The unitary model for estrogen deficiency and the pathogenesis of osteoporosis: Is a revision needed?

Abstract

Over a decade ago, we proposed a “unitary” model for the pathogenesis of osteoporosis that identified estrogen deficiency as the predominant cause of both the early, accelerated, and late slow phases of bone loss in postmenopausal women and as a contributing cause of the continuous phase of bone loss in aging men. While this was a plausible model then, new data over the intervening years suggest a need to modify these concepts. Indeed, based largely on rodent studies, a “revisionist” view of the pathogenesis of osteoporosis has been proposed recently that attempts a paradigm shift from the estrogen-centric model to one in which bone loss is largely independent of estrogen deficiency and is driven instead by cell-autonomous age-related factors. However, detailed clinical investigative studies using quantitative computed tomography demonstrate that the onset of cortical bone loss in humans is closely tied to estrogen deficiency; thus the estrogen-centric view is likely correct for cortical bone, which comprises over 80% of the skeleton and is the major structural determinant of fracture risk at most skeletal sites. By contrast, these same studies also demonstrate that trabecular bone loss begins in sex hormone–replete young adults of both sexes. This suggests that a significant proportion of trabecular bone loss is either estrogen-independent or, as suggested by some studies, requires higher levels for its regulation. In this perspective, we critically review these and other findings, leading us to conclude that our original model requires modification but not revision. © 2011 American Society for Bone and Mineral Research.

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References 91

1. 1.

   Riggs BL, Melton LJ. Evidence for two distinct syndromes of involutional osteoporosis. Am J Med. 1983;75:899-901.

   Not in our library10.1016/0002-9343(83)90860-4

2. 2.

   Riggs BL, Khosla S, Melton LJ. 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. 1998;13:763-773.

   Not in our library10.1359/jbmr.1998.13.5.763

3. 3.

   Manolagas SC. From estrogen-centric to aging and oxidative stress: a revised perspective of the pathogenesis of osteoporosis. Endocr Rev. 2010;31:266-300.

   Not in our library10.1210/er.2009-0024

4. 4.

   Riggs BL, Melton LJ, Robb RA, et al. Population-based study of age and sex differences in bone volumetric density, size, geometry, and structure at different skeletal sites. J Bone Miner Res. 2004;19:1945-1954.

   Not in our library10.1359/jbmr.040916

5. 5.

   Riggs BL, Melton LJI, Robb RA, et al. A population-based assessment of rates of bone loss at multiple skeletal sites: evidence for substantial trabecular bone loss in young adult women and men. J Bone Miner Res. 2008;23:205-214.

   Not in our library10.1359/jbmr.071020

6. 6.

   Bonnick SL, Bonnick SL. Skeletal anatomy in densitometry. Bone Densitometry in Clinical Practice. 1998;35-78.

   Not in our library

7. 7.

   Rockoff SD, Sweet E, Bleustein J. The relative contribution of trabecular and cortical bone to the strength of human lumbar vertebrae. Calcif Tissue Res. 1969;3:163-175.

   Not in our library10.1007/bf02058659

8. 8.

   Boutroy S, Van Rietbergen B, Sornay-Rendu E, Munoz F, Bouxsein ML, Delmas P. Finite element analysis based on in vivo HR-pQCT images of the distal radius is associated with wrist fracture in postmenopausal women. J Bone Miner Res. 2008;23:392-399.

   Not in our library10.1359/jbmr.071108

9. 9.

   Cooper C, Melton LJ. Epidemiology of osteoporosis. Trends Endocrinol Metab. 1992;3:224-229.

   Not in our library10.1016/1043-2760(92)90032-v

10. 10.

    van Staa TP, Dennison EM, Leufkens HG, Cooper C. Epidemiology of fractures in England and Wales. Bone. 2001;29:517-522.

    Not in our library10.1016/s8756-3282(01)00614-7

11. 11.

    Riggs BL, Melton LJ. Bone turnover matters: the raloxifene treatment paradox of dramatic decreases in vertebral fractures without commensurate increases in bone density. J Bone Miner Res. 2002;17:11-14.

    Not in our library10.1359/jbmr.2002.17.1.11

12. 12.

