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Available online at www.sciencedirect.com
www.elsevier.com/locate/semss
Can medical management with teriparatide improve spinal surgery outcomes in patients with spinal osteoporosis/osteopenia? Muhammad Shakib Akhter, BScN, MSc(c), Hussein Ali El-Khechen, BSc, Rakesh Patel, MD, and Ilyas S. Aleem, MD, MSc, FRCSCn Department of Orthopaedic Surgery, University of Michigan, 1500 E Medical Center Dr, Ann Arbor, MI
abstra ct
Osteopenia and osteoporosis have become increasingly common in the elderly population, as has the concern from treating spinal surgeons. Many adverse surgical outcomes have been associated with poor bone quality, including decreased fusion rates, hardware complications, and osteoporotic fractures. Teriparatide, a recombinant form of parathyroid hormone, has been used as a major pharmaceutical intervention in osteoporosis treatment. This article provides an overview of the mechanism of teriparatide followed by a detailed review of the literature concerning outcomes of medical management with teriparatide in both animal models and humans with osteoporosis/osteopenia. Improved fusion rates and duration, as well as reduced osteoporosis-related complications are evident upon reviewing clinical and radiographic outcomes of teriparatide therapy in spinal surgery patients. & 2018 Elsevier Inc. All rights reserved.
1.
Introduction
Osteoporosis is now the most common metabolic bone disorder, with approximately 200 million afflicted individuals worldwide.1 Due to its relatively hidden early symptomatology, osteoporosis is often diagnosed late in its progression or after an osteoporotic fracture.1 However, increasing awareness and improved diagnostic techniques have allowed this chronic disorder to be much more easily diagnosed. Management of osteoporosis is multimodal and involves a multidisciplinary approach consisting of a detailed history, physical examination, and assessment of common risk factors. Teriparatide, a recombinant form of parathyroid hormone (PTH), has been used as a major pharmaceutical intervention in osteoporosis treatment.2 As osteopenia and osteoporosis have become increasingly common in the elderly population, so too has the concern from treating spinal surgeons. Many adverse outcomes have n
Corresponding author. E-mail address:
[email protected] (I.S. Aleem).
http://dx.doi.org/10.1053/j.semss.2017.09.001 1040-7383/& 2018 Elsevier Inc. All rights reserved.
been previously associated with poor bone quality, including decreased fusion rates, screw loosening, and osteoporotic fractures.3–5 Advances in medical management of osteopenia have modified surgical and nonsurgical treatment algorithms of spinal pathologies. The use of bisphosphonates, biologics and bone substitutes, and the widespread recognition and treatment of vitamin D deficiency have made spinal fusion an option where previously it may have been inadvisable. Teriparatide is an approved treatment of osteoporosis, particularly in postmenopausal women, to help prevent vertebral and non-vertebral fractures, pain, and to speed up the healing of fractures and nonunions.2–4,6–9 Teriparatide has been shown to be effective in improving surgical outcomes in patients undergoing spinal fusion in a number of ways including increasing bone mineral density (BMD), bone mineral content (BMC), fusion rates, fusion duration, and reducing hardware complications.3–5,10
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Mechanism of action
Teriparatide is a recombinant form of PTH. Due to their similarities in structure, teriparatide and PTH both follow the same metabolic pathway.11 Teriparatide is the PTH analog that has the greatest binding affinity to the PTH 25–34 subunit of the PTHrl receptor, its main binding target, resulting in a net anabolic effect on bone.11 PTHrl receptors are found on various cell types including osteoblasts, which mediate effects on osteoclasts, as well as immune cells and mildly differentiated bone marrow cells.11 The binding of teriparatide on osteoblasts results in the activation of adenyl cyclase and phospholipase, which results in the formation of cAMP, an increase in intracellular calcium concentration, as well as the activation of protein kinase C (PKC) through phospholipase C (PLC) dependent and independent pathways.11 This subsequently results in osteoblast activation, promoting bone formation. Similar to PTH, teriparatide also indirectly stimulates bone resorption by osteoclasts due to the production of receptor activator of nuclear factor-kB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF).11 RANKL then binds to the osteoclast cell-surface receptor RANK, activating signaling pathways that promote osteoclast differentiation and survival. The binding of teriparatide also results in the production of osteoprotegerin (OPG), which is similar in structure to the RANK receptor on osteoclasts, functioning as a decoy on osteoclast precursors, thus preventing osteoclast formation and activation.11
3.
