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.
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Author, Year Country Study Design Sample Size |
Population Intervention Outcome Measure |
Results |
| Bone Composition and Osteoporosis | ||
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(Zebracki et al., 2013b) USA Observational N=279 |
Population: Age: 14.9±4.9 yr; Gender: males=46, females=36; Time since injury: 4.3±3.3 yr; Level of injury: paraplegia=50, tetraplegia=32; Severity of injury: AIS A=34. Intervention: None. Chart review. Outcome Measures: Serum 25(OH) D level. |
1. Serum 25(OH) D levels ranged from 4.1 to 89.4 ng/ml with a mean of 24.7ng/ml (SD=13.1). 2. Most of the youth demonstrated vitamin D deficiency (39%) or insufficiency (40%), whereas only 21% had sufficient levels of vitamin D. 3. There was no difference in vitamin D status as a function of gender or injury level. 4. Vitamin D status differed by age groups (p<0.05); although the percent sufficient was similar for the two age groups, the percent deficient relative to the percent insufficient was greater in the ’13-21 yr’ age group. |
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(Biggin et al., 2013) Australia Observational N=19 |
Population: Age: 6.6±4.1 yr; Gender: males=10, females=9; Injury etiology: traumatic=10, non-traumatic=9; Time since injury: 5.6±3.6 yr; Level of injury: C3-4=5, C5-7=5, T1-6=6, T7-12=3; Severity of injury: complete tetraplegia=5, incomplete tetraplegia=5, complete paraplegia=6, incomplete paraplegia=3. Intervention: None. Chart review. Outcome Measures: Using Peripheral Quantitative Computer Tomography (pQCT) the following measurements were made: volumetric Bone Mineral Density (vBMD, mg/cm3), total and Cortical Cross-sectional Area (CSA, mm2), Muscle CSA (mm2), total and cortical Bone Mineral Content (BMC, mg/mm) and polar SSI (pSSI, mm3) |
1. There was no statistical difference in the radial data from those with paraplegia compared to able-body control data. 2. In the radius of subjects with tetraplegia, there was a significant reduction in BMC at both the metaphysis and diaphysis (p<0.05 for both), trabecular vBMD was significantly reduced, and cortical vBMD was indistinguishable from able-bodied controls; total CSA at the radial metaphyseal site and diaphyseal sites was reduced (p<0.05 for both). 3. In the tibia, there was no statistical difference between those with paraplegia versus tetraplegia so data were pooled. 4. vBMD of the metaphysis showed significant reduction (p<0.05). 5. In the tibial diaphysis, the bone cortex was thinner with decreased bone mineral as reflected by a reduction in CSA and cortical thickness. 6. Despite the thinner cortex, vBMD of the tibial diaphysis was preserved. 7. The PSSI (surrogate measure of bone strength) was significantly reduced. 8. There was a significant loss of muscle CSA in the calves of all patients; however, when examining the cortical BMC for muscle CSA, there was a significant increase compared to able-bodied controls. 9. Patients who were able to load bear (even if only in a standing frame) had significantly greater tibial trabecular vBMD, cortical CSA and improved muscle CSA than those who could not (p<0.05). 10. There was no association between pQCT parameters and the occurrence of fractures. 11. Fractures were femoral or tibial in six out of seven patients (86%); lower limb fractures did not occur if tibial trabecular vBMD was greater than 100 mg/cm3. 12. There was no correlation between the occurrence of fractures and load-bearing status. 13. There was a reduction in trabecular vBMD between 7.6 yr and 10.7 yr post SCI (p<0.01), while cortical vBMD did not change. 14. There was no statistically significant change in BMC, cortical thickness or pSSI Z-scores. 15. Following SCI, there was a statistically significant reduction in circularity Z-score (p<0.001) which resulted in a change from the typically teardrop appearance of the tibia to a more circular shape. 16. Circularity Z-scores did not change over time in those individuals with serial pQCT scans and was not associated with fracture risk; those who were not mobile had significantly lower circularity Z-scores compared to those who were mobile but there was no difference between those who could load bear (i.e., stand in a standing frame) compared to those who could not. |
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(Castello et al., 2012) USA Pre-Post N=6 |
