Osteoporosis International

, Volume 14, Issue 10, pp 814–822

Effects of raloxifene, hormone replacement therapy, and placebo on bone turnover in postmenopausal women

  • Robert S. Weinstein
  • A. Michael Parfitt
  • Robert Marcus
  • Maria Greenwald
  • Gerald Crans
  • Douglas B. Muchmore
Original Article

Abstract

Raloxifene, a nonsteroidal selective estrogen receptor modulator (SERM), increases bone mineral density (BMD), decreases biochemical markers of bone turnover, and prevents incident vertebral fractures in postmenopausal women, while sparing the breast and endometrium from the undesirable stimulation caused by estrogen. How the long-term beneficial effects of raloxifene on bone turnover, as assessed by bone histomorphometry, compare with hormone replacement therapy (HRT) and placebo are not known. We studied 66 healthy postmenopausal women (age 55 to 75 years, mean 63 years) who were randomized to either raloxifene 150 mg/day, HRT (Premarin 0.625 mg/day, and Provera 2.5 mg/day), or placebo for 1 year. All women received 1–1.5 g of calcium/day. Following double tetracycline labeling, transiliac bone biopsies were obtained at baseline and 1 year and analyzed for changes in histologic indexes of bone remodeling on the cancellous surface as well as at the endocortical subdivision of the endosteal envelope, the location of the greatest fraction of postmenopausal bone loss. BMD and biochemical markers of bone turnover were also determined at baseline and 1 year. Four paired biopsies were obtained in the HRT group, six in the raloxifene group, and five in the placebo group. The frequency of remodeling events on cancellous bone and rate of bone formation in both cancellous and endocortical bone increased in the placebo group, while these measurements decreased in both drug treatment groups. Using analysis of mean percentage changes, when compared with the placebo group, these changes were significantly different for both raloxifene and HRT treatment groups (p<0.02). In all subjects, the bone was lamellar with discrete tetracycline labels and there was no evidence of marrow fibrosis or abnormal bone cells. BMD increased from baseline at the lumbar spine (p<0.05 in the HRT group) and in the total body (p<0.05 for both raloxifene and HRT). Compared with that of the raloxifene group, the increase in BMD was greater in the HRT group at the lumbar spine but not in the total body. Serum bone alkaline phosphatase, serum osteocalcin, and urine C-terminal cross-linking telopeptide of type I collagen significantly decreased (p<0.05) in both active treatment groups, changes significantly different from those seen with placebo. Overall, these results support the hypothesis that raloxifene preserves bone mass by reducing the elevated bone turnover found in postmenopausal women receiving placebo, by mechanisms similar to those operative in postmenopausal women receiving HRT.

Keywords

Activation frequency Bone formation Bone histomorphometry Cancellous bone Endocortical bone SERM 

