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Unlabelled: : By using surgical mouse models, this study investigated how the tissue environment influences the osteogenic potential of muscle progenitors (m-progenitors) and potentially contributes to heterotopic ossification (HO). Injury was induced by clamping the gluteus maximus and medius (group M) or osteotomy of greater trochanter (group O) on the right hip, as well as combined muscle injury and osteotomy of greater trochanter (group M+O). The gluteus maximus and medius of the operated hips were harvested at days 1, 3, 5, and 10 for isolation of m-progenitors. The cells were cultured in an osteogenic medium for 3 weeks, and osteogenesis was evaluated by matrix mineralization and the expression of osteogenesis-related genes. The expression of type I collagen, RUNX2 (runt-related transcription factor 2), and osteocalcin by the m-progenitors of group M+O was significantly increased, compared with groups M and O. Osteogenic m-progenitors in group O increased the expression of bone morphogenetic protein 2 and also bone morphogenetic protein antagonist differential screening-selected gene aberrative in neuroblastoma. On histology, there was calcium deposition mostly in the muscles of group M+O harvested at day 10. CD56, representing myogenic progenitors, was highly expressed in the m-progenitors isolated from group M (day 10), but m-progenitors of group M+O (day 10) exhibited the highest expression of platelet-derived growth factor receptor α (PDGFR-α), a marker of muscle-derived mesenchymal stem cells (M-MSCs). The expressions of PDGFR-α and RUNX2 were colocalized in osteogenic m-progenitors. The data indicate that the tissue environment simulated in the M+O model is a favorable condition for HO formation. Most likely, M-MSCs, rather than myogenic progenitors, in the m-progenitors participate in HO formation., Significance: The prevalence of traumatic heterotopic ossification (HO) is high in war injury. The pathogenesis of HO is still unknown. This study clarified the contribution of a tissue environment created by bone or muscle injury to the formation of HO. The study also found that muscle-derived mesenchymal stem cells, but not myogenic progenitors, are involved in the formation of HO. The findings of this study could be used to strategize the prevention and treatment of HO., (©AlphaMed Press.)

Unlabelled: The cartilage regeneration potential of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) with a hyaluronic acid (HA) hydrogel composite has shown remarkable results in rat and rabbit models. The purpose of the present study was to confirm the consistent regenerative potential in a pig model using three different cell lines. A full-thickness chondral injury was intentionally created in the trochlear groove of each knee in 6 minipigs. Three weeks later, an osteochondral defect, 5 mm wide by 10 mm deep, was created, followed by an 8-mm-wide and 5-mm-deep reaming. A mixture (1.5 ml) of hUCB-MSCs (0.5×10(7) cells per milliliter) and 4% HA hydrogel composite was then transplanted into the defect on the right knee. Each cell line was used in two minipigs. The osteochondral defect created in the same manner on the left knee was untreated to act as the control. At 12 weeks postoperatively, the pigs were sacrificed, and the degree of subsequent cartilage regeneration was evaluated by gross and histological analysis. The transplanted knee resulted in superior and more complete hyaline cartilage regeneration compared with the control knee. The cellular characteristics (e.g., cellular proliferation and chondrogenic differentiation capacity) of the hUCB-MSCs influenced the degree of cartilage regeneration potential. This evidence of consistent cartilage regeneration using composites of hUCB-MSCs and HA hydrogel in a large animal model could be a stepping stone to a human clinical trial in the future., Significance: To date, several studies have investigated the chondrogenic potential of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs); however, the preclinical studies are still limited in numbers with various results. In parallel, in the past several years, the cartilage regeneration potential of hUCB-MSCs with a hyaluronic acid (HA) hydrogel composite have been investigated and remarkable results in rat and rabbit models have been attained. (These experimental results are currently in preparation for publication.) Before applying the cartilage regeneration technique in a human clinical trial, it seemed necessary to confirm the consistent result in a larger animal model. At 12 weeks postoperatively, the minipigs were sacrificed, and the degree of subsequent cartilage regeneration was evaluated by gross and histological analysis. The transplanted knee resulted in superior and more complete hyaline cartilage regeneration compared with the control knee. This evidence of consistent cartilage regeneration with composites of hUCB-MSCs and HA hydrogel in a large animal model could be a stepping stone to a human clinical trial in the future., (©AlphaMed Press.)

Background: Clinical features of patients with castration-resistant prostate cancer (CRPC) are characterized by a high incidence of bone metastases, which are associated with impairment of quality of life, pain, skeletal-related events (SREs), and a negative impact on prognosis. Advances in the understanding of cancer cell-bone stroma interactions and molecular mechanisms have recently permitted the development of new agents., Purpose: We review the merits, applications, and limitations of emerging data sets on bone-metastatic CRPC with a focus on radium-223, an α-emitting radiopharmaceutical, and its use in therapy for this disease., Methods: References for this review were identified through searches of PubMed and Medline databases, and only papers published in English were considered. Related links in the databases were reviewed, along with relevant published guidelines, recently published abstracts from major medical meetings, and transcripts from a recent round table of clinical investigators., Results: Prior to radium-223, available bone-targeted therapies demonstrated the ability to delay SREs and palliate bone pain in patients with metastatic CRPC but without evidence of improvement in overall survival (OS). In a randomized controlled phase III trial, radium-223 demonstrated the ability to improve OS and delay SREs in docetaxel-pretreated or docetaxel-unfit men with symptomatic bone-metastatic CRPC and was not associated with significantly more grade 3 or 4 adverse events than placebo., Conclusion: Radium-223 has a targeted effect on bone metastases in CRPC and has an important role in docetaxel-pretreated or docetaxel-unfit men with symptomatic bone-metastatic CRPC., (©AlphaMed Press.)

