Skip to main content

Advertisement

SpringerLink
Log in

Combination therapy for osteoporosis: Considerations and controversy

  • Published:
Current Rheumatology Reports Aims and scope Submit manuscript

Abstract

Combination therapy, the simultaneous use of two pharmaceutical agents with the goal being reduction of fracture risk, is an area of substantial clinical interest. This paper summarizes the rationale, existing clinical trials data, and other considerations relevant to combination therapy for osteoporosis. Combinations of antiresorbers (eg, estrogen plus bisphosphonates) produce greater increases in bone mass than either treatment alone. Conversely, combining anabolic agents (parathyroid hormone) with bisphosphonates does not produce additive effects. None of the existing studies are large enough to determine whether combination treatment reduces fracture risk to a greater extent than use of a single agent. However, it is certain that combination treatment will increase cost and likely that it will increase side effects and reduce therapy adherence. Given the absence of demonstrated fracture reduction benefit, increased cost and likely increase in adverse events, combination therapy is not currently recommended.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Aloia JF, Zanzi I, Vaswani A, et al.: Combination therapy for osteoporosis. Metabolism 1977, 26:787–792.

    Article  PubMed  CAS  Google Scholar 

  2. Stepan JJ, Burckardt P, Hana V: The effects of three month intravenous ibandronate on bone mineral density and bone remodeling in Klinefelter’s syndrome: the influence of vitamin D deficiency and hormone status. Bone 2003, 33:589–596.

    Article  PubMed  CAS  Google Scholar 

  3. Krueger D, Nest L, Krause P, et al.: Vitamin D status, risedronate and bone turnover in nursing home residents. J Bone Miner Res 2004, 19(Suppl 1):S171.

    Google Scholar 

  4. 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.

    Article  PubMed  CAS  Google Scholar 

  5. Black DM, Cummings SR, Karpf DB, et al.: Randomized trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet 1996, 348:1535–1541.

    Article  PubMed  CAS  Google Scholar 

  6. Harris ST, Watts NB, Genant HK, et al.: Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis. JAMA 1999, 282:1344–1352.

    Article  PubMed  CAS  Google Scholar 

  7. Crandall C: Combination treatment of osteoporosis: a clinical review. J Womens Health Gend Based Med 2002, 11:211–224.

    Article  PubMed  Google Scholar 

  8. Rosenblatt M: Is it ethical to conduct placebo-controlled clinical trials in the development of new agents for osteoporosis? An industry perspective. J Bone Miner Res 2003, 18:1142–1145. An insightful perspective into the challenges associated with performance of fracture reduction trials. "Superiority" trials, which would be necessary to document that combination therapy provides fracture risk reduction would require approximately 30,000 patients.

    Article  PubMed  Google Scholar 

  9. The Writing Group for the PEPI Trial: Effects of hormone therapy on bone mineral density. JAMA 1996, 276:1389–1396.

  10. Meschia M, Brincat M, Barbacini P, et al.: A clinical trial on the effects of a combination of elcatonin and conjugated estrogens on vertebral bone mass in early postmenopausal women. Calcif Tissue Int 1993, 53:17–20.

    Article  PubMed  CAS  Google Scholar 

  11. Lindsay R, Cosman F, Lobo RA, et al.: Addition of alendronate to ongoing hormone replacement therapy in the treatment of osteoporosis: a randomized, controlled clinical trial. J Clin Endocrinol Metab 1999, 84:3076–3081.

    Article  PubMed  CAS  Google Scholar 

  12. Bone HG, Greenspan SL, McKeever C, et al.: Alendronate and estrogen effects in postmenopausal women with low bone mineral density. J Clin Endocrinol Metab 2000, 85:720–726.

    Article  PubMed  CAS  Google Scholar 

  13. Greenspan SL, NM Nesnick, RA Parker: Combination therapy with hormone replacement and alendronate for prevention of bone loss in elderly women. JAMA 2003, 289:2525–2533. In 373 postmenopausal women, combined treatment with conjugated equine estrogen 0.625 mg and alendronate 10 mg daily increased BMD to a greater extent than either therapy alone.

