Abstract
Objective
To present an up-to-date literature review of osteoporosis in spinal cord injury (SCI) patients, in view of the seriousness of this complication (with a high risk of fractures) and the complexity of its diagnosis, evaluation and treatment.
Methods
A Medline search with the following keywords: immobilization osteoporosis, spinal cord injury, bone loss, dual energy X-ray absorptiometry (DEXA), bisphosphonate.
Results
Our analysis of the literature noted a bone metabolism imbalance in SCI patients, with accelerated early bone resorption (particularly during the first 6 months post-injury). Although dual energy X-ray absorptiometry constitutes the “gold standard” diagnostic method, the decrease in bone mineral density only becomes significant 12 months after the injury. Bisphosphonate therapy has proven efficacy. Despite the frequent use of various physical therapies, these methods have not been found to be effective.
Conclusion
Although our literature review did not identify any guidelines on the strategy for diagnosing and treating osteoporosis in SCI patients, several findings provide guidance on procedures for early diagnosis and preventive treatment.
Résumé
Objectif
Établir une revue de la littérature sur l’ostéoporose chez les blessés médullaires, car elle constitue une complication fréquente, importante à prendre en compte en raison du risque fracturaire qui en découle, et en raison des conditions difficiles de diagnostic et de traitement.
Méthode
Recherche bibliographique sur Medline à partir des mots-clés suivants: immobilization osteoporosis , spinal cord injuries , bone loss , dual energy X-ray absorptiometry (DEXA) , bisphosphonate .
Résultats
L’analyse de la littérature rapporte un déséquilibre du métabolisme osseux avec une accélération de la résorption osseuse précoce, en particulier les six premiers mois, chez le blessé médullaire. L’ostéodensitométrie constitue l’examen diagnostic de référence, mais significatif qu’à partir de 12 mois post-lésion. Le traitement par bisphosphonate a fait la preuve de son efficacité dans plusieurs études mais pas les moyens physiques, pourtant encore souvent utilisés.
Conclusion
Il n’y a pas dans la littérature de recommandation sur la conduite à tenir diagnostique et thérapeutique de l’ostéoporose chez le blessé médullaire, mais certaines données peuvent contribuer à proposer une conduite à tenir.
1
English version
1.1
Introduction
Osteoporosis in spinal cord injury (SCI) patients was first described in 1948 . Since then, many publications have addressed this condition and its characteristics, such as the most frequently affected bone sites and the kinetics of bone resorption. These studies have revealed the speed and extent of bone loss – even in the young subject. Since this loss is related to the decrease in mechanical stress on the bone, the term “immobilization osteoporosis” is often used. However, damage to the neurovegetative system also appears to be partly responsible for the occurrence of this type of osteoporosis by inducing vascular changes . Furthermore, hormone deficiencies may also be involved . Hence, in view of these various factors, it would be correct to state that the exact physiopathology of this bone disorder is not well characterized.
Studies of bone metabolism in the acute and subacute post-injury phases have revealed a progressive elevation of bone resorption marker levels from the first week onwards and a peak between 3 and 6 months later . There is a concomitant, moderate rise in levels of bone formation markers , which explains the imbalance and thus the bone loss. From the 16 th month post-injury onwards, the bone metabolism tends towards a new stable state . This hyper-remodelling translates into a decrease in the bone mineral density (BMD) from 12 months post-injury onwards .
In the SCI patient, osteoporosis primarily affects sub-lesional areas which tend to be weight-bearing (such as the proximal and distal femur) or have a high trabecular bone content (such as the proximal tibia) . In contrast, strongly cortical sites (such as the femoral and tibial diaphyses) are relatively unaffected . In contrast to the legs, the spinal column does not appear to be affected by demineralization (regardless of the time since injury) . Some authors (such as Biering-Sorensen and Schaadt ) have even reported that the BMD of the lumbar region increases. The increased stress on the spinal cord caused by sitting in a wheelchair for a long time may have an osteogenic effect on the vertebrae and could thus contribute to the maintenance of or increase in vertebral BMD. For the upper limbs, the outcome depends on the lesion level: only tetraplegic patients present a decrease in BMD in the arms and forearms . Hence, the level of neurological damage determines the extent of demineralization but not its intensity.
Furthermore, bone alterations are more marked in complete spinal cord lesions than in incomplete forms . In a cross-sectional study, Demirel et al. reported a significant difference in BMD when comparing a group of tetraplegic patients (Z-score: −2.29 ± 0.51) with a group of paraplegics (Z-score: −0.12 ± 0.22). In contrast, there was no correlation between BMD and age or gender. Neither is spasticity a factor which influences the kinetics of bone loss .