The physiological role of Dickkopf-1 (Dkk1) during postnatal bone growth in rodents and in adult rodents was examined utilizing an antibody to Dkk1 (Dkk1-Ab) that blocked Dkk1 binding to both low density lipoprotein receptor-related protein 6 (LRP6) and Kremen2, thereby preventing the Wnt inhibitory activity of Dkk1. Treatment of growing mice and rats with Dkk1-Ab resulted in a significant increase in bone mineral density because of increased bone formation. In contrast, treatment of adult ovariectomized rats did not appreciably impact bone, an effect that was associated with decreased Dkk1 expression in the serum and bone of older rats. Finally, we showed that Dkk1 plays a prominent role in adult bone by mediating fracture healing in adult rodents. These data suggest that, whereas Dkk1 significantly regulates bone formation in younger animals, its role in older animals is limited to pathologies that lead to the induction of Dkk1 expression in bone and/or serum, such as traumatic injury., (Copyright © 2011 American Society for Bone and Mineral Research.)

Sex steroids are important for the growth and maintenance of both the female and the male skeleton. However, the relative contribution of androgens versus estrogens in the regulation of the male skeleton is unclear. Experiments using mice with inactivated sex steroid receptors demonstrated that both activation of the estrogen receptor (ER)alpha and activation of the androgen receptor result in a stimulatory effect on both the cortical and trabecular bone mass in males. ERbeta is of no importance for the skeleton in male mice while it modulates the ERalpha-action on bone in female mice. Previous in vitro studies suggest that the membrane G protein-coupled receptor GPR30 also might be a functional ER. Our in vivo analyses of GPR30-inactivated mice revealed no function of GPR30 for estrogen-mediated effects on bone mass but it is required for normal regulation of the growth plate and estrogen-mediated insulin-secretion. Recent clinical evidence suggests that a threshold exists for estrogen effects on bone in men: rates of bone loss and fracture risk seem to be the highest in men with estradiol levels below this threshold. Taken together, even though these findings do not exclude an important role for testosterone in male skeletal homeostasis, it is now well-established that estrogens are important regulators of bone health in men.

Unlabelled: Bone regeneration is challenging in sites where the blood supply has been compromised by radiation. We examined the potential of a growth factor (VEGF) delivery system to enhance angiogenesis and bone formation in irradiated calvarial defects. VEGF-releasing polymers significantly increased blood vessel density and vascular perfusion in irradiated defects and increased bone formation relative to control conditions., Introduction: Radiation therapy causes damage to tissues and inhibits its regenerative capacity. Tissue injury from radiation is in large part caused by a compromised vascular supply and reduced perfusion of tissues. The aim of this study was to determine if delivery of vascular endothelial growth factor (VEGF) from a biodegradable PLGA (copolymer of D,L-lactide and glycolide) scaffold could enhance neovascularization and bone regeneration in irradiated osseous defects., Materials and Methods: An isolated area of the calvarium of Fisher rats was irradiated (12 Gy) 2 weeks preoperatively, and two 3.5-mm osseous defects were created in this area, followed by the placement of PLGA scaffolds or VEGF scaffolds (PLGA scaffolds with incorporated VEGF) into the defects. Laser Doppler perfusion imaging was performed to measure perfusion of these areas at 1, 2, and 6 weeks. Implants were retrieved at 2, 6, and 12 weeks, and histologic and muCT analyses were performed to determine neovascularization and bone regeneration., Results: Histological analyses revealed statistically significant increases in blood vessel formation (>2-fold) and function (30%) within the VEGF scaffolds compared with PLGA scaffolds. Additionally, evaluation of bone regeneration through bone histomorphometric and muCT analyses revealed significantly greater bone coverage (26.36 +/- 6.91% versus 7.05 +/- 2.09% [SD]) and increased BMD (130.80 +/- 58.05 versus 71.28 +/- 42.94 mg/cm(3)) in VEGF scaffolds compared with PLGA scaffolds., Conclusions: Our findings show that VEGF scaffolds have the ability to enhance neovascularization and bone regeneration in irradiated osseous defects, outlining a novel approach for engineering tissues in hypovascular environments.

