Low Bone Density is Not Associated with Aortic Calcification

The aging process is associated with an increasing prevalence of osteoporosis and aortic calcification, but it is uncertain if these two conditions are interrelated. We examined the relationship between bone mineral density (BMD) and evidence of aortic calcification on spinal radiographs among 524 Japanese-American women living in Hawaii. The prevalence of aortic calcification increased with age from less than 10% below age 55 to essentially all women over age 75. Unadjusted BMD was significantly lower among women with aortic calcification at all measured sites (distal and proximal radius and calcaneus). However, the differences in BMD between women with and without calcification were diminished and no longer significant after adjustment for age. Aortic calcification was positively associated with body mass index (BMI), systolic blood pressure, diabetes, current smoking, and thiazide use, but negatively associated with physical activity index. Multivariate logistic regression analysis showed that age, systolic blood pressure, physical activity index (protective), and current smoking (common etiological factors for aortic calcification) were independently associated with aortic calcification, whereas BMD (mean Z-score) was not. We conclude that there is little evidence to support a direct relationship between osteoporosis (low BMD) and aortic calcification. Osteoporosis and aortic calcification appear to be independent processes that occur as women age. However, potential confounding factors may be involved, and prospective studies are needed to investigate this issue further.     

Arterial Micro‐Calcification of Vascular Access is Associated with Aortic Arch Calcification and Arterial Stiffness in Hemodialysis Patients

Vascular calcification of the coronary arteries or aorta is an independent risk factor for cardiovascular outcome, but clinical significance of arterial micro‐calcification (AMC) of vascular access is unclear in hemodialysis (HD) patients. Sixty‐five patients awaiting vascular access operation were enrolled. We compared surrogate markers of cardiovascular morbidity such as aortic arch calcification (AoAC) by chest radiography, arterial stiffness by brachial‐ankle pulse wave velocity (baPWV) and endothelial dysfunction by flow‐mediated dilatation (FMD) between patients with and without AMC of vascular access on von Kossa staining. AMC of vascular access was detected in 36 (55.4%). The AMC‐positive group had significantly higher incidence of AoAC (63.9% vs. 20.7%, p < 0.001) and higher baPWV (26.5 ± 9.4 m/s vs. 19.8 ± 6.6 m/s, p = 0.006) than the AMC‐negative group. There was no significant difference in FMD between the two groups (5.4 ± 2.6% vs. 5.7 ± 3.5%, p = 0.764). The AMC‐positive group had higher incidence of diabetes mellitus, higher systolic blood pressure and wider pulse pressure than the AMC‐negative group. This study suggests that AMC of vascular access may be associated with cardiovascular morbidity via AoAC and arterial stiffness in HD patients.     

Withdrawal of Hormone Replacement Therapy is Associated with Significant Vertebral Bone Loss in Postmenopausal Women

This study aimed to assess the changes in vertebral bone mineral density (BMD) after cessation of hormone replacement therapy (HRT) in postmenopausal women who had been treated on a long-term basis. Fifty healthy postmenopausal women who had been followed both during the course of HRT and after cessation of treatment in our menopause clinic were included in this study. All women had started HRT within the first 3 years after the postmenopause and had received HRT (either 1.5 mg/day of 17β-estradiol given percutaneously or 50 μg/day of 17β-estradiol given as a transdermal patch, combined in all women with natural progesterone or a 19-norprogesterone derivative) for a mean 5 ± 2.4 years. In all women, vertebral BMD was assessed during the course of HRT up to the last 6 months before estrogen withdrawal, then at least once within the first 18 months after cessation of treatment. Of the initial population, 30 women were additionally reviewed later on and up to 8 years after cessation of treatment (mean duration of follow-up for the whole population: 3.9 ± 1.7 years). Rates of changes in vertebral BMD were compared with those determined in a group of healthy untreated women who had been followed within the first years of postmenopause during the same time period as the study population. In the study group, bone loss was found to accelerate within the first 2 years after HRT withdrawal and the annual rate of loss was identical to that which occurs within the first 2 years of postmenopause in untreated women (−1.64%± 1.3% vs −1.52 ± 0.9%, NS). Beyond this first 2-year time period, the annual rate of bone loss decreased as a function of time following cessation of treatment, as was observed following the menopause in untreated women (between 3 and 5 years: −0.83%+ 1.35% in the study group vs −0.70%± 0.8% in the control group, NS). On average, 3 years after cessation of HRT mean vertebral BMD when expressed as a Z-score was significantly higher (−0.13 vs −0.89, p<0.01) than at baseline, before HRT was started, which suggested a lasting beneficial effect on bone mass. However, even though our findings do not support the hypothesis that bone loss might continue to be accelerated several years after cessation of treatment we cannot fully address the question as to whether any residual benefit on bone mass over a longer period of time may be observed. In conclusion, the pattern of bone loss observed after cessation of estrogen therapy was found to be comparable to that which occurs in younger women within the first years after the menopause. Such a pattern needs to be kept in mind when the decision to stop HRT is taken, especially in women who were given HRT to prevent osteoporosis. The issue of assessing their risk of fracture several years after cessation of treatment thus needs to be addressed. Received: 25 July 2000 / Accepted: 5 December 2000     