Effect of teriparatide in animal models
The effects of teriparatide have been extensively studied in numerous animal models. Some studies have shown rats to have increased cortical bone mass and strength with teriparatide treatment.12,14 While the positive effects of teriparatide have been well documented in osteoporotic patients, effects on patients' trabecular bone balance are less clear. Ejersted et al. (1993) sought to clarify whether this positive effect is a result of a trade-off in the cortical bone. To address this, they treated groups of rats either with PTH or teriparatide daily and as hypothesized, no differences between the two treatments was found.12 Both groups of rats experienced increased strength and cross sectional area in their femurs.12 Furthermore, teriparatide treatment has been shown to increase proximal femur strength in ovariectomized nonhuman primates, despite increasing bone porosity.13 Sugie-Oya et al.15 conducted a study in ovariectomized rats comparing the effects of teriparatide and the bisphosphonate risedronate. They found that the teriparatide group showed increased vertebral bone mineral density (BMD), bone strength, and bone structure.15 This effect was prominent in the L5 vertebra, which showed greater trabecular thickening.15 Furthermore, teriparatide showed greater increases in lumbar vertebral BMD and bone strength as compared to risedronate treated ovariectomized rats.15 Other studies have reported increased rates of lumbar fusion with teriparatide therapy in rabbits following posterolateral fusion surgery compared to a saline placebo and similar results were seen
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with a different study that used calcitonin in addition to saline as a placebo.9,16,17 Diffuse idiopathic skeletal hyperostosis (DISH) is a skeletal disorder, which disproportionately effects the elderly, and may result in periosteal hyperostosis and trabecular osteoporosis.18 Hamano et al.18 explored the efficacy of teriparatide in DISH mice models, tiptoe-walking Yashimura (TWY) mice, and in ICR mice. The mice were administered teriparatide injections either once or three times a day or saline injections once a day.18 While the control group experienced decreased vertebral and distal femur volume, the TWY mice administered teriparatide three times a day showed drastic increases in vertebral and distal femur volume.18 However, teriparatide treatment resulted in the accelerated progression of ankylosis of the spine, as well as promoting the ossification of spinal ligaments.18 Teriparatide treatment was also shown to increase bone formation at the vertebrae enthesis region and in the trabecular bone.18 As a result, it was concluded that while teriparatide is efficacious in treating trabecular osteoporosis, it potentially promotes ankylosis of the spine in DISH patients.18 While bone morphogenetic protein (BMP) has been reliably used to promote spinal fusion, it is not without side effects and often relatively high doses are required to achieve desired results.19 Morimoto and colleagues conducted a study to determine the efficacy of teriparatide in conjunction with BMP therapy. Rats had undergone posterolateral lumbar arthrodesis and either given a low dose (2 μg) of BMP, high dose (50 μg) of BMP, or no BMP, with all three conditions either receiving intermittent injections of teriparatide or saline solution.19 While the fusion rates of the high dose and control conditions of BMP remained unchanged, the low dose condition saw its fusion rate substantially increase from 57% to 100% with intermittent teriparatide administration.19 Both low- and high-dose treated mice, were observed to have increased bone volume density.19 Micro-CT scans showed that the newly formed bone had substantial trabecular bone formation.19 This study demonstrated teriparatide's ability to be extremely effective when used in conjunction with BMP therapy to improve bone formation after spinal fusion surgery.
