Osteoporosis in Individuals with Spinal Cord Injury

PM R 7 (2015) 188-201 www.pmrjournal.org Narrative RevieweCME Osteoporosis in Individuals with Spinal Cord Injury

William A. Bauman, MD, Christopher P. Cardozo, MD

The pathophysiology, clinical considerations, and relevant experimental findings with regard to osteoporosis in individuals with spinal cord injury (SCI) will be discussed. The bone loss that occurs acutely after more neurologically motor complete SCI is unique for its sublesional skeletal distribution and rate, at certain skeletal sites approaching 1% of bone mineral density per week, and its resistance to currently available treatments. The areas of high bone loss include the distal femur, proximal tibia, and more distal boney sites. Evidence from a study performed in monozygotic twins discordant for SCI indicates that sublesional bone loss in the twin with SCI increases for several decades, strongly suggesting that the heightened net bone loss after SCI may persist for an extended period of time. The increased frequency of fragility fracture after paralysis will be discussed, and a few risk factors for such fractures after SCI will be examined. Because vitamin D deficiency, regardless of disability, is a relevant consideration for bone health, as well as an easily reversible condition, the increased prevalence of and treatment target values for vitamin D in this deficiency state in the SCI population will be reviewed. Pharmacological and mechanical approaches to preserving bone integrity in persons with acute and chronic SCI will be reviewed, with emphasis placed on efficacy and practicality. Emerging osteoanabolic agents that improve functioning of WNT/b-catenin signaling after paralysis will be introduced as therapeutic interventions that may hold promise.

Bone Loss After Acute and Chronic Spinal Cord Injury is richly innervated by sensory and sympathetic nerves, and the former has been suggested to have osteoana- Bone loss after more neurologically motor complete bolic influences, the loss of positive central and pe- forms of spinal cord injury (SCI) is unique for its rate, ripheral neural influences to the sublesional skeleton distribution, and resistance to currently available may be a prime contributor to the rapidity and magni- treatments. In individuals with neurologically motor tude of bone loss [9]. Other possible mechanisms that complete SCI, regional bone loss may occur at rates may be speculated to be, at least in part, responsible approaching 1% of bone mineral density (BMD) per week for this phenomenon include the severity of immobili- at specific regional sites for the first several months zation, loss of anabolic factors (eg, circulating testos- after injury [1-3]. Long bone is lost at varying rates, terone and/or growth hormone), factors in the local depending on the particular bone and region [4] bone milieu (ie, paracrine influences from atrophying (Figure 1). The increased rate of bone loss continues muscle), and the presence of catabolic factors at the beyond the first 12 months of injury for at least the next time of injury (ie, administration of methylprednisolone 3 to 8 years, albeit at a slower rate than that at which it at high doses within hours of the acute event, and/or had initially occurred [5]. The rate of bone loss after SCI the systemic and/or local production of inflammatory is substantially greater than that observed with other mediators or cytokines). types of immobilization that are not associated with The areas of high bone loss include the distal femur muscle paralysis (ie, microgravity [0.25% per week] or and proximal tibia, and fractures predominantly occur bed rest [0.1% per week]) or in postmenopausal women at these bony sites. In a cross-sectional study of 31 pa- who are not taking antiresorptive medications (3%-5% tients with SCI for more than 1 year, Dauty et al [10] per year) [6-8]. The mechanisms responsible for the demonstrated a demineralization of e52% for the more accelerated rate of bone loss after sustaining a distal femur and e70% for the proximal tibia, bone motor complete SCI compared to that of immobilization losses at the knee that are in agreement with the find- have not been identified, but this dramatic phenomenon ings of several other investigators [4,11-13]. In a cross- may be related to any number of factors. Because bone sectional study of men with motor complete SCI,

1934-1482/$ - see front matter ª 2015 by the American Academy of Physical Medicine and Rehabilitation http://dx.doi.org/10.1016/j.pmrj.2014.08.948 W.A. Bauman, C.P. Cardozo / PM R 7 (2015) 188-201 189