Once osteoporosis has been diagnosed, managing the condition’s complications (i.e. fractures, above all) remains a real problem. Fractures occur in SCI patients during minor trauma, such as wheelchair-bed transfers . The prevalence of fractures is hard to judge (probably because of the few apparent symptoms) but has been variously estimated at between 1 and 34% . However, it is known that the fracture prevalence increases with time since injury and that the proximal and distal femur and the proximal tibia (i.e. the most demineralized areas) are the most affected areas . Given that:
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these fractures are associated with additional risks (such as the occurrence of bedsores, increased spasticity and the formation of malunions );
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their treatment involves lengthy immobilization, the prevention and treatment of osteoporosis remains a major challenge.
Even though the literature data on this subject are abundant, there is no consensus on the criteria for “early” or “preventive” diagnosis of osteoporosis before fracture or the subsequent treatment procedures.
In this context, we decided to review the literature with a view to making practice recommendations.
1.2
Objectives
The objective of this work was to suggest (on the basis of a literature review) criteria and procedures for screening for osteoporosis in SCI patients and for implementing preventive and/or curative treatments.
1.3
Methodology
The Medline database was searched with the following keywords: immobilization osteoporosis , spinal cord injuries, bone loss , dual energy X-ray absorptiometry (DEXA), bisphosphonate.
1.4
Results
Our literature search identified 104 articles which were directly related to the subject of interest. The set of articles included several English-language reviews which facilitated our work but did not feature any practice recommendations . A high proportion of these 104 articles dealt with descriptions of the physiopathology of the condition, the most frequently affected sites and the factors influencing bone loss. In terms of the diagnosis of osteoporosis in SCI patients, only eight studies suggested a diagnostic approach of some kind. The published reviews mainly covered the physiopathology of osteoporosis, the various treatments having been trialled but not the diagnostic procedures.
1.4.1
The diagnosis of osteoporosis
At present, the diagnosis of osteoporosis is based on bone densitometry (determination of the BMD). This examination can confirm the decrease in bone mass and estimate the subsequent risk of fractures by evaluating the degree of bone loss . According to the 1994 WHO criteria , osteoporosis is indicated by a T-score of more than – 2.5 standard deviations for the spinal column, the neck of the femur or the radius. In many studies in SCI patients, this method has been used to diagnose and quantify post-injury osteoporosis and monitor the efficacy of treatment. According to Leduc et al. , it is not necessary to perform this examination systematically to evaluate the fracture risk in SCI patients (except in very active individuals) but it is recommended once a fracture has occurred. According to Jones et al. , this examination is the most appropriate one for assessing bone mass and should be used much more widely in the population of SCI patients. Only the 1998 study by Szollar et al. concluded that the performance of densitometry at 12 months would be a good way to screen for bone loss. However, the available evidence concerning the kinetics of osteoclastogenesis markers suggests that screening should be performed in the acute post-injury phase because the bone resorption peak occurs between 3 and 6 weeks after the spinal injury. Furthermore, the bone densitometry used in routine practice explores the wrist, the L1–L4 lumbar spine and the whole of the hip (Ward’s triangle, the neck of the femur, the trochanter and the intertrochanter area). Hence, the sites most exposed to the risk of fracture in SCI patients are not analyzed at all, with a concomitant risk of underestimating the degree of bone loss. This is why Shields et al. suggested (in 2005) a protocol for evaluating the BMD in the distal femur and proximal tibia (i.e. high fracture risk zones in SCI patients). Morse et al. subsequently emphasized that the BMD of the distal femur is higher than that of the proximal tibia . Furthermore, the WHO diagnostic criteria for osteoporosis were defined for menopaused women and so do not necessarily apply to other populations or to the physiopathology of osteoporosis in SCI patients. Lastly, in SCI patients, one must take account of heterotopic ossification (a frequent complication which can lead to overestimation of the true BMD ) and the presence of lumbar osteosynthesis materials (which perturb examination of the spine). Even though bone densitometry can be used for diagnosis of osteoporosis in SCI patients, it is important to bear in mind these limitations when interpreting the results.
Other investigative techniques have been used to evaluate bone density and/or structure. Several authors report the use of quantitative computed tomography ([QCT], also referred to as a high-resolution scanner or bone microscanner ) for measuring the cortical and trabecular zones separately, analyzing the bone architecture and identifying subjects with a greater fracture risk. The measurement unit is the apparent bone density (in mg/cm 3 ) and the reference values depend on the subject’s age. Liu et al. emphasized that this examination can (in contrast to bone densitometry) reveal the presence of lumbar osteoporosis. Although a lumbar examination can be performed on most of today’s CT systems, dedicated machines (peripheral QCTs) are required for the peripheral bones. The latter give highly reproducible results but are expensive and are only found in certain specialized centres.
Evaluation with quantitative ultrasonography has also been reported; the technique provides information on bone architecture, elasticity and density and thus facilitates evaluation of the fracture risk. The ultrasound measurements are performed on the heel bone or the phalanges. A study by Warden et al. showed that there was no significant difference between bone densitometry and quantitative ultrasonography in terms of the diagnostic precision for short-term bone loss in the calcaneus. However, this technique has not been validated in the diagnosis of osteoporosis and is thus limited to research use only.
