bluuebunny/crossref_metadata_2025 huggingface dataset:
Hyperkyphotic Posture and Risk of Future Osteoporotic Fractures: The Rancho Bernardo Study
Authors: Huang Mei-Hua , Barrett-Connor Elizabeth , Greendale Gail A , Kado Deborah M
Published: April 2006

It is unknown whether kyphosis of the thoracic spine is an independent risk factor for future osteoporotic fractures. In 596 community-dwelling women, we found that with increasing kyphosis, there was a significant trend of increasing fracture risk that was independent of previous history of fractures or BMD.

Introduction: It is unknown whether kyphosis of the thoracic spine is an independent risk factor for future osteoporotic fractures.

Materials and Methods: We conducted a prospective cohort study of 596 community-dwelling women, 47-92 years of age. Between 1988 and 1991, BMD of the hip and spine and kyphosis were measured. Kyphosis was measured by counting the number of 1.7-cm blocks necessary to place under the occiput so participants could lie flat without neck hyperextension. New fractures were reported over an average follow-up of 4 years.

Results: Using a cut-off of at least one block, 18% of the participants had hyperkyphotic posture (range, one to nine blocks). There were 107 women who reported at least one new fracture (hip, spine, wrist, clavicle, shoulder, arm, hand, rib, pelvis, leg, or ankle). In logistic regression analyses, older women with hyperkyphotic posture (defined as at least one block) had a 1.7-fold increased risk of having a future fracture independent of age, prior fracture, and spine or hip BMD (95% CI: 1.00-2.97; p = 0.049). There was a significant trend of increasing fracture risk with increasing number of blocks, with ORs ranging from 1.5 to 2.6 as the number of blocks increased from one to at least three blocks compared with those with zero blocks (trend p = 0.03; models adjusted for age, baseline fracture, spine or hip BMD). Stratification by baseline fracture status and controlling for other possible confounders or past year falls did not change the results.

Conclusions: Whereas hyperkyphosis may often result from vertebral fractures, our study findings suggest that hyperkyphotic posture itself may be an important risk factor for future fractures, independent of low BMD or fracture history.
Fractures Attributable to Osteoporosis: Report from the National Osteoporosis Foundation
Authors: Melton L. J. , Thamer M. , Ray N. F. , Chan J. K. , Chesnut C. H. , Einhorn T. A. , Johnston C. C. , Raisz L. G. , Silverman S. L. , Siris E. S.
Published: April 2006

To assess the cost-effectiveness of interventions to prevent osteoporosis, it is necessary to estimate total health care expenditures for the treatment of osteoporotic fractures. Resources utilized for the treatment of many diseases can be estimated from secondary databases using relevant diagnosis codes, but such codes do not indicate which fractures are osteoporotic in nature. Therefore, a panel of experts was convened to make judgments about the probabilities that fractures of different types might be related to osteoporosis according to patient age, gender, and race. A three-round Delphi process was applied to estimate the proportion of fractures related to osteoporosis (i.e., the osteoporosis attribution probabilities) in 72 categories comprised of four specific fracture types (hip, spine, forearm, all other sites combined) stratified by three age groups (45–64 years, 65–84 years, 85 years and older), three racial groups (white, black, all others), and both genders (female, male). It was estimated that at least 90% of all hip and spine fractures among elderly white women should be attributed to osteoporosis. Much smaller proportions of the other fractures were attributed to osteoporosis. Regardless of fracture type, attribution probabilities were less for men than women and generally less for non-whites than whites. These probabilities will be used to estimate the total direct medical costs associated with osteoporosis-related fractures in the United States.
Medical Expenditures for the Treatment of Osteoporotic Fractures in the United States in 1995: Report from the National Osteoporosis Foundation
Authors: Ray Nancy Fox , Chan Julien K. , Thamer Mae , Melton L. Joseph
Published: April 2006

Osteoporotic fractures are a significant public health problem, resulting in substantial morbidity and mortality. Previous estimates of the economic burden of osteoporosis, however, have not fully accounted for the costs associated with treatment of nonhip fractures, minority populations, or men. Accordingly, the 1995 total direct medical expenditures for the treatment of osteoporotic fractures were estimated for all persons aged 45 years or older in the United States by age group, sex, race, type of fracture, and site of service (inpatient hospital, nursing home, and outpatient). Osteoporosis attribution probabilities were used to estimate the proportion of health service utilization and expenditures for fractures that resulted from osteoporosis. Health care expenditures attributable to osteoporotic fractures in 1995 were estimated at $13.8 billion, of which $10.3 billion (75.1%) was for the treatment of white women, $2.5 billion (18.4%) for white men, $0.7 billion (5.3%) for nonwhite women, and $0.2 billion (1.3%) for nonwhite men. Although the majority of U.S. health care expenditures for the treatment of osteoporotic fractures were for white women, one-fourth of the total was borne by other population subgroups. By site-of-service, $8.6 billion (62.4%) was spent for inpatient care, $3.9 billion (28.2%) for nursing home care, and $1.3 billion (9.4%) for outpatient services. Importantly, fractures at skeletal sites other than the hip accounted for 36.9% of the total attributed health care expenditures nationally. The contribution of nonhip fractures to the substantial morbidity and expenditures associated with osteoporosis has been underestimated by previous researchers.
The Thickness of Human Vertebral Cortical Bone and its Changes in Aging and Osteoporosis: A Histomorphometric Analysis of the Complete Spinal Column from Thirty-Seven Autopsy Specimens
Authors: Ritzel Holger , Amling Michael , Pösl Martin , Hahn Michael , Delling Günter
Published: April 2006