Figure 1. Percentage of normal bone loss of regions of interest against time since spinal cord injury. Percentage of normal bone loss of femoral neck (top panel), femoral shaft (middle panel), and proximal tibia (lower panel) months after motor complete SCI (lesions: C7 to L1). The median duration of injury for the baseline determination was 43 days (range: 9-167 days), and subjects were followed up for a median of 41 months (range: 31-53 months). A median of 8 DXA measurements (range: 3-13) were performed on each of the 8 subjects (6 men and 2 women). Note that the percentage of normal bone mineral content for each region is dependent on the speciﬁc bone, region of bone, and duration of injury [4, reproduced with permission]. 190 Osteoporosis in SCI which used peripheral quantitative computed tomogra- can result in the development of joint stiffness, reduced phy in individuals with SCI to describe trabecular and range of motion, skin breakdown, greater pain, and cortical bone compartments until steady state levels heightened spasticity [23]. were achieved, loss of epiphyseal bone was 50% at the femur and 60% at the tibia (Figure 2); in the diaphysis, Bone Metabolism After SCI which is predominantly cortical bone, losses were 35% in the femur and 25% in the tibia, and involved erosion of As a consequence of acute SCI, abrupt skeletal the thickness of cortical bone by 0.25 mm/y over the unloading results in uncoupling of the functional rela- initial 5 to 7 years after SCI [13]. Zehndler et al reported tionship of the osteoblasts and osteoclasts. Of note, that BMD of the legs decreased markedly over time, immediately after injury, an increase in the function of with the femoral neck and distal tibial epiphyseal losses both osteoclasts and osteoblasts appears to occur [24]. initially being exponential before leveling off at 1 to 3 Eventually, over the ensuing months, a profound years after injury, whereas the z scores of the distal depression in osteoblastic bone formation and a marked tibial diaphysis decreased progressively beyond 10 years increase in trabecular osteoclastic resorptive surfaces is after injury [14] (Figure 3). From a study of monozygotic observed [25], which is reﬂected in preclinical studies twins discordant for SCI, the difference in sublesional by the increased numbers of osteocyctes from ex vivo BMD between the twins increased with time after SCI for cultures of bone marrow cells, and clinical studies with several decades, suggesting that the heightened net the onset of hypercalciuria and elevated markers of bone loss may continue for an extended period of time bone resorption [25-29]. Although not reported, one in individuals with SCI [15] (Figure 4), possibly because would assume that bone turnover rate would be mark- of a chronically depressed bone formation rate at edly depressed in individuals with long-standing SCI. cortical bone sites. This level of bony depletion places the knee in particular, but also the entire lower extremity, at greatly increased risk for fracture. Vitamin D and Calcium

Fracture After SCI Serum ionized calcium levels are often elevated after acute SCI because of rapid bone resorption, and these Fracture of the extremities below the level of lesion elevated levels are reflected in a markedly increased is a well-appreciated complication of the development renal clearance of calcium [30]. Parathyroid hormone of osteoporosis after SCI [14] (Figure 5). Fractures most (PTH) levels are suppressed in the presence of elevated often involve the tibia or fibula [14,16-20] (Table 1), but ionized serum calcium levels (Figure 6), which serves to upper extremity fractures also occur, most commonly in reduce PTH-mediated tubular absorption of calcium and those with higher cord lesions. Falls from a wheelchair contributes to increased calciuria. Another previously and transfers are the most common causes of fracture, unrecognized consequence of suppression of serum PTH although fractures can also result from low-impact ac- levels is that low or absent levels would be anticipated tivities, such as performing range-of-motion activities. to contribute to increased levels of sclerostin, a known One recent longitudinal study reported that 15 of 98 potent inhibitor of WNT/b-catenin signaling in osteo- persons with SCI sustained 39 fragility fractures of the cytes, with potentially adverse effects on bone health legs over 1,010 years of combined observation; the [31,32], which will be discussed subsequently in greater mean time to first fracture was about 9 years, with a 1% detail. fracture rate within the first 12 months and 4.6%/y Persons with severe chronic conditions have long fracture rate if the duration of injury was more than 20 been recognized to be at heighened risk for the devel- years [14]. Increasing risk for fracture was associated opment of vitamin D deficiency because of reduced with motor complete SCI, lower level of lesion (eg, in- sunlight exposure secondary to lifestyle changes, dividuals with paraplegia tend to be more active than institutionalization, and/or medications (eg, anti- those with tetraplegia), longer duration of injury, convulsants and psychotropic agents) that may in- greater alcohol consumption [14,17], and use of anti- crease renal clearance of vitamin D [33,34]. Possibly convulsant medications [21]. The risk of fractures has because of the risk of hypercalcemia and/or hyper- been found to be closely related to the BMD of epiph- calciuria, and the associated heightened risk of calcium yseal trabecular bone [22]. Since persons with SCI may renal stones early after SCI due to high bone turnover, often lack awareness of the acute occurrence of frac- misguided dietary counseling has encouraged avoidance ture because of the lack of pain secondary to interrup- of dairy products even in persons with chronic SCI (Note: tion of somatic afferent nerves, they may seek medical Even in the setting of acute SCI, there is no need to attention only for resultant symptoms of swelling at the reduce calcium intake because PTH is suppressed, fracture site, fever, increased muscle spasticity, and/or resulting in low gut calcium absorption) [30,35]; this inexplicable and more frequent occurrence of auto- dietary advice has often resulted in lower calcium nomic dysreflexia. Fractures of the lower extremities intake than that in the general population, including W.A. Bauman, C.P. Cardozo / PM R 7 (2015) 188-201 191

