Are low levels of 25(OH) vitamin D and testosterone clinically relevant in men with paraplegia?

Keywords:

• Vitamin D
• Testosterone
• Paraplegia
• Elderly men

The incidence of fractures is twice as common in persons with paraplegia as in the general population (there is limited data on men with tetraplegia). It is related to increased loss of bone mass and altered bone structure and function.¹ Deficiency of 25(OH) vitamin D based on serum levels in men with paraplegia ranges between 32% to 73.5%.^1–3 A small subset of these men have elevated parathormone (PTH) levels, which the Institute of Medicine has used as a biomarker of 25(OH)D deficiency. Elevations in PTH result in calcium being drawn off bone resulting in accelerated osteopenia. While there are numerous other putative effects of vitamin D, at present the evidence suggests that the major role of vitamin D is to maintain calcium homeostasis and bone integrity.⁴

In recent times the measurement of 25(OH) D levels has become problematic. This is because there are marked ethnic differences in the level of the binding protein for vitamin D.⁵ Persons with dark skin have very low levels of vitamin D binding protein, and therefore lower levels of 25(OH) D.⁶ A longitudinal study has shown that with aging 25(OH) D levels decline, due to decreased skin synthesis of cholecalciferol, decreased vitamin D absorption from the gut and decreased sun exposure.⁷ Thus, in younger persons with paraplegia 25(OH) D levels should be measured with PTH to determine whether the low level is having a biological effect. In persons over 50 years of age, it is reasonable to give 1000 IU of vitamin D daily, without measurement of 25(OH) D. Higher doses should be avoided as there is emerging evidence that higher levels of calcium, even within the normal range, may result in memory loss and cardiovascular disease.^8,9

The role of testosterone in persons with paraplegia is more complex. The original studies in the 1970s showed that a small percentage of young males with paraplegia have low testosterone, a larger group have seminiferous tubule abnormalities and that there are minor alterations in gonatrophin dynamics.^10–12 In 2014, Bauman et al.² examined both old and young males with paraplegia and found that in those over 50 years of age more than 50% had low testosterone levels compared to 15% aged 30 to 39 years. His data suggested that paraplegia results in an accelerated rate of decline in testosterone levels associated with an increase in sex hormone binding globulin and, therefore, an even greater decrease in free testosterone. In a controlled study, testosterone given for 12 months was shown to increase lean body mass.¹³ A case report suggested “substantial” improvement in muscle function when the patient received testosterone pellets for 6 months after a rock climbing accident.¹⁴

Besides the effects of testosterone on muscle mass and strength, it also decreases fat mass and enhances bone mineral density in persons who are hypogonadal.¹⁵ In younger persons hypogonadism is associated with cardiovascular disease, but in older persons testosterone replacement may increase myocardial infarction.^16,17 Barbonetti et al.¹⁸ found that low testosterone was independently associated with non-alcoholic fatty liver disease in men with paraplegia. Testosterone increases hematocrit. It may aggravate sleep apnea. The long term treatment of testosterone in young people on prostate disease is unknown.

Low levels of testosterone and 25(OH) vitamin D are seen in persons with poor health. This seems the most likely reason for the correlation seen by Barbonetti et al.¹ This is particularly likely as another study in males with paraplegia failed to find a correlation.¹⁹ In addition, both 25(OH) vitamin D and testosterone decline with age.^7,20 Vitamin D has been showed to increase steroidogenesis in testicular cell cultures.²¹ In human replacement studies vitamin D replacement increased testosterone in 1 out of 3 studies.^22–24 Overall, it would appear that the direct effect of vitamin D on testosterone is not statistically significant.

In conclusion, 25(OH) vitamin D deficiency and hypogonadism may both produce clinically significant deleterious effects on males with paraplegia. Vitamin D replacement at 1000 IU daily appears warranted in most males with paraplegia over 50 years of age and in a smaller subset of younger men with paraplegia. There would appear to be an advantage of testosterone replacement, at least in younger males. Because of the potential side effects of testosterone, a large controlled trial of testosterone replacement in males with paraplegia and hypogonadism should be undertaken.

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