Osteoporosis in Spinal Cord Injuries

Etiology

SCIs involve a classic bimodal distribution pattern.[4] Younger patients are injured via high-energy mechanisms with the following approximate associated incidence rates:

• Motor vehicle collisions: 50% to 75%
• Falls: 10% to 15%
• Gunshot wounds: 10% to 15%
• Sports: 10% to 15%
• Iatrogenic: Estimated incidence ranges from 3% to 25% of all SCIs occurring secondary to improper immobilization and patient transport [4][5][6]

The older adult patient population sustains the majority of SCIs via minor trauma or mechanical falls. Older adults are predisposed to injury secondary to an underlying degenerative spine and associated spinal stenosis.[6]

Epidemiology

The prevalence of SCIs in the United States rose by 30% between 1994 and 2012.[3] In 2016, estimates indicated that approximately 17,000 new cases of SCI occurred nationwide, equating to an annual incidence of 54 cases per million population.[4] Osteoporosis affects 10 million individuals in the United States, while an additional 34 million are considered at risk due to a diagnosis of osteopenia—a condition defined by BMD levels below the normal reference range but not low enough to meet the diagnostic criteria for osteoporosis.[2]

These aforementioned epidemiologic trends and patterns merge to result in over 50% of patients with a complete SCI developing osteoporosis by 1 year after the injury.[7] Long-term follow-up increases the prevalence rate to >80%.[7] However, the most devastating complication secondary to osteoporosis developing after an SCI is the fragility fracture. Over half of these patients will sustain at least 1 low-impact fracture at some point after the SCI during long-term follow-up.[3]

Pathophysiology

Disuse Osteoporosis and Osteopenia

Patients sustaining SCIs are predisposed to disuse osteopenia from prolonged immobilization and overall decreased mobility and independent functional capabilities. Normal bone physiology relies on a process of active remodeling in a constant cycle of bone formation and bone resorption. In SCI, the generalized loss of mobility and ability to perform normal weight-bearing activities of daily living eventually uncouples the active remodeling process. The first 2 weeks after the initial injury are recognized as the most vulnerable period for decreased bone formation.[8]

Sclerostin, Vitamin D, Parathyroid Hormone

Recent studies suggest that sclerostin plays a critical role in SCI-induced bone loss. Sclerostin is produced primarily by osteocytes and inhibits bone formation via multiple mechanisms, including the upregulation of receptor activator of nuclear factor-kappa B ligand (RANKL) and downregulation of osteoprotegerin (OPG).[9] The end result of these pathways yields a net increase in bone resorption. 

Several studies have demonstrated increased levels of sclerostin in patients afflicted with clinical conditions resulting in disability and immobility. In addition to SCI patients, stroke patients are considered particularly vulnerable and at risk for acute and chronic compromise to BMD levels. Moreover, sclerostin levels appear to be highest during the initial postinjury phase, followed by decreasing levels detected in chronic SCI osteoporosis patients.[3]

SCI patients typically have abnormally low levels of vitamin D and parathyroid hormone (PTH) levels in both the acute and chronic phases of SCI injury and recovery. Acutely, PTH levels are low secondary to the initial hypercalcemia resulting from the sclerostin-induced bone resorption.[3]

Wnt ligands promote bone formation by promoting osteoblast differentiation, growth, and activity and suppressing osteoblast apoptosis.[10] One animal study demonstrated that Wnt signaling decreases, while sclerostin-stained osteocytes increase, at the distal femur and proximal tibia in mice with SCI.[11]

Long-Term Implications

After the initial 2 weeks following SCI, studies have suggested that, while bone formation rates can return to normal levels, the regions of the body below the level of the lesion (ie, sublesion levels) continue to experience a 4% per month reduction in BMD. In addition, trabecular BMD is decreased by 40% by 2 years after the injury. Similarly, the long bones in the lower extremity undergo appreciable cortical thinning following SCI, predisposing to low-energy impact fractures.[12]

Beyond 2 to 5 years post-SCI, controversy persists in the literature regarding ongoing decremental BMD rates that may continue into perpetuity. Some reports suggest that bone loss plateaus after 3 to 5 years, while others demonstrate a steady decremental loss in BMD.[3]

Fragility Fractures

SCIs represent conditions associated with substantial morbidity and mortality. In the context of osteoporosis, fragility fractures stand out as the most evident and devastating clinical consequence.[1] A rapid decline in bone mineral density, even among the youngest patients, often results in multiple subsequent fragility fractures. Many of these fractures may occur spontaneously, frequently leading to missed or delayed diagnoses.[3]