    Richelson LS, Wahner HW, Melton LJI, Riggs BL. Relative contributions of aging and estrogen deficiency to postmenopausal bone loss. N Engl J Med. 1984;311:1273-1275.

    Not in our library10.1056/nejm198411153112002

13. 13.

    Syed FA, Modder UI, Roforth M, et al. Effects of chronic estrogen treatment on modulating age-related bone loss in female mice. J Bone Miner Res. 2010;25:2438-2446.

    Not in our library10.1002/jbmr.129

14. 14.

    Nelson JF, Felicio LS, Randall PK, Simms C, Finch CE. A longitudinal study of estrous cyclicity in C57BL/6J mice: I. cycle frequency, length and vaginal cytology. Biol Reprod. 1982;27:327-339.

    Not in our library10.1095/biolreprod27.2.327

15. 15.

    Felicio LS, Nelson JF, Finch CE. Longitudinal studies of estrous cyclicity in aging C57BL/6J mice: II. cessation of cyclicity and the duration of persistent vaginal cornification. Biol Reprod. 1984;31:446-453.

    Not in our library10.1095/biolreprod31.3.446

16. 16.

    Riggs BL, Khosla S, Melton LJ. Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev. 2002;23:279-302.

    Not in our library10.1210/edrv.23.3.0465

17. 17.

    Nelson JF, Felicio LS, Osterburg HH, Finch CE. Altered profiles of estradiol and progesterone associated with prolonged estrous cycles and persistent vaginal cornification in aging C57BL/6J mice. Biol Reprod. 1981;24:784-794.

    Not in our library10.1095/biolreprod24.4.784

18. 18.

    Glatt V, Canalis E, Stadmeyer L, Bouxsein ML. Age-related changes in trabecular architecture differ in female and male C57BL/6J mice. J Bone Miner Res. 2007;22:1197-1207.

    Not in our library10.1359/jbmr.070507

19. 19.

    Slemenda CW, Longcope C, Zhou L, Hui SL, Peacock M, Johnston C. Sex steroids and bone mass in older men: positive associations with serum estrogens and negative associations with androgens. J Clin Invest. 1997;100:1755-1759.

    Not in our library10.1172/jci119701

20. 20.

    Khosla S, Melton LJ, Atkinson EJ, O'Fallon WM, Klee GG, Riggs BL. Relationship of serum sex steroid levels and bone turnover markers with bone mineral density in men and women: A key role for bioavailable estrogen. J Clin Endocrinol Metab. 1998;83:2266-2274.

    Not in our library10.1210/jcem.83.7.4924

21. 21.

    Greendale GA, Edelstein S, Barrett-Connor E. Endogenous sex steroids and bone mineral density in older women and men: the Rancho Bernardo study. J Bone Miner Res. 1997;12:1833-1843.

    Not in our library10.1359/jbmr.1997.12.11.1833

22. 22.

    Center JR, Nguyen TV, Sambrook PN, Eisman JA. Hormonal and biochemica parameters in the determination of osteoporosis in elderly men. J Clin Endocrinol Metab. 1999;84:3626-3635.

    Not in our library10.1210/jcem.84.10.6051

23. 23.

    Ongphiphadhanakul B, Rajatanavin R, Chanprasertyothin S, Piaseau N, Chailurkit L. Serum oestradiol and oestrogen-receptor gene polymorphism are associated with bone mineral density independently of serum testosterone in normal males. Clin Endocrinol. 1998;49:803-809.

    Not in our library10.1046/j.1365-2265.1998.00631.x

24. 24.

    van den Beld AW, de Jong FH, Grobbee DE, Pols HAP, Lamberts SWJ. Measures of bioavailable serum testosterone and estradiol and their relationships with muscle strength, bone density, and body composition in elderly men. J Clin Endocrinol Metab. 2000;85:3276-3282.

    Not in our library10.1210/jcem.85.9.6825

25. 25.

    Amin S, Zhang Y, Sawin CT, et al. Association of hypogonadism and estradiol levels with bone mineral density in elderly men from the Framingham study. Ann Intern Med. 2000;133:951-963.

