Mechanisms of osteoporosis in spinal cord injury
Li-Yang Dai, Department of Orthopaedic Surgery, Xinhua Hospital, 1665 Kongjiang Road, Shanghai 200092, China. Fax: +862165795173; E-mail: email@example.com or firstname.lastname@example.org
Osteoporosis is a known complication of spinal cord injury (SCI), but its mechanism remains unknown. The pathogenesis of osteoporosis after SCI is generally considered disuse. However, although unloading is an important factor in the pathogenesis of osteoporosis after SCI, neural lesion and hormonal changes also seem to be involved in this process. Innervation and neuropeptides play an important role in normal bone remodelling. SCI results in denervation of the sublesional bones and the neural lesion itself may play a pivotal role in the development of osteoporosis after SCI. Although upper limbs are normally loaded and innervated, bone loss also occurs in the upper extremities in patients with paraplegia, indicating that hormonal changes may be associated with osteoporosis after SCI. SCI-mediated hormonal changes may contribute to osteoporosis after SCI by different mechanisms: (1) increased renal elimination and reduced intestinal absorption of calcium leading to a negative calcium balance; (2) vitamin D deficiency plays a role in the pathogenesis of SCI-induced osteoporosis; (3) SCI antagonizes gonadal function and inhibits the osteoanabolic action of sex steroids; (4) hyperleptinaemia after SCI may contribute to the development of osteoporosis; (5) pituitary suppression of TSH may be another contributory factor to bone loss after SCI; and (6) bone loss after SCI may be caused directly, at least in part, by insulin resistance and IGFs. Thus, oversupply of osteoclasts relative to the requirement for bone resorption and/or undersupply of osteoblasts relative to the requirement for cavity repair results in bone loss after SCI. Mechanisms for the osteoporosis following SCI include a range of systems, and osteoporosis after SCI should not be simply considered as disuse osteoporosis. Unloading, neural lesion and hormonal changes after SCI result in severe bone loss. The aim of this review is to improve understanding with regard to the mechanisms of osteoporosis after SCI. The understanding of the pathogenesis of osteoporosis after SCI can help in the consideration of new treatment strategies. Because bone resorption after SCI is very high, intravenous bisphosphonates and denosumab should be considered for the treatment of osteoporosis after SCI.
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Osteoporosis is a disease of the skeletal system characterized by low bone mass and deterioration of bone tissue; it leads to an increased risk of bone fractures. Osteoporosis is one of the inevitable complications of spinal cord injury (SCI), occurring predominantly in the pelvis and the lower extremities.1–5 The decline in bone mineral density (BMD) and bone mineral content (BMC) has been amply documented in acute and chronic SCI patients.6–10 In addition, trabecular microarchitecture in the sublesional bones deteriorates in SCI patients.11,12 Several clinical studies have reported a high incidence, ranging from 1% to 34%, of lower extremity fractures in SCI patients.13–16 Currently, the acute treatment of patients with SCI always focuses on the neural lesion itself and the immediate complications that arise subsequently. Historically, osteoporosis as a consequence of SCI has been of secondary concern. The pathogenesis of osteoporosis after SCI is generally considered disuse.17,18 However, recent work suggests that bone remodelling is regulated by nerve-derived signals, such as vasoactive intestinal polypeptide (VIP), calcitonin gene-related peptide (CGRP), pituitary adenylate cyclase activating peptides (PACAPs), neuropeptide Y (NPY) and substance P (SP), as well as classical neuromediators such as noradrenaline, serotonin and glutamate.19 Although unloading plays a role in the pathogenesis of osteoporosis after SCI, neuronal mechanisms should not be overlooked. In addition to mechanical and neuronal mechanisms, hormonal changes should be considered because bone loss also occurs in the upper extremities in patients with paraplegia,8,20,21 although in these patients, the upper extremities are normally loaded and innervated. If the diagnosis, treatment and prevention of SCI-induced osteoporosis are to be improved, the mechanisms involved need to be understood in greater detail. This review focuses on the mechanisms of osteoporosis after SCI, with special reference to the effects of unloading, and the neural lesion and hormonal changes in the pathogenesis of osteoporosis.
Methods of acquiring literature
All published literature written in English was obtained from MEDLINE until July 2006 using the search terms ‘spinal cord injury’ and ‘bone mineral density’ or ‘osteoporosis’. All articles on the possible mechanisms of osteoporosis after SCI were included in this review.
