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A novel therapeutic strategy for adolescent idiopathic scoliosis based on osteoporotic concept
Medical Hypotheses 80 (2013) 773–775
Contents lists available at SciVerse ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
A novel therapeutic strategy for adolescent idiopathic scoliosis based on osteoporotic concept Lingyun Lu a, Zhehao Dai a,b,⇑, Guohua Lv a, Yijun Kang a, Yebin Jiang b a b
Department of Spine Surgery, The 2nd Xiangya Hospital of Central South University, Changsha 410011, China Osteoporosis and Arthritis Lab, University of Michigan, Ann Arbor, MI 48109, USA
a r t i c l e
i n f o
Article history: Received 13 May 2012 Accepted 9 March 2013
a b s t r a c t Adolescent idiopathic scoliosis (AIS) is a complex three dimensional spinal deformity which occurs mostly in prepubertal and pubertal girls. Although bracing and surgery have been the mainstays of treatment for AIS, because of the complications and poor compliance, many patients with this disorder continue to experience significant residual symptoms. The etiology and pathogenesis of AIS is unclear, but recent studies show the association between osteopenia and AIS and imply that osteopenia play a causative role in the development of AIS. Anti-osteoporosis treatment can improve bone strength, prevent osteoporosis and rebalance the OPG–RANK–RANKL system, which may help to prevent curve progression in AIS. This report proposes that anti-osteoporosis treatment may be an effective treatment for AIS. Ó 2013 Elsevier Ltd. All rights reserved.
Background The skeletal system functions were based on the continuous remodeling by the coupled activity of osteoclasts and osteoblasts [1]. The balance between the activities of both cell types is related with bone diseases [1]. Osteoporosis is a skeletal disease with bone resorption exceeding bone formation characterized by low bone mass and micro-architectural deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to fracture. Adolescent idiopathic scoliosis (AIS) is a complex three dimensional deformity of the spine [2]. It is seen in 2–4% of the adolescent population, more commonly in girls [3], especially during prepubertal and pubertal growth, when bone acquisition is highest. The etiology and pathogenesis of AIS is unclear, but recent studies show the association between osteopenia and AIS and imply that osteopenia play a causative role in the development of AIS. So that we propose the hypothesis that anti-osteoporosis medicine may be an option for treatment of AIS. Hypothesis and reasoning Current treatment for AIS Treatment of AIS consists of non-operative treatment and surgical operation. Bracing has been the mainstay of non-operative treatment for AIS for nearly 50 years. Other non-operative ⇑ Corresponding author at: Department of Spine Surgery, The 2nd Xiangya Hospital of Central South University, Changsha 410011, China. Tel.: +86 731 85295125; fax: +86 731 85295124. E-mail address: [email protected] (Z. Dai). 0306-9877/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mehy.2013.03.008
treatment including electrical stimulation, biofeedback, manipulation, physical therapy, and exercise do not have convincing evidence of their effectiveness [4]. Although the similar surgery rate for unbraced patients compared with braced patients was reported by Goldberg [5,6], many other studies demonstrate that bracing is an effective modality preventing curve progression [7–10]. That bracing provided an external force to the trunk during the adolescent growth phase helps prevent progression. Surgery is another option which rebuilt coronal and sagittal balance to prevent curve progression through rigid spinal fusion [11–13]. However, bracing and surgery still have obvious disadvantages. The former always created great mental pressure and physical discomfort so that the compliance was poor. Pseudoarthrosis, back pain and instrument failure were obstacles to successful surgical treatment. Nonetheless, the only two accepted treatment methods implied that the reconstruction of spine