Figure 2. Upper and lower extremity cortical and trabecular bone mineral density (BMD) and cortical thickness in men with spinal cord injury (SCI). Findings are shown for 89 men with SCI and 21 able-bodied controls in the reference group. The abscissa shows the time after injury. The first row displays trabecular BMD of the distal epiphyses of the (A) femur, (B) tibia, and (C) radius. The second row displays cortical BMD of the diaphyses of the (D) femur, (E) tibia, and (F) radius. The third row displays mean cortical thickness (THIcort) of the diaphyses of the (G) femur, (H) tibia, and (I) radius. Symbols are “o” for subjects with paraplegia and “x” for subjects with tetraplegia. The mean value of the reference group is indicated with a solid line 2 standard deviations (SD) with the broken lines. To avoid partial volume effect, the cortical BMD (BMDcort) of subjects with cortical wall thickness <1.6 mm were excluded. Data from 6 participants were excluded in D and from 2 participants in F[13, reproduced with permission]. vitamin Defortified milk, which is the major dietary retrospective study of 100 SCI patients who were source of vitamin D [36]. consecutively admitted to an acute inpatient rehabili- Vitamin D deficiency has been reported to be far tation facility [39]. more prevalent in SCI cohorts than in the general pop- If 25(OH)D levels are insufficient to provide adequate ulation [37,38]. About one third of a veteran SCI popu- gut absorption of calcium when potent suppression of lation in the early 1990s had an absolute deficiency of 25 bone resorption occurs with the use of antiresorptive hydroxyvitamin D (25(OH)D <16 ng/mL) [37]. In a report agents, such as bisphosphonates or denosumab, pro- by Oleson and Wuermser in subjects with chronic SCI, found iatrogenic hypocalcemia may quickly develop. 81% had 25(OH)D levels that were defined as insufficient Thus, before initiating such therapies, vitamin D levels (<32 ng/mL) in the summer, which increased to 96% in should be determined, and when low, vitamin D winter, with 54% of these SCI subjects having an abso- replacement should be initiated before starting anti- lute deficiency of 25(OH)D levels (<13 ng/dL) [38]. The resorptive therapy. prevalence of relative or absolute 25(OH)D deficiency Vitamin D supplementation, if at appropriate doses, was 93%, with a mean level of 16.3 7.7 ng/mL, in a is effective in restoring vitamin D levels in individuals 192 Osteoporosis in SCI

Figure 3. Bone mineral density (BMD) z scores (standard deviation [SD]) at various skeletal sites as a function of time after spinal cord injury [14, reproduced with permission]. with SCI. In a study evaluating the efficacy of supple- values <50 ng/mL) [42]. The recommendation of the mental vitamin D in this population, cholecalciferol Institute of Medicine for the general population of North (vitamin D3) 2000 IU/d was administered to vitamin America is to maintain vitamin D levels >20 ng/mL [43], Dedeficient subjects with SCI for 3 months, which raised which, in the absence of more compelling evidence, the level of vitamin D into the normal range in 85% of may certainly be appropriate for the vast majority of subjects, and the mean level of vitamin D after sup- healthy adults and would serve to reduce the risk of plementation for the total group was well above the potential adverse events. lower limit of the normal range [25(OH)D >30 ng/mL] [40] (Figure 7), a cutoff level for 25(OH)D that would be Potential Pharmacological Therapies to Prevent or anticipated to optimize gastrointestinal absorption of Reduce Bone Loss calcium [41]. The Endocrine Society, an organization concerned with patients with metabolic bone diseases, Bisphosphonates have been used in an effort to pre- has recommended a goal for replacement of 25(OH)D of vent or reduce bone resorption associated with acute >30 ng/mL because of the belief that higher values SCI. This class of drugs has a strong affinity for bone and correlate with increased bone density and increased inhibits osteoclast bone resorption. The potent amino- antifracture efficacy; their reasoning also posits that bisphosphonates, such as alendronate or zoledronate, values should be raised above 30 ng/mL because of the act by inhibiting farnesyl pyrophosphate synthase, variability in vitamin D determination and the relative which interferes with isoprenylation of GTPases at the absence of toxicity with moderately higher values (eg, ruffled border of osteoclasts and prevents attachment W.A. Bauman, C.P. Cardozo / PM R 7 (2015) 188-201 193

Figure 5. Fracture rate and incidence in persons with spinal cord injury. Cumulative fracture rate (triangles) and fracture incidence (rectangles) observed in 1,010 patient-years among 98 paraplegic male patients 0 to 30 years after spinal cord injury [14, reproduced with permission].