The object of this study was to analyze the cortical thickness (Ct.Th) of the ventral and dorsal shell of the vertebral bodies throughout the human spine in aging and in osteoporosis. Therefore, the complete front column of the spine of 26 autopsy cases (aged 17–90, mean 42 years) without diseases affecting the skeleton and of 11 cases (aged 58–92, mean 77 years) with proven osteoporosis were removed. A sagittal segment prepared through the center of all vertebral bodies was undecalcified, embedded in plastic, ground to a 1 mm thick block, and stained using a modification of the von Kossa method. The analysis included the measurement of the mean cortical thickness of both the ventral and dorsal shell, respectively (from the third cervical to the fifth lumbar vertebral body). The qualitative investigation of the structure of the cortical ring completed the analysis. The presented data revealed a biphasic curve for both the ventral and dorsal shell, skeletally intact with high values of the cortical thickness in the cervical spine (285 μm), and a decrease in the thoracic (244 μm) and an increase in the lumbar spine (290 μm). The mean thickness of the ventral shell is in general greater than the thickness of the dorsal shell in both skeletally normal and osteoporotic cases. The cortical thickness of the spine showed no gender-specific differences (p = NS). There was a slight decrease of the cortical thickness with aging; however, this decrease and the correlation of cortical thickness to age was only significant below vertebral body T8 (r = 0.225–0.574; pr < 0.05–0.005). Most interestingly, however, osteoporosis presents itself with a highly significant loss of cortical thickness throughout the whole spine. This decrease of cortical thickness was more marked in the dorsal shell (p < 0.05) than in the ventral shell (ventral from C3 to T6 [p < 0.05] below T6 [p = NS]). We therefore conclude that in osteoporosis the loss of spinal bone mass is not only a loss of trabecular structure but also a loss of cortical thickness. Furthermore, these results may explain the development of regions of least resistance within the spine in aging and the clustering of osteoporotic fractures in the lower thoracic and lumbar spine.
Localization and Quantification of Proliferating Cells During Rat Fracture Repair: Detection of Proliferating Cell Nuclear Antigen by Immunohistochemistry
Authors: Iwaki Akira , Jingushi Seiya , Oda Yoshinao , Izumi Toshihiro , Shida Jun-Ichi , Tsuneyoshi Masazumi , Sugioka Yoichi
Published: April 2006

Bilateral femurs of 12-week-old female Sprague-Dawley rats were fractured, and the fractured femurs were harvested 36 h, 3, 7, 10, and 14 days after the fracture. Localization of cell proliferation in the fracture calluses was investigated using immunohistochemistry with antiproliferating cell nuclear antigen (PCNA) monoclonal antibodies. Thirty-six hours after the fracture, many PCNA-positive cells were observed in the whole callus. The change was not limited to mesenchymal cells at the fracture site where the inflammatory reaction had occurred, but extended in the periosteum along almost the entire femoral diaphysis where intramembranous ossification was initiated. On day 3, periosteal cells or premature osteoblasts in the newly formed trabecular bone during intramembranous ossification still displayed intense staining. On day 7, many premature chondrocytes and proliferating chondrocytes were PCNA positive. Endochondral ossification appeared on days 10 and 14, and the premature osteoblasts and endothelial cells in the endochondral ossification front were stained with anti-PCNA antibodies. Quantification of PCNA-positive cells was carried out using an image analysis computer system, obtaining a PCNA score for each cellular event. The highest score was observed in the periosteum early after the fracture near the fracture site. Immunohistochemistry using anti-PCNA antibodies showed that the distribution of proliferating cells and the degree of cell proliferation varied according to the time lag after the fracture, suggesting the existence of local regulatory factors such as growth factors, and that significant cell proliferation was observed at the beginning of each cellular event.
Effect of Metabolic Acidosis on the Potassium Content of Bone
Authors: Bushinsky David A. , Gavrilov Konstantin , Chabala Jan M. , Featherstone John D. B. , Levi-Setti Riccardo
Published: April 2006

Metabolic acidosis induces resorption of cultured bone, resulting in a net efflux of calcium (Ca) from the bone and an apparent loss of mineral potassium (K). However, in these organ cultures, there is diffusion of K between the medium and the crystal lattice, causing difficulty in interpretation of the acid-induced changes in mineral ion composition. To determine the effects of acidosis on bone mineral K, we injected 4-day-old neonatal mice with pure stable isotope41K, equal to ∼5% of their total body K. Calvariae were dissected 24 h later and then cultured for 24 h in medium without added41K, either at pH ∼7.4 (Ctl) or at pH ∼7.1 (Ac), with or without the osteoclastic inhibitor calcitonin (3 × 10−9 M, CT). The bone isotopic ion content was determined with a high-resolution scanning ion microprobe utilizing secondary ion mass spectrometry.41K is present in nature at 6.7% of total K. The injected41K raised the ratio of bone41K/(39K+41K) to 9.8 ± 0.5% on the surface (ratios of counts per second of detected secondary ions, mean ±95% confidence interval) but did not alter the ratio in the interior (6.9 ± 0.4%), indicating biological incorporation of the41K into the mineral surface. The ratios of41K/40Ca on the surface of Ctl calvariae was 14.4 ± 1.2, indicating that bone mineral surface is rich in K compared with Ca. Compared with Ctl, Ac caused a marked increase in the net Ca efflux from bone that was blocked by CT. Ac also induced a marked fall in the ratio of41K/40Ca on the surface of the calvariae (4.3 ± 0.5, p < 0.01 vs. Ctl), which was partially blocked by CT (8.2 ± 0.9, p < 0.01 vs. Ctl and vs. Ac), indicating that Ac causes a greater release of bone mineral K than Ca which is partially blocked by CT. Thus, bone mineral surface is rich in K relative to Ca, acidosis induces a greater release of surface mineral K than Ca, and osteoclastic function is necessary to support the enriched levels of surface mineral K in the presence of acidosis.
Elimination and Biochemical Responses to Intravenous Alendronate in Postmenopausal Osteoporosis
Authors: Khan Sohail A. , Kanis John A. , Vasikaran Samuel , Kline W. F. , Matuszewski B. K. , McCloskey Eugene V. , Beneton Monique N. C. , Gertz Barry J. , Sciberras David G. , Holland S. D. , Orgee Jane , Coombes Gillian M. , Rogers Suzanne R. , Porras A. G.
Published: April 2006