4. Teriparatide and clinical outcomes in spine surgery Clinical outcomes after spine surgery are significantly improved with teriparatide administration.9 Numerous studies have shown increased rates of and time to spinal fusion, bone formation, and reduced vertebral fractures and hardware loosening and associated increases in functional and clinical outcomes with teriparatide therapy.6,9,10,20 Although teriparatide has been shown to affect both bone resorption and formation, greater effects are seen with bone formation than resorption.6,11,13,21 Teriparatide has had a significant impact on fracture treatment. In an observational study conducted by Fahrleitner-Pammer et al.,22 1576 postmenopausal women suffering from severe osteoporosis from across Europe were recruited prior to commencing teriparatide treatment. The incidence of clinical fractures and back
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pain levels were collected over the 18-month teriparatide treatment and subsequent 18 months following treatment.22 Patients were followed throughout the duration of the study, with back pain being measured with the visual analogue scale (VAS) and an outcomes questionnaire.22 At the end of the study, it was found that 208 patients suffered 258 fractures with 34% being clinical vertebral fractures and 66% being non-vertebral fractures.22 It was concluded that fractures had decreased over the 18-month teriparatide treatment and the reduction in fracture rates remained steady over the following 18-month period. The reduction in fractures was also found to be accompanied by a significant reduction in back pain.22 In another double-blind randomized controlled trial that is discussed below, it was found that weekly teriparatide injections reduced the risk of vertebral fractures as well as increased the bone mineral density of the lumbar spine.6,9 With teriparatide's positive effects in osteoporosis and fracture patients well documented, Ohtori et al.3 investigated the efficacy of teriparatide treatment in lumbar posterolateral fusion in postmenopausal women with osteoporosis. In their study, 57 postmenopausal women with osteoporosis and lumbar degeneration spondylolisthesis were recruited.3 After all the patients had undergone decompression and posterolateral fusion surgery using bone grafting, the patients were either given daily teriparatide injections or weekly oral doses of bisphosphonate.3 While pain scores decreased in both groups, difference was not significant between the groups.3 However, significant differences were noted in fusion rate as well as the duration of bone union.3 The rate of bone fusion was found to be 82% in the teriparatide group as compared to the 68% in the bisphosphonate group.3 The average time to union in the teriparatide group was 8 months as compared to the 10 months experienced by the bisphosphonate group.3 This apparent superiority of teriparatide may be attributable to teriparatide's efficacy in both bone formation and resorption, while bisphosphonate simply functions to inhibit bone resorption.11 The authors concluded that daily teriparatide injections were more effective in bone union in local bone graft instrumental lumbar posterolateral fusion in postmenopausal women.3 Further expanding on their previous work, Ohtori et al.23 later performed a similar study, however, this time they investigated the ideal duration of teriparatide administration. Forty-five women with osteoporosis and degenerative lumbar spondylolisthesis were retrospectively evaluated.23 Patients underwent instrumented lumbar posterolateral fusion, after which they were treated in one of three treatment groups. One group was administered daily injections of teriparatide over a period of 5.5 months (short duration), the next group was given daily teriparatide injections over a period of 13 months (long duration), and the last group was administered bisphosphonate over a period of 13 months. Using radiographs, union was evaluated to determine fusion rates and time to fusion. In line with their previous work, it was found that both teriparatide groups significantly outperformed the bisphosphonate group. However, they also found significant differences between the two teriparatide groups. The longduration treatment exhibited an average fusion rate of 92% as compared to 80% and 70% as compared to the short-duration