    Article  PubMed  CAS  Google Scholar 

  14. Wimalawansa SJ: A four-year randomized controlled trial of hormone replacement and bisphosphonate, alone or in combination, in women with postmenopausal osteoporosis. Am J Med 1988, 104:219–226.

    Article  Google Scholar 

  15. Harris ST, Eriksen EF, Davidson M, et al.: Effect of combined risedronate and hormone replacement therapies on bone mineral density in postmenopausal women. J Clin Endocrinol Metab 2001, 86:1890–1897. The largest study of combination osteoporosis therapy published to date. In this study, 524 women received conjugated equine estrogen 0.625 mg alone or combined with risedronate 5 mg daily. Combination therapy produced a greater increase in femur but not lumbar spine BMD.

    Article  PubMed  CAS  Google Scholar 

  16. Johnell O, Scheele WH, Lu Y, et al.: Additive effects of raloxifene and alendronate on bone density and biochemical markers of bone remodeling in postmenopausal women with osteoporosis. J Clin Endocrinol Metab 2002, 87:985–992. A 1 year evaluation of combination raloxifene and alendronate treatment on bone mass and turnover markers in 331 postmenopausal osteoporotic women. The combination increased bone mass and reduced turnover more than either alone.

    Article  PubMed  CAS  Google Scholar 

  17. Erdtsieck RJ, Pols HA, van Kuijk C, et al.: Course of bone mass during and after hormonal replacement therapy with and without addition of nandrolone decanoate. J Bone Miner Res 1994, 9:277–283.

    Article  PubMed  CAS  Google Scholar 

  18. Morabito N, Gaudio A, Lasco A, et al.: Three-year effectiveness of intravenous pamidronate versus pamidronate plus slowrelease sodium fluoride for postmenopausal osteoporosis. Osteoporos Int 2003, 14:500–506.

    Article  PubMed  CAS  Google Scholar 

  19. Holloway L, Kohlmeier L, Kent K, Marcus R, et al.: Skeletal efffects of cyclic recombinant human growth hormone and salmon calcitonin in osteopenic postmenopausal women. J Clin Endocrinol Metab 1997, 82:1111–1117.

    Article  PubMed  CAS  Google Scholar 

  20. Murphy MG, Weiss S, McClung M, et al.: Effect of alendronate and MK-677 (a growth hormone secretagogue), individually and in combination, on markers of bone turnover and bone mineral density in postmenopausal osteoporotic women. J Clin Endocrinol Metab 2001, 86:1116–1125.

    Article  PubMed  CAS  Google Scholar 

  21. Gutteridge DH, Stewart GO, Prince RL, et al.: A randomized tiral of sodium fluoride ±estrogen in postmenopausal osteoporotic vertebral fractures: increased vertebral fractures and peripheral bone loss with sodium fluoride; concurrent estrogen prevents peripheral loss, but not vertebral fractures. Osteoporos Int 2002, 13:158–170.

    Article  PubMed  CAS  Google Scholar 

  22. Reginster JY, Felsenberg D, Pavo I, et al.: Effect of raloxifene combined with monofluorophosphate as compared with monofluorophosphate alone in postmenopausal women with low bone mass: a randomized, controlled trial. Osteoporos Int 2003, 14:741–749.

    Article  PubMed  CAS  Google Scholar 

  23. Cosman F, Nieves J, Woelfert L, et al.: Parathyroid hormone added to established hormone therapy: effects on vertebral fracture and maintenance of bone mass after parathyroid hormone withdrawal. J Bone Miner Res 2001, 16:925–931.

    Article  PubMed  CAS  Google Scholar 

  24. Finkelstein JS, Hayes A, Hunzelman JL, et al.: The effects of parathyroid hormone, alendronate, or both in men with osteoporosis. N Engl J Med 2003, 349:1216–1226. A small, but well-conducted trial of 83 men treated with alendronate, PTH, or the combination. Alendronate reduced the effect of PTH to increase BMD at the spine and femur neck. This study does not support combination of PTH with alendronate.

    Article  PubMed  CAS  Google Scholar 

  25. Black DM, Greenspan SL, Ensrud KE, et al.: The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med 2003, 349:1207–1215. The largest published study evaluating the combination of PTH with a bisphosphonate. Two hundred thirty-eight women were treated with PTH 1–84, alendronate 10 mg daily, or the combination. Bone formation was increased by PTH but not by combined therapy. BMD did not differ between the PTH and combined groups. These results do not support concurrent use of PTH and alendronate.

