Bone Composition and Complications (Osteoporosis, Heterotopic Ossification, Hypercalcemia)

The skeleton develops during the first two decades of life. During this period, there is objective accrual of both bone mineral content (BMC) and BMD, with a fairly steady pace through childhood, pace that is markedly accelerated during adolescence, with close to 40% of total body bone mineral accrual occurring within 2 years of the adolescent growth spurt (Baxter‐Jones et al. 2011). Bone health is insured by bone remodeling, which consists of the continuous, balanced removal/deposition of small portions of bone performed by osteoclasts and osteoblasts; this process is under endocrine, paracrine, neural, and mechanical factors regulation (Siddiqui & Partridge 2016). In the case of pediatric SCD-related paralysis, in addition to abnormal bone development, all 4 regulatory mechanisms are affected through immobility/lack of weight loading, autonomic nervous system dysfunction (especially in mid-thoracic and higher injuries), endocrine dysfunction triggered by exodus of calcium from the bones and paracrine abnormalities related to disrupted cytokines and growth factors secretion.  Bone mineral loss has been documented as early as 6 weeks post SCI onset (Warden et al. 2002), with the greatest loss occurring within the first 2 years (Mohr et al. 1997). Few interventions have been shown to stave off or improve bone loss post-SCI, with FES ergometry being one of the researched ones in pediatric SCI.


Our search identified 9 papers that assessed BMC and BMD in the pediatric post-SCI population and looked at the effect of FES on bone health in the context of SCD-related paralysis. Moynahan et al. (1996) compared the BMD at 3 areas in the hip in children with SCI and age and sex-matched able body controls and noted that there was a trend toward lower BMD at the hip in SCI subjects as compared with their non-disabled peers. 10/51 participants experienced fractures and there was a trend toward lower BMD in subjects with fractures. There was no significant hip BMD difference between individuals with tetraplegia and paraplegia (except at the intertrochanteric area) and children with lower limb spasticity generally had higher bone densities than those without (femoral neck and Ward’s triangle).

Biggin (2013) used Peripheral Quantitative Computer Tomography to evaluate the BMD and morphology of tibia and radius in 19 subjects (10 males and 9 females) with SCI (mean age at injury was 6.6, mean time to first Peripheral Quantitative Computer Tomography 5.6 years post-SCI). The analysis showed that, in children with tetraplegia, but not in those with paraplegia, trabecular bone density in the radius was decreased while the cortical one was similar with able body controls. In the tibia, the bone cortex was thinner with decreased bone minerals in both children with paraplegia and tetraplegia. Despite the thinner cortex, the BMD of the tibial diaphysis was preserved, but the polar stress-strain index, a surrogate measure of bone strength, was significantly reduced. In addition, individuals with SCI that were able to weight load (even if only in a standing frame) had significantly better BMD and muscle mass than those who did not. The mean tibial trabecular BMD in children who sustained fractures (7/19, 6 of them occurring in the lower limbs) was 57 +/- 34 mg/cm3 compared with 120 +/- 72 mg/cm3 in the group who did not sustain fractures and lower limb fractures did not occur if tibial trabecular BMD was greater than 100 mg/cm3. 7/19children had serial Peripheral Quantitative Computer Tomography’s that revealed a further reduction in trabecular BMD between 7.6 years -10.7 years post-SCI, while cortical BMD did not change.

Liu (2008) described BMD, BMC and lean tissue mass within 0.2-3.3 years median time post-injury in 18 children (9 males), median age 5.3 with traumatic and non-traumatic SCI, C3 to T12 level (six cervical and 12 thoracic lesions),13 of them non-weight bearing paraplegia American Spinal Injury Association Impairment Scale (AIS) A, B, C and two non-weight bearing tetraplegia AIS A-C + one weight-bearing individual with paraplegia and functional walking. They had multiple Dual X-ray Absorptiometry’s over the ensuing <9.6 years post SCI which allowed for descriptive follow-up of both clinical and Dual X-ray Absorptiometry measures. Three children (17%) sustained a minimal trauma fracture; all fractures were femoral and occurred within 18 months post-SCI in non-ambulatory children. BMD, BMC, and lean tissue mass fell significantly in the first year post-SCI, more in nonambulatory children, as expected. In the second year, there were no significant changes in BMD, BMC for any region, suggesting an age-appropriate accrual of bone mass. Like in Kannisto’s paper (Kannisto et al. 1998), no reduction in arm BMD was seen, and actually, an increase in arm BMD and lean tissue mass was noted over time.