In individuals with SCI, the most frequent sites for fragility fractures are the epiphysis and metaphysis of the distal femur and proximal tibia.[13] These anatomical areas are particularly vulnerable due to the significant and rapid bone loss that occurs following SCI, especially in the early postinjury period.[13] The loss of mechanical loading and muscle activity below the level of injury leads to profound reductions in BMD, predominantly affecting trabecular-rich regions near joints.[14] As a result, these areas become structurally compromised and highly susceptible to low-impact or even spontaneous fractures.

Fragility fractures in this population are not only common but also associated with a significantly increased risk of secondary complications.[15] These include pressure injuries due to prolonged immobility, venous thromboembolism resulting from decreased circulation and immobilization, and chronic pain or joint deformities that can further impair mobility and quality of life.[15] Moreover, fracture management in SCI patients is often complicated by impaired sensation, muscle spasticity, and delayed healing, which can prolong rehabilitation and increase healthcare utilization.[15] The prevention and early detection of fragility fractures, therefore, represent critical components of long-term care and risk management in individuals with SCI.

Histopathology

Histologic osteoporotic specimens demonstrate thinning of the trabeculae, decreased osteon size, and enlarged haversian and marrow spaces.[16]

History and Physical

Clinical History

Clinicians should begin the evaluation of a patient with a history of SCI by obtaining a complete clinical history, noting the time elapsed since the initial index event. The first 2 weeks following an SCI mark a critical period during which BMD declines most rapidly.

Furthermore, a thorough history must include identification of predisposing conditions and patient age, both of which may exacerbate conditions associated with already compromised BMD levels. For instance, older adults presenting 2 weeks after an SCI often carried a prior diagnosis of osteopenia or osteoporosis, placing them at high risk for spontaneous fractures without a discernible underlying cause.

Additional key elements in the history include:

• History of fragility fractures (eg, hip fractures, vertebral compression fractures)
• Predisposing chronic medical conditions (eg, eating disorders, asthma, malignancy, inflammatory conditions, endocrinopathies, and malnutrition states)
• Medication use (eg, antiseizure medications, chronic steroid use, proton-pump inhibitors, methotrexate)
• History of early menopause or current postmenopausal status for female patients
• History of anti-osteoporosis medication treatments [1]

Assessment of secondary bone loss also requires a detailed social history to identify potential risk factors. Smoking, chronic alcohol consumption, and overall nutritional status warrant attention, including current or prior calcium and vitamin D supplementation. Documentation of any family history of osteoporosis remains essential. Patients should also be asked about previous fractures, especially those resulting from low-energy ground-level falls or occurring after age 40.[2] Research has shown that postmenopausal women with complete SCIs exhibit greater trabecular bone loss than ambulatory postmenopausal women.[2]

Physical Examination

Patients with SCI can present with varying clinical presentations, depending on the level of the injury. The clinician should note the specific type and classification of the injury. Clinical findings may fall into several categories, including:

• Paraplegia
  • SCI that causes dysfunction from the trunk and pelvic regions to the lower extremities.
  • Patients have spared upper extremity function, which preserves varying levels of independent mobility.

• Tetraplegia
• SCI injuries at the level of the cervical spine lead to dysfunction of the upper extremities, trunk and pelvic regions, and lower extremities.
• Patients are particularly susceptible to progressive losses in BMD as well as spontaneous VCFs without an apparent mechanism.

• Complete SCI
• Patient is diagnosed with a complete SCI in the acute setting after resolution of the spinal shock state (ie, after the return of the patient’s bulbocavernosus reflex).
• Patients have no spared motor or sensory function below the defined level of injury (ie, American Spinal Injury Association A injuries).

• Incomplete SCI
• Injuries are subdivided into syndromes of clinical manifestation based on the anatomic area of injury to the spinal cord.
• All of these syndromes demonstrate some preserved motor or sensory function below the defined level of injury.
• Syndromes include the following:
• Anterior cord 
• Posterior cord 
• Central cord 
• Cauda equina 
• Conus medullaris 
• Brown-Sequard [17][18]

In addition to documenting a comprehensive motor and sensory exam, careful palpation and heightened clinical suspicion for spontaneous or occult fractures are critical. The most common location for spontaneous fractures is in the sublesion regions, especially the lower extremity long bones.[19] The clinician should note any focal or diffuse areas of swelling, including deformity and overall limb alignment.

