The Effect of Calcium and Vitamin D<Subscript>3</Subscript> Supplementation on the Healing of the Proximal Humerus Fracture: A Randomized Placebo-Controlled Study

The purpose of this study was to (1) quantify the healing process of the human osteoporotic proximal humerus fracture (PHF) expressed in terms of callus formation over the fracture region using BMD scanning, and (2) quantify the impact of medical intervention with vitamin D₃ and calcium on the healing process of the human osteoporotic fracture. The conservatively treated PHF was chosen in order to follow the genuine fracture healing without influence of osteosynthetic materials or casts. Thirty women (mean age = 78 years; range = 58–88) with a PHF, osteoporosis or osteopenia (based on a hip scan, WHO criteria), and not taking any drugs related to bone formation, including calcium or vitamin D supplementation, were randomly assigned to either oral 800 IU vitamin D₃ plus 1 g calcium or placebo, in a double-blind prospective study. We measured biochemical, radiographic, and bone mineral density effect parameters to evaluate the impact on the healing process. Scanning procedures of the fractured shoulder included use of a fixation device to obtain the highest possible precision. Double scans of the fractured shoulder revealed a coefficient of variation (CV) on BMD measurements that improved from 2.8% immediately after fracture occurrence to 1.7% at 12 weeks (P = 0.003) approaching the 1.2% levels observed over the healthy shoulder. BMD was similar in the two groups at baseline (active 0.534 g/cm² vs. placebo 0.518 g/cm²), and both increased over the 12-week observation period, with peak levels in week 6. By week 6 BMD levels were higher in the active group (0.623 g/cm²) compared with the placebo group (0.570 g/cm², P = 0.006). Thirty seven percent of the patients presented with vitamin D levels below 30 nmol/l, indicative of mild vitamin D insufficiency. In conclusion, we have demonstrated that it is possible to quantify callus formation of the PHF with sufficiently high precision to demonstrate the positive influence of vitamin D₃ and calcium over the first 6 weeks after fracture. Whether this results in more stable fractures, extends to other fracture types, or applies to other osteogenic bone agents such as bisphosphonates remains to be examined.     

Bone mineral density and prevalent vertebral fractures in men and women

To test the hypothesis that the association between bone mineral density (BMD) and estimated volumetric BMD and prevalent vertebral fractures differs in men and women, we studied 317 Caucasian men and 2,067 Caucasian women (average age 73 years). A total of 43 (14%) men and 386 (19%) women had a vertebral fracture identified on lateral spine radiographs using vertebral morphometry. Hip and spine areal BMD was about 1/3 standard deviation lower among men and women with a vertebral fracture. A 0.10 g/cm² decrease in areal BMD was associated with 30–40% increased odds of having a fracture in men and 60–70% increased likelihood in women. Low bone mineral apparent density (BMAD) was also associated with 40–50% increased odds of a vertebral fracture in both genders. The probability of a man having a fracture was observed at higher absolute areal BMD values than observed for women (P=values for interaction of BMD × gender: trochanter, P=0.05; femoral neck, P=0.10; total hip, P=0.09). In contrast, the probability of fracture was similar in men and women across the range of estimated volumetric BMD (BMAD). In conclusion, low BMD and low BMAD are associated with increased odds of vertebral fracture in both men and women. Measures of bone mass that partially correct for gender differences in bone size may yield universal estimates of fracture risk. Prospective studies are needed to confirm this observation.     

Evaluation of the possibility to assess bone age on the basis of DXA derived hand scans—preliminary results

The classical method of skeletal age assessment is based on the recognition of changes in the radiographic appearance of the maturity indicators in hand-wrist radiographs by comparison with a reference atlas. The purpose of this study was the evaluation of the possibility to assess bone age using a less invasive method such as dual-energy X-ray absorptiometry (DXA). Bone ages of 50 children free of any chronic diseases (5–18 years old) and ten with multihormonal pituitary deficiency (MPD) (8–20 years old) were assessed using an Expert-XL densitometer. Hand scans and classical hand-wrist radiographs were evaluated by two independent observers for bone age by visual comparison with reference standards of skeletal development published in the atlas. The precision errors of duplicate bone age ratings were low both for radiographs (<1%) and DXA hand scans (<0.9%). A high degree of agreement between bone age ratings done by two observers was assessed by intraclass correlation coefficients. The same bone age based on radiographs and DXA hand scans was assessed in 44 of 60 cases (73.3%); in 16 cases the differences between bone age were no higher than 0.5 year. No significant difference between mean bone age based on radiographs and DXA hand scans was observed (P>0.05). Moreover, there was a very strong correlation between bone age results (r=0.998; r ²=0.996; P<0.0001), indicating agreement of bone age assessments based on DXA and radiographic images. Remarkable differences (up to 3 years) between bone age and chronological age were observed in healthy subjects, probably reflecting the effect of the secular trend towards earlier maturation or alterations in pubertal development. The study indicates that evaluation of skeletal maturity using DXA images is less invasive (up to 8 µSv) than radiography, giving results comparable to the classical method.     