Postmenopausal women with established vertebral osteoporosis were studied for 2 years to determine the terminal elimination half-life and the duration of response to treatment with intravenous alendronate (30 mg) given over 4 days. The urinary excretion of alendronate followed a multiexponential decline. Approximately 50% of the total dose was excreted over the first 5 days, and a further 17% was excreted in the succeeding 6 months. Thereafter, there was a much slower elimination phase with an estimated mean terminal half-life of greater than 10 years (n = 11). Urinary excretion of hydroxyproline and calcium decreased significantly from pretreatment values by day 3, reaching a nadir by 1 week (40% and 67% decrease, respectively). Thereafter, hydroxyproline remained suppressed for the following 2 years. In contrast, urinary calcium excretion returned gradually toward pretreatment values over the first year and during the second year was comparable to pretreatment values. Serum activity of alkaline phosphatase activity decreased over 3 months (23% reduction), increased gradually thereafter, and returned to pretreatment values at month 24. Bone mineral density measured at the spine increased by approximately 5% during the first year and remained significantly higher than pretreatment values at 2 years. We conclude that a short course of high doses of intravenous alendronate is associated with a prolonged skeletal retention of the agent. This open study also suggests that this regimen has a sustained effect on bone turnover persisting for at least 1 year.
Skeletal Involvement in Female Acromegalic Subjects: The Effects of Growth Hormone Excess in Amenorrheal and Menstruating Patients
Authors: Scillitani Alfredo , Chiodini Iacopo , Carnevale Vincenzo , Giannatempo Giuseppe M. , Frusciante Vincenzo , Villella Massimo , Pileri Mauro , Guglielmi Giuseppe , Di Giorgio Anna , Modoni Sergio , Fusilli Saverio , Di Cerbo Alfredo , Liuzzi Antonio
Published: April 2006

Bone involvement is a common clinical feature in acromegalic patients, though previous studies gave divergent results possibly because of the different gonadal status of the patients studied. To study the influence of estrogen milieu in these patients, we evaluated 23 acromegalic patients with active disease, subdivided into two groups: menstruating and amenorrheal patients, comparable for duration and activity of disease. Forty-two matched women served as controls. Skeletal involvement was studied by measuring: (a) the main biomarkers of bone turnover: serum alkaline phosphatase total activity (AP), bone GLA protein (BGP), serum carboxy-terminal propeptide of type I collagen (PICP), serum type I cross-linked N-telopeptide (ICTP), and urinary pyridinoline and deoxypyridinoline corrected for creatinine (Pyr/Cr, D-Pyr/Cr) and urinary calcium/creatinine ratio (Ca/Cr); (b) bone mineral density (BMD), as measured by quantitative computed tomography both at lumbar spine and distal radius, and by dual X-ray absorptiometry both at lumbar spine and at three femoral sites (Ward's triangle, femoral neck, and great trochanter). AP, BGP, ICTP, Pyr/Cr, D-Pyr/Cr were significantly higher in patients than in controls, independent of the menstrual pattern. Higher PICP levels were found in the whole group and in menstruating acromegalics when compared with control women; no difference was found in amenorrheal patients, who in turn showed higher urinary Ca/Cr values. When patients were considered all together, BMD at spine, femoral neck, and trochanter was higher than in controls. In contrast, when the gonadal status was taking into account and, menstruating and amenorrheal subjects were considered separately, BMD at spine, but not in other sites, was significantly higher in menstruating patients than in controls. In contrast, no difference of BMD values at any site was observed between amenorrheal patients and controls. The mean BMD Z scores allowed us to detect an unequal involvement of different skeletal sites. Our results show that bone turnover is increased in acromegalic women and suggest that GH anabolic effect on bone is more evident in the presence of estrogens and that different skeletal sites may be affected differently by hormone excess.
Monoclonal Antibodies Against Synthetic Peptides Corresponding to the Extracellular Domain of the Human Ca2+ Receptor: Characterization and Use in Studying Concanavalin A Inhibition
Authors: Goldsmith Paul K. , Fan Gaofeng , Miller Jeffery L. , Rogers Kimberly V. , Spiegel Allen M.
Published: April 2006

We generated monoclonal antibodies against two synthetic peptides corresponding to residues 214–235 (ADD) and 374–391 (LRG) of the human Ca2+ receptor (hCaR) extracellular domain (ECD). Although both antibodies reacted well with their respective immunizing peptides on peptide-based enzyme linked immunosorbent assay, ADD was much more strongly reactive with the hCaR than LRG in assays such as immunoblots done under denaturing conditions. The opposite pattern was seen in flow cytometry analysis of the native receptor stably expressed in transfected 293 cells. We speculate that the ADD epitope is unexposed in the native receptor while the reverse is true for the LRG epitope. The ability to measure cell surface expression of the hCaR under native conditions using flow cytometry with the LRG monoclonal allowed us to study the basis for Concanavalin A (Con A) inhibition of CaR activation by Ca2+. Our studies show that Con A inhibition is partially accounted for by receptor internalization but, additionally, Con A may prevent Ca2+ stimulation directly by binding to carbohydrate residues in the receptor ECD.
OP-1 (BMP-7) Affects mRNA Expression of Type I, II, X Collagen, and Matrix Gla Protein in Ossifying Long Bones In Vitro
Authors: Haaijman A. , D'Souza R. N. , Bronckers A. L. J. J. , Goei S. W. , Burger E. H.
Published: April 2006

