The Effects of Exercise and Activity-Based Physical Therapy on Bone after Spinal Cord Injury.

Spinal cord injury (SCI) produces paralysis and a unique form of neurogenic disuse osteoporosis that dramatically increases fracture risk at the distal femur and proximal tibia. This bone loss is driven by heightened bone resorption and near-absent bone formation during the acute post-SCI recovery phase and by a more traditional high-turnover osteopenia that emerges more chronically, which is likely influenced by the continual neural impairment and musculoskeletal unloading. These observations have stimulated interest in specialized exercise or activity-based physical therapy (ABPT) modalities (e.g., neuromuscular or functional electrical stimulation cycling, rowing, or resistance training, as well as other standing, walking, or partial weight-bearing interventions) that reload the paralyzed limbs and promote muscle recovery and use-dependent neuroplasticity. However, only sparse and relatively inconsistent evidence supports the ability of these physical rehabilitation regimens to influence bone metabolism or to increase bone mineral density (BMD) at the most fracture-prone sites in persons with severe SCI. This review discusses the pathophysiology and cellular/molecular mechanisms that influence bone loss after SCI, describes studies evaluating bone turnover and BMD responses to ABPTs during acute versus chronic SCI, identifies factors that may impact the bone responses to ABPT, and provides recommendations to optimize ABPTs for bone recovery.

1. Introduction

An estimated 250,000 to 500,000 new spinal cord injuries (SCI) occur worldwide each year [1], with males representing ~80% of the population [2]. Roughly one-third of these are motor-complete SCIs that result in permanent sublesional paralysis, while the remainder are incomplete and retain voluntary contractility in some muscles that are innervated below the lesion [2]. Locomotor dysfunction is the most recognizable symptom of SCI and is accompanied by other medical consequences that develop in this population [3], including severe osteoporosis and high fracture risk [4], which worsen with increasing SCI severity [5,6,7,8,9] and injury duration [10,11].

Bone loss after SCI is termed neurogenic or disuse osteoporosis and is confined to the sublesional skeleton [10,11,12], with the most rapid and prevalent bone deficits occurring at the distal femur and proximal tibia regions [11,13,14]. At these sites, 50–100% lower trabecular bone mineral density (BMD) develops in individuals within the first two to three years of SCI [11,13,14], and 40–80% lower cortical bone mass exists several years after injury [14]. Some evidence also indicates that cortical bone becomes more porous after SCI [15]. Collectively, these bone deficits imply a significant weakening of skeletal integrity which likely influences the 20- to 100-fold higher fracture risk in persons with SCI when compared with the general population [16].

After SCI, fractures are usually non-traumatic, due to the mobility limitations in persons with SCI, and result from low-velocity compressive forces or torsional stresses [17] that develop while seated or during transfers to, or falls from, a wheelchair. These fractures most commonly occur at the epiphysis or metaphysis [5] of the distal femur [18] or proximal tibia [7,8], where bone loss is the most severe and may require extended inpatient hospitalization [5]. Moreover, a single fracture more than doubles the risk for other secondary medical comorbidities after SCI, including venous thromboembolic events, respiratory illnesses, and pressure ulcers, among others [19]. These comorbidities influence the 30% higher five-year mortality risk for those of any age who fracture after SCI and the more than three-fold higher five-year mortality risk for persons with SCI who fracture after age 50 years [20]. The severe bone loss, high fracture incidence, and the associated morbidity and mortality indicate the need to improve osteoporosis screening and to develop evidence-based guidelines to prevent and treat osteoporosis in the SCI population [21,22].

2. Determining BMD and Fracture Risk after SCI

Dual-energy X-ray absorptiometry (DXA) is the standard to assess osteoporosis and fracture risk at traditional osteoporosis sites (e.g., lumbar spine and hip), via the quantification of areal (a)BMD and T-scores [23]. Specialized DXA techniques have also been developed to assess distal femur and/or proximal tibia aBMD after SCI [17,24,25], although not all the DXA systems are capable of imaging these locations and T-scores have not been established at these sites. As such, some have suggested using traditional osteoporosis sites as surrogates for the distal femur and proximal tibia. However, BMD changes occur more rapidly at the knee than at other bone sites after SCI [26]. Furthermore, after SCI, aBMD changes at the knee are only moderately correlated with the total hip and femoral neck aBMD and T-scores [26,27] and may not correspond with the degree of bone loss at the hip or femoral neck [28,29,30,31], with significant predictive inaccuracy between the sites that surround the knee and hip [27]. Alternatively, peripheral quantitative computerized tomography (pQCT) yields volumetric (v)BMD of the trabecular and cortical bone compartments and has been used to estimate vBMD fracture thresholds at the distal femur epiphysis (<114 mg/cm3) and distal tibia epiphysis (<71 mg/cm3) in persons with SCI [32]. High-resolution (HR)-pQCT with finite element analysis (FEA) [33] can also measure vBMD, along with the bone microstructural parameters, and can simultaneously model bone tensile properties, providing insight into bone microarchitecture and mechanical alterations that contribute to increased fracture risk after SCI [34,35]. For example, the reduction in proximal femur bone strength that was estimated via FEA was three times greater than the aBMD loss that was determined by DXA over the first few months after SCI [36], likely because DXA cannot discern trabecular vs. cortical BMD nor quantify other bone parameters that influence fracture risk [37]. Regardless, the limited availability of pQCT systems restricts their practicality and highlights the continued need for DXA evaluations to identify fracture risk in persons with SCI.

3. Pathophysiology of SCI-Induced Bone Loss

Within the SCI population, persons with complete paralysis display the most extensive bone loss [9,26] and highest fracture risk [8], likely because the residual voluntary muscle function lessens bone loss. As evidence, persons with incomplete SCI display less bone loss in the lesser impaired limb [38]. Moreover, cast immobilization (a technique that limits muscle contraction and restricts voluntary joint motions) has been shown to worsen bone loss in a rat severe SCI model [39], demonstrating that even a minimal degree of residual muscle contractility that accompanies severe SCI assists in preserving BMD. These observations support the understanding that disuse is a factor mediating SCI-induced bone loss. However, bone loss after SCI is distinct from that which is occurring in response to other disuse conditions in both severity and mechanism. For example, in humans with complete SCI, trabecular and cortical bone loss occurs at a rate nearing 1% per week over the initial few months post-SCI [40], which is 4–10 times faster than in other types of disuse (e.g., prolonged bed rest or microgravity exposure) [41]. Similarly, in rodent SCI models, bone loss is two or more times faster than that resulting from cast immobilization [39] or sciatic neurectomy [42]. These findings suggest that other factors that are occurring secondary to SCI may worsen bone loss, including systemic hormonal changes, altered bone innervation [43], and/or impaired bone perfusion [44]. For further discussion, readers are directed to the following review [4].

4. Bone Turnover after SCI

Bone undergoes continuous remodeling throughout the lifespan, which is balanced during homeostasis via integrated resorption and formation processes that maintain skeletal integrity. However, after severe SCI, a unique form of unopposed bone resorption drives bone loss [4]. As evidence, Minaire et al. examined persons with SCI and observed signs of increased osteoclastic resorption that accompanied a near-absence of surface-level bone formation at the iliac crest [45] that is suggestive of uncoupled bone turnover. Circulating bone resorption markers are also several-fold higher than the upper reference ranges in persons with SCI throughout the acute (10,46,47,48,49,50,51]. Similarly, in rodent models of severe SCI, the use of dynamic histomorphometry has revealed that trabecular bone resorption persists at the distal femur and proximal tibia in the near absence of bone formation throughout the initial one to three-weeks post-SCI [44,52,53,54,55,56,57], when nearly all the trabecular bone loss occurs. Thereafter, trabecular bone formation renormalizes [58,59] and bone loss slows [52].

5. Mechanisms Regulating Bone Loss after SCI

The molecular mechanisms that propagate the uncoupled bone turnover that is present in the paralyzed limbs after SCI and that drive the exceedingly rapid bone loss in this population, in comparison with other disuse conditions, require further elucidation. Given that disuse is a factor that mediates SCI-induced bone loss, it is likely that osteocytes (primary bone mechanosensor) influence neurogenic osteoporosis. Osteocytes reside within the calcified bone matrix and communicate with other osteocytes and with osteoclasts, osteoblasts, and other cells that reside on bone surfaces via dendritic projections that emerge from the osteocyte cell body to form an interconnected dendritic network. Dendrites provide one means by which the osteocytes sense alterations in localized bone strains that result from disuse or imposed loading and transduce this information to the osteocyte cell body, a process that is referred to as mechanotransduction. In response to this stimulus, osteocytes release a host of nuclear-derived signaling molecules (e.g., receptor activator of NF-κB ligand (RANKL), osteoprotegrin (OPG), sclerostin, and others) that orchestrate osteoclastic and/or osteoblastic bone remodeling. Readers are directed to the following reviews that discuss osteocyte mechanosensors and mechanotransduction-associated signaling pathways [60,61].

While it is likely that osteocytes orchestrate the skeletal responses to SCI, few studies have directly assessed this possibility or described how osteocytes respond to paralysis or to imposed bone loading after SCI. Qin et al. observed osteocyte morphological aberrations in rats within seven-weeks of spinal transition, including reductions in the dendritic length and dendritic number, along with altered osteocyte cell body shape [62]. The molecular mechanisms that regulate these morphologic changes require further elucidation. However, administration of a monoclonal sclerostin antibody that binds and inactivates the circulating sclerostin was shown to preserve the dendritic length and osteocyte cell body morphology in this model [62], suggesting potential autocrine regulation. Regardless, it remains unknown whether the osteocyte morphological aberrations that are occurring in the paralyzed limbs produce functional consequences (e.g., impaired ability to detect imposed bone strains) within the dendritic network.

6. RANKL Signaling

RANKL is an osteocyte-derived protein that is necessary for the differentiation of hematopoietic progenitors of the monocyte-macrophage lineage into osteoclasts. RANKL stimulates osteoclastogenesis and bone resorption by binding RANK receptors on the cell surfaces of osteoclast precursors and osteoclasts, respectively [63]. RANKL-mediated osteoclastic resorption is primarily modified in response to secreted concentrations of RANKL and OPG, an endogenous decoy receptor for RANKL that is produced by osteoblast-lineage cells and prevents RANK binding. The relative abundance of RANKL to OPG is a key factor that influences RANKL signaling, with higher RANKL and/or lower OPG stimulating bone resorption and osteoclastogenesis. Readers are directed to the following review for an overview of RANKL signaling in bone biology [63].

Signs of altered RANKL signaling coexist with bone loss in rodent SCI models. For example, cultured bone marrow mesenchymal or stromal cells that were isolated from spinalized mice exhibit higher RANKL and lower OPG vs. the controls, which may underlie the two- to three-fold increase in tartrate-resistant acid phosphatase (TRAP)+ osteoclast-like cells that develop in bone marrow culture that are derived from spinalized mice [64]. Similarly, in rodent SCI models, RANKL mRNA and protein expressions were 75–300% higher and OPG mRNA and protein were 30–75% lower at the distal femur and proximal tibia when compared with the controls. Recently, Cirnigliaro et al. [65] reported that 12-mo treatment with Denosumab, a human monoclonal antibody that binds and antagonizes RANKL activity, completely prevented distal femur and proximal tibia aBMD loss in a small cohort of persons with acute SCI. Gifre et al. reported that Denosumab increased total hip, femoral neck, and lumbar spine aBMD in persons with subacute to chronic SCI [66], with BMD gains being associated with the magnitude of RANKL suppression [67]. Collectively, these data indicate that rodent SCI models display an altered RANKL:OPG ratio in a manner that would be expected to promote bone loss, and that pharmacologic RANKL inhibition prevents aBMD loss at the most fracture prone sites after SCI and increases aBMD at other sites.

Recently, RANK [68] and RANKL [69] have also been identified as functional components of extracellular vesicles (EVs) that are secreted directly from osteoclasts and osteoblasts, respectively, providing a mechanism for intercellular communication [70]. In this regard, RANK in osteoclast-derived EVs can bind osteoblastic RANKL and stimulate a reverse RANKL signaling pathway that promotes bone formation and that couples bone resorption and formation processes [71]. Osteoblast-derived RANKL-containing EVs can also promote osteoclastogenesis in vivo, at least when delivered to transgenic RANKL deficient mice [72]. Given these observations, it is enticing to imagine that the uncoupled bone turnover that is present in the paralyzed limbs after SCI may be influenced by transient alterations in RANK or RANKL containing EVs, although, this remains to be determined.

7. Canonical Wnt/β-Catenin Signaling and Sclerostin

The canonical Wnt/β-catenin signaling cascade promotes bone formation by stimulating osteoblast differentiation and osteoblast growth rate, by inhibiting osteoblast apoptosis, and by stimulating osteoblast activity. This signaling pathway is initiated when the various Wnt ligands (e.g., Wnt1 and Wnt3a) bind the low-density lipoprotein receptor-related protein (LRP)5/6 and Frizzled receptor complex on osteoblasts and prevent the Axin-adenomatous polyposis coli-glycogen synthase kinase 3-casein kinase 1 (APC-GSK-3-Ck1) complex from phosphorylating cytoplasmic β-catenin, which traditionally marks β-catenin for proteasomal degradation. In response, unphosphorylated β-catenin accumulates within the cytoplasm, where it can be shuttled to the nucleus to interact with DNA binding proteins (e.g., TCF/LEF) to promote the activation of Wnt responsive gene transcription pathways [61]. Several negative regulators of Wnt-signaling exist, including sclerostin, which binds the LRP5/6 receptors and prevents Wnt ligands from initiating Wnt-signaling. Sclerostin is known to mediate bone loss that develops in response to unloading [73] and bone gain resulting from imposed skeletal strains, with sclerostin suppression being essential for the osteogenic responses to mechanical loading [74]. Readers are directed to the following review for further discussion on Wnt signaling in bone [61].

