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Bone Health and Orthopedic Surgery

  • Linda A. RussellEmail author
Chapter
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Abstract

Traditionally, orthopedists have not evaluated the quality of bone prior to orthopedic procedures. Nonetheless, in recent years an assortment of pharmacological agents targeting bone quality have been developed and are in common use, mainly in the treatment of osteoporosis. Growing evidence suggests that the maximization of bone quality and health perioperatively will result in better surgical outcomes. This chapter reviews current knowledge concerning this clinical experience, examining specifically vitamin D, its putative role in orthopedic surgery; the use of various medications in the setting of total joint arthroplasty, in spinal fusion, and in the fracture repair is presented.

Keywords

Bone density Osteoporosis Vitamin D Calcium Bisphosphonates PTH Denosumab 

References

  1. 1.
    Smith MD, Ross W, Ahern MJ. Missing a therapeutic window of opportunity: an audit of patients attending a tertiary teaching hospital with potentially osteoporotic hip and wrist fractures. J Rheumatol. 2001;28(11):2504–8.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Castel H, Bonneh DY, Sherf M, Liel Y. Awareness of osteoporosis and compliance with management guidelines in patients with newly diagnosed low-impact fractures. Osteoporos Int. 2001;12(7):559–64.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Sprague S, Madden K, Slobogean G, Petrisor B, Adachi JDR, Bogoch E, et al. A missed opportunity in bone health: vitamin D and calcium use in elderly femoral neck fracture patients following arthroplasty. Geriatr Orthop Surg Rehabil. 2017;8(4):215–24.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Maier GS, Kolbow K, Lazovic D, Maus U. The importance of bone mineral density in hip arthroplasty: results of a survey asking orthopaedic surgeons about their opinions and attitudes concerning osteoporosis and hip arthroplasty. Adv Orthop. 2016;2016:8079354. Epub 2016 Nov 23.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Adachi JD, Rizzoli R, Boonen S, Li Z, Meredith MP, Chesnut CH 3rd. Vertebral fracture risk reduction with risedronate in post-menopausal women with osteoporosis: a meta-analysis of individual patient data. Aging Clin Exp Res. 2005;17(2):150–6.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Rebolledo BJ, Unnanuntana A, Lane JM. A comprehensive approach to fragility fractures. J Orthop Trauma. 2011;25(9):566–73.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Fini M, Giavaresi G, Salamanna F, Veronesi F, Martini L, De Mattei M, et al. Harmful lifestyles on orthopedic implantation surgery: a descriptive review on alcohol and tobacco use. J Bone Miner Metab. 2011;29(6):633–44.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Bogunovic L, Kim AD, Beamer BS, Nguyen J, Lane JM. Hypovitaminosis D in patients scheduled to undergo orthopaedic surgery: a single-center analysis. J Bone Joint Surg Am. 2010;92(13):2300–4.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Breijawi N, Eckardt A, Pitton MB, Hoelzl AJ, Giesa M, von Stechow D, et al. Bone mineral density and vitamin D status in female and male patients with osteoarthritis of the knee or hip. Eur Surg Res. 2009;42(1):1–10.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Bergink AP, Uitterlinden AG, Van Leeuwen JP, Buurman CJ, Hofman A, Verhaar JA, et al. Vitamin D status, bone mineral density, and the development of radiographic osteoarthritis of the knee: the Rotterdam study. J Clin Rheumatol. 2009;15(5):230–7.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Unnanuntana A, Rebolledo BJ, Gladnick BP, Nguyen JT, Sculco TP, Cornell CN, et al. Does vitamin D status affect the attainment of in-hospital functional milestones after total hip arthroplasty? J Arthroplast. 2012;27(3):482–9.CrossRefGoogle Scholar
  12. 12.
