Optimum duration and safety of long-term use of potent anti-resorptive medications in osteoporosis

References

• NIH. Consensus Conference. Osteoporosis prevention, diagnosis, and therapy. JAMA. 2001;285:785–795.
   PubMed Web of Science ®Google Scholar
• Russell RG, Watts NB, Ebetino FH, et al. Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int. 2008;19(6):733–759.
   PubMed Web of Science ®Google Scholar
• Fleisch H. Osteoclasts in the reticule. Molecular mechanisms of bisphosphonates. Pharm Unserer Zeit. 2001;30:500–504.
   PubMedGoogle Scholar
• Bone HG, Hosking D, Devogelaer JP, et al. Ten years’ experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med. 2004;350:1189–1199.
   PubMed Web of Science ®Google Scholar
• Papapoulos SE, Cremers SC. Prolonged bisphosphonate release after treatment in children. N Engl J Med. 2007;356:1075–1076.
   PubMed Web of Science ®Google Scholar
• Khosla S. Minireview: the OPG/RANKL/RANK system. Endocrinology. 2001;142:5050–5055.
   PubMed Web of Science ®Google Scholar
• McClung MR, Lewiecki EM, Cohen SB, et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006;354:821–831.
   PubMed Web of Science ®Google Scholar
• Bone HG, Dempster DW, Eisman JA, et al. Odanacatib for the treatment of postmenopausal osteoporosis: development history and design and participant characteristics of LOFT, the long-term odanacatib fracture trial. Osteoporos Int. 2015;26:699–712.
   PubMed Web of Science ®Google Scholar
• Rizzoli R, Benhamou CL, Halse J, et al. Continuous treatment with odanacatib for up to 8 years in postmenopausal women with low bone mineral density: a phase 2 study. Osteoporos Int. 2016;27(6):2099–2107.
   Web of Science ®Google Scholar
• McClung MR. Emerging therapies for osteoporosis. Endocrinol Metab (Seoul). 2015;30:429–435.
   PubMedGoogle Scholar
• Prezelj J, Ostanek B, Logar DB, et al. Cathepsin K predicts femoral neck bone mineral density change in nonosteoporotic peri- and early postmenopausal women. Menopause. 2008;15:369–373.
   PubMed Web of Science ®Google Scholar
• Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361:756–765.
   PubMed Web of Science ®Google Scholar
• Siris ES, Harris ST, Eastell R, et al. Skeletal effects of raloxifene after 8 years: results from the continuing outcomes relevant to Evista (CORE) study. J Bone Miner Res. 2005;20:1514–1524.
   PubMed Web of Science ®Google Scholar
• Vega D, Maalouf NM, Sakhaee K. CLINICAL review #: the role of receptor activator of nuclear factor-kappaB (RANK)/RANK ligand/osteoprotegerin: clinical implications. J Clin Endocrinol Metab. 2007;92:4514–4521.
   PubMed Web of Science ®Google Scholar
• Collin-Osdoby P, Rothe L, Bekker S, et al. Basic fibroblast growth factor stimulates osteoclast recruitment, development, and bone pit resorption in association with angiogenesis in vivo on the chick chorioallantoic membrane and activates isolated avian osteoclast resorption in vitro. J Bone Miner Res. 2002;17:1859–1871.
   PubMed Web of Science ®Google Scholar
• Dempster DW, Lambing CL, Kostenuik PJ, et al. Role of RANK ligand and denosumab, a targeted RANK ligand inhibitor, in bone health and osteoporosis: a review of preclinical and clinical data. Clin Ther. 2012;34:521–536.
   PubMed Web of Science ®Google Scholar
• Kostenuik PJ, Smith SY, Jolette J, et al. Decreased bone remodeling and porosity are associated with improved bone strength in ovariectomized cynomolgus monkeys treated with denosumab, a fully human RANKL antibody. Bone. 2011;49:151–161.
   PubMed Web of Science ®Google Scholar
• Fleisch H. Bisphosphonates: mechanisms of action. Endocr Rev. 1998;19:80–100.
   PubMed Web of Science ®Google Scholar
• Russell RG, Xia Z, Dunford JE, et al. Bisphosphonates: an update on mechanisms of action and how these relate to clinical efficacy. Ann N Y Acad Sci. 2007;1117:209–257.
   PubMed Web of Science ®Google Scholar
• Zittermann A, Schleithoff SS, Koerfer R. Vitamin D and vascular calcification. Curr Opin Lipidol. 2007;18:41–46.
   PubMed Web of Science ®Google Scholar
• Fleisch H. Bisphosphonates in osteoporosis: an introduction. Osteoporos Int. 1993;3(Suppl 3):S3–5.
   Google Scholar
• Wimalawansa SJ. Insight into bisphosphonate-associated osteomyelitis of the jaw: pathophysiology, mechanisms and clinical management. Expert Opin Drug Saf. 2008;7:491–512.
   PubMed Web of Science ®Google Scholar
• Khosla S, Burr D, Cauley J, et al. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2007;22:1479–1491.
   PubMed Web of Science ®Google Scholar
• Shane E, Burr D, Abrahamsen B, et al. Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the american society for bone and mineral research. J Bone Miner Res. 2014;29:1–23.
   PubMed Web of Science ®Google Scholar
• Shane E, Burr D, Ebeling PR, et al. Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2010;25:2267–2294.
   PubMed Web of Science ®Google Scholar
• Heaney RP, Yates AJ, Santora AC II. Bisphosphonate effects and the bone remodeling transient. J Bone Miner Res. 1997;12:1143–1151.
   PubMed Web of Science ®Google Scholar
• Roelofs AJ, Thompson K, Gordon S, et al. Molecular mechanisms of action of bisphosphonates: current status. Clin Cancer Res. 2006;12:6222s–6230s.
   PubMed Web of Science ®Google Scholar
• Fleisch H. Bisphosphonates in bone disease: from laboratory to the patient. Berne (Switzerland): Stampfl Co Ltd; 1993.