Alterations in Wnt signaling accompany bone loss in the paralyzed limbs in rodent SCI models. For example, several proteins that are involved in Wnt signaling (LRP5, Wnt1, and Wnt3) are repressed at the distal femur and proximal tibia within a few weeks of SCI, while the number of osteocytes that stain for sclerostin are increased [75] and SOST (gene encoding sclerostin) is 300% higher. These changes likely influence the 50% lower β-catenin protein expression that has been observed at the proximal tibia after SCI, along with the reduced β-catenin expression that is present in cultured mesenchymal cells that are derived from spinal transected mice. Elevated sclerostin also appears to mediate SCI-induced bone loss, given that SOST-/- mice are protected against bone loss and suppressed osteoblastogenesis after spinal transition [76]. Moreover, a pharmacologic sclerostin antibody that binds and inactivates sclerostin has been shown to completely prevent distal femur and proximal tibia bone loss in rodents when it is delivered immediately after severe incomplete [53] to complete SCI [62] by promoting bone formation, and to reverse trabecular and cortical bone loss when it is delivered after bone loss emerges [77].

8. Activity-Based Physical Therapy (ABPT) after SCI

Given the role of disuse in mediating the musculoskeletal decline after SCI, a large body of research has focused on ABPTs and other exercise-based regimens that reload the impaired limbs to restore muscle integrity [78]. Common ABPTs include overground locomotor training and/or bodyweight-supported treadmill training (BWSTT) that is accompanied by manual or robotic-assisted placement of the impaired limbs into normal gait patterns, passive cycling, or functional electrical stimulation (FES) that is coupled with cycling, rowing, or resistance training (RT). With intense repetitive training, ABPTs are theorized to activate and optimize sublesional spinal networks, enabling the improved performance of task-specific motor activities [79]. For example, BWSTT and other locomotor-based modalities have shown promise in promoting use-dependent neuroplasticity after mild to moderate motor-incomplete SCI and result in improved walking speed, temporal gait parameters, and lower limb muscle activation patterns [80,81,82], along with increased muscle strength and rate of torque development in some persons with incomplete SCI [78]. Structural and functional plasticity likely drives motor recovery resulting from these ABPTs and stems from the reorganization of both supraspinal and spinal cord neural circuits [83,84]. As evidence, beneficial adaptations to spinal neuronal pathways have been observed in response to ABPT by probing soleus Hoffmann reflex during walking in which homosynaptic facilitation normalized, homosynaptic depression reversed, and presynaptic inhibition of Ia afferents improved [83,85,86]. The functional recovery in persons with incomplete SCI undergoing ABPT has also been associated with findings that indicate greater descending corticospinal drive, including increased ankle dorsiflexor and knee extensor maximal motor-evoked potentials, a probe of corticospinal tract excitability [87], and improved ankle dorsiflexor and plantar flexor muscle co-activation patterns during walking [88]. Possible mechanisms underlying ABPT-mediated neuroplasticity may involve the upregulation of brain-derived neurotrophic factor and/or its receptor, tyrosine kinase B mRNA, in the spinal cord, which mediate improvements of synaptic transmission, axon regeneration, and motor neuron survival [89]. For further discussion on this topic, we refer readers to the following review [78].

9. Effects of ABPT and Reloading Modalities on Bone after SCI

In uninjured persons, weight-bearing exercise that produces high peak strains and/or high strain rates increases BMD [90] and prevents disuse-mediated bone loss [91]. In various models, cyclical loading has also been shown to stimulate bone formation and increase bone mass in a manner that is dependent upon the compressive strain that is applied to bone, the loading frequency (Hz), and the loading duration. In contrast, stationary/static loading does not typically alter bone parameters [92]. This knowledge has contributed to an emphasis on ABPTs to increase BMD after SCI [17] and to recommendations from healthcare providers to utilize weight-bearing activities to improve BMD after SCI [93]. However, evidence demonstrating the skeletal benefits of ABPTs is sparse in persons with SCI with several meta-analyses concluding that insufficient evidence exists to establish their effectiveness in improving BMD [94,95]. Likewise, the existing evidence is contradictory when assessing the ability of ABPTs to alter bone turnover in a manner that would be expected to improve BMD after SCI. For example, Bloomfield et al. [96] reported that nine-months of FES cycling increased serum osteocalcin (bone formation marker) >75% in persons with chronic complete SCI. Similarly, Mobarke et al. [97] reported that 12-weeks of BWSTT starting at 50% bodyweight support and progressing to full weight-bearing increased osteocalcin when compared with stretching and RT exercises, while others have reported that six- to eight-months of BWSTT suppressed urinary deoxypyridinoline/creatinine (bone resorption marker) without altering osteocalcin [50]. In comparison, Craven et al. [98] reported that those with chronic incomplete SCI displayed no change in circulating osteocalcin, CTX (bone resorption marker), or sclerostin in response to four-months of FES assisted BWSTT. Similarly, others reported that persons with incomplete to complete SCI exhibit little change in circulating bone formation markers or circulating/urinary bone resorption markers in response to FES-based cycling [30] or RT [51,99], BWSTT [100], seated [101] or standing vibration [102], or a multimodal ABPT regimen [103].

Relatively few preclinical SCI studies have evaluated the possibility that ABPTs alter bone turnover or improve BMD, likely because few preclinical modalities exist to reload the paralyzed limbs. In this regard, Qin et al. developed an implantable electrical stimulation (ES) system that elicited unilateral near-maximal contractions of the paralyzed soleus and plantaris muscles in spinal transected rats, with ES delivered 60 min/day for one-week (40 Hz at 1.5 V, (2 s on/18 s off), 1.5 V) [64]. This brief ES protocol improved plantaris muscle mass but did not alter BMD or bone microstructure when compared with SCI rats not receiving ES. However, ES suppressed circulating CTX by ~50% and reduced the number of osteoclast-like TRAP-positive osteoclasts that develop in ex vivo cultures, suggesting ES suppressed osteoclastogenesis and bone resorption. ES also reversed the suppression of OPG mRNA in ex vivo osteoblast cultures, without altering RANKL mRNA, and suppressed mRNA expression of SOST, along with several other genes that negatively regulate Wnt-signaling. Despite these changes, ES did not reverse the SCI-induced suppression of osteocalcin nor did it alter the reduction in alkaline phosphatase-positive or von Kossa-stained colonies that develop in ex vivo osteoblast cultures that are derived from tibia or femur bone marrow, suggesting that one-week of ES did not stimulate osteoblastogenesis or bone formation. More recently, the same group reported that a four-week ES protocol lessened distal femur and proximal tibia aBMD loss and increased several trabecular and cortical bone microstructural variables at the distal femur and femoral midshaft [104]. This four-week ES protocol also increased the circulating osteocalcin, suggesting an increased whole-body bone formation. However, distal femur mineralizing surface (index of active bone formation), mineral apposition rate (index of osteoblast activity), and surface-level bone formation were similarly suppressed in SCI+ES and SCI groups vs. the controls, providing no direct evidence that ES stimulated bone formation at this site. Furthermore, ES did not prevent the suppression of osteoblastogenesis that resulted from SCI, nor did it increase osteoblast SOST mRNA expression. However, ES reduced the RANKL:OPG mRNA ratio within the hindlimbs, reduced the number of TRAP+ osteoclasts in ex vivo cultures, and produced a 50% reduction in the percentage of trabecular bone that was covered by osteoclasts when compared with the untreated SCI animals, providing evidence of an antiresorptive effect.

Beyond the studies that are described above, we are aware of only a few others assessing bone responses to loading in preclinical SCI models. Zamarioli et al. [105] evaluated two loading protocols in spinal transected rats: (1) ES of the quadriceps and triceps surae muscles [300 µs pulses, 50 Hz (5 s on/15 s off), 20–150 mA, 3 days/week, 30 min/day] and (2) a custom-built bipedal standing frame that resulted in 70% of total body mass being supported by the hindlimbs. Neither modality prevented distal femur or proximal tibia aBMD loss nor lessened the reduction in bone strength at these sites, although, the maximal strength of the lumbar vertebrae increased by ~30% in response to bipedal standing. We have also reported that hindlimb cast immobilization worsened trabecular and cortical bone loss at the distal femur and proximal tibia and reduced the distal femur bone strength in a severe SCI model [39]. In this study, two-weeks of quadrupedal (q)BWSTT reversed the bone loss that resulted from cast immobilization but did not lessen bone loss that resulted directly from SCI. In a follow-up study, three-weeks of qBWSTT was also shown not to attenuate trabecular bone deterioration after SCI [59].

Based on the evidence that is presented above, it remains unknown whether ABPTs that reload the impaired limbs after SCI alter bone turnover in a manner that is sufficient to improve BMD. With the above considered, the next sections summarize the findings of clinical studies that met the following criteria: (1) enrolled adults with incomplete and/or complete SCI and (2) reported BMD at the distal femur or proximal tibia, or BMD or T-scores at other sublesional sites, both before and after an ABPT intervention regardless of other study characteristics. In doing so, we considered several important questions. First, did the study enroll persons with acute to subacute (0–12-months) SCI when bone loss is the most rapid, or during the chronic (>12-month) period when bone loss is more gradual? Secondly, did the study assess the bone changes at the relevant fracture-prone sites after SCI (i.e., distal femur or proximal tibia) or at other bone sites? Thirdly, did the study report that an ABPT attenuated bone loss or increased BMD? We considered trials that reported attenuated bone loss or increased BMD vs. the baseline or a control group to have demonstrated improvement, while those not meeting these criteria were considered to have shown no effect. For studies that combined an ABPT with a pharmacologic intervention, we only discuss the groups that were receiving ABPT alone. Case studies, case series, and cross-sectional studies that did not statistically assess the pre-post differences are discussed from a qualitative perspective.

10. ABPT Interventions and BMD after Acute/Subacute SCI

A visual summary of the studies examining the effects of different ABPT modalities at knee and non-knee sites in acute and subacute SCI is presented in Figure 1A,B. Case studies or case series that enrolled persons in the acute to subacute post-SCI period utilized BWSTT with manual- [50] or robotic-assistance [38], or FES rowing [106]. Of these, none reported increased BMD vs. baseline. Only FES rowing appeared to attenuate the distal femur BMD loss when compared with the expected bone loss rate during the subacute SCI phase [106], while neither BWSTT with manual- [50] or robotic-assistance [38] produced an apparent effect on BMD (Table 1). Using a cross-sectional design, Goemaere et al. [107] also reported that those with incomplete or complete SCI who initiated passive standing during the acute SCI phase displayed less aBMD deficits at the lumbar spine [0% difference (standing) vs. −7.4% (non-standing)] and femoral shaft [−21% (standing) vs. −29.2% (non-standing)] when compared with normative aBMD values that were derived from a non-SCI cohort, although, standing did not appear to attenuate aBMD deficits at the total hip or femoral neck or trochanter.

Figure 1

Summary of the effects of activity-based physical therapy (ABPT) on changes in bone mineral density (BMD) at the knee (distal femur and proximal tibia) or all other sublesional non-knee sites in persons with acute/sub-acute SCI for (A) case studies, case series, and cross-sectional studies or (B) controlled and cohort studies. The total number of studies that reported decreased BMD, no BMD change, attenuated BMD loss, or improved BMD after an ABPT modality are provided in the corresponding bars. Some studies examined both knee and non-knee sites – in these instances, the individual results for knee and non-knee sites were included in each bar. If a study compared more than one modality, the individual results for each modality were included if available. If no studies were found that fit a certain category, the category was omitted from the chart. Overall, most acute studies showed no effect or attenuated BMD loss over time. FES, functional electric stimulation; RT, resistance training; “Standing+” refers to interventions that combined standing modalities with other modalities that increase muscle activation such as FES or vibration.

Table 1

Case studies, case series, and cross-sectional studies evaluating the effects of activity-based physical therapy (ABPT) and/or loading on bone mineral density (BMD) in adults with acute or subacute spinal cord injury (SCI).