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group and bisphosphonate group, respectively.23 The longduration group's average of 7.5 months for fusion was also significantly better than the 8.5 and 10 months for the shortduration group and bisphosphonate group, respectively.23 These two studies further establish teriparatide's role in promoting fusion in postmenopausal women with osteoporosis undergoing spine surgery. More recently, Zhao et al.24 sought to investigate the efficacy of teriparatide in neurologically deficient patients following new unstable osteoporotic vertebral compression fracture (OVCF) in patients with surgical contraindications. Over a 12-month period, 49 patients were randomly assigned into either a daily self-administered teriparatide injection group, or a weekly orally administered alendronate group.24 At the 12-month mark, pain scores measured by the visual analog scale (VAS) in both treatment groups were significantly decreased.24 However, teriparatide showed a greater decrease in VAS, mean kyphotic angle of the fractured vertebrae, and the occurrence of new OVCFs were significantly less in the teriparatide group as compared to the alendronate group.24 Using specific biochemical markers for bone formation and bone resorption, it was found that teriparatide showed greater efficacy in increasing bone turnover.24 Zhao et al.24 also found mean spine bone mineral density (BMD), and mean anterior-border height and spinal canal diameter of the fractured vertebrae were significantly greater in the teriparatide group than in the alendronate group. The authors concluded that teriparatide proved to be more efficacious in improving bone turnover and BMD as well as clinical outcomes in patients with neurological deficits who experience new unstable OVCF and with surgical contraindications.24 Further, Perumal et al.20 recruited 62 elderly patients and divided them into two groups. Group 1 consisted of 30 patients with a mean age of 69.83 years, administered 20 μg teriparatide injections daily for a period of 7 months, while group 2, consisting of 32 patients with a mean age of 70.38 years, did not receive the treatment.20 When compared to the group 2, where only 50% of patients obtained solid fusion, 66.7% of group 1 patients obtained solid fusion.20 While this result is not significant, it is indicative of the efficacy of teriparatide. Screw loosening was also significantly decreased in group 1, at 13.4%, as compared to group 2, at 24.4%.20 Studies evaluating back pain and health related quality of life (HRQoL) indicate that teriparatide therapy improved HRQoL and significantly reduced the prevalence of back pain as measured on the visual analogue scale (VAS).25 Effects were observed during an 18-month period of teriparatide administration and for another 18 months after cessation of therapy.25 These results can be explained by teriparatide's desired effect of reducing the incidence of vertebral fractures and bone resorption, increasing osseous union, spinal fusion, bone formation, and remodeling. Additionally, teriparatide treatment led to reductions in limitations with activities due to pain as well as the severity and frequency of pain. Followup evaluations indicated these changes persisted after cessation of teriparatide therapy. The observed significant improvements in HRQoL were also seen to persist after cessation of treatment.25 Other studies suggest that there is a positive correlation between length of teriparatide therapy
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and non-vertebral fractures and associated pain.26 Findings indicate that a longer period of teriparatide therapy will lead to favorable outcomes with pain, non-vertebral fracture protection, and associated side effects.26
5. Teriparatide and radiographic outcomes in spine surgery Spinal fusion patients often face many postoperative challenges and a long road to recovery. However, the duration of recovery is heavily influenced by the possible complications which could arise, including hardware complications such as pedicle screw (PS) loosening and proximal junctional kyphosis.4,5 PS loosening has been found to be correlated with BMD.4 While attempts to change the shape and material of the screw along with addition of adhesive have decreased PS loosening, these methods also increase the risk of pedicle fracture, neural or visceral injury, and cement leakage.4 In order to improve treatment outcomes, Ohtori et al.4 investigated the efficacy of teriparatide in reducing PS loosening, while comparing it to bisphosphonate in postmenopausal women with osteoporosis which had undergone instrumental lumbar posterolateral fusion. Exploring the effect of teriparatide on PS loosening, Ohtori and colleagues recruited 62 postmenopausal women with osteoporosis diagnosed with degenerative spondylolisthesis. The patients were either administered daily teriparatide injections, oral bisphosphonate doses, or no treatment at all.4 After undergoing decompression and 1- or 2-level instrumented posterolateral fusion with a local bone graft, PS loosening and surgical comes were evaluated using CT scans and radiographs.4 At the 12-month follow-up, it was found that PS loosing ranged from 7% to 13% for the teriparatide treatment, from 13% to 26% for the bisphosphonate treatment, and from 15% to 25% in the control group.4 The significant