   Google Scholar
• Weinstein RS, Roberson PK, Manolagas SC. Giant osteoclast formation and long-term oral bisphosphonate therapy. N Engl J Med. 2009;360:53–62.
   PubMed Web of Science ®Google Scholar
• Roelofs AJ, Thompson K, Gordon S, et al. Molecular mechanisms of action of bisphosphonates: current status. Clin Cancer Res. 2006;12:6222s–6230s.
   PubMed Web of Science ®Google Scholar
• Black DM, Schwartz AV, Ensrud KE, et al. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA. 2006;296:2927–2938.
   PubMed Web of Science ®Google Scholar
• Schwartz AV, Bauer DC, Cummings SR, et al. Efficacy of continued alendronate for fractures in women with and without prevalent vertebral fracture: the FLEX trial. J Bone Miner Res. 2010;25:976–982.
   PubMed Web of Science ®Google Scholar
• Sorensen OH, Crawford GM, Mulder H, et al. Long-term efficacy of risedronate: a 5-year placebo-controlled clinical experience. Bone. 2003;32:120–126.
   PubMed Web of Science ®Google Scholar
• Mellstrom DD, Sorensen OH, Goemaere S, et al. Seven years of treatment with risedronate in women with postmenopausal osteoporosis. Calcif Tissue Int. 2004;75:462–468.
   PubMed Web of Science ®Google Scholar
• Devogelaer JP, Brown JP, Burckhardt P, et al. Zoledronic acid efficacy and safety over five years in postmenopausal osteoporosis. Osteoporos Int. 2007;18:1211–1218.
   PubMed Web of Science ®Google Scholar
• Bone HG, Chapurlat R, Brandi ML, et al. The effect of three or six years of denosumab exposure in women with postmenopausal osteoporosis: results from the FREEDOM extension. J Clin Endocrinol Metab. 2013;98:4483–4492.
   PubMed Web of Science ®Google Scholar
• Baron R, Ferrari S, Russell RG. Denosumab and bisphosphonates: different mechanisms of action and effects. Bone. 2011;48:677–692.
   PubMed Web of Science ®Google Scholar
• Khosla S. Minireview: the OPG/RANKL/RANK system. Endocrinology. 2001;142:5050–5055.
   PubMed Web of Science ®Google Scholar
• Lewiecki EM. Treatment of osteoporosis with denosumab. Maturitas. 2010;66:182–186.
   PubMed Web of Science ®Google Scholar
• Varenna M, Gatti D. The role of rank-ligand inhibition in the treatment of postmenopausal osteoporosis. Reumatismo. 2010;62:163–171.
   PubMedGoogle Scholar
• Ominsky MS, Stouch B, Schroeder J, 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;49:162–173.
   PubMed Web of Science ®Google Scholar
• Ominsky MS, Li X, Asuncion FJ, et al. RANKL inhibition with osteoprotegerin increases bone strength by improving cortical and trabecular bone architecture in ovariectomized rats. J Bone Miner Res. 2008;23:672–682.
   PubMed Web of Science ®Google Scholar
• Anonymus. Denosumab. Limited efficacy in fracture prevention, too many adverse effects. Prescrire Int. 2011;20:145–148.
   PubMedGoogle Scholar
• Cryer B, Bauer DC. Oral bisphosphonates and upper gastrointestinal tract problems: what is the evidence? Mayo Clin Proc. 2002;77:1031–1043.
   PubMed Web of Science ®Google Scholar
• Famularo G, De Simone C. Fatal esophageal perforation with alendronate. Am J Gastroenterol. 2001;96:3212–3213.
   PubMedGoogle Scholar
• Bauer DC, Black D, Ensrud K, et al. Upper gastrointestinal tract safety profile of alendronate: the fracture intervention trial. Arch Intern Med. 2000;160:517–525.
   PubMed Web of Science ®Google Scholar
• Fraunfelder FW, Fraunfelder FT. Bisphosphonates and ocular inflammation. N Engl J Med. 2003;348:1187–1188.
   PubMed Web of Science ®Google Scholar
• De Groen PC, Lubbe DF, Hirsch LJ, et al. Esophagitis associated with the use of alendronate. N Engl J Med. 1996;335:1016–1021.
   PubMed Web of Science ®Google Scholar
• Abrahamsen B, Eiken P, Eastell R. More on reports of esophageal cancer with oral bisphosphonate usex. Eastell R. 2009;360:1789; author reply 1791-1782.
   Google Scholar
• Watts N, Freedholm D, Daifotis A. The clinical tolerability profile of alendronate. Int J Clin Pract Suppl. 1999;101:51–61.
   PubMedGoogle Scholar
• Wimalawansa SJ. Long-term bisphosphonates therapy and increase fracture risks. JBMR. 2007;22:S456.
   Google Scholar
• Adami S, Bhalla AK, Dorizzi R, et al. The acute-phase response after bisphosphonate administration. Calcif Tissue Int. 1987;41:326–331.
   PubMed Web of Science ®Google Scholar
• Strampel W, Emkey R, Civitelli R. Safety considerations with bisphosphonates for the treatment of osteoporosis. Drug Saf. 2007;30:755–763.
   PubMed Web of Science ®Google Scholar
• FDA. Ongoing safety review of oral osteoporosis drugs (bisphosphonates) and potential increased risk of esophageal cancer; 2012. Available from: http://1.usa.gov/R0Zb2S.
   Google Scholar
• FDA. Background Document for Meeting of Advisory Committee for Reproductive Health Drugs and Drug Safety and Risk Management Advisory Committee; 2011. Available from: http://1.usa.gov/oQbZNn
   Google Scholar
• O’Ryan FS, Khoury S, Liao W, et al. Intravenous bisphosphonate-related osteonecrosis of the jaw: bone scintigraphy as an early indicator. J Oral Maxillofac Surg. 2009;67:1363–1372.