Evidence that Abnormal High Bone Mineralization in Growing Children with Osteogenesis Imperfecta is not Associated with Specific Collagen Mutations

Osteogenesis imperfecta type I (OI-I) represents the mildest form of OI. The collagen I mutations underlying the disorder can be classified as quantitative mutations that lead to formation of a decreased amount of normal collagen or qualitative mutations where structurally aberrant collagen chains are generated. However, the phenotypic consequences of a particular mutation are not well understood. Transiliac bone biopsies from 19 young OI-I patients (age range 2.0–14.1 years) and 19 age-matched controls were used to assess bone histomorphometric parameters and bone mineralization density distribution, measured by quantitative backscattered electron imaging. Thirteen of the OI-I patients were affected by quantitative and six patients by qualitative mutations. Compared to age-matched controls, iliac bone samples in the OI group were smaller and had thinner cortices and less trabecular bone. Resorption parameters were similar between groups, whereas surface-based parameters of bone formation were considerably higher in OI patients than in controls with the exception of bone formation rate per osteoblast surface, which was reduced in OI. Backscattered electron imaging revealed a higher mean mineralization density (+7%, P < 0.001) in OI-I patients than in age-matched controls, which was accompanied by a reduced heterogeneity of mineralization (−13%, P < 0.001). However, the increase of mean degree of mineralization in OI did not exceed the average level of normal adult bone. No differences were found between the two mutation types. In summary, the tissue- and material-level abnormalities found in OI-I (low bone mass and increased mineral content of the matrix) seem to be independent of the collagen mutations.     

Effects of Oxytetracycline on Mineralization of Bone in Young Rats

The metabolism of minerals and collagen in young rats receiving oxy—tetracycline was studied by employing double—isotope techniques. the dosage of the antibiotic was adjusted to obtain plasma concentrations comparable with human therapeutic levels. Reduced mineralization and possibly increased resorption of bone were observed after oxy tetracycline administration, whereas no effect on the rate of collagen synthesis could be detected.     

Peritoneal Delivery of Sodium Pyrophosphate Blocks the Progression of Pre-existing Vascular Calcification in Uremic Apolipoprotein-E Knockout Mice

Chronic kidney disease (CKD) is generally associated with disturbances of mineral and bone metabolism. They contribute to the development of vascular calcification (VC), a strong, independent predictor of cardiovascular risk. Pyrophosphate (PPi), an endogenous inhibitor of hydroxyapatite formation, has been shown to slow the progression of VC in uremic animals. Since in patients with CKD treatment is usually initiated for already existing calcifications, we aimed to compare the efficacy of PPi therapy with that of the phosphate binder sevelamer, using a uremic apolipoprotein-E knockout mouse model with advanced VCs. After CKD creation or sham surgery, 12-week-old female mice were randomized to one sham group and four CKD groups (n = 18–19/group). Treatment was initiated 8 weeks after left nephrectomy allowing prior VC development. Uremic groups received either intraperitoneal PPi (high dose, 1.65 mg/kg or low dose, 0.33 mg/kg per day), oral sevelamer (3 % in diet), or placebo treatment for 8 weeks. Both intima and media calcifications worsened with time in placebo-treated CKD mice, based on both quantitative image analysis and biochemical measurements. Progression of calcification between 8 and 16 weeks was entirely halted by PPi treatment, as it was by sevelamer treatment. PPi did not induce consistent bone histomorphometry changes. Finally, the beneficial vascular action of PPi probably involved mechanisms different from that of sevelamer. Further studies are needed to gain more precise insight into underlying mechanisms and to see whether PPi administration may also be useful in patients with CKD and VC.     