Osteoblasts and osteoclasts
The maintenance of bone homeostasis relies on bone remodelling, which continually replaces old and damaged bone with a new bone in order to maintain bone strength and elasticity.22 Two types of cells are involved in the bone remodelling process: osteoclasts, originating from haematopoietic cells, are responsible for bone resorption; and osteoblasts, originating from mesenchymal cells, are responsible for bone formation.23 SCI-induced bone loss results from unbalanced bone remodelling. Thus, an oversupply of osteoclasts, relative to the need for bone resorption, and/or an undersupply of osteoblasts, relative to the need for cavity repair, may be crucial pathogenic factors in osteoporosis after SCI.
Increased bone resorption after SCI has been demonstrated clinically. Thus, SCI has been shown to lead to increased urinary excretion of hydroxyproline, pyridinoline, deoxypyridinoline and type I collagen C-telopeptide.2,10,24,25 Consistent with these findings, SCI was found to promote human osteoclast formation ex vivo.26 The key molecule for osteoclast development is the receptor activator of the NF-κB ligand (RANKL),27 which is expressed on the surface of bone marrow stromal/osteoblast precursor cells, T cells and also B cells. RANKL binds its cognate receptor, RANK, on osteoclast lineage cells,28 and is neutralized by the soluble, decoy receptor, osteoprotegerin (OPG), which is also produced by osteoblastic lineage cells.29 One study has now demonstrated that RANKL mRNA and protein expression in cultured osteoblast-like cells from SCI rats was significantly increased, while OPG expression was significantly decreased, and an enhanced RANKL/OPG ratio may result in increased osteoclastogenesis, thus leading to osteoporosis after SCI.30 In addition to the effects of SCI on RANKL and OPG expression, SCI also regulates the production of additional cytokines in bone marrow cells, thus modulating osteoclastic activity in a paracrine fashion. There is evidence that bone-resorbing cytokines, such as interleukin (IL)-6, may be a potential candidate for mediating the bone loss following SCI.26 Bisphosphonates have a high affinity for calcium and therefore target bone minerals, where they appear to be internalized selectively by bone-resorbing osteoclasts and inhibit their function, promote apoptosis, and thus reduce bone resorption and bone loss.31 In addition, alendronate has been demonstrated to be effective in preventing bone loss in SCI patients.24,32
Findings with respect to SCI-mediated effects on osteoblasts are less consistent. With regard to the essential role of osteoblasts in the process of bone remodelling, changes in osteoblastic activity have been evaluated. Histomorphometric analysis showed increased bone formation within 1 month of injury, and then the bones below the lesion appeared to be involved in a second onset of reduced bone formation.33 However, normal or elevated serum osteocalcin and alkaline phosphatase (AKP) were noted in SCI patients.2,10,25 It has also been demonstrated that there is no obvious change in core binding factor alpha-1 (Cbfa-1) and AKP mRNA expression in cultured osteoblast-like cells from SCI rats 3 weeks after injury, indicating that SCI may have no effect on osteoblast function at the early stage of injury.30
Current data on the function of bone cells impaired by SCI indicate that the development of osteoporosis is due more to increased bone resorption than to bone formation. However, it should be emphasized that the effects of SCI on both types of bone cells should always be considered not in isolation, but together. The factors that potentially influence these two types of bone cells are discussed below.
In SCI patients, demineralization predominates in the long bones of the lower limbs, and the most affected sites are the trabecular metaphyseal–epiphyseal areas of the distal femora and proximal tibiae.21,34,35 However, maximal bone loss occurs in the calcaneus and the hip after loss of mechanical stimulation, with less involvement of the tibiae, and the bone loss after SCI is much more severe than that after loss of mechanical stimulation.36 In addition, the levels of serum bone resorption markers after SCI are extremely high,2,10 compared with those reported after disuse.37–39 Functional electrical stimulation (FES) cycle ergometry, which produces active muscle contractions in the paralysed limbs, was expected to increase BMD in SCI patients; however, some studies found no difference in the BMD of the lower limbs before and after the FES-cycling intervention of 3–12 months.40–42 In one animal study, we found that SCI resulted in more bone loss, more trabecular deterioration, poorer mechanical properties, and higher bone turnover than loss of mechanical stimulation.43 Reduced osteoblastogenesis contributes to the observed bone loss after loss of mechanical stimulation,44 while cultured mesenchymal stem cells from SCI rats showed no reduction in osteoblastogenesis compared with those from sham-operated rats. From the pathophysiological point of view, it seems that some factors other than loss of mechanical stimulation, such as neural lesion and hormonal changes, may also play a pivotal role in the development of osteoporosis after SCI.