decrease in PS loosening suggests that teriparatide increases the quality of bone density.4 This is in keeping with other studies showing that teriparatide administration increases BMD, which has been linked to decreased PS loosening.4,5,24 Proximal junctional kyphosis (PJK) is a known complication following spinal deformity surgery.5 Yagi et al.5 sought to study the efficacy of teriparatide in preventing PJK in patients with adult spinal deformity after undergoing corrective surgery. The authors recruited 76 female patients over the age of 50, with 43 of them receiving the treatment.5 The patients were followed for at least 2 years. After 6 months, it was found that the treatment group had significantly increased BMD and bone mineral content (BMC), along with increased bone volume/tissue volume ratio, and trabecular bone thickness and number.5 Further, the incidence of PJK was significantly lower in the teriparatide treatment group.5 A plethora of radiographic evidence exists evaluating the outcomes of teriparatide administration for spinal osteoporosis and associated disorders. A recent study by Shigeto et al.9 demonstrated significantly higher bone fusion, increased bone formation, and a reduced fusion score with respect to CT imaging, along with no evidence of intervertebral disc instability or disk-space narrowing with teriparatide administration.6 Shigeto et al.9 recruited 75 postmenopausal patients 50, years of age or older, of which only 66 completed treatment. Patients
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recruited had a BMC of less than 80% of the young female adult mean or had previously undergone spinal decompression, and suffered from lumbar degenerative disease. The patients were randomly sorted either into a teriparatide treatment group (N ¼ 36), which received weekly teriparatide injections over a 6-month period, or a control arm (N ¼ 38). Radiography and CT were used to conduct blinded radiographic evaluations. It is important to note that no disc-space narrowing was seen for both treatment and control groups during 2- and 6-month postoperative radiological follow-up.9 Further studies employed radiographic imaging and CT scans to evaluate bone union and fusion times, all of which identifying significantly shorter times with the teriparatide subjects.9,27 In other studies, for the patients who received teriparatide CT scans showed grade I trabeculae and fusion with remodeling.10,28 These studies also showed significantly higher rates of bone formation and complete bone fusion at the 6-month postoperative radiological follow-up.9 When evaluated using the Fisher's exact test, the teriparatide group had significantly higher complete fusion rates compared to the control group.9 In radiological comparison to risedronate, another study found increased rates of osseous union with 2-month preoperative and 8-month postoperative teriparatide therapy following posterolateral fusion.9,29 Additionally, Chaudhary et al.10 evaluated transiliac bone biopsies to provide direct evidence of increased bone formation and bone remodeling seen on the quiescent surface following teriparatide therapy. In this recent review, researchers investigated the evidence for the preclinical and clinical use of teriparatide in osteoporotic patients undergoing spinal fusion surgery.10 They found that preclinical teriparatide treatment increases the rate of spinal fusion. As would be expected from the previous findings, early clinical studies were found to support the increase in spinal fusion rates in patients, while also decreasing hardware loosening in postmenopausal patients diagnosed with osteoporosis undergoing spinal fusion surgery. This study also highlights the need to further investigate the formation of preoperative screening along with the optimal duration of teriparatide treatment pre- and postoperatively along with the treatment's efficacy in males.10
6.
Conclusion
Beyond its initial use in treating osteoporosis, teriparatide has demonstrated to be an integral component in improving outcomes in patients undergoing spinal surgery. It has repeatedly demonstrated clinical and radiographic efficacy in numerous orthopaedic and spine surgery applications.6,9,30,31 Improved rates and time to spinal fusion and reduced osteoporosis-related complications are evident upon reviewing clinical and radiographic outcomes of teriparatide therapy in the spine surgery population.6,9,10,20,29 However, teriparatide therapy is costly, and little research is done on its cost effectiveness in relation to outcomes, therefore providing an opportunity for future research. Additionally, there is no clear literature evaluating the efficacy of daily teriparatide administration versus weekly administration. Further high quality studies evaluating specific clinical indications and various dose regimens of teriparatide are warranted.