Population: Age: 16.6±4.4 yr; Gender: males=3, females=3; Time since injury: 3.9±3.1 yr; Level of injury: Cervical=4, Thoracic=2; Severity of injury: AIS A=3, AIS B=1, AIS C=1, AIS D=1. Intervention: Functional Electrical Stimulation (FES) cycling. Stimulators were placed on hamstrings, quadriceps and gluteal muscles (45-50 rpm, 250 µs, 33.3 Hz, 70-120 mA). Sessions were 30 min, 3 times/wk over 9 mo. Outcome Measures: Bone mineral density (BMD) measured using Dual X-ray Absorptiometry (DXA) scans. |
1. A positive, non-significant, relationship was found between change in BMD and the total number of FES biking sessions from their first to last DXA scan (rs=0.77). 2. A positive, non-significant, relationship was found between the change in BMD and the number of months using the FES cycle from their first to last DXA scan (rs= 0.77). 3. A weakly positive, non-significant, relationship was found between the change in BMD and the average number of biking sessions per month (rs=0.60), as well as between the change in BMD and the time from injury at the initial evaluation (rs=0.49). |
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(Lauer et al., 2011) USA RCT N=28 PEDro=6 |
Population: Age: 9.6±2.4 (5-12) yr; Gender: males=17, females=11; Time since injury: 5.1±2.9 yr; Level of injury: cervical=9, thoracic=19; Severity of injury: AIS A=20, AIS B=5, AIS C=3. Intervention: Subjects were randomized to one of three groups: 1) Functional Electrical Stimulation while Cycling (FESC): 50 rpm while seated in wheelchair (pulse duration (150 ls) and frequency (33 Hz) were fixed; current amplitude (max 140 mA) increased automatically to generate sufficient force to maintain the cadence); 2) Passive Cycling (PC): Passive cycling at 50 rpm; or 3) Electrical Stimulation (ES): contraction of bilateral hamstrings, quadriceps, and gluteal muscles, 20 min each, 33 Hz, 300us, and 100mA. Sessions were conducted for 1 hour, 3 times/wk for 6 mo. Outcome Measures: Hip, distal femur, and proximal tibia Bone Mineral Density (BMD). |
1. Following the interventions, there were no significant increases in BMD between or within any of the groups. 2. The FESC group exhibited non-significant increases in hip, distal femur and proximal tibia BMD. 3. The PC group exhibited a non-significant increase in hip BMD but not distal femur or proximal tibia. 4. The ES group exhibited no change in hip and distal femur BMD, but a non-significant loss at the proximal tibia. 5. There were no hip BMD differences between groups with respect to time post SCI. |
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(Liu et al., 2008) Australia Observational N=18 |
Population: Median age: 5.3 (0.5-15.6) yr; Gender: males=9, females=9; Time since injury: 5.0±3.6 yr; Level of injury: Cervical=6, Thoracic=12; Severity of injury: complete paraplegia=13, incomplete paraplegia=1, complete tetraplegia=2, incomplete tetraplegia=2. Intervention: Functional Electrical Stimulation (FES) cycling. Stimulators were placed on hamstrings, quadriceps and gluteal muscles (45-50 rpm, 250 µs, 33.3 Hz, 70-120 mA). Sessions were 30 min, 3 times/wk over 9 mo. Outcome Measures: Bone mineral density (BMD) and Bone Mineral Content (BMC) of the total body, lumbar vertebrae, and femoral neck (FN), Lean Tissue Mass (LTM). |
Total Group Data Combined, Cross-Sectionally 1. The 10 children with a complete motor lesion had significantly lower Legs BMC, FN and Legs BMD Z-scores at baseline; with the exception of the Arms and FN, Z-scores decreased during the 1st year, and in the 2nd year Z-scores remained low but did not decrease further. 2. Children with incomplete motor lesions showed age-appropriate scans. 3. BMD Z-scores were significantly less than zero in the Legs (p<0.001), total body (p=0.02), L2-L4 (p=0.04), and the FN (p<0.001), but not in the Arms. 4. BMC Z-scores of the total body (p=0.002) and Legs (p<0.001) were also less than zero. 5. With increasing time post-injury, there was a decrease in total body BMD (p=0.02) and BMC Z-scores (p=0.04). 6. The three ambulant children had normal Legs BMD and BMC; when they were excluded the time-related decrease in either Legs BMD or BMC became non-significant (p=0.08) and LTM Z-score was reduced in the Legs (p<0.001) and remained stable with time. 7. Ambulant children had higher Legs LTM Z-scores; in contrast, Arms BMD and LTM Z-scores were normal and increased with time (p=0.003 and p=0.01, respectively). 8. L2–L4 BMD Z-scores were stable with time (p>0.05). 9. There were no changes seen in body fat (% and Z-scores).