During remodelling, alignment of new bone is along the dominant local loading direction, suggesting local regulation of bone formation by mechanical stimulus.45 Mechanical loading is known to be a crucial stimulus for bone formation and resorption, thereby controlling bone mass, structure and strength. The skeleton possesses an inherent biological control system that directs bone formation in response to high mechanical stresses (or strains), thus strengthening the skeleton in highly stressed regions. This system, sometimes called the ‘mechanostat’, involves the resident cells within bone tissue that detect and respond to mechanical loads. It has become clear over the past several years that the osteocytes are the professional mechanosensory cells of bone. Osteocytes situated in the bone matrix respond to mechanical load signals,46,47 and the gap junction of the long processes of osteocytes transmits mechanical load signals48 via intracellular signal transmitters (Ca2+, IP3, cAMP, cGMP)49,50 and extracellular signal transmitters (PGE2, PGI2, IGF-1, IGF-2 and TGF-β)51 to induce bone formation by osteoblasts, inhibition of bone resorption by osteoclasts, or a combination of the two. The effect of mechanical loading on bone tissue is an increase in bone formation on the periosteal bone surfaces, thus improving bone strength and reducing bone turnover and bone porosity. Consequently, mechanical loading can improve both bone size and shape and strengthen the bone tissue by improving tissue density. Unloading induces osteoblastic cell suppression and osteoclastic cell activation to lead to bone loss.44,52
SCI causes unloading and restricted movement of the lower limb joints for substantial periods of time, and substantial muscle atrophy has been reported in SCI patients.53 Unloading may play an important role in the development of osteoporosis after SCI.54 If bone loss following SCI results from unloading, this raises the question of whether functional exercise can prevent bone loss after SCI, as osteopaenia following bed rest or weightlessness can be reversed by ambulation or return to normal gravity.55,56 However, most studies have reported that weight-bearing exercises with standing frames and bikes, using forms of FES, are ineffective in preventing osteoporosis or restoring bone mineral in SCI patients.40–42,57 By contrast, Shields et al.58 and Mohr et al.59 have reported that electrically induced muscle contractions influence bone density decline after SCI. Therefore, from the pathophysiological viewpoint, it is hypothesized that unloading may not be the only factor in the pathogenesis of SCI-induced osteoporosis, and other factors should be taken into account. It has been demonstrated that the sympathetic nervous system (SNS) is a transmitter of mechanical loading on bone,60 and the ineffectiveness of mechanical loading on bone in SCI patients may be related to the denervation of the SNS.
It is well documented that both sympathetic and sensory nerve fibres are present in the periosteum, bone marrow and mineralized bone.61–67 In cortical bone, nerve fibres run within Haversian or Volkmann channels. In the ephiphysis and metaphysis of long bones, nerve fibres run along the trabeculae facing the growth plate.68,69 In these areas, sympathetic and sensitive nerve processes form dense parallel networks around blood vessels adjacent to bone trabeculae, in close contact with bone cells.68–70 In addition, nerve endings corresponding to dilatations of these nerve processes have been found in contact with medullary cells and bone cells. Bone deprived of its sympathetic innervation shows reduced bone deposition and mineralization as well as increased bone resorption.71,72 Furthermore, osteoporosis has been induced in nonweight-bearing mandibular bones in animals that have been sympathectomized. Sensory nerves also appear to be important in normal bone metabolism.73 Innervation of bone is reported to have trophic effects on bone metabolism and a growing number of experimental and clinical studies indicate that innervation is important for bone remodelling.