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re fe r en ces
1. Lin JT, Lane JM. Osteoporosis: a review. Clin Orthop Relat Res. 2004;425(425):126–134. 2. Marcus R. Present at the beginning: a personal reminiscence on the history of teriparatide. Osteoporos Int. 2011;22(8): 2241–2248. http://dx.doi.org/10.1007/s00198-011-1598-x. 3. Ohtori S, Inoue G, Orita S, et al. Teriparatide accelerates lumbar posterolateral fusion in women with postmenopausal osteoporosis. Spine. 2012;37(23): http://dx.doi.org/10.1097/brs. 0b013e31826ca2a8. 4. Ohtori S, Inoue G, Orita S, et al. Comparison of teriparatide and bisphosphonate treatment to reduce pedicle screw loosening after lumbar spinal fusion surgery in postmenopausal women with osteoporosis from a bone quality perspective. Spine. 2013;38(8): http://dx.doi.org/10.1097/brs.0b013e31828826dd. 5. Yagi M, Ohne H, Konomi T, et al. Teriparatide improves volumetric bone mineral density and fine bone structure in the UIVþ1 vertebra, and reduces bone failure type PJK after surgery for adult spinal deformity. Osteoporos Int. 2016;27 (12):3495–3502. http://dx.doi.org/10.1007/s00198-016-3676-6. 6. Eriksen EF, Robins DA. Teriparatide: a bone formation treatment for osteoporosis. Drugs Today (Barc). 2004;40(11):935–948. 7. Fukuda F, Kurinomaru N, Hijioka A. Weekly teriparatide for delayed unions of atypical subtrochanteric femur fractures. Biologics Ther. 2014;4(1–2):73–79. 8. Pietrogrande L, Raimondo E. Teriparatide in the treatment of non-unions: scientific and clinical evidences. Injury. 2013;44 (13):s54–s57. 9. Shigeto E, Jun T, Tomohiko H, et al. Role of weekly teriparatide administration in osseous union enhancement within six months after posterior or transforaminal lumbar interbody fusion for osteoporosis-associated lumbar degenerative disorders: a multicenter, prospective randomized study. J Bone Joint Surg Am Vol. 2017;99(5):365–372. http://dx.doi.org/10.2106/ JBJS.16.00230. 10. Chaudhary N, Lee JS, Wu JY, Tharin S. Evidence for Use of Teriparatide in Spinal Fusion Surgery in Osteoporotic Patients. World Neurosurg. 2017;100:551–556. http://dx.doi. org/10.1016/j.wneu.2016.11.135. 11. Aslan D, Andersen MD, Gede LB, et al. Mechanisms for the bone anabolic effect of parathyroid hormone treatment in humans. Scand J Clin Lab Invest. 2011;72(1):14–22. 12. Ejersted C, Andreassen TT, Oxlund H, Jorgensen PH, Bak B. Human parathyroid hormone (1-34) and (1-84) increase the mechanical strength and thickness of cortical bone in rats. J Bone Miner Res. 1993;8:1097–1101. 13. Sato M, Westmore M, Ma YL, et al. Teriparatide [PTH (1–34)] strengthens the proximal femur of ovariectomized nonhuman primates despite increasing porosity. J Bone Miner Res. 2004;19(4):623–629. 14. Oxlund H, Ejersted C, Andreassen TT, Torring O, Nilsson MH. Parathyroid hormone (1–34) and (1–84) stimulate cortical bone formation both from periosteum and endosteum. Calcif Tissue Int. 1993;53(6):394–399. 15. Sugie-Oya A, Takakura A, Takao-Kawabata R, et al. Comparison of treatment effects of teriparatide and the bisphosphonate risedronate in an aged, osteopenic, ovariectomized rat model under various clinical conditions. J Bone Miner Metab. 2016;34(3):303–314. 16. O’Loughlin PF, Cunningham ME, Bukata SV, et al. Parathyroid hormone (1–34) augments spinal fusion, fusion mass volume, and fusion mass quality in a rabbit spinal fusion model. Spine (Phila Pa 1976). 2009;34(2):121–130. 17. Lehman RA Jr, Dmitriev AE, Cardoso MJ, et al. Effect of teriparatide [rhPTH(1,34)] and calcitonin on intertransverse process fusion in a rabbit model. Spine. 2010;35(2):146–152.