In long bone development, a regulating role of OP-1 is suggested by the local correlated expression of both OP-1 ligand and OP-1 binding receptors in developing mouse hind limbs. OP-1 is expressed in the interdigital mesenchyme, whereas OP-1 binding receptors are found in the bordering perichondrium, and both OP-1 ligand and receptors are present in the zone of (pre)hypertrophic chondrocytes. We investigated the role of OP-1 in long bone development experimentally by treating organ cultures of embryonic mouse metatarsals with rhOP-1. The mRNA expression patterns of type I, II, X collagen, and matrix Gla protein (MGP) were studied using in situ hybridization and cell proliferation using [3H]thymidine and BrdU labeling. In the epiphyseal perichondrium, treatment with 40 ng/ml OP-1 enhanced cell proliferation after day 2, while 6-day treatment caused a shift in expression from type I collagen to type II collagen mRNA. This supports previous histochemical findings that OP-1 induced the transition of perichondrium into cartilage. In the center of the rudiment, OP-1 inhibited the expression of type X collagen mRNA, indicating inhibition of chondrocyte hypertrophy. An arrest of differentiation at the prehypertrophic chondrocyte stage was also indicated by the large area of cells expressing MGP mRNA in the OP-1–treated rudiments. We conclude that OP-1 affected the expression of marker genes of chondrocyte differentiation by acting on two steps in endochondral ossification. First, cell proliferation was enhanced, particularly so in the perichondrium where cells started to express the chondrocyte phenotype. Second, the terminal differentiation of mature chondrocytes into hypertrophic chondrocytes was inhibited. These results, combined with the known pattern of OP-1 ligand and BMP receptor expression in the embryo, suggest that OP-1 plays a local role in the cascade of events during endochondral ossification.
Hypophosphatemia and the Development of Rickets in Osteopetrotic (op/op) Mice
Authors: Mccary Laura C. , Smith Connie M. , Deluca Hector F.
Published: April 2006

Our previous work has shown that op/op mice hyperabsorb dietary calcium in the vitamin D–deficient state and shunt that calcium into bone. Under these conditions, the op/op mice are hypocalcemic. The purpose of this study was to examine calcium metabolism and bone mineralization in vitamin D–deficient op/op mice. First, the op/op mice and their normal littermates were placed on a vitamin D–deficient, low phosphorus diet to limit bone mineralization. Under these circumstances, op/op mice survived, even when calcium was also removed from the diet. If the diet contained phosphate, op/op mice died from hypocalcemic tetany when calcium was also removed from the diet. Furthermore, serum calcium levels became similar to wild type in the op/op mice administered the vitamin D–deficient, low phosphorus diet, and op/op mice were able to increase serum calcium in response to 1,25-dihydroxyvitamin D3. The op/op mice developed rickets when their serum phosphorus level was too low to support bone mineralization. The op/op mice became hypophosphatemic on regimens in which normal mice were able to maintain normal serum phosphorus levels. It appears that the op/op mouse simply requires a higher dietary calcium and phosphorus level to prevent rickets and hypocalcemic tetany since the bone is not available as a source of these minerals. However, the ability of the op/op mouse to mineralize bone at low serum calcium and phosphorus levels remains unexplained.
Expression of an Extracellular Calcium-Sensing Receptor in Human and Mouse Bone Marrow Cells
Authors: House Michael G. , Kohlmeier Lynn , Chattopadhyay Naibedya , Kifor Olga , Yamaguchi Toru , Leboff Meryl S. , Glowacki Julie , Brown Edward M.
Published: April 2006

The cloning of a G protein–coupled, extracellular calcium (Ca2+e)-sensing receptor (CaR) from bovine parathyroid provided direct evidence that Ca2+e-sensing can occur through receptor-mediated activation of G proteins and their associated downstream regulators of cellular function. CaR transcripts and protein are present in various tissues of humans and other mammals that are involved in Ca2+e homeostasis, including parathyroid, kidney, and thyroidal C-cells. The present study was performed to determine whether bone marrow cells express the CaR, since cells within the marrow space could be exposed to substantial changes in Ca2+e related to bone turnover. Using DNA and RNA probes from the human parathyroid CaR cDNA, we identified CaR transcripts of 5.2 and ∼4.0 kilobases by Northern analysis of poly(A+) RNA from low-density mononuclear cells isolated from whole human bone marrow that are putatively enriched in marrow progenitor cells, including bone cell precursors. In situ hybridization also identified CaR transcripts in the same cell preparations. Reverse transcription-polymerase chain reaction demonstrated >99% nucleotide identity between transcripts from human bone marrow cells and the corresponding regions of the human CaR cDNA. Antisera specific for several different regions within the extracellular domain of the CaR were reactive with low-density human marrow cells that were either adherent or nonadherent to plastic. About one-third of the adherent, CaR-immunoreactive cells were also positive for alkaline phosphatase, a nonspecific marker of preosteoblasts, osteoblasts, and assorted cells of the colony-forming unit-fibroblast lineage. In addition, a substantial fraction (∼60%) of low density murine marrow cells cultured for 1 week at 4.8 mM Ca2+e expressed both CaR immunoreactivity and nonspecific esterase, an enzyme expressed by monocyte/macrophages and fibroblasts. Finally, erythroid precursors and megakaryocytes from murine marrow as well as blood platelets expressed abundant CaR immunoreactivity, while peripheral blood erythrocytes and most polymorphonuclear leukocytes did not. These studies indicate that the CaR is present in low-density mononuclear bone marrow cells as well as in cells of several hematopoietic lineages and could potentially play a role in controlling the function of various cell types within the marrow space.
Gene Expression Patterns of Murine Dentin Matrix Protein 1 (Dmp1) and Dentin Sialophosphoprotein (DSPP) Suggest Distinct Developmental Functions In Vivo
Authors: D'souza R. N. , Cavender A. , Sunavala G. , Alvarez J. , Ohshima T. , Kulkarni A. B. , MacDougall M.
Published: April 2006