range of patients with varying degrees of completeness of motor lesions and ability to weight bear [49,50]. These studies provide an important insight that must be considered when evaluating studies of bisphosphonates Figure 4. Intrapair difference (IPD) scores for leg bone in monozygotic or other bone-active agents in which the study cohort twins discordant for spinal cord injury plotted against duration of comprised patients with varying degrees of motor spinal cord injury. Linear regression analyses for IPD for leg (A) bone mineral density (BMD) (r2 ¼ 0.70, P < .01) and (B) bone mineral con- impairment who have vastly different abilities to weight tent (BMC) (r2 ¼ 0.60, P < .05) in twins discordant for spinal cord injury bear and to ambulate. Specifically (as will be discussed (SCI) [15, reproduced with permission]. shortly), in our experience, bisphosphonates do not positively influence bone loss at the knee after SCI in of osteoclasts to the bone surface, thus halting resorp- persons with motor complete SCI, or those in those tion and initiating cell death [44]. Although there is cannot weight bear. Thus, interpretation of such reports some evidence that bisphosphonates are efficacious in should be made with caution, and conclusions are reducing bone loss in individuals with motor incomplete possible only when the study design and data analysis lesions permitting weight bearing activity [45,46], our take motor completeness and weight bearing into experience with the use of bisphosphonates has raised consideration. As the field moves forward, it is imper- troubling questions concerning the efficacy of this class ative that investigators prospectively address varying of medications in persons with SCI who are unable to degrees of motor impairment and associated functional weight bear or to ambulate (ie, those with more com- capacity in their experimental designs. plete motor deficits). This will be discussed subse- Another consideration is that high-dose glucocorti- quently in greater detail. coids may have been administered in an attempt to Bisphosphonate administration was not effective at preventing bone loss or maintaining cortical bone strength in preclinical models of disuse osteoporosis Table 1 [47,48], which appears to differentiate disuse osteo- Sites of femoral and tibial fractures in individuals with spinal cord porosis from other postmenopausal models of osteopo- injury rosis in which bisphosphonates have been shown to be Supracondylar/ efficacious. Condylar Femoral Shaft Tibia Total In persons with incomplete motor SCI who are able to Ragnarsson et al [27] 33% 30% 18% 81% bear weight and to ambulate, 2 small case series have Ingram et al [23] 27% 15% 42% 84% Martinez et al [25] 19% 8% 46% 73% demonstrated the benefit of bisphosphonate treatment Zehnder et al [21] 20% 12% 52% 72% [45,46]; this work does support the administration of Percentage of fracture for each skeletal site (supracondylar/condylar, bisphosphonates to patients with SCI who weight bear or femoral shaft, and tibia) and total percentage of fractures for these 3 ambulate. Several encouraging reports on the effect of sites vs all other sites of fracture, based on data from references bisphosphonates on BMD after acute SCI have studied a cited. 194 Osteoporosis in SCI

Figure 6. Calcium metabolism after acute spinal cord injury. Values are displayed for serum calcium, fasting calcium excretion, 24 hour calcium excretion, and vitamin D [25 hydroxyvitamin D (25 OH D) and 1,25-dihydroxyvitamin D (1,25 (OH)2D]. The mean is denoted by the horizontal lines, and the normal range by the hatched area. Although the mean serum calcium level was normal, marked hypercalciuria was present, suggesting a reduced effect of parathyroid hormone on the distal nephron. Both the biologic and immunologic indexes revealed a reduction in circulating PTH concentration. GF denotes glomerular filtrate. Despite normal plasma 25 OH D values, 1,25 (OH)2D values were reduced, suggesting a reduction in circulating PTH levels [30, reproduced with permission]. preserve neurological function in prior studies [50-52], [50]. It should be appreciated that patients with but potential effects of glucocorticoids were not chronic SCI tend to fracture the distal femur and controlled for, or even captured, in the experimental proximal tibia, unlike those in the general population, design, potentially confounding interpretation of the who tend to fracture at the hip. The knee and more findings. Shapiro et al administered zoledronic acid to distal lower extremity were not studied in these prior neurologically motor complete patients with acute SCI, reports [49,50,52]. In a study that determined the BMD and observed apparent benefit at the hip at 6 months of the total leg and knee, pamidronate was repetitively (eg, endpoints determined were BMD, cross-sectional administered over the course of the year after acute area, and measures of bone strength), but these early SCI, with measurements failing to find a significant beneficial effects were almost completely absent at 12 effect of drug administration at 1 and 2 years [53].In months [52]. Bubbear et al also treated patients with recent work, Bauman et al showed that zolendronic acute SCI and varying degrees of completeness of acid successfully preserved BMD at the hip 6 and 12 lesion with zoledronic acid, and demonstrated a more months after acute SCI compared to no treatment, but sustained beneficial effect of drug at the total hip, this agent appeared to result in the increased loss of trochanter, and lumbar spine at 12 months; no mention BMD at the knee [54]. An obvious, but profound, was made of glucocorticoid administration at the time shortcoming of all prior studies with bisphosphonate of presentation for acute injury in the study cohort prescription in the SCI population is the lack of data W.A. Bauman, C.P. Cardozo / PM R 7 (2015) 188-201 195

90 osteoclastosis/bone resorption that develops shortly after the acute immobilization of paralysis. 80 Paralysis, casting of limbs, prolonged bed rest, or weightlessness in preclinical trials of immobilization 70 resulted in substantial bone loss due to uncoupling of

60 the osteoclast from the osteoblast, with an observed 1 initial phase of accelerated bone resorption and a pro- 2 50 3 longed phase of decreased formation [58,59]. In several 4 animal models of disuse (eg, spaceﬂight, tail suspen- 40 5 sion, and sciatic nerve injury), appropriate manipula- 6 tion of the OPG/RANKL system was highly efﬁcacious at 30 7