In SCI patients, clinical biochemistry results may constitute diagnostic evidence. In contrast to postmenopausal osteoporosis (in which the blood chemistry profile is normal), the acute post-SCI phase is associated with an increase in calciuria and phosphaturia . Maïmoun et al.’s study of seven patients having sustained a SCI an average of 3 months previously showed that bone densitometry did not detect any variation in BMD at this acute stage, whereas specific biochemical markers of bone turnover revealed a significant elevation of calciuria and a decrease in serum intact parathyroid hormone and 1,25 (OH)(2) vitamin D levels. Furthermore, the blood and urine biochemistry profiles (reflecting the activity of bone remodelling) may be useful for screening for osteoporosis in SCI patients. According to Craven et al. , the most frequently assayed biological markers of bone remodelling are osteocalcin, N-telopeptide (NTX) and hydroxyprolinuria. However, one must take account of the fact that a high proportion of SCIs results from vertebral fractures, which perturbs the levels of bone markers like C-telopeptide (CTX) for several months. Thus, the best markers for the diagnosis of osteoporosis in SCI patients and the ideal time point for performance of a putative diagnostic test have not yet been determined.
1.4.2
The treatment of osteoporosis
The question of osteoporosis treatment in SCI patients has been addressed by many different studies. A wide range of would-be preventive or curative pharmacological or physical therapies has been suggested.
Pharmacological approaches mainly involve antiosteoclastic compounds.
Calcitonin is a strong inhibitor of bone resorption, with a direct effect on osteoclasts and (by inhibiting fusion) their precursors. It temporarily reduces immobilization hypercalcaemia and hypercalciuria . The compound was used in the 1980s but has since been abandoned, due to the lack of a true effect on bone loss.
As strong inhibitors of bone resorption and soft tissue calcification, bisphosphonates have been considered as the most appropriate therapy for SCI patients for several decades. The results of the many studies to have been performed in this patient population tend to show a reduction in hypercalcaemia and bone loss when bisphosphonates are administered on either a preventive or curative basis ( Tables 1 and 2 , respectively). On the whole, preventive treatment initiated within 12 months of the injury appears to be effective, particularly for bisphosphonates which are administered either orally (such as clodronate, tiludronate, etidronate and alendronate ) or intravenously (such as zoledronate and pamidronate ). However, some studies have shown limited efficacy for etidronate in paraplegic subjects and for pamidronate and the tibial site and no benefit whatsoever versus controls for pamidronate . Treatment with a single dose of zoledronate leads to an increase in BMD at 6 months but not at 12 months . This time-limited efficacy differs from the situation in women with post-menopausal osteoporosis. In terms of curative treatment with bisphosphonates, reports are only available for alendronate but have revealed a significant beneficial effect. However, these were recent studies performed over a maximum period of 2 years and so the treatment’s long-term impact on BMD is not yet known.
| Study | Number of subjects | Time since injury | Compound used | Dose | Treatment duration | Effects on biological markers | BMD/other markers |
|---|---|---|---|---|---|---|---|
| Minaire et al. (1980) | 21 SCI 7 controls | Mean: 17.6 days (5–29 days) | Clodronate | 400 or 1600 mg/d | 3 months 1/2 | Decrease in calcaemia Decrease in calciuria Decrease in hydroxyprolinuria | BMD: increased after 3 months Histomorphometry: a drop in the osteoclast count after 3 months |
| Chappard et al. (1995) | 20 SCI 6 controls | 4–19 days | Tiludronate | 400 mg/d or 200 mg/d | 3 months | Histomorphometry: a slight increase in bone volume in subjects having received 400 mg/d; a decrease in the osteoclast count | |
| Pearson et al. (1997) | 13 SCI 7 controls | 6 weeks | Etidronate | 800 mg/d | 2 cycles of 2 weeks | BMD: decreased in tetraplegics and was stable in paraplegics | |
| Nance et al. (1999) | 24 SCI 10 controls | 6 weeks | Pamidromate | 30 mg/4 weeks | 6 months | Decrease in urine NTX levels | BMD: increased in lumbar and femoral areas (neck and metaphysis) |
| Luethi et al. (2001) | 60 SCI No controls | 10.6 years | Alendronate | 10 mg/d | 18 months | BMD: increased in lumbar region and stable at the hip and the tibia | |
| Sniger et al. (2002) | 1 SCI No controls | 27 years | Alendronate | 10 mg/d | 2 years | BMD: increased for the lumbar region and the hips | |
| Bubbear et al. (2004) | 4 SCI No controls | 12.75 years (2–30 years) | Alendronate | 10 mg/d | 2 years | BMD: increased in the lumbar region, the neck of the femur and the hips as a whole | |
| Bauman et al. (2005) | 6 SCI 5 controls | 22–65 days | Pamidronate | 60 mg at 0, 1, 2, 3, 6, 9 and 12 months | 12 months | Lower 24-hour calciuria at 1 month | BMD: same decrease as in control subjects |
| Gilchrist et al. (2007) | 31 SCI 16 controls | 10 days | Alendronate | 70 mg per week | 12 months | Decrease in calciuria Decrease in CTX | BMD: smaller decrease in treated subjects |
