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Combination Therapy Using Exercise and Pharmaceutical Agents to Optimize Bone Health

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Clinical Reviews in Bone and Mineral Metabolism Aims and scope Submit manuscript

Abstract

Aging is associated with a reduction in bone strength and resultant increase in low trauma fractures. These so-called osteoporotic fractures represent a prominent and growing societal problem. To reduce the individual and societal cost of osteoporosis there is a need for efficacious interventions. Two frequently prescribed interventions are load-bearing exercise and pharmaceutical agents. These modalities have similar, yet somewhat contrasting influences on the underlying processes responsible for bone health. Exercise affects both osteoblastic bone formation and osteoclastic bone resorption to have both anabolic and anti-resorptive effects. Pharmaceutical agents target these processes also; however, they are typically specific to one process or the other. For instance, anti-resorptive agents such as bisphosphonates target osteoclast-mediated bone resorption, whereas anabolic agents such as intermittent parathyroid hormone (PTH) target osteoblast-mediated bone formation. In light of the similar targets of both exercise and pharmaceutical agents, questions have been raised of whether combining the two modalities may result in greater enhancements in bone health than with their isolated introduction. This article discusses the tissue-level processes regulating bone health, mechanisms of action of exercise and pharmaceutical agents, and rationale and current evidence for combined exercise and pharmaceutical intervention for optimizing bone health.

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References

  1. Burge R, Dawson-Hughes B, Solomon DH, Wong JB, King A, Tosteson A. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005–2025. J Bone Miner Res. 2007;22(3):465–75.

    Article  PubMed  Google Scholar 

  2. Frost HM. Tetracycline-based histological analysis of bone remodeling. Calcif Tissue Res. 1969;3:211–37.

    Article  PubMed  CAS  Google Scholar 

  3. Parfitt AM. Osteonal and hemi-osteonal remodeling: the spatial and temporal framework for signal traffic in adult human bone. J Cell Biochem. 1994;55(3):273–86.

    Article  PubMed  CAS  Google Scholar 

  4. Parfitt AM. The coupling of bone resorption to bone formation: a critical analysis of the concept and of its relevance to the pathogenesis of osteoporosis. Metab Bone Dis Relat Res. 1982;4:1–6.

    Article  PubMed  CAS  Google Scholar 

  5. Ahlborg HG, Johnell O, Turner CH, Rannevik G, Karlsson MK. Bone loss and bone size after menopause. N Engl J Med. 2003;349(4):327–34.

    Article  PubMed  Google Scholar 

  6. Duan Y, Beck TJ, Wang XF, Seeman E. Structural and biomechanical basis of sexual dimorphism in femoral neck fragility has its origins in growth and aging. J Bone Miner Res. 2003;18(10):1766–74.

    Article  PubMed  Google Scholar 

  7. Szulc P, Seeman E, Duboeuf F, Sornay-Rendu E, Delmas PD. Bone fragility: failure of periosteal apposition to compensate for increased endocortical resorption in postmenopausal women. J Bone Miner Res. 2006;21(12):1856–63.

    Article  PubMed  Google Scholar 

  8. Seeman E. Reduced bone formation and increased bone resorption: rational targets for the treatment of osteoporosis. Osteoporos Int. 2003;14(Suppl 3):S2–S8.

    PubMed  Google Scholar 

  9. Hind K, Burrows M. Weight-bearing exercise and bone mineral accrual in children and adolescents: a review of controlled trials. Bone. 2007;40(1):14–27.

    Article  PubMed  CAS  Google Scholar 

  10. MacKelvie KJ, Khan KM, McKay HA. Is there a critical period for bone response to weight-bearing exercise in children and adolescents? a systematic review. Br J Sports Med. 2002;36(4):250–7. discussion 257.

    Article  PubMed  CAS  Google Scholar 

  11. Bass SL, Saxon L, Daly RM, Turner CH, Robling AG, Seeman E, et al. The effect of mechanical loading on the size and shape of bone in pre-, peri-, and postpubertal girls: a study in tennis players. J Bone Miner Res. 2002;17(12):2274–80.

    Article  PubMed  CAS  Google Scholar 

  12. Torrance AG, Mosley JR, Suswillo RF, Lanyon LE. Noninvasive loading of the rat ulna in vivo induces a strain-related modeling response uncomplicated by trauma or periostal pressure. Calcif Tissue Int. 1994;54(3):241–7.