Author; Citation;Sample Size/Sex;Group (G): Modality	SCI Level; Severity; Duration	Training Duration;Frequency; Time;Parameters	Skeletal Site Evaluated and Outcomes Reported	Baseline BMD	BMD (% Difference)
CASE STUDIES AND CASE SERIES
		BWSTT
Giangregorio et al. [50]N = 2 M, 3 FBWSTT	C3-C8;AIS B-C;66–170 d	6–8 mo (48 sessions); 2 d/wk;Three 5–15 min bouts/dTraining parameters:0–97% BWSTT, 0.6–2.0 km/h bodyweight support reduced, and speed and duration increased over time	Total body aBMDLumbar spine aBMDProximal femur aBMDDistal femur aBMDProximal tibia aBMDFemur diaphysis vBMDTibia diaphysis vBMD	Baseline1.21 g/cm21.09 g/cm21.03 g/cm21.10 g/cm20.96 g/cm2795 g/cm3796 g/cm3	6–8 mo−2.7%−3.1%−2.9%−13%−4.3%−5.5%−6.2%
Lichy and Groah [38]N = 1 MBWSTT	T4;AIS C;11 wk	3 mo; 3 d/wk; 1 h/dTraining parameters:16–32 kg BWSTT, 1.9–2.5 km/h, bodyweight support reduced and speed increased over time	Lumbar spine aBMDLeft proximal femur aBMDRight proximal femur aBMD	Baseline1.12 g/cm20.92 g/cm2 0.93 g/cm2	5 mo−2.8%−11%−4.0%	1.5 yrs+2.5%−19%−5.0%
		FES
Lambach et al. [106]N = 4 MFES KE/KF RT + FES rowing	C7-T10;AIS A-B;10–16 mo	9–12 mo (90 sessions); 3 d/wk;30–60 min/dTraining parameters:FES RT: 0–120 mA, 40 Hz, 450 µs, 5 s on:1 s offFES Rowing: N/R	Entire cohortDistal femur trabecular vBMDDistal tibia trabecular vBMDAcute cohortDistal femur trabecular vBMDDistal tibia trabecular vBMD	Baseline207 mg/cm3168 mg/cm3169 mg/cm3121 mg/cm3	30 sessions−8.4%−14%−8.1%−19%	60 sessions−5.9%−17%−3.9%−21%	90 sessions−8.2%−19%−3.7%−24%
	Note: Lambach et al. included N = 2 <1 yr and N = 2 chronic SCI. Baseline and % difference BMD values are reported separately for the entire cohort and the subacute SCI cohort. Values for the chronic cohort are in Table 3
CROSS-SECTIONAL STUDIES
Goemaere et al. [107]N = 42 M, 11 FG1: Standing, N = 34 M, 4 FG2: Non-standing, N = 8 M, 7 F	T-L; complete to incomplete;standing began as early as possible after SCI, usually within 3 mo	12–180 mo; 3–7 d/wk; 1 h/dTraining parameters:Long leg braces (N = 20), standing frame (N = 9), or standing wheelchair (N = 9)	G1: L3 aBMDG2: L3 aBMDG1: L4 aBMDG2: L4 aBMDG1: Femur neck aBMDG2: Femur neck aBMDG1: Femur trochanter aBMDG2: Femur trochanter aBMDG1: Total hip aBMDG2: Total hip aBMDG1: Femur shaft aBMDG2: Femur shaft aBMD	BaselineN/RN/RN/RN/RN/RN/RN/RN/RN/RN/RN/RN/R	% uninjured value+0.0%−7.4% †+3.8%−4.7%−25%−25%−27%−30%−30%−31%−21%−29% †

G, Group; BWSTT, bodyweight-supported treadmill training; FES, functional electrical stimulation; RT, resistance training; KE/KF, knee extension/knee flexion; F, female; M, male; C, cervical; T, thoracic; AIS, American Spinal Injury Association Impairment Scale; SCI Duration: time since SCI in relation to start of intervention; aBMD, areal bone mineral density; vBMD, volumetric bone mineral density; min, minute; h, hour; d, day; wk, week; mo, month; N/R, not reported. The % change was reported in individual papers or was manually calculated from the data in tables and/or figures; † indicates a p value of <0.05 between the groups; a lack of symbols indicates no statistical differences that were reported versus the baseline or between the groups.

No trial without a control comparator [103,108] nor any controlled trial [28,31,51,99,109,110,111,112,113,114,115] that enrolled persons in the acute/subacute period reported increased sublesional BMD vs. the baseline, irrespective of the site that was evaluated (Table 2). There were two uncontrolled trials that reported no obvious attenuation of sublesional bone loss after ABPT. Rodgers et al. [108] reported that distal tibia trabecular vBMD was 5.4% lower vs. the baseline in a cohort of persons with subacute or chronic SCI involved in a 12-week FES RT protocol, with the subacute SCI participant displaying the greatest bone loss (−26% vs. the baseline) among all the participants. Astorino et al. [103] also reported that a cohort of persons with acute/subacute SCI or chronic SCI exhibited progressively lower aBMD at most sites that were examined, including the distal femur and proximal tibia, while undergoing a six-month multimodal ABPT regimen that involved lower extremity RT, BWSTT, overground walking, vibration training, and FES cycling. Similarly, 5 of the 11 controlled trials did not detect attenuated sublesional BMD loss at any skeletal site that was examined [51,99,110,111,114]. These trials ranged from 6-weeks to 12-months in duration (training frequency three to five days/week) and used the following modalities: passive unilateral standing [110], BWSTT with standing [114], and FES-based RT [51,99,111]. Of these, only Groah et al. [51] examined BMD at the knee.

Table 2

Uncontrolled and controlled interventional studies evaluating the effects of activity-based physical therapy (ABPT) and/or loading on bone mineral density (BMD) in adults with acute or subacute spinal cord injury (SCI).

Author; Citation;Sample Size/Sex;Group (G): Modality	SCI Level;Severity; Duration	Training Duration; Frequency; Time;Parameters	Skeletal Site Evaluated and Outcomes Reported	Baseline BMD	BMD (% Difference versus Baseline)
UNCONTROLLED INTERVENTIONAL TRIALS
		FES
Rodgers et al. [108]N = 9 M, 3 FFES KE RT	C4-T10; incomplete and complete;0.7–17 yr	12 wk (actual 12–18 wk); 3 d/wk; 30 min/dTraining parameters:100 mA, 35 Hz, 300 µs	Total cohortDistal tibia trabecular vBMDAcute participantDistal tibia trabecular vBMD	Baseline235 mg/cm3400 mg/cm3	12–18 wk−5.4%−26%	Note: vBMD assessed on N = 1 acute and N = 7 chronic SCI. Values = avg of the total and acute cohorts. Chronic cohort data are in Table 4.
		MULTIMODAL
Astorino et al. [103]N = 11 M, 2 FMultimodal ABPT regimen	C4-L1;Complete and incomplete; 1.9 ± 2.7 yr (0.2–9.3 yr)	6 mo;>2 d/wk;2–3 h/dTraining parameters: Individualized protocol that included active assistive exercise, lower extremity, and core RT, upper extremity cycle ergometry, bodyweight supported elliptical training, BWSTT, OGW, vibration training, and/or FES cycling	Total body aBMD Lumbar spine aBMDR Total hip aBMD L Total hip aBMDR Femur neck aBMDL Femur neck aBMDR Femur trochanter aBMDL Femur trochanter aBMDR Distal femur aBMDL Distal femur aBMDR Proximal tibia aBMDL Proximal tibia aBMD	Baseline1.24 g/cm21.27 g/cm20.96 g/cm20.99 g/cm20.98 g/cm20.99 g/cm20.75 g/cm20.79 g/cm20.92 g/cm20.92 g/cm20.88 g/cm20.89 g/cm2	3 mo−1.6% *+3.2% *−3.1% *−4.0% *−2.0% *−3.0% *−2.7%−5.1% *−5.4%−4.4%−3.4%−4.5%	6 mo−2.5% *+4.7% *−6.3% *−7.1% *−5.1% *−4.0% *−6.7% *−8.9% *−11%−7.6%−8.0%−11%	Note: BMD determined on N = 8 <1 yr SCI and N = 5 chronic SCI. Values are avg of the total cohort and were not determined separately for acute and chronic SCI cohorts.
CONTROLLED INTERVENTIONAL TRIALS
		BWSTT
de Bruin et al. [112]N = 13 MG1: BWSTT + standing, N = 4 MG2: Standing, N = 5 MG3: Low activity, N = 4 M	C4-L1; AIS A-D;1–5 wk	6 mo; 5 d/wk; 60 min/dTraining parameters:G1: 20–80% BWSTT (30 min/d), standing (30 min/d),≥5 h/wkG2: Standing, ≥5 h/wkG3: Loading, 0–5 h/wk	Distal tibia + diaphysisG1: Trabecular vBMDG2: Trabecular vBMDG3: Trabecular vBMDG1: Cortical vBMDG2: Cortical vBMDG3: Cortical vBMD	BaselineN/RN/RN/RN/RN/RN/R	6 mo−0.4% †−0.5% †−8.0% †−0.7%−1.1%−0.6%	Note: † indicates statistically significant difference between G1 and G2 vs. G3, when indicated.
Frey-Rindova et al. [114]N = 24 MG1: BWSTT + standing, N = 13 MG2: Low activity, N = 11 M	C4-L1;Frankel A-C;1–4 wk	12 mo; ≥3 d/wk; 30 min/dTraining parameters:G1: Partial bodyweight support, ~1.3 km/hG2: Same parameters performed <3 d/wk or <30 min/d	Distal TibiaG1: Trabecular vBMDG2: Trabecular vBMDG1: Cortical vBMDG2: Cortical vBMD	Baseline316 mg/cm3302 mg/cm3935 mg/cm3910 mg/cm3	6 mo−7%−3%−2%−1%	12 mo−8% *−20% *−6% **−8% **
		STANDING
Alekna et al. [109]N = 44 M, 10 FG1: Standing, N = 22 M, 5 FG2: No standing, N = 22 M, 5 F	C2-L1; AIS A-B;11 ± 3 wk	2 yr; ≥5 d/wk;≥1 h/dTraining parameters:G1: Passive standingG2: No standing	G1: Total body aBMDG2: Total body aBMDG1: Lumbar spine aBMDG2: Lumbar spine aBMDG1: Pelvis aBMDG2: Pelvis aBMDG1: Whole leg aBMDG2: Whole leg aBMD	1.26 g/cm21.26 g/cm21.28 g/cm21.26 g/cm21.18 g/cm21.18 g/cm21.36 g/cm21.38 g/cm2	1 yr−8.9% *−12% *−11%−14%−12%−15%−20% *−24% *	2 yr−11% *−15% *−14%−17%−15% *†−21% *†−25% *††−34% *††
Ben et al. [110]N = 16 M, 4 FG1: Unilateral standing, N = 20G2: Untrained limb, N = 20	N/R; Nonambulatory; 4 ± 2 mo	12 wk; 36 sessions; 30 min/dTraining parameters:G1: Passive unilateral standingG2: No loading	G1: Proximal femur aBMDG2: Proximal femur aBMD	Baseline0.91 g/cm20.91 g/cm2	12 wk−6.1%−6.7%
		FES/NMES
Arija-Blazquez et al. [99]N = 8 MG1: FES RT, N = 5 MG2: SHAM FES, N = 3 M	T4-T12; AIS A;G1: 5.5 ± 1.1 wkG2: 5.8 ± 1.7 wk	14 wk; 5 d/wk;47 min/dTraining parameters:Both: 8 sets × 10 contractionsG1: 0–140 mA, 30 Hz, 200 µsG2: 0 mA, 30Hz, 200 µs	G1: Lumbar spine aBMDG2: Lumbar spine aBMDFemurG1: Total hip aBMDG2: Total hip aBMDG1: Femur neck aBMDG2: Femur neck aBMDG1: Ward triangle aBMDG2: Ward triangle aBMDG1: Trochanter aBMDG2: Trochanter aBMDG1: Intertrochanteric aBMDG2: Intertrochanteric aBMDG1: Whole leg aBMDG2: Whole leg aBMD	Baseline0.91 g/cm21.23 g/cm20.92 g/cm21.08 g/cm20.79 g/cm20.96 g/cm20.65 g/cm20.86 g/cm20.70 g/cm20.83 g/cm21.05 g/cm21.22 g/cm21.19 g/cm21.44 g/cm2	14 wk+3.5%+2.1%−7.0%−0.4%−7.6%−8.3%−6.5%−7.7%−9.9%−8.1%−5.9%−1.0%−2.9%−3.3%
Clark et al. [29]N = 33 (N per sex N/R)G1: FES RT, N = 23G2: Inactive SCI control, N = 10	C4-T12;AIS A-D;3 wk	6 mo; 5 d/wk;30 min/dTraining parameters:G1: 2 × 15 min/d; 4:8 s on:offG2: Inactive control	G1: Total body aBMDG2: Total body aBMDG1: Lower extremity aBMDG2: Lower extremity aBMDG1: Femur neck aBMDG2: Femur neck aBMDG1: Femur proximal aBMDG2: Femur proximal aBMD	BaselineN/RN/RN/RN/RN/RN/RN/RN/R	3 mo−2.2% ††+0.7% ††−2.4%−2.3%−4.5%−3.2%−6.0%−3.7%	6 mo−3.0%−1.9%−7.1%−4.7%−11.6%−6.5%−11%−8.4%
Dudley-Javoroski et al. [113]N = 24 M, 9 F G1: FES standing, N = 6 M, 1 FG2: Passive standing, N = 5 MG3: No standing, N = 13 M, 3 F	C5-T12;AIS A-B;G1: 0.2–2.1 yrG2: 0.2–0.7 yrG3: 0.2–24 yrNote: G2 had N = 5 acute and N = 2 chronic SCI	3 yr; 5 d/wk; 30 min/d Training parameters:G1: FES 10 min/d while unilateral standing, 0–200 mA, 20 Hz, 200 µs, 5:5 s on:off (2 bouts × 60 100-pulse trains), produced 150% bodyweight compressive loadG2: 40% bodyweightcompressive loadG3: 0% BW (no standing)	G1: Distal femur vBMDG2: Distal femur vBMDG3: Distal femur vBMDG1: Proximal tibia vBMDG1: Proximal tibia vBMDG1: Proximal tibia vBMDG1: Distal tibia vBMDG2: Distal tibia vBMDG3: Distal tibia vBMD	BaselineN/RN/RN/RN/RN/RN/RN/RN/RN/R	1 yrvs. G2+30% †+23%+13%	1 yrvs. G3+48% †+29%−11%	3 yrvs. G2+41% †+21%−14%	3 yrvs. G3+102% †+47%−37%
Dudley-Javoroski et al. [116]N = 11 M, 1 F G1: FES standing, N = 6 M, 1 F G2: Passive standing, N = 5 M	C5-T12; AIS A-B;G1: 0.2–2.1 yrG2: 0.2–0.7 yr	3 yr; 3 d/wk; 30 min/dTraining parameters:G1: FES 10 min/d while unilateral standing, 0–200 mA, 20 Hz, 200 µs, 5:5 s on:off (2 bouts × 60 100-pulse trains), produced 150% bodyweight compressive loadG2: 40% bodyweight compressive load	Femur distal (trabecular)G1: Antero-lateral vBMDG2: Antero-lateral vBMDG1: Antero-medial vBMDG2: Antero-medial vBMDG1: Postero-lateral vBMDG2: Postero-lateral vBMDG1: Postero-medial vBMDG2: Postero-medial vBMD	Baseline233 mg/cm3233 mg/cm3188 mg/cm3188 mg/cm3220 mg/cm3220 mg/cm3224 mg/cm3224 mg/cm3	0.25-0.50 yr−1.6%−22%+3.8%−25%+3.3%−20%+6.4%−15%	0.50-0.75 yr−3.5%−19%−1.8%−20%−0.5%−12%+2.4%−9%	0.75-1.0 yr−0.6%−24%+2.3%−26%−4.8%−21%+0.9%−15%	1.0-1.5 yr−12%−19%−9.2%−17%−12%−23%−6.3%−14%
Groah et al. [51]N = 22 M, 4 F G1: FES RT, N = 15 M, 1 FG2: SCI control, N = 7 M, 3 F	>T12; AIS A-B;35.9 ± 23.3 d	6 wk;5 d/wk;1 h/dTraining parameters:G1: 0–125 mA, 25 Hz, 300 µs, 5:5 s on:offG2: Standard of care control	G1: Lumbar spine aBMDG2: Lumbar spine aBMDG1: Total hip aBMDG2: Total hip aBMDG1: Distal femur aBMDG2: Distal femur aBMDG1: Proximal tibia aBMDG2: Proximal tibia aBMD	Baseline1.32 g/cm21.27 g/cm21.19 g/cm21.19 g/cm21.11 g/cm20.96 g/cm21.04 g/cm20.86 g/cm2	6 wk+1.2%−7.2%−1.9%−13%−4.0%−3.5%−0.9%−4.6%	F/U 3 mo −1.3%−1.9%−15%−12%−7.4%−15%−12%−17%
Lai et al. [31]N = 20 M, 4 F G1: FES cycling, N = 10 M, 2 FG2: SCI control, N = 10 M, 2 F	C5-T9; AIS A;26–51 d	3 mo; 3 d/wk; 30 min/dTraining parameters:G1: mA controlled by microprocessor, 20 Hz, 300 µsG2: Control	G1: Femur neck aBMDG2: Femur neck aBMDG1: Distal femur aBMDG2: Distal femur aBMD	Baseline0.93 g/cm20.91 g/cm21.00 g/cm21.00 g/cm2	3 mo−4.6% *−5.1% *−2.2% *†−6.7% *†	F/U 3 mo −9.1% #−9.8% #−9.0% #−14% #
Shields et al. [28]N = 6 (sex N/R)G1: NMES trained limb, N = 6G2: Untrained limb, N = 6	C5-T10; AIS A;0.16–0.35 yr	1.65–3.0 yr; 5 d/wk; 20 min/dTraining parameters:G1: 4 bouts × 120 trains (10 pulse train, 15 Hz, 667 ms every 2 s), 140% bodyweight compressive force on tibia G2: No NMES	G1: Hip aBMDG2: Hip aBMDG1: Proximal tibia aBMDG2: Proximal tibia aBMDBoth: Lumbar spine aBMD	Baseline0.97 g/cm20.96 g/cm20.29 g/cm20.31 g/cm21.10 g/cm2	1.5–6 mo−14%−13%+4% †−8% †−12%	6–12 mo−22% #−22% #−4% #†−17% #†−14%	12–18 mo−36% #−31% #−3% #†−27% #†−13%	18–36 mo−35% #−34%#−17% #†−32%#†−15%
Shields & Dudley-Javoroski [115]N = 7 (sex N/R)G1: NMES trained limb G2: Untrained limb	C5-T10; AIS A;<6 wk	2–3 yr; 5 d/wk; 35 min/dTraining parameters:G1: 0–200 mA at 400 V, 15 Hz, 667 ms, 4 bouts × 10-pulse train every 2 sG2: No NMES	Tibia DiaphysisG1: Cortical vBMDG2: Cortical vBMDTibia Distal EpiphysisG1: Trabecular vBMDG2: Trabecular vBMD	BaselineN/RN/RN/RN/R	2–3 yr % untrained limbN/R–Not differentN/R–Not different+31% vs. untrained