balance and the improvement of bone strength will help prevent the curve progression. Anti-osteoporosis treatment provides an internal force to the trunk during the adolescent growth phase which may prevent curve progression of AIS. Anti-osteoporosis treatment, which includes anti-catabolic therapy and anabolic therapy, is an established medical treatment for the patients with osteoporosis. These therapies have been shown to reduce the risk of vertebral and non-vertebral fracture by approximately 50% and 30%, respectively in large randomized controlled trials [14], which rebalance the activity of osteoclasts and osteoblasts to enhance bone strength. Bone strength is determined by bone density (expressed as grams of mineral per area or volume) and bone quality (architecture, bone turnover, microfractures, mineralization). Anabolic therapy with recombinant human parathyroid hormone (rhPTH 1-34 or rhPTH 1-84) can
774
L. Lu et al. / Medical Hypotheses 80 (2013) 773–775
stimulates bone formation first and stimulates both resorption and formation subsequently, though the balance remains positive [15– 17].The growth of new bone induced by PTH restores the bone micro-architecture, including improved trabecular connectivity and enhanced cortical thickness [18,19]. Bone formation may on the outer periosteal surface affects bone size and geometry, with additional beneficial effects to bone strength [20–23]. Denosumab, a new anti-catabolic agent approved by FDA in 2010, can significantly increase area bone mineral density (aBMD) at the lumbar spine, total hip, femur neck, and distal radius and cortical volumetric bone mineral content (vBMC) of the central radius and tibia and greater peak load for femur neck, L3–L4 vertebral bodies, and L5– L6 cancellous cores in ovariectomized cynomolgus monkeys [24]. These finding suggests that anti-osteoporosis treatment may provide an internal force to the trunk during the adolescent growth phase to prevent curve progression for AIS patients. Prevention of osteopenia could be as important as controlling spinal progression in the management of AIS Since Burner and his co-workers used the Singh index to evaluate the femoral trabecular pattern and conclude that children with AIS had relative osteoporosis compared with healthy control individuals in 1982 [25], the relationship between osteoporosis and AIS had attracted attention increasingly. The skeletal sites involved thoracolumbar spine, bilateral proximal femurs, lumbar spine, bilateral distal tibias and radius in AIS patients showed a low BMD compared with controls [26–28]. It seemed that low BMD was a generalized and systematic phenomenon in AIS patients. Histomorphometric and micro CT (lCT) data on iliac crest biopsies and vertebrae of scoliosis patient showed a deteriorated bone structure too [26,29]. Deteriorated bone structure along with the axial loading will lead to microfractures which may result in a spinal asymmetry, which may be aggravated by the aid of bone remodeling according to Hueter–Volkmann law, where the concave side would diminish in growth, while the convex side would have an enhanced growth. The presence of low BMD in the preand early menarche in AIS girls [26,30,31] and the reduction in osteoclasts and osteoblasts number and dynamic activity which were found in the histomorphometry [32] revealed the abnormal bone metabolic activity and growth disturbance and indicated that osteopenia could be a causative factor rather than the result of the deformity. The report by Warren et al. found that girls with AIS indeed had lower BMD and BMC in lumbar spine, proximal femur and distal tibia compared with healthy non-AIS counterparts, and conclude that curve severity was an inverse and independent associated factor on bone mineral mass of AIS during peripuberty [27]. These finding may indicate that prevention of osteopenia could be as important as controlling spinal progression in the management of AIS. Anti-osteoporosis therapies which re-balance OPG–RANK–RANKL system may be an option for treatment of AIS The exact mechanisms and causes of the