| Shapiro et al. (2007) | 8 SCI 9 controls | 10–12 weeks | Zoledronate | 4 mg ( n = 4) or 5 mg ( n = 4) IV | Single dose | Decrease in urine NTX levels | BMD At 6 months: increased BMD at all doses At 12 months: lower for the neck of the femur |
| Studies | Number of subjects | Time since injury | Compound used | Dose | Treatment duration | Effects on biological markers | BMD |
|---|---|---|---|---|---|---|---|
| Luethi et al. (2001) | 60 treated No controls | 10.6 years | Alendronate | 10 mg/d | 18 months | Increased in the lumbar region, stable for the hip and the tibia | |
| Sniger et al. (2002) | 1 treated | 27 years | Alendronate | 10 mg/d | 2 years | Increased in the lumbar region and hips | |
| Bubbear et al. (2004) | 4 treated | 12.75 years (2–30 years) | Alendronate | 10 mg/d | 2 years | Increased in the lumbar region, the neck of the femur and hip total | |
| Zehnder et al. (2004) | 55 treated 32 controls | 9.8 years (0.1–29.5 years) | Alendronate | 10 mg/d | 2 years | Increase in bone alkaline phosphatases, decrease in deoxypyridinoline and osteocalcin | Increased in the lumbar region, stable for the tibia and the neck of the femur |
| Moran de Brito et al. (2005) | 19 treated Over 6 months 9 controls | Alendronate | 10Moran de Britomg/d | 6 months | Increased at 9 out of 12 sites | ||
On the whole, the results of the various studies on bisphosphonate treatment in SCI patients remain difficult to extrapolate to daily practice, in view of the heterogeneous inclusion criteria, the generally small study populations and methodological differences (notably concerning the BMD measurement sites).
Furthermore, vitamin D has a major role in phosphate-calcium homeostasis. It is therefore important to first identify and treat any vitamin D deficiency. The minimum recommended serum level of vitamin D is 30 ng/mL (i.e. 75 nmol/L) and this parameter probably influences the efficacy of bisphosphonates. Bauman et al.’s 2005 study revealed that a vitamin D analogue had a significant effect on the maintenance of leg BMD in 40 tetraplegic SCI patients .
A more mechanical, rehabilitational approach aimed at stimulating sublesional bone segments may be a useful adjunct to drug treatment, in order to re-establish the initial physiological and biomechanical conditions as much as possible. This approach would encompass various physical techniques, such as supported standing, physical exercise, assisted walking, electrical muscle stimulation and ultrasound. In fact, the reduction in mechanical load appears to be one of the most important factors in demineralization in SCI patients, since it has been observed in several experimental conditions (such as prolonged bed rest or microgravity exposure . This reduction in mechanical stress decreases bone mass and damages bone architecture . Dauty et al. have shown that the duration of the patients’ initial immobilization is the most important factor in terms of changes in the BMD of the trochanter.
Supported standing (with prone or supine standing frames) and assisted walking in the acute post-SCI phase have long been promoted as therapy for reducing calcium loss and delaying immobilization osteoporosis . However, Morse et al. have shown that the locomotive mode is not associated with the levels of biological markers of bone turnover. At the chronic post-injury stage, daily sessions of standing or walking with various types of orthosis do not have any significant effect on the BMD. Early-phase supported standing or assisted walking continues to be recommended and De Bruin et al. have reported the absence of demineralization in tibial trabecular bone in SCI patients who stood regularly (for 1 hour a day, 5 days a week) during the first 25 weeks post-injury. However, Frey-Rindova et al. have emphasized the problem of low patient motivation levels during this type of programme. Lastly, the effects of standing do not appear to persist over the long-term .
Physical exercise and sport have beneficial but rather localised and nonsystematized effects on bone. According to Maïmoun et al. , the beneficial effects of physical activity on bone tissue observed in athletes may help prevent osteoporosis in patients. Jones et al. reported that although very active SCI patients displayed significant demineralization of the lower body, the bone mass in their arms was maintained. This fits with data on the protective role of physical activities on the upper arms (regardless of the level of spinal injury) in tetraplegics in whom these sites are considered as being at risk of demineralization .
Functional electrical muscle stimulation (fEMS) has been recommended as having a positive, local effect on the BMD of the stimulated sites; however, this effect does not persist over time and thus requires early-stage, prolonged and difficult to maintain treatment. In a 2000-study of a population of 14 chronic SCI patients, Belanger et al. reported that 1 hour of quadriceps fEMS per day (5 days a week for 24 weeks) induced a significant increase in the BMD of the distal femur and the proximal tibia. However, many other months-long fEMS programmes (sometimes combined with cycling or assisted walking) have not displayed significant efficacy .