    Article  PubMed  CAS  Google Scholar 

  13. Pead MJ, Skerry TM, Lanyon LE. Direct transformation from quiescence to bone formation in the adult periosteum following a single brief period of bone loading. J Bone Miner Res. 1988;3(6):647–56.

    PubMed  CAS  Google Scholar 

  14. Pead MJ, Suswillo R, Skerry TM, Vedi S, Lanyon LE. Increased 3H-uridine levels in osteocytes following a single short period of dynamic bone loading in vivo. Calcif Tissue Int. 1988;43(2):92–6.

    Article  PubMed  CAS  Google Scholar 

  15. Forwood MR, Owan I, Takano Y, Turner CH. Increased bone formation in rat tibiae after a single short period of dynamic loading in vivo. Am J Physiol. 1996;270(3 Pt 1):E419–23.

    PubMed  CAS  Google Scholar 

  16. Forwood MR, Turner CH. The response of rat tibiae to incremental bouts of mechanical loading: a quantum concept for bone formation. Bone. 1994;15(6):603–9.

    Article  PubMed  CAS  Google Scholar 

  17. Robling AG, Hinant FM, Burr DB, Turner CH. Improved bone structure and strength after long-term mechanical loading is greatest if loading is separated into short bouts. J Bone Miner Res. 2002;17(8):1545–54.

    Article  PubMed  Google Scholar 

  18. Warden SJ, Hurst JA, Sanders MS, Turner CH, Burr DB, Li J. Bone adaptation to a mechanical loading program significantly increases skeletal fatigue resistance. J Bone Miner Res. 2005;20(5):809–16.

    Article  PubMed  Google Scholar 

  19. Lieberman DE, Pearson OM, Polk JD, Demes B, Crompton AW. Optimization of bone growth and remodeling in response to loading in tapered mammalian limbs. J Exp Biol. 2003;206(Pt 18):3125–38.

    Article  PubMed  Google Scholar 

  20. Raab DM, Crenshaw TD, Kimmel DB, Smith EL. A histomorphometric study of cortical bone activity during increased weight-bearing exercise. J Bone Miner Res. 1991;6(7):741–9.

    PubMed  CAS  Google Scholar 

  21. Burr DB. Targeted and nontargeted remodeling. Bone. 2002;30(1):2–4.

    Article  PubMed  CAS  Google Scholar 

  22. Pavy-Le Traon A, Heer M, Narici MV, Rittweger J, Vernikos J. From space to Earth: advances in human physiology from 20 years of bed rest studies (1986–2006). Eur J Appl Physiol. 2007;101(2):143–94.

    Article  PubMed  CAS  Google Scholar 

  23. Barengolts EI, Lathon PV, Curry DJ, Kukreja SC. Effects of endurance exercise on bone histomorphometric parameters in intact and ovariectomized rats. Bone Miner. 1994;26(2):133–40.

    Article  PubMed  CAS  Google Scholar 

  24. Peng ZQ, Vaananen HK, Tuukkanen J. Ovariectomy-induced bone loss can be affected by different intensities of treadmill running exercise in rats. Calcif Tissue Int. 1997;60(5):441–8.

    Article  PubMed  CAS  Google Scholar 

  25. Kim CH, You L, Yellowley CE, Jacobs CR. Oscillatory fluid flow-induced shear stress decreases osteoclastogenesis through RANKL and OPG signaling. Bone. 2006;39(5):1043–7.

    Article  PubMed  CAS  Google Scholar 

  26. Tan SD, de Vries TJ, Kuijpers-Jagtman AM, Semeins CM, Everts V, Klein-Nulend J. Osteocytes subjected to fluid flow inhibit osteoclast formation and bone resorption. Bone. 2007;41(5):745–51.

    Article  PubMed  CAS  Google Scholar 

  27. You L, Temiyasathit S, Lee P, Kim CH, Tummala P, Yao W, et al. Osteocytes as mechanosensors in the inhibition of bone resorption due to mechanical loading. Bone. 2008;42(1):172–9.

    Article  PubMed  CAS  Google Scholar 

  28. Riggs BL, Parfitt AM. Drugs used to treat osteoporosis: the critical need for a uniform nomenclature based on their action on bone remodeling. J Bone Miner Res. 2005;20(2):177–84.

    Article  PubMed  CAS  Google Scholar 

  29. Rogers MJ, Gordon S, Benford HL, Coxon FP, Luckman SP, Monkkonen J, et al. Cellular and molecular mechanisms of action of bisphosphonates. Cancer. 2000;88(12 Suppl):2961–78.

