The Association between Environmental Lead Exposure and Bone Density in Children

Osteoporosis is a decrease in bone mineral density (BMD) that predisposes individuals to fractures. Although an elderly affliction, a predisposition may develop during adolescence if a sufficient peak BMD is not achieved. Rat studies have found that lead exposure is associated with decreased BMD. However, human studies are limited. We hypothesized that the BMD of children with high lead exposure would be lower than the BMD of children with low lead exposure. We collected data on 35 subjects; 16 had low cumulative lead exposure (mean, 6.5 μg/dL), and 19 had high exposure (mean, 23.6 μg/dL). All were African American; there was no difference between the groups by sex, age, body mass index, socioeconomic status, physical activity, or calcium intake. Significant differences in BMD between low and high cumulative lead exposure were noted in the head (1.589 vs. 1.721 g/cm(2)), third lumbar vertebra (0.761 vs. 0.819 g/cm(2)), and fourth lumbar vertebra (0.712 vs. 0.789 g/cm(2)). Contrary to our hypothesis, subjects with high lead exposure had a significantly higher BMD than did subjects with low lead exposure. This may reflect a true phenomenon because lead exposure has been reported to accelerate bony maturation by inhibiting the effects of parathyroid hormone–related peptide. Accelerated maturation of bone may ultimately result in a lower peak BMD being achieved in young adulthood, thus predisposing to osteoporosis in later life. Future studies need to investigate this proposed model

Analysis of Vertical Ground Reaction Force Variables during a Sit to Stand Task in Participants Recovering from a Hip Fracture

Background: A Sit to Stand task following a hip fracture may be achieved through compensations (e.g. bilateral arms and uninvolved lower extremity), not restoration of movement strategies of the involved lower extremity. The primary purpose was to compare upper and lower extremity movement strategies using the vertical ground reaction force during a Sit to Stand task in participants recovering from a hip fracture to control participants. The secondary purpose was to evaluate the correlation between vertical ground reaction force variables and validated functional measures. Methods: Twenty eight community dwelling older adults, 14 who had a hip fracture and 14 control participants completed the Sit to Stand task on an instrumented chair designed to measure vertical ground reaction force, performance based tests (Timed up and go, Berg Balance Scale and Gait Speed) and a self report Lower Extremity Measure. A MANOVA was used to compare functional scales and vertical ground reaction force variables between groups. Bivariate correlations were assessed using Pearson Product Moment correlations. Findings: The vertical ground reaction force variables showed significantly higher bilateral arm force, higher uninvolved side peak force and asymmetry between the involved and uninvolved sides for the participants recovering from a hip fracture (Wilks\u27 Lambda=3.16, P=0.019). Significant correlations existed between the vertical ground reaction force variables and validated functional measures. Interpretation: Participants recovering from a hip fracture compensated using their arms and the uninvolved side to perform a Sit to Stand. Lower extremity movement strategies captured during a Sit to Stand task were correlated to scales used to assess function, balance and falls risk

Influence of Upper Extremity Assistance on Lower Extremity Force Application Symmetry in Individuals Post–Hip Fracture During the Sit-to-Stand Task

STUDY DESIGN: Controlled laboratory study using a cross-sectional design. OBJECTIVES: To compare lower extremity force applications during a sit-to-stand (STS) task with and without upper extremity assistance in older individuals post–hip fracture to those of age matched controls. BACKGROUND: A recent study documented the dependence on upper extremity assistance and the uninvolved lower limb during an STS task in individuals post–hip fracture. This study extends this work by examining the effect of upper extremity assistance on symmetry of lower extremity force applications. METHODS: Twenty-eight community-dwelling elderly subjects, 14 who had recovered from a hip fracture and 14 controls, participated in the study. All participants were independent ambulators. Four force plates were used to determine lower extremity force applications during an STS task with and without upper extremity assistance. The summed vertical ground reaction forces (vGRFs) of both limbs were used to determine STS phases (preparation/rising). The lower extremity force applications were assessed statistically using analysis of variance models. RESULTS: During the preparation phase, sideto-side symmetry of the rate of force development was significantly lower for the hip fracture group for both STS tasks (P\u3c.001). During the rising phase, the vGRF impulse of the involved limb was significantly lower for the hip fracture group for both STS tasks (P = .045). The vGRF impulse for the uninvolved limb was significantly increased when participants with hip fracture did not use upper extremity assistance compared to elderly controls (P = .002). This resulted in a significantly lower vGRF symmetry for the hip fracture group during both STS tasks (P\u3c.001). CONCLUSION: Participants with hip fracture who were discharged from rehabilitative care demonstrated decreased side-to-side symmetry of lower extremity loading during an STS task, irrespective of whether upper extremity assistance was provided. These findings suggest that learned motor control strategies may influence movement patterns post–hip fracture