Unlabelled: Neridronate therapy in adult patients with OI significantly increases the cross-sectional area of the proximal radius. This observation may provide an additional explanation for the antifracture efficacy of bisphosphonates., Introduction: Bisphosphonate therapy decreases by 70-90% the fracture risk in patients with osteogenesis imperfecta (OI). This decrease is somewhat greater than that expected from the BMD changes, supporting the hypothesis that bisphosphonate therapy is associated with structural changes, not detectable by BMD measurements., Materials and Methods: To explore this hypothesis, pQCT measurements at the nondominant radius were obtained in a group of adult OI patients participating in a randomized clinical trial with neridronate., Results: The total volumetric BMD of the ultradistal radius rose significantly in patients treated with neridronate and calcium + vitamin D (neridronate group) compared with patients treated with calcium + vitamin D alone (control group). No significant differences were observed in trabecular BMD and in volumetric cortical density in either group. In the neridronate group, the cross-sectional area rose significantly versus both baseline values and the control group. These latter changes were associated with approximately 20% increases in bending breaking resistance index (BBRI)., Conclusion: Our observation, if extended to postmenopausal osteoporosis, may provide a new explanation for the fracture risk reduction observed in osteoporotic patients treated with bisphosphonates.

Unlabelled: In a random and prospective study, Alzheimer's disease (AD) patients were assigned to regular sunlight exposure (n = 132) or sunlight deprivation (n = 132) and followed for 1 year. Serum 25-OHD level increased by 2.2-fold in the sunlight-exposed group. Eleven patients sustained fractures in the sunlight-deprived group, and three fractures occurred among the sunlight-exposed group (p = 0.0362; odds ratio = 3.7)., Introduction: A high incidence of fractures, particularly of the hip, represents an important problem in patients with Alzheimer's disease (AD), who are prone to falls and have osteoporosis. We previously showed that 25-hydroxyvitamin D (25-OHD) deficiency caused by sunlight deprivation with compensatory hyperparathyroidism causes reduced BMD in elderly women with AD. This study was undertaken to address the possibility that sunlight exposure with calcium supplementation may maintain BMD and reduce the incidence of nonvertebral fractures in elderly women with AD., Materials and Methods: In a random and prospective study, AD patients were assigned to regular sunlight exposure (n = 132) or sunlight deprivation (n = 132) and followed for 1 year. BMD of the second metacarpal bone was measured using a computed X-ray densitometer (CXD). The CXD method measures BMD and cortical thickness at the middle of the second metacarpal bone on a radiogram of the hand and an aluminum step wedge as a standard (20 steps; 1 mm/step). Incidence of nonvertebral fractures in the two patient groups during the 1-year follow-up period was assessed., Results and Conclusion: At baseline, average hospitalization period was 1.7 years in both groups, and activity of daily living (ADL) was decreased. Patients of both groups showed vitamin D deficiency caused by sunlight deprivation and decreased dietary intake of vitamin D with compensatory hyperparathyroidism. The exposed group patients were exposed to sunlight (3615 minutes/year). BMD increased by 2.7% in the sunlight-exposed group and decreased by 5.6% in the sunlight-deprived group (p < 0.0001). Serum 25-OHD level increased from 24.0 to 52.2 nM in the sunlight-exposed group. Eleven patients sustained fractures in the sunlight-deprived group, and three fractures occurred among the sunlight-exposed group (p = 0.0362; odds ratio = 3.7). Sunlight exposure can increase the BMD of vitamin D-deficient bone by increasing 25-OHD concentration and lead to the prevention of nonvertebral fractures.

Unlabelled: The role of smoking on fracture risk in older men was studied within a longitudinal population-based cohort study. Using time-dependent exposure information and analysis, smoking was detected to be a stronger, dose-dependent and a more long lasting risk factor for fracture than has previously been estimated., Introduction: Although several studies have indicated a negative influence of smoking on fracture risk in women, there are few studies in men. No study in either sex has considered that smoking exposure may vary during follow-up in a cohort study. There is a need for a prospective study with repeated measures to analyze smoking exposure and fracture risk in men., Materials and Methods: A total of 2322 men, 49-51 years of age, were enrolled in a longitudinal, population-based cohort study. Smoking status and other lifestyle habits were established at baseline and additionally at 60, 70, and 77 years of age. One or more fractures were documented in 272 men during 30 years of follow-up. Cox proportional hazards regression was used to determine the rate ratio (RR) of fracture according to time-dependent smoking habits and covariates., Results: The overall adjusted fracture risk was increased in current (RR, 2.71; 95% CI, 1.86-3.95) and former smokers (RR, 1.66, 95% CI; 1.18-2.34), and persistent until 30 years after cessation. Among current smokers, the adjusted risk of any fracture increased by 30% (95% CI, 6-58%) for every 5 g of tobacco smoked each day. Smoking duration did not substantially influence fracture risk in either current or former smokers. One-half (52%; 95% CI, 35-65%) of all fractures were attributable to current smoking., Conclusions: Tobacco smoking seems to be a long-lasting major risk factor for fracture in older men, and the risks depends both on recency of smoking and on the daily amount of tobacco smoked, rather than smoking duration.