Patients who sustain a fragility fracture require close attention, and prompt follow-up with an appropriate healthcare professional remains strongly encouraged to initiate timely treatment. Despite the clinical importance, follow-up rates for osteoporosis continue to remain low, even after a fragility fracture has occurred. Automated follow-up systems and fracture liaison services have gained traction as effective strategies to address this issue and improve historically low follow-up rates, which have been reported to range from 1% to 10%.[20]

Evaluation

In general, osteoporosis follow-up trends and patterns have received increasing attention over the last 5 to 10 years. Still, SCI-induced osteoporosis follow-up patterns and treatment recommendations lag behind those of the more generalized osteoporosis diagnostic category. These issues are further exacerbated by the overall complexity of the SCI injury, in addition to those previously mentioned, as well as the notoriously low follow-up rates for treating osteoporosis in general.

Osteoporosis Evaluation

Dual-energy x-ray absorptiometry

The WHO has established dual-energy x-ray absorptiometry (DXA) scans as the gold standard for assessing BMD levels. DXA scans utilize an x-ray beam to measure calcified tissue in targeted regions of the body. DXA scans are reported to be the most accurate diagnostic imaging modality with the least amount of radiation exposure. The lumbar spine (L2 to L4), the hip (compiled from the femoral neck, trochanters, and intertrochanteric regions), and the wrist are routinely included in the scan. The BMD reported reflects the absolute, patient-specific score determined from these measured anatomic areas.[1][2]

In addition, the scan also reports a t-score and a z-score. The t-score is measured in standard deviations and reflects the difference between the patient's measured BMD and the mean value of BMD in healthy, young, matched controls (eg, 30-year-old women). By definition, a normal BMD measurement is within 1 standard deviation of the young adult mean. The WHO defines t-scores between -1 and -2.5 as osteopenic and scores below -2.5 as osteoporotic. The z-score is also measured in standard deviations, but the z-score is compared to a healthy, age-matched control group. The z-score is most clinically relevant when obtaining a DXA scan in younger patients when secondary osteoporosis is being considered. A z-score less than -1.5 warrants a comprehensive secondary osteoporosis workup.[1][2]

Serum laboratory studies

Standard laboratory workup includes checking calcium, phosphorus, albumin, alkaline phosphatase, liver function tests, creatinine (both serum and urine), 25-hydroxyvitamin D, thyroid-stimulating hormone (TSH), free T4, and intact parathyroid hormone (PTH) levels. Males should have a free testosterone level checked to rule out hypogonadism. 

The routine use of checking bone turnover markers (BTM) is debated. The utility of obtaining markers of bone resorption can be considered if the possible underlying cause of secondary osteoporosis is considered. Although reports question the reproducibility of such values, available tests include checking serum or urinary cross-links of type I collagen (deoxypyridinoline), N-telopeptide of type I collagen (NTx), or C-telopeptide of type I collagen (CTx).

Fracture risk assessment tool

The WHO created a fracture risk assessment tool (FRAX score) to predict the 10-year risk of sustaining a hip or other major osteoporotic fracture. These other major fragility fractures include fractures of the spine, wrist, forearm, or humerus. The assessment consists of 12 questions, weighted according to the relative risk associated with a future fragility fracture event. Assessment includes age, sex, personal history of fracture, low BMI, oral steroid use, secondary osteoporosis, parental history of hip fracture, smoking status, and alcohol intake. In addition, optional BMD measurement values can be included from a prior DXA scan (if available) to provide a more comprehensive score report. 

The utility of the FRAX score is particularly emphasized in patients with osteopenia. Although fracture risk increases with decreases in BMD, the concept that the vast majority of these fragility fractures occur in osteopenic (as opposed to osteoporotic) patients poses a conflicting treatment paradigm. Thus, clinicians rely on the FRAX score to stratify which osteopenic patients exceed the risk threshold, warranting more aggressive pharmacologic treatments.[21][22]

Peripheral quantitative computed tomography 

Peripheral quantitative computed tomography (pQCT) serves as a valuable alternative imaging modality for assessing osteoporosis and evaluating fracture risk in patients with spinal cord injury.[14] Unlike traditional methods such as dual-energy X-ray absorptiometry (DXA), pQCT offers the unique capability to provide detailed insights into bone microarchitecture as well as the mechanical and tensile properties of bone tissue.[14]