G, group; BWSTT, bodyweight-supported treadmill training; RT, resistance training; NMES, neuromuscular electrical stimulation; FES, functional electrical stimulation; F, female; M, male; C, cervical; T, thoracic; L, lumbar; AIS, American Spinal Injury Association Impairment Scale; SCI Duration, time since SCI in relation to intervention; aBMD, areal bone mineral density; vBMD, volumetric bone mineral density; min, minute; h, hour; d, day; wk, week; mo, month; yr, year; N/R, not reported; F/U, follow-up after intervention complete; Note: % change was reported in individual papers or was manually calculated from data in tables and/or figures; * indicates <0.05, ** <0.01 vs. the baseline; # indicates <0.05 vs. the initial BMD assessment after the baseline; † indicates a p-value of <0.05, †† <0.01 between the marked groups; a lack of symbols indicates no statistical differences that were reported versus the baseline or between groups.

In comparison, 6 of the 11 controlled trials reported that an ABPT attenuated BMD loss at different sublesional sites [28,31,109,112,113,115]. Lai et al. [31] reported that 3-months of FES cycling attenuated aBMD loss at the distal femur (−2.2% from the baseline) as compared to the controls (−6.7% from the baseline). Dudley-Javoroski et al. [113] reported that FES-mediated quadriceps contractions attenuated distal femur vBMD loss in the limb that was undergoing unilateral standing (25% less bone loss at 1-year and 39% less bone loss at three-years vs. the non-stimulated limbs), with a follow-up analysis confirming that FES attenuated trabecular vBMD loss in a roughly similar pattern in the anterior and posterior distal femur quadrants [116]. Shields et al. [28] also reported ~50% less proximal tibia aBMD loss in the leg that underwent >1.6-years of NMES (−17% from the baseline) vs. the untrained leg of the same participant (−32% from the baseline). Additionally, three controlled trials reported attenuated BMD loss at sites other than the knee. Shields and Dudley-Javoroski [115] reported a 31% higher trabecular vBMD at the distal tibia epiphysis in the limb that received FES strengthening 5 days/week for two- to three-years vs. the untrained limb and De Bruin et al. [112] reported that BWSTT or use of standing frames lessened distal tibia trabecular vBMD loss over six-months (−0.4% from the baseline for both interventions) vs. the controls (−8% from the baseline). Lastly, Alekna et al. [109] reported that passive standing (>one hour/day, five days/week, for two-years) lessened aBMD loss vs. controls within the whole leg (−25% vs. −34% from the baseline), and pelvis (−15% vs. −21% from the baseline). Regardless, five of six controlled trials that observed attenuated BMD loss at the sites that were described above also reported no BMD differences in the treatment vs. control groups at other sites [28,31,109,112,115]. Of note, four of six trials that reported attenuated BMD loss utilized FES exercises [28,31,113,115] and two used standing exercise without FES [109,112]. However, a similar number of FES [51,99,111] and standing trials [110,114] observed no improvement in BMD at any site that was evaluated.

11. ABPT Interventions and BMD after Chronic SCI

A visual summary of studies examining the effects of different ABPT modalities at knee and non-knee sites in chronic SCI is presented in Figure 2A,B. Case studies or case series that enrolled participants with chronic SCI ranged from 10-weeks to 8-years in duration, instituted training frequencies of two- to five-days/week, and utilized the following modalities (Table 3): passive standing in a frame that was combined with leg or whole-body vibration [117], overground walking that was assisted by reciprocating gait orthosis [118], BWSTT alone [119] or in combination with epidural electrical stimulation [120] or nerve stimulation [121], or FES-based cycling [122,123] or rowing [124] that was delivered alone or after FES RT [106,125,126]. These reports produced inconsistent results with four case studies [117,121,123,125] and one case series [118] observing an apparent BMD increase ranging from 2–20% vs. the baseline, three case studies [121,122,124] and one case series [120] reporting no clear bone change (<2% change vs. baseline), and two case studies [117,119] and three case series [106,118,126] observing an apparent BMD reduction ranging from 2–21% vs. the baseline, depending on the site that was evaluated. Goktepe et al. [127] also reported no differences in T-scores among persons with chronic SCI who performed ≥one hour/day or 106] reported distal femur trabecular vBMD was ~13% lower in two persons with chronic SCI after 9–12 months of FES RT and rowing, while Coupaud et al. [121] reported inconsistent distal femur and proximal tibia total and trabecular vBMD changes (range: −2.8% to +2.5% vs. the baseline) in a person with chronic SCI who underwent BWSTT with unilateral peroneal nerve stimulation for seven-months. Within a cross-sectional design, Gibbons et al. also reported that a person with chronic SCI displayed 31% higher proximal tibia trabecular vBMD after completing eight-years of FES rowing [124] and 80–125% higher total and trabecular vBMD at the distal tibia after 10-years, [15] when compared with a historical cohort of persons with chronic SCI, although, vBMD remained 7–19% lower in this person compared with uninjured persons. Of note, three of five case studies/series that reported higher BMD vs. a baseline incorporated FES [123,125] or nerve stimulation [121], while four others that utilized FES reported no BMD change [122,124] or reduced BMD vs. the baseline [106,126].

Figure 2

Summary of the effects of activity-based physical therapy (ABPT) on the changes in bone mineral density (BMD) at the knee (distal femur and proximal tibia) or all other sublesional non-knee sites for persons with chronic SCI in (A) case studies, case series, and cross-sectional studies, or (B) controlled and cohort studies. The data are reported as described in Figure 1A,B. Overall, most studies on persons with chronic SCI reported that ABPT did not alter BMD with only four studies reporting improved BMD at the knee. FES, functional electric stimulation; RT, resistance training; “Walking+” refers to interventions that combined walking ABPT with FES or nerve stimulation; “Standing+” refers to interventions that combined standing modalities with other modalities that increase muscle activation such as FES or vibration.

Table 3

Case studies, case series, and cross-sectional studies evaluating the effects of activity-based physical therapy (ABPT) and/or loading on bone mineral density (BMD) or T-scores in adults with chronic spinal cord injury (SCI).