25 (OH) D Concentration (ng/mL) D 25 (OH) Concentration preserving cortical bone mass [60]. Findings in an animal

20 model of acute SCI suggest that a several-fold increase in RANKL expression after acute SCI occurs together 10 with an almost 2-fold increase in osteoclast differentiation markers in ex vivo cell cultures [61]. Because of 0 Baseline Month 1 Month 3 excessive RANKL expression after acute SCI in a rodent model of acute SCI, it may be postulated that an Figure 7. Serum vitamin D [25(OH)D] levels after supplementation with 2000 IU/d. Values are displayed for 7 subjects after months 1 and appropriate agent in human clinical trials would be one 3 of replacement vitamin administration. Note that 6 of 7 subjects had that directly and effectively antagonizes RANKL to 25(OH)D levels >30 ng/mL by month 3; the only subject who did not markedly reduce function of the osteoclast. It should be normalize the 25(OH)D level by month 3 approached the lower limit of appreciated that, as yet, there is no report on the normal (ie, 28 ng/mL) from a baseline value of 17 ng/mL [40, repro- efficacy of denosumab administration in mitigating duced with permission]. the high bone turnover state of acute SCI. In contrast to the marked osteoclastosis, osteoblast differentiation addressing the effect of this class of agents on fracture markers were found to be profoundly depressed [61].As incidence. such, there appears to be the dual challenge in SCI to A review addressing the efficacy of this class of agents preserve bone integrity in the presence of both in patients with acute SCI concluded the following: “Data increased osteoclastic activity and reduced osteoblastic were insufficient to recommend routine use of function. bisphosphonates for fracture prevention in these pa- Teriparatide (recombinant PTH 1-34) is the only tients. Current studies are limited by heterogeneity of agent available at present with the ability to stimulate patient populations and outcome measures. Uniform osteoblast activity and function. The effects of ter- bone density measurement sites with rigorous quality iparatide on bone mass or metabolism after SCI are control and compliance monitoring are needed to unclear. In one small case series, effects of teriparatide improve reliability of outcomes. Future studies should combined with robotically assisted gait training were address specific populations (acute or chronic SCI) and evaluated in 12 chronically injured nonambulatory should assess fracture outcomes [55].” subjects; trabecular thickness increased by magnetic A potent inducer of bone resorption is the cytokine resonance imaging at the knee at 3 months but not 6 or receptor activator of nuclear factor-kB ligand (RANKL), 12 months; BMD measurements after treatment at the which stimulates both osteoclastogenesis and function. spine and hips were not statistically significant [62]. RANKL is produced primarily in bone in response to Teriparatide administration activates both osteoblasts unloading, menopause, or other stimuli for bone and osteocytes. The net accrual of bone substance remodeling. Denosamub (XGEVA) is a human mono- observed with teriparatide administration in able- clonal antibody to RANKL that represents a novel bodied populations is lost after about 2 years of immunological/pharmacological Food and Drug starting its administration, and drug holidays or dis- Administration (FDA)eapproved approach to the continuation of treatment are recommended for this treatment of osteoporosis. The mechanism of action of reason. If teriparatide is prescribed acutely after SCI, denosamub is distinctly different from that of when hypercalciuria and/or hypercalcemia are often bisphosphonates, although both agents inhibit the present, close monitoring of serum calcium levels is osteoclast. Analyses of bone density and bone turnover suggested. rate demonstrated that the effects of denosumab on Sclerostin, one of the inhibitors of the conical Wnt bone remodeling appear to be more potent than those signaling pathway in bone, has recently been demon- of bisphosphonates [56,57]; denosumab dramatically strated to be a crucial regulator of bone cells that is a reduced eroded bone surfaces compared to the effect critical molecule in the pathogenesis of osteoporosis of bisphosphonates, which may be requisite for drug due to disuse [63,64]. Anti-sclerostin antibodies efficacy after acute SCI because of the robust increased BMD in a phase I clinical trial in healthy men 196 Osteoporosis in SCI and postmenopausal women [65].InaphaseIItrialof isometric contraction of the soleus muscle over 4 to 6 romosozumab, a monoclonal anti-sclerostin antibody, years and initiated within several months of acute SCI was administered monthly to postmenopausal women were examined for the tibia as compared to the with low BMD, and this approach was reported to be contralateral tibia. Whereas the untreated leg lost BMD more potent than alendronate or teriparatide at progressively over time, ES partially preserved increasing the percentage of BMD from baseline at the trabecular bone along the posterior aspect of the tibia lumbar spine, total hip, or femoral neck [66].This (where the forces applied by ES were greatest) [75] agent is currently in phase 3 clinical trials in post- (Figure 8); trabecular bone in the tibia from the ES- menopausal osteoporosis. In a preclinical trial, trained leg was about double that for the untrained reduction in sclerostin, either by the administration of leg and was only 25% lower than the corresponding antisclerostin antibody or by use of a sclerostin knock- region of interest in able-bodied controls. A separate out mouse model, almost completely prevented the study suggested that combining ES with standing may SCI-induced reduction of BMD at the femur and tibia, have a greater beneficial effect on BMD of the hip and as well as at several other regions of interest; reducing the knee in a subset of subjects with subacute SCI than sclerostin decreased the production of osteoclasts and ES alone, and that standing alone resulted in a increased the number of osteoblasts in ex vivo decrease in BMD of these regions [76]. cultured bone marrow stem cells [67]. Therefore, the FES was less effective in its ability to increase bone prescription of antisclerostin antibody may be a highly mass in individuals with chronic SCI who had long- efficacious anticatabolic, as well as an anabolic, established and fairly marked bone loss, possibly therapy to prevent, reduce, and/or