Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 Sep 15;100(6):1475–1480. doi: 10.1172/JCI119668

Histomorphometric assessment of the long-term effects of alendronate on bone quality and remodeling in patients with osteoporosis.

P M Chavassieux 1, M E Arlot 1, C Reda 1, L Wei 1, A J Yates 1, P J Meunier 1
PMCID: PMC508326  PMID: 9294113

Abstract

Treatment effects on bone quality and remodeling was assessed in postmenopausal women with osteoporosis treated with oral alendronate. One transiliac bone biopsy was obtained from 231 women at either 24 mo (n = 11) or 36 mo (n = 120) from the start of treatment with alendronate at doses of between 5 and 20 mg/d, or placebo. 64 biopsies at 24 mo (31 from the placebo group and 33 alendronate-treated patients) and 95 biopsies at 36 mo (40 from the placebo group and 55 alendronate-treated patients) provided adequate cancellous tissue, and were analyzed by histomorphometry. Mineral apposition rate was unaffected by treatment. At 24 and 36 mo, osteoid thickness, volume, and surface significantly decreased. At each of the doses studied, mineralizing surface and activation frequency significantly decreased at each time point (e.g., -92% and -87%, respectively, for the 10 mg daily dose after 2 yr). These diminutions were of the same magnitude for each dose at 24 mo, and for the two highest doses at 36 mo. A significant increase in wall thickness accompanied by a reduction in erosion depth was detected in biopsies obtained at 24 mo. These findings confirm that mineralization is normal, and trabecular bone turnover markedly decreased in patients receiving long-term dosing with alendronate. The findings also suggest that the observed increases in bone mineral density could result both from a reduction in the remodeling space due to a decreased activation frequency and a possible trend to a positive bone balance. In addition, further studies focused on a possible increase in the degree of mineralization of bone are required.