Many neuropeptides, previously identified in the central nervous system (CNS), have also been localized in bone and play an important role in bone cell functions, thus affecting bone formation and resorption.74–77 These neuropeptides include VIP, PACAPs, NPY, SP, CGRP, noradrenaline, glutamate and serotonin.63 For most of these neuropeptides, receptors on bone cells have been identified and a number of in vivo and in vitro studies have shown that these receptors are functional and can affect osteoclast and osteoblast activities.63,74
As indicated earlier, the alterations in bone remodelling observed after sympathectomy and sensory denervation are associated with changes in skeletal nerve fibres. Innervation density has been shown to decrease dramatically after sciatic neurectomy.78 Similarly, SCI may lead to a significant decrease in innervation density and neuropeptides in the sublesional bones, thus distorting the balance of bone formation and resorption.
In addition to the direct role of denervation on bone metabolism, denervation after SCI can cause disordered vasoregulation, thus affecting bone remodelling. Complete SCI results in an interruption of the pathways from the brain to the peripheral SNS,79–81 and this interruption leads to pathological changes in the sympathetic innervation through the anatomical reorganization of pathways in the spinal cord.82 The disorders of the SNS after SCI cause the opening of the bone intravenous shunts, thus leading to a venous and capillary vascular stasis.83,84 The vascular modification below the neurological lesion may have an influence on the development of osteoporosis after SCI. This plays a role in the increased bone resorption by inducing a local modification of the endosteal surface. The decrease in gas exchange and blood nutritive supplies to the bone due to venous stasis could promote osteoclast formation because of local hyperpressure, thus accelerating bone resorption.85 This clear predominance of bone demineralization in the highly vascularized metaphyseal–epiphyseal areas of the long bones constitutes an additional argument. However, there is indeed a significant local vascularization at the level of these areas, which would be particularly affected by a secondary intramedullary blood stasis due to the sublesional vasomotor disorders. The interrupted vasoregulation after SCI may be another contributory factor to the pathogenesis of osteoporosis after SCI.
Bone remodelling is a process of bone renewal accomplished by two opposing activities of bone cells: bone resorption by osteoclasts and bone formation by osteoblasts. Although upper limbs are normally loaded and innervated, bone loss also occurs in the upper extremities in patients with paraplegia. Therefore, systemic hormones such as PTH, vitamin D3, sex steroids, thyroid hormone and leptin may also be involved in bone loss following SCI.
In general, SCI patients showed negative calcium balance with hypercalciuria after the injury.2,86–92 The increased osteoclastic bone resorption is mainly responsible for hypercalciuria following SCI. In addition, reduced renal function has been observed in acute SCI patients,92 and the increased urinary elimination of calcium that occurs in response to SCI may be related to diminished renal tubular reabsorption. Exercises and ambulation significantly decrease the hypercalciuria and modify the calcium balance in a positive direction,90,91 indicating that immobilization may be an important factor resulting in this negative calcium balance. Absorption of calcium from the gastrointestinal tract has been found to decrease in the acute phase following SCI.93 In particular, dietary calcium reduction has been commonly recommended to decrease calcium excretion and prevent the complications of hypercalciuria,92 which may lead to the negative calcium balance. Therefore, dietary restriction of calcium should not be applied to SCI patients. Kaplan et al.91 reported that a diet with 1600 mg calcium daily was applied to SCI patients to modify the calcium balance. In this study, those with spinal cord injuries of less than 3 months’ duration had a calcium balance of −27 mg, and patients with spinal cord injuries of 6 months’ duration or more had a calcium balance of 55 mg. Injury duration appears to have an influence on the calcium balance. This raises the question: does the high level of dietary calcium intake result in an increased risk of renal calculi? Kohli et al.94 reported no relationship between serum calcium levels and kidney stone formation in SCI patients.
PTH and vitamin D
After acute SCI, the PTH–vitamin D axis is suppressed, with depressed PTH and 1,25(OH)2 vitamin D. A decrease in serum PTH levels was observed in patients 3 weeks after SCI in a longitudinal study.10 In other cross-sectional studies, it was demonstrated that PTH and 1,25(OH)2 vitamin D levels were suppressed in acute SCI patients compared with controls.2,25 PTH suppression in SCI patients is also associated with the degree of neurological impairment. In a cross-sectional study, Mechanick et al.95 investigated serum PTH and 1,25(OH)2 vitamin D levels in SCI patients, who were tested at a mean of 76·5 days postinjury, and found that patients with complete SCI, when compared to those with incomplete injury, had a greater suppression of the PTH–vitamin D axis. Secretion of PTH and the increase in circulating 1,25(OH)2 vitamin D are subjected to control by negative feedback mechanisms related to serum calcium level. In addition, hypercalcaemia after injury may lead to this PTH–vitamin D axis suppression in the acute phase of SCI. Considering all these data, the dysfunction of the PTH–vitamin D axis soon after SCI is unlikely to be involved in the pathogenesis of bone loss after the injury.