Although the precise mechanisms of the conversion of predentin to dentin are not well understood, several lines of evidence implicate the noncollagenous proteins (NCPs) as important regulators of dentin biomineralization. Here we compared the in vivo temporospatial expression patterns of two dentin NCP genes, dentin matrix protein 1 (Dmp1), and dentin sialophosphoprotein (DSPP) in developing molars. Reverse transcription-polymerase chain reaction was performed on embryonic day 13 to 1-day-old first molars using Dmp1- and DSPP-specific primer sets. Dmp1 transcripts appeared at the late bud stage, while DSPP mRNA was seen at the cap stage. Expression of both genes was sustained throughout odontogenesis. In situ hybridization analysis revealed interesting differences in the expression patterns of these genes. While Dmp1 and DSPP showed coexpression in young odontoblasts before the start of mineralization, the expression of these genes was notably distinct at later stages. Dmp1 expression decreased in secretory odontoblasts after the appearance of mineral, while high levels of DSPP were sustained in odontoblasts. In early secretory ameloblasts, DSPP expression was transient and down-regulated with the appearance of dentin matrix. Interestingly, Dmp1 expression became evident in ameloblasts during the maturative phase of amelogenesis. In contrast to Dspp expression that was tooth-specific, Dmp1 was expressed by osteoblasts throughout ossification in the skeleton. Probes directed to the “DSP” and “DPP” regions of the DSPP gene showed identical patterns of mRNA expression. These data show that the developmental expression patterns of Dmp1 and DSPP are distinct, implying that these molecules serve different biological functions in vivo.
Genetic Influences on Muscle Strength, Lean Body Mass, and Bone Mineral Density: A Twin Study
Authors: Arden N. K. , Spector T. D.
Published: April 2006

Lean body mass and muscle strength are both associated with bone mineral density (BMD), which is known to be under strong genetic control. In this classical twin study, we examine the size of the genetic component of both muscle strength and lean body mass and to what degree they account for the genetic component of BMD. In all, 706 postmenopausal women were examined; 227 pairs of monozygous (MZ) twins and 126 pairs of dizygous (DZ) twins. Grip strength was measured using a hand-help grip bulb and leg strength using a dynamic leg extensor power rig. Lean body mass and BMD at multiple sites were measured by dual-energy X-ray absorptiometry. BMD correlated with both leg extensor strength (r = 0.16–0.26) and grip strength (r = 0.12–0.21). Lean mass was significantly correlated with BMD at all sites (r = 0.20–0.39). All three muscle variables have a moderate genetic component with heritability estimates of 0.52 for lean body mass, 0.46 for leg extensor strength, and 0.30 for grip strength (all p < 0.05). The genetic component of BMD was not significantly reduced after adjusting for lean mass and muscle strength, with less than 20% of the genetic variance of BMD explained by the muscle variables. In conclusion, these data suggest that the three muscle variables have a modest genetic component, suggesting the potential for clinical intervention and lifestyle modifications. The genetic component to muscle bulk and strength accounts for little of the genetic component to BMD, confirming the rationale for research into bone-specific genes.
Intermittent On/Off Prostaglandin E2 and Risedronate Are Equally Anabolic as Daily PGE2 Alone Treatment in Cortical Bone of Ovariectomized Rats
Authors: Ma Yan Fei , Pan Zeng , Jee Webster S. S. , Lin Chao Hua , Liang Hao Hai , Chen Hongka , Pun Sunwah , Li Xiao Jian
Published: April 2006

In this study, we evaluated the rat cortical bone changes after a two-cycle, 60-day each (ON/OFF/ON/OFF) treatment with either prostaglandin E2 (OVX/c-PGE2) alone or in combination with risedronate (OVX/c-PGE2+Ris), in comparison with daily treatment with PGE2 for 240 days (OVX/PGE2−240d) in ovariectomized (OVX) rats. At the end of the study, we found that: (1) the overall effectiveness of the treatment on bone mass in the tibial shaft indicates the following ranking: OVX/PGE2−240d = OVX/c-PGE2+Ris > OVX/c-PGE2 > OVX/c-Ris ≥ OVX = aging; (2) the same bone mass and architecture were produced in the OVX/PGE2−240d and the OVX/c-PGE2+Ris groups, but the histomorphometric profiles differed in that the former exhibited a higher bone turnover and index of resorption; (3) OVX/c-PGE2+Ris treatment prevented endocortical bone loss and minimized trabecular bone loss during the OFF periods; and (4) the OVX/c-PGE2 alone treatment resulted in the accumulation of less total bone than OVX/PGE2−240d and OVX/c-PGE2+Ris because it could not maintain most of the new subendocortical and marrow trabecular bone generated earlier. In summary, both continuous daily PGE2 and two cycles ON/OFF combined PGE2 and Ris treatments result in more bone mass than two cycles ON/OFF PGE2 alone and Ris alone in estrogen-deficient rats. This study showed that the anabolic effects of PGE2 can be induced and maintained either by continuous administration or by cyclical PGE2+Ris.
Age-Related (Type II) Femoral Neck Osteoporosis in Men: Biochemical Evidence for Both Hypovitaminosis D– and Androgen Deficiency–Induced Bone Resorption
Authors: Boonen Steven , Vanderschueren Dirk , Cheng Xiao Guang , Verbeke Geert , Dequeker Jan , Geusens Piet , Broos Paul , Bouillon Roger
Published: April 2006