   PubMed Web of Science ®Google Scholar
• Tanvetyanon T, Stiff PJ. Management of the adverse effects associated with intravenous bisphosphonates. Ann Oncol. 2006;17:897–907.
   PubMed Web of Science ®Google Scholar
• Loke YK, Jeevanantham V, Singh S. Bisphosphonates and atrial fibrillation: systematic review and meta-analysis. Drug Saf. 2009;32:219–228.
   PubMed Web of Science ®Google Scholar
• Cummings SR, Schwartz AV, Black DM. Alendronate and atrial fibrillation. N Engl J Med. 2007;356:1895–1896.
   PubMed Web of Science ®Google Scholar
• Chang JT, Green L, Beitz J. Renal failure with the use of zoledronic acid. N Engl J Med. 2003;349:1676-1679; discussion 1676-1679.
   Google Scholar
• Lewiecki EM. Safety and tolerability of denosumab for the treatment of postmenopausal osteoporosis. Drug Healthc Patient Saf. 2011;3:79–91.
   PubMedGoogle Scholar
• Borrelli J Jr, Lane J, Bukata S, et al. Atypical femur fractures. J Orthop Trauma. 2014;28(Suppl 1):S36–42.
   PubMedGoogle Scholar
• Lee SH, Gong HS, Kim TH, et al. Position statement: drug holiday in osteoporosis treatment with bisphosphonates in South Korea. J Bone Metab. 2015;22:167–174.
   PubMedGoogle Scholar
• Mashiba T, Turner CH, Hirano T, et al. Effects of suppressed bone turnover by bisphosphonates on microdamage accumulation and biomechanical properties in clinically relevant skeletal sites in beagles. Bone. 2001;28:524–531.
   PubMed Web of Science ®Google Scholar
• Mashiba T, Mori S, Burr DB, et al. The effects of suppressed bone remodeling by bisphosphonates on microdamage accumulation and degree of mineralization in the cortical bone of dog rib. J Bone Miner Metab. 2005;23:36–42.
   PubMed Web of Science ®Google Scholar
• Burr DB, Forwood MR, Fyhrie DP, et al. Bone microdamage and skeletal fragility in osteoporotic and stress fractures. J Bone Miner Res. 1997;12:6–15.
   PubMed Web of Science ®Google Scholar
• Seraphim A, Al-Hadithy N, Mordecai SC, et al. Do bisphosphonates cause femoral insufficiency fractures? J Orthop Traumatol. 2012;13:171–177.
   PubMedGoogle Scholar
• Chapurlat RD, Delmas PD. Bone microdamage: a clinical perspective. Osteoporos Int. 2009;20:1299–1308.
   PubMed Web of Science ®Google Scholar
• Schneider DL. Long-term bisphosphonate use: when to stop? when to restart? Today’s Geriatr Med. 2015;8:10–12.
   Google Scholar
• Wimalawansa SJ. Bisphosphonate-associated osteomyelitis of the jaw: guidelines for practicing clinicians. Endocr Pract. 2008;14:1150–1168.
   PubMedGoogle Scholar
• Gutta R, Louis PJ. Bisphosphonates and osteonecrosis of the jaws: science and rationale. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007;104:186–193.
   PubMed Web of Science ®Google Scholar
• Tella SH, Gallagher JC. Biological agents in management of osteoporosis. Eur J Clin Pharmacol. 2014;70:1291–1301.
   PubMed Web of Science ®Google Scholar
• Charopoulos I, Orme S, Giannoudis PV. The role and efficacy of denosumab in the treatment of osteoporosis: an update. Expert Opin Drug Saf. 2011;10:205–217.
   PubMed Web of Science ®Google Scholar
• Rachner TD, Khosla S, Hofbauer LC. Osteoporosis: now and the future. Lancet. 2011;377:1276–1287.
   PubMed Web of Science ®Google Scholar
• Farooki A, Fornier M, Boland P. Atypical femur fractures associated with use of bisphosphonates and denosumab. Ann Oncol. 2015;26:819–820.
   PubMed Web of Science ®Google Scholar
• Cating-Cabral MT, Clarke BL. Denosumab and atypical femur fractures. Maturitas. 2013;76:1–2.
   PubMed Web of Science ®Google Scholar
• Fusco V, Galassi C, Berruti A, et al. Osteonecrosis of the jaw after zoledronic acid and denosumab treatment. J Clin Oncol. 2011;29:e521-522; author reply e523-524.
   PubMed Web of Science ®Google Scholar
• Qi WX, Tang LN, He AN, et al. Risk of osteonecrosis of the jaw in cancer patients receiving denosumab: a meta-analysis of seven randomized controlled trials. Int J Clin Oncol. 2014;19:403–410.
   PubMed Web of Science ®Google Scholar
• Hoefert S, Hoefert CS, Albert M, et al. Zoledronate but not denosumab suppresses macrophagic differentiation of THP-1 cells. An aetiologic model of bisphosphonate-related osteonecrosis of the jaw (BRONJ). Clin Oral Investig. 2015;19:1307–1318.
   PubMed Web of Science ®Google Scholar
• Bone HG, Bolognese MA, Yuen CK, et al. Effects of denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass. J Clin Endocrinol Metab. 2011;96:972–980.
   PubMed Web of Science ®Google Scholar
• Aubry-Rozier B, Gonzalez-Rodriguez E, Stoll D, et al. Severe spontaneous vertebral fractures after denosumab discontinuation: three case reports. Osteoporos Int. 2015;27(5):1923–1925.
   Google Scholar
• Yue B, Ng A, Tang H, et al. Delayed healing of lower limb fractures with bisphosphonate therapy. Ann R Coll Surg Engl. 2015;97:333–338.
   PubMedGoogle Scholar
• Egol KA, Park JH, Rosenberg ZS, et al. Healing delayed but generally reliable after bisphosphonate-associated complete femur fractures treated with IM nails. Clin Orthop Relat Res. 2014;472:2728–2734.