possibly reverse because of greater antecedent loss of trabecular ar- bone loss after acute and chronic SCI. chitecture [77]; however, after ES training, either on a cycle ergometer or with knee extension against resis- Effects of Mechanical Loading and Electromagnetic tance, bone mass was increased in those with chronic Fields on Bone injury [78,79], demonstrating that even years after SCI it may be possible to stimulate net accrual of bone. Appropriate and sufficient mechanical loading of the Summarizing these findings, ES training administered at skeleton is obligate for maintenance of bone health. the time of acute injury appears to markedly reduce Mechanical stress and strain is sensed sensed by the bone loss at the site applied or, if administered to osteocyte by the osteocyte to induce a coordinated, those with chronic SCI, is also efficacious, albeit with a regional response by osteoclasts and osteoblasts reduced magnitude of effect, at the site to which the [64,68]. Loading forces to bone must be delivered with load is applied. Translation to clinical care has been sufficient intensity and frequency to stimulate bone fraught with considerable difficulty due to the labor- formation and to inhibit bone resorption. For a dis- intensive nature of the present approaches and the cussion of this topic that addresses the variety and appreciation that any effect on bone is rapidly lost efficacy of various mechanical interventions on pre- when the ES training is either reduced in frequency or serving bone after acute injury or reversing bone loss terminated. As such, a modality that provides after chronic injury, the reader is referred to a review by Biering-Sørensen et al [69]. Microgravity, or spaceflight, results in significant bone loss, but 1 year of gravitational loading by returning to earth generally leads to significant reversal of these bony changes in most astronauts [70]. Thus, it may also be possible to prevent or reverse loss of bone mass and strength, even after complete motor lesions, by devising an approach that will appropriately and consistently restore mechanical forces to the sublesional skeleton. Static mechanical loading of the sublesional skeleton after SCI has been ineffective in reducing loss of BMD [71,72]. Partial body weightesupported treadmill training is associated with cyclical reloading but has also proved to be ineffective in reducing bone loss after acute SCI or increasing bone mass in individuals with chronic paralysis [73,74]. However, functional Figure 8. Bone mineral density (BMD) of the posterior tibia region. e electrical stimulation (ES) using cyclical muscle Values are expressed as mean (standard error [SE]) for non spinal cord injury (SCI) cohort (provided on right side of figure) and chronic SCI contraction has been shown to be beneficial to bone cohort (provided on left side of figure). Data from all other subjects mass. During ES with surface electrodes activates are presented longitudinally, with each limb displayed separately [75, muscular contraction. In one study, the effects of reproduced with permission]. W.A. Bauman, C.P. Cardozo / PM R 7 (2015) 188-201 197 sufficient skeletal loading which can be successfully osteoclastogenic potential of marrow precursors by 70% incorporated into activities of daily living with initial and favorably altered gene expression in osteoblasts, rehabilitation would be the optimal strategy to main- completely reversing the 2-fold elevation in mRNA tain bone mass. levels for SOST and the 40% reduction in mRNA for Low-intensity, high-frequency vibration has been Runx2. However, in a trial in 9 subjects with motor found to reduce bone loss in children with disuse complete SCI with durations of injury of 2 or more osteoporosis due to neurological impairments and in years, LIV administered for 20 minutes per day for 5 postmenopausal women [80,81]. Low-intensity me- days per week over 6 months had no effect on BMD or chanical signals can be feasibly delivered through the trabecular bone architecture [84]. Additional preclini- lower appendicular and axial skeleton even while su- cal models or human studies are needed to establish pine in subjects with SCI; however, as expected, the potential beneficial effects of LIV on bone in in- transmission of mechanical signal is increased with dividuals with SCI and the optimal frequency, intensity, additional load applied by increasingly upright posture and duration of low intensity vibration. [82] (Figure 9). The value of low-intensity vibration as a In tissue culture and animal models, electromag- mechanical intervention has yet to be adequately netic stimulation has shown a remarkable effect to tested in the prevention or reduction of bone loss in modulate human mesenchymal stem cell osteogenesis, patients with acute or subacute SCI. In a female rat favorably alter cytokine profiles during disuse osteo- model of moderate severity contusion injury of the porosis, promote bone formation and repair, regulate mid-thoracic spinal cord, the effect of low intensity proteoglycan and collagen synthesis, and increase bone vibration initiated 28 days after SCI (15 minutes twice formation in models of endochondral ossification [85- daily for 35 days) was investigated; LIV did not signifi- 88]. The effect of pulsed electromagnetic fields cantly increase BMD or trabecular bone (BV/TV), applied unilaterally at the knee in subjects who were although the length of stimulation was relatively short injured at least 2 years revealed increased BMD of the and the bone lost was modest (5% decrease in BMD at stimulated knee and decreased BMD of the contralat- the distal tibia and proximal femur); thus, any benefits eral knee at 3 months, a return to baseline levels of may have been below the detection thresholds for BMD at 6 months, and a fall in BMD of both knees by 12 these measurements [83]. Of note, LIV increased serum months, with generally larger magnitude of changes osteocalcin, an indirect measure of bone formation, closer to the site of stimulation; these complex and and reduced the SCI-induced 2-fold elevation of constantly evolving findings for BMD in this experimental model suggest both local and systemic effects of pulsed electromagnetic field stimulation on bone above and below the knee [89].Itshouldbeevident that additional studies with the application of electromagnetic field stimulation on bone may hold promise, albeit, to date, the direction of effect over time was unpredictable and unsustainable.

