Effect of Recent Spinal Cord Injury on Wnt Signaling Antagonists (Sclerostin and Dkk-1) and Their Relationship With Bone Loss. A 12-Month Prospective Study

Abstract

Spinal cord injury (SCI) has been associated with a marked increase in bone loss and bone remodeling, especially short-term after injury. The absence of mechanical load, mediated by osteocyte mechanosensory function, seems to be a causative factor related to bone loss in this condition. However, the pathogenesis and clinical management of this process remain unclear. Therefore, the aim of the study was to analyze the effect of recent SCI on the Wnt pathway antagonists, sclerostin and Dickkopf (Dkk-1), and their relationship with bone turnover and bone mineral density (BMD) evolution. Forty-two patients (aged 35 AE 14yrs) with a recent (<6months) complete SCI were prospectively included. Sclerostin and Dkk-1, bone turnover markers (bone formation: PINP, bone ALP; resorption: sCTx) and BMD (lumbar spine, proximal femur, total body and lower extremities [DXA]) were assessed at baseline and at 6 and 12 months. The results were compared with a healthy control group. 22/42 patients completed the 12-month follow-up. At baseline, SCI patients showed a marked increase in bone markers (PINP and sCTx), remaining significantly increased at up to 6 months of follow-up. Additionally, they presented significantly increased Dkk-1 values throughout the study, whereas sclerostin values did not significantly change. BMD markedly decreased at the proximal femur (-20.2 AE 5.4%, p < 0.01), total body (-5.7 AE 2.2%, p ¼ 0.02) and lower extremities (-13.1 AE 4.5%, p ¼ 0.01) at 12 months. Consequently, 59% of patients developed densitometric osteoporosis at 12 months. Patients with higher Dkk-1 values (>58 pmol/L) at baseline showed higher sublesional BMD loss. In conclusion, this study shows that short-term after SCI there is a marked increase in bone turnover and bone loss, the latter associated with an increase in Dkk-1 serum levels. The persistence of increased levels of this Wnt antagonist throughout the study and their relationship with the magnitude of bone loss suggests a contributory role of this mediator in this process.

Risk factors for the development of osteoporosis after spinal cord injury. A 12-month follow-up study

“…Thus, patients with increased P1NP serum values >140 ng/ml presented a 3.08-fold increased risk for osteoporosis development, with a similar figure in patients with bone ALP values >14 ng/ml, who presented a 2.4-fold increased risk. These results are consistent with the marked increase in bone turnover that has been described after injury, especially during the first year of injury coinciding with the highest bone loss that seems to occur during the first 1-2 years after SCI [1,2,[16][17][18][19][20][21]. Nevertheless, although patients who developed osteoporosis presented higher values of both markers, which were also risk factors for osteoporosis development, their evaluation did not seem to add significant clinical value for predicting osteoporosis development in our study, since BMD evaluation alone identified nearly all the patients who would develop osteoporosis during the 12-month period.…”

“…This finding may be partly explained by the lack of studies identifying patients with a high risk for developing osteoporosis especially short-term after injury, when the highest bone loss is produced [10,11]. Indeed, in a prospective follow-up study in patients with recent complete SCI, we observed the development of osteoporosis in more than 50 % of subjects within the first year after injury [2]. Therefore, it seems logical to assume that the identification of high-risk patients for osteoporosis short-term after injury would improve the therapeutic approach to this clinical complication.…”

“…However, it should be pointed out that most subjects included in our study were young males, with nearly 50 % being under 30 years of age, thereby making it difficult to apply these specific criteria (Tscore) and explaining why we have proposed risk BMD thresholds in absolute values. Previous studies have also indicated a marked bone loss and increased incidence of osteoporosis ranging from 21 to 81 % after SCI [2][3][4][5][6][7]. Nevertheless, in these studies, risk factors for osteoporosis development were analyzed long-term after SCI, and consequently, no early cutoff risk values for BMD have been previously proposed.…”

“…The present study is an ongoing prospective observational trial in patients with recent complete SCI aimed to evaluate the pathophysiology and factors related to bone mineral density (BMD) loss in these patients [2]. Herein, we present the analysis of the risk factors related to the development of osteoporosis after a 12-month follow-up.…”

“…Thus, depending on the characteristics of the patients and the diagnostic criteria, 21 to 81 % of subjects will develop osteoporosis after SCI [2][3][4][5][6][7], with age, gender, timesince-injury, and severity of SCI being risk factors related to osteoporosis development long-term after injury [3,4]. However, in spite of this common complication, the clinical evaluation and therapeutic approach to these patients is clearly insufficient, with several authors describing the frequent absence of preventive antiosteoporotic treatment in this condition [8,9].…”