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

Abstract

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.

Allogeneic and Autogenous Bone Grafts Are Affected by Historical Donor Environmental Exposure

“…Lead has been shown to have deleterious effects on bone formation and cellular remodeling at concentrations as low as 2 parts per million [6,18,20]. In children, exposure results in impairment in skeletal development, reduced chest circumference, diminished stature, and can be assessed with blood tests for markers of bone turnover in this population [5,6,[10][11][12].…”

“…In animal models and clinical studies, lead has specifically been shown to be a source of adverse cellular effects resulting in skeletal disease [3,5,20,22]. The mechanism for the skeletal effects is thought to be related to release of lead from the bone compartment with subsequent molecular consequences on key signaling pathways in the osteoblasts [6]. Commercially available graft materials and substitutes are subjected to quality measures based on FDA regulations.…”

Retained Bullet Removal in Civilian Pelvis and Extremity Gunshot Injuries: A Systematic Review

“…Previous studies in animals have shown that bone lead levels significantly affect bone healing [3]. Several authors have shown the adverse effects of lead on bone formation and resorption by demonstrating its impact on osteoblast and osteoclast activity [6,14,17,20,26,27].…”

“…Several authors have shown the adverse effects of lead on bone formation and resorption by demonstrating its impact on osteoblast and osteoclast activity [6,14,17,20,26,27]. One such study investigated the response bone lead levels exhibited on tibial fractures treated with intramedullary fixation in mice [3]. A dose-dependent relationship was found to negatively affect fracture healing with increasing bone lead levels.…”

“…It has been our observation that fractures with a substantial amount of retained bullet fragments near the fracture site are at risk for delayed or nonunion. Previous studies in animals have shown that bone lead levels significantly affect bone healing [3]. We believe the first step in addressing this issue is to use the literature to determine, if possible, the most correct indications for bullet removal.…”