Combined Pharmacological and Mechanical Therapy

A combination of mechanical and pharmacological interventions would be a logical approach to prevent or reduce bone loss after acute SCI. It may be necessary to begin therapy with drug intervention(s) because of the inherent difficulty of instituting a mechanical intervention immediately after the injury. A pharmacological approach to target and inhibit RANKL in an effort to suppress rampant osteoclastosis may be effective as well as practical even for the acutely ill or Figure 9. Transmission of vibration. Percentage of transmission (P2P% bedridden patient. To provide hormone replacement Transmission) for able-bodied control (solid cicles) and spinal cord injury (SCI) (open squares) subjects for the vibrating plate (delivering therapy for the frequently encountered hypogonadal 0.27 g at 34 Hz). The percentage of transmission is the percentage of state in men after acute or subacute SCI is another the vibration signal detected at the mouth. The percentage of body approach worth considering [90]; a relative or absolute weight (%BWT) is that which is loaded on the vibrating plate. The testosterone deficiency state may occur precipitously slopes of the regression lines associated with transmission are 0.923 after paralysis and may be assumed to worsen bone for the control group and 0.861 for the SCI group, which are not significantly different (P ¼ .98). There is increased transmission for loss, as it does in men on androgen ablation therapy for increased %BWT for control (P < .01) and SCI (P < .05) groups [82, prostate cancer [91]. Another reason to consider reduced with permission]. testosterone replacement therapy in those who may be 198 Osteoporosis in SCI hypogonadal shortly after paralysis is that high-dose References methylprednisolone is prescribed at time of acute SCI [51], and it is well appreciated that such administra- 1. Szollar SM, Martin EM, Sartoris DJ, Parthemore JD, Deftos LJ. Bone tion is likely to exacerbate bone loss due to the sudden mineral density and indexes of bone metabolism in spinal cord unweighting of the skeleton after an SCI; studies in injury. Am J Phys Med Rehabil 1998;77:28-35. 2. Garland DE, Adkins RH, VKushwaha V, Stewart C. Risk factors for both animals and humans have demonstrated that osteoporosis at the knee in the spinal cord injury population. testosterone attenuates the adverse effects of gluco- J Spinal Cord Med 2004;27:202-206. corticoids on muscle and bone [92-94]. 3. Warden SJ, KBennell KL, Matthews B, Brown DJ, McMeeken JM, An approach combining a mechanical intervention Wark JD. Quantitative ultrasound assessment of acute bone loss with at least one pharmacological therapy may have following spinal cord injury: A longitudinal pilot study. Osteoporos Int 2002;13:586-592. synergistic effects, as exemplified by the apparent 4. Biering-Sorensen F, HBohr HH, Schaadt OP. Longitudinal study of benefit of bisphosphonates in patients with SCI who can bone mineral content in the lumbar spine, the forearm and the weight bear or ambulate [45,46], the suggestive pre- lower extremities after spinal cord injury. Eur J Clin Invest 1990; liminary results observed with the combination of ter- 20:330-335. iparatide and gait training [62] and by findings that in 5. Eser P, Frotzler A, Zehnder Y, et al. Relationship between the duration of paralysis and bone structure: A pQCT study of spinal animals, release from bone cells of sclerostin is cord injured individuals. Bone 2004;34:869-880. inversely related to bone loading [32,95,96].Itis 6. Vico L, Collet P, Guignandon A, et al. Effects of long-term micro- reasonable to assume that the sooner an efficacious gravity exposure on cancellous and cortical weight-bearing bones physical intervention can be integrated into the plan of of cosmonauts. Lancet 2000;355:1607-1611. care in the form of a practical and cost-effective 7. Leblanc AD, Schneider VS, Evans HJ, Engelbretson DA, Krebs JM. Bone mineral loss and recovery after 17 weeks of bed rest. J Bone approach to restore the forces that had been suddenly Miner Res 1990;5:843-850. removed from the skeleton at time of injury, the greater 8. Recker R, Lappe J, Davies K, Heaney R. Characterization of peri- the likelihood of preserving bone mass. Although there menopausal bone loss: A prospective study. J Bone Miner Res 2000; are