bone loss and bone structure deterioration in AIS have not been identified yet, but recent data demonstrated that the imbalance of OPG–RANK–RANKL system might be one of the mechanisms. Receptor activator of nuclear factor-kB ligand. RANKL regulates osteolysis and osteoclast differentiation directly by binding receptor activator of nuclear factor kB (RANK) which located in the cell membrane of osteoclasts and their precursors. In contrast, osteoprotegerin (OPG) is a soluble decoy receptor for RANKL which interferes with RANKL/RANK binding [33]. Suh et al. [34] and Chiru [35] found that the mean serum RANKL and RANKL to OPG ratio in patients with AIS were increased
and negatively correlated to the lumbar spinal bone mineral density and serum OPG levels. These findings mean that the imbalance and the disturbed interaction of RANKL and OPG may be an important cause and pathogenesis in reduced BMD in AIS. A study about the therapeutic application of melatonin for AIS showed that 12 in 16 patients with low melatonin levels were treated with oral melatonin and developed stable scoliosis [36]. This is the first clinical report to demonstrate the melatonin supplementation could prevent the scoliosis progression. Melatonin promotes the osteogenic differentiation of bone marrow stem cells and the synthesis OPG [37]. In mouse, melatonin increases the mRNA and protein levels OPG and decreases the expression of RANK mRNA even at micromolar doses [38]. Although no clinical trials have focused on the melatonin in the treatment of osteoporosis, many experimental studies suggest that melatonin [37,39] and its synthetics [40,41] can prevent bone degradation and promote bone formation in ovariectomized rats. These findings showed that the OPG–RANK– RANKL system played a central role in both osteoporosis and AIS and was one of the mechanisms leading to low bone mass in AIS; therefore, we believed that some established anti-osteoporosis therapies which restored the unbalanced OPG–RANK–RANKL system may be an option for treatment of AIS. rhPTH, the only anabolic drug with FDA-approved labeling for prevention or treatment of osteoporosis, not only binds to the PTH/PTH-related protein (PTH/PTHrP) receptor on the surface of the osteoblasts to induce a cascade that activates protein kinase 1-cyclic AMP, protein kinase C, and phospholipase C [42] which increase the number of active osteoblasts, decreases osteoblast apoptosis, and may recruit bone-lining cells as newly formed osteoblasts, but also stimulate the expression of an osteoclast differentiating factor (ODF) by the marrow stromal cells and osteoblasts. ODF binds to RANK to activate the bone resorption, but this binding can be inhibited by OPG. Denosumab, a fully human monoclonal antibody of the IgG2 immunoglobulin isotype, binds to RANKL with a high affinity and specificity to prevent RANKL– RANK interaction as the same way as OPG does, resulting in a decrease in osteoclastic bone resorption. Consequently, rhPTH and denosumab may have the potential ability to re-balance OPG– RANK–RANKL system. Hypotheses Taken together, these strands of clinical and experimental evidence suggest that some established anti-osteoporosis therapies may provide an internal force to the trunk, prevent osteopenia and restore the unbalanced OPG–RANK–RANKL system during the adolescent growth phase to prevent curve progression for AIS patients. We hypothesize that anti-osteoporosis therapies may become an effective treatment for AIS. Testing our hypothesis This hypothesis could be easily tested with AIS models in twofeet-rat with making linkage between scapula and pelvis. From a baseline period, all the rats would be randomized to receive rhPTH, denosumab or placebo during the treatment phase of the study. Cobb angle and vertebral rotation angle, BMD and bone structure, bone biomechanics, the level of RANK, RANKL, OPG and ODF in serum would be tested and compared among all groups. Our hypothesis, after testing and confirmation, may provide a novel therapeutic strategy for AIS patients. Conflict of interest statement None declared.