   PubMed Web of Science ®Google Scholar
• Schilcher J, Sandberg O, Isaksson H, et al. Histology of 8 atypical femoral fractures: remodeling but no healing. Acta Orthop. 2014;85:280–286.
   PubMed Web of Science ®Google Scholar
• Miyakoshi N, Aizawa T, Sasaki S, et al. Healing of bisphosphonate-associated atypical femoral fractures in patients with osteoporosis: a comparison between treatment with and without teriparatide. J Bone Miner Metab. 2015;33:553–559.
   PubMed Web of Science ®Google Scholar
• Teo BJ, Koh JS, Goh SK, et al. Post-operative outcomes of atypical femoral subtrochanteric fracture in patients on bisphosphonate therapy. Bone Joint J. 2014;96-B:658–664.
   PubMed Web of Science ®Google Scholar
• Grady MK, Watson JT, Cannada LK. Treatment of femoral fracture nonunion after long-term bisphosphonate use. Orthopedics. 2012;35:e991–995.
   PubMed Web of Science ®Google Scholar
• Lewiecki EM. Odanacatib, a cathepsin K inhibitor for the treatment of osteoporosis and other skeletal disorders associated with excessive bone remodeling. IDrugs. 2009;12:799–809.
   PubMedGoogle Scholar
• Ng KW. Potential role of odanacatib in the treatment of osteoporosis. Clin Interv Aging. 2012;7:235–247.
   PubMed Web of Science ®Google Scholar
• Boonen S, Rosenberg E, Claessens F, et al. Inhibition of cathepsin K for treatment of osteoporosis. Curr Osteoporos Rep. 2012;10:73–79.
   PubMed Web of Science ®Google Scholar
• Duong Le T, Leung AT, Langdahl B. Cathepsin K inhibition: a new mechanism for the treatment of osteoporosis. Calcif Tissue Int. 2016;98:381–397.
   PubMed Web of Science ®Google Scholar
• Watanabe R, Okazaki R. Reducing bone resorption by cathepsin K inhibitor and treatment of osteoporosis. Clin Calcium. 2014;24:59–67.
   PubMedGoogle Scholar
• Nakamura T, Shiraki M, Fukunaga M, et al. Effect of the cathepsin K inhibitor odanacatib administered once weekly on bone mineral density in Japanese patients with osteoporosis–a double-blind, randomized, dose-finding study. Osteoporos Int. 2014;25:367–376.
   PubMed Web of Science ®Google Scholar
• Duong LT, Pickarski M, Cusick T, et al. Effects of long term treatment with high doses of odanacatib on bone mass, bone strength, and remodeling/modeling in newly ovariectomized monkeys. Bone. 2016;88:113–124.
   PubMed Web of Science ®Google Scholar
• Rietbrock S, Olson M, Van Staa TP. The potential effects on fracture outcomes of improvements in persistence and compliance with bisphosphonates. QJM. 2009;102:35–42.
   PubMed Web of Science ®Google Scholar
• Kelley GA, Kelley KS, Kohrt WM. Effects of ground and joint reaction force exercise on lumbar spine and femoral neck bone mineral density in postmenopausal women: a meta-analysis of randomized controlled trials. BMC Musculoskelet Disord. 2012;13:177.
   PubMed Web of Science ®Google Scholar
• Christensen PM, Brosen K, Brixen K, et al. A randomized trial of laypersons’ perception of the benefit of osteoporosis therapy: number needed to treat versus postponement of hip fracture. Clin Ther. 2003;25:2575–2585.
   PubMed Web of Science ®Google Scholar
• Curtis JR, Westfall AO, Cheng H, et al. Benefit of adherence with bisphosphonates depends on age and fracture type: results from an analysis of 101,038 new bisphosphonate users. J Bone Miner Res. 2008;23:1435–1441.
   PubMed Web of Science ®Google Scholar
• Seeman E. Osteoporosis: trials and tribulations. Am J Med. 1997;103:74S-87S; discussion 87S-89S.
   PubMedGoogle Scholar
• Ruggiero SL, Mehrotra B. Ten years of alendronate treatment for osteoporosis in postmenopausal women. N Engl J Med. 2004;351:190-192; author reply 190-192.
   PubMedGoogle Scholar
• Abrahamsen B, Eiken P, Eastell R. Subtrochanteric and diaphyseal femur fractures in patients treated with alendronate: a register-based national cohort study. J Bone Miner Res. 2009;24:1095–1102.
   PubMed Web of Science ®Google Scholar
• Hill BT. The establishment of criteria for “quiescence” in ageing human embryo cell cultures and their response to a proliferative stimulus. Gerontology. 1977;23:245–255.
   PubMed Web of Science ®Google Scholar
• Khan AA, Morrison A, Hanley DA, et al. International task force on osteonecrosis of the J. Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J Bone Miner Res. 2015;30:3–23.
   PubMed Web of Science ®Google Scholar
• Yamashita J, McCauley LK. Antiresorptives and osteonecrosis of the jaw. J Evid Based Dent Pract. 2012;12:233–247.
   PubMedGoogle Scholar
• Foster RL. Reporting guidelines: CONSORT, PRISMA, and SQUIRE. J Spec Pediatr Nurs. 2012;17:1–2.
   PubMed Web of Science ®Google Scholar
• Welch V, Petticrew M, Tugwell P, et al. PRISMA-equity 2012 extension: reporting guidelines for systematic reviews with a focus on health equity. PLoS Med. 2012;9:e1001333.
   PubMed Web of Science ®Google Scholar
• Ziegler A, Konig IR. Guidelines for research reports: German translation of CONSORT 2010, PRISMA and STARD. Dtsch Med Wochenschr. 2011;136:357–358.
   PubMed Web of Science ®Google Scholar
• Wimalawansa SJ. Hypercalcaemia of malignancy: etiology, pathophysiology, and management. Rev Endocr Relat Cancer. 1993;45:5–24.