Author; Citation;Sample Size/Sex;Group (G): Modality	SCI Level;Severity;Duration	Training Duration; Frequency; Time;Parameters	Skeletal Site and Outcome Reported	Baseline BMD/T-Score	BMD (% Difference)/T-Score (Actual Change)
CASE STUDIES AND CASE SERIES
		STANDING/VIBRATION
Davis et al. [117]N = 1 FPhase 1: StandingPhase 2: Standing + seated vibrationPhase 3: Standing + standing vibration	T10;N/R;4 yr	Three 10 wk phases with 7 wk break between phases; 3 d/wk Training parameters:Phase 1: Standing 40 min/dPhase 2: Standing 20 min/d + vibration (seated) 20 min/dPhase 3: Standing + vibration (standing) 7 min/dVibration:30–50 Hz, 2.16–5.83 g	Phase 1: Trunk aBMDPhase 1: Whole spine aBMDPhase 1: Pelvis aBMDPhase 2: Trunk aBMDPhase 2: Whole spine aBMDPhase 2: Pelvis aBMDPhase 3: Trunk aBMDPhase 3: Whole spine aBMDPhase 3: Pelvis aBMD	Baseline0.92 g/cm21.21 g/cm20.99 g/cm20.89 g/cm21.19 g/cm20.94 g/cm20.84 g/cm21.12 g/cm20.90 g/cm2	Post Phase 1−8.4% ‡−4.5%−15% ‡N/AN/AN/AN/AN/AN/A	Post Phase 2N/AN/AN/A−5.5% ‡−7.7% ‡−2.2%N/AN/AN/A	Post Phase 3N/AN/AN/AN/AN/AN/A+5.5% ‡+8.3% ‡+1.9%
		BWSTT/OGW
Forrest et al. [119]N = 1 MBWSTT + standing	C6; AIS B;1 yr	9 mo; 35 sessions (8 wk break) then 62 sessions; 1 h/d Training parameters:20–60% BWSTT, 0.83 m/s, bilateral standing, bodyweight support reduced over time	Total body aBMD Total hip aBMDFemur neck aBMDLeg aBMD	Baseline1.30 g/cm21.05 g/cm21.01 g/cm21.34 g/cm2	9 mo−1.5%−21%−18%−6.7%
Ogilvie et al. [118]N = 2 M, 2 FRGO walking	Level N/R;Paraplegia;>1 yr	24–30 mo; 5 d/wk; 3 h/d	Femur neck vBMD	BaselineN/R	6 mo−5.9%	18 mo−1.9%	24 mo+4.2%	30 mo+1.1%
		FES, EES, or NMES
Beck et al. [120]N = 2 MBWSTT + OGW + EES	T3-T6;AIS A;>3 yr	18 mo (6 mo without EES + 12 mo with EES); 3 d/wkTraining parameters:45 min BWSTT + 30 min OGW + ≤3 h/d of EES enabled exercise at home	Left hip T-scoreR hip T-score	Baseline−2.4−2.3	6 mo−0.1−0.1	12 mo+0.1+0.0
Coupaud et al. [121]N = 1 MBWSTT + unilateral peroneal nerve stimulation to left (L) side	T6;AIS C14.5 yr	7 mo; 2–3 d/wk; 15–30 min/dTraining parameters:30% BWSTTUnilateral FES (L side) peroneal nerve: 40 mA, 40 Hz, 117–351 µs	Femur (vBMD)R diaphysis cortical L diaphysis corticalR distal epiphysis total L distal epiphysis total R distal epiphysis trabecularL distal epiphysis trabecularTibia (vBMD)R proximal epiphysis total L proximal epiphysis total R proximal epiphysis trabecularL proximal epiphysis trabecularR diaphysis corticalL diaphysis corticalR distal epiphysis total L distal epiphysis total R distal epiphysis trabecularL distal epiphysis trabecular	Baseline1103 mg/cm31108 mg/cm3198 mg/cm3191 mg/cm3159 mg/cm3147 mg/cm3136 mg/cm3131 mg/cm383.1 mg/cm385.5 mg/cm31122 mg/cm31119 mg/cm3184 mg/cm3169 mg/cm3118 mg/cm3108 mg/cm3	7 mo+0.5%+0.3%+1.2%+1.1%+2.2%+0.5%+0.0%+2.5%+1.1%−2.8%−0.3%−0.3%+2.1% ‡+13% ‡+4.9% ‡+20% ‡
Deley et al. [125]N = 1 FFES RT + FES rowing	T4-T5; AIS A;2 yr	12 mo (3 mo RT, 9 mo rowing); 3 d/wk; 30 min/dTraining parameters:RT: 0–110 mA, 40 Hz, 450 µs, 6:6 s on:offRowing: 40 Hz, 450 µs	Femur neck aBMD	Baseline0.53 g/cm2	12 mo+19%
Dolbow et al. [123]N = 1 FFES cycling	T6; AIS A;2 yr	12 mo; 3 d/wk; 1 h/dTraining parameters:140 mA, 33.3–50 Hz, 250–300 µs, 0.64–1.28 Nm avg resistance, 36–43 rpm	Total body aBMD	Baseline0.93 g/cm2	12 mo+9.5%
Dolbow et al. [122]N = 1 MFES cycling	C4; AIS C;33 yr	56 mo; 3 d/wk;40–60 min/dTraining parameters:120–140 mA, 33.3–35.7 Hz, 250–300 µs, 0.5–2.0 Nm avg resistance, 40–50 rpm	Total body aBMD	Baseline1.02 g/cm2	56 mo−0.6%
Gibbons et al. [124]N = 1 MFES rowing, N = 1 M	G1: T4; AIS A; 13.5 yr	>8 yr; 2–4 d/wk; 15–45 min/dTraining parameters:0–115 mA, 50 Hz, 450 µs	Total hip T-score	T-score−2.3	>8 yr+0.6	Note:Proximal tibia trabecular vBMD values are reported in the cross-sectional study section below.
Lambach et al. [106]N = 4 MFES KE/KF RT + FES rowing	C7-T10;AIS A-B;10–16 mo	9–12 mo (90 sessions);3 d/wk; 30–60 min/d Training parameters:FES RT: 0–120 mA, 40 Hz, 450 µs, 5 s on:1 s offFES Rowing: N/R	Entire cohortDistal femur trabecular vBMDDistal tibia trabecular vBMDChronic cohortDistal femur trabecular vBMDDistal tibia trabecular vBMD	Baseline207 mg/cm3168 mg/cm3245 mg/cm3215 mg/cm3	30 sessions−8.4%−14%−8.8%−8.8%	60 sessions−5.9%−17%−7.9%−13%	90 sessions−8.2%−19%−13%−14%
	Note: Lambach et al. included N = 2 <1 yr and N = 2 chronic SCI. Baseline and % difference values are reported for the entire cohort and the chronic SCI cohort. BMD values for the subacute cohort are in Table 1.
Pacy et al. [126]N = 4 MFES KE RT + FES cycling	T4-T6;AIS A;1–8 yr	10 wk RT; 5 d/wk; 15 min/d then 32 wk cycle; 5 d/wk; 15 min/dTraining parameters:FES RT: 65–90 V, 40 Hz, 300 µs, 6:6 s on:offFES Cycle: 80–125 V, 50 rpm, 0–18.75 W	Distal tibia vBMD	Baseline0.16 g/cm2	42 wk−3.2%
CROSS-SECTIONAL STUDIES
		STANDING
Goktepe et al. [127]N = 60 M, 11 FG1: Standing ≥1 h/d, N = 15 M, 5 FG2: Standing <1 h/d, N = 9 M, 2 FG3: No standing, N = 36 M, 4 F	Level N/R;AIS A-B;All groups:≥1 yr (4.41 ± 2.99 yr)	Duration N/R; daily; G1: ≥1 h/dG2: <1 h/dG3: No standing	G1: L2-L4 T-scoreG2: L2-L4 T-scoreG3: L2-L4 T-scoreG1: Femur neck T-scoreG2: Femur neck T-scoreG3: Femur neck T-scoreG1: Ward triangle T-scoreG2: Ward triangle T-scoreG3: Ward triangle T-scoreG1: Femur trochanter T-scoreG2: Femur trochanter T-scoreG3: Femur trochanter T-scoreG1: Total femur T-scoreG2: Total femur T-scoreG3: Total femur T-score	BaselineN/RN/RN/RN/RN/RN/RN/RN/RN/RN/RN/RN/RN/RN/RN/R	Actual T-score−0.3−0.2+0.1−1.6−2.0−2.0−1.3−1.5−1.5−2.3−2.2−2.5−2.1−2.3−2.4
		FES
Gibbons et al. [124]N = 1 MG1: FES rowing, N = 1 MG2: Historical SCI cohort, N = 9G3: Normative non-SCI, N = 14	G1: T4; AIS A; 13.5 yrG2: C6–T10; AIS A; 6.6 ± 2.8 yr	>8 yr; 2–4 d/wk; 15–45 min/dTraining parameters:0–115 mA, 50 Hz, 450 µs	Proximal tibia trabecular vBMD	BaselineN/R	vs. G2+31%	vs. G3−19%
Gibbons et al. [15]N = 1 MG1: FES rowing, N = 1 MG2: Historical SCI cohort, N = 9G3: Normative non-SCI, N = 22	G1: T4; AIS A; 14 yrG2: T3–T12; AIS A-B; 11.4 ± 9.4 yr	>10 yr; 3 d/wk; 30 min/dTraining parameters:0–115 mA, 50 Hz, 450 µs	Distal tibia total vBMDDistal tibia trabecular vBMD	BaselineN/RN/R	vs. G2+82%+125%	vs. G3−6.5%−15%

G, group; BWSTT, bodyweight-supported treadmill training; RGO, reciprocating gait orthosis; OGW, overground walking; EES, epidural electrical stimulation; NMES, neuromuscular electrical stimulation; FES, functional electrical stimulation; RT, resistance training; F, female; M, male; C, cervical; T, thoracic; AIS, American Spinal Injury Association Impairment Scale; SCI Duration: time since SCI in relation to intervention reported as range, mean ± SD, or mean and (range); aBMD, areal bone mineral density; vBMD, volumetric bone mineral density; avg, average; min, minute; h, hour; d, day; wk, week; mo, month; yr, year; m, meter; N/R, not reported. Note: % change was reported in individual papers or was manually calculated from data in tables and/or figures; ‡ indicates exceeded least significant change; lack of symbols indicates no statistical differences that were reported versus baseline or between the groups.

Inconsistent results also exist in uncontrolled and controlled trials that evaluated the effects of ABPT on bone in persons with chronic SCI. In total, we identified 14 trials without a control comparator group (Table 4), which ranged from 6-weeks to 16-months in duration with a training frequency of two- to seven-days/week and assessed: passive loading in a standing frame [128], standing that was combined with whole body vibration [102], BWSTT alone [100], over ground walking in an exoskeleton [129] or reciprocating gait orthosis [130], a multimodal ABPT regimen (described above) [103], or FES-based overground walking [131], RT [108], cycling [29,30,132], or a combination of RT and cycling [133,134,135]. Three uncontrolled trials reported increased BMD [29,30,134] vs. a baseline at some sublesional sites, while 10 reported no bone change at any sublesional site evaluated [100,102,128,129,130,131,132,133,134,135] and one enrolling persons with acute and chronic SCI observed BMD reductions at most sites assessed [103]. In addition, we identified 10 controlled trials (Table 5) that ranged from 12-weeks to 12-months in duration, utilized a training frequency of three- to five-days/week and evaluated: seated vibration to the lower limbs [101,136], a combined protocol involving BWSTT, overground walking, and RT [97], or FES while undergoing BWSTT [98], RT [137,138], cycling [139], or RT and cycling [96,140] or rowing [141]. A total of two controlled trials reported increased BMD vs. a baseline at select bone sites [96,137] and two indicated higher BMD vs. a control group [97,140], while five reported no difference vs. a baseline or a control group at any site evaluated [98,101,136,138,139] and one acquired but did not report BMD [141].

Table 4

Uncontrolled interventional studies evaluating the effects of activity-based physical therapy (ABPT) and/or loading on bone mineral density (BMD) or T-scores in adults with chronic spinal cord injury (SCI).