L. Lu et al. / Medical Hypotheses 80 (2013) 773–775
References [1] Matsuo K, Irie N. Osteoclast–osteoblast communication. Arch Biochem Biophys 2008;473:201–9. [2] Lonstein JE. Scoliosis: surgical versus nonsurgical treatment. Clin Orthop Relat Res 2006;443:248–59. [3] Armstrong GW, Livermore 3rd NB, Suzuki N, Armstrong JG. Nonstandard vertebral rotation in scoliosis screening patients. Its prevalence and relation to the clinical deformity. Spine (Phila Pa 1976) 1982;7:50–4. [4] Dickson RA. Spinal deformity – adolescent idiopathic scoliosis. Nonoperative treatment. Spine (Phila Pa 1976) 1999;24:2601–6. [5] Goldberg CJ, Dowling FE, Hall JE, Emans JB. A statistical comparison between natural history of idiopathic scoliosis and brace treatment in skeletally immature adolescent girls. Spine (Phila Pa 1976) 1993;18:902–8. [6] Goldberg CJ, Moore DP, Fogarty EE, Dowling FE. Adolescent idiopathic scoliosis: the effect of brace treatment on the incidence of surgery. Spine (Phila Pa 1976) 2001;26:42–7. [7] Lange JE, Steen H, Brox JI. Long-term results after Boston brace treatment in adolescent idiopathic scoliosis. Scoliosis 2009;4:17. [8] Nie WZ, Ye M, Liu ZD, Wang CT. The patient-specific brace design and biomechanical analysis of adolescent idiopathic scoliosis. J Biomech Eng 2009;131:041007. [9] Rivett L, Rothberg A, Stewart A, Berkowitz R. The relationship between quality of life and compliance to a brace protocol in adolescents with idiopathic scoliosis: a comparative study. BMC Musculoskelet Disord 2009;10:5. [10] Rowe DE, Bernstein SM, Riddick MF, Adler F, Emans JB, Gardner-Bonneau D. A meta-analysis of the efficacy of non-operative treatments for idiopathic scoliosis. J Bone Joint Surg Am 1997;79:664–74. [11] Goldberg CJ, Moore DP, Fogarty EE, Dowling FE. Scoliosis: a review. Pediatr Surg Int 2008;24:129–44. [12] Helenius I, Remes V, Lamberg T, Schlenzka D, Poussa M. Long-term healthrelated quality of life after surgery for adolescent idiopathic scoliosis and spondylolisthesis. J Bone Joint Surg Am 2008;90:1231–9. [13] Glancy GL. Advances in idiopathic scoliosis in children and adolescents. Adv Pediatr 2007;54:55–66. [14] Marcus R, Wong M, Heath 3rd H, Stock JL. Antiresorptive treatment of postmenopausal osteoporosis: comparison of study designs and outcomes in large clinical trials with fracture as an endpoint. Endocr Rev 2002;23:16–37. [15] McClung MR, San Martin J, Miller PD, Civitelli R, Bandeira F, Omizo M, Donley DW, Dalsky GP, Eriksen EF. Opposite bone remodeling effects of teriparatide and alendronate in increasing bone mass. Arch Intern Med 2005;165:1762–8. [16] Arlot M, Meunier PJ, Boivin G, Haddock L, Tamayo J, Correa-Rotter R, et al. Differential effects of teriparatide and alendronate on bone remodeling in postmenopausal women assessed by histomorphometric parameters. J Bone Miner Res 2005;20:1244–53. [17] Lindsay R, Cosman F, Zhou H, Bostrom MP, Shen VW, Cruz JD, et al. A novel tetracycline labeling schedule for longitudinal evaluation of the short-term effects of anabolic therapy with a single iliac crest bone biopsy: early actions of teriparatide. J Bone Miner Res 2006;21:366–73. [18] Jiang Y, Zhao JJ, Mitlak BH, Wang O, Genant HK, Eriksen EF. Recombinant human parathyroid hormone (1-34) [teriparatide] improves both cortical and cancellous bone structure. J Bone Miner Res 2003;18:1932–41. [19] Dempster DW, Cosman F, Kurland ES, Zhou H, Nieves J, Woelfert L, et al. Effects of daily treatment with parathyroid hormone on bone microarchitecture and turnover in patients with osteoporosis: a paired biopsy study. J Bone Miner Res 2001;16:1846–53. [20] Burr DB. Does early PTH treatment compromise bone strength? The balance between remodeling, porosity, bone mineral, and bone size. Curr Osteoporos Rep 2005;3:19–24. [21] Lindsay R, Zhou H, Cosman F, Nieves J, Dempster DW, Hodsman AB. Effects of a one-month treatment with PTH(1-34) on bone formation on cancellous, endocortical, and periosteal surfaces of the human ilium. J Bone Miner Res 2007;22:495–502.