   Google Scholar
• Wimalawansa SJ. Optimal frequency of administration of pamidronate in patients with hypercalcaemia of malignancy. Clin Endocrinol (Oxf). 1994;41:591–595.
   PubMed Web of Science ®Google Scholar
• Wimalawansa SJ. Hypercalcaemia of malignancy: etiology, pathogenesis and clinical management (medical intelligence unit, monograph). Springer, NY and R.G. Landes Co. Austin (TX): Medical Publishers; 1995.
   Google Scholar
• Cooper C, Li H, Wimalawansa SJ. Cancer-associated hypercalcemia and parathyroid hormone-related peptide: a new peptide with diverse roles. Reg Peptide Letters. 1997;7:39–42.
   Google Scholar
• Pickett FA. Bisphosphonate-associated osteonecrosis of the jaw: a literature review and clinical practice guidelines. J Dent Hyg. 2006;80:10.
   PubMedGoogle Scholar
• Pozzi S, Marcheselli R, Sacchi S, et al. Bisphosphonate-associated osteonecrosis of the jaw: a review of 35 cases and an evaluation of its frequency in multiple myeloma patients. Leuk Lymphoma. 2007;48:56–64.
   PubMed Web of Science ®Google Scholar
• You TM, Lee KH, Lee SH, et al. Denosumab-related osteonecrosis of the jaw: a case report and management based on pharmacokinetics. Oral Surg Oral Med Oral Pathol Oral Radiol. 2015;120:548–553.
   PubMed Web of Science ®Google Scholar
• Akhtar NH, Afzal MZ, Ahmed AA. Osteonecrosis of jaw with the use of denosumab. J Cancer Res Ther. 2011;7:499–500.
   PubMed Web of Science ®Google Scholar
• Uyanne J, Calhoun CC, Le AD. Antiresorptive drug-related osteonecrosis of the jaw. Dent Clin North Am. 2014;58:369–384.
   PubMedGoogle Scholar
• Zarychanski R, Elphee E, Walton P, et al. Osteonecrosis of the jaw associated with pamidronate therapy. Am J Hematol. 2006;81:73–75.
   PubMed Web of Science ®Google Scholar
• Olson KB, Hellie CM, Pienta KJ. Osteonecrosis of jaw in patient with hormone-refractory prostate cancer treated with zoledronic acid. Urology. 2005;66:658.
   PubMed Web of Science ®Google Scholar
• Migliorati CA, Siegel MA, Elting LS. Bisphosphonate-associated osteonecrosis: a long-term complication of bisphosphonate treatment. Lancet Oncol. 2006;7:508–514.
   PubMed Web of Science ®Google Scholar
• La Verde N, Bareggi C, Garassino M, et al. Osteonecrosis of the jaw (ONJ) in cancer patients treated with Bisphosphonates: how the knowledge of a phenomenon can change its evolution. Support Care Cancer. 2008;16(11):1311–1315.
   PubMed Web of Science ®Google Scholar
• Kajizono M, Sada H, Sugiura Y, et al. Incidence and risk factors of osteonecrosis of the jaw in advanced cancer patients after treatment with zoledronic acid or denosumab: a retrospective cohort study. Biol Pharm Bull. 2015;38:1850–1855.
   PubMed Web of Science ®Google Scholar
• Im GI, Lee SH. Effect of teriparatide on healing of atypical femoral fractures: a systemic review. J Bone Metab. 2015;22:183–189.
   PubMedGoogle Scholar
• Neuprez A, Rompen E, Crielaard JM, et al. Teriparatide therapy for denosumab-induced osteonecrosis of the jaw in a male osteoporotic patient. Calcif Tissue Int. 2014;95:94–96.
   PubMed Web of Science ®Google Scholar
• Jiang Y, Liu C, Chen W, et al. Tetramethylpyrazine enhances vascularization and prevents osteonecrosis in steroid-treated rats. Biomed Res Int. 2015;2015:315850.
   PubMedGoogle Scholar
• Cao HJ, Zheng LZ, Wang N, et al. Src blockage by siRNA inhibits VEGF-induced vascular hyperpemeability and osteoclast activity - an in vitro mechanism study for preventing destructive repair of osteonecrosis. Bone. 2015;74:58–68.
   PubMed Web of Science ®Google Scholar
• Ikeda T, Kuraguchi J, Kogashiwa Y, et al. Successful treatment of bisphosphonate-related osteonecrosis of the jaw (BRONJ) patients with sitafloxacin: new strategies for the treatment of BRONJ. Bone. 2015;73:217–222.
   PubMed Web of Science ®Google Scholar
• Porcaro G, Amosso E, Scarpella R, et al. Doxycycline fluorescence-guided Er: YAGlaser ablation combined with Nd: YAG/diodelaser biostimulation for treating bisphosphonate-related osteonecrosis of the jaw. Oral Surg Oral Med Oral Pathol Oral Radiol. 2015;119:e6–e12.
   PubMed Web of Science ®Google Scholar
• Piccioli A. Bisphosphonate-related osteonecrosis of the jaw in patients with breast cancer. Eur J Orthop Surg Traumatol. 2015;25:29–37.
   PubMedGoogle Scholar
• Khosla S, Burr D, Cauley J, et al. ASBMR task force on bisphosphonate-associated ONJ: report of a task force of the American society for bone and mineral research. J Bone Miner Res. 2007;22(10):1471–1491.
   Google Scholar
• Jeffcoat M, Watts NB. Osteonecrosis of the jaw: balancing the benefits and risks of oral bisphosphonate treatment for osteoporosis. Gen Dent. 2008;56:96-102; quiz 103-104, 111-102.
   PubMedGoogle Scholar
• Hellstein JW, Marek CL. Bisphosphonate induced osteochemonecrosis of the jaws: an ounce of prevention may be worth a pound of cure. Spec Care Dentist. 2006;26:8–12.
   PubMedGoogle Scholar
• Coskun Benlidayi I, Guzel R. Oral bisphosphonate related osteonecrosis of the jaw: a challenging adverse effect. ISRN Rheumatol. 2013;2013:215034.
