Abstract
The most devastating consequence of osteoporosis is bone fracture, particularly at the vertebral or femoral level. As defined by the WHO, patients with osteoporosis who have had one or more fragility fractures have severe osteoporosis. Those who sustain a vertebral fracture represent a particularly vulnerable group whose risk of another vertebral fracture within the following year is increased by a factor of 3–5. In addition, the presence of a vertebral fracture is associated with an increased risk of hip fracture. In light of these data, treatment of established osteoporosis is extremely important to prevent other fragility fractures. This review examines the therapies approved by the US FDA for the treatment of osteoporosis that have been shown to reduce the incidence of new fractures in patients with established osteoporosis. We evaluated the mechanisms of action, available formulations, efficacy in preventing fractures and increasing bone mineral density (BMD), duration of treatment, adverse effects and contraindications to use of alendronic acid (alendronate), risedronic acid (risedronate), calcitonin, raloxifene and teriparatide. All these drugs are able to prevent new vertebral fractures in patients with established osteoporosis. Only alendronic acid and risedronic acid have also been shown to reduce the risk of fracture at the femoral level, but they are contraindicated in patients with upper gastrointestinal diseases. Calcitonin is a good option in subjects with back pain because of its analgesic effect. Raloxifene is useful when patients have high plasma lipid levels or a family history of breast cancer. Teriparatide is indicated in subjects with very low BMD and multiple vertebral fractures. Patient characteristics should determine selection of therapy but the decision is always difficult and fraught with uncertainty.
Similar content being viewed by others
References
Cauley JA. Risk of mortality following clinical fractures. Osteoporos Int 2000; 11: 556–61
National Osteoporosis Foundation. America’s bone health: the state of osteoporosis and low bone mass [online]. Available from URL: http://www.nof.org/advocacy/prevalence/index.htm [Accessed 2004 Mar 25]
Hodgson SF, Watts NB, Bilezikian JP, et al. American Association of Clinical Endocrinologists. 2001 medical guidelines for clinical practice for the prevention and management of postmenopausal osteoporosis. Endocr Pract. 2001; 7(4): 293–312
European Commission. Report on osteoporosis in the European Community: action on prevention. Luxembourg: Office for Official Publications of the European Communities, 2002: 2
National Institutes of Health (USA). Osteoporosis prevention, diagnosis and therapy. NIH Consensus Statements 2000; 17(1): 1–45
World Health Organization Study Group. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: WHO Technical Report Series. Geneva: WHO, 1994: 843
Zuckerman JD. Hip fracture. N Engl J Med 1996; 334: 1519–25
Center JR, Nguyen TV, Schneider D, et al. Mortality after all major types of osteoporotic fracture in men and women: an observational study. Lancet 1999; 353: 878–82
Kado DM, Browner WS, Palermo L, et al. Vertebral fractures and mortality in older women. Arch Intern Med 1999; 159: 1215–20
Cooper C, Atkinson EJ, O’Fallon WM, et al. Incidence of clinically diagnosed vertebral fractures: a population based study in Rochester, Minnesota, 1985–1989. J Bone Miner Res 1992; 7: 221–7
Lindsay R, Silverman SL, Cooper C, et al. Risk of new vertebral fracture in the year following a fracture. JAMA 2001; 285: 320–3
Klotzbuecher CM, Ross PD, Landsman PB, et al. Patients with prior fractures have an increased risk of future fractures: a summary of the literature and statistical synthesis. J Bone Miner Res 2000; 4: 721–39
Black DM, Arden NK, Palmero L, et al. Prevalent vertebral deformities predict hip fractures and new vertebral deformities but not wrist fractures. J Bone Miner Res 1999; 14: 821–8
Davidson M, DeSimone ME. Confronting osteoporosis: what we know, where we’re headed. Clin Rev 2002; 12: 76–82
Kannus P, Parkkari J, Niemi S, et al. Prevention of hip fracture in elderly people with use of a hip protector. N Engl J Med 2000; 343: 1506–13