The problem of osteoporosis in men has recently been recognized as an important public health issue. To test the hypothesis that endocrine deficiency–mediated alterations in bone metabolism might contribute to osteoporotic fracture risk in elderly men, serum levels of 25-hydroxycholecalciferol (25(OH)D), 1,25-dihydroxycholecalciferol (1,25(OH)2D), intact parathyroid hormone (PTH), testosterone, and estradiol were measured in 40 males (mean age 73 years) who were consecutively recruited within 18 h following a fracture of the proximal femur, and in an equal number of community-living older men (mean age 72 years) who served as controls. In addition, circulating osteocalcin and urinary excretion of (deoxy)pyridinoline were determined as markers of bone formation and resorption, respectively. No differences were observed between the mean serum concentrations of osteocalcin and estradiol. Serum levels of 25(OH)D, 1,25(OH)2D, and testosterone, however, were decreased in hip fracture patients. When correcting for differences in vitamin D binding protein, differences in 1,25(OH)2D did not persist, whereas serum 25(OH)D was still significantly lower in patients than in controls (6.1 ± 4.3 vs. 7.6 ± 2.8, p = 0.01). Similarly, a highly significant deficit was observed in the free testosterone index, calculated from total testosterone and the level of sex hormone binding globulin (2.6 ± 1.3 vs. 8.2 ± 2.9, p < 0.001). Serum PTH and urinary pyridinium cross-links, however, were markedly increased in the fracture group. Moreover, in fracture patients, free 25(OH)D and free testosterone were both significant and mutually independent negative predictors of (deoxy)pyridinoline excretion. Although limited by its cross-sectional design, the present study suggests that both hypovitaminosis D and androgen deficiency may predispose to bone resorption in elderly men and in turn to remodeling imbalance and fracture risk.
A New Method of Bone Tissue Measurement Based upon Light Scattering
Authors: Takeuchi Akira , Araki Ryuichiro , Proskurin S. G. , Takahashi Yukari , Yamada Yukio , Ishii Jun , Katayama Shigehiro , Itabashi Akira
Published: April 2006

In recent years, time-resolved spectroscopy systems using near infrared pulsed laser have been applied to develop optical computed tomography. We applied this technique to measure the optical properties of osseous tissue. First, we gradually demineralized 10 mm blocks of bovine trabecular bone with EDTA, maintaining the absorption characteristics and structure but varying the hydroxyapatite content, thus creating specimens differing only in light scattering properties. We used computer densitograms to assess light penetration, and analyzed the correlation with bone mineral density (BMD) as with dual-energy X-ray absorptiometry scans. The light penetration increased with decreasing BMD. Second, using the above-mentioned pulsed laser time-resolved spectroscopy system, we investigated the correlation between the BMD and the time response waveforms of 10-mm blocks of bovine cortical bone, trabecular bone, and surrounding tissue as well as human trabecular bone. The human lumbar vertebral bone also displayed an inverse correlation between BMD and maximum light penetration and a positive correlation between BMD and peak time delay. This is the first demonstration of a correlation between BMD and light scattering properties showing that BMD can indeed be measured with light. Our results show the possibility of obtaining information on internal bone structure and composition in vivo through assessment of the waveforms obtained by a time-resolution system in the near infrared region.
Bone Mineral Density and Blood Flow to the Lower Extremities: The Study of Osteoporotic Fractures
Authors: Vogt Molly T. , Cauley Jane A. , Kuller Lewis H. , Nevitt Michael C.
Published: April 2006

This study tests the hypothesis that reduced blood flow to the lower extremities may affect bone remodeling, resulting in a decrease in bone mineral density (BMD). BMD was measured in the axial and appendicular skeleton of 1292 elderly women (mean age, 71 years) enrolled in the Study of Osteoporotic Fractures. The ratio of the posterior tibial and brachial systolic blood pressures, the ankle/arm index, was used as a measure of blood flow to the legs. In the cross-sectional analysis, this index was positively correlated with BMD at the radius, calcaneus, and hip, but not at the spine. A decrease in the index of 2 standard deviations (SD) (as might occur in patients with moderate arterial disease) was associated with a decrease of 3.7% (95% CI, 1.7%, 5.8%) in hip BMD. The effect size at the hip decreased from 3.7 to 1.8% (and was not statistically significant) when adjustment was made for smoking and/or body mass index (BMI). In the prospective analysis, the rate of bone loss at the hip and calcaneus was greater (p < 0.05) among women whose annual decrease in ankle/arm index was more than 1 SD greater than the mean decrease. This increase was independent of estrogen use, smoking, BMI, pattern of fat distribution, history of diabetes, exercise, and ability to walk. The results from this prospective community-based study provide the first evidence that among relatively healthy older women decreased vascular flow in the lower extremities may be associated with an increased rate of bone loss at the hip and calcaneus.
The Role of Testosterone in Cyclosporine-Induced Osteopenia
Authors: Bowman A. R. , Sass D. A. , Dissanayake I. R. , Ma Y. F. , Liang H. , Yuan Z. , Jee W. S. S. , Epstein S.
Published: April 2006