    Article  PubMed  CAS  Google Scholar 

  26. Ettinger B, San Martin J, Crans G, Pavo I: Differential effects of teriparatide on BMD after treatment with raloxifene or alendronate. J Bone Miner Res 2004, 19:745–751.

    Article  PubMed  CAS  Google Scholar 

  27. Black DM, Rosen CJ, Palermo L, et al.: The effect of 1-year of alendronate following 1 year of PTH 1–84: Second year results from the PTH and alendronate trial. J Bone Miner Res 2004, 19(Suppl 1):S26.

    Google Scholar 

  28. Rittmaster RS, Bolognese M, Ettinger MP, et al.: Enhancement of bone mass in osteoporotic women with parathyroid hormone followed by alendronate. J Clin Endocrinol Metab 2000, 85:2129–2134. An important study evaluating sequential osteoporosis treatment; PTH followed-up by alendronate. Sixty-six postmenopausal women with osteoporosis were treated with PTH 1–84 for 1 year followed-up by daily alendronate for an additional year. A considerable increment in BMD was observed at 1 and 2 years of study. Sequential therapy with an anabolic agent followed-up by an antiresorber may produce substantial increases in BMD.

    Article  PubMed  CAS  Google Scholar 

  29. Hodsman AB, Fraher LJ, Watson PH, et al.: A randomized controlled trial to compare the efficacy of cyclical parathyroid hormone versus cyclical parathyroid hormone and sequential calcitonin to improve bone mass in postmenopausal women with osteoporosis. J Clin Endocrinol Metab 1997, 82:620–628.

    Article  PubMed  CAS  Google Scholar 

  30. Ringe JD, Rovati LC: Treatment of osteoporosis in men with fluoride alone or in combination with bisphosphonates. Calcif Tissue Int 2001, 69:252–255.

    Article  PubMed  CAS  Google Scholar 

  31. Recker R, Gallagher R, Amonkar M, et al.: Medication persistence is better with weekly bisphosphonates, but it remains suboptimal. J Bone Miner Res 2004, 19(Suppl 1):S172.

    Google Scholar 

  32. Meschia M, Brincat M, Barbacini P, et al.: Effect of hormone replacement therapy and calcitonin on bone mass in postmenopausal women. Eur J Obstet Gynecol Reprod Biol 1992, 47:53–57.

    Article  PubMed  CAS  Google Scholar 

  33. Haynes RB, McDonald HP, Garg AX: Helping patients follow prescribed treatment. JAMA 2002, 288:2880–2883.

    Article  PubMed  Google Scholar 

  34. Williams CM: Using medications appropriately in older adults. Am Fam Physician 2002, 66:1917–1924.

    Google Scholar 

  35. Bootman JL, Harrison DL, Cox E: The health care cost of drugrelated morbidity and mortality in nursing facilities. Arch Intern Med 1997, 157:2089–2096.

    Article  PubMed  CAS  Google Scholar 

  36. Cohen JS: Avoiding adverse reactions: effective lower-dose drug therapies for older patients. Geriatrics 2000, 55:54–64.

    PubMed  CAS  Google Scholar 

  37. Mashiba T, Hirano T, Turner CH, et al.: Suppressed bone turnover by bisposphonates increases microdamage accumulation and reduces some biomechanical properties in dog rib. J Bone Miner Res 2000, 15:613–620.

    Article  PubMed  CAS  Google Scholar 

  38. 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.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. University of Wisconsin-Madison, Osteoporosis Clinical Center and Research Program, 2870 University Avenue, Suite 100, 53705, Madison, WI, USA

    Neil Binkley MD

Authors
  1. Neil Binkley MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Diane Krueger BS, CDT, CCRC
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Binkley, N., Krueger, D. Combination therapy for osteoporosis: Considerations and controversy. Curr Rheumatol Rep 7, 61–65 (2005). https://doi.org/10.1007/s11926-005-0010-2

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11926-005-0010-2

Keywords

Search

Navigation