Lead Exposure Inhibits Fracture Healing and Is Associated with Increased Chondrogenesis, Delay in Cartilage Mineralization, and a Decrease in Osteoprogenitor Frequency

Lead exposure continues to be a significant public health problem. In addition to acute toxicity, Pb has an extremely long half-life in bone. Individuals with past exposure develop increased blood Pb levels during periods of high bone turnover or resorption. Pb is known to affect osteoblasts, osteoclasts, and chondrocytes and has been associated with osteoporosis. However, its effects on skeletal repair have not been studied. We exposed C57/B6 mice to various concentrations of Pb acetate in their drinking water to achieve environmentally relevant blood Pb levels, measured by atomic absorption. After exposure for 6 weeks, each mouse underwent closed tibia fracture. Radiographs were followed and histologic analysis was performed at 7, 14, and 21 days. In mice exposed to low Pb concentrations, fracture healing was characterized by a delay in bridging cartilage formation, decreased collagen type II and type X expression at 7 days, a 5-fold increase in cartilage formation at day 14 associated with delayed maturation and calcification, and a persistence of cartilage at day 21. Fibrous nonunions at 21 days were prevalent in mice receiving very high Pb exposures. Pb significantly inhibited ex vivo bone nodule formation but had no effect on osteoclasts isolated from Pb-exposed animals. No significant effects on osteoclast number or activity were observed. We conclude that Pb delays fracture healing at environmentally relevant doses and induces fibrous nonunions at higher doses by inhibiting the progression of endochondral ossification

Reduced COX-2 Expression in Aged Mice Is Associated With Impaired Fracture Healing

The cellular and molecular events responsible for reduced fracture healing with aging are unknown. Cyclooxygenase 2 (COX-2), the inducible regulator of prostaglandin E2 (PGE2) synthesis, is critical for normal bone repair. A femoral fracture repair model was used in mice at either 7–9 or 52–56 wk of age, and healing was evaluated by imaging, histology, and gene expression studies. Aging was associated with a decreased rate of chondrogenesis, decreased bone formation, reduced callus vascularization, delayed remodeling, and altered expression of genes involved in repair and remodeling. COX-2 expression in young mice peaked at 5 days, coinciding with the transition of mesenchymal progenitors to cartilage and the onset of expression of early cartilage markers. In situ hybridization and immunohistochemistry showed that COX-2 is expressed primarily in early cartilage precursors that co-express col-2. COX-2 expression was reduced by 75% and 65% in fractures from aged mice compared with young mice on days 5 and 7, respectively. Local administration of an EP4 agonist to the fracture repair site in aged mice enhanced the rate of chondrogenesis and bone formation to levels observed in young mice, suggesting that the expression of COX-2 during the early inflammatory phase of repair regulates critical subsequent events including chondrogenesis, bone formation, and remodeling. The findings suggest that COX-2/EP4 agonists may compensate for deficient molecular signals that result in the reduced fracture healing associated with aging

In vitro synthesis of 1 alpha,25-dihydroxycholecalciferol and 24,25-dihydroxycholecalciferol by isolated calvarial cells.

The question of whether the skeleton metabolizes 25-hydroxycholecalciferol [25(OH)D3] to more-polar products was studied. Calvarial cells were dispersed from 16-day old chicken embryos by using collagenase and then grown in culture in serum-free medium. Confluent cell cultures were incubated with 7 nM 25(OH)[3H]D3 for 2 hr, and the vitamin D metabolites were then extracted. At least four polar metabolites were produced. Based on separation by Sephadex LH-20 chromatography followed by high-pressure liquid chromatography, two of these metabolites were identified as 1,25-dihydroxycholecalciferol [1,25(OH)2D3] and 24,25-dihydroxycholecalciferol [24,25(OH)2D3]. These metabolites were also produced by cultured kidney cells but not by liver, heart muscle, or skin cells isolated from the same embryos. The specific activities of the calvarial 1- and 24-hydroxylases were similar in magnitude to those in isolated kidney cells. The specific activity of the calvarial 25(OH)D3:1-hydroxylase was inhibited by an 8-hr preincubation with 1,25(OH)2D3, whereas the 24-hydroxylase was enhanced. It is concluded that (i) vitamin D metabolism by isolated cells is organ-specific, (ii) calvarial cells produce active metabolites of vitamin D in significant amounts, (iii) vitamin D metabolism by calvarial cells is regulated by 1,25(OH)2D3, and (iv) locally produced, active metabolites could act locally, thereby adding a new dimension to the regulation of mineral metabolism by vitamin D metabolites