Our laboratory has demonstrated that the immunosuppressants Cyclosporin A (CsA) and tacrolimus (FK506), in vivo in the rat, produce a high-turnover osteopenia. CsA is known to decrease serum testosterone (Test) levels both in the rat and in human transplant patients. Less is known of FK506's effect on androgens. CsA-induced hypogonadism may contribute to the aforementioned bone loss because hypogonadism itself is a risk factor for osteoporosis and fracture. The aim of this study was to assess serum androgen levels following CsA and FK506 therapy and to see whether Test replacement therapy, in the form of 28-day controlled release subcutaneous pellet implants, could prevent CsA-induced osteopenia. Two experiments were conducted. In experiment I, four groups of 6-month-old male Sprague-Dawley rats received the following: (A) CsA vehicle and placebo pellet, (B) Test 15 mg pellet and CsA vehicle, (C) CsA 10 mg/kg and placebo pellet, (D) Test 15 mg pellet and CsA 10 mg/kg. In experiment II, two groups of rats received (E) FK506 vehicle and (F) FK506 4 mg/kg. CsA, FK506, and vehicles were given for 28 days by daily oral gavage. The rats were weighed and bled on days 0, 14, and 28. All rats received double fluorescent labeling, and on day 28 the tibiae were removed for histomorphometry. Whole blood was assayed for CsA and FK506 levels. Serum was assayed for total and free Test as well as for osteocalcin (BGP), blood urea nitrogen (BUN), creatinine, and calcium. Whole blood monoclonal CsA levels measured by fluorescent immunoassay were in the therapeutic range, while a drug concentration profile showed good absorption of FK506. Those rats receiving Test and FK506 lost weight, while those receiving CsA remained constant. BUN was only marginally elevated in the CsA-treated groups on day 28 (p < 0.05), while creatinine was unchanged. On day 28, total and free Test was significantly reduced in the CsA-treated rats versus control (p < 0.05), while Test replacement therapy maintained total Test levels above vehicle (p < 0.01) and free Test levels similar to vehicle on day 28. FK506 did not lower total or free Test levels. BGP levels were significantly increased in the CsA (p < 0.01) and FK506 (p < 0.001) groups on day 28. BGP in the groups receiving Test alone and in combination with CsA remained similar to vehicle. Histomorphometry confirmed CsA- and FK506-induced high-turnover osteopenia. The Test alone group marginally increased bone formation. Test replacement failed to prevent the CsA-induced bone loss. In conclusion, immunosuppressive doses of CsA, but not FK506, lowers serum total and free Test. Hypoandrogenemia does not seem to be a major factor in CsA-induced osteopenia because bone loss occurs despite Test replacement.
Effect of Resistance Exercise Training on Bone Formation and Resorption in Young Male Subjects Assessed by Biomarkers of Bone Metabolism
Authors: Fujimura Rei , Ashizawa Noriko , Watanabe Manami , Mukai Naoki , Amagai Hitoshi , Fukubayashi Toru , Hayashi Koichiro , Tokuyama Kumpei , Dr. Suzuki Masashige
Published: April 2006

We studied the effects of high intensity resistance exercise training on bone metabolism in 17 young adult Oriental males (23–31 years) by measuring sensitive biomarkers of bone formation and resorption. The subjects were assigned to a training group and a sedentary group. The training group followed a weight training program three times per week for 4 months. In the training group, serum osteocalcin concentration and serum bone-specific alkaline phosphatase activity were significantly increased within the first month after the beginning of resistance exercise training, and the elevated levels remained throughout the training period, while there was no significant change in plasma procollagen type-I C-terminal concentration. Urinary deoxypyridinoline excretion was transiently suppressed and returned to the initial value but was never stimulated during the 4 months. These results suggest that the resistance exercise training enhanced bone formation without prior bone resorption. In the sedentary group, there was no significant difference in bone metabolic markers except plasma procollagen type-I C-terminal, which continuously decreased during the experimental period. There were no significant changes in total and regional bone mineral density in either group. In conclusion, (1) resistance exercise training increased markers of bone formation, while it transiently suppressed a marker of bone resorption, and (2) such adaptive changes of bone metabolism to resistance exercise training occurred during the early period of the training, before changes in bone density were observable through densitometry.
Dexamethasone Stimulates Osteoclast-like Cell Formation by Directly Acting on Hemopoietic Blast Cells and Enhances Osteoclast-like Cell Formation Stimulated by Parathyroid Hormone and Prostaglandin E2
Authors: Kaji Hiroshi , Sugimoto Toshitsugu , Kanatani Masanori , Nishiyama Katsuhito , Chihara Kazuo
Published: April 2006