Bone Mass Density and Risk of Breast Cancer and Survival in Older Women

STUDY OBJECTIVE: Older women with high bone mineral density (BMD) have an increased risk of breast cancer but it is not well known whether this association is associated with the stage of the tumor. The objective of the study is to determine if older women with high BMD are likely to develop a more aggressive form of breast cancer, as defined by mortality. PATIENTS: We prospectively studied 1504 women who were 75 years of age or older at the entry in the study (range, 75-90 years), between 1992 and 1994. BMD was measured by dual-photon X-ray absorptiometry at three skeletal sites (trochanter, Ward's triangle, femoral neck). The women were followed for a mean of 7 years for the occurrence of breast cancer. Cox proportional-hazards models were used to obtain estimates of the relative risk of breast cancer and relative risk of death according to the BMD. MAIN RESULTS: Forty-five incident breast cancer cases were identified. In multivariate analyses of the risk of breast cancer for women in the highest tertile of BMD was greater than for women in the lowest tertile. Indeed, the women with a trochanter BMD in the highest tertile were at 2.3-fold increased risk compared with women in the lowest tertile. The women with highest tertile BMD measured at the Ward's triangle and at the femoral neck were respectively at 2.2-and 3.3-fold increased risk compared with women at the lowest risk. The 7-year survival rates were markedly less favorable for women in the second and third tertile of the three skeletal sites compared with the lowest tertile. The risk of death was greater for women in the highest tertile of BMD than for women in the lowest tertile at every skeletal site. CONCLUSION: Elderly women with high BMD have an increased risk of breast cancer, especially advanced cancer, compared with women with low BMD.     

Lack of relationships between cumulative methylprednisolone dose and bone mineral density in healthy men and postmenopausal women with chronic low back pain

 The medical use of glucocorticoids (GCs) is related to low bone mineral density (BMD). In this study we tested the hypothesis that the cumulative dose of GC is not related to BMD outcome. The study was cross-sectional in design and included healthy individuals with chronic low back pain resistant to conventional treatments. In two steroid-naive subjects cortisol and methylprednisolone (MP) concentrations were serially assessed after a single MP depot injection (160 mg epidurally). Furthermore, in 14 men and 14 postmenopausal women, previously treated with multiple epidural MP depots, endocrine parameters were analysed in relation to BMD outcomes. The minimal cumulative MP dose received by all 28 subjects was 3 g. In the two steroid-naive subjects, cortisol concentrations were completely suppressed for at least 6 days and partly recovered over the course of 30 days. During this period, MP concentrations remained detectable in plasma. In the 28 subjects, the cumulative MP dose received was 7.76±4.23 g in the men and 8.50±3.13 g in the women (mean±1SD). None of the men had osteoporosis, but osteopenia was prevalent in 78.5% according to WHO criteria extrapolated to men. Half of the women had osteoporosis and half of them had osteopenia. The body mass index (BMI) and endogenous oestradiol levels of the men were not related to BMD outcomes. Univariate linear relationships in women were found between BMI and spinal (r 0.62; P=0.02) and total hip BMD (r 0.61; P=0.03), but not femoral neck BMD. In women, relationships were also found between the total and, for protein binding-corrected oestradiol levels, and spinal BMD (r 0.70; P=0.01 and r 0.72; P=0.01, respectively) and total hip BMD (r 0.53; P=0.08 and r 0.56; P=0.05, respectively). No significance was observed between endogenous oestradiol levels and the BMD of the femoral neck. The administration of a single MP depot injection (160 mg) resembled a systemic low peak dose GC exposure. The administration of multiple MP depots in men and women with chronic low back pain revealed no relationship between cumulative GC dose and BMD. These findings support the hypothesis of a non-existent relationship between cumulative GC dose and BMD outcomes in healthy men and women with a prior GC administration of at least 3 g. Received: 18 February 2002 / Accepted: 14 June 2002 Acknowledgements We are indebted to Dr Oscar L.H. van Hemel for advice during the performance of the study and to Ineke Bosman for excellent laboratory support.     

