body, hip, and lumbar spine. During the follow-up period (until 2013), all new fractures were registered by date and type. Associations between BMD and U-Cd were assessed using multiple linear regression, and associations between incident fractures and baseline U-Cd were analyzed using Cox regression. In both cases, a number of potential confounders and other risk factors (eg, age, smoking, body mass index [BMI], and physical activity) were included in the models. We found significant negative associations between U-Cd and BMD, with lower BMD (4% to 8%) for all sites in the fourth quartile of U-Cd, using the first quartile as the reference. In addition, we found positive associations between U-Cd and incident fractures, especially nonvertebral osteoporosis fractures in the fourth quartile of U-Cd, with hazard ratios of 1.8 to 3.3 in the various models. U-Cd as a continuous variable was significantly associated with nonvertebral osteoporosis fractures (adjusted hazard ratio 1.3 to 1.4 per µg Cd/g creatinine), also in never-smokers, but not with the other fracture groups (all fractures, hip fractures, vertebral fractures, and other fractures). Our results indicate that even relatively low cadmium exposure through diet and smoking increases the risk of low BMD and osteoporosis-related fractures in elderly men.

Methylation of bone SOST, its mRNA, and serum sclerostin levels correlate strongly with fracture risk in postmenopausal women.

Inhibition of sclerostin, a glycoprotein secreted by osteocytes, offers a new therapeutic paradigm for treatment of osteoporosis (OP) through its critical role as Wnt/catenin signaling regulator. This study describes the epigenetic regulation of SOST expression in bone biopsies of postmenopausal women. We correlated serum sclerostin to bone mineral density (BMD), fractures, and bone remodeling parameters, and related these findings to epigenetic and genetic disease mechanisms. Serum sclerostin and bone remodeling biomarkers were measured in two postmenopausal groups: healthy (BMD T-score > -1) and established OP (BMD T-score < -2.5, with at least one low-energy fracture). Bone specimens were used to analyze SOST mRNAs, single nucleotide polymorphisms (SNPs), and DNA methylation changes. The SOST gene promoter region showed increased CpG methylation in OP patients (n = 4) compared to age and body mass index (BMI) balanced controls (n = 4) (80.5% versus 63.2%, p = 0.0001) with replication in independent cohorts (n = 27 and n = 36, respectively). Serum sclerostin and bone SOST mRNA expression correlated positively with age-adjusted and BMI-adjusted total hip BMD (r = 0.47 and r = 0.43, respectively; both p < 0.0005), and inversely to serum bone turnover markers. Five SNPs, one of which replicates in an independent population-based genomewide association study (GWAS), showed association with serum sclerostin or SOST mRNA levels under an additive model (p = 0.0016 to 0.0079). Genetic and epigenetic changes in SOST influence its bone mRNA expression and serum sclerostin levels in postmenopausal women. The observations suggest that increased SOST promoter methylation seen in OP is a compensatory counteracting mechanism, which lowers serum sclerostin concentrations and reduces inhibition of Wnt signaling in an attempt to promote bone formation.

Prevalence and causes of low bone density and fractures in kidney transplant patients.

Osteoporosis is known to occur in patients with kidney transplants, but limited information is available about the prevalence and causes of this complication. We asked all 330 patients with kidney transplants in our unit to participate in this study of whom 165 (50%) agreed to do so. The characteristics of the participating patients were similar to the remaining 165 nonparticipants. Seventy of 165 (42%) of the participants were women of whom 40 were postmenopausal in contrast to the men of whom only one was hypogonadal. Bone mineral density (BMD) was significantly reduced at the radius (Z score, -1.5) and femoral neck (Z score, -0.7), but the lumbar spine was normal. BMD was lower in women than men at all skeletal sites. Osteoporosis was found in 10-44% and osteopenia was found in 35-50% of women depending on the site. BMD was related inversely to time since transplantation and cumulative prednisolone dose. Twenty-seven of the 165 (16%) patients had either vertebral deformities or a history of a low trauma fracture after transplantation. This fracture group consisted of 10/27 (37%) men and 17/27 (63%) women, of whom 14 were postmenopausal. Fracture patients tended to be older and have a longer duration of renal failure, dialysis, transplantation, greater cumulative steroid dose, and higher bone resorption markers than the nonfracture group. No differences were found for cumulative doses of cyclosporin or tacrolimus. Logistic regression showed that only duration of dialysis and time since transplantation significantly increased fracture risk, with odds ratio (OR) for each year of dialysis or transplantation being 1.21 (CI, 1.00-1.48) and 1.14 (CI, 1.05-1.23), respectively. These data show that low bone density and fractures are common in patients with kidney transplant and are determined by both pre- and posttransplant variables. Fracture risk was greatest in women, particularly if they were postmenopausal and we recommend that this subgroup is targeted for assessment and treatment.

Type I collagen racemization and isomerization and the risk of fracture in postmenopausal women: the OFELY prospective study.