Although an excess of glucocorticoid induces secondary osteoporosis, the mechanism still remains unclear, particularly in regard to glucocorticoid-stimulated bone resorption. We examined the effects of dexamethasone (Dex) on osteoclast-like cell formation and bone-resorbing activity by employing mouse bone and spleen cell cultures and further investigated whether Dex would modulate osteoclast-like cell formation stimulated by several bone-resorbing factors. Dex stimulated osteoclast-like cell formation in stromal cell-containing mouse bone cell cultures in a concentration-dependent manner. Also, Dex significantly stimulated osteoclast-like cell formation from hemopoietic blast cells in spleen cell cultures derived from 5-fluorouracil-pretreated mice. In contrast, Dex (10−8 M) did not affect the bone-resorbing activity of mature osteoclasts. Pretreatment with 10−8 M Dex significantly enhanced osteoclast-like cell formation in unfractionated mouse bone cell cultures stimulated by 10−8 M human (h) parathyroid hormone (PTH) (1–34), 10−8 M hPTH-related protein (1–34) and 10−6 M prostaglandin E2, but not by 10−8 M 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). Moreover, pretreatment with 10−8 M Dex significantly enhanced osteoclast-like cell formation stimulated by both forskolin and dbcAMP. In contrast, pretreatment with 10−8 M Dex significantly inhibited osteoclast-like cell formation in mouse spleen cell cultures stimulated by both 10−8 M hPTH(1–34) and 10−8 M 1,25(OH)2D3. These findings suggest that Dex stimulates osteoclast-like cell formation, at least in part by directly acting on hemopoietic blast cells. They further suggest that Dex enhances osteoclast-like cell formation stimulated by PTH and prostaglandin E2 through an indirect pathway via cells other than hemopoietic blast cells.
Microgravity Reduces the Differentiation of Human Osteoblastic MG-63 Cells
Authors: Carmeliet Geert , Nys Guy , Bouillon Roger
Published: April 2006

Spaceflight leads to osteopenia in both humans and animals, principally as a result of decreased bone formation, which might be the consequence of impaired osteoblast differentiation. The effect of microgravity on osteoblast differentiation in vitro was investigated using the human osteosarcoma cell line MG-63. Genes related to matrix formation and maturation were quantified both at the protein and mRNA level in untreated and hormone-treated (dihydroxyvitamin D3 [1,25(OH)2D3], 10−7 M; transforming growth factor β2 (TGF-β2), 10 ng/ml) cells cultured for 9 days under microgravity conditions aboard the Foton 10 satellite and compared with ground and inflight unit-gravity cultures. The expression of alkaline phosphatase (ALP) activity following treatment at microgravity increased only by a factor of 1.8 compared with the 3.8-fold increase at unit-gravity (p < 0.01), whereas no alteration was detected in the production of collagen type I between unit- and microgravity. In addition, gene expression for collagen Iα1, ALP, and osteocalcin following treatment at microgravity was reduced to 51, 62, and 19%, respectively, of unit-gravity levels (p < 0.02). The lack of correlation between collagen type I gene and protein expression induced by microgravity is most likely related to the different kinetics of gene and protein expression observed at unit-gravity: following treatment with 1,25(OH)2D3 and TGF-β2, collagen Iα1 mRNA increased gradually during 72 h, but collagen type I production was already maximal after treatment for 48 h. In conclusion, microgravity decreases the activity of osteoblasts in vitro; in particular the differentiation of osteoblasts in response to systemic hormones and growth factors is reduced by microgravity.
Hip Fracture and Osteoporosis in a XIIth Dynasty Female Skeleton from Lisht, Upper Egypt
Authors: Dequeker Jan , Ortner Donald J. , Stix Agnes I. , Cheng Xiao-Gguang , Brys Peter , Boonen Steven
Published: April 2006

Osteoporosis and complications arising from loss of bone mass have been present in human populations for thousands of years. However, reports of this disease in antiquity remain uncommon. The purpose of this report is to describe an important case of osteoporosis in ancient Egypt because of its intrinsic interest and to provide perspectives on factors contributing to this condition today. The case providing the focus for this report is from Lisht, Upper Egypt and is dated to the XIIth Dynasty (1990–1786 B.C.). Methods used to characterize the pathology include gross anatomical study, radiology, and radiographic measurements. Observations, measurements, and indices all indicate osteoporosis complicated by fracture of the femoral neck and compression fractures of some vertebrae. The Lisht case adds to a small corpus of reports on osteoporosis and complicating factors of this disease in antiquity. Long-term survival of an extracapsular fracture of the femoral neck in this case is remarkable and may reflect supportive social conditions.
Peyronie's Disease Is Associated with Paget's Disease of Bone
Authors: Lyles Kenneth W. , Gold Deborah T. , Newton Rebecca A. , Parekh Sohail , Shipp Kathy M. , Pieper Carl F. , Krishan Ramesh , Carson Culley C.
Published: April 2006

Peyronie's disease is an idiopathic disorder in which an inflammatory fibrosis occurs in the tunica albuginea of the corpora cavernosa which causes the erect penis to become deformed. Peyronie's disease has a prevalence of 1% in men over age 50 years. Paget's disease of bone is a chronic skeletal disease with areas of increased bone turnover leading to pain, deformity, and in some cases arthritis. Because of a high rate of Peyronie's disease in subjects in a Paget's disease industry-sponsored drug trial, we asked whether there was an association between Peyronie's disease and Paget's disease of bone. We evaluated 61 men with Paget's disease attending our clinic for metabolic bone disease in a tertiary referral hospital, reviewed hospital records of all men discharged from our three hospitals with the diagnosis of Peyronie's disease, and mailed a validated questionnaire about shape of the erect penis to 1500 male members of the Paget Foundation. In the clinic population of men with Paget's disease of bone, 51 of 61 (83.6%) reported having normal erections; 10 patients (16.4%) were impotent. Sixteen of the 51 men (31.4%) had developed a bend or deformity in their erect penis which was confirmed by a urologist's examination to be Peyronie's disease. When the men with Paget's disease with and without Peyronie's disease were compared, there was no difference in their ages, years with Paget's disease, or serum alkaline phosphatase level. Upon medical record review, 1 patient of 262 (0.4%) with Peyronie's disease was found to have Paget's disease of bone. The men with Paget's disease returned their questionnaires for a response rate of 44.8% and reported Peyronie's disease with a prevalence of 14.5%. We suggest that Peyronie's disease is associated with Paget's disease of bone. Furthermore, we suggest that Peyronie's disease may be a previously unrecognized complication of Paget's disease of bone.