Specifically, pQCT enables the separate and precise measurement of volumetric bone mineral density (vBMD) in both trabecular and cortical compartments, providing a 3-dimensional perspective that enhances diagnostic accuracy.[14] This distinction is critical, as changes in trabecular and cortical bone contribute differently to overall bone strength and fracture susceptibility.[14] However, despite its diagnostic advantages, the clinical application of pQCT remains limited due to restricted availability, higher costs, and the need for specialized equipment and trained personnel.[1][2]

Treatment / Management

Clinicians are encouraged to recognize the similarities and subtle differences when managing osteoporotic patients versus SCI-induced osteoporotic patients. While some general underlying principles in treatment exist, an evolving treatment paradigm is also recognized in the subgroup of patients with SCI-induced osteoporosis.

Mechanical Loading

Weight-bearing activity stimulates and creates an ideal stress environment to promote physiologic bone remodeling, as outlined in the Wolff law. Mechanical loading has demonstrated reversal capabilities in the SCI-induced osteoporotic process in long bones in the lower extremity. Specifically, cortical thickening is noted in response to applied mechanical stress and strain even after disuse osteopenia has ensued. However, studies have demonstrated that the ideal environment for maximizing osteogenic potential and creating a net anabolic activity in bone turnover is achieved through intermittent force application. Constant stimulation can lead to desensitization of the bone to the applied mechanical forces.[3][22]

Rehabilitation Interventions for Osteoporosis in the Setting of Spinal Cord Injury 

Current inpatient and outpatient physical therapy interventions for individuals with SCI focus on mitigating disuse-mediated bone loss and enhancing bone mineral density BMD through repetitive, load-bearing activities.[14] These therapeutic strategies often incorporate advanced rehabilitation technologies designed to facilitate mechanical loading of the skeletal system.[13] Such modalities include overground locomotor training, bodyweight-supported treadmill training, passive cycling, and functional electrical stimulation integrated with cycling, rowing, or resistance training.[13] These approaches aim to simulate natural movement patterns and promote muscle contractions that, in turn, apply mechanical forces to bones, potentially stimulating bone formation and slowing resorption.[13]

Additional assistive technologies, including standing frames, powered exoskeletons, treadmill walking devices, orthotic supports, and powered wheelchairs with standing seating systems, are also utilized to encourage upright positioning and weight-bearing activity, both of which are critical factors in bone health maintenance. Emerging approaches (eg, activity-based restorative therapy) build upon existing technologies by promoting intensive, task-specific, and weight-bearing activities aimed at activating the neuromuscular system below the level of injury.[23] However, the clinical evidence supporting the efficacy of these interventions in significantly improving BMD in SCI populations remains inconclusive.[13] Studies conducted to date have yielded mixed results, and no single modality has demonstrated consistent, robust improvements in bone density outcomes across diverse patient populations.[13]

Vibration Therapy

Low-magnitude mechanical signals, as a therapeutic modality, have demonstrated bone formation capabilities in both human and rodent models. However, beyond limited case reports, limited evidence is available to advocate for its definitive therapeutic potential. Similarly, low-intensity vibration treatment protocols have shown promising results in a small case series of patients with SCI-induced osteoporosis.[22][24](A1)

Calcium and Vitamin D

Without a doubt, all patients should take calcium and vitamin D supplementation. Patients should be educated on the recommended daily intake for calcium and vitamin D. The National Osteoporosis Foundation (NOF) recommends 1200 to 1500 mg of calcium per day and 800 to 1000 IUs of daily vitamin D for adults older than 50. In the setting of SCI-induced osteoporosis, all patients should begin supplementation regardless of age at presentation.[25]

Anti-Osteoporotic Pharmacotherapy Options

Pharmacotherapy agents work through either anti-resorptive or anabolic means. In general, bisphosphonates are the most commonly prescribed medication class for the treatment of osteoporosis. These drugs are divided into non-nitrogen and nitrogen-containing compounds. The latter are considered first-line therapy for osteoporosis.[2] However, a significant concern with SCI-induced osteoporosis, coupled with the bisphosphonate anti-resorptive mechanism on bone, is the inability to actually demonstrate measurable increases in BMD levels.[3]