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[22] Rehman Q, Lang TF, Arnaud CD, Modin GW, Lane NE. Daily treatment with parathyroid hormone is associated with an increase in vertebral crosssectional area in postmenopausal women with glucocorticoid-induced osteoporosis. Osteoporos Int 2003;14:77–81. [23] Uusi-Rasi K, Semanick LM, Zanchetta JR, Bogado CE, Eriksen EF, Sato M, et al. Effects of teriparatide [rhPTH (1–34)] treatment on structural geometry of the proximal femur in elderly osteoporotic women. Bone 2005;36:948–58. [24] Ominsky MS, Stouch B, Schroeder J, Pyrah I, Stolina M, Smith SY, et al. Denosumab, a fully human RANKL antibody, reduced bone turnover markers and increased trabecular and cortical bone mass, density, and strength in ovariectomized cynomolgus monkeys. Bone 2011;49:162–73. [25] Burner 3rd WL, Badger VM, Sherman FC. Osteoporosis and acquired back deformities. J Pediatr Orthop 1982;2:383–5. [26] Cheng JC, Qin L, Cheung CS, Sher AH, Lee KM, Ng SW, et al. Generalized low areal and volumetric bone mineral density in adolescent idiopathic scoliosis. J Bone Miner Res 2000;15:1587–95. [27] Lee WT, Cheung CS, Tse YK, Guo X, Qin L, Lam TP, et al. Association of osteopenia with curve severity in adolescent idiopathic scoliosis: a study of 919 girls. Osteoporos Int 2005;16:1924–32. [28] Yeung HY, Qin L, Hung VW, Lee KM, Guo X, Ng BW, et al. Lower degree of mineralization found in cortical bone of adolescent idiopathic scoliosis (AIS). Stud Health Technol Inform 2006;123:599–604. [29] Cheng JC, Guo X. Osteopenia in adolescent idiopathic scoliosis. A primary problem or secondary to the spinal deformity? Spine (Phila Pa 1976) 1997;22:1716–21. [30] Snyder BD, Katz DA, Myers ER, Breitenbach MA, Emans JB. Bone density accumulation is not affected by brace treatment of idiopathic scoliosis in adolescent girls. J Pediatr Orthop 2005;25:423–8. [31] Thomas KA, Cook SD, Skalley TC, Renshaw SV, Makuch RS, Gross M, et al. Lumbar spine and femoral neck bone mineral density in idiopathic scoliosis: a follow-up study. J Pediatr Orthop 1992;12:235–40. [32] Cheng JC, Tang SP, Skalley TC, Guo X, Chan CW, Qin L, et al. Osteopenia in adolescent idiopathic scoliosis: a histomorphometric study. Spine (Phila Pa 1976) 2001;26:E19–23. [33] Wada T, Nakashima T, Hiroshi N, Penninger JM. RANKL–RANK signaling in osteoclastogenesis and bone disease. Trends Mol Med 2006;12:17–25. [34] Suh KT, Lee SS, Hwang SH, Kim SJ, Lee JS. Elevated soluble receptor activator of nuclear factor-kappaB ligand and reduced bone mineral density in patients with adolescent idiopathic scoliosis. Eur Spine J 2007;16:1563–9. [35] Chiru M. Adolescent idiopathic scoliosis and osteopenia. Maedica (Buchar) 2011;6:17–22. [36] Machida M, Dubousset J, Yamada T, Kimura J. Serum melatonin levels in adolescent idiopathic scoliosis prediction and prevention for curve progression – a prospective study. J Pineal Res 2009;46:344–8. [37] Cardinali DP, Ladizesky MG, Boggio V, Cutrera RA, Mautalen C. Melatonin effects on bone: experimental facts and clinical perspectives. J Pineal Res 2003;34:81–7. [38] Krane SM. Genetic control of bone remodeling – insights from a rare disease. N Engl J Med 2002;347:210–2. [39] Witt-Enderby PA, Radio NM, Doctor JS, Davis VL. Therapeutic treatments potentially mediated by melatonin receptors: potential clinical uses in the prevention of osteoporosis, cancer and as an adjuvant therapy. J Pineal Res 2006;41:297–305. [40] Suzuki N, Somei M, Seki A, Reiter RJ, Hattori A. Novel bromomelatonin derivatives as potentially effective drugs to treat bone diseases. J Pineal Res 2008;45:229–34. [41] Suzuki N, Somei M, Kitamura K, Reiter RJ, Hattori A. Novel bromomelatonin derivatives suppress osteoclastic activity and increase osteoblastic activity: implications for the treatment of bone diseases. J Pineal Res 2008;44:326–34. [42] Thomas T. Intermittent parathyroid hormone therapy to increase bone formation. Joint Bone Spine 2006;73:262–9.