Allogeneic Bone Marrow Transplantation is Associated with a Preferential Femoral Neck Bone Loss

Osteoporosis is a major complication of organ transplantation. Little is known about the risk of developing osteoporosis in bone marrow transplant (BMT) recipients. We studied early and late changes in bone mineral density (BMD), as well as biochemical markers of bone remodeling, in patients at the time of allogeneic BMT (alloBMT) and up to 13 years thereafter. In a cross-sectional study, 102 patients (40 women, 62 men, mean age ± SEM, 38.9 ± 1.6 years) were segregated into a first group (A, n= 48) and evaluated before or during the first weeks (mean ± SD 0.3 ± 0.1 month, range –0.5 to 3 months) following alloBMT, and a second group (B, n= 54) studied 60.1 ± 5.6 months (range 6–156 months) following alloBMT. Lumbar spine (LS) BMD was similar in groups A and B and was within normal limits. In contrast, femoral neck (FN) Z- and T-scores were significantly decreased in group B compared with group A (–0.68 ± 0.14 vs –0.03 ± 0.14 SD and –0.84 ± 0.14 vs –0.22 ± 0.14 SD, respectively; p≤0.002). Osteopenia (T-score between –1 and –2.5 SD) was present in 35% of group A and 43% of group B patients (NS). Osteoporosis (T-score <–2.5 SD) was detected in 7% of group B patients, but in none of those in group A (p= 0.05). In a longitudinal study, 56 subjects were evaluated at the time of alloBMT, and 33 and 23 were studied 6 or 12 months later, respectively (13 women, 20 men, 37.5 ± 1.6 years). All were treated with supplements of calcium and vitamin D. Amenorrheic women received hormone replacement therapy (HRT). Three-monthly pamidronate infusions were given to 15 men and 10 non-amenorrheic women who were osteopenic/osteoporotic or had elevated baseline bone turnover markers. Mean baseline LS and FN Z- and T-scores were within normal range. Six months after BMT, FN BMD decreased by 4.2 ± 0.7% (p<0.001), and whole body BMD and bone mineral content by 1.5 ± 0.4% and 3.1 ± 0.6%, respectively (p≤0.0001). Twelve months after the graft, there was no further significant bone loss and only FN BMD decrease remained significantly different compared with baseline (–5.6 ± 1.1%, p≤0.0001). These results indicate that the risk of decreased BMD is higher for the femoral neck than the lumbar spine and whole body levels in patients with allogeneic bone marrow transplantation, and that bone loss occurs mainly during the first 6 months after the graft. Received: 9 February 2001 / Accepted: 23 May 2001     

Nonenzymatic Cross-Linking Pentosidine Increase in Bone Collagen and Are Associated with Disorders of Bone Mineralization in Dialysis Patients

Disorders of bone and mineral metabolism are common complications in chronic kidney disease (CKD) patients and lead to significantly increased fracture risk, morbidity, and mortality of cardiovascular disease due to ectopic calcifications, contributing to a worsening prognosis. Bone strength is determined by not only bone mineral density but also bone quality, which is dependent on bone collagen cross-links. Collagen cross-links are classified into enzymatic immature and mature types and nonenzymatic advanced glycation end products (AGEs). Pentosidine is well established as one of the AGEs that accumulates markedly in CKD patients. The chemistry, function, and clinical relevance of cross-links have been revealed, whereas bone quality and the relationship with bone mineralization in CKD patients are not clear. We performed transiliac bone biopsies on 22 dialysis patients (mean age 56 ± 9 years) with severe secondary hyperparathyroidism and measured cross-links by evaluating bone histomorphometry. Cross-links data were compared with age-matched non-CKD subjects (mean age 58 ± 8 years, n = 17). Enzymatic collagen cross-links were formed to a similar extent compared with non-CKD subjects and showed a positive correlation with plasma intact parathyroid hormone. Pentosidine was remarkably increased in dialysis patients and inversely correlated with bone-formation rate/bone volume and mineral apposition rate. This study suggests that AGE collagen cross-links strongly associate with disorders of bone metabolism in dialysis patients.     