Unlabelled: A role for osteoblastic beta-adrenoreceptors in bone regulation is suggested by the finding that beta-blockers increase bone mass in mice. We studied the association of beta-blocker use with BMD and fractures in the Study of Osteoporotic Fractures. beta-blocker use and BMD are unrelated in this cohort, and associations with fracture risk are inconsistent., Introduction: The central nervous system has been shown to regulate bone mass in mice, possibly by way of the beta(2)-adrenoreceptors on osteoblasts. beta-blockers have been shown to increase bone mass in mice. Because these agents are widely used therapeutically, it is possible that they may influence fracture epidemiology in humans, and they are a potential therapy for osteoporosis., Materials and Methods: We have studied the association of beta-blocker use with BMD and fracture rates in the Study of Osteoporotic Fractures. beta-blocker use was recorded at the fourth visit, in 8412 women, of whom 1099 were users, and these women were followed for 7 years., Results: Users had significantly higher weight, more thiazide use, more estrogen use, less glucocorticoid use, more statin use, and more hypertension than nonusers, and they smoked less. Total hip BMD at the fourth visit was higher in the beta-blocker users (0.746 versus 0.735 g/cm(2), p = 0.02), but adjustment for weight alone, or together with these other variables, eliminated this difference (p = 0.62). There was no effect of beta-blocker use on loss of hip BMD over a mean follow-up of 4 years (p = 0.48). Os calcis BMD at visit 4 was also higher in those taking beta-blockers (0.385 versus 0.375 g/cm(2), p = 0.005), but weight adjustment eliminated this difference (p = 0.14). The frequencies of hip or any fracture (since age 50) were similar in users and nonusers (p = 0.80 and p = 0.51, respectively). Over a mean follow-up of 7 years, there were 2167 total fractures, including 431 at the wrist and 585 at the hip. Among beta-blocker users, hazards ratios were 0.92 (0.81, 1.05) for any fracture, 0.74 (0.54, 1.01) for wrist fracture, and 0.76 (0.58, 0.99) for hip fracture. Adjustment for weight and other factors previously shown to influence hip fracture incidence in this cohort made little difference to the outcome. When fracture data were analyzed for nonselective and beta(1)-selective agents separately, trends toward fewer fractures were confined to the users of selective beta(1)-blockers., Conclusions: beta-Blocker use and BMD are unrelated in this cohort, and associations with fracture risk are inconsistent. Therefore, a history of use of these drugs is not useful in assessing fracture risk, nor do they have a role in osteoporosis management at this time. The relationship between beta-blocker use and hip fracture deserves further study.

Unlabelled: Fracture risk among patients diagnosed with asthma in childhood is greater in males and oral corticosteroid users, but most fractures are of the appendicular skeleton and may relate to impaired skeletal development., Introduction: There are no population-based data on fracture outcomes among the growing number of patients with asthma diagnosed in childhood., Materials and Methods: We conducted a population-based retrospective (historical) cohort study among 279 Rochester, Minnesota, residents who were <35 years of age (mean, 6.2 years) when first diagnosed with asthma. Fractures were ascertained by review of comprehensive community medical records, and cases were compared directly with age- and sex-matched controls in a stratified proportional hazards model. Risk factors for fractures among the asthma cases were assessed using Andersen-Gill time-to-fracture regression models., Results: During 6649 person-years of follow-up (median, 24.3 years/subject), 107 asthma patients experienced 189 fractures, for a crude fracture incidence rate of 2.8 per 100 person-years. The actuarially estimated cumulative fracture incidence after 20 years was 40% compared with 34% among controls (p = 0.122). There was no significant increase in overall fracture risk among cases compared to their age- and sex-matched controls (hazard ratio [HR], 1.3; 95% CI, 0.9-1.9), but males with asthma had a 2.6-fold greater risk of hand and finger fractures than control males. The independent predictors of overall fracture risk among the asthma patients included male gender (HR, 2.2; 95% CI, 1.5-3.2) and use of oral corticosteroids (HR, 2.0; 95% CI, 1.2-3.1) or anti-cholinergic agents (HR, 3.9; 95% CI, 1.5-10)., Conclusions: Rather than osteoporotic fractures of the axial skeleton, oral corticosteroid therapy was associated here with limb fractures, suggesting a relationship with impaired development of a biomechanically competent skeleton. Additional studies are needed to assess this possibility.