    Fakler JK, Grafe A, Dinger J, Josten C, Aust G. Perioperative risk factors in patients with a femoral neck fracture-influence of 25-hydroxyvitamin D and C-reactive protein on postoperative medical complications and 1-year mortality. BMC Musculoskelet Disord. 2016;17:51.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Diamond T, Wong YK, Golombick T. Effect of oral cholecalciferol 2,000 versus 5,000 IU on serum vitamin D, PTH, bone and muscle strength in patients with vitamin D deficiency. Osteoporos Int. 2013;24(3):1101–5.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Mastaglia SR, Seijo M, Muzio D, Somoza J, Nunez M, Oliveri B. Effect of vitamin D nutritional status on muscle function and strength in healthy women aged over sixty-five years. J Nutr Health Aging. 2011;15(5):349–54.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Muir SW, Montero-Odasso M. Effect of vitamin D supplementation on muscle strength, gait and balance in older adults: a systematic review and meta-analysis. J Am Geriatr Soc. 2011;59(12):2291–300.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Glendenning P, Zhu K, Inderjeeth C, Howat P, Lewis JR, Prince RL. Effects of three monthly oral 150,000 IU cholecalciferol supplementation on falls, mobility and muscle strength in older postmenopausal women: a randomised controlled trial. J Bone Miner Res. 2012;27(1):170–6.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Lingard EA, Mitchell SY, Francis RM, Rawlings D, Peaston R, Birrell FN, et al. The prevalence of osteoporosis in patients with severe hip and knee osteoarthritis awaiting joint arthroplasty. Age Ageing. 2010;39(2):234–9.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Makinen TJ, Alm JJ, Laine H, Svedstrom E, Aro HT. The incidence of osteopenia and osteoporosis in women with hip osteoarthritis scheduled for cementless total joint replacement. Bone. 2007;40(4):1041–7.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Kamath S, Chang W, Shaari E, Bridges A, Campbell A, McGill P. Comparison of peri-prosthetic bone density in cemented and uncemented total knee arthroplasty. Acta Orthop Belg. 2008;74(3):354–9.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Meek RM, Norwood T, Smith R, Brenkel IJ, Howie CR. The risk of peri-prosthetic fracture after primary and revision total hip and knee replacement. J Bone Joint Surg Br. 2011;93(1):96–101.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Kim K, Kim YH, Park WM, Rhyu KH. Stress concentration near pin holes associated with fracture risk after computer navigated total knee arthroplasty. Comput Aided Surg. 2010;15(4–6):98–103.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Lee DH, Padhy D, Lee SH, Nha KW, Park JH, Han SB. Osteoporosis affects component positioning in computer navigation-assisted total knee arthroplasty. Knee. 2012;19(3):203–7.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Linde KN, Puhakka KB, Langdahl BL, Søballe K, Krog-Mikkelsen I, Madsen F, et al. Bone mineral density is lower in patients with severe knee osteoarthritis and attrition. Calcif Tissue Int. 2017;101(6):593–601.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Huang TW, Wang CJ, Shih HN. Bone turnover and periprosthetic bone loss after cementless total hip arthroplasty can be restored by zoledronic acid: a prospective, randomized, open-label, controlled study. BMC Musculoskelet Disord. 2017;18(1):209–24.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Yang L. The efficiency of risedronate in reducing bone resorption after total hip arthroplasty: a meta-analysis of randomized control trial at a minimum of 6 months follow-up. J Orthop Surg Res. 2018;13(1):88.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Jaroma AV, Soininvaara TA, Kroger H. Effect of one-year post-operative alendronate treatment on periprosthetic bone after total knee arthroplasty. A seven-year randomized controlled trial of 26 patients. Bone Joint J. 2015;97-B(3):337–45.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Nagoya S, Tateda K, Okazaki S. Restoration of proximal periprosthetic bone loss by denosumab in cementless total hip arthroplasty. Eur J Orthop Surg Traumatol. 2018 Dec;28(8):1601–7.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Huang TW, Huang KC, Lin SJ, Chuang PY, Shih HN, Hsu RWW, et al. Effects of teriparatide on cementless bipolar hemiarthroplasty in patients with osteoporotic neck fractures. BMC Musculoskelet Disord. 2016;17:300.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Suzuki T, Sukezaki F, Shibuki T, Toyoshima Y, Nagai T, Inagaki K. Teriparatide administration increases periprosthetic bone mineral density after total knee arthroplasty: a prospective study. J Arthroplast. 2018;33(1):7–85.CrossRefGoogle Scholar
  30. 30.
