Spinal cord injury (SCI) causes rapid severe bone loss. In the first four months following a motor complete lesion, urine markers of bone resorption rise to nearly ten times normal levels1. At the same time, paralyzed limbs below the site of injury lose integral bone mineral content and bone mineral density at a rate of 3% per month2,3. This rapid bone loss eventually plateaus with trabecular bone mineral density decreasing by a total of 50-70% and cortical bone cross sectional area decreasing by 30%4, 5, 6, 7, 8. SCI-induced osteoporosis is unique in that the most severe bone loss is often observed in the lower extremities9, with the distal femur and proximal tibia being common fracture sites10. Over 50% of people with SCI will sustain a fracture in their lower extremity11, and low-energy fractures (resulting from standing height or lower falls) are particularly common10. Such large effects following SCI motivate thorough understanding of bone loss in this population in order to provide effective treatment.

The bone loss and the affected sites during SCI-induced osteoporosis are distinct from osteoporosis following menopause or aging. Quantitative computed tomography (QCT)-based methods have therefore become preferred, compared to dual energy x-ray absorptiometry (DXA), for measuring the unique spatial and temporal patterns of bone loss following SCI12. Also unlike osteoporosis where women make up 75% of patients, approximately 80% of new spinal cord injuries occur in men13. Thus, the majority of studies either enroll exclusively men4,9,14, 15, 16, 17 or enroll very few women without investigating the effect of sex as a biological variable3,18, 19, 20. However, sex hormones have a strong influence on bone metabolism and the omission or small numbers of women in these studies makes it difficult to fully understand the possible interactions between sex, SCI, and age on bone. Furthermore, even with high-resolution, quantitative, 3-dimensional scans, high variation in rate and magnitude of bone loss exists between individuals following SCI2,3,21, suggesting that additional variables such as sex may affect bone loss and fracture risk.

Studies that investigate the effect of sex on bone loss following SCI show mixed results. In acute SCI, Coupaud et al21 reported more pronounced loss of cortical bone mineral density (BMD; g/cm3) as measured by peripheral QCT (pQCT) in women (n=5) than men (n=21), though these groups were not statistically compared in the small dataset. DXA scans of men (n=25) and women (n=18) with chronic SCI revealed a nonsignificant trend towards lower Z-scores in women with SCI22. pQCT data from the distal tibia of women (n=9) versus men (n=38) with SCI also showed significantly lower bone mineral content (BMC; g) in women5. Garland et al.23 found lower BMD values in women (n=3) than men (n=13), as well as significant differences in percent change over time between the women and men. In contrast, Haider et al8 observed no effect of sex on total loss of bone stiffness in chronic SCI versus a recently-injured reference groups (n=9 female SCI participants). Overall, generalization of the existing data is made difficult by the low numbers of women included in each study and by the variation in scan methodology and timepoints studied.

To overcome these challenges in quantifying the role of sex as a biological variable in SCI-induced osteoporosis, this investigation combined QCT scans from four completed or ongoing studies with nearly identical imaging protocols2,20,24,25. We compared QCT outcomes in male and female participants as a function of time since SCI to quantify sex-specific differences in bone following SCI. A secondary analysis investigated the effect of age, a surrogate for menopausal status, on women with longer injury durations.