Lastly, even though some in vitro studies have shown that low-intensity, pulsed ultrasound may be an osteogenic stimulus , efficacy has not been observed in SCI patients. Warden et al.’s study of a 6-week application of ultrasound to the calcaneus of 15 SCI patients (time since injury: 1 to 6 months) was not conclusive.
1.5
Discussion
When considering the set of data encompassed by this literature review, one can draw the following conclusions.
It is important to consider bone demineralization after SCI, in view of the nonnegligible fracture risk at sub-lesion bone sites (even though the fracture prevalence is poorly known). Physicians must be more aware of this problem and the need to provide information and health education to SCI patients (especially very active subjects), in order to screen more reliably for fractures which may not be highly symptomatic.
Bone demineralization is intense in the acute post-SCI stage (the first 6 months) and then tends towards a stable state after 12 months; this mirrors metabolic characteristics which are more associated with the neurological damage than with immobilization per se. Today’s rehabilitation programmes are based on the idea that the changes in bone physiology observed in SCI patients are due to immobilization. However, the literature indicates that changes inherently related to neurological damage can play a more significant role in the appearance of osteoporosis. As a consequence, the term “neurological osteoporosis” proposed by Bedell et al. may better define the process of bone loss after SCI than “immobilization osteoporosis”.
The “gold standard” diagnostic examination for osteoporosis in SCI patients is still bone densitometry. However, it appears that the decrease in BMD (only detectable after 12 months) occurs rather late, considering the kinetics of bone resorption observed in these patients and the fact that the reference values for osteoporosis were established for healthy, menopaused women. Evaluation of the distal femur’s BMD is recommended in this respect . Assaying for bone metabolism markers (bone alkaline phosphatases or osteocalcin for bone formation and CTX or NTX for bone resorption) from the acute phase onwards could be useful in the early detection and prevention of bone demineralization.
Studies on the use of physical therapies to treat bone demineralization have not been conclusive and can be broadly criticized in view of heterogeneous patient inclusion criteria, small study populations, various protocol differences and insufficiently long follow-up periods and times since injury. One can legitimately question the true value of these techniques, in view of the fact that immobilization is not the only factor involved and given the practical difficulties in implementing and monitoring these treatments.
Today’s drug treatments do not stop the demineralization process. Bisphosphonates appear to be capable of reducing intense bone resorption activity (notably during the acute post-SCI phase). Their efficacy has certainly been demonstrated by a variety of studies, although the latter were performed on small numbers of patients and over short treatment periods. None of these compounds have received marketing authorization for the indication of osteoporosis prevention or treatment in SCI patients.
Szollar suggested starting preventive drug treatment 1 year after injury, with six-monthly densitometric monitoring. However, this type of follow-up would be hard to set up in practice. Furthermore, the introduction of preventive treatments from the 12 th month onwards would come too late, since bone resorption peaks at between 3 and 6 months post-injury. Randomized studies starting sooner after injury and on larger patient populations are thus required.
Furthermore, the pharmacological treatments currently given to SCI patients with osteoporosis are derived from those developed for women with post-menopausal osteoporosis. In fact, the physiopathological mechanisms leading to bone demineralization in these two situations appear to differ. In order to develop a more well-suited drug treatment, a more accurate understanding of the aetiology of bone loss in SCI patients is still required; this justifies further studies on bone metabolism during the first 6 months post-SCI. Different posologies, the use of recently marketed drugs (strontium ranelate, for example) and the possible adjunction of rehabilitation programmes must be studied in SCI patients. Recently, Morse et al. studied 66 men with SCI (time since injury: at least 1.6 years) and reported that the severity of the injury was predictive of serum osteoprotegerin levels. They also showed that levels of this bone marker were not related to locomotive mode. According to these researchers:
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there is currently no way to prevent or treat osteoporosis in SCI patients;
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osteoprotegerin may be a potential biological marker of osteoporosis in this population.
Osteoprotegerin is part of the RANK/RANKL system and inhibits bone resorption. Morse et al. concluded that it might be possible to prevent post-SCI bone loss by administering recombinant osteoprotegerin. Denosumab is an anti-RANKL antibody and it has much the same action as osteoprotegerin. Studies on the effect of denosumab on osteoporosis in SCI patients would thus be necessary. Furthermore, sclerostin is an osteocyte-synthesized protein which has a significant role in the regulation of bone formation by osteoblasts. Recent trials of biological therapies have shown that the injection of antisclerostin antibody increases bone formation and density and has an effect on bone resistance and architecture . These novel potential treatments could represent a new therapeutic approach to osteoporosis in SCI patients.
1.6
Conclusion
The term “neurological osteoporosis” appears to be more appropriate than “immobilization osteoporosis”, in view of the condition’s location and dependence on the level of the SCI . The observed changes in levels of bone metabolism markers in the acute post-SCI phase show that there is an imbalance between bone resorption and formation. The imbalance decreases from the 12 th month post-injury onwards but is never completely resolved. Biological screening in the first 12 months post-SCI might help prevent this osteoporosis and avoid fractures. Bone densitometry only becomes useful as a treatment indicator 12 months after injury. Of course, as part of secondary prevention, this examination is necessary after a fracture occurs. The various physical therapies may be of interest but do not have proven efficacy in this indication. Pharmacological treatment with bisphosphonates is thus necessary. Studies (particularly long-term ones) in this field are scarce. Screening and treatment guidelines for osteoporosis in SCI patients have not been established; this type of initiative is necessary for better patient management.
Conflicts of interest statement
The authors declare the absence of conflicts of interest.
2
Version française
2.1
Introduction
L’ostéoporose chez le blessé médullaire a été décrite pour la première fois en 1948 . Depuis, ce sujet a fait l’objet de nombreuses publications, concernant notamment ses caractéristiques particulières comme les sites d’atteinte préférentielle ou encore la cinétique de la résorption osseuse. Ces études révèlent une perte osseuse rapide et importante, touchant même le sujet jeune. Cette perte osseuse est liée à une baisse de la contrainte mécanique sur l’os, c’est pourquoi le terme « d’ostéoporose d’immobilisation » est souvent utilisé, mais la lésion du système neurovégétatif semble avoir aussi une part de responsabilité dans la survenue de cette ostéoporose en entraînant des modifications vasculaires . Par ailleurs, des déficiences hormonales seraient aussi en cause . De fait, considérant ces différents facteurs, il apparaît plutôt que la physiopathologie exacte du trouble osseux n’est pas précisément connue.
Les études du métabolisme osseux aux phases aiguë et subaigüe de la lésion médullaire ont montré une augmentation continue des marqueurs de la résorption osseuse dès les premières semaines pour atteindre un maximum entre le troisième et le sixième mois . Parallèlement, les marqueurs de la formation osseuse augmentent modérément , ce qui explique le déséquilibre et donc la perte osseuse. À partir du 16 e mois post-lésionnel, le processus métabolique osseux tend vers un nouvel état stable . Cet hyperremodelage osseux se traduit par une diminution de la densité minérale osseuse (DMO) à partir de 12 mois après la lésion médullaire .
Les sites préférentiellement concernés par l’ostéoporose chez le blessé médullaire sont des zones sub-lésionnelles, et principalement les sites porteurs du squelette, tels que le fémur proximal et distal, ainsi que le tibia proximal, riches en os trabéculaire , alors que les diaphyses fémorale et tibiale, qui sont des sites fortement corticaux, sont relativement épargnés . Contrairement aux membres inférieurs, la colonne vertébrale ne semble pas être affectée par la déminéralisation, quel que soit le délai post-traumatique . Certains auteurs, comme Biering-Sorensen et Schaadt , montrent même que la DMO est augmentée au niveau lombaire. La mise en charge du segment rachidien liée aux durées prolongées en station assise sur un fauteuil roulant aurait un effet ostéogénique sur les vertèbres et contribuerait ainsi au maintien ou à l’augmentation de la DMO vertébrale. Aux membres supérieurs, les résultats rapportés dépendent du niveau lésionnel: seuls les patients tétraplégiques présentent une diminution de la DMO au niveau des bras et des avant-bras . Ainsi, le niveau neurologique détermine l’étendue, mais pas le degré de déminéralisation.
Par ailleurs, les altérations osseuses sont plus marquées dans les lésions médullaires complètes que dans les formes incomplètes . Demirel et al. montrent, dans une étude transversale, une différence significative de DMO entre un groupe de patients ayant une lésion complète (Z-score à −2,29 ± 0,51) par rapport à un groupe ayant une lésion incomplète (Z-score à −0,12 ± 0,22). En revanche, ils ne retrouvent pas de corrélation entre les mesures de densité osseuse et l’âge ou le sexe. Par ailleurs, la spasticité n’est pas un facteur influençant la cinétique de la perte osseuse .
Au-delà du diagnostic d’ostéoporose, ce sont surtout ses complications, à savoir essentiellement les fractures, qui demeurent un réel problème. Celles-ci surviennent chez le blessé médullaire lors de traumatismes mineurs, le plus souvent lors des transferts du fauteuil roulant au lit . Leur fréquence reste encore difficile à apprécier, probablement du fait de leur caractère paucisymptomatique, étant estimée selon les études entre 1 et 34 % . On peut rapporter cependant que la prévalence augmente avec le délai post-lésionnel et que les sites préférentiels sont le fémur proximal et distal ainsi que le tibia proximal, zones les plus déminéralisées . Comme ces fractures induisent elles-mêmes des risques tels que la survenue d’escarre, une augmentation de la spasticité, la formation de cals vicieux et que leur traitement comporte une longue immobilisation, la prévention et la gestion de l’ostéoporose reste toujours un grand défi. En effet, si les données de la littérature sur le sujet sont nombreuses, les conditions d’un diagnostic « précoce » ou « préventif » d’une ostéoporose avant fracture, de même que les critères et les modalités de la thérapeutique ne font pas preuve de données consensuelles.
Dans ce contexte, nous proposons une analyse de la littérature en vue de propositions de conduite à tenir.
2.2
Objectifs
L’objectif de ce travail est de proposer, à partir d’une revue de la littérature, les conditions et les modalités du dépistage d’une ostéoporose chez le blessé médullaire, et la mise en place d’une thérapeutique préventive et/ou curative.
2.3
Méthodologie
Une recherche bibliographique a été réalisée sur Medline à partir des mots-clés suivants: immobilisation osteoporosis , spinal cord injuries , bone loss , dual energy X-ray absorptiometry (DEXA) , diphosphonates .
2.4
Résultats
Cette recherche a permis d’identifier 104 articles en rapport direct avec le sujet. Il a surtout été rapporté plusieurs revues déjà établies en anglais, permettant cette analyse mais sans proposition stratégique . De ces 104 articles répertoriés au total, un grand nombre porte sur la description physiopathologique, les localisations préférentielles et les facteurs influençant cette perte osseuse. Concernant le diagnostic de l’ostéoporose du blessé médullaire, seules huit études proposent des éléments diagnostiques. Les revues déjà effectuées portent essentiellement sur la physiopathologie de cette ostéoporose et les différents traitements expérimentés. Les modalités diagnostiques n’y sont pas analysées.
2.4.1
Le diagnostic d’ostéoporose
Il repose à l’heure actuelle sur l’ostéodensitométrie (DMO). Cet examen permet de confirmer la diminution de la masse osseuse et d’estimer le risque ultérieur de fractures en évaluant l’amplitude de la perte osseuse . Selon les critères de l’OMS définis en 1994 , le stade d’ostéoporose correspond à un T-score inférieur à −2,5 D.S. au niveau de la colonne vertébrale, de l’extrémité supérieure du fémur ou du radius. Cet examen a été utilisé lors de nombreuses études réalisées chez le blessé médullaire pour prouver l’existence de l’ostéoporose post-lésionnelle, la quantifier, ou bien comme moyen de contrôle d’efficacité des thérapeutiques proposées. Selon Leduc et al. , il n’est pas nécessaire de réaliser cet examen de façon systématique sauf chez les blessés médullaires très sportifs afin d’évaluer le risque fracturaire et il est recommandé chez tous les blessés médullaires à la suite d’une fracture. Pour Jones et al. , cet examen serait le plus approprié pour évaluer la masse osseuse et devrait être beaucoup plus employé dans la population des blessés médullaires. Seule l’étude de Szollar et al. en 1998 permet de considérer que la réalisation d’une densitométrie à 12 mois serait alors un moyen de détecter une perte osseuse, mais les indications concernant la cinétique des marqueurs de l’ostéoclastogénèse suggèrent que le dépistage devrait se faire dès la phase aiguë puisque le pic de résorption osseuse se situe entre la troisième et la sixième semaine après la lésion médullaire. Par ailleurs, l’ostéodensitométrie utilisée en pratique courante explore le poignet, le rachis lombaire de L1 à L4, et la hanche totale (triangle de Ward, col fémoral, trochanter et région intertrochantérienne). Les sites les plus soumis au risque de fracture chez le blessé médullaire ne sont donc pas tous analysés, ce qui peut induire un risque de sous-estimation du niveau de perte osseuse. C’est pourquoi Shields et al., en 2005 , proposent un protocole d’évaluation de la DMO du fémur distal et du tibia proximal, zones à plus haut risque fracturaire chez les blessés médullaires. Par la suite, Morse et al. soulignent que la DMO du fémur distal est plus significative que la DMO du tibia proximal . Par ailleurs, les critères diagnostiques d’ostéoporose retenus par l’OMS ont été définis pour les femmes ménopausées, ce qui ne correspond pas à l’ensemble de la population et à la physiopathologie de l’ostéoporose du blessé médullaire. Enfin, concernant les blessés médullaires, il faut prendre en compte les paraostéoarthropathies qui sont des complications fréquentes, pouvant augmenter faussement la DMO évaluée et le matériel d’ostéosynthèse lombaire qui perturbe au niveau rachidien l’interprétation de l’examen. Ainsi, si le diagnostic de l’ostéoporose du blessé médullaire est possible par examen ostéodensitométrique, il est important d’en retenir ces quelques limites d’interprétation.