Unlabelled: Among the potential risk factors for fragility fractures, bone turnover is considered an important determinant. In a case-cohort control study of 151 elderly men followed prospectively over 6.3 years, high bone resorption as assessed by S-ICTP was associated with increased risk of osteoporotic fracture, independent of BMD. Combining measurements of BMD and bone turnover may improve fracture prediction in elderly men., Introduction: Approximately one-third of osteoporotic fractures occur in men. Among the potential risk factors for fragility fractures, bone turnover is considered an important determinant. The association between fracture risk and rates of bone turnover has not been well established in men. We examined this relationship in elderly community-dwelling men., Materials and Methods: This case-cohort control study included 50 men with incident low-trauma fractures (cases; age, 72.3 +/- 6.7 years) and 101 men without fracture (controls; age, 70.4 +/- 4.1 years), who have been prospectively followed in the Dubbo Osteoporosis Epidemiology Study for a median of 6.3 years (range, 2-13 years). BMD at the lumbar spine (LSBMD) and at the femoral neck (FNBMD) and markers of bone turnover were measured at baseline. Bone resorption was assessed by measuring nonfasting serum concentrations of the carboxyterminal cross-linked telopeptide of type I collagen (S-ICTP) and of a linear octapeptide derived from the carboxyterminal type I collagen telopeptide (S-CTX). Bone formation was assessed by measuring the serum levels of the aminoterminal propeptide of type I procollagen (S-PINP)., Results: Men with subsequent fractures had lower BMD at baseline, both at the femoral neck and the spine, lower dietary calcium intake, and higher S-ICTP levels than age-and weight-matched controls. Smoking habits, S-CTX, and S-PINP did not differ between groups. Based on univariate regression analyses, S-ICTP (relative risk [RR] for 1 SD change: 1.8; 95% CI, 1.4-2.3) and serum creatinine levels (RR, 1.4; 95% CI, 1.1-1.7) were associated with increased risk of fracture. In multivariate regression analyses, S-ICTP (RR, 1.4; 95% CI, 1.0-1.9) and FNBMD (RR, 1.8; 95% CI, 1.4-2.3) remained independent predictors of fracture risk. Men within the highest quartile of S-ICTP had a 2.8-fold (95% CI 1.4-5.4) increased risk of fracture compared with those in the lowest quartile. The incidence of osteoporotic fractures was 10 times higher in men with high S-ICTP and low FNBMD compared with men with low S-ICTP and high FNBMD. Of the fracture risk in the population, 20% was attributable to high S-ICTP and low FNBMD, and S-ICTP contributed 17% to this increased risk., Conclusion: High bone resorption is associated with an increased risk of osteoporotic fracture in elderly men, independent of BMD. Combining measurements of BMD and bone turnover, which correlated with fracture in this cohort, could improve fracture risk prediction in elderly men.

Unlabelled: The NOF cost-effectiveness model, based on clinical risk factors and femoral neck aBMD, predicted overall fracture risk in a cohort of postmenopausal women followed for up to 22 years., Introduction: To assess the ability of a statistical model to predict long-term fracture risk for a population of postmenopausal women, we compared observed fractures to those predicted by the National Osteoporosis Foundation's (NOF) cost-effectiveness model., Materials and Methods: In this population-based study, 393 postmenopausal Rochester, MN, women had baseline measurements of femoral neck areal BMD (aBMD) and assessment of the clinical risk factors (personal fracture history, family history of osteoporotic fracture, low body weight, and smoking status) that were included in the NOF model. They were then followed prospectively for up to 22 years. Fractures were ascertained by periodic interview and review of community medical records. Standardized incidence ratios (SIRs) compared observed fractures to predicted numbers., Results: During 4782 person-years of follow-up, 212 women experienced 503 fractures, two-thirds of which were caused by moderate trauma. When undiagnosed (incidentally noted) vertebral and rib fractures were excluded, there was general concordance between observed and predicted fractures of the hip (SIR, 0.78; 95% CI, 0.56-1.01), distal forearm (SIR, 1.22; 95% CI, 0.86-1.68), spine (SIR, 0.76; 95% CI, 0.50-1.11), and all other sites combined (SIR, 1.18; 95% CI, 0.97-1.42). Fracture prediction by the NOF model was about as good after 10 years as it was earlier during follow-up., Conclusions: This study validates the ability of a statistical model based on femoral neck aBMD and common clinical risk factors to predict the actual occurrence of fractures in a cohort of postmenopausal white women.

Hyperhomocysteinemia (elevated plasma homocysteine levels) has been linked to increased risk of neural tube defects, cardiovascular disease, Alzheimer's dementia, pregnancy complications, and inflammatory bowel disease. Evidence for a role of hyperhomocysteinemia in the etiology of osteoporosis has recently been strengthened by the findings of two separate studies, which both reported that high homocysteine levels significantly increased risk of osteoporotic fracture. While the etiology of hyperhomocysteinemia is considered to be multifactorial (including genetic, nutritional, and lifestyle factors), a deficiency of one or more B vitamins certainly has a role. These vitamins are involved in the metabolism and clearance of homocysteine, and thus may have a protective effect against osteoporotic fracture risk.

The aim of this population-based case-control study was to examine the association between bone mass and upper limb fractures in children aged 9-16 yr. Areal bone mineral density and bone mineral apparent density (BMAD) were measured by both dual energy absorptiometry (DXA) and metacarpal index (MI) by hand radiograph. A total of 321 fracture cases and 321 randomly selected individually matched controls were studied. For all fractures, cases had lower DXA measures at all sites (1.1-3.3%; all P < 0.05). A larger reduction was observed for those with wrist and forearm fractures (1.2-4.5%; all P < 0.05, except total body BMAD) but not other upper limb fractures (hand, -1.6 to +1.2%; upper arm: 0.9-4.8%; all P > 0.05). For metacarpal measures, cases had a thinner cortical width and lower MI for wrist and forearm fractures only. In multivariate modeling, both spine BMAD (odds ratio, 1.4/SD reduction) and MI (odds ratio, 1.5/SD reduction) remained statistically significant predictors of wrist and forearm fractures. In conclusion, both DXA measures and MI are independently associated with wrist and forearm but not other upper limb fractures. The magnitude of this association is somewhat weaker than in adults but suggests that optimizing age-appropriate bone mass will lessen the risk of fracture in children.