The Interaction Between Sillence Type and BMD in Osteogenesis Imperfecta

Clinical studies with bisphosphonates in children with osteogenesis imperfecta (OI) show an increase in BMD and a decrease in fracture rate. Bone strength in children with OI is not only influenced by changes in BMD but also by changes in collagen I structure of the organic bone matrix. Therefore, we studied the interaction between these two factors in a cross-sectional, single center study including 54 children. We assumed that vertebral deformities in OI represent an unbalance between load and bone strength. Body weight was considered to be a well quantifiable load on vertebral bodies. BMD served as a marker, representing the amount of bone tissue available for vertebral load bearing, and the Sillence classification, either type I or III/IV, as a marker representing the quality of the organic bone matrix. Independent associations were observed between the prevalence of vertebral deformities and (1) Sillence type (OR: 5.7, 95%Cl:1.2–26.8), (2) BMD (OR: 0.003, 95%Cl: 0–0.25) and (3) body weight (OR: 1.15, 95%Cl: 1.05–1.25). Regarding the anthropometrical differences among the different types of OI, the BMD/body weight ratio was introduced to evaluate the BMD in relation to body size. Prevalent vertebral deformities were associated with low BMD/body weight ratios (OR: 0.04, 95%Cl: 0.008–0.2) in OI type I, but no association was found in type III/IV. It was concluded that BMD and Sillence type have independent relationships with vertebral deformities. The BMD/body weight ratio correlates with vertebral deformities in children with OI type I. Its meaning in types III/IV needs further research with larger samples because of the relatively high prevalence of vertebral deformities in this group.     

Association and Linkage Disequilibrium Analyses Suggest Genetic Effects of Estrogen Receptor α and Collagen IA1 Genes on Bone Mineral Density in Caucasian Women

Estrogen receptor alpha (ER) and collagen IA1 (COLIA1) genes have been suggested as possibly implicated in reduced bone mineral density (BMD). The present study investigated the occurrence of association and linkage disequilibrium between radiographic hand BMD and polymorphic alleles of ER and COLIA1 genes, in human pedigrees of a Chuvasha population in Russia. The study sample included 463 members of 113 pedigrees, mostly nuclear families. We performed association and transmission disequilibrium test (TDT) analyses of the combined PvuII and XbaI RFLPs alleles on the same chromosome (haplotype) of the ER gene with BMD Z scores of cancellous or cortical bone in the hand phalanges. The association analyses were performed separately for both genders in the parental generation, i.e., fathers (n = 114; average age 64.2 y) and mothers (n = 122; average age 62.7 y). The Px haplotype was associated significantly with lower BMD Z scores in mothers only. The difference between subjects who carried one or two copies of the Px haplotype and those lacking it was 0.68 Z scores, P = 0.003 and 0.51 Z scores, P = 0.025 for cancellous and cortical bone, respectively. Multiple linear regression model with age, height, weight, and Px haplotype status as predictors explained 26.7% and 28.3% of the total observed variance in BMD with Px haplotype as independent predictor explaining 5.9%; P = 0.002 and 3%; P = 0.028 (cancellous and cortical bone, respectively). Results of t-TDT for triads of two parents and just one of their female offspring (but not male offspring) suggested the existence of linkage disequilibrium between the two loci of Px haplotype and BMD trait (P = 0.047). No association was found between polymorphic alleles of COLIA1 gene and BMD, but mothers with combined genotypes of Px haplotype of ER gene and s allele of COLIA1 gene had the lowest mean Z scores (–0.944 and –0.788 for cancellous and cortical bone, respectively). We conclude that the Px haplotype of the ER gene is associated with low BMD values in females, as the phenotype is gender dependent (the association was not observed in males), and the s allele of COLIA1 gene in combination with this haplotype contributes to reduced BMD.     