    Kobayashi N, Inaba Y, Uchiyama M, Ike H, Kubota S, Saito T. Teriparatide versus alendronate for the preservation of bone mineral density after total hip arthroplasty–a randomized controlled trial. J Arthroplast. 2016;31(1):333–8.CrossRefGoogle Scholar
  31. 31.
    Namba RS, Inacio MC, Cheetham TC, Dell RM, Paxton EW, Khatod MX. Lower total knee arthroplasty revision risk associated with bisphosphonate use, even in patients with normal bone density. J Arthroplast. 2016;31(2):537–41.CrossRefGoogle Scholar
  32. 32.
    Khatod M, Inacia MC, Dell RM. Association of bisphosphonate use and risk of revision after THA: outcomes from a US total joint replacement registry. Clin Orthop Relat Res. 2015;473(11):3412–20.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Beaupre LA, Rezansoff A, Clark M, Jen H, Lambert RG, Majumdar S, et al. Bone mineral density changes in the hip and spine of men and women 1-year after primary cemented total knee arthroplasty: prospective cohort study. J Arthroplast. 2015;30(12):2185–9.CrossRefGoogle Scholar
  34. 34.
    Moritz N, Alm JJ, Lankinen P, Makinen TJ, Mattila K, Aro HT. Quality of intertrochanteric cancellous bone as predictor of femoral stem RSA migration in cementless total hip arthroplasty. J Biomech. 2011;44(2):221–7.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Popescu D, Ene R, Cirstoiu C. Resurfacing total hip replacement—a therapeutical approach in postmenopausal women with osteoporosis and hip arthrosis. J Med Life. 2011;4(2):178–81.PubMedPubMedCentralGoogle Scholar
  36. 36.
    McDonald MM, Dulai S, Godfrey C, Amanat N, Sztynda T, Little DG. Bolus or weekly zoledronic acid administration does not delay endochondral fracture repair but weekly dosing enhances delays in hard callus remodeling. Bone. 2008;43(4):653–62.CrossRefGoogle Scholar
  37. 37.
    Li J, Mori S, Kaji Y, Kawanishi J, Akiyama T, Norimatsu H. Concentration of bisphosphonate (incadronate) in callus area and its effects on fracture healing in rats. J Bone Miner Res. 2000;15(10):2042–51.CrossRefGoogle Scholar
  38. 38.
    Jorgensen NR, Schwarz P. Effects of anti-osteoporosis medications on fracture healing. Curr Osteoporos Rep. 2011;9(3):149–55.CrossRefGoogle Scholar
  39. 39.
    Adachi JD, Lyles KW, Colon-Emeric CS, Boonen S, Pieper CF, Mautalen C, et al. Zoledronic acid results in better health-related quality of life following hip fracture: the HORIZON-recurrent fracture trial. Osteoporos Int. 2011;22(9):2539–49.CrossRefGoogle Scholar
  40. 40.
    Bukata SV. Systemic administration of pharmacological agents and bone repair: what can we expect. Injury. 2011;42(6):605–8.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Barrett JG, Sample SJ, McCarthy J, Kalscheur VL, Muir P, Prokuski L. Effect of short-term treatment with alendronate on ulnar bone adaptation to cyclic fatigue loading in rats. J Orthop Res. 2007;25(8):1070–7.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Milgrom C, Finestone A, Novack V, Pereg D, Goldich Y, Kreiss Y, et al. The effect of prophylactic treatment with risedronate on stress fracture incidence among infantry recruits. Bone. 2004;35(2):418–24.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Gerstenfeld LC, Sacks DJ, Pelis M, Mason ZD, Graves DT, Barrero M, et al. Comparison of effects of the bisphosphonate alendronate versus the RANKL inhibitor denosumab on murine fracture healing. J Bone Miner Res. 2009;24(2):196–208.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Adami S, Libanati C, Boonen S, Cummings SR, Ho PR, Wang A, et al. Denosumab treatment in postmenopausal women with osteoporosis does not interfere with fracture-healing: results from the Freedom Trial. J Bone Joint Surg Am. 2012;94(23):2113–9.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Friedl G, Turner RT, Evans GL, Dobnig H. Intermittent parathyroid hormone (PTH) treatment and age-dependent effects on rat cancellous bone and mineral metabolism. J Orthop Res. 2007;25(11):1454–64.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Andreassen TT, Ejersted C, Oxlund H. Intermittent parathyroid hormone (1-34) treatment increases callus formation and mechanical strength of healing rat fractures. J Bone Miner Res. 1999;14(6):960–8.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Aspenberg P, Genant HK, Johansson T, Nino AJ, See K, Krohn K, et al. Teriparatide for acceleration of fracture repair in humans: a prospective, randomized, double-blind study of 102 postmenopausal women with distal radial fractures. J Bone Miner Res. 2010;25(2):404–14.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Huang TW, Chuang PY, Lin CY, Lee CY, Huang KC, Shih HN, et al. Teriparatide improves fracture healing and early functional recovery in treatment osteoporotic intertrochanteric fractures. Medicine (Baltimore). 2016;95(19):e3626.CrossRefGoogle Scholar
  49. 49.