Author; Citation;Sample Size/Sex;Modality	SCI Level;Severity; Duration	Training Duration; Frequency; Time;Parameters	Bone Site Evaluated	Baseline BMD/T-Score	BMD (% Difference) T-Score (Actual Change)
		STANDING/VIBRATION
Kunkel et al. [128]N = 6 MStanding	C5-T12;Incomplete and complete;10–39 yr	6 mo (mean ~135 d);45 min twice daily Training parameters:Standing frame	Lumbar spine aBMDFemur neck aBMD	Baseline1.26 g/cm20.51 g/cm2	3 mo−1.6%+18%	6 mo−5.6%+9.8%
Wuermser et al. [102]N = 5 M, 4 FStanding + vibration	AIS A-B; T3-T12;2–27 yr	6 mo; 5 d/wk; 20 min/dTraining parameters:0.3 g, 34 Hz sinusoidal movement of 50 µm w/lower extremities supporting ~86% body weight	Total hip aBMDFemur neck aBMDDistal tibia total vBMDDistal tibia trabecular vBMDDistal tibia cortical vBMD	Baseline0.71 g/cm20.75 g/cm2168 g/cm367.5 g/cm3810 g/cm3	3 mo+0.0%−1.3%−2.8%−2.0%−2.6%	6 mo+1.5%+1.4%−3.1%−6.5%−0.9%	F/U6 mo+2.9%+2.7%−5.0%−7.4%−2.2%
		BWSTT/OGW
Giangregorio et al. [100]N = 11 M, 2 FBWSTT	C4-T12;AIS B-C;1.2–24 yr	12 mo (144 sessions); 3 d/wk;≤3 bouts of 5–50 min eachTraining parameters:0–80% bodyweight support, progressively reduced	Whole body aBMDLumbar spine aBMDProximal femur total aBMDRight distal femur total aBMDRight proximal tibia total aBMD Femur diaphysis total vBMDFemur diaphysis cortical vBMDTibial diaphysis total vBMDTibial diaphysis cortical vBMD	Baseline1.12 g/cm2N/RN/RN/RN/R770 g/cm3848 g/cm3745 g/cm3851 g/cm3	12 mo−2.2%N/R−0.2%+1.7%+1.4%−1.6%−0.8%−2.3%−2.0%
Karelis et al. [129]N = 4 M, 1 FExoskeleton walking	C7-T10; AIS A;7.6 ± 4.6 yr	6 wk; 3 d/wk; 60 min/dTraining parameters:Walking: 27.0 ± 5.4 min/dStanding: 48.4 ± 7.4 min/d	Total body aBMDLeg aBMDTibia diaphysis vBMD	Baseline1.19 g/cm21.11 g/cm2466 mg/cm3	6 wk−1.7%+0.5%+14%
Thoumie et al. [130]N = 6 M, 1 FRGO walking	T2-T10;Severity N/R;15–60 mo	16 mo; 3 d/wk; 2 h/dTraining parameters:RGO walking	Lumbar spine aBMD Femur neck aBMD	Z-score0.771.02	16 mo+0.01−0.06	Note: Z-score was reported without BMD or T-score values
		MULTIMODAL
Astorino et al. [103]N = 11 M, 2 FMultimodal ABPT regimen	C4-L1;Complete and Incomplete; 1.9 ± 2.7 yr (0.2–9.3 yr)	6 mo;>2 d/wk;2–3 h/dTraining parameters: Individualized protocol that included active assistive exercise, lower extremity and core RT, upper extremity cycle ergometry, bodyweight supported elliptical training, BWSTT, OGW, vibration training, and/or FES cycling	Total body aBMD Lumbar spine aBMDR Total hip aBMD L Total hip aBMDR Femur neck aBMDL Femur neck aBMDR Femur trochanter aBMDL Femur trochanter aBMDR Distal femur aBMDL Distal femur aBMDR Proximal tibia aBMDL Proximal tibia aBMD	Baseline1.24 g/cm21.27 g/cm20.96 g/cm20.99 g/cm20.98 g/cm20.99 g/cm20.75 g/cm20.79 g/cm20.92 g/cm20.92 g/cm20.88 g/cm20.89 g/cm2	3 mo−1.6% *+3.2% *−3.1% *−4.0% *−2.0% *−3.0% *−2.7%−5.1% *−5.4%−4.4%−3.4%−4.5%	6 mo−2.5% *+4.7% *−6.3% *#−7.1% *#−5.1% *#−4.0% *−6.7% *#−8.9% *−11%−7.6%−8.0%−11%	Note: BMD determined on N = 8 <1 yr SCI and N = 5 chronic SCI. Values are an average of the total cohort and were not determined separately for acute and chronic SCI cohorts.
		FES
BeDell et al. [133]N = 12 MPhase 1: FES KE RTPhase 2: FES cycling progressionPhase 3a: FES cyclingPhase 3b: FES cycling + armergometry	C5-T12;AIS A;9.7 ± 5.1 yr(3–19 yr)	Phase 1–3a: 34 ± 8 wk; 3 d/wk (actual 2.0 ± 0.3 d/wk); 30 min/d Phase 3b: 25 ± 9 wk;3 d/wk; 30 min/dTraining parameters:10–132 mA, 30 Hz, 400 µs	Lumbar 2–4 aBMDFemur neck aBMDWard’s triangle aBMDFemur trochanter aBMD	Baseline1.27 g/cm20.78 g/cm20.71 g/cm20.61 g/cm2	Phase 3a+1.6%+1.3%+0.0%+4.9%	Phase 3b+5.5%+5.1%−1.4%+0.0%
Chen et al. [29]N = 15 MFES cycling, N = 15 M	C5-T8;AIS A;2.6–15.7 yr	6 mo;5 d/wk;30 min/dTraining parameters:0–120 mA, 20 Hz, 300 µs	L2-L4 spine aBMDFemur neck aBMDDistal femur aBMDProximal tibia aBMDHeel aBMD	Baseline1.05 g/cm20.69 g/cm20.72 g/cm20.55 g/cm20.35 g/cm2	6 mo+0.1%−2.2%+11% *+13% *+3.2%	F/U 6 mo+0.1%−8.7% #−1.4% #−1.6% #−6.6% #
Frotzler et al. [134]N = 10 M, 2 FFES RT + cycle	T3-T12;AIS A;3.6–25.5 yr	12 mo (actual: 19 ± 2.1 mo); FES RT: 3–4 d/wk for 3 mo; 30–60 min/d; FES cycle: 5 d/wk for 9 mo; 60 min/dTraining parameters:FES RT: 80–150 mA, 50 Hz, 300–400 µs, 5 s on/offFES cycles: 50 Hz, 0–500 µs	FemurDiaphysis cortical vBMD Distal epiphysis total vBMD Distal epiphysis trabecular vBMD TibiaProximal total vBMDProximal trabecular vBMD Diaphysis cortical vBMD Distal total vBMDDistal trabecular vBMD	Baseline1102 mg/cm3158 mg/cm3122 mg/cm3124 mg/cm371.6 mg/cm31112 mg/cm3166 mg/cm3101 mg/cm3	6 mo−0.4% *+5.3%+9.3%−0.7%−2.8%+0.7%−0.7%−0.8%	12 mo−0.4% *+6.7% *+13% *−1.6%−3.4%+0.8%+0.3%+0.2%
Griffin et al. [132]N = 13 M, 5 FFES cycling	C4-T7; Complete-Incomplete; 2–53 yr	10 wk; 2–3 d/wk; 30 min/dTraining parameters:0–140 mA, 50 Hz, 49 rpm	Total body bone mass	Baseline6.03 lbs	10 wk−0.66%	Note: Data are bone mass (lbs), BMD not reported.
Leeds et al. [135]N = 6 MFES KE RT + FES cycling	C4-C6; AIS A;2–9 yr	1 mo RT; 3 d/wk; up to 45 KEthen 6 mo cycle; 3 d/wk; up to 30 min/dTraining parameters: 0–130 mA, ≤220 V, 30–60 Hz, 350 µs	Femur neck aBMDWard’s triangle aBMDTrochanter aBMD	Baseline0.65 g/cm20.52 g/cm20.46 g/cm2	6 mo−1.5%+0.0%−6.5%
Mohr et al. [30]N = 8 M, 2 FFES cycle	C6-T4;Complete;12.5 ± 2.7 yr (2–24 yr)	3 d/wk for 12 mo, then 1 d/wk for 6 mo; 30 min/dTraining parameters:0–130 mA, 30 Hz, 350 ms, 50 rpm	Femur neck aBMDLumbar spine aBMD Proximal tibia aBMD	Baseline0.63 g/cm21.21 g/cm20.49 g/cm2	12 mo−3.2%+0.8%+10% *	18 mo−13%+1.7%−2.0%
Needham-Shropshire et al. [131]N = 13 M, 3 FFES + OGW	T4-T11; AIS A;>6 mo3.8 yrs (avg)	20 wk; 3 d/wk; ≤120 min/dTraining parameters:0–300 mA, 24 Hz, 150 300 µs	G1: Femur neck aBMDG1: Ward’s triangle aBMDG1: Femur Trochanter aBMD	Baseline0.77 g/cm20.69 g/cm20.58 g/cm2	12 wk−1.3%−1.5%−1.7%	20 wk−1.3%−1.5%0%
Rodgers et al. [108]N = 9 M, 3 FFES KE RT	C4-T10; incomplete and complete;0.7–17 yr	12 wk/36 bouts (actual 12–18 wk); 3 d/wk (actual 2.5 d/wk); 30 min/dTraining parameters:100 mA, 35 Hz, 300 µs	Total cohortDistal tibia trabecular vBMDChronic cohortDistal tibia trabecular vBMD	Baseline235 mg/cm3214 mg/cm3	12–18 wk−5.4%−2.9%	Note: BMD determined on N = 1 <1 yr and N = 7 chronic SCI. Values are an average of total and chronic cohorts. Acute cohort data are in Table 2.

BWSTT, bodyweight-supported treadmill training; RGO, reciprocating gait orthosis; FES, functional electrical stimulation; RT, resistance training; OGW, overground walking; F, female; M, male; C, cervical; T, thoracic; L, lumbar; AIS, American Spinal Injury Association Impairment Scale; SCI Duration: time since SCI in relation to intervention reported as range, mean ± SD, or mean and (range); aBMD, areal bone mineral density; vBMD, volumetric bone mineral density; avg, average; min, minute; h, hour; d, day; wk, week; mo, month; yr, year; N/R, not reported; F/U, follow-up after intervention complete; Note: % change was reported in individual papers or was manually calculated from data in tables and/or figures; * indicates a p-value of <0.05 vs. the baseline; # indicates <0.05 vs. the initial BMD assessment after the baseline; a lack of symbols indicates no statistical differences that were reported versus the baseline or between groups.

Table 5

Controlled interventional studies evaluating the effects of activity-based physical therapy (ABPT) and/or loading on bone mineral density (BMD) or T-scores in adults with chronic spinal cord injury (SCI).