Polymorphisms of four bone mineral density candidate genes in Chinese populations and comparison with other populations of different ethnicity

 Studies on polymorphisms of candidate genes and their association with bone mineral density (BMD) have been reported in many populations, but few have been reported in Chinese populations. We investigated polymorphisms of the following five commonly used markers of four prominent BMD candidate genes with the purpose of identifying useful genetic markers for osteoporosis genetic research in Chinese: the Sp1 and RsaI polymorphisms of the collagen type 1 alpha l (Col1a1) gene, the −174G/C promoter polymorphism of the interleukin 6 (IL-6) gene, the Asn363Ser polymorphism of the glucocorticoid receptor (GR) gene, and the T → C polymorphism in intron 5 of the transforming growth factor β₁ (TGF-β₁) gene. We evaluated these polymorphisms using PCR-RFLP in samples of at least 124 random individuals. We compared the polymorphisms of these five markers with other populations using the χ² test and Fisher's exact two-tailed test. For the RsaI polymorphism, only three heterozygotes but no variant homozygote were identified. For the −174G/C polymorphic site, only one GC heterozygote and no CC homozygote were found. Alleles s, Ser, and A ₁ at the Sp1, Asn363Ser, and T → C marker sites that have been found to be polymorphic in other populations were not found in Chinese. Significant differences of allele and genotype frequency distributions were observed at these polymorphisms (P < 0.001) after comparing with other populations. Our results suggest that variant alleles of the five markers are absent or too rare to be useful genetic makers in Chinese, despite the fact that they have been commonly used as polymorphic markers in osteoporosis genetic research in other populations. Received: April 22, 2002 / Accepted: July 2, 2002 Acknowledgments. The study was partially supported by the Hunan Province Special Professor Start-up Fund (25000612), Chinese National Science Foundation (CNSF) Outstanding Young Scientist Award (30025025), CNSF Grant (30170504), a grant from Huo Ying-Dong Education Foundation, and a Seed Fund from the Ministry of Education of P.R. China (25000106). Some investigators (R.R.R., V.D., H.W.D.) were partially supported by grants from the Health Future Foundation of USA, grants of National Health Institute (K01 AR02170-01, R01 GM60402-01A1), grants from the State of Nebraska Cancer and Smoking Related Disease Research Program, and U.S. Department of Energy grant (DE-FG03-00ER63000/A00). We thank all the study subjects for volunteering to participate in the study. Offprint requests to: H.-W. Deng     

Loss of bone mineral of the hip and proximal tibia following rupture of the Achilles tendon

In a prospective uncontrolled study 12 patients suffering from a rupture of the Achilles tendon treated operatively with surgical repair and post-operative immobilization in a short plaster cast for 6 weeks had bilateral measurements of bone mineral content (BMC) of the proximal tibia and bone mineral density (BMD) of the femoral neck and greater trochanter. The measurements were performed by dual energy X-ray absorptiometry (DEXA) and scans were performed post-operatively within 7 days after the operation and with follow up after 6 weeks, 3, 6, and 12 months. In the operated legs, BMC of the proximal tibia showed a progressive decrease reaching a total bone loss of 6.4% (95%-CL: -10.6%; -2.3%) 1 year after the injury. Bone mineral density at the hip of the operated legs also decreased significantly and 1 year after the injury BMD was 2.5% (95%-CL: -5.5%; 0.5%) and 6.8% (95%-CL: -9.8%; -3.7%) below the initial value in, respectively, the femoral neck and greater trochanter. Patients with a previous Achilles tendon rupture must be considered to be some years ahead in their natural osteoporotic process of the bones of the affected legs, and an increased risk of osteoporotic fractures must be considered not to be only theoretical.     

营养素干预对绝经妇女骨质疏松的影响

目的 观察血脂正常但骨密度降低的绝经妇女补充钙、维生素D和大豆异黄酮后，机体骨密度和血脂成分的变化。方法 2004年4月从武汉郊区绝经妇女中筛选血脂正常伴骨量减少或骨质疏松的绝经妇女60名，随机均分为两干预组，每组30人。一组给予液体钙（含维生素D）；一组给予液体钙（含维生素D）和大豆异黄酮，跟踪观察一年。测定每位受试对象骨骼骨密度和血脂成分。结果 试验结束后，补钙组和补钙＋大豆异黄酮组，全身及股骨颈的骨密度（BMD）都较基线时显著降低（P〈0．05），组间变化无显著性差异（P〉0．05）；而腰椎、大转子BMD与基线相比，略微升高，但尚无统计学差异。补钙和补钙＋大豆异黄酮均能显著降低血总胆固醇（P〈0．05）。结论 对已出现骨量减少的绝经后妇女补钙一年能降低绝经后BMD的丢失速率，但补充大豆异黄酮一年尚未观察到对BMD的保护作用。绝经妇女补充钙和大豆异黄酮补可能干扰机体的血脂代谢。