Although recent epidemiological studies found a positive correlation between dietary vitamin C intake and bone mineral density, data on plasma levels of vitamin C or other antioxidants in osteoporotic subjects are scanty. The aim of this study was to evaluate whether antioxidant defenses are decreased in elderly osteoporotic women and, if this is the case, to understand whether osteoporosis is a condition characterized by increased oxidative stress. To answer these questions, plasma vitamins C, E, and A; uric acid; and the enzymatic activities of superoxide dismutase in plasma and erythrocytes and of glutathione peroxidase in plasma were measured in 75 subjects with osteoporosis and 75 controls. Dietary and endogenous antioxidants were consistently lower in osteoporotic than in control subjects. On the other hand, plasma levels of malondialdehyde, a byproduct of lipid peroxidation, did not differ between groups. Our results reveal that antioxidant defenses are markedly decreased in osteoporotic women. The mechanisms underlying antioxidant depletion and its relevance to the pathogenesis of osteoporosis deserve further investigation.

Teriparatide (rDNA origin) injection [recombinant human PTH (1-34)] stimulates bone formation, increases bone mineral density (BMD), and restores bone architecture and integrity. In contrast, bisphosphonates reduce bone resorption and increase BMD. We compared the effects of teriparatide and alendronate sodium on BMD, nonvertebral fracture incidence, and bone turnover in 146 postmenopausal women with osteoporosis. Women were randomized to either once-daily sc injections of teriparatide 40 micro g plus oral placebo (n = 73) or oral alendronate 10 mg plus placebo injection (n = 73). Median duration of treatment was 14 months. At 3 months, teriparatide increased lumbar spine BMD significantly more than did alendronate (P < 0.001). Lumbar spine-BMD increased by 12.2% in the teriparatide group and 5.6% in the alendronate group (P < 0.001 teriparatide vs. alendronate). Teriparatide increased femoral neck BMD and total body bone mineral significantly more than did alendronate, but BMD at the one third distal radius decreased, compared with alendronate (P < or = 0.05). Nonvertebral fracture incidence was significantly lower in the teriparatide group than in the alendronate group (P < 0.05). Both treatments were well tolerated despite transient mild asymptomatic hypercalcemia with teriparatide treatment. In conclusion, teriparatide, a bone formation agent, increased BMD at most sites and decreased nonvertebral fractures more than alendronate.

Osteocyte apoptosis appears to play a key role in the mechanism by which osteoclastic resorption activity targets bone for removal, because osteocyte apoptosis occurs in highly specific association with microdamage and subsequent remodeling after fatigue. However, beyond terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP)-biotin nick end labeling (TUNEL) assay, little is known about the mechanisms controlling osteocyte apoptosis in vivo. In the current studies, expression of Bax, a proapoptotic gene product, and Bcl-2, an antiapoptotic gene product, was determined in osteocytes of fatigued rat bone using immunocytochemical staining and compared with TUNEL staining patterns. Bax and Bcl-2 were evident in osteocytes by 6 h after loading. Moreover, Bax and Bcl-2 in osteocytes were expressed differently as a function of distance from microdamage sites. The peak of Bax expression and TUNEL+ staining in osteocytes was observed immediately at the microcrack locus, which is where bone resorption occurs in this system; in contrast, Bcl-2 expression, the antiapoptotic signal, reached its greatest level at some distance (1-2 mm) from microcracks. These data suggest that near sites of microinjury in bone, those osteocytes that do not undergo apoptosis are prevented from doing so by active protection mechanisms. Moreover, the zone of apoptotic osteocytes around microcracks was effectively "walled in" by a surrounding halo of surviving osteocytes actively expressing Bc1-2. Thus, the expression pattern of apoptosis-inhibiting gene products by osteocytes surrounding the apoptotic osteocyte at microdamage sites also may provide important signals in the guidance of resorption processes that occur in association with osteocyte apoptosis after fatigue.

Skill mix and role extension initiatives have highlighted the difficulty of establishing quality standards for the accuracy of plain film reporting. An acceptable performance might be one which is indistinguishable from that of a group of experienced consultant radiologists. In order to assess the feasibility of setting such a standard, the variation between experienced observers must first be established. This study examines the variation found between three observers with the three major types of plain film examination. 402 plain film examinations (205 skeletal, 100 chest and 97 abdominal) performed on accident and emergency patients were reported retrospectively and independently by three experienced radiologists. The clinical data supplied on the request cards were available to the readers. Each examination was categorized by each reader as being normal, as showing significant abnormality relevant to the current clinical problem, or as showing insignificant or irrelevant abnormality. Concordance between all three readers was found in 51%, 61% and 74% of abdominal, chest and skeletal radiographs, respectively. Weighted kappa values confirmed that the level of agreement between pairs of observers was higher with skeletal radiographs (kappa w = 0.76-0.77) than with chest (kappa w = 0.63-0.68), or abdominal (kappa w = 0.50-0.78) examinations. However, the frequency of major disagreements (at least one reader reporting "normal" and one reporting "relevant abnormality") was similar for abdominal (11%), chest (12%) and skeletal (10%) radiographs. When the reports were reclassified into only two groups--either significantly abnormal or not--pairs of observers disagreed on 9-10% of skeletal, 11-19% of chest and 8-18% of abdominal cases. The average incidence of errors per observer was estimated to be in the range 3-6%. The magnitude of interobserver variation in plain film reporting is considerable, and must be taken into account when designing assessment techniques and setting quality standards for this activity.