    Miyakoshi N, Aizawa T, Sasaki S. Healing of bisphosphonate-associated atypical femoral fractures in patients with osteoporosis: a comparison between treatment with and without teriparatide. J Bone Miner Metab. 2015;33(5):553–9.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Kim HJ, Lee HM, Kim HS, Park JO, Moon ES, Park H, et al. Bone metabolism in postmenopausal women with lumbar spinal stenosis: analysis of bone mineral density and bone turnover markers. Spine (Phila Pa 1976). 2008;33(22):2435–9.CrossRefGoogle Scholar
  51. 51.
    Schmidt T, Ebert K, Roivien T, Oehler N, Lohmann J, Papavero L, et al. A retrospective analysis of bone mineral status in patients requiring spinal surgery. BMC Musculoskelet Disord. 2018;19(1):53.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Bennett GJ, Serhan HA, Sorini PM, Willis BH. An experimental study of lumbar destabilization. Restabilization and bone density. Spine (Phila Pa 1976). 1997;22(13):1448–53.CrossRefGoogle Scholar
  53. 53.
    Huang RC, Khan SN, Sandhu HS, Metzl JA, Cammisa FP Jr, Zheng F, et al. Alendronate inhibits spine fusion in a rat model. Spine (Phila Pa 1976). 2005;30(22):2516–22.CrossRefGoogle Scholar
  54. 54.
    Sama AA, Khan SN, Myers ER, Huang RC, Cammisa FP Jr, Sandhu HS, et al. High-dose alendronate uncouples osteoclast and osteoblast function: a study in a rat spine pseudarthrosis model. Clin Orthop Relat Res. 2004;425:135–42.CrossRefGoogle Scholar
  55. 55.
    Xue Q, Li H, Zou X, Bünger M, Egund N, Lind M, et al. The influence of alendronate treatment and bone graft volume on posterior lateral spine fusion in a porcine model. Spine (Phila Pa 1976). 2005;30(10):1116–21.CrossRefGoogle Scholar
  56. 56.
    Babat LB, McLain R, Milks R, Ferrara L, Sohn MJ. The effects of the antiresorptive agents calcitonin and pamidronate on spine fusion in a rabbit model. Spine J. 2005;5(5):542–7.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Bransford R, Goergens E, Briody J, Amanat N, Cree A, Little D. Effect of zoledronic acid in an L6-L7 rabbit spine fusion model. Eur Spine J. 2007;16(4):557–62.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Xue Q, Li H, Zou X, Lind M, Christensen FB, Bünger C. Alendronate treatment improves bone-pedicle screw interface fixation in posterior lateral spine fusion: an experimental study in a porcine model. Int Orthop. 2010;34(3):447–51.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Xue QY, Ji Q, Li HS, Zou XN, Egund N, Lind M, et al. Alendronate treatment does not inhibit bone formation within biphasic calcium phosphate ceramics in posterolateral spinal fusion: an experimental study in porcine model. Chin Med J. 2009;122(22):2770–4.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Nagahama K, Kanayama M, Togawa D, Hashimoto T, Minami A. Does alendronate disturb the healing process of posterior lumbar interbody fusion? A prospective randomized trial. J Neurosurg Spine. 2011;14(4):500–7.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Nakao S, Minamide A, Kawakami M, Boden SD, Yoshida M. The influence of alendronate on spine fusion in an osteoporotic animal model. Spine (Phila Pa 1976). 2011;36(18):1446–52.CrossRefGoogle Scholar
  62. 62.