Full Text

The Full Text of this article is available as a PDF (156.1 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adami S., Mian M., Gatti P., Rossini M., Zamberlan N., Bertoldo F., Lo Cascio V. Effects of two oral doses of alendronate in the treatment of Paget's disease of bone. Bone. 1994 Jul-Aug;15(4):415–417. doi: 10.1016/8756-3282(94)90818-4. [DOI] [PubMed] [Google Scholar]
  2. Adami S., Passeri M., Ortolani S., Broggini M., Carratelli L., Caruso I., Gandolini G., Gnessi L., Laurenzi M., Lombardi A. Effects of oral alendronate and intranasal salmon calcitonin on bone mass and biochemical markers of bone turnover in postmenopausal women with osteoporosis. Bone. 1995 Oct;17(4):383–390. doi: 10.1016/s8756-3282(95)00262-6. [DOI] [PubMed] [Google Scholar]
  3. Balena R., Markatos A., Seedor J. G., Gentile M., Stark C., Peter C. P., Rodan G. A. Long-term safety of the aminobisphosphonate alendronate in adult dogs. II. Histomorphometric analysis of the L5 vertebrae. J Pharmacol Exp Ther. 1996 Jan;276(1):277–283. [PubMed] [Google Scholar]
  4. Balena R., Toolan B. C., Shea M., Markatos A., Myers E. R., Lee S. C., Opas E. E., Seedor J. G., Klein H., Frankenfield D. The effects of 2-year treatment with the aminobisphosphonate alendronate on bone metabolism, bone histomorphometry, and bone strength in ovariectomized nonhuman primates. J Clin Invest. 1993 Dec;92(6):2577–2586. doi: 10.1172/JCI116872. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bone H. G., Downs R. W., Jr, Tucci J. R., Harris S. T., Weinstein R. S., Licata A. A., McClung M. R., Kimmel D. B., Gertz B. J., Hale E. Dose-response relationships for alendronate treatment in osteoporotic elderly women. Alendronate Elderly Osteoporosis Study Centers. J Clin Endocrinol Metab. 1997 Jan;82(1):265–274. doi: 10.1210/jcem.82.1.3682. [DOI] [PubMed] [Google Scholar]
  6. Boyce B. F., Smith L., Fogelman I., Johnston E., Ralston S., Boyle I. T. Focal osteomalacia due to low-dose diphosphonate therapy in Paget's disease. Lancet. 1984 Apr 14;1(8381):821–824. doi: 10.1016/s0140-6736(84)92272-4. [DOI] [PubMed] [Google Scholar]
  7. Chavassieux P. M., Arlot M. E., Meunier P. J. Intermethod variation in bone histomorphometry: comparison between manual and computerized methods applied to iliac bone biopsies. Bone. 1985;6(4):221–229. doi: 10.1016/8756-3282(85)90004-3. [DOI] [PubMed] [Google Scholar]
  8. Chesnut C. H., 3rd, McClung M. R., Ensrud K. E., Bell N. H., Genant H. K., Harris S. T., Singer F. R., Stock J. L., Yood R. A., Delmas P. D. Alendronate treatment of the postmenopausal osteoporotic woman: effect of multiple dosages on bone mass and bone remodeling. Am J Med. 1995 Aug;99(2):144–152. doi: 10.1016/s0002-9343(99)80134-x. [DOI] [PubMed] [Google Scholar]
  9. Cohen-Solal M. E., Shih M. S., Lundy M. W., Parfitt A. M. A new method for measuring cancellous bone erosion depth: application to the cellular mechanisms of bone loss in postmenopausal osteoporosis. J Bone Miner Res. 1991 Dec;6(12):1331–1338. doi: 10.1002/jbmr.5650061210. [DOI] [PubMed] [Google Scholar]
  10. Devogelaer J. P., Broll H., Correa-Rotter R., Cumming D. C., De Deuxchaisnes C. N., Geusens P., Hosking D., Jaeger P., Kaufman J. M., Leite M. Oral alendronate induces progressive increases in bone mass of the spine, hip, and total body over 3 years in postmenopausal women with osteoporosis. Bone. 1996 Feb;18(2):141–150. doi: 10.1016/8756-3282(95)00436-x. [DOI] [PubMed] [Google Scholar]
  11. Eriksen E. F., Gundersen H. J., Melsen F., Mosekilde L. Reconstruction of the formative site in iliac trabecular bone in 20 normal individuals employing a kinetic model for matrix and mineral apposition. Metab Bone Dis Relat Res. 1984;5(5):243–252. doi: 10.1016/0221-8747(84)90066-3. [DOI] [PubMed] [Google Scholar]
  12. Fleisch H. Bisphosphonates. Pharmacology and use in the treatment of tumour-induced hypercalcaemic and metastatic bone disease. Drugs. 1991 Dec;42(6):919–944. doi: 10.2165/00003495-199142060-00003. [DOI] [PubMed] [Google Scholar]
  13. Fleisch H. Bisphosphonates. Pharmacology and use in the treatment of tumour-induced hypercalcaemic and metastatic bone disease. Drugs. 1991 Dec;42(6):919–944. doi: 10.2165/00003495-199142060-00003. [DOI] [PubMed] [Google Scholar]
  14. Garnero P., Shih W. J., Gineyts E., Karpf D. B., Delmas P. D. Comparison of new biochemical markers of bone turnover in late postmenopausal osteoporotic women in response to alendronate treatment. J Clin Endocrinol Metab. 1994 Dec;79(6):1693–1700. doi: 10.1210/jcem.79.6.7989477. [DOI] [PubMed] [Google Scholar]
  15. Harris S. T., Gertz B. J., Genant H. K., Eyre D. R., Survill T. T., Ventura J. N., DeBrock J., Ricerca E., Chesnut C. H., 3rd The effect of short term treatment with alendronate on vertebral density and biochemical markers of bone remodeling in early postmenopausal women. J Clin Endocrinol Metab. 1993 Jun;76(6):1399–1406. doi: 10.1210/jcem.76.6.8501142. [DOI] [PubMed] [Google Scholar]