However, a reversal in parathyroid activity from 1 to 9 years after injury has been noted. The parathyroid gland is stimulated to the point where PTH levels are above the reference range. Secondary hyperparathyroidism has always been thought to accelerate the development of SCI-induced osteoporosis. Bauman et al.96 showed mild secondary hyperparathyroidism in a subgroup of subjects with chronic SCI. In other studies, chronic SCI has been reported to result in either no change25 or a decrease in plasma PTH levels.87 Therefore, the current balance of evidence does not support secondary hyperparathyroidism as a contributory mechanism in the pathogenesis of SCI-induced osteoporosis.
Findings on vitamin D metabolism in chronic SCI patients are also less consistent. Bauman et al.96 reported that the average serum 1,25(OH)2 vitamin D levels in chronic SCI patients were significantly higher than those in controls. This elevation reflects an augmented PTH effect on 1-α-hydroxylase activity in renal tubular cells, and absolute elevation in serum PTH levels in some SCI patients may result in significantly higher 1,25(OH)2 vitamin D levels.96 However, in another cross-sectional study, serum 1,25(OH)2 vitamin D levels in chronic SCI patients were reduced as compared to controls.87 These discrepancies have been assigned to differences in racial mix, diet, and sunlight exposure. Besides this difference in the 1,25(OH)2 vitamin D levels in chronic SCI patients, an increased prevalence of vitamin D deficiency has been reported in patients with chronic SCI.96,97 Because of the tendency for calcium nephrolithiasis soon after SCI, patients with chronic SCI are often instructed to restrict calcium intake, chiefly from dairy products. This dietary restriction may also result in vitamin D deficiency because dairy products, especially milk, are fortified with vitamin D and generally serve as the main source of dietary vitamin D. Those with SCI may also have reduced sunlight exposure or may receive anticonvulsants and other medications that induce hepatic microsomal enzymes, thus accelerating vitamin D metabolism.98–100 Therefore, vitamin D deficiency may contribute to the development of SCI-induced osteoporosis. In a randomized, placebo-controlled trial of 40 chronic SCI patients, a vitamin D analogue [1-alpha D(2)] was demonstrated to increase leg BMD 24 months after treatment, and urinary N-telopeptide, a marker of bone resorption, was significantly reduced during treatment with 1-alpha D(2), but not in the placebo group.101 In some countries fluid milk products have been fortified with vitamin D to reduce the incidence of disorders caused by vitamin D deficiency, but the levels of fortification may vary.102
Insulin and IGF-1 and IGF-2 are known to influence bone metabolism. Receptors for insulin and IGF-1 are present on osteoblastic cells103,104 and both substances promote osteoblast differentiation and survival, and prevent apoptosis.105–107
SCI patients were found to have a marked reduction in whole-body glucose transport that seemed to be due to a proportional reduction in muscle mass,108 and denervation of skeletal muscle has been shown to cause insulin resistance.109 Insulin resistance may be another contributing factor leading to osteoporosis following SCI. In addition, growth factors and their second messengers, such as IGF-1, have been reported to be depressed in patients with chronic SCI. Bauman et al.110 reported a blunted GH release in SCI patients, to provocative stimulation with intravenous arginine. The average plasma IGF-1 level was significantly lower in SCI patients as compared to controls. Similarly, Shetty et al.111 reported that the average plasma IGF-1 level in patients with tetraplegia was depressed when compared with ambulatory controls. Reduced GH and IGF-I levels may also lead to the development of insulin resistance.112–115 These studies suggest that bone loss after SCI may be caused, at least in part, by the depressed IGFs. However, in a recent study with SCI patients, Maimoun et al.116 did not demonstrate a role of growth factors in accelerated bone resorption following SCI.