Contents lists available at SciVerse ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
A novel therapeutic strategy for adolescent idiopathic scoliosis based on osteoporotic concept Lingyun Lu a, Zhehao Dai a,b,⇑, Guohua Lv a, Yijun Kang a, Yebin Jiang b a b
Department of Spine Surgery, The 2nd Xiangya Hospital of Central South University, Changsha 410011, China Osteoporosis and Arthritis Lab, University of Michigan, Ann Arbor, MI 48109, USA
a r t i c l e
i n f o
Article history: Received 13 May 2012 Accepted 9 March 2013
a b s t r a c t Adolescent idiopathic scoliosis (AIS) is a complex three dimensional spinal deformity which occurs mostly in prepubertal and pubertal girls. Although bracing and surgery have been the mainstays of treatment for AIS, because of the complications and poor compliance, many patients with this disorder continue to experience significant residual symptoms. The etiology and pathogenesis of AIS is unclear, but recent studies show the association between osteopenia and AIS and imply that osteopenia play a causative role in the development of AIS. Anti-osteoporosis treatment can improve bone strength, prevent osteoporosis and rebalance the OPG–RANK–RANKL system, which may help to prevent curve progression in AIS. This report proposes that anti-osteoporosis treatment may be an effective treatment for AIS. Ó 2013 Elsevier Ltd. All rights reserved.
Background The skeletal system functions were based on the continuous remodeling by the coupled activity of osteoclasts and osteoblasts [1]. The balance between the activities of both cell types is related with bone diseases [1]. Osteoporosis is a skeletal disease with bone resorption exceeding bone formation characterized by low bone mass and micro-architectural deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to fracture. Adolescent idiopathic scoliosis (AIS) is a complex three dimensional deformity of the spine [2]. It is seen in 2–4% of the adolescent population, more commonly in girls [3], especially during prepubertal and pubertal growth, when bone acquisition is highest. The etiology and pathogenesis of AIS is unclear, but recent studies show the association between osteopenia and AIS and imply that osteopenia play a causative role in the development of AIS. So that we propose the hypothesis that anti-osteoporosis medicine may be an option for treatment of AIS. Hypothesis and reasoning Current treatment for AIS Treatment of AIS consists of non-operative treatment and surgical operation. Bracing has been the mainstay of non-operative treatment for AIS for nearly 50 years. Other non-operative ⇑ Corresponding author at: Department of Spine Surgery, The 2nd Xiangya Hospital of Central South University, Changsha 410011, China. Tel.: +86 731 85295125; fax: +86 731 85295124. E-mail address: [email protected] (Z. Dai). 0306-9877/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mehy.2013.03.008
treatment including electrical stimulation, biofeedback, manipulation, physical therapy, and exercise do not have convincing evidence of their effectiveness [4]. Although the similar surgery rate for unbraced patients compared with braced patients was reported by Goldberg [5,6], many other studies demonstrate that bracing is an effective modality preventing curve progression [7–10]. That bracing provided an external force to the trunk during the adolescent growth phase helps prevent progression. Surgery is another option which rebuilt coronal and sagittal balance to prevent curve progression through rigid spinal fusion [11–13]. However, bracing and surgery still have obvious disadvantages. The former always created great mental pressure and physical discomfort so that the compliance was poor. Pseudoarthrosis, back pain and instrument failure were obstacles to successful surgical treatment. Nonetheless, the only two accepted treatment methods implied that the reconstruction of spine balance and the improvement of bone strength will help prevent the curve progression. Anti-osteoporosis treatment provides an internal force to the trunk during