    Article  PubMed  CAS  Google Scholar 

  30. Flanagan AM, Chambers TJ. Dichloromethylenebisphosphonate (Cl2MBP) inhibits bone resorption through injury to osteoclasts that resorb Cl2MBP-coated bone. Bone Miner. 1989;6(1):33–43.

    Article  PubMed  CAS  Google Scholar 

  31. Sato M, Grasser W, Endo N, Akins R, Simmons H, Thompson DD, et al. Bisphosphonate action. Alendronate localization in rat bone and effects on osteoclast ultrastructure. J Clin Invest. 1991;88(6):2095–105.

    Article  PubMed  CAS  Google Scholar 

  32. Thompson K, Rogers MJ, Coxon FP, Crockett JC. Cytosolic entry of bisphosphonate drugs requires acidification of vesicles after fluid-phase endocytosis. Mol Pharmacol. 2006;69(5):1624–32.

    Article  PubMed  CAS  Google Scholar 

  33. Russell RG. Bisphosphonates: mode of action and pharmacology. Pediatrics. 2007;119(Suppl 2):S150–62.

    Article  PubMed  Google Scholar 

  34. Sato M, Grasser W. Effects of bisphosphonates on isolated rat osteoclasts as examined by reflected light microscopy. J Bone Miner Res. 1990;5(1):31–40.

    PubMed  CAS  Google Scholar 

  35. Chavassieux PM, Arlot ME, Reda C, Wei L, Yates AJ, Meunier PJ. Histomorphometric assessment of the long-term effects of alendronate on bone quality and remodeling in patients with osteoporosis. J Clin Invest. 1997;100(6):1475–80.

    Article  PubMed  CAS  Google Scholar 

  36. Chavassieux PM, Arlot ME, Roux JP, Portero N, Daifotis A, Yates AJ, et al. Effects of alendronate on bone quality and remodeling in glucocorticoid-induced osteoporosis: a histomorphometric analysis of transiliac biopsies. J Bone Miner Res. 2000;15(4):754–62.

    Article  PubMed  CAS  Google Scholar 

  37. Canalis E, Giustina A, Bilezikian JP. Mechanisms of anabolic therapies for osteoporosis. N Engl J Med. 2007;357(9):905–16.

    Article  PubMed  CAS  Google Scholar 

  38. Martin TJ, Sims NA, Ng KW. Regulatory pathways revealing new approaches to the development of anabolic drugs for osteoporosis. Osteoporos Int. 2008. [Epub ahead of print]. doi:10.1007/s00198-008-0575-5.

  39. Frolik CA, Black EC, Cain RL, Satterwhite JH, Brown-Augsburger PL, Sato M, et al. Anabolic and catabolic bone effects of human parathyroid hormone (1–34) are predicted by duration of hormone exposure. Bone. 2003;33(3):372–9.

    Article  PubMed  CAS  Google Scholar 

  40. Dempster DW, Cosman F, Parisien M, Shen V, Lindsay R. Anabolic actions of parathyroid hormone on bone. Endocr Rev. 1993;14(6):690–709.

    Article  PubMed  CAS  Google Scholar 

  41. Dobnig H, Turner RT. Evidence that intermittent treatment with parathyroid hormone increases bone formation in adult rats by activation of bone lining cells. Endocrinology. 1995;136(8):3632–8.

    Article  PubMed  CAS  Google Scholar 

  42. Jilka RL, Weinstein RS, Bellido T, Roberson P, Parfitt AM, Manolagas SC. Increased bone formation by prevention of osteoblast apoptosis with parathyroid hormone. J Clin Invest. 1999;104(4):439–46.

    Article  PubMed  CAS  Google Scholar 

  43. Hodsman AB, Bauer DC, Dempster DW, Dian L, Hanley DA, Harris ST, et al. Parathyroid hormone and teriparatide for the treatment of osteoporosis: a review of the evidence and suggested guidelines for its use. Endocr Rev. 2005;26(5):688–703.

    Article  PubMed  CAS  Google Scholar 

  44. Johnston S, Andrews S, Shen V, Cosman F, Lindsay R, Dempster DW, et al. The effects of combination of alendronate and human parathyroid hormone(1–34) on bone strength are synergistic in the lumbar vertebra and additive in the femur of C57BL/6 J mice. Endocrinology. 2007;148(9):4466–74.

    Article  PubMed  CAS  Google Scholar 

  45. Pettway GJ, Meganck JA, Koh AJ, Keller ET, Goldstein SA, McCauley LK. Parathyroid hormone mediates bone growth through the regulation of osteoblast proliferation and differentiation. Bone. 2008;42(4):806–18.