Effects on gonadal function
Sex steroids play a pivotal role in regulating bone remodelling. Oestrogens as well as androgens have been shown to inhibit osteoblastic release of local stimulating factors of osteoclastogenesis.117 Thus, a decrease in the circulating concentrations of these hormones increases osteoclast precursor formation in the bone marrow and thus increases the number of mature osteoclasts in cancellous bone.118 Lower circulating concentrations of sex steroids in females after menopause or ovariectomy and in males after orchidectomy have led to increased bone loss. In addition, FSH directly increases osteoclastogenesis and bone resorption.119 Therefore, sex steroid replacement can help to prevent these changes. If no replacement is given, osteoporosis can develop as a result of reduced bone formation and stimulated bone resorption.120,121
The inhibitory effect of SCI on the synthesis and secretion of sex steroids therefore contributes to the pathogenesis of SCI-induced osteoporosis. Although the literature provides conflicting data, there are subsets of SCI men with relative or absolute androgen deficiency.122–126 Maimoun et al.116 reported recently that total testosterone and the free androgen index were significantly lower in SCI patients than in able-bodied controls. The aetiology of a relative deficiency of testosterone in SCI patients has not been elucidated. Several medications, such as psychotropic medications, are known to affect testicular secretory function,127,128 and prolonged sitting and euthermia of the scrotal sac and testis may itself have a deleterious local effect on testosterone production.129 No significant change in serum gonadotrophin concentration was observed in SCI men by Tsitouras et al.125 and Wang et al.,130 while in another cross-sectional study, it was demonstrated that there was a high prevalence of low serum gonadotrophins and a delayed appearance of the gonadotrophin peak response to LH-releasing hormone (LHRH) in SCI men.131 These studies suggest that SCI may suppress the hypothalamic–pituitary–testis axis at different levels, including the hypothalamus, the anterior pituitary gland and the gonads. These endocrine abnormalities may be the mechanisms contributing to the development of osteoporosis after SCI.
Serum oestrogen levels in SCI women are also significantly lower than in controls.132 An enhanced gonadotrophin response to LHRH has been reported in a group of SCI women, indicating a hypothalamic disorder within the hypothalamus–pituitary–ovary axis.133 These studies suggest that there is a high prevalence of hypothalamic–pituitary–ovary axis disorders in SCI women, and these disorders may be involved in the pathogenesis of osteoporosis after SCI. It would seem appropriate to recommend hormone replacement therapy (HRT) for short-term relief of menopausal symptoms, but to consider alternative managements for osteoporosis prevention in women with SCI.134 However, HRT may result in an increased risk of thromboembolism in postmenopausal women with SCI.
The leptin receptor is located in human osteoblasts and mesenchymal stem cells undergoing osteogenic differentiation, as well as in the hypothalamus. Leptin is a significant factor in the regulation of bone metabolism, and is thought to regulate bone mass by alternate pathways, one involving a direct, stimulatory effect on bone growth when administered peripherally,135,136 and another that is indirect, involving a hypothalamic relay that suppresses bone formation when administered centrally.137–139 As leptin is a systemic hormone, it seems that the peripheral effects of leptin on the skeleton outweigh its central action.140
SCI may result in progressive loss of the percentage of total lean body mass and an increase in percentage fat mass.141 Denervation atrophy and reduced energy expenditure after injury may be implicated in this.142 However, regardless of the mechanism, the increase in fat mass would be expected to stimulate the release of leptin. Plasma leptin concentration is markedly elevated in SCI patients compared with able-bodied controls.143–145 Although the higher leptin levels simply reflect the presence of more of the adipose tissue producing the hormone, the increased plasma concentration of leptin in SCI patients with augmented body fat accumulation suggests that these individuals may have become insensitive to leptin.146 The mechanism for the possible leptin resistance is not known. SCI patients are less physically active and have a lowered activity of the SNS so that leptin production and secretion might be augmented.147,148 The increased plasma concentration of leptin in SCI patients and the accompanying augmented circadian variation might distort the normal turnover of bone tissue in SCI patients, leading to osteoporosis.143
Effects on thyroid function
Any condition of traumatic stress in which caloric intake is reduced, especially a reduction in carbohydrate intake, will be associated with changes in serum thyroid hormone levels. Medications, especially corticosteroid administration, frequently prescribed immediately after SCI, may also alter serum thyroid hormone levels.149 It has been demonstrated that serum T3 and T4 levels remain depressed in acute SCI patients.150–154 After acute stress, there may also be associated changes in thyroid hormone binding that could lower serum thyroid hormone levels.155 Similarly, in chronic SCI patients, serum T3 and T4 levels were also reduced as compared with controls.156 Of note, patients with tetraplegia had lower serum T3 levels than did those with paraplegia.130 These data suggest a thyroid disorder within the hypothalamic–pituitary–thyroid axis. As many in vivo and in vitro studies have demonstrated that T3 or T4 can directly enhance osteoclastic activity, dysfunction of the thyroid gland after injury is unlikely to be involved in the pathogenesis of SCI-induced osteoporosis.157–159
Several studies have reported normal plasma concentrations of TSH in chronic SCI patients.133,153,154,160,161 However, these studies have relied on a single morning sample in the determination of TSH concentration. While TSH displays a daily rhythmicity, and a single time point is insufficient to assess the 24-h profile, Zeitzer et al.162 investigated the 24-h average and the circadian amplitude of the TSH rhythm in the chronic SCI patients and found that they were within the low end of the normal range. This suggests that there may be pituitary suppression of TSH after SCI.163 Abe et al.164 demonstrated a crucial role for TSH in bone remodelling that is independent of its effects on circulating thyroid hormone. TSHR knockout mice display high turnover osteoporosis. These data suggest that a small decline in TSH amplitude in chronic SCI patients may be a contributory factor in the pathogenesis of osteoporosis.