Kannisto et al. (1998) looked at BMD assessed by Dual X-ray Absorptiometry (spine and proximal femur) of 35 adults with pediatric-onset SCI (median age at injury was 12.9 years old and the median time period from the injury was 19 years). The researchers combined the Dual X-ray Absorptiometry data with measurement of blood and 24 urine testing of bone metabolic markers like urinary calcium, phosphate, alkaline phosphatase bone isoenzyme, osteocalcin, carboxyterminal propeptide of human type I procollagen, and carboxyterminal telopeptide of type I collagen, urinary hydroxyproline, and deoxypyridinoline. He found that lumbar spine BMD was similar to age and sex-adjusted values from able-body individuals, supporting the concept that bone deposition proceeds fairly normal in adolescents post-SCI; the hip BMD values were around 2 standard deviations below compared with age and sex-matched able-body normal, which the authors attributed to lack of weight loading. Individuals with C1-T6 lesions had lower lumbar spine and hip BMD than those with levels T7 and below. BMD at the proximal femur and in the femoral neck (but not at the spine) correlated with body weight but not with body height, age at time of injury, age at examination, or the time elapsed since injury. Measurement of bone metabolic markers did not show ongoing loss at the time of the evaluation.

Three papers examined the effects of FES/electrical stimulation (e-stim) on BMD/BMC in the lower limbs. In an observational study conducted as part of a larger FES intervention study, Lauer (2007) assessed BMD of the hip, distal femur, and proximal tibia in 28 children with chronic SCI. Higher BMD values were observed for individuals with lower injury levels (thoracic versus cervical) and injury duration less than 2 years; boys had higher BMD compared with girls. BMD at the hip in children with SCI were approximately 60% of the able body values. The Philadelphia Shriner’s group conducted a prospective, randomized study on 28 children aged 5-13 with chronic SCI, to determine the effect of cycling and/or electrical stimulation on hip and knee BMD and muscle mass. Johnston (2008b) described the musculoskeletal effects of long-term (6 months, 1 hr x 3 times/week) FES and passive cycling in 4 of the enrolled children (2 FES +2 passive): 3 of the 4 (2 undergoing FES and 1 passive cycling) were found to have improvements in BMD at the femoral neck, distal femur, and proximal tibia; quadriceps muscle volume was also found to be increased (as measured by magnetic resonance imaging); the 4th child (passive cycling) only had improvements in femoral neck BMD. In a more recent study, Lauer (2011) published the findings on all 28 children that completed the protocol (which also included an electrical stimulation noncycling arm) and concluded that there were no significant increases in BMD between or within the 3 groups; the FES group exhibited non-significant increases in hip, distal femur and proximal tibia BMD and the passive cycling group exhibited a non-significant increase in hip BMD, but no change at the distal femur or the proximal tibia; the noncycling e-stim group exhibited no change in hip and distal femur BMD, and a non-significant loss at the proximal tibia.

Castello (2012) reported on 6 children and adolescents (9.6-20.4 years old) with chronic traumatic and nontraumatic SCI undergoing 15-69 FES sessions lasting 30 minutes over a 2-9-month period. Dual X-ray Absorptiometry scans assessing the BMD at R1 region of the right distal femur were obtained at baseline, after 3 and 6 months of intervention, and for the 2 participants who biked for the full duration of the study, at the completion of 9 months of intervention. Positive, but non-significant, relations were found between the change in BMD and the total number of FES biking sessions, the number of months using the FES cycle, the average number of biking sessions per month, and the time from injury at the initial evaluation.