Immediate group (scans <2 yr post SCI; n=13) 10. Only Legs BMD, Legs BMC and FN Z-scores were significantly less than zero at baseline. 11. In the first year post-SCI, BMD and BMC Z-scores of the total body fell significantly and trended towards lower values in the Legs -(p=0.07; bone mass did not increase at the expected rate); there was no reduction in BMD Z-scores in the arms. 12. In the second year, there were no significant changes in BMD or BMC Z-scores for any region, suggesting an age-appropriate accrual of bone mass. 13. Legs LTM Z-score and total body BMC/LTM Z-score decreased significantly in the first year post-SCI but not during the 2nd year of follow-up; in contrast, Arms LTM Z-score increased over the 2-yr period.
Long-term group (scans >2 yr post SCI; n=5) 14. At the first scan they had similar BMD and BMC Z-scores to the 2-yr results of the Immediate group (p>0.05); there was no significant change in Z-scores over the following 2 yr (age-appropriate accrual of bone mass). 15. All children had age-appropriate increases LTM in all regions. |
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(Johnston, Smith, et al., 2008b) USA Case Series* N=4 *Subjects were a subset from a larger RCT by (Johnston, Smith, et al., 2009) |
Population: Case 1: 7 yr, female, T4-T6, ASIA A SCI at 2 yr of age; Case 2: 9 yr, female, C7, ASIA A SCI at 4 yr of age; Case 3: 7 yr, male, T3, ASIA A SCI at 3 yr of age; Case 4: 11 yr, male, C7, ASIA A SCI at 3 yr of age. Intervention: Intervention Group: Functional Electrical Stimulation while cycling at 50 rpm while seated in wheelchair (pulse duration (150 ls) and frequency (33 Hz) were fixed; current amplitude (max 140 mA) increased automatically to generate sufficient force to maintain the cadence). Control Group: Passive cycling at 50 rpm. Sessions were conducted for 1 hr, 3 times/wk for 6 mo. Outcome Measures: Bone mineral density (BMD) of the left femoral neck, distal femur, and proximal tibia; left quadriceps muscle volume; electrically stimulated strength of the left quadriceps; quadriceps and hamstrings muscles Ashworth scale scores; fasting lipid profile via high density lipoprotein (HDL) and low-density lipoprotein (LDL); heart rate (HR); and oxygen consumption (VO2/kg). |
Case 1: FES Cycling 1. Improvements in BMD at the femoral neck, distal femur, and proximal tibia; quadriceps muscle volume; stimulated strength of the quadriceps muscles; HDL cholesterol; resting HR; peak VO2/kg; and peak HR; however, cholesterol, LDL, and triglyceride levels and the cholesterol/HDL ratio increased compared to baseline. 2. No changes in Ashworth scores, but parents reported decreased spasticity and looser muscles.
Case 2: FES Cycling 3. Improvements in BMD at the femoral neck, distal femur, and proximal tibia; quadriceps muscle volume; stimulated quadriceps muscle strength; and hamstring muscle spasticity; however, cholesterol, LDL, HDL, and triglyceride levels and the cholesterol/HDL ratio worsened as compared to baseline. 4. The parents reported bigger, firmer muscles; decreased bowel program completion times; increased appetite; and increased spasticity that did not require medical intervention.
Case 3: Passive Cycling 5. Improvements in femoral neck BMD, hamstring spasticity, and triglyceride levels. 6. Distal femur and proximal tibia BMD and stimulated quadriceps strength were lower as compared to baseline, and LDL levels and the cholesterol/HDL ratio were elevated. 1. Parents reported decreased bowel accidents and new sensation in his knees and stomach.