    Article  PubMed  CAS  Google Scholar 

  46. Samadfam R, Xia Q, Goltzman D. Co-treatment of PTH with osteoprotegerin or alendronate increases its anabolic effect on the skeleton of oophorectomized mice. J Bone Miner Res. 2007;22(1):55–63.

    Article  PubMed  CAS  Google Scholar 

  47. Black DM, Greenspan SL, Ensrud KE, Palermo L, McGowan JA, Lang TF, et al. The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med. 2003;349(13):1207–15.

    Article  PubMed  CAS  Google Scholar 

  48. Finkelstein JS, Hayes A, Hunzelman JL, Wyland JJ, Lee H, Neer RM. The effects of parathyroid hormone, alendronate, or both in men with osteoporosis. N Engl J Med. 2003;349(13):1216–26.

    Article  PubMed  CAS  Google Scholar 

  49. Khosla S. Parathyroid hormone plus alendronate: a combination that does not add up. N Engl J Med. 2003;349(13):1277–9.

    Article  PubMed  Google Scholar 

  50. Black DM, Bilezikian JP, Ensrud KE, Greenspan SL, Palermo L, Hue T, et al. One year of alendronate after one year of parathyroid hormone (1–84) for osteoporosis. N Engl J Med. 2005;353(6):555–65.

    Article  PubMed  CAS  Google Scholar 

  51. Cosman F, Nieves J, Zion M, Woelfert L, Luckey M, Lindsay R. Daily and cyclic parathyroid hormone in women receiving alendronate. N Engl J Med. 2005;353(6):566–75.

    Article  PubMed  CAS  Google Scholar 

  52. Jarvinen TL, Sievanen H, Khan KM, Heinonen A, Kannus P. Shifting the focus in fracture prevention from osteoporosis to falls. BMJ. 2008;336(7636):124–6.

    Article  PubMed  Google Scholar 

  53. Fuchs RK, Shea M, Durski SL, Winters-Stone KM, Widrick J, Snow CM. Individual and combined effects of exercise and alendronate on bone mass and strength in ovariectomized rats. Bone. 2007;41(2):290–6.

    Article  PubMed  CAS  Google Scholar 

  54. Tamaki H, Akamine T, Goshi N, Kurata H, Sakou T. Effects of exercise training and etidronate treatment on bone mineral density and trabecular bone in ovariectomized rats. Bone. 1998;23(2):147–53.

    Article  PubMed  CAS  Google Scholar 

  55. Braith RW, Conner JA, Fulton MN, Lisor CF, Casey DP, Howe KS, et al. Comparison of alendronate vs alendronate plus mechanical loading as prophylaxis for osteoporosis in lung transplant recipients: a pilot study. J Heart Lung Transplant. 2007;26(2):132–7.

    Article  PubMed  Google Scholar 

  56. Braith RW, Magyari PM, Fulton MN, Aranda J, Walker T, Hill JA. Resistance exercise training and alendronate reverse glucocorticoid-induced osteoporosis in heart transplant recipients. J Heart Lung Transplant. 2003;22(10):1082–90.

    Article  PubMed  Google Scholar 

  57. Chilibeck PD, Davison KS, Whiting SJ, Suzuki Y, Janzen CL, Peloso P. The effect of strength training combined with bisphosphonate (etidronate) therapy on bone mineral, lean tissue, and fat mass in postmenopausal women. Can J Physiol Pharmacol. 2002;80(10):941–50.

    Article  PubMed  CAS  Google Scholar 

  58. Grigoriev AI, Morukov BV, Oganov VS, Rakhmanov AS, Buravkova LB. Effect of exercise and bisphosphonate on mineral balance and bone density during 360 day antiorthostatic hypokinesia. J Bone Miner Res. 1992;7(Suppl 2):S449–55.

    Article  PubMed  Google Scholar 

  59. Iwamoto J, Takeda T, Sato Y, Uzawa M. Effect of whole-body vibration exercise on lumbar bone mineral density, bone turnover, and chronic back pain in post-menopausal osteoporotic women treated with alendronate. Aging Clin Exp Res. 2005;17(2):157–63.

    PubMed  CAS  Google Scholar 

  60. Uusi-Rasi K, Kannus P, Cheng S, Sievanen H, Pasanen M, Heinonen A, et al. Effect of alendronate and exercise on bone and physical performance of postmenopausal women: a randomized controlled trial. Bone. 2003;33(1):132–43.