In one study, alendronate was able to prevent further bone loss in 55 patients with chronic SCI-induced osteoporosis at the 2-year follow-up. However, this is a stark contrast to alendronate’s proven track record and documented capabilities to increase BMD values measured in ambulatory (ie, not SCI-induced), postmenopausal women with osteoporosis.[3]

While alendronate, risedronate, and intravenous zoledronic acid have all demonstrated reduced fragility fracture rates in the general osteoporosis population, the clinical evidence has yet to be shown in the SCI-induced osteoporosis population.[26] Clinicians are encouraged to recognize the subtle differences in efficacy and evidence-based approaches for the pharmacologic management of these vulnerable patients. A few studies have demonstrated site-specific improvements in BMD.(B3)

Denosumab

Denosumab, a monoclonal antibody targeting the receptor activator of nuclear factor kappa-B ligand (RANKL), has recently been studied specifically in patients with osteoporosis induced by SCI. In 2016, a study demonstrated increases in lumbar and femoral BMD values, as measured by DXA scans, after 1 year of treatment compared to baseline BMD values. Denosumab was administered at a dosage of 60 mg every 6 months during the study period.[3]

Anabolic Agents and Emerging Pharmacotherapy Agents

Teriparatide is a recombinant form of PTH that stimulates osteoblasts to produce more bone. Teriparatide is now FDA-approved for osteoporosis treatment in males and females, but more studies are needed to improve our understanding of its effects on BMD levels and clinical outcomes in SCI-induced osteoporotic patients.[24][27] (A1)

Romosozumab, a humanized monoclonal antibody sclerostin inhibitor, increases the formation and reduces the resorption of bone by binding and inhibiting sclerostin.[28] In doing so, the Wnt/β-catenin pathway increases osteoblastic activity and reduces osteoclastic activity, leading to decreased bone resorption.[29] Currently, romosozumab has FDA approval for the treatment of osteoporosis in women at high risk of fractures (eg, postmenopausal).[30]

Activins are a group of agents belonging to the transforming growth factor-beta family and are highly expressed in bone. Studies have demonstrated that blocking the type II activin receptor promotes bone formation secondary to the inhibition of activin A ligand signaling. Similarly, studies have also suggested the same conclusion when targeting cathepsin-K inhibitors. To date, there is little, if any, literature specifically targeting patients with SCI-induced osteoporosis. Future studies are warranted to delineate clinical efficacy.[3]

Differential Diagnosis

The key clinical elements in diagnosing SCI-induced osteoporosis include recognizing the time since the original SCI injury, establishing a baseline BMD value via a DXA scan, and closely monitoring these patients to track the progression of bone loss. A relevant differential diagnosis pattern would entail initially categorizing a patient based on the bone loss spectrum via the following established WHO criteria:

• Normal BMD = t-score of -1.0 or greater (ie, within 1 standard deviation below normal, healthy control group reference values)
• Osteopenia = t-score between -1.0 and -2.5
• Osteoporosis = t-score below -2.5 [25]

Also relevant in the differential diagnosis is considering underlying pre-existing medical conditions and medication use, which may have already predisposed the patient to compromised BMD levels. Finally, always keep a heightened clinical suspicion for spontaneous fragility fractures, especially in the most compromised patients with SCI.

Prognosis

Compared to the general at-risk osteoporosis population, patients with SCI experience a worse prognosis and a more pronounced decline in BMD levels. Within 1 year of the initial injury, over 50% develop osteoporosis, and more than 80% of individuals with chronic SCI eventually meet diagnostic criteria for osteoporosis. Treatment responses to anti-osteoporosis therapies remain less consistent in this group than in postmenopausal ambulatory women.

Key prognostic milestones include:

• Approximately 2 weeks following SCI, the patient is at risk for rapid decreases in BMD levels.
• Sublesion level bone loss of approximately a 4% per month reduction in BMD can be expected.
• Trabecular BMD bone loss of approximately 40% occurs by 2 years after SCI injury.
• Beyond 2 to 5 years postinjury, controversy remains in the literature concerning ongoing decremental BMD rates into perpetuity. Some reports suggest that bone loss plateaus after 3 to 5 years, while others demonstrate chronic decreases in BMD.[3][8][31]

Complications

The major complication of SCI-induced osteoporosis is the fragility fracture.[3][12] The majority of fragility fractures occur at the sublesion levels, especially in long bones.[12] Many fragility fractures in patients with SCI occur spontaneously and can be missed or delayed in diagnosis.[12]