almost no data regarding the effects of combined 15:1965-1973. mechanical and pharmacologic therapies, one would 9. Qin W, Bauman WA, Cardozo CP. Evolving concepts in neurogenic osteoporosis. Curr Osteoporos Rep 2010;8:212-218. imagine that optimal approaches would combine a me- 10. Dauty M, Perrouin Verbe B, Maugars Y, Dubois C, Mathe JF. chanical intervention with some combination of anti- Supralesional and sublesional bone mineral density in spinal cord- resorptive agent (eg, denosumab) and, possibly, an injured patients. Bone 2000;27:305-309. anabolic agent such as teriparatide or antisclerostin 11. Finsen V, Indredavik B, Fougner KJ. Bone mineral and hormone antibody. Further studies will be necessary before it is status in paraplegics. Paraplegia 1992;30:343-347. 12. Frey-Rindova P, de Bruin ED, Stussi E, Dambacher MA, Dietz V. possible to establish whether combinations of mechan- Bone mineral density in upper and lower extremities during 12 ical stimulation and administration of bone-acting months after spinal cord injury measured by peripheral quantita- agents will increase the benefit observed with pharma- tive computed tomography. Spinal Cord 2000;38:26-32. cological therapy alone. 13. Eser P, Frotzler A, Zehnder Y, et al. 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Lower limb fractures in the chronic spinal cord injured patient. Paraplegia 1989;27:133-139. prove to be efficacious in the preservion of bone mass 17. Morse LR, Battaglino RA, Stolzmann KL, et al. Osteoporotic frac- after paralysis. Inhibitors of cathepsin K, a protease tures and hospitalization risk in chronic spinal cord injury. Osteo- critical to resorption of bone by the osteoclast, are now in poros Int 2009;20:385-392. clinical trials for postmenopausal osteoporosis and could 18. Martinez A, Cuenca J, Herrera A, Domingo J. Late lower extremity be beneficial in attenuating bone loss after SCI. Synthetic fractures in patients with paraplegia. Injury 2002;33:583-586. 19. Frisbie JH. Fractures after myelopathy: The risk quantified. J androgens that do not stimulate prostate but that retain Spinal Cord Med 1997;20:66-69. full anabolic activity toward muscle and bone have been 20. Ragnarsson KT, Sell GH. Lower extremity fractures after spinal developed by several pharmaceutical companies and are cord injury: A retrospective study. Arch Phys Med Rehabil 1981;62: currently in clinical trials. As androgens mitigate bone 418-423. loss in animal models of SCI [98,99], these agents are 21. Carbone L, Chin AS, Lee TA, et al. The association of anticonvul- sant use with fractures in spinal cord injury. Am J Phys Med Rehabil additional promising candidates in the search for safe and 2013;92:1037-1046; quiz 1047e1050. effective candidates to preserve bone and to reduce the 22. Eser P, Frotzler A, Zehnder Y, Denoth J. Fracture threshold in the risk after SCI. femur and tibia of people with spinal cord injury as determined by W.A. Bauman, C.P. Cardozo / PM R 7 (2015) 188-201 199

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Disclosure

W.A.B. Department of Veterans Affairs Rehabilitation Research & Development C.P.C. Department of Veterans Affairs Rehabilitation Research & Development Service, National Center of Excellence for the Medical Consequences of Spinal Service, National Center of Excellence for the Medical Consequences of Spinal Cord Cord Injury, James J. Peters Veterans Affairs Medical Center, 130 West Kings- Injury, James J. Peters Veterans Affairs Medical Center, Bronx, NY; Medical Service, bridge Road, Bronx, NY 10468; Medical Service, James J. Peters VA Medical James J. Peters VA Medical Center, Bronx, NY; Departments of Medicine and Center, Bronx, NY; Departments of Medicine and Rehabilitation Medicine, The Rehabilitation Medicine, The Icahn School of Medicine at Mount Sinai, New York, NY Icahn School of Medicine at Mount Sinai, New York, NY. Address correspondence Disclosure: nothing to disclose to: W.A.B.; e-mail: [email protected] Supported by the Veterans Affairs Rehabilitation Research and Development Disclosure: nothing to disclose Service (grant no. B9212C) and the James J. Peters VA Medical Center. Accepted August 21, 2014.

CME Question What is the weekly rate of bone loss during the ﬁrst several months after a spinal cord injury? a. 0.1% b. 1.0% c. 3.0% d. 0.25% Answer online at me.aapmr.org