Case 4: Passive Cycling 2. Improvements in BMD at the femoral neck, distal femur, and proximal tibia; quadriceps muscle volume; stimulated quadriceps strength; hamstring spasticity; cholesterol; LDL cholesterol; resting HR; and peak VO2/kg. 3. HDL cholesterol decreased as compared to baseline but the cholesterol/HDL ratio was unchanged. 4. Parents reported decreased spasticity, looser muscles, increased energy, decreased lower extremity swelling, and increased appetite. |
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(Lauer et al., 2007) USA Observational N=28 |
Population: Age: 9.6±2.5 yr; Gender: males=17, females=11; Time since injury: 4.5±2.9 yr; Level of injury: Cervical=8, Thoracic=20; Severity of injury: AIS A=25, AIS B=3. Intervention: None. Outcome Measures: Bone mineral density (BMD) of the left hip, distal femur, and proximal tibia. |
1. For the group as a whole, BMD values at the hip were 0.48±0.17 g/cm2, 0.41±0.17 g/cm2, and 0.47±0.17 g/cm2 for femoral neck, greater trochanter, and Ward’s triangle, respectively. 2. Total hip BMD was 0.48±0.17 g/cm2. 3. At the knee, BMD values were 0.38±0.10 and 0.37±0.07 g/cm2 for the distal femur and proximal tibia, respectively. 4. In the regions where the Z-scores could be calculated, overall BMDs were 64.4%, 64.2%, and 57.8% of age- and sex-matched normative values for the femoral neck, greater trochanter, and Ward’s triangle, respectively. **Given the large variations and small sample size, no statistical tests were performed. |
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(Kannisto et al., 1998) Finland Observational N=35 |
Population: Pediatric-onset SCI: Median age at interview: 31 (18-63) yr; Median age at injury: 12.9 (0-17.1) yr; Gender: males=25, females=10; Median time since injury: 19 (1.5-57) yr; Level of injury: complete paraplegia=24, incomplete paraplegia=3, complete tetraplegia=3, incomplete tetraplegia=5. Intervention: None. Densitometry and laboratory assays. Outcome Measures: Bone Mineral Density (BMD) of lumbar spine, proximal femur and regional sites (femoral neck, trochanteric area, intertrochanteric area, Ward’s triangle), presence of osteoporosis (decrease of more than 2.5 SD compared to peak bone density reference data), urinary calcium, phosphate and creatinine, Alkaline Phosphatase (AP), Bone isoenzyme (BAP), Osteocalcin (OC) assay, urinary Hydroxyproline (HYP) and deoxypyridinoline (DPD). |
1. BMD levels were within the normal range in the lumbar spine; mean BMD at the lumbar spine was 1.08±0.17 g/cm2 which represents 99.5% of the age and sex adjusted mean (Z-score) and 70.04 SD of peak bone mass measured in 30-yr old persons of the same gender as the patients (T- score). 2. At the hips, accurate subtraction between bone and soft tissues with the densitometer failed in seven out of the 34 patients. 3. BMD at the proximal femur was on an average 0.72±0.23 g/cm2 which is 72.05 SD of the age and gender adjusted mean value (Z-score); mean T-score was 72.61 which represents established osteoporosis. 4. BMD in the femoral neck was 0.69±0.19 g/cm2. 5. BMD in Ward’s triangle was 0.60±0.24 g/cm2. 6. Lowest measurements were at the intertrochanteric level where mean BMD was 0.52 g/cm2. 7. At the lumbar spine 10/29 of the patients had a T-score which was under 71 SD and 3/29 of the patients had T-scores less than 72 SD; none of the patients had a T-score less than 72.5 SD at the lumbar spine. 8. At the femoral neck 21/27 of the patients had T-scores under 71 SD, 19/27 had T-scores less than 72 SD and 16/27 had a T-score less than 72.5 SD. 9. The dissociation between axial and peripheral BMD (lumbar spine versus total femoral area) was significant (p<0.001). 10. Though statistically significant (p=0.04), there was no clinical difference in BMD between those with tetraplegia or paraplegia at the lumbar level. 11. There was no statistically significant difference in hip BMD between those with paraplegia versus tetraplegia. 12. In comparing individuals with lesions at C1±T6 to those with lesions ≤T7, there were significant differences in BMD at lumbar (p=0.004) and hip (p<0.01) with those sustaining higher injuries having lower BMD. 13. Regression showed BMD of the proximal femur (b=0.49, p<0.01) and the femoral neck (b=0.57, p<0.01) was correlated with bodyweight but not body height, age at the time of injury, age at the time of examination or to the time elapsed since injury. 14. Biochemical markers of bone metabolism showed no signs of still ongoing accelerated bone formation or resorption. |
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(Moynahan, Betz, et al., 1996) USA Observational N=51 |
Population: Age: 14.5±4.2 (3-20) yr; Gender: males=30, females=21; Level of injury: cervical=19, thoracic/lumbar=32. Intervention: None. Densitometry and laboratory assays. Outcome Measures: Bone Mineral Density (BMD) of femoral neck, Ward’s triangle and intertrochanteric region of the hip, presence of spasticity, number of pathological fractures. |
