Mechanism of Bone Loss after Spinal Cord Injury or Disease

Sublesional bone mass loss and structural changes in individuals with SCI/D-related paralysis have several recognized mechanisms, among which (1) immobility, (2) denervation, (3) vascular, and (4) endocrine changes play essential roles.

Bone health depends on the balance of deposition and resorption, as per Wolff’s law and mechanostat theory—bone strength depends on forces exerted on it. In SCI/D, paralysis reduces bone loading due to neurologic weakness and limited mobility.

The neurologic deficit leads to denervation of the bone itself, negatively impacting pain perception, trophic signals, and vascular control. It also negatively affects muscle mass, which, in turn, impairs the functional muscle–bone unit, resulting in subsequent biomechanical and paracrine consequences.

SCI/D-related paralysis significantly disrupts the autonomic nervous system’s functioning, which is recognized to play a role in maintaining a normal BMD.

There are also cascading systemic endocrine consequences of paralysis. The parathyroid–calcitriol–vitamin D endocrine pathway is altered after paralysis onset; the initial immobilization hypercalcemia and hypercalciuria lead to parathyroid hormone (PTH) suppression and decreased conversion of 25 HO vitamin D to 1, 25 HO vitamin D, with subsequent hypocalcemia and accelerated bone resorption. Androgen and estrogens play essential roles in modulating bone health, and hypogonadism, characterized by low testosterone and estrogen levels, has been documented in individuals with SCI/D-related paralysis.

In addition to the mechanisms mentioned earlier, the decrease in muscle mass related to paralysis induces local paracrine changes, with impaired myokines-based biochemical cross talk, further affecting the integrity of the muscle–bone unit; and if paralysis occurs during development and growth, normal bone mass is not achieved, further compounding bone pathology.

Certain drugs commonly used postparalysis onset and altered nutrition can magnify bone mass changes.

The paralysis related to spinal cord dysfunction also alters bone’s structure, not only mass, with more significant impairment of trabecular rather than cortical bone.

Timeline of Bone Changes

Sublesional BMD loss in the SCI population begins early and progresses rapidly, with significant variability likely due to the diverse SCI population. Most studies report higher rates and degrees of bone loss in those with more complete injuries and longer SCI duration.

One of the first clinical signs of altered bone metabolism in the acute setting is hypercalcemia and hypercalciuria within the first 3 months after injury associated with increased bone reabsorption. This matches the reported maximum rate of bone loss between the first 10 and 16 weeks postinjury, primarily due to losses in trabecular bone.

Elevated calciuria can persist for over a year, indicating ongoing bone density loss. The lower limbs show the most bone density loss in the first year, measured by dual-energy x-ray absorptiometry (DXA) at the proximal tibia, distal femur, and total hip, progressing up to 50% at the knee. Bone loss accelerates at about 1% per week, leading to 4% trabecular and 2% cortical bone loss per month in motor-complete SCI in the first year. Over 1 to 2 years, more than 50% of patients with SCI meet the criteria for osteopenia or osteoporosis. Accelerated bone loss is not seen in the lumbar spine.

There are conflicting data about when BMD may reach a new steady state in this population. It has been reported this occurs at about 1 year; however, more recent studies have indicated that accelerated bone density loss may persist for more than 2 years, with a reported average of 3.5 years postinjury in another study. It has also been shown that individuals over 5 years postinjury continue to have lower BMD compared to those at 5 years, supporting that BMD loss lasts well into the chronic SCI phase. Lowest BMD measurements have been reported in those in their second or third decade postinjury. It is unclear when normal aging patterns after SCI dominate bone density losses.

Assessment of Bone Mass and Bone Mineral Density

While numerous ways exist to assess bone mass and BMD ( Table 1 ), DXA is considered the gold standard.

In 2019, the International Society of Clinical Densitometry (ISCD) published an official position regarding BMD assessment utilizing DXA in individuals with SCI of traumatic and nontraumatic etiology. A task force of specialists in paralysis and BMD established that all adults with SCI/D-related paralysis should have their BMD assessed to diagnose osteoporosis, predict lower limb fracture risk, and monitor response to therapy as soon as medically stable. The recommended assessment sites are total hip, distal femur, and proximal tibia, as lumbar spine BMD values do not reflect bone mass and density loss in individuals with SCI/D-related paralysis. Imaging both hips is recommended, as analysis of only one hip can lead to missing as much as 24% of osteoporosis diagnoses in this population. Serial scans every 1 to 2 years are recommended to analyze treatment effectiveness. In addition, the panel specifically advised that there is no minimal BMD threshold below which weight-bearing activities are absolutely contraindicated.

Technically, DXA can yield 2 scores: (1) The Z score compares the subjects’ bone density to the average values for a person of the same age, gender, and race. (2) The T score compares it to the average bone density of a young, healthy adult of the same gender and race who is presumed to have achieved peak bone mass.

In adults aged over 50 years, the World Health Organization international reference standard for normal BMD is defined by having a T score higher than −1; in osteopenia, a T score is lower than −1, but equal to/higher than −2.4 while in osteoporosis, the T score is equal or lower than −2.5 standard deviations below peak BMD. In addition, having a low impact/fragility fracture with any T score can also establish the diagnosis of osteoporosis.

In children, BMD is assessed utilizing the Z score at the lumbar spine, total body (minus head), and distal femur, as peak skeletal mass is not yet achieved. Additionally, the hip can present confounding factors like immature skeletal development, hip dysplasia, contractures, and femoral anteversion. A Z score lower than −2.0 establishes a diagnosis of low bone mass for chronologic age, and a low impact/fragility fracture establishes the diagnosis of osteoporosis.

When performing serial DXAs to monitor BMD changes, ISCD recommends that assessment be done on the same DXA testing machine, as bone and soft tissue measurements are not standardized across all technologies. For strict accuracy, each center performing DXA assessments should have calculated precision errors and least significant change values that allow for the comparison of BMD obtained at different times and by different technicians. DXA machines’ cross-calibration is essential to monitor the small physiologic changes in BMD for an accurate clinical management (see Table 1 ).

Bone Mass Preservation and Treatment