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18. Hamano H, Takahata M, Ota M, et al. Teriparatide improves trabecular osteoporosis but simultaneously promotes ankylosis of the spine in the twy mouse model for diffuse idiopathic skeletal hyperostosis. Calcif Tissue Int. 2016;98 (2):140–148. http://dx.doi.org/10.1007/s00223-015-0068-4. 19. Morimoto T, Kaito T, Kashii M, et al. Effect of intermittent administration of teriparatide (parathyroid hormone 1-34) on bone morphogenetic protein-induced bone formation in a rat model of spinal fusion. J Bone Joint Surg Am Vol. 2014;96(13): http://dx.doi.org/10.2106/jbjs.m.01097. 20. Kaliya-Perumal A, Meng-Ling L, Chi-An L, et al. Retrospective radiological outcome analysis following teriparatide use in elderly patients undergoing multilevel instrumented lumbar fusion surgery. Medicine. 2017;94(5):1–6. http://dx.doi.org/ 10.1097/MD.0000000000005996. 21. Parfitt A. Plasma calcium control at quiescent bone surfaces: a new approach to the homeostatic function of bone lining cells. Bone. 1989;10(2):87–88. http://dx.doi.org/10.1016/ 8756-3282(89)90003-3. 22. Fahrleitner-Pammer A, Langdahl B, Marin F, et al. Fracture rate and back pain during and after discontinuation of teriparatide: 36-month data from the european forsteo observational study (EFOS). Osteoporos Int. 2011;22(10):2709–2719. 23. Ohtori S, Orita S, Yamauchi K, et al. More than 6 months of teriparatide treatment was more effective for bone union than shorter treatment following lumbar posterolateral fusion surgery. Asian Spine J. 2015;9(4):573. http://dx.doi.org/ 10.4184/asj.2015.9.4.573. 24. Zhao Y, Xue R, Shi N, et al. Aggravation of spinal cord compromise following new osteoporotic vertebral compression fracture prevented by teriparatide in patients with surgical contraindications. Osteoporos Int. 2016;27(11): 3309–3317. http://dx.doi.org/10.1007/s00198-016-3651-2. 25. Jakob F, Oertel H, Langdahl B, et al. Effects of teriparatide in postmenopausal women with osteoporosis pre-treated with bisphosphonates: 36-month results from the European Forsteo Observational Study. Eur J Endocrinol. 2012;166(1):87–97. http://dx.doi.org/10.1530/EJE-11-0740. 26. Lindsay R, Miller P, Pohl G, Glass EV, Chen P, Krege JH. Relationship between duration of teriparatide therapy and clinical outcomes in postmenopausal women with osteoporosis 2009. Osteoporos Int. 2009;20(6):943–948. http://dx.doi.org/ 10.1007/s00198-008-0766-0. 27. Inoue G, Orita S, Yamauchi K, et al. Teriparatide accelerates lumbar posterolateral fusion in women with postmenopausal osteoporosis: prospective study. Spine (Phila Pa 1976). 2012;37(23): E1464–E1468. http://dx.doi.org/10.1097/BRS.0b013e31826ca2a8. 28. Seki S, Hirano N, Kawaguchi Y, et al. Teriparatide versus lowdose bisphosphonates before and after surgery for adult spinal deformity in female Japanese patients with osteoporosis. Eur Spine J. http://dx.doi.org/10.1007/s00586-017-4959-0. 29. Cho PG, Ji GY, Shin DA, Ha Y, Yoon DH, Kim KN. An effect comparison of teriparatide and bisphosphonate on posterior lumbar interbody fusion in patients with osteoporosis: a prospective cohort study and preliminary data. Eur Spine J. 2015;26(3):691–697. 30. Nakamura T, Sugimoto T, Nakano T, et al. Randomized teriparatide [human parathyroid hormone (PTH) 1-34] onceweekly efficacy research (TOWER) trial for examining the reduction in new vertebral fractures in subjects with primary osteoporosis and high fracture risk. J Clin Endocrinol Metab. 2012;97(9):3097–3106. Epub June 20, 2012. 31. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001;344(19):1434–1441.