References

  1. 1.
    Grady D, Hulley SB (2000) Editorial: hormones to prevent coronary heart disease in women; when are observational studies adequate evidence? Ann Intern Med 133:999–1001PubMedGoogle Scholar
  2. 2.
    Writing Group for the Women's Health Initiative Investigators (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 288(3):321–333Google Scholar
  3. 3.
    Grant C, Gray A, Paoletti R et al (1999) Clinical synthesis conference: hormone replacement therapy. Lancet 354:152–155PubMedGoogle Scholar
  4. 4.
    Mitlak BH, Cohen FJ (1999) Selective estrogen receptor modulators: a look ahead. Drugs 57:653–663PubMedGoogle Scholar
  5. 5.
    Delmas PD, Bjarnason NH, Mitlak BH, Ravoux A-C, Shah AS, Huster WJ, Draper M, Christiansen C (1997) Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med. 337:1641–1647Google Scholar
  6. 6.
    Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, Christiansen C, Delmas PD, Zanchetta JR, Stakkestad J, Glüer CC, Krueger K, Cohen FJ, Eckert S, Ensrud KE, Avioli LV, Lips P, Cummings SR (1999) Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE). JAMA 282:637–645PubMedGoogle Scholar
  7. 7.
    Prestwood KM, Gunness M, Wong M, Lu Y, Muchmore D, Raisz L (2000) A comparison of the effects of raloxifene and estrogen on bone in postmenopausal women. J Clin Endocrinol Metab 85:2197–2202Google Scholar
  8. 8.
    Keshawarz NM, Recker RR (1984) Expansion of the medullary cavity at the expense of cortex in postmenopausal osteoporosis. Metab Bone Dis Rel Res 5:223–228Google Scholar
  9. 9.
    Brown JB, Delmas PD, Arlot M, Meunier PJ (1987) Active bone turnover of the cortico-endosteal envelope in postmenopausal osteoporosis. J Clin Endocrinol Metab 64:654–659Google Scholar
  10. 10.
    Weinstein RS, Bell NH (1988) Diminished rates of bone formation in normal black adults. N Engl J Med 319:1698–1701PubMedGoogle Scholar
  11. 11.
    Parfitt AM, Drezner MK, Glorieux FH, Kanis JA, Malluche H, Meunier PJ, Ott SM, Recker RR (1987) Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res 2:595–610PubMedGoogle Scholar
  12. 12.
    Arlot ME, Delmas PD, Chappard D, Meunier PJ (1990) Trabecular and endocortical bone remodeling in postmenopausal osteoporosis: comparison with normal postmenopausal women. Osteoporos Int 1:41–49PubMedGoogle Scholar
  13. 13.
    Riggs BL, Khosla S, Melton LJ (1998) A unitary model for involutional osteoporosis; estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men. J Bone Miner Res 12:763–773Google Scholar
  14. 14.
    Weinstein RS, Manolagas SC (2000) Apoptosis and osteoporosis. Am J Med 108:153–164PubMedGoogle Scholar
  15. 15.
    Parfitt AM (1992) The two-stage concept of bone loss revisited. Triangle 31:99–110Google Scholar
  16. 16.
    Balena R, Shih M-S, Parfitt AM (1992) Bone resorption and formation on the periosteal envelope of the ilium; a histomorphometric study in healthy women. J Bone Miner Res 7:1475–1482PubMedGoogle Scholar
  17. 17.
    Shih M-S, Cook MA, Spence CA, Palnitkar S, McElroy H, Parfitt AM (1993) Relationship between bone formation rate and osteoblast surface on different subdivisions of the endosteal envelope in aging and osteoporosis. Bone 14:519–521PubMedGoogle Scholar
  18. 18.
    Han Z-H, Palnitkar S, Rao DS, Nelson D, Parfitt AM (1997) Effects of ethnicity and age or menopause on the remodeling and turnover of iliac bone: implications for mechanisms of bone loss. J Bone Miner Res 12:498–508PubMedGoogle Scholar
  19. 19.
    Reid I, Fogelman I, Eastell R, Sarkar S, Wu W, Ciaccia A, Draper M (2000) Impact of hysterectomy in studies of raloxifene in healthy and osteoporotic postmenopausal women [abstract]. In: 11th international congress of endocrinology abstract book, Sydney, Australia, 29 October–2 November, 2000 (Abstract P340)Google Scholar
  20. 20.
    Bone HG, Greenspan SL, McKeever C, Bell N, Davidson M, Downs RW, Emkey R, Meunier PJ, Miller SS, Mulloy AL, Recker RR, Weiss SR, Heyden N, Musliner T, Suryawanshi S, Yates J, Lombardi A (1999) Alendronate and estrogen effects in postmenopausal women with low bone mineral density. J Clin Endocrinol Metab 85:720–726Google Scholar
  21. 21.
    Vedi S, Compston JE (1996) The effects of long-term hormone replacement therapy on bone remodeling in postmenopausal women. Bone 19:535–539PubMedGoogle Scholar
  22. 22.
    Johnson CC, Bjarnason NH, Cohen FJ, Shah A, Lindsay R, Mitlak BH, Huster W, Draper MW, Harper KD, Heath H, Gennari C, Christiansen C, Arnaud CD, Delmas PD (2000) Long-term effects of raloxifene on bone mineral density, bone turnover, and serum lipid levels in early postmenopausal women. Arch Intern Med 160:3444–3450CrossRefPubMedGoogle Scholar
  23. 23.
    Meunier PJ, Vignot E, Garnero P, Confavreux E, Paris E, Liu-Leage S, Sarkar S, Liu T, Wong M, Draper MW (1999) Treatment of postmenopausal women with osteoporosis or low bone density with raloxifene. Osteoporos Int 10:330–336PubMedGoogle Scholar
  24. 24.
    Agnusdei D, Iori N (2000) Raloxifene: results from the MORE study. J Musculoskel Neuron Interact 1:127–132Google Scholar
  25. 25.
    Lufkin EG, Whitaker MD, Nickelsen T, Argueta R, Caplan RH, Knickerbocker RK, Riggs BL (1998) Treatment of established postmenopausal with raloxifene: a randomized trial. J Bone Miner Res 13:1747–1754PubMedGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2003

Authors and Affiliations

  • Robert S. Weinstein
    • 1
  • A. Michael Parfitt
    • 1
  • Robert Marcus
    • 2
    • 5
  • Maria Greenwald
    • 3
  • Gerald Crans
    • 4
  • Douglas B. Muchmore
    • 4
  1. 1.Center for Osteoporosis and Metabolic Bone Diseases, Division of Endocrinology and Metabolism, Central Arkansas Veterans Healthcare SystemUniversity of Arkansas for Medical SciencesLittle RockUSA
  2. 2.VA Medical CenterPalo AltoUSA
  3. 3.Osteoporosis Medical CenterPalm DesertUSA
  4. 4.Eli Lilly and CompanyIndianapolisUSA
  5. 5.Eli Lilly and CompanyIndianapolisUSA

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