   PubMedGoogle Scholar
• Khosla S, Bilezikian JP, Dempster DW, et al. Benefits and risks of bisphosphonate therapy for osteoporosis. J Clin Endocrinol Metab. 2012;97:2272–2282.
   PubMed Web of Science ®Google Scholar
• Park-Wyllie LY, Mamdani MM, Juurlink DN, et al. Bisphosphonate use and the risk of subtrochanteric or femoral shaft fractures in older women. JAMA. 2011;305:783–789.
   PubMed Web of Science ®Google Scholar
• Odvina CV, Zerwekh JE, Rao DS, et al. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab. 2005;90:1294–1301.
   PubMed Web of Science ®Google Scholar
• Nieves JW, Cosman F. Atypical subtrochanteric and femoral shaft fractures and possible association with bisphosphonates. Curr Osteoporos Rep. 2010;8:34–39.
   PubMedGoogle Scholar
• Leung F, Lau TW, To M, et al. Atypical femoral diaphyseal and subtrochanteric fractures and their association with bisphosphonates. BMJ Case Rep. 2009;2009:bcr10.2008.1073.
   Google Scholar
• Goh SK, Yang KY, Koh JS, et al. Subtrochanteric insufficiency fractures in patients on alendronate therapy: a caution. J Bone Joint Surg Br. 2007;89:349–353.
   PubMed Web of Science ®Google Scholar
• Aspenberg P. Denosumab and atypical femoral fractures. Acta Orthop. 2014;85:1.
   PubMed Web of Science ®Google Scholar
• Rashad A, Smeets R, Heiland M. RANK-ligand inhibitor associated osteonecrosis of the jaw. GMS Interdiscip Plast Reconstr Surg DGPW. 2013;2:Doc17.
   PubMedGoogle Scholar
• Franceschetti P, Bondanelli M, Caruso G, et al. Risk factors for development of atypical femoral fractures in patients on long-term oral bisphosphonate therapy. Bone. 2013;56:426–431.
   PubMed Web of Science ®Google Scholar
• Shane E, Burr D, Ebeling PR, et al. Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American society for bone and mineral research. J Bone Miner Res. 2010;25:2267–2294.
   PubMed Web of Science ®Google Scholar
• Allison MB, Markman L, Rosenberg Z, et al. Atypical incomplete femoral fractures in asymptomatic patients on long term bisphosphonate therapy. Bone. 2013;55:113–118.
   PubMed Web of Science ®Google Scholar
• Odvina CV, Levy S, Rao S, et al. Unusual mid-shaft fractures during long-term bisphosphonate therapy. Clin Endocrinol (Oxf). 2010;72:161–168.
   PubMed Web of Science ®Google Scholar
• Ernat J, Song D, Fazio M, et al. Radiographic changes and fracture in patients having received bisphosphonate therapy for >/=5 years at a single institution. Mil Med. 2015;180:1214–1218.
   PubMed Web of Science ®Google Scholar
• Bhadada SK, Sridhar S, Muthukrishnan J, et al. Predictors of atypical femoral fractures during long term bisphosphonate therapy: a case series & review of literature. Indian J Med Res. 2014;140:46–54.
   PubMed Web of Science ®Google Scholar
• Tyler W, Bukata S, O’Keefe R. Atypical femur fractures. Clin Geriatr Med. 2014;30:349–359.
   PubMed Web of Science ®Google Scholar
• Chen F, Wang Z, Bhattacharyya T. Absence of femoral cortical thickening in long-term bisphosphonate users: implications for atypical femur fractures. Bone. 2014;62:64–66.
   PubMed Web of Science ®Google Scholar
• Kim YS, Park WC. Atypical subtrochanteric femur fracture in patient with metastatic breast cancer treated with zoledronic acid. J Breast Cancer. 2012;15:261–264.
   PubMed Web of Science ®Google Scholar
• Fowler JR, Craig MR. Association of low-energy femoral shaft fractures and bisphosphonate use. Orthopedics. 2012;35:e38–40.
   PubMed Web of Science ®Google Scholar
• Ahlman MA, Rissing MS, Gordon L. Evolution of bisphosphonate-related atypical fracture retrospectively observed with DXA scanning. J Bone Miner Res. 2012;27:496–498.
   PubMed Web of Science ®Google Scholar
• Puhaindran ME, Farooki A, Steensma MR, et al. Atypical subtrochanteric femoral fractures in patients with skeletal malignant involvement treated with intravenous bisphosphonates. J Bone Joint Surg Am. 2011;93:1235–1242.
   PubMed Web of Science ®Google Scholar
• Kwek EB, Goh SK, Koh JS, et al. An emerging pattern of subtrochanteric stress fractures: a long-term complication of alendronate therapy? Injury. 2008;39:224–231.
   PubMed Web of Science ®Google Scholar
• Ing-Lorenzini K, Desmeules J, Plachta O, et al. Low-energy femoral fractures associated with the long-term use of bisphosphonates: a case series from a Swiss university hospital. Drug Saf. 2009;32:775–785.
   PubMed Web of Science ®Google Scholar
• Girgis CM, Sher D, Seibel MJ. Atypical femoral fractures and bisphosphonate use. New Engl J Med. 2010;362:1848–1849.
   PubMed Web of Science ®Google Scholar
• Bradke BS, Vashishth D. N-phenacylthiazolium bromide reduces bone fragility induced by nonenzymatic glycation. PLoS One. 2014;9:e103199.
   PubMedGoogle Scholar
• Yang S, Litchfield JE, Baynes JW. AGE-breakers cleave model compounds, but do not break Maillard crosslinks in skin and tail collagen from diabetic rats. Arch Biochem Biophys. 2003;412:42–46.
   PubMed Web of Science ®Google Scholar
• Campbell EJ, Campbell GM, Hanley DA. The effect of parathyroid hormone and teriparatide on fracture healing. Expert Opin Biol Ther. 2015;15:119–129.
   PubMed Web of Science ®Google Scholar
• Miller PD, McCarthy EF. Bisphosphonate-associated atypical sub-trochanteric femur fractures: paired bone biopsy quantitative histomorphometry before and after teriparatide administration. Semin Arthritis Rheum. 2015;44:477–482.
   PubMed Web of Science ®Google Scholar
• Hsiao FY, Huang WF, Chen YM, et al. Hip and subtrochanteric or diaphyseal femoral fractures in alendronate users: a 10-year, nationwide retrospective cohort study in Taiwanese women. Clin Ther. 2011;33:1659–1667.
   PubMed Web of Science ®Google Scholar
• Black DM, Thompson DE, Bauer DC, et al. Fracture risk reduction with alendronate in women with osteoporosis: the fracture intervention trial. FIT research group. J Clin Endocrinol Metab. 2000;85:4118–4124.
   PubMed Web of Science ®Google Scholar
• Ruggiero SL, Mehrotra B, Rosenberg TJ, et al. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg. 2004;62:527–534.
   PubMed Web of Science ®Google Scholar
• Drampalos E, Skarpas G, Barbounakis N, et al. Atypical femoral fractures bilaterally in a patient receiving denosumab. Acta Orthop. 2014;85:3–5.
   PubMed Web of Science ®Google Scholar
• Desai PA, Vyas PA, Lane JM. Atypical femoral fractures: a review of the literature. Curr Osteoporos Rep. 2013;11:179–187.
   PubMed Web of Science ®Google Scholar
• Kong SY, Kim DY, Han EJ, et al. Effects of a ‘drug holiday’ on bone mineral density and bone turnover marker during bisphosphonate therapy. J Bone Metab. 2013;20:31–35.
   PubMedGoogle Scholar
• Watts NB, Diab D. Long-term use of bisphosphonates in osteoporosis. J Clin Endocrinol Metab. 2010;95(4):1555–1565.
   PubMedGoogle Scholar
• Adler RA, Fuleihan GE, Bauer DC, et al. Managing osteoporosis in patients on long-term bisphosphonate treatment: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2015;31(1):16–35.
   Google Scholar
• Black D, Boonen S, Cauley J, et al. Effect of once-yearly infusion of zoledronic acid 5 mg on spine and hip fracture reduction in postmenopausal women with osteoporosis: the HORIZON pivotal fracture trial (abstract). J Bone Miner Res. 2006;21:S16.
   Web of Science ®Google Scholar
• Colon-Emeric CS, Caminis J, Suh TT, et al. The HORIZON recurrent fracture trial: design of a clinical trial in the prevention of subsequent fractures after low trauma hip fracture repair. Curr Med Res Opin. 2004;20:903–910.
   PubMed Web of Science ®Google Scholar
• Eastell R, Lang T, Boonen S, et al. Effect of once-yearly zoledronic acid on the spine and hip as measured by quantitative computed tomography: results of the HORIZON pivotal fracture trial. Osteoporos Int. 2009;21(7):1277–1285.
   Web of Science ®Google Scholar
• Husada G, Libberecht K, Peeters T, et al. Bilateral mid-diaphyseal femoral stress fractures in the elderly. Europ J Trauma. 2005;1:68–71.
   Google Scholar
• FDA. Ongoing safety review of oral osteoporosis drugs (bisphosphonates) and potential increased risk of esophageal cancer. Available from: http://1.usa.gov/R0Zb2S
   Google Scholar
• FDA. Safety update for osteoporosis drugs, bisphosphonates, and atypical fractures; 2010. Available from: http://www.fda.gov/Drugs/DrugSafety/ucm229009.htm
   Google Scholar
• FDA. Background document for meeting of advisory committee for reproductive health drugs and drug safety and risk management advisory committee; 2013. Available from: http://1.usa.gov/oQbZNn
   Google Scholar
• Purcell PM, Boyd IW. Bisphosphonates and osteonecrosis of the jaw. Med J Aust. 2005;182:417–418.
   PubMed Web of Science ®Google Scholar
• Yeo E, Campbel P. New FDA Labeling Suggests Stopping bisphosphonates after 3 to 5 years in low risk patients - LECOM Education System; 2011. Available from: http://lecom.edu/new-fda-labeling-suggests-stopping-bisphosphonates-after-3-to-5-years-in-low-risk-patients/
   Google Scholar
• Edwards BJ, Bunta AD, Lane J, et al. Bisphosphonates and nonhealing femoral fractures: analysis of the FDA Adverse Event Reporting System (FAERS) and international safety efforts: a systematic review from the Research on Adverse Drug Events And Reports (RADAR) project. J Bone Joint Surg Am. 2013;95:297–307.
   PubMed Web of Science ®Google Scholar
• Richer E, Lewis MA, Odvina CV, et al. Reduction in normalized bone elasticity following long-term bisphosphonate treatment as measured by ultrasound critical angle reflectometry. Osteoporos Int. 2005;16:1384–1392.
   PubMed Web of Science ®Google Scholar
• Crandall CJ, Newberry SJ, Diamant A, et al. Comparative effectiveness of pharmacologic treatments to prevent fractures: an updated systematic review. Ann Intern Med. 2014;161:711–723.
   PubMed Web of Science ®Google Scholar
• Cross MB, Nam D, Van Der Meulen MC, et al. A rare case of a bisphosphonate-induced peri-prosthetic femoral fracture. J Bone Joint Surg Br. 2012;94:994–997.
   PubMedGoogle Scholar
• Sellmeyer DE. Atypical fractures as a potential complication of long-term bisphosphonate therapy. Jama. 2010;304:1480–1484.
   PubMed Web of Science ®Google Scholar
• Gallagher JC, Genant HK, Crans GG, et al. Teriparatide reduces the fracture risk associated with increasing number and severity of osteoporotic fractures. J Clin Endocrinol Metab. 2005;90:1583–1587.