As a part of a larger chart review of the medical record of 279 children with SCI, Zebracki (2013b) looked at 82 children with SCI who had recorded levels of 25 heterotopic ossification (HO) vitamin D and found that majority of youth demonstrated vitamin D deficiency (39%) or insufficiency (40%), with only 21% having sufficient levels of vitamin D. Finally, Ooi et al. (2012) reported metaphyseal and diaphyseal BMC and volumetric BMD increase (assessed by Dual X-ray Absorptiometry and Peripheral Quantitative Computer Tomography) in a 9- year-old child treated with 18 months of intravenous zolendronic acid following femoral fracture occurring a little more than 1 year after transverse myelitis related paralysis onset. Because the case report involves a growing child and administration of oral prednisolone to minimize the acute phase reaction associated with zolendronic acid administration, it is unclear if a conclusion on the effects of the drug itself can be drawn.

Heterotopic ossification

Heterotopic ossification (HO) is a pathologic process that is characterized by deposition of extra-skeletal bone in soft tissues. The pathophysiology of bone deposition varies according to the trigger (trauma, burns, neurologic injury) and can involve intramembranous or endochondral pathways (Meyers et al. 2019).

Pediatric and adult SCI-related HO present notable differences. Garland et al. (1989) retrospectively evaluated the charts of 152 children with SCI admitted to one center between June 1976 and July 1984. The researchers divided the HO occurrences into neurogenic-only HO (occurring early after SCI, without associated complicating factors) and secondary HO, occurring in neurologically affected individuals but having an extra compromising factor (e.g., local pressure ulcers, hip dislocation, additional local trauma including surgery). Of the 152 individuals (aged 14.9 +/- 4.9 years old, average of 8.5 years post SCI) whose charts were reviewed, only 15 developed HO (9.9%), with 5/15 having neurogenic only HO (3.3 %); most of the times, the trigger for diagnosis was therapist detected limitation in range of motion, specifically flexion and extension of hip, although some of the HO was detected incidentally on IV pyelograms. The HO was detected in 19 different locations, with hip being the most common. Average time from SCI to HO onset was 6.5 years (2 months-19 years), with neurogenic-only HO having a shorter onset time (average 14 months; range 3-16 months). Alkaline phosphatase was measured in 8/15 patients at the time of HO diagnosis and was found high in 5 of the cases. Follow-up x-rays at > 6 months post-HO diagnosis were done 11/15 cases and showed some degree of resorption (decrease in exoskeletal bone mass size) in 3/11. Surgical interventions (in 5 cases) at the site of HO (described as debridement for pressure injuries and osteomyelitis and femoral head and neck resection) were followed by HO recurrence and need for more surgeries.

Vogel et al. (2002b) presented results from a survey administered to 216 adults with pediatric-onset SCI aiming to quantify the prevalence of medical complications and found that HO was reported by only 24 subjects (11%), more common in those with more severe injuries (24% in those with C1-4, AIS A, B or C).

The last topic related to bone metabolism in pediatric SCI that needs to be noted is hypercalcemia of immobility, a condition more commonly occurring in the first 6 months post neurologic deficit onset in children, adolescents and young adults. Typically, immobilization triggers bone resorption and a dump of calcium into the bloodstream; if calcium filtration by the kidneys if overwhelmed by the amount of calcium extracted from bones (a process accentuated in the case of ongoing skeletal growth), clinically relevant hypercalcemia occurs. Massagli and Cardenas (1999) retrospectively reported on 9 individuals (mean age =22 years, 7 males, 2 women) treated with Pamidronate for immobilization hypercalcemia in two centers between 1994-1998. Immobilization hypercalcemia was more common in higher and more severe injuries, nausea was the most common complaint, pamidronate (with or without associated hydration) was the initial treatment in 6/9 cases and a 60 mg dose was sufficient to alleviate the clinical symptoms and calcium level 6-15 days post-administration in 7/9 patients. Because of the retrospective nature of the convenience case series, systematic conclusions about incidence and natural course of immobilization hypercalcemia cannot be drawn.