Reid IR, Ames RW, Evans MC, et al. Long-term effects of calcium supplementation on bone loss and fractures in postmenopausal women: a randomized controlled trial. Am J Med 1995; 98: 331–5
Cumming RG, Nevitt MC. Calcium for prevention of osteoporotic fractures in postmenopausal women. J Bone Miner Res 1997; 12: 1321–9
Dawson-Hughes B, Harris SS, Krall EA, et al. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. N Engl J Med 1997; 337: 670–6
Reid IR. The role of calcium and vitamin D in the prevention of osteoporosis. Endocrinol Metab Clin North Am 1998; 27: 389–98
Lips P, Graafmans WC, Ooms ME, et al. Vitamin D supplementation and fracture incidence in elderly persons. Ann Intern Med 1996; 124: 400–6
Fleisch HA. Bisphosphonates: preclinical aspects and use in osteoporosis. Ann Med 1997; 29: 55–62
Russell RG, Rogers MJ. Bisphosphonates: from the laboratory to the clinic and back again. Bone 1999; 25: 97–106
Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA 1998; 280: 2077–82
Pols HA, Felsenberg D, Hanley DA, et al. Multinational, placebo-controlled, randomized trial of the effects of alendronate on bone density and fracture risk in postmenopausal women with low bone mass: results of the FOSIT study. Fosamax International Trial Study Group. Osteoporos Int 1999; 9: 461–8
Harris ST, Watts NB, Genant HK, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA 1999; 282: 1344–52
Chesnut III CH, McClung M, Ensrud KE, et al. Alendronate treatment of the postmenopausal osteoporotic woman: effect of multiple dosages on bone mass and bone remodeling. Am J Med 1995; 99: 144–52
Liberman UA, Weiss SR, Broil J, et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med 1995; 333: 1437–43
Schneider PF, Fischer M, Allolio B, et al. Alendronate increases bone density and bone strength at the distal radius in postmenopausal women. J Bone Miner Res 1999; 14: 1387–93
Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures: Fracture Intervention Trial Research Group. Lancet 1996; 348: 1535–41
Schnitzer T, Bone HG, Crepaldi G, et al. Therapeutic equivalence of alendronate 70mg once-weekly and alendronate 10mg daily in the treatment of osteoporosis. Aging (Milano) 2000; 12: 1–12
Rizzoli R, Greenspan SL, Bone III G, et al. Alendronate Once-Weekly Study Group: two-year results of once-weekly administration of alendronate 70mg for the treatment of postmenopausal osteoporosis. J Bone Miner Res 2002; 17(11): 1988–96
Bone HG, Hosking D, Devogelaer JP, et al. Alendronate Phase III Osteoporosis Treatment Study Group: ten years’ experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med 2004; 350(12): 1189–99
Chavassieux PM, Arlot ME, Reda C, et al. Histomorphometric assessment of the long-term effects of alendronate on bone quality and remodeling in patients with osteoporosis. J Clin Invest 1997; 100: 1475–80
Boivin GY, Chavassieux PM, Santora AC, et al. Alendronate increases bone strength by increasing the mean degree of mineralization of bone tissue in osteoporotic women. Bone 2000; 27: 687–94
Boivin G, Meunier PJ. Changes in bone remodeling rate influence the degree of mineralization of bone. Connect Tissue Res 2002; 43: 535–7
Ensrud KE, Barrett-Connor EL, Schwartz A, et al. Randomized trial of effect of alendronate continuation versus discontinuation in women with low BMD: results from the Fracture Intervention Trial long-term extension. J Bone Miner Res 2004; 19: 1259–69
Donahue JG, Chan KA, Andrade SE, et al. Gastric and duodenal safety of daily alendronate. Arch Intern Med 2002 Apr 22; 162(8): 936–42
Fosamax® (alendronate sodium) package insert. Whitehouse Station NJ): Merck & Co., 2001 Jan
McClung MR, Geusens P, Miller PD, et al. Effects of risedronate on the risk of hip fracture in elderly women. N Engl J Med 2001; 344: 333–40
Delmas PD, Balena R, Confravreux E, et al. Bisphosphonate risedronate prevents bone loss in women with artificial menopause due to chemotherapy of breast cancer: a double-blind, placebo-controlled study. J Clin Oncol 1997; 15: 955–62
Reginster JY, Minne HW, Sorensen OH, et al. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Osteoporos Int 2000; 11: 83–91
Watts NB, Josse RG, Hamdy RC, et al. Risedronate prevents new vertebral fractures in postmenopausal women at high risk. JCEM 2003; 88: 542–9