Glucocorticoids impair the proliferative and metabolic activity of osteoblasts, decrease osteoblastogenesis and promote osteoblast apoptosis,165–168 thus leading to a reduction in bone formation and bone loss.
Hypercortisolism found in acute SCI patients may be therapeutic or stress related.151 Therefore, glucocorticoids may contribute to the bone loss following SCI. However, findings on the effects of chronic SCI on serum cortisol levels are less consistent. A number of studies have provided conflicting data on the glucococorticoid amplitude in chronic SCI patients, with some claiming low, others claiming normal, and yet others claiming high circulating concentrations of cortisol or its metabolite 17-hydroxycorticosteroid in such patients.169–174 These discrepant findings have been assigned to differences in time points in the determination of amplitude. The current balance of evidence does not support the idea that the changes in serum cortisol levels may be a contributory factor in the pathogenesis of osteoporosis in chronic SCI patients.
Summary and perspective
Osteoporosis is one of the most frequent complications following SCI, resulting from an imbalance in bone formation and resorption. It has been suggested that increased bone resorption is due predominantly to the increased number of osteoclasts. However, SCI has no obvious effects on osteoblast function. Although unloading after SCI is considered to be the most important factor in the development of osteoporosis after SCI, it is not the only factor. Thus, it was hypothesized that the neural lesion itself after SCI may play a pivotal role in the pathogenesis of osteoporosis by taking a direct role in denervation on bone, or indirectly by disrupting vasoregulation. SCI-mediated effects have been reported in a wide variety of tissues. They may occur in the intestine, the kidneys, the gonads, the fat and the parathyroid glands and could thus contribute to the pathogenesis of SCI-induced osteoporosis.
The pathogenesis of osteoporosis after SCI is a complex process, and should not be simply considered disuse osteoporosis. Understanding the pathogenesis of osteoporosis after SCI helps in the consideration of new treatment strategies. If functional exercises seem ineffective in increasing BMD in SCI patients, can the application of selected neuropeptides increase BMD? The observed changes in BMD in SCI patients treated with alendronate were below what was observed in postmenopausal women or in osteoporotic men at the standard treatment dose of 10 mg daily,24 and many problems in the application of oral bisphosphonates on SCI patients, such as the ideal timing and dose, should be further investigated. Bisphosphonates are administered intravenously for the treatment of hypercalcaemia of malignancy and Paget's disease of bone,175,176 in which either the osteoclast is abnormal or bone resorption is excessively high. Similarly, bone resorption after SCI is extremely high, but are intravenous bisphosphonates more effective than oral bisphosphonates? Denosumab is a human monoclonal antibody that binds to RANKL with high affinity and specificity and blocks the interaction of RANKL with RANK, mimicking the endogenous effects of OPG. Denosumba may be an alternative for the treatment of osteoporosis after SCI. HRT is the first choice for prevention of postmenopausal osteoporosis, but there are still no clinical reports on the efficacy of oestrogen with regard to osteoporosis following SCI. However, an increased risk of thromboembolism is likely to complicate HRT in women with SCI.