    Article  PubMed  CAS  Google Scholar 

  61. Ryder KD, Duncan RL. Parathyroid hormone modulates the response of osteoblast-like cells to mechanical stimulation. Calcif Tissue Int. 2000;67(3):241–6.

    Article  PubMed  CAS  Google Scholar 

  62. Ryder KD, Duncan RL. Parathyroid hormone enhances fluid shear-induced [Ca2+]i signaling in osteoblastic cells through activation of mechanosensitive and voltage-sensitive Ca2+ channels. J Bone Miner Res. 2001;16(2):240–8.

    Article  PubMed  CAS  Google Scholar 

  63. Miyauchi A, Notoya K, Mikuni-Takagaki Y, Takagi Y, Goto M, Miki Y, et al. Parathyroid hormone-activated volume-sensitive calcium influx pathways in mechanically loaded osteocytes. J Biol Chem. 2000;275(5):3335–42.

    Article  PubMed  CAS  Google Scholar 

  64. Zhang J, Ryder KD, Bethel JA, Ramirez R, Duncan RL. PTH-induced actin depolymerization increases mechanosensitive channel activity to enhance mechanically stimulated Ca2+ signaling in osteoblasts. J Bone Miner Res. 2006;21(11):1729–37.

    Article  PubMed  CAS  Google Scholar 

  65. Chow JW, Fox S, Jagger CJ, Chambers TJ. Role for parathyroid hormone in mechanical responsiveness of rat bone. Am J Physiol. 1998;274(1 Pt 1):E146–54.

    PubMed  CAS  Google Scholar 

  66. Hagino H, Okano T, Akhter MP, Enokida M, Teshima R. Effect of parathyroid hormone on cortical bone response to in vivo external loading of the rat tibia. J Bone Miner Metab. 2001;19(4):244–50.

    Article  PubMed  CAS  Google Scholar 

  67. Kim CH, Takai E, Zhou H, von Stechow D, Muller R, Dempster DW, et al. Trabecular bone response to mechanical and parathyroid hormone stimulation: the role of mechanical microenvironment. J Bone Miner Res. 2003;18(12):2116–25.

    Article  PubMed  CAS  Google Scholar 

  68. Li J, Duncan RL, Burr DB, Gattone VH, Turner CH. Parathyroid hormone enhances mechanically induced bone formation, possibly involving L-type voltage-sensitive calcium channels. Endocrinology. 2003;144(4):1226–33.

    Article  PubMed  CAS  Google Scholar 

  69. Ma Y, Jee WS, Yuan Z, Wei W, Chen H, Pun S, et al. Parathyroid hormone and mechanical usage have a synergistic effect in rat tibial diaphyseal cortical bone. J Bone Miner Res. 1999;14(3):439–48.

    Article  PubMed  CAS  Google Scholar 

  70. Lindsay R, Nieves J, Henneman E, Shen V, Cosman F. Subcutaneous administration of the amino-terminal fragment of human parathyroid hormone-(1–34): kinetics and biochemical response in estrogenized osteoporotic patients. J Clin Endocrinol Metab. 1993;77(6):1535–9.

    Article  PubMed  CAS  Google Scholar 

  71. Khan SA, Kanis JA, Vasikaran S, Kline WF, Matuszewski BK, McCloskey EV, et al. Elimination and biochemical responses to intravenous alendronate in postmenopausal osteoporosis. J Bone Miner Res. 1997;12(10):1700–7.

    Article  PubMed  CAS  Google Scholar 

  72. Mitchell DY, Heise MA, Pallone KA, Clay ME, Nesbitt JD, Russell DA, et al. The effect of dosing regimen on the pharmacokinetics of risedronate. Br J Clin Pharmacol. 1999;48(4):536–42.

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Physical Therapy, School of Health and Rehabilitation Sciences, Indiana University, 1140 West Michigan Street, CF-326, Indianapolis, IN, 46202, USA

    R. K. Fuchs & S. J. Warden

  2. Department of Anatomy and Cell Biology, School of Medicine, Indiana University, Indianapolis, IN, USA

    R. K. Fuchs & S. J. Warden

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Correspondence to R. K. Fuchs.

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Fuchs, R.K., Warden, S.J. Combination Therapy Using Exercise and Pharmaceutical Agents to Optimize Bone Health. Clinic Rev Bone Miner Metab 6, 37–45 (2008). https://doi.org/10.1007/s12018-008-9017-3

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