Roux C, Seeman E, Eastell R, et al. Efficacy of risedronate on clinical vertebral fractures within six months. Curr Med Res Opin 2004; 20(4): 433–9
Harrington JT, Ste-Marie LG, Brandi ML, et al. Risedronate rapidly reduces the risk for nonvertebral fractures in women with postmenopausal osteoporosis. Calcif Tissue Int 2004; 74(2): 129–35
Brown JP, Kendler DL, McClung MR, et al. The efficacy and tolerability of risedronate once a week for the treatment of postmenopausal osteoporosis. Calcif Tissue Int 2002; 71: 103–11
Sorensen OH, Crawford GM, Mulder H, et al. Long-term efficacy of risedronate: a 5-year placebo-controlled clinical experience. Bone 2003; 32(2): 120–6
Mellstrom DD, Sorensen OH, Goemaere S, et al. Seven years of treatment with risedronate in women with postmenopausal osteoporosis. Calcif Tissue Int 2004; 75(6): 462–8
Actonel® (risedronate sodium) package insert. Cincinatti OH): Procter & Gamble, 2002 May
Kanis JA, McCloskey EV. Effect of calcitonin on vertebral and other fractures. QJM 1999; 92: 143–9
Chesnut III CH, Silverman S, Andriano K, et al. A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the Prevent Recurrence of Osteoporotic Fractures Study. Am J Med 2000; 109: 267–76
Silverman SL, Azria M. The analgesic role of calcitonin following osteoporotic fracture. Osteoporos Int 2002; 13: 858–67
Lyritis GP, Ioannidis GV, Karachalios T, et al. Analgesic effect of salmon calcitonin suppositories in patients with acute pain due to recent osteoporotic vertebral crush fractures: a prospective double-blind, randomized, placebo-controlled clinical study. Clin J Pain 1999; 15: 284–9
Repchinsky C. Compendium of Pharmaceuticals and specialities. 36th ed. Ottawa: Canadian Pharmacists Association, 2001: 236–7
Goldstein SR. Selective estrogen receptors modulators: a new category of therapeutic agents for extending the health of postmenopausal women. Am J Obstet Gynecol 1998; 179: 1479–8
Khovidhunkit W, Shoback DM. Clinical effects of raloxifene hydrochloride in women. Ann Intern Med 1999; 130: 431–9
Walsh BW, Kuller LH, Wild R, et al. Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. JAMA 1998; 279: 1445–51
Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in post-menopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA 1999; 282: 637–45
Cummings SR, Eckert S, Krueger KA, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women. JAMA 1999; 281: 2189–97
Walsh BW, Kuller LH, Wild RA, et al. Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. JAMA 1998; 279: 1445–51
Draper MW, Flowers DE, Huster WJ, et al. A controlled trial of raloxifene (LY139481) HC1: impact on bone turnover and serum lipid profile in healthy postmenopausal women. J Bone Miner Res 1996; 11: 835–42
Delmas PD, Bjarnason NH, Mitlak BH, et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 1997; 337: 1641–7
Lilly Forteo. Osteoporosis indication approval recommended with restrictions: FDA Endocrinological and Metabolic Drugs Advisory Committee. Pink Sheet 2001 Jul 30; 63(31): 3
Jilka RL, Weinstein RS, Bellido T, et al. Increased bone formation by prevention of osteoblast apoptosis with parathyroid hormone. J Clin Invest 1999; 104: 439–46
Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1–34) on fracture and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001; 344: 1434–41
Ettinger B, San Martin J, Crans G, et al. Differential effects of teriparatide on BMD after treatment with raloxifene or alendronate. J Bone Miner Res 2004; 19(5): 745–51
Reid IR, Brown JP, Burckhardt P, et al. Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med 2002; 346: 653–61
Chesnut III CH, Skag A, Christiansen C, et al. Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res 2004; 19: 1241–9
Meunier PJ, Roux C, Seeman E, et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med 2004; 350(5): 459–68
Acknowledgements
No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Gaudio, A., Morabito, N. Pharmacological Management of Severe Postmenopausal Osteoporosis. Drugs Aging 22, 405–417 (2005). https://doi.org/10.2165/00002512-200522050-00005
Published:
Issue Date:
DOI: https://doi.org/10.2165/00002512-200522050-00005