the adolescent growth phase which may prevent curve progression of AIS. Anti-osteoporosis treatment, which includes anti-catabolic therapy and anabolic therapy, is an established medical treatment for the patients with osteoporosis. These therapies have been shown to reduce the risk of vertebral and non-vertebral fracture by approximately 50% and 30%, respectively in large randomized controlled trials [14], which rebalance the activity of osteoclasts and osteoblasts to enhance bone strength. Bone strength is determined by bone density (expressed as grams of mineral per area or volume) and bone quality (architecture, bone turnover, microfractures, mineralization). Anabolic therapy with recombinant human parathyroid hormone (rhPTH 1-34 or rhPTH 1-84) can
774
L. Lu et al. / Medical Hypotheses 80 (2013) 773–775
stimulates bone formation first and stimulates both resorption and formation subsequently, though the balance remains positive [15– 17].The growth of new bone induced by PTH restores the bone micro-architecture, including improved trabecular connectivity and enhanced cortical thickness [18,19]. Bone formation may on the outer periosteal surface affects bone size and geometry, with additional beneficial effects to bone strength [20–23]. Denosumab, a new anti-catabolic agent approved by FDA in 2010, can significantly increase area bone mineral density (aBMD) at the lumbar spine, total hip, femur neck, and distal radius and cortical volumetric bone mineral content (vBMC) of the central radius and tibia and greater peak load for femur neck, L3–L4 vertebral bodies, and L5– L6 cancellous cores in ovariectomized cynomolgus monkeys [24]. These finding suggests that anti-osteoporosis treatment may provide an internal force to the trunk during the adolescent growth phase to prevent curve progression for AIS patients. Prevention of osteopenia could be as important as controlling spinal progression in the management of AIS Since Burner and his co-workers used the Singh index to evaluate the femoral trabecular pattern and conclude that children with AIS had relative osteoporosis compared with healthy control individuals in 1982 [25], the relationship between osteoporosis and AIS had attracted attention increasingly. The skeletal sites involved thoracolumbar spine, bilateral proximal femurs, lumbar spine, bilateral distal tibias and radius in AIS patients showed a low BMD compared with controls [26–28]. It seemed that low BMD was a generalized and systematic phenomenon in AIS patients. Histomorphometric and micro CT (lCT) data on iliac crest biopsies and vertebrae of scoliosis patient showed a deteriorated bone structure too [26,29]. Deteriorated bone structure along with the axial loading will lead to microfractures which may result in a spinal asymmetry, which may be aggravated by the aid of bone remodeling according to Hueter–Volkmann law, where the concave side would diminish in growth, while the convex side would have an enhanced growth. The presence of low BMD in the preand early menarche in AIS girls [26,30,31] and the reduction in osteoclasts and osteoblasts number and dynamic activity which were found in the histomorphometry [32] revealed the abnormal bone metabolic activity and growth disturbance and indicated that osteopenia could be a causative factor rather than the result of the deformity. The report by Warren et al. found that girls with AIS indeed had lower BMD and BMC in lumbar spine, proximal femur and distal tibia compared with healthy non-AIS counterparts, and conclude that curve severity was an inverse and independent associated factor on bone mineral mass of AIS during peripuberty [27]. These finding may indicate that prevention of osteopenia could be as important as controlling spinal progression in the management of AIS. Anti-osteoporosis therapies which re-balance OPG–RANK–RANKL system may be an option for treatment of AIS The exact mechanisms and causes of the bone loss and bone structure deterioration in AIS have not been identified yet, but recent data demonstrated that the imbalance of OPG–RANK–RANKL system might be one of the mechanisms. Receptor activator of nuclear factor-kB ligand. RANKL regulates osteolysis and osteoclast differentiation directly by binding receptor activator of nuclear factor kB (RANK) which located in the cell membrane of osteoclasts and their precursors. In contrast, osteoprotegerin (OPG) is a soluble decoy receptor for RANKL which interferes with RANKL/RANK binding [33]. Suh et al. [34] and Chiru [35] found that the mean serum RANKL and RANKL to OPG ratio in patients with AIS were increased