D’autres moyens d’études ont été proposés pour évaluer la densité ou la structure osseuse. Plusieurs auteurs font état de l’utilisation de la tomodensitométrie quantitative ( quantitative computed tomography [QCT]) , encore appelée scanner à haute résolution ou microscanner osseux, permettant de mesurer les zones corticales et trabéculaires séparément et d’analyser l’architecture osseuse, afin d’identifier les sujets étant plus à risque de fracture. L’unité de mesure est la densité osseuse apparente (en milligramme par centimètre cube), les normes dépendent de l’âge du patient. Liu et al. soulignent que cet examen révèlerait la présence d’ostéoporose au niveau lombaire, contrairement à l’ostéodensitométrie. Il peut être réalisé avec la plupart des appareils de tomodensitométrie sur la colonne lombaire mais nécessite des appareils spécifiques pour les os périphériques: les tomographes dédiés aux sites périphériques (pQCT). Ces derniers ont une très bonne reproductibilité mais leur coût est élevé et ils se trouvent uniquement dans certains centres spécialisés.
La technique d’évaluation par ultrasonographie quantitative est aussi rapportée, renseignant non seulement sur la densité osseuse mais aussi sur l’architecture et l’élasticité osseuses, afin d’évaluer le risque fracturaire. Les mesures sont effectuées au calcanéum ou aux phalanges. Dans son étude, Warden et al. montre qu’il n’y a pas de différence significative de précision entre l’ostéodensitométrie et l’ultrasonographie quantitative pour le diagnostic de perte osseuse à court terme au niveau du calcanéum. Mais cette technique n’est pas validée pour diagnostiquer l’ostéoporose et de ce fait, elle est actuellement réservée à la recherche.
Chez le blessé médullaire, le bilan biologique pourrait constituer un élément du diagnostic. Contrairement à l’ostéoporose post-ménopausique dont le bilan biologique est normal, on retrouve à la phase aiguë chez le blessé médullaire une augmentation de la calciurie et de la phosphaturie . Maïmoun et al., dans leur étude croisée de sept patients ayant une lésion médullaire datant de trois mois , montrent qu’à ce stade aigu, aucune variation de la DMO n’est détectée par ostéodensitométrie, alors que le dosage des marqueurs biologiques de l’homéostasie calcique montre une élévation significative de la calciurie, et une diminution de la PTH et de la 25(OH)D3. Par ailleurs, le bilan biologique sanguin et urinaire mesurant l’activité du remodelage osseux serait intéressant pour dépister cette ostéoporose. Selon Craven et al. , les marqueurs biochimiques les plus souvent dosés pour évaluer le turnover du remodelage osseux sont l’ostéocalcine, le N-télopeptide (NTX) et l’hydroxyprolinurie. Cependant, il faut prendre en compte le fait qu’une grande partie des lésions médullaires sont la conséquence de fractures vertébrales, qui induisent une perturbation des marqueurs osseux comme le CTX pendant plusieurs mois. Ainsi, les marqueurs nécessaires pour le diagnostic d’ostéoporose chez le blessé médullaire de même que le moment le plus adapté ne sont pas définis.
2.4.2
Le traitement de l’ostéoporose
Cette question chez le blessé médullaire a fait l’objet de nombreuses études et propositions, tant à visée préventive que curative, tant par médication que par moyens physiques.
Les possibilités pharmacologiques retenues concernent essentiellement les substances antiostéoclastiques.
La calcitonine, puissant inhibiteur de la résorption osseuse avec une action directe sur les ostéoclastes et sur leurs précurseurs en évitant leur fusion, réduit temporairement l’hypercalcémie et l’hypercalciurie d’immobilisation . Elle fut utilisée dans les années 1980 mais elle est actuellement abandonnée car elle ne présente pas d’efficacité réelle sur la perte osseuse.
Les bisphosphonates, inhibiteurs puissants de la résorption osseuse et de la calcification des tissus mous, sont considérés comme l’approche thérapeutique la plus adaptée pour les blessés médullaires depuis plusieurs décennies. Ils ont fait l’objet de nombreuses études chez cette population de patients, avec des résultats tendant à montrer une réduction de l’hypercalcémie et de la perte osseuse, que ce soit en préventif ( Tableau 1 ) ou en curatif ( Tableau 2 ). Globalement, un traitement préventif débuté dans la première année post-lésionnelle semble efficace, particulièrement avec des bisphosphonates administrés par voie orale comme le clodronate, le tiludronate, l’étidronate ou l’alendronate , ou par voie intraveineuse comme le zolédronate ou le pamidronate . Certaines études ont montré cependant une efficacité limitée, par exemple pour les lésions incomplètes et l’étidronate , pour la localisation tibiale et le pamidronate , ou même aucun effet par rapport à un groupe témoin pour le pamidronate . Le traitement par zolédronate, en dose unique entraîne une augmentation de la DMO à six mois mais non persistante à 12 mois . Cette durée limitée de l’utilisation du zolédronate diffère du cas de la femme présentant une ostéoporose postménopausique. Concernant le traitement curatif par bisphosphonates, seules des études utilisant l’alendronate ont été réalisées, mettant en évidence un effet bénéfique significatif. Ces études récentes, réalisées sur une durée maximale de traitement de deux ans, ne permettent pas de connaître l’évolution ultérieure de la DMO après traitement.
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