Chronic spinal cord injury (SCI) is associated with osteopenia, increasing the prevalence of long-bone fractures. Although disuse may be the primary cause of osteopenia, identification of any additional mechanisms of bone loss may lead to potential therapeutic interventions. We investigated the relationships of serum calcium (Ca), phosphorus (PO4), albumin, alkaline phosphatase (Alk P), and parathyroid hormone (PTH) with serum 25-hydroxyvitamin D [25(OH)D] in 100 subjects with chronic SCI and 50 control subjects. in a subgroup of 50 subjects with SCI and 50 control subjects, we correlated these parameters with serum 1,25-dihydroxyvitamin D [1,25(OH)2D]. Mean ages for the group with SCI and the controls were the same. In subjects with SCI, the duration of injury was 20 +/- 1 years (mean +/- SD). Thirty-two of 100 subjects with SCI, as compared with eight of 50 controls, had serum 25(OH)D levels less than the normal range (chi2 = 4.36, P < .05). In subjects with SCI, a negative correlation was demonstrated between serum 25(OH)D and PTH (r = .29, P < .005). Mean serum 1.25(OH)2D levels were significantly elevated in subjects with SCI as compared with controls (61 +/- 21 v 46 +/- 18 pg/mL, P < .0005). Twenty of 50 subjects with SCI had serum 1.25(OH)2D levels greater than 62 pg/mL, as compared with 10 of 50 controls (chi2 = 4.76 P < .05). A positive correlation was found between serum PTH and 1,25(OH)2D in subjects with SCI and controls (r = .41, P < .005 and r = .30, P < .05, respectively). Twelve subjects with SCI had serum PTH levels greater than the normal range. In this high-serum PTH subgroup, serum 15(OH)D concentration was significantly lower (P < .05) and serum 1,25(OH)2D and Alk P concentrations were significantly higher (P < .005 and P < .05, respectively) as compared with the subgroup with serum PTH values within the normal range. In subjects with SCI, 17 had a serum Ca concentration less than 8.5 mg/dL. In persons with SCI, depressed levels of serum 25(OH)D, as well as other factors, may result in forces inclined to reduce the serum calcium concentration. A state of mild secondary hyperparathyroidism may result, thus increasing the conversion of serum 25(OH)D to 1.25(OH)2D. These data suggest that in chronic SCI subjects, as in the general population, secretion of PTH and the increase of circulating 1.25(OH)2D are subject to control by negative-feedback mechanisms. Higher levels of serum PTH would be expected to accelerate bone resorption of a skeleton already regionally osteoporotic as a consequence of the bone mineral loss due to acute immobilization.