and negatively correlated to the lumbar spinal bone mineral density and serum OPG levels. These findings mean that the imbalance and the disturbed interaction of RANKL and OPG may be an important cause and pathogenesis in reduced BMD in AIS. A study about the therapeutic application of melatonin for AIS showed that 12 in 16 patients with low melatonin levels were treated with oral melatonin and developed stable scoliosis [36]. This is the first clinical report to demonstrate the melatonin supplementation could prevent the scoliosis progression. Melatonin promotes the osteogenic differentiation of bone marrow stem cells and the synthesis OPG [37]. In mouse, melatonin increases the mRNA and protein levels OPG and decreases the expression of RANK mRNA even at micromolar doses [38]. Although no clinical trials have focused on the melatonin in the treatment of osteoporosis, many experimental studies suggest that melatonin [37,39] and its synthetics [40,41] can prevent bone degradation and promote bone formation in ovariectomized rats. These findings showed that the OPG–RANK– RANKL system played a central role in both osteoporosis and AIS and was one of the mechanisms leading to low bone mass in AIS; therefore, we believed that some established anti-osteoporosis therapies which restored the unbalanced OPG–RANK–RANKL system may be an option for treatment of AIS. rhPTH, the only anabolic drug with FDA-approved labeling for prevention or treatment of osteoporosis, not only binds to the PTH/PTH-related protein (PTH/PTHrP) receptor on the surface of the osteoblasts to induce a cascade that activates protein kinase 1-cyclic AMP, protein kinase C, and phospholipase C [42] which increase the number of active osteoblasts, decreases osteoblast apoptosis, and may recruit bone-lining cells as newly formed osteoblasts, but also stimulate the expression of an osteoclast differentiating factor (ODF) by the marrow stromal cells and osteoblasts. ODF binds to RANK to activate the bone resorption, but this binding can be inhibited by OPG. Denosumab, a fully human monoclonal antibody of the IgG2 immunoglobulin isotype, binds to RANKL with a high affinity and specificity to prevent RANKL– RANK interaction as the same way as OPG does, resulting in a decrease in osteoclastic bone resorption. Consequently, rhPTH and denosumab may have the potential ability to re-balance OPG– RANK–RANKL system. Hypotheses Taken together, these strands of clinical and experimental evidence suggest that some established anti-osteoporosis therapies may provide an internal force to the trunk, prevent osteopenia and restore the unbalanced OPG–RANK–RANKL system during the adolescent growth phase to prevent curve progression for AIS patients. We hypothesize that anti-osteoporosis therapies may become an effective treatment for AIS. Testing our hypothesis This hypothesis could be easily tested with AIS models in twofeet-rat with making linkage between scapula and pelvis. From a baseline period, all the rats would be randomized to receive rhPTH, denosumab or placebo during the treatment phase of the study. Cobb angle and vertebral rotation angle, BMD and bone structure, bone biomechanics, the level of RANK, RANKL, OPG and ODF in serum would be tested and compared among all groups. Our hypothesis, after testing and confirmation, may provide a novel therapeutic strategy for AIS patients. Conflict of interest statement None declared.
L. Lu et al. / Medical Hypotheses 80 (2013) 773–775
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