The Asp1211 residue of the 1209AHDGGR1214 sequence of the C-terminal cross-linking telopeptide of type I collagen (CTX) can undergo spontaneous post-translational modifications, namely, racemization and isomerization, which result in the formation of four isomers: the native form (alpha-L) and three age-related forms, that is, an isomerized form (beta-L), a racemized form (alpha-D), and an isomerized/racemized (beta-D) form. Previous studies have suggested that changes in the pattern of type I collagen racemization/isomerization, which can be assessed in vivo by measuring the degradation products of the CTX isoforms, may be associated with alterations of bone structure. The aim of this study was to examine prospectively the value of the different urinary CTX isoforms and their related ratio in the prediction of osteoporotic fractures in 408 healthy untreated postmenopausal women aged 50-89 years (mean, 64 years) who were part of the OFELY cohort. During a median 6.8 years follow-up, 16 incident vertebral fractures and 55 peripheral fractures were recorded in 65 women. The baseline levels of the four CTX isoforms in women who subsequently had a fracture were compared with those of the 343 women who did not fracture. At baseline, women with fractures had increased levels of ratios of native alpha-L-CTX to age-related isoforms (beta-L, alpha-D, and beta-D) compared with controls (p < 0.01). In logistic regression analysis after adjustment for age, prevalent fractures, and physical activity, women with levels of alpha-L/beta-L, alpha-L/alpha-D, and alpha-L/beta-D-CTX ratios in the highest quartile had a 1.5- to 2-fold increased risk of fractures compared with women with levels in the three lowest quartiles with relative risk (RR) and 95% CI of 2.0 (1.2-3.5), 1.8 (1.02-2.7), and 1.5 (0.9-2.7), respectively. Adjustment of alpha-L/beta-L and alpha-L/alpha-D-CTX ratios by the level of bone turnover assessed by serum bone alkaline phosphatase (ALP)- or femoral neck bone mineral density (BMD) decreased slightly the RR, which remained significant for the alpha-L/beta-L-CTX ratio (RR [95%] CI, 1.8 [1.1-3.2] after adjustment for bone ALP, 1.8 [1.03-3.1] after adjustment for BMD, and 1.7 [0.95-2.9] after adjustment for both bone ALP and BMD). Women with both high alpha-L/beta-L-CTX ratio and high bone ALP had a 50% higher risk of fracture than women with either one of these two risk factors. Similarly, women with both increased CTX ratio and low femoral neck BMD (T score < -2.5) had a higher risk of fracture with an RR (95% CI) of 4.5 (2.0-10.1). In conclusion, increased urinary ratio between native and age-related forms of CTX, reflecting decreased degree of type I collagen racemization/isomerization, is associated with increased fracture risk independently of BMD and partly of bone turnover rate. This suggests that alterations of type I collagen isomerization/racemization that can be detected by changes in urinary CTX ratios may be associated with increased skeletal fragility.

Biochemical markers of bone turnover, endogenous hormones and the risk of fractures in postmenopausal women: the OFELY study.

The mechanisms leading to increased bone loss and skeletal fragility in women with postmenopausal osteoporosis are still poorly understood. Increased bone resorption, low serum estradiol and high serum sex-hormone-binding globulin (SHBG) recently have been reported as predictors of vertebral and hip fractures in elderly women. In a cohort of healthy untreated younger postmenopausal women aged 50-89 years (mean, 64 years), we compared baseline levels of bone markers and endogenous hormones in 55 women who subsequently had a fracture (20 vertebral and 35 peripheral fractures) with levels in the 380 women who did not fracture during a mean 5 years of follow-up. Women with levels in the highest quartile of four bone resorption markers including urinary-free deoxypyridinoline (D-Pyr), urinary type I collagen N-telopeptides (NTX), and urinary and serum type I collagen C-telopeptides (CTX) had about a 2-fold increased risk of fractures compared with women with levels in the three lowest quartiles with relative risk (RR) and 95% CI of 1.8 (1.0-3.4) for free D-Pyr, 1.7 (0.9-3.2) for urinary NTX, 2.3 (1.3-4.1) for urinary CTX, and 2.1 (1.2-3.8) for serum CTX. Serum levels of bone alkaline phosphatase (BAP) in the highest quartile were associated with an RR of fracture of 2.4 (1.3-4.2). Women with serum levels of estradiol and dehydroepiandrosterone (DHEA) sulfate in the lowest quartile had an RR of fracture of 2.2 (1.2-4.0) and 2.1 (1.2-3.8), respectively. Increased levels of SHBG and intact parathyroid hormone (PTH) were moderately associated with an increased risk of fracture. Similar results were obtained when the analysis was restricted to symptomatic vertebral and nonvertebral fractures. Adjustment of biochemical markers by hormone levels did not significantly alter the results. Women with both high bone resorption markers and low estradiol (or low DHEA sulfate) had a higher risk of fracture with RRs of 3.0-3.3 (p < 0.001). After adjustment for bone mineral density (BMD) of the hip, spine, radius, or total body, bone markers and hormones were still predictive of fracture risk with similar RRs. We conclude that high levels of some biochemical markers of bone turnover, low serum estradiol, low DHEA sulfate, high SHBG, and high PTH are associated with increased risk of osteoporotic fracture in postmenopausal women, independently of each other and of BMD. The mechanism by which some postmenopausal women have an increased rate of bone turnover leading to an increased risk of fracture remains to be elucidated.