1. Baseline measurements at the femoral neck, Ward’s Triangle and intertrochanteric region were normalized by sex and age and then averaged; there was a trend toward lower BMD at the hip in SCI subjects as compared with their non-disabled peers: femoral neck=64.2±17.6%, Ward’s Triangle=64.4±17.6% and intertrochanteric region=55.9±16.0%. 2. In total, 10 subjects had one or more pathological fractures of the leg. 3. Normalized BMD were compared to non-fracture SCI subjects and there was a trend toward lower BMD in subjects with fractures (p<0.05); the upper limit of the fracture group (the value above which no subject showed a fracture) was 87 percent for the femoral neck, 90 percent for Ward's Triangle and 65 percent for the intertrochanteric region. 4. At only the intertrochanteric region, those with tetraplegia had lower BMD than those with paraplegia (p<0.05). 5. In total, 46 subjects had spastic legs and 5 subjects had flaccid legs. 6. Subjects with spasticity generally showed higher bone densities than those without spasticity at the femoral neck and Ward’s triangle (p<0.05 for both) but not the intertrochanteric region (analysis lacked statistical power). |
| Heterotopic Ossification | ||
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(Vogel et al., 2002b) Part II USA Observational N=216 |
Population: Age at injury: 14.1±4.0 yr; Age at interview: 28.6±3.4 yr; Gender: males=150, females=66; Time since injury: 14.2±4.6 yr; Level of injury: tetraplegia=123, paraplegia=93. Severity of injury: C1-4 ABC=41, C5-8 ABC=67, T1-S5 ABC=82, tetra/para D=26. Intervention: None. Survey. Outcome Measures: Prevalence of heterotopic ossification. |
1. Heterotopic ossification was reported by only 24 subjects. Heterotopic ossification was more common in those with more severe injuries (C1-4 A-B-C) (23%), compared to the other injury severity groups (9%) (p=0.013). |
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(Garland et al., 1989) USA Observational N=152 |
Population: Heterotopic Ossification Group: Age: 8.5 yr (3 mo-15 yr); Gender: males=12, females=3; Injury etiology: trauma=11, vascular compromise=2, infection=1, progressive kyphosis=1. Level and severity of injury: thoracic complete=13, cervical incomplete=2. Intervention: None. Chart Review. Outcome Measures: Heterotopic Ossification (HO) incidence location, signs and symptoms, incidence of pressure ulcers, hip dislocations, alkaline phosphatase levels, surgical treatment. |
1. Among 152 individuals, 15 developed HO (9.9%). 2. There were 19 different HO locations, most commonly the hip. 3. Three ossification patterns of the hip were identified: anterior, abductor muscle region, and inferomedial. 4. The femur was the only area of non-joint HO formation. 5. Two patients had HO at two joints and one patient had HO at three joints. 6. Average time from spinal insult to diagnosis of HO was 6 yr 5mo (2 mo-19 yr); considering only neurogenic HO, the average time was 14 mo (3-36 mo). 7. Most common sign of HO was a reduction in joint motion. 8. At the hip, 11 patients had pressure ulcers. 9. At the hip, 3 patients had dislocations, two of which had pressure ulcers as well. 10. When HO was detected, eight patients had alkaline phosphatase levels obtained of which they were elevated in five (3 primary, 2 secondary). 11. Three patients had resorption of HO of at least one grade. 7. Five patients were treated with surgery at the hip (mean 3.2 surgeries) for wound debridement, resection of HO, etc. |
| Hypercalcemia | ||
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(Massagli & Cardenas, 1999) USA Case Series N=9 |
Population: Age: 0-18 yr=3, 19-25 yr=4, 26-41 yr=2; Gender: males=7, females=2; Level of injury: C1-4=1, C5-7=6, T1-12=1; Severity of injury: AIS A=6, AIS B=1, AIS C=1, AIS D=1. Intervention: 60 mg pamidronate. Outcome Measures: Calcium levels. |
1. Hypercalcemia onset occurred 3-16 weeks post injury with typical symptoms including nausea. 2. Ionized calcium levels at the time of treatment ranged from 1.29 to 1.53 mmol/L and the corrected serum calcium was 12.7 mg/dL. 3. Original 60 mg pamidronate dose sufficiently treated seven of nine patients; the remaining two required additional doses. 4. One patient experienced transient drug-related fever. 5. For four patients, the serum or ionized calcium level decreased to the hypocalcemic range after treatment, but they were asymptomatic. |
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Author, Year Country Study Design |
Population Intervention Outcome Measure |
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(Ooi et al., 2012) Australia Case Report N=1 |
Population: 12 yr, male, transverse myelitis (at 8 yr), C3 tetraplegia. Intervention: Zoledronic acid (0.05 mg/kg/dose) for 6 mo. Outcome Measures: Calcium, phosphate, alkaline phosphatase, parathyroid hormone, 25-hydroxyvitamin D, osteocalcin, calcium/creatinine ratio, deoxypyridinoline/creatinine ratio, bone mineral content, bone mineral density |
Discussion
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.