Alendronate (ALN) is an aminobisphosphonate employed as an antiresorptive agent in the treatment of osteoporosis. The present study was carried out to determine dose-response relationships, particularly the effects of relatively low doses of ALN, on bone mineral density (BMD), biochemical indexes of bone and mineral metabolism, and bone histology, with particular attention to effects in elderly women. This prospective, randomized, double blind, 2-yr multicenter study compared the effects of placebo with those of 1.0, 2.5, or 5.0 mg ALN daily. All subjects received supplemental calcium (500 mg daily) as the carbonate. We studied 359 women with lumbar spine BMD at least 2.0 SD below the peak young adult mean. Subjects were stratified by age, with 135 aged 60-69 yr and 224 aged 70-85 yr. Histomorphometry was performed on transiliac bone biopsies obtained from 104 subjects after 1 yr and from 83 subjects after 2 yr. This study elucidated the previously uninvestigated lower region of the dose-response curve for ALN in osteoporosis. Over 2 yr, treatment with 1.0, 2.5, or 5.0 mg/day increased lumbar spine BMD, on the average, by 0.65%, 3.54%, and 5.67%, respectively, compared with that in the placebo group (P < 0.001 vs. placebo for the 2.5 and 5 mg groups). Significant dose-related increases were also seen in BMD at appendicular sites and in total body BMD. Dose-dependent reductions in bone turnover to new steady states were indicated by serum and urine biochemical markers as well as by histomorphometry. There was also a dose-related reduction in the proportion of subjects suffering nonvertebral fractures (P < 0.05). Safety profiles were similar for the ALN and placebo groups and for both age strata. Efficacy was similar for both age strata. There was no evidence of impaired mineralization or other histological abnormalities due to ALN treatment. We conclude that treatment with ALN over a period of 2 yr was well tolerated and produced dose-dependent increases in BMD without evidence of a plateau over the dose range of 1.0-5.0 mg daily. One milligram daily did not result in a significant effect on BMD, and 5.0 mg daily produced favorable effects at all sites measured. Other studies have demonstrated somewhat greater effects on 10 mg daily. ALN, was equally effective and well tolerated in osteoporotic women over 70 yr old as in younger women with the same condition.

Atraumatic bone fractures are a frequent complication in orthotopic liver transplantation (OLT). A retrospective study of 91 adult OLT patients was carried out to detect the prevalence of bone fractures, and to isolate predictive factors for their development. After OLT 22 patients (24%) developed 56 atraumatic bone fractures. All fractures occurred within the first 13 months following OLT. No predictive pre- or post-OLT risk factors for the development of bone fractures were identified.

We determined the incidence of soft-tissue/musculoskeletal injury occurring during 8,076 recruit-months at risk among recruits undergoing basic training at Marine Corps Recruit Depot, San Diego, California, between January and April 1990. We analyzed International Classification of Disease codes relating to initial visit for injuries, and calculated recruit-months from weekly strength figures. Training-related injuries occurred at a rate of 19.9 injuries per 100 recruit-months. Within the sports medicine clinic, iliotibial band syndrome (22.4%), patellar tendinitis (15.1%), and mechanical low back pain (11.4%) occurred most frequently, with rates per 100 recruit-months of 2.1, 1.4, and 1.1, respectively.

To determine whether measurement of hip and spine bone mass by dual-energy x-ray absorptiometry (DEXA) predicts fractures in women and to compare the predictive value of DEXA with that of single-photon absorptiometry (SPA) of appendicular sites, we prospectively studied 8134 nonblack women age 65 years and older who had both DEXA and SPA measurements of bone mass. A total of 208 nonspine fractures, including 37 wrist fractures, occurred during the follow-up period, which averaged 0.7 years. The risk of fracture was inversely related to bone density at all measurement sites. After adjusting for age, the relative risks per decrease of 1 standard deviation in bone density for the occurrence of any fracture was 1.40 for measurement at the proximal femur (95% confidence interval 1.20-1.63) and 1.35 (1.15-1.58) for measurement at the spine. Results were similar for all regions of the proximal femur as well as SPA measurements at the calcaneus, distal radius, and proximal radius. None of these measurements was a significantly better predictor of fractures than the others. Furthermore, measurement of the distal radius was not a better predictor of wrist fracture (relative risk 1.64: 95% CI 1.13-2.37) than other sites, such as the lumbar spine (RR 1.56; CI 1.07-2.26), the femoral neck (RR 1.65; CI 1.12-2.41), or the calcaneus (RR 1.83; CI 1.26-2.64). We conclude that the inverse relationship between bone mass and risk of fracture in older women is similar for absorptiometric measurements made at the hip, spine, and appendicular sites.