  16. Hosking D. J. Advances in the management of Paget's disease of bone. Drugs. 1990 Dec;40(6):829–840. doi: 10.2165/00003495-199040060-00005. [DOI] [PubMed] [Google Scholar]
  17. Kanis J. A., Gertz B. J., Singer F., Ortolani S. Rationale for the use of alendronate in osteoporosis. Osteoporos Int. 1995 Jan;5(1):1–13. doi: 10.1007/BF01623652. [DOI] [PubMed] [Google Scholar]
  18. Keshawarz N. M., Recker R. R. Expansion of the medullary cavity at the expense of cortex in postmenopausal osteoporosis. Metab Bone Dis Relat Res. 1984;5(5):223–228. doi: 10.1016/0221-8747(84)90063-8. [DOI] [PubMed] [Google Scholar]
  19. Kragstrup J., Gundersen H. J., Melsen F., Mosekilde L. Estimation of the three-dimensional wall thickness of completed remodeling sites in iliac trabecular bone. Metab Bone Dis Relat Res. 1982;4(2):113–119. doi: 10.1016/0221-8747(82)90024-8. [DOI] [PubMed] [Google Scholar]
  20. Lafage M. H., Balena R., Battle M. A., Shea M., Seedor J. G., Klein H., Hayes W. C., Rodan G. A. Comparison of alendronate and sodium fluoride effects on cancellous and cortical bone in minipigs. A one-year study. J Clin Invest. 1995 May;95(5):2127–2133. doi: 10.1172/JCI117901. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Liberman U. A., Weiss S. R., Bröll J., Minne H. W., Quan H., Bell N. H., Rodriguez-Portales J., Downs R. W., Jr, Dequeker J., Favus M. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group. N Engl J Med. 1995 Nov 30;333(22):1437–1443. doi: 10.1056/NEJM199511303332201. [DOI] [PubMed] [Google Scholar]
  22. Parfitt A. M., Drezner M. K., Glorieux F. H., Kanis J. A., Malluche H., Meunier P. J., Ott S. M., Recker R. R. Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res. 1987 Dec;2(6):595–610. doi: 10.1002/jbmr.5650020617. [DOI] [PubMed] [Google Scholar]
  23. Parfitt A. M., Mundy G. R., Roodman G. D., Hughes D. E., Boyce B. F. A new model for the regulation of bone resorption, with particular reference to the effects of bisphosphonates. J Bone Miner Res. 1996 Feb;11(2):150–159. doi: 10.1002/jbmr.5650110203. [DOI] [PubMed] [Google Scholar]
  24. Reid I. R., Nicholson G. C., Weinstein R. S., Hosking D. J., Cundy T., Kotowicz M. A., Murphy W. A., Jr, Yeap S., Dufresne S., Lombardi A. Biochemical and radiologic improvement in Paget's disease of bone treated with alendronate: a randomized, placebo-controlled trial. Am J Med. 1996 Oct;101(4):341–348. doi: 10.1016/s0002-9343(96)00227-6. [DOI] [PubMed] [Google Scholar]
  25. Rosen H. N., Dresner-Pollak R., Moses A. C., Rosenblatt M., Zeind A. J., Clemens J. D., Greenspan S. L. Specificity of urinary excretion of cross-linked N-telopeptides of type I collagen as a marker of bone turnover. Calcif Tissue Int. 1994 Jan;54(1):26–29. doi: 10.1007/BF00316285. [DOI] [PubMed] [Google Scholar]
  26. Rossini M., Gatti D., Zamberlan N., Braga V., Dorizzi R., Adami S. Long-term effects of a treatment course with oral alendronate of postmenopausal osteoporosis. J Bone Miner Res. 1994 Nov;9(11):1833–1837. doi: 10.1002/jbmr.5650091121. [DOI] [PubMed] [Google Scholar]
  27. Roux J. P., Arlot M. E., Gineyts E., Meunier P. J., Delmas P. D. Automatic-interactive measurement of resorption cavities in transiliac bone biopsies and correlation with deoxypyridinoline. Bone. 1995 Aug;17(2):153–156. doi: 10.1016/s8756-3282(95)00174-3. [DOI] [PubMed] [Google Scholar]
  28. Sato M., Grasser W. Effects of bisphosphonates on isolated rat osteoclasts as examined by reflected light microscopy. J Bone Miner Res. 1990 Jan;5(1):31–40. doi: 10.1002/jbmr.5650050107. [DOI] [PubMed] [Google Scholar]
  29. Sato M., Grasser W., Endo N., Akins R., Simmons H., Thompson D. D., Golub E., Rodan G. A. Bisphosphonate action. Alendronate localization in rat bone and effects on osteoclast ultrastructure. J Clin Invest. 1991 Dec;88(6):2095–2105. doi: 10.1172/JCI115539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Sietsema W. K., Ebetino F. H., Salvagno A. M., Bevan J. A. Antiresorptive dose-response relationships across three generations of bisphosphonates. Drugs Exp Clin Res. 1989;15(9):389–396. [PubMed] [Google Scholar]
  31. Siris E., Weinstein R. S., Altman R., Conte J. M., Favus M., Lombardi A., Lyles K., McIlwain H., Murphy W. A., Jr, Reda C. Comparative study of alendronate versus etidronate for the treatment of Paget's disease of bone. J Clin Endocrinol Metab. 1996 Mar;81(3):961–967. doi: 10.1210/jcem.81.3.8772558. [DOI] [PubMed] [Google Scholar]
  32. Tucci J. R., Tonino R. P., Emkey R. D., Peverly C. A., Kher U., Santora A. C., 2nd Effect of three years of oral alendronate treatment in postmenopausal women with osteoporosis. Am J Med. 1996 Nov;101(5):488–501. doi: 10.1016/s0002-9343(96)00282-3. [DOI] [PubMed] [Google Scholar]
  33. Tukey J. W., Ciminera J. L., Heyse J. F. Testing the statistical certainty of a response to increasing doses of a drug. Biometrics. 1985 Mