The effects of spinal cord injury on bone loss and dysregulation of the calcium/parathyroid hormone loop in mice

Abstract

ObjectiveTo map the progression of osteoporosis following spinal cord injury in mice in specific areas and analyze changes in parathyroid hormone (PTH) and ion levels which could be responsible for overall bone loss.Summary of background dataSpinal cord injury rapidly induces severe bone loss compared to other conditions, yet the cause of this bone loss has not been identified. Studies suggest the bone loss after injury is not solely due to disuse.MethodsTo quantify bone loss we weighed individual bones and measured bone mineral density using dual energy X-ray absorptiometry at acute (1 week) and chronic (4 week) time points following a T9 contusion. An ELISA was used to measure blood PTH levels at 1 and 4 weeks after injury. Calcium and phosphate levels were also analyzed at 4 weeks following injury at the University of Miami pathology core.ResultsWe observed a significant decrease in bone mineral density in hind limbs after an acute injury, and found this bone loss to progress over time. Furthermore, following chronic injury a decrease in bone mineral density is also observed in bones above the level of injury and in the total bone mineral density. We observed a significant decrease in parathyroid hormone levels in injured mice at the chronic time point, but not at the acute time point which suggests this could be involved in the global bone loss following injury. We also observed a significant increase in serum calcium levels following injury which could account for the imbalance of PTH levels.

Rapid bone loss occurs as early as 2 days after complete spinal cord transection in young adult rats

“…Specifically, SCI results in to rapid reduction of sublesional cancellous bone mass [e.g., BMD and bone volume (BV/TV)] as well as deleterious microarchitectural changes (e.g., increased Tb.Sp and higher SMI for rod-like geometry, as well as reduced Tb.N, Conn.D and stiffness), indicative of compromised structural integrity and reduced mechanical strength. These skeletal deficits due to SCI become more evident at 7 days, which is consistent with the previous findings [10][11][12]. The rapid decline in bone mass and deterioration of bone microstructure highlight a clinical need that any intervention for the prevention of bone loss after the acute event should start as soon as possible after paralysis and immobilization.…”

“…We previously showed that substantial loss of bone mineral content and bone volume was found for the distal femur and proximal tibia of rats at 56 days after spinal cord transection [24,25,27,28]. Recent studies demonstrated that SCI causes bone loss and deterioration of trabecular bone microstructure at 10 days [9] or even as early as 1 week [10][11][12] after injury. The present study is the first to report that bone loss and deterioration of trabecular bone microstructure occur as early as 2 days after neurologically motor-complete SCI.…”

“…In studies performed in acute models of SCI in rats, loss of trabecular bone in the proximal tibia approaches 70% at 3 weeks after a complete spinal cord transection [8] and over 60% at the distal femoral metaphysis at 10 days after severe spinal cord contusion [9]. Recent studies reported that SCI reduced bone mass and caused deterioration of trabecular bone microstructure as early as 1 week after injury [10][11][12]. Considering the fact that as much as −50% of reduction in bone mass can be induced by SCI within a short period time of 1 week [12], we hypothesize that bone loss can occur even much earlier time points after SCI.…”

The Pathophysiology of Osteoporosis after Spinal Cord Injury

“…The first phase is characterized by rapid bone reabsorption, which plateaus 18–24 months post-injury. The second chronic phase is characterized by gradual bone loss and inhibited bone formation [ 9 , 10 ]. As a result, about 40% of individuals with chronic SCI experience fractures; thus, twice the likelihood of fracture formation compared to individuals without SCI [ 9 ].…”

“…Consequently, decreased gas exchange and nutrient delivery promotes local hyperpressure and increased stimulation of osteoclasts. Significant bone resorption and demineralization also occurs [ 10 , 11 ]. This mechanism suggests a link between neural and physiological disorders in the pathogenesis of bone loss [ 11 , 12 ].…”