The rate of remodeling in the region of a bone defect exceeds normal tissue activity. It was Frost who described this reaction as a regional acceleratory phenomenon (RAP). We investigated the local healing process with rats with a burr hole defect (1.2 mm in diameter) in the left tibia. We differentiated an initial phase of bone formation followed by a phase of predominant resorption. To determine whether this regional enhancement of bone formation would result in a systemic impact on bone metabolism, we analyzed both tibiae and femora and the fourth lumbar vertebra. On day 7 both femora of rats with the tibial defect showed a significant increase in computerized x-ray density, dry weight, ash weight, and Ca2+ content. Both tibiae and the fourth lumbar vertebra showed a significant increase in mineralizing surface, mineral apposition rate, and bone formation rate. Because of these results we conclude that a systemic acceleratory phenomenon (SAP) accompanies the RAP. SAP affects only the cancellous, but not the cortical bone compartment. SAP is associated closely with the occurrence of woven bone during the formation phase of the healing process. Thus we assume that woven bone formation plays a pivotal role in the mediation of SAP.

It is well documented that residency-trained family physicians can effectively manage the majority of nonsurgical acute orthopedic injuries with a relatively small rate of consultation. The frequency of both fracture location and orthopedic review in our series are remarkably similar to the study from NRMC Charleston reported in 1981. Our program, however, is unique because of the comprehensive management, 3-year continuous training, and multidimensional educational experience. A critical element to the program is the excellent working relationship shared by the family practice and orthopedic departments. A clinic similar to the Davis Grant USAF Medical Center cast clinic could be implemented easily and would better train the family practice resident to manage nonsurgical orthopedic trauma.

The treatment of high-velocity missile injury to the limbs is often associated with segmental bone loss, as well as damage to neurovascular and soft tissue. In such "limb threatening" cases, massive bone allograft can fill the bone defect and offer stability to the soft tissue reconstruction. The return of function in the affected limb is relatively rapid when using this method as a primary procedure. The indications for use of this technique and illustrative case reports are presented and discussed.

A retrospective analysis of the radiographic records of 1653 sailors aboard the USS Enterprise was performed during the author's recent reserve assignment. For the period 1985 to 1987, 102 radiographically recognizable injuries were discovered in the study group. The high rate (53.9%) of hand injuries aboard ship typifies that of a wage-earning population (age 20 to 50). However, analysis of the fracture pattern in the hand indicates that many of the most frequently encountered hand injuries may be preventable. Since the rates of anterior shoulder dislocation and gamekeeper's thumb may also be increased, initiating the necessary investigation and control measures for these injuries seems warranted.

Eight divers who developed permanent scintigraphic bone changes following dives to various depths took part in a study to determine the nature of these lesions. Only one of these divers had radiologically evident bone changes in his scintigraphic lesion. Dynamic scintigrams of the bones containing the lesions were obtained from all eight divers and functional images generated of both amplitude (osteoblastic activity) and accretion (microvasculature) rate constants. All had increased amplitude in the area of the scintigraphic lesion indicating continuing osteoblastic activity. Three divers showed a decreased accretion rate in the lesions, indicating impairment or absence of local microcirculation; one of these was the diver who showed radiological changes prior to the study and the other two subsequently developed radiologically evident osteonecrosis. It is concluded that functional images, generated from dynamic bone scintigrams, can successfully predict dysbaric osteonecrosis.

A study of 64 cases and 124 friend and neighbor controls was conducted to identify factors associated with the occurrence of osteosarcoma in young persons. Two types of information were collected: questionnaire data from telephone interviews with mothers, and data on height since birth from family, physician, and school records. Cases were not taller at the time of diagnosis than controls, nor were growth rates higher--either overall or during the 3-4 years prior to diagnosis. An excess risk, however, was observed among subjects whose birth length was at or below the 25th percentile, based on national standards. An excess risk was also found among subjects born more than one week early, but the positive association with short birth length remained when duration of pregnancy was taken into account. Positive associations were also found for prior trauma to the tumor site; congenital skeletal defects or other treated bone conditions; fetal x-ray; and maternal employment during pregnancy in manufacturing industries.

A series of 19 patients, who were clinically suspected of developing avascular necrosis of bone following fracture, were entered into a pilot study comparing the use of bone marrow scintigraphy with conventional skeletal scintigraphy. Two-phase bone scintigraphy, using 600 MBq of 99Tcm-HMDP, and perfusion and late-phase nanocolloid scintigraphy, using 370 MBq of 99Tcm-nanocolloid, were performed on each patient. In both methods, photon deficiency at the site of interest was taken to indicate avascularity. The perfusion phase of both methods was found to be unhelpful. Agreement between methods was obtained in 18 patients (95%). Six patients had abnormal nanocolloid scans, one of which was normal on the conventional bone scintigram. The remaining 13 patients had no evidence to suggest avascularity in either method. Three of the patients with abnormal scans have had hip replacement surgery following which avascularity of the femoral head was confirmed. 99Tcm-nanocolloid scintigraphy is thus shown to be a very sensitive method of demonstrating avascularity of bone following trauma.