    O’Loughlin PF, Cunningham ME, Bukata SV, Tomin E, Poynton AR, Doty SB, 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):121–30.CrossRefGoogle Scholar
  63. 63.
    Lehman RA Jr, Dmitriev AE, Cardoso MJ, Helgeson MD, Christensen CL, Raymond JW, et al. Effect of teriparatide [rhPTH(1,34)] and calcitonin on intertransverse process fusion in a rabbit model. Spine (Phila Pa 1976). 2010;35(2):146–52.CrossRefGoogle Scholar
  64. 64.
    Ohtori S, Inoue G, Orita S, Yamauchi K, Eguchi Y, Ochiai N, et al. Teriparatide accelerates lumbar posterolateral fusion in women with postmenopausal osteoporosis: prospective study. Spine (Phila Pa 1976). 2012;37(23):E1464–8.CrossRefGoogle Scholar
  65. 65.
    Ohtori S, Inoue G, Orita S, Yamauchi K, Eguchi Y, Ochiai N, 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 (Phila Pa 1976). 2013;38(8):E487–92.CrossRefGoogle Scholar
  66. 66.
    Ebata S, Takahashi J, Hasegawa T. Role of weekly teriparatide administration in osseous union enhancement within six months after posterior of transforaminal interbody fusion for osteoporosis-associated lumbar degenerative disorders: a multicenter prospective randomized study. J Bone Joint Surg Am. 2017;99(5):365–72.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Sugiura T, Kashi M, Matsuo Y, Morimoto T, Honda H, Kaito T, et al. Intermittent administration of teriparatide enhances graft bone healing and accelerates spinal fusion in rats with glucocorticoid-induced osteoporosis. Spine J. 2015;15(2):298–306.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Ohtori S, Orita S, Yamauchi K, Eguchi Y, Ochiai N, Kuniyoshi 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):573–80.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    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 Soine J. 2017;26(3):691–7.CrossRefGoogle Scholar
  70. 70.
    Seki S, Hirano N, Kawaquchi Y. Teriparatide versus low-dose bisphosphonates before and after surgery for adult spinal deformity in female Japanese patients with osteoporosis. Eur Spine J. 2017;26(8):2121–7.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Ohtori S, Orita S, Yamauchi K, Eguchi Y, Aoki Y, Nakamura J, et al. Does discontinuing teriparatide treatment and replacing it with bisphosphonate maintain the volume of the bone fusion mass after lumbar posterolateral fusion in women with postmenopausal osteoporosis. Asian Spine J. 2017;11(2):272–7.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Buerba RA, Sharma A, Ziino C. Bisphosphonate and teriparatide use in thoracolumbar fusion: a systemic review and meta-analysis of comparative studies. Spine. 2018;43(17):E1014–23.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Johnell O, Kannus P, Obrant KJ, Jarvinen M, Parkkari J, Nordic Orthopedic Federation. Management of the patient after an osteoporotic fracture: guidelines for orthopedic surgeons—consensus conference on treatment of osteoporosis for orthopedic surgeons, Nordic Orthopedic Federation, Tampere, Finland 2000. Acta Orthop Scand. 2001;72(4):325–30.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
  75. 75.
    McLellan AR, Gallacher SJ, Fraser M, McQuillian C. The fracture liaison service: success of a program for the evaluation and management of patients with osteoporotic fracture. Osteoporos Int. 2003;14(12):1028–34.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Skedros JG. The orthopaedic surgeon’s role in diagnosing and treating patients with osteoporotic fractures: standing discharge orders may be the solution for timely medical care. Osteoporos Int. 2004;15(5):405–10.CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.The Osteoporosis and Metabolic Bone Health Center, Department of MedicineHospital for Special Surgery, Weill Cornell MedicineNew YorkUSA

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