   PubMed Web of Science ®Google Scholar
• Kraenzlin ME, Meier C. Parathyroid hormone analogues in the treatment of osteoporosis. Nat Rev Endocrinol. 2011;7:647–656.
   PubMed Web of Science ®Google Scholar
• 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;344:1434–1441.
   PubMed Web of Science ®Google Scholar
• Giannotti S, Bottai V, Dell’Osso G, et al. Atrophic femoral nonunion successfully treated with teriparatide. Eur J Orthop Surg Traumatol. 2013;23(Suppl 2):S291–294.
   PubMedGoogle Scholar
• Carvalho NN, Voss LA, Almeida MO, et al. Atypical femoral fractures during prolonged use of bisphosphonates: short-term responses to strontium ranelate and teriparatide. J Clin Endocrinol Metab. 2011;96:2675–2680.
   PubMed Web of Science ®Google Scholar
• Huang HT, Kang L, Huang PJ, et al. Successful teriparatide treatment of atypical fracture after long-term use of alendronate without surgical procedure in a postmenopausal woman: a case report. Menopause. 2012;19:1360–1363.
   PubMed Web of Science ®Google Scholar
• Ng YH, Gino PD, Lingaraj K, et al. Femoral shaft fractures in the elderly–role of prior bisphosphonate therapy. Injury. 2011;42:702–706.
   PubMed Web of Science ®Google Scholar
• Tarazona-Santabalbina FJ, Aguilella-Fernandez L. Bisphosphonate long-term treatment related bilateral subtrochanteric femoral fracture. Can teriparatide be useful? Aging Clin Exp Res. 2013;25:605–609.
   PubMed Web of Science ®Google Scholar
• Fukuda F, Kurinomaru N, Hijioka A. Weekly teriparatide for delayed unions of atypical subtrochanteric femur fractures. Biol Ther. 2014;4(1):73–79.
   PubMedGoogle Scholar
• Lee YK, Ha YC, Koo KH. Teriparatide, a nonsurgical solution for femoral nonunion? A report of three cases. Osteoporos Int. 2012;23:2897–2900.
   PubMed Web of Science ®Google Scholar
• Chintamaneni S, Finzel K, Gruber BL. Successful treatment of sternal fracture nonunion with teriparatide. Osteoporos Int. 2010;21:1059–1063.
   PubMed Web of Science ®Google Scholar
• Anonumus. Recombinant human parathyroid hormone (Natpara). Med Lett Drugs Ther. 2015;57:87–88.
   PubMed Web of Science ®Google Scholar
• Leder BZ, O’Dea LS, Zanchetta JR, et al. Effects of abaloparatide, a human parathyroid hormone-related peptide analog, on bone mineral density in postmenopausal women with osteoporosis. J Clin Endocrinol Metab. 2015;100:697–706.
   PubMed Web of Science ®Google Scholar
• Prasarn ML, Ahn J, Helfet DL, et al. Bisphosphonate-associated femur fractures have high complication rates with operative fixation. Clin Orthop Relat Res. 2012;470:2295–2301.
   PubMed Web of Science ®Google Scholar
• Rizzoli R, Reginster JY. Adverse drug reactions to osteoporosis treatments. Expert Rev Clin Pharmacol. 2011;4:593–604.
   PubMedGoogle Scholar
• Schneider JP, Hinshaw WB, Su C, et al. Atypical femur fractures: 81 individual personal histories. J Clin Endocrinol Metab. 2012;97:4324–4328.
   PubMed Web of Science ®Google Scholar
• Dreyfus D, Lauer E, Wilkinson J. Characteristics associated with bone mineral density screening in adults with intellectual disabilities. J Am Board Fam Med. 2014;27:104–114.
   PubMed Web of Science ®Google Scholar
• Carmel AS, Shieh A, Bang H, et al. The 25(OH)D level needed to maintain a favorable bisphosphonate response is 33 ng/ml. Osteoporos Int. 2012;23:2479–2487.
   PubMed Web of Science ®Google Scholar
• Wimalawansa S. Four-year randomized prospective study: an efficacious therapy for established postmenopausal osteoporosis with the combination of estrogen and bisphosphonate. Am J Med. 1998;104:219–226.
   PubMed Web of Science ®Google Scholar
• Parfitt A. Osteomalacia and related disorders. In: Avioli LV, Krane SM, editors. Metabolic bone disease and clinically related disorders. Philadelphia: WB Saunders Company; 1990. p. 329–396.
   Google Scholar
• Wimalawansa SJ. Vitamin D in the new millennium. Curr Osteoporos Rep. 2012;10:4–15.
   PubMed Web of Science ®Google Scholar
• Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. treatment, and prevention of vitamin D deficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2011;96:1911–1930.
   PubMed Web of Science ®Google Scholar
• Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266–281.
   PubMed Web of Science ®Google Scholar
• Wimalawansa SJ. Vitamin D: an essential component for skeletal health. Ann NYAS. 2012;1240:90–98.
   Google Scholar
• Wimalawansa SJ. Vitamin D: everything you need to know. Homagama (Sri Lanka): Karunaratne & Sons; 2012. ISBN: 978-955-9098-94-2.
   Google Scholar
• Hodsman AB, Bauer DC, Dempster DW, 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;26:688–703.
   PubMed Web of Science ®Google Scholar
• Saleh A, Hegde VV, Potty AG, et al. Management strategy for symptomatic bisphosphonate-associated incomplete atypical femoral fractures. HSS J. 2012;8:103–110.
   PubMedGoogle Scholar
• Capeci CM, Tejwani NC. Bilateral low-energy simultaneous or sequential femoral fractures in patients on long-term alendronate therapy. J Bone Joint Surg Am. 2009;91:2556–2561.
   PubMed Web of Science ®Google Scholar
• Visekruna M, Wilson D, McKiernan FE. Severely suppressed bone turnover and atypical skeletal fragility. J Clin Endocrinol Metab. 2008;93:2948–2952.
   PubMed Web of Science ®Google Scholar