Author; Citation; Sample Size/Sex; Group (G): Modality	SCI Level; Severity; Duration	Training Duration; Frequency; Time; Parameters	Skeletal Site Evaluated and Outcomes Reported	Baseline BMD/T-Score	BMD (% Difference) T-Score (Actual Change)
		VIBRATION
Dudley-Javoroski et al. [136]N = 4 M, 2 FG1: Unilateral seated vibrationG2: Untrained limb	C7-T8;AIS A-B;3.8–14.7 yr	12 mo; 3 d/wk; 20 min/dTraining parameters:0.6 g, 30 Hz, 10–15% body weight loading	G1: Distal femur (14–16%) vBMDG2: Distal femur (14–16%) vBMDG1: Distal femur (8–10%) vBMDG2: Distal femur (8–10%) vBMDG1: Distal femur (4–6%) vBMDG2: Distal femur (4–6%) vBMDG1: Distal tibia (4–6%) vBMDG2: Distal tibia (4–6%) vBMDG1: Distal tibia (8–10%) vBMDG2: Distal tibia (8–10%) vBMDG1: Distal tibia (14–16%) vBMDG2: Distal tibia (14–16%) vBMD	Baseline43.9 mg/cm370.8 mg/cm345.5 mg/cm337.0 mg/cm363.7 mg/cm354.4 mg/cm3124 mg/cm3105 mg/cm3106 mg/cm3105 mg/cm395.9 mg/cm3116 mg/cm3	12 mo−28%−56%−5.2%−16%+2.9%−2.9%−18%−4.8%−24%−26%−13%−3.2%	Note: vBMD was assessed at multiple sites at the distal femur and proximal tibia. Skeletal sites are listed as the distance from the distal end of the femur or the proximal end of the tibia, as a % of whole bone length.
Edwards et al. [101]N = 47 M, 14 FG1: Seated vibration, N = 14 M, 6 FG2: Teriparatide, M = 17 M, 3 FG3: Vibration + teriparatide, N = 16 M, 5 F	C-L;AIS A-D;19 ± 13.8 yr	12 mo;Training frequency N/R;10 min/dTraining parameters:0.5 g, 30 Hz	G1: Lumbar spine aBMDG2: Lumbar spine aBMDG3: Lumbar spine aBMDG1: Total hip aBMDG2: Total hip aBMDG3: Total hip aBMDG1: Femur neck aBMDG2: Femur neck aBMDG3: Femur neck aBMDG1: Proximal femur aBMDG2: Proximal femur aBMDG3: Proximal femur aBMDG1: Distal femur aBMDG2: Distal femur aBMDG3: Distal femur aBMDG1: Proximal tibia aBMDG2: Proximal tibia aBMDG3: Proximal tibia aBMDFemur (vBMD)G1: Epiphyseal trabecular vBMDG2: Epiphyseal trabecular vBMDG3: Epiphyseal trabecular vBMDG1: Metaphyseal trabecular vBMDG2: Metaphyseal trabecular vBMDG3: Metaphyseal trabecular vBMDTibia (vBMD)G1: Epiphyseal trabecular vBMDG2: Epiphyseal trabecular vBMDG3: Epiphyseal trabecular vBMDG1: Metaphyseal trabecular vBMDG2: Metaphyseal trabecular vBMDG3: Metaphyseal trabecular vBMD	Baseline1.00 g/cm21.04 g/cm21.02 g/cm20.63 g/cm20.66 g/cm20.64 g/cm20.63 g/cm20.66 g/cm20.62 g/cm20.45 g/cm20.50 g/cm20.50 g/cm20.62 g/cm20.59 g/cm20.61 g/cm20.47 g/cm20.44 g/cm20.49 g/cm270 mg/cm350 mg/cm350 mg/cm320 mg/cm300 mg/cm300 mg/cm350 mg/cm330 mg/cm330 mg/cm320 mg/cm300 mg/cm300 mg/cm3	12 mo+1.7%+5.5%+4.8%*+0.6%+0.9%+0.4%−0.1%−0.6%+1.7%+2.8%+2.8%−0.5%−0.2%+0.5%−0.6%+2.7%+4.8%−0.4%+10%−24%−14%+16%−42%−29% *−68%−85%−33%−85%−30%−74%
		BWSTT/OGW
Mobarake et al. [97]N = 17 MG1: BWSTT + OGW + RT, N = 10 M G2: OGW + RT, N = 7 M	Level N/R;AIS B-C;>6 mo	12 wk; 4 d/wk; 60 min/dTraining parameters:G1: 0–50% BWSTT, bodyweight support reduced over time, 0.3 km/hG2: OGW and RT	G1: Femur neck aBMDG2: Femur neck aBMDG1: Lumbar spine aBMDG2: Lumbar spine aBMD	Baseline0.78 g/cm20.75 g/cm20.89 g/cm20.85 g/cm2	12 wk+17% ††+1.3%+9.0% ††+1.2%
		FES
Belanger et al. [137]N = 22 M, 6 FG1: FES KE PRT limb, N = 11 M, 3 FG2: FES KE no PRT limb, N = 11 M, 3 FG3: Normative non-SCI, N = 11 M, 3 F	C5-T5;AIS A-C;1.2–23 yr	24 wk; 5 d/wk; 1 h/dTraining parameters:10–150 mA, 25 Hz, 300 µs, 5 s on:off	G1: Distal femur aBMDG2: Distal femur aBMDG3: Distal femur aBMDG1: Proximal tibia aBMDG2: Proximal tibia aBMDG3: Proximal tibia aBMDG1: Tibia diaphysis aBMDG2: Tibia diaphysis aBMDG3: Tibia diaphysis aBMD	Baseline0.7 g/cm20.5 g/cm20.4 g/cm20.5 g/cm20.4 g/cm20.3 g/cm21.5 g/cm21.1 g/cm21.1 g/cm2	24 wk+18% *+18% *N/R+15% *+15% *N/R+0.0%+0.0%N/R	Note: Post-training BMD change was not different between G1 and G2. % difference is an average change for G1 and G2 combined.
Bloomfield et al. [96]N = 10 M, 7 FG1: FES KE RT + cycling, N = 5 M, 4 FG2: SCI controls, N = 5 M, 3 F	G1: C5-T7; Frankel A-B;6 ± 1.2 yrG2: C4-T12; Frankel A-B; 8.3 ± 2.3 yr	5.9 ± 1.0 wk FES KE RT6 mo FES cycling (80 sessions); 3 d/wk; 30 min/dTraining parameters:0–130 mA, 30 Hz, 350 ms, 50 rpm	G1: Lumbar spine aBMDG2: Lumbar spine aBMDG1: Femur neck aBMDG2: Femur neck aBMDG1: Distal femur aBMDG2: Distal femur aBMDG1: Proximal tibia aBMDG2: Proximal tibia aBMD	Baseline1.23 g/cm21.28 g/cm20.80 g/cm20.70 g/cm20.47 g/cm20.52 g/cm20.36 g/cm20.39 g/cm2	3 mo+1.6%+2.4%−2.1%−1.9%+6.8%+2.1%−2.8%−0.3%	6 mo+1.4%+0.4%−2.0%−1.7%+4.9%−2.3%−5.3%−3.9%	9 mo+3.8% *N/R−3.9%N/R+10%N/R+4.2%N/R
Craven et al. [98]N = 34 MG1: BWSTT + FES, N = 14 M, 3 FG2: Aerobic + RT, N = 12 M, 5 F	C2-T12; AIS C-D; ≥18 moG1: 5 ± 6.6 yrG2: 5 ± 18 yr	4 mo; 3 d/wk; 45 min/dTraining parameters:G1: 8–125 mA, 20–50 Hz, 0–250−300 µsBWSTT individualized bodyweight support reduced and speed increased as training progressedG2: 20–25 min aerobic exercise (arm or leg cycling, walking in parallel bars or on treadmill), 2–3 sets of 12–15 reps RT for muscles capable of voluntary contraction	G1: Total hip aBMDG2: Total hip aBMDG1: Distal femur aBMDG2: Distal femur aBMDG1: Proximal tibia aBMDG2: Proximal tibia aBMDG1: Tibial diaphysis cortical vBMDG2: Tibial diaphysis cortical vBMDG1: Tibial diaphysis trabecular vBMDG2: Tibial diaphysis trabecular vBMDG1: Distal tibia trabecular vBMDG2: Distal tibia trabecular vBMD	Baseline0.89 g/cm20.86 g/cm20.89 g/cm20.81 g/cm20.71 g/cm20.68 g/cm21089 g/cm31107 g/cm387.7 g/cm388.5 g/cm3202 g/cm3171 g/cm3	4 mo−2.2%+1.2%−2.2%−2.4%+0.0%−4.3%−0.1%+0.5%+4.0%−0.3%−6.4%−3.5%	F/U12 mo−1.1%+4.7%−2.2%+0.0%−2.8%−1.4%−0.6%+0.5%+1.7%+6.5%−0.5%+4.6%
Hangartner et al. [140]N = 30 M, 7 F (sex N/R for groups)G1: FES KE RT or FES cycling, N = 15G2: SCI control, N = 22	C5-T10;Severity N/R;0.3–15.4 yr	12 wk cycles [n = 9 underwent 1, 2 (n = 3), 3 (n = 2), 4 (n = 1) additional 12 wk blocks]; 3 d/wk; 30 min/dTraining parameters:FES KE: 25% max weight, 2 sets x 30 reps, 5 min rest, then 12.5% max weight, 60 reps or to fatigueFES Cycle: 80–130 mA, 35 Hz, 375 µs, 50 rpm,0–36.4 W power output	G1: Proximal tibia cortical vBMDG2: Proximal tibia cortical vBMDG1: Proximal tibia sub-cortical vBMD G2: Proximal tibia sub-cortical vBMDG1: Proximal tibia trabecular vBMDG2: Proximal tibia trabecular vBMDG1: Distal tibia cortical vBMDG2: Distal tibia cortical vBMDG1: Distal tibia sub-cortical vBMDG2: Distal tibia sub-cortical vBMDG1: Distal tibia trabecular vBMDG2: Distal tibia trabecular vBMD	BaselineN/RN/RN/RN/RN/RN/RN/RN/RN/RN/RN/RN/R	Per Yr+0.2%+1.0%+3.4% †+1.7% †+2.8% ††+2.7% ††	Note: % difference represents the estimated % less bone loss occurring per year in G1 vs. G2. For example, 0.2% indicates that G1 exhibited an estimated 0.2% less bone loss per yr when compared with G2. Study included N = 2 <1 yr and N = 13 chronic SCI. Values not available for acute/subacute vs. chronic.
Johnston et al. [139]N = 14 M, 3 F (sex N/R for groups)G1: FES cycling high cadence, N = 8G2: FES cycling low cadence, N = 9	C4-T6;AIS A-B;12 ± 10 yr (1–27.5 yr)	6 mo; 3 d/wk; 1 h/dTraining parameters:FES: 0–140 mA, 33 Hz, 250 µs against increasing resistanceG1: 50 rpmG2: 20 rpm	G1: Distal femur aBMDG2: Distal femur aBMD	Baseline0.80 g/cm20.67 g/cm2	6 mo−13%−6.0%
Morse et al. [141]N = 18M, 2F (sex N/R for groups)G1: FES RT + rowing + ZA, N = 10G2: FES RT + FES rowing, N = 10	C4 or lower;AIS A-C;11.6 ± 12.7 yr (0.4–37.9 yr)	FES RT: 2–12 wk; 3–5 d/wkFES ROW: 12 mo; 3 d/wk (actual 1.6 ± 0.1 d/wk);30 min/dTraining parameters:FES RT: 0–110 mA, 40 Hz, 450 ms, 6 s per contractionRow: 40 Hz, 450 ms	G1: Total hip aBMDG2: Total hip aBMDG1: Femur neck aBMDG2: Femur neck aBMDG1: Distal femur aBMDG2: Distal femur aBMDG1: Proximal tibia aBMDG2: Proximal tibia aBMD	Baseline0.77 g/cm20.82 g/cm20.82 g/cm20.85 g/cm20.76 g/cm20.83 g/cm20.76 g/cm20.82 g/cm2	12 moN/RN/RN/RN/RN/RN/RN/RN/R	Note: BMD determined on N = 2 <1 yr and N = 18 chronic SCI. Values are the average of the total cohort. Data on acute/subacute versus chronic SCI was not reported.
Shields et al. [138]N = 4 MG1: FES RT trained limbG2: Untrained limb	T1-T7;AIS A;2–12 yr	6–11 mo; 5 d/wk; 30 min/dTraining parameters:0–200 mA, 400 V, 10-pulse train (15 Hz, 667 ms) every 2 s, 125 total trains, 89–116% bodyweight compressive load	G1: Proximal tibia aBMDG2: Proximal tibia aBMD	Baseline0.20 g/cm20.21 g/cm2	6–11 mo+3.1%−6.9%

G, group; BWSTT, bodyweight-supported treadmill training; FES, functional electrical stimulation; RT, resistance training; PRT, progressive resistance training; OGW, overground walking; ZA, zoledronic acid; F, female; M, male; C, cervical; T, thoracic; L, lumbar; AIS, American Spinal Injury Association Impairment Scale; SCI Duration: time since SCI in relation to intervention reported as range, mean ± SD, or mean and (range); aBMD, areal bone mineral density; vBMD, volumetric bone mineral density; min, minute; h, hour; d, day; wk, week; mo, month; yr, year; N/R, not reported; Note: % change was reported in individual papers or was manually calculated from data in tables and/or figures; * indicates a p-value of <0.05 vs. the baseline; † indicates <0.05, †† <0.01 between the groups; a lack of symbols indicates no statistical differences were reported versus the baseline or between the groups.

In total, five uncontrolled [13,29,30,100,103] and nine controlled trials [96,98,101,136,137,138,139,140,141] evaluated distal femur and/or proximal tibia BMD. Most of these studies reported neither an attenuation of BMD loss nor increased BMD at areas surrounding the knee [96,98,100,101,103,136,138,139,141]. However, a small subset of these trials reported improved BMD at the knee, with each study using FES-based RT and/or cycling [29,30,134,137,140]. For example, the distal femur and/or proximal tibia aBMD increased 10–15% vs. the baseline in studies that utilized 6–18 months of FES knee extension RT (distal femur: +18%, proximal tibia: +15%) [137] or cycling (distal femur: +11%, proximal tibia: +10–13%) [29,30]. Similarly, the total and trabecular vBMD at the distal femur were improved 7% to 13% vs. the baseline, respectively, in a study that utilized three-months of FES knee extension RT followed by nine-months of FES cycling [134], suggesting that trabecular bone responds more robustly to FES than cortical bone. In this regard, Hangartner et al. reported that 12-weeks of FES knee extension RT followed by 12- to 36-weeks of FES cycling produced an estimated 3.3% less proximal tibia trabecular vBMD loss per year when compared with non-exercised controls, while no apparent cortical vBMD improvement existed [140]. A total of two trials that incorporated bodyweight-supported [97] or full weight-bearing activity without FES [103] also observed an increased aBMD at sites other than the knee. Mobarake et al. [97] reported that a 12-week BWSTT regimen increased the lumbar spine and femoral neck aBMD by +9% and +17% from the baseline, respectively, vs. a +1.2–1.3% change for the controls. Similarly, Astorino et al. [103] reported that a six-month multimodal ABPT regimen increased lumbar spine aBMD by +4.7% vs. the baseline. However, as indicated above, seven trials that assessed FES-based modalities [108,132,133,135,138,139,141] and several that incorporated standing without FES [102,128] or exoskeleton/assisted walking/BWSTT without FES [100,129,130] reported no BMD improvement, irrespective of the site that was examined.

12. Common Parameters to Improve BMD after SCI

Several common parameters existed among studies that reported improved proximal tibia or distal femur BMD or increased BMD at other sites. First, studies that reported attenuated BMD loss at the knee all enrolled persons with acute/subacute SCI and used FES-based modalities that were performed 3–5 days/week, 20–60 min/day, for ≥3-months [28,31,106,113] and studies reporting increased BMD at the knee all enrolled persons with chronic SCI and used FES-based regimens performed 3–5 days/week, 30+ min/day, for ≥6-months [29,30,134,137]. Second, no study that incorporated standing without FES observed improvements in the distal femur or proximal tibia BMD, although, some that utilized these regimens 3–7 days/week, 60+ min/day, for >3-months reported attenuated BMD loss [107,109,112] or increased BMD at other sites [97,103]. These observations highlight the need to target ABPTs to the specific region(s) where BMD improvements are most warranted and to use a training intensity, frequency, and duration that is sufficient to improve BMD. Regardless, it is important to reiterate that not all FES modalities or passive/active standing regimens that met these criteria produced BMD improvements. For example, Clark et al. [111] and Arija-Blazquez et al. [99] reported that FES-based RT regimens lasting 14-weeks to 5-months (performed 5-days/week for 30+ min/day) did not attenuate sublesional aBMD loss in persons with acute/subacute SCI and other FES studies that met the chronic criteria reported no BMD improvement at the distal femur or proximal tibia [96,138,139], or at other skeletal sites [108,131,135].

Several other factors that were associated with BMD improvements were also identified. First, higher total work output was associated with greater BMD gain. For example, Lambach et al. [106] reported that a higher magnitude of loading and more weekly training sessions were both associated with less trabecular vBMD loss at the proximal femur in persons that were undergoing FES rowing, and Draghici et al. [142] reported that total distance rowed and peak foot reaction force were positively associated with the preservation of the distal tibia trabecular thickness in persons that were undergoing FES rowing, when these factors and SCI duration were incorporated into stepwise regression models. Similarly, Bloomfield et al. [96] reported that distal femur aBMD was improved (+17.8% vs. the baseline) in a subgroup of persons who achieved power outputs >18 watts (W) during FES cycling, while aBMD was not improved in those with lower power output (<12 W, BMD change +0.2%) or in non-exercising controls (−2.3% vs. the baseline) and Frotzler et al. [134] reported that FES cycling improved the total and trabecular vBMD at the distal femur with participants averaging ~18 W power output. Regardless, 18 W may be difficult to sustain for many persons with SCI. As evidence, Eser et al. [143] reported that power outputs ranged from 10.8 to 13.6 W in persons with acute SCI who completed an average of 47 FES cycling bouts, with higher FES frequency producing higher power outputs. Of these participants, less than one-third achieved an average power output >18 W. Second, a continued training stimulus is required to maintain BMD if skeletal improvements are achieved. As evidence, in two studies that reported FES increased aBMD vs. the baseline, a regression of BMD to the baseline occurred after a six-month period involving no FES cycling [29] or once weekly FES [30].