The relation between cortisol excretion and fractures in healthy older people: results from the MacArthur studies-Mac.

BACKGROUND: In persons with depression, higher urinary cortisol is associated with lower bone mineral density. OBJECTIVE: To examine the relation between urinary free cortisol (UFC) and fractures. SETTING: Community-based samples from Durham, NC, East Boston, MA, and New Haven, CT. PARTICIPANTS: 684 men and women, aged 70 to 79 at baseline, who were part of the MacArthur Study of Successful Aging. DESIGN: Cohort study. Participants with previous history of fractures at baseline were excluded. MEASURES: The primary exposure variable was overnight (8:00 p.m. to 8:00 a.m.) UFC (microg/g creatinine) at baseline (1988). Outcomes were self-reported hip, arm, spine, wrist, or other fracture during the follow-up period (1988-1995). Covariates were baseline age, gender, race, body mass index, current physical activity, lower extremity strength, depression subscale of the Hopkins Symptom Checklist, and current use of cigarettes and alcohol. ANALYSIS: Logistic regression was used to predict the occurrence of incident fractures (1988-1995) as a function of quartiles of baseline UFC. Models were adjusted for age, gender, and race and were also multiply adjusted for the remaining covariates listed above. Gender-stratified models and models that excluded corticosteroid users were also run. RESULTS: In multiply adjusted models, higher baseline levels of UFC were significantly associated with incident fractures. Odds of fracture (95% Confidence Intervals) for increasing quartiles of baseline UFC, multiply adjusted, were: 2.28 (.91, 5.77); 3.40 (1.33, 8.69); 5.38 (1.68, 17.21). Results were not materially influenced by exclusion of persons using corticosteroids. CONCLUSIONS: Higher baseline UFC is an independent predictor of future fracture.

Measurements of urinary nonisomerized form of type I collagen degradation products (alpha-CTx) in aging, menopause, and osteoporosis with fractures.

We have evaluated the effect of aging, menopause, and osteoporosis on the measurements of urinary nonisomerized form of type I collagen degradation products (alpha-CTx). In 18 children, 86 premenopausal healthy women, 144 postmenopausal healthy women, 74 patients with vertebral fractures and 61 patients with hip fractures, alpha-CTx excretions were measured by a RIA. The age-related changes of alpha-CTx in healthy females show that the values were extremely high before the age of 16 years and decreased between ages 16 and 29, and that after the age of 40 years, the values tended to increase and to vary widely with age. In menopause, alpha-CTx in postmenopausal subjects was significantly higher than those in premenopausal subjects. There was no significant correlation between alpha-CTx and years since menopause in 102 postmenopausal subjects. Alpha-CTx in the vertebral fracture group were higher than those in the postmenopause group, but not significantly. Alpha-CTx in the hip fracture group were significantly higher than those in postmenopause and vertebral fracture groups. In age-matched comparisons, the values of the patients with vertebral fracture and the patients with hip fracture were significantly higher than those of corresponded age-matched postmenopausal women. Alpha-CTx well reflects an increase of bone resorption associated with bone modeling at childhood and high bone resorption after the menopause and higher bone resorption in osteoporotic patients with fractures.

Urinary zinc, copper, nitrogen, and potassium losses in response to trauma.

The urinary losses of zinc, copper, nitrogen and potassium were measured for 14 trauma patients for periods ranging from nine to 30 days and for nine normal subjects over four days each. The mean losses per day as well as peak losses by patients were compared to the mean normal losses. The mean peak losses of all elements were 2 to 10 times greater than normal. The ratios of the urinary concentrations of these catabolites in relation to each other were calculated. Since nutritional support was predominantly by routine intravenous solutions, the large amounts of urinary zinc, copper, nitrogen and potassium excreted represent a severe drain on the body's reserves of these elements.

Urinary hydroxyproline in multiple myeloma: correlation with clinical stages and bone disease.

Twenty-four-hour urinary hydroxyproline excretion (HOP) (normal values: 6-22 mg/day/m2) was measured by the Hypronosticon test in 50 untreated patients with plasma cell myeloma. At diagnosis, HOP was elevated in 36 of 50 patients (72%) with a mean value of 35.9 mg/day/m2. Extent of bone lesions and clinical stage were accurately assessed in all patients. Higher HOP values were found in patients with a higher degree of bone lesions (multiple lytic areas and/or destruction of skeletal segments). According to clinical stages, HOP was very elevated only in stage III (mean value: 43.7); in stages I and II the mean value (25.2) was just above the normal range. Our data indicate that HOP in multiple myeloma at diagnosis is closely related to the extension of skeletal lesions and that during the clinical course it may be useful in the follow-up of bone disease.