    Not in our library10.7326/0003-4819-133-12-200012190-00010

26. 26.

    Szulc P, Munoz F, Claustrat B, Garnero P, Marchand F. Bioavailable estradiol may be an important determinant of osteoporosis in men: the MINOS study. J Clin Endocrinol Metab. 2001;86:192-199.

    Not in our library10.1210/jcem.86.1.7126

27. 27.

    Khosla S, Melton LJ, Atkinson EJ, O'Fallon WM. Relationship of serum sex steroid levels to longitudinal changes in bone density in young versus elderly men. J Clin Endocrinol Metab. 2001;86:3555-3561.

    Not in our library10.1210/jcem.86.8.7736

28. 28.

    Gennari L, Merlotti D, Martini G, et al. Longitudinal association between sex hormone levels, bone loss, and bone turnover in elderly men. J Clin Endocrinol Metab. 2003;88:5327-5333.

    Not in our library10.1210/jc.2003-030736

29. 29.

    Van Pottelbergh I, Goemaere S, Kaufman JM. Bioavailable estradiol and an aromatase gene polymorphism are determinants of bone mineral density changes in men over 70 years of age. J Clin Endocrinol Metab. 2003;88:3075-3081.

    Not in our library10.1210/jc.2002-021691

30. 30.

    Falahati-Nini A, Riggs BL, Atkinson EJ, O'Fallon WM, Eastell R, Khosla S. Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men. J Clin Invest. 2000;106:1553-1560.

    Not in our library10.1172/jci10942

31. 31.

    Leder BZ, LeBlanc KM, Schoenfeld DA, Eastell R, Finkelstein JS. Differential effects of androgens and estrogens on bone turnover in normal men. J Clin Endocrinol Metab. 2003;88:204-210.

    Not in our library10.1210/jc.2002-021036

32. 32.

    Doran PM, Riggs BL, Atkinson EJ, Khosla S. Effects of raloxifene, a selective estrogen receptor modulator, on bone turnover markers and serum sex steroid and lipid levels in elderly men. J Bone Miner Res. 2001;16:2118-2125.

    Not in our library10.1359/jbmr.2001.16.11.2118

33. 33.

    Uebelhart B, Herrmann F, Pavo I, Draper MW, Rizzoli R. Raloxifene treatment is associated with increased serum estradiol and decreased bone remodeling in healthy middle-aged men with low sex hormone levels. J Bone Miner Res. 2004;19:1518-1524.

    Not in our library10.1359/jbmr.040503

34. 34.

    Amin S, Zhang Y, Felson DT, et al. Estradiol, testosterone, and the risk for hip fractures in elderly men from the Framingham Study. Am J Med. 2006;119:426-433.

    Not in our library10.1016/j.amjmed.2005.10.048

35. 35.

    Mellstrom D, Vandenput L, Mallmim H, et al. Older men with low serum estradiol and high serum SHBG have an increased risk of fractures. J Bone Miner Res. 2008;23:1552-1560.

    Not in our library10.1359/jbmr.080518

36. 36.

    Khosla S, Melton LJ, Robb RA, et al. Relationship of volumetric BMD and structural parameters at different skeletal sites to sex steroid levels in men. J Bone Miner Res. 2005;20:730-740.

    Not in our library10.1359/jbmr.041228

37. 37.

    Khosla S, Amin S, Orwoll E. Osteoporosis in men. Endocr Rev. 2008;29:441-464.

    Not in our library10.1210/er.2008-0002

38. 38.

    Lufkin EG, Wahner HW, O'Fallon WM, et al. Treatment of postmenopausal osteoporosis with transdermal estrogen. Ann Intern Med. 1992;117:1-9.

    Not in our library10.7326/0003-4819-117-1-1

39. 39.

    Bonewald LF. Osteocyte messages from a bony tomb. Cell Metab. 2007;5:410-411.

    Not in our library10.1016/j.cmet.2007.05.008

40. 40.

    Almeida M, Martin-Millan M, Plotkin LI, et al. Skeletal involution by age-associated oxidative stress and its acceleration by loss of sex steroids. J Biol Chem. 2007;282:27285-27297.

    Not in our library10.1074/jbc.m702810200

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