13. Future Directions

As discussed above, only limited evidence supports the notion that ABPTs attenuate BMD loss in persons with acute/subacute SCI or increase BMD in the paralyzed limbs after chronic SCI, especially when considering the most fracture-prone sites that surround the knee. Moreover, few studies have evaluated whether ABPTs improve trabecular or cortical bone microstructure at the distal femur or proximal tibia (Table 6) and none have assessed whether the potential BMD gains or bone microstructural changes mitigate the fracture risk. Interestingly, Fang et al. [144] and Edwards et al. [101] both used FEA to predict the bone mechanical characteristics in response to 12-months of FES rowing or seated vibration, respectively, and observed no tensile or compressive strength improvements at the distal femur or proximal tibia. However, neither study observed BMD or bone microstructural changes at areas surrounding the knee in response to the respective modalities. Given these observations, we suggest future research focuses on optimizing the FES parameters to improve the distal femur and proximal tibia bone parameters, with emphasis on the following questions:

Table 6

Interventional studies evaluating the effects of activity-based physical therapy (ABPT) and/or loading on bone microstructural in adults with subacute and/or chronic spinal cord injury (SCI).

Author; Citation;Sample Size/Sex;Group (G): Modality	SCI Level;Severity; Duration	Training Duration; Frequency; Time;Parameters	Skeletal Site Evaluated and Outcomes Reported	Baseline Values	% Difference
		FES
Craven et al. [98]N = 34 MG1: BWSTT + FES, N = 14 M, 3 FG2: Aerobic training + RT, N = 12 M, 5F	C2-T12; AIS C-D; ≥18 moG1: 5 ± 6.6 yrG2: 5 ± 18 yr	4 mo; 3 d/wk; 45 min/dTraining parameters:G1: 8–125 mA, 20–50 Hz, 0–250−300 µsBWSTT individualized bodyweight support reduced and speed increased as training progressedG2: 20–25 min aerobic exercise (arm or leg cycling, walking in parallel bars or on treadmill), 2–3 sets of 12–15 reps RT for muscles capable of voluntary contraction	Tibial DiaphysisG1: Cortical thicknessG2: Cortical thickness	Baseline3.88 mm4.14 mm	4 mo−1.3%+1.7%	F/U 12 mo−5.2%−1.4%
Johnston et al. [139]N = 14 M, 3 F (sex N/R for groups)G1: FES cycling high cadence, N = 8G2: FES cycling low cadence, N = 9	C4-T6;AIS A-B;12 ± 10 yr (1–27.5 yr)	6 mo; 3 d/wk;1 h/dTraining parameters:FES: 0–140 mA, 33 Hz, 250 µs against increasing resistanceG1: 50 rpmG2: 20 rpm	Distal FemurG1: Trabecular bone volumeG2: Trabecular bone volumeG1: Trabecular numberG2: Trabecular numberG1: Trabecular thicknessG1:Trabecular thicknessG1: Trabecular spacingG2: Trabecular spacingG1: Cortical bone volumeG2: Cortical bone volume	Baseline19.2%21.1%1.17/mm1.08/mm0.179 mm0.171 mm0.71 mm0.85 mm50.7 mm350.5 mm3	6 mo−2.8%+3.3%−2.6%+4.6%−1.1%+0.0%+2.8%−9.4%−3.4%−0.8%
Morse et al. [141]N = 18 M, 2 F (sex N/R for groups)G1: FES RT + rowing + ZA, N = 10G2: FES RT + rowing, N = 10	C4 or lower;AIS A-C;11.6 ± 12.7 yr (0.4–37.9 yr)	FES RT: 2–12 wk; 3–5 d/wkFES Row: 12 mo; 3 d/wk (actual 1.6 ± 0.1 d/wk);30 min/dTraining parameters:FES RT: 0–110 mA, 40 Hz, 450 ms, 6 s per contractionFES row: no ramp, 40 Hz, 450 ms	Distal FemurG1: Cortical bone volumeG2: Cortical bone volumeG1: Cortical thicknessG2: Cortical thicknessProximal TibiaG1: Cortical bone volumeG2: Cortical bone volumeG1: Cortical thicknessG2: Cortical thickness	Baseline12.5 cm311.9 cm30.3 mm0.3 mm13.2 cm313.3 cm30.13 mm0.14 mm	12 mo+1.7% †+1.4%+0.3%−1.0%+0.1% ††−5.7%+0.0%−7.0%
		STANDING/VIBRATION
Dudley-Javoroski et al. [136]N = 4 M, 2 FG1: Unilateral seated vibrationG2: Untrained limb	C7-T8;AIS A-B;3.75–14.7 yr	12 mo;3 d/wk;20 min/dTraining parameters:0.6 g, 30 Hz, 10–15% body weight loading	Distal Femur (14–16% length)G1: Trabecular thicknessG2: Trabecular thicknessDistal Femur (8–10% length)G1: Trabecular thicknessG2: Trabecular thicknessDistal Femur (4–6% length)G1: Trabecular thicknessG2: Trabecular thicknessDistal Tibia (4–6% length)G1: Trabecular thicknessG2: Trabecular thicknessDistal Tibia (8–10% length)G1: Trabecular thicknessG2: Trabecular thicknessDistal Tibia (14–16% length)G1: Trabecular thicknessG2: Trabecular thickness	Baseline0.205 mm0.241 mm0.101 mm0.088 mm0.133 mm0.124 mm0.126 mm0.129 mm0.129 mm0.127 mm0.547 mm0.341 mm	12 mo−52%−56%+20%+23%−14%−7.7%−2.1%−5.8%+1.1%+8.9%−1.2%+41%
Edwards et al. [101]N = 47 M, 14 FG1: Seated vibration, N = 14 M, 6 FG2: TA, M = 17 M, 3 FG3: Seated vibration + TA, N = 16 M, 5 F	C-L;AIS A-D;19 ± 13.8 yr	12 mo; Frequency N/R; 10 min/dTraining parameters:0.5 g, 30 Hz	Femur DiaphysisG1: Cortical bone volumeG2: Cortical bone volumeG3: Cortical bone volumeDistal Femur MetaphysisG1: Cortical bone volumeG2: Cortical bone volumeG3: Cortical bone volumeDistal Femur EpiphysisG1: Cortical bone volumeG2: Cortical bone volumeG3: Cortical bone volumeProximal Tibia EpiphysisG1: Cortical bone volumeG2: Cortical bone volumeG3: Cortical bone volumeProximal Tibia MetaphysisG1: Cortical bone volumeG2: Cortical bone volumeG3: Cortical bone volumeTibia DiaphysisG1: Cortical bone volumeG2: Cortical bone volumeG3: Cortical bone volume	Baseline13.0 cm313.9 cm313.2 cm310.4 cm311.5 cm311.3 cm32.95 cm32.43 cm32.52 cm32.64 cm32.79 cm33.17 cm311.8 cm311.9 cm311.9 cm313.2 cm314.7 cm314.0 cm3	12 mo−0.1%+0.2%−0.1%+1.1%+3.8%+1.7%+3.8%+11%+1.3%+10%+14%+7.1%+0.9%+1.7%+2.1%+22%+0.8%+0.4%
Wuermser et al. [102]N = 5 M, 4 FStanding + vibration	AIS A-B; T3-T12;2–27 yr	6 mo; 5 d/wk; 20 min/dTraining parameters:0.3 g, 34 Hz sinusoidal movement of 50 µm w/lower extremities supporting ~86% body weight	Distal TibiaTrabecular numberTrabecular thicknessTrabecular separationCortical thicknessCortical area	Baseline1.09/mm0.04 mm1.15 mm0.80 mm86.5 mm2	3 mo +0.9%+0.0%+8.7%−2.5%−3.3%	6 mo −5.5%+0.0%+7.6%−1.3%−1.8%	F/U6 mo−7.3%+0.0%+15%−3.8%−3.5%

G, group; BWSTT, bodyweight supported treadmill training; FES, functional electrical stimulation; RT, resistance training; ZA, zoledronic acid; TA, teriparatide F, female; M, male; C, cervical; T, thoracic; L, lumbar; AIS, American Spinal Injury Association Impairment Scale; SCI Duration: time since SCI in relation to intervention reported as range, mean ± SD, or mean and (range); avg, average; min, minute; h, hour; d, day; wk, week; mo, month; yr, year; N/R, not reported; FEA, finite element analysis; F/U, follow-up after intervention complete; Note: % change was reported in individual papers or was manually calculated from data in tables and/or figures; † indicates <0.05, †† <0.01 between groups; a lack of statistical symbols indicates no statistical differences that were reported versus the baseline or between the groups.

What are the optimal FES and modality-specific parameters (e.g., stimulation frequency, amplitude, pulse width, power output, tibio-femoral strain, and pedaling cadence) to stimulate and/or maintain bone improvements?

What is the optimal training frequency (number of sessions per day or per week) and training duration (time per bout and intervention length) to improve bone parameters?

What is the minimum training frequency and duration to maintain bone after SCI?

Is the magnitude of BMD or bone microstructural gains that result from FES sufficient to improve bone strength or bone mechanical characteristics and/or to reduce the fracture risk at the distal femur and/or proximal tibia after SCI?

Clinical trials focused on optimizing FES would require a large, concerted effort over many years to discern optimal parameters, due to the relatively slow bone remodeling in humans and the number of potential parameter combinations. To lessen this burden, percutaneous ES [105,145,146] or direct nerve stimulation [64,104,147] techniques could be used to optimize the FES parameters and to identify the optimal training frequency and duration in preclinical SCI models, with only the most successful protocols advancing. Preclinical SCI models can also be used to evaluate combinatory strategies to improve BMD. In this regard, several recent preclinical and clinical studies have assessed ABPTs combined with antiresorptive drugs, such as zoledronic acid [141,144] or testosterone [59,104,148], or bone anabolic drugs such as teriparatide [101], with varying success.

Regardless of the intervention that is used, we suggest the following practices be implemented when evaluating bone changes after SCI. First, studies should quantify the distal femur and/or proximal tibia bone parameters before and after an intervention using an established imaging modality (e.g., DXA or pQCT) and a validated protocol, instead of assessing surrogate bone sites. We recognize that DXA is used to quantify whole-body fat-free mass or fat mass changes, and thus, aBMD that is assessed in the whole-body or at other traditional osteoporosis sites may be reported out of convenience. Future work should explain the relevance of BMD changes at these traditional osteoporosis sites in relation to the more fracture-prone distal femur and proximal tibia sites after SCI. Second, clinical trials should last a minimum of 6–12 months with ABPT performed ≥3 days/week for ≥30 min/day across the intervention, given the slow bone turnover and BMD improvements that are present in humans in response to loading. Third, a control group or control comparator (e.g., untrained limb) should be assessed to ensure the appropriate data interpretation. Fourth, interventions should attempt to quantify the tibio-femoral forces during training, as has been previously reported [149], and/or attempt to achieve average power outputs >18 W when utilizing FES cycling as regimens exceeding this threshold appear to have a higher likelihood to improve BMD [96]. Fifth, studies should assess the fracture risk and/or evaluate the bone tensile properties via FEA or another method, if available, to establish ABPT effectiveness because the reduction in bone strength over the first few months after SCI has been estimated to be three times greater than the aBMD loss as determined by DXA [36] and because any given percentage increase in whole-bone BMD resulting from loading has been associated with 10 times greater percentage increase in bone strength in preclinical models [90], suggesting that BMD changes do not reflect the bone mechanical properties that may influence non-traumatic fracture risk.

14. Conclusions

A visual summary of all the reviewed studies examining the effects of ABPT modalities at knee and non-knee sites in acute and chronic SCI is presented in Figure 3A,B. Various ABPTs promote neuromuscular benefits and use-dependent neuroplasticity in persons with SCI [78]. Despite this, no known ABPT completely prevents bone loss that develops in the lower extremities over the acute/subacute post-SCI period, regardless of the skeletal site that is evaluated. Moreover, no ABPT has shown universal success in increasing BMD at the highly fracture-prone sites surrounding the knee. However, a small subset of trials that evaluated FES modalities reported attenuated BMD loss at the distal femur and/or proximal tibia in persons with acute to subacute SCI and increased BMD in those with chronic SCI, suggesting such regimens hold promise. Additionally, a small subset of studies that utilized weight-bearing ABPTs without FES reported BMD gains at other sites but no BMD changes in areas near the knee. As such, research is needed to understand why ABPTs produce variable BMD responses after SCI and to optimize the training parameters for bone gain. Moreover, routine monitoring of the distal femur and proximal tibia BMD appears important to assess the fracture risk before engaging in ABPTs and to monitor bone changes at these highly fracture-prone sites.

Figure 3

Summary of the effects of activity-based physical therapy (ABPT) on changes in bone mineral density (BMD) at the knee (distal femur and proximal tibia) or all other sublesional non-knee sites for persons with acute/sub-acute (A) or chronic (B) SCI in aggregate. Overall, half of all acute studies and most chronic studies showed no effect on BMD at the knee or non-knee sites. For data on specific ABPT modalities see Figure 1A,B (acute/subacute SCI) or Figure 2A,B (chronic SCI).