High Bone Turnover is Associated with Low Bone Mass and Spinal Fracture in Postmenopausal Women

A group of 366 healthy, white postmenopausal women, aged 50–81 years, mean age 66 years, were selected from the screened population of Scandinavians who were part of a multicenter study of the efficacy of tiludronate, a new bisphosphonate, in established postmenopausal osteoporosis. Eighty-eight women had a lumbar spine bone mineral density (BMD) above 0.860 g/cm², and 278 women had a BMD below 0.860 g/cm². Spinal fracture was diagnosed from lateral spine X-ray studies and defined as at least 20% height reduction (wedge, compression, or endplate fracture) in at least one vertebra (T4–L4). Bone resorption was assessed by measurement of the urinary excretion of type I collagen degradation products by the CrossLaps™ enzyme-linked immunoassay (ELISA). Bone formation was assessed by ELISA measurement of the N-terminal-mid-fragment as well as the intact serum osteocalcin (OC_N-MID), thus omitting the influence of the instability of osteocalcin caused by the labile 6 amino acid C-terminal sequence. The women were divided into groups with high or low bone turnover according to the concentrations of urinary CrossLaps™ or OC_N-MID. Women in the quartiles with the highest concentrations of CrossLaps [519 ± 119 μg/mmol (SD)] or OC_N-MID [44.6 ± 7.5 ng/ml (SD)] had 10–16% lower spinal BMD compared with women in the lowest quartiles (CrossLaps 170 ± 48 μg/mmol (SD), and OC_N-MID [22.1 ± 3.0 ng/ml (SD)] (P < 0.0004). The prevalences of spinal fracture were 25 to 29% in the lowest quartiles, whereas the prevalences in the highest quartiles were almost double—53–54% (P < 0.006). If the women were subgrouped according to spinal BMD and prevalence of spinal fracture, corresponding results were found. Women with a BMD less than 0.860 g/cm², without or with spinal fracture (n = 136 and n = 142), had 36–43% higher concentration of CrossLaps (P= 0.0001) and 11–15% higher concentration of OC_N-MID (P < 0.02), as compared with women with a BMD above 0.860 g/cm² and no spinal fracture (n = 84). In conclusion, the results indicate a strong association among high bone turnover, low bone mass, and prevalence of spinal fracture, which supports the theory that high bone turnover is a risk factor for spinal fracture and osteoporosis. Received: 29 February 1996 / Accepted: 9 August 1996     

The Asn19Lys Substitution in the Osteoclast Inhibitory Lectin (OCIL) Gene is Associated with a Reduction of Bone Mineral Density in Postmenopausal Women

Osteoclast inhibitory lectin (OCIL) is a newly recognized inhibitor of mouse and human osteoclast differentiation whose cellular expression is similar to that of receptor activator of nuclear factor kappaB (RANKL). The main objective of the present work was to elucidate whether naturally occurring single-nucleotide polymorphisms (SNPs) in this gene could be associated with bone mass in postmenopausal women. To that end, we studied the association of bone mineral density (BMD) measured by dual-energy X-ray absorptiometry with two nonsynonymous SNPs in the OCIL gene resulting in Asn19Lys and Leu23Val substitutions in a population of 500 postmenopausal Spanish women. A weak association was detected for Asn19Lys SNP with femoral neck (FN) BMD and lumbar spine (LS) BMD in the whole population. When the population was stratified by age, however, the association was strong in older women (> or =53 years). Thus, in this group of participants, women with CG/GG genotype displayed reductions of 5.6% and 6.7% in FN BMD and LS BMD adjusted by age and body mass index (BMI), respectively, compared to women with CC genotype. The Asn19Lys SNP alleles explained about 7% of BMD variance in older women but only 1.7-3.9% in the whole population in regression models including age and BMI. In conclusion, women with a lysine (GG genotype) at position 19 of the OCIL protein displayed lower BMD at femoral neck and at lumbar spine sites than women having an asparagine residue. Since the OCIL protein inhibits osteoclast differentiation, this amino acid substitution could have consequences for OCIL functionality.     

Glossopharyngeal Neuralgia Associated with a Vascular Loop Demonstrated by Magnetic Resonance Imaging

Summary  We report two cases of glossopharyngeal neuralgia associated with a vascular loop of the postero-inferior cerebellar artery, diagnosed by magnetic resonance imaging. Reviewing the literature, we found this to be the first report of a magnetic resonance-validated vascular abnormality related to such a condition. One patient was cured by surgical decompression, confirming the role of the abnormal vessel in the pain. As with trigeminal neuralgia, a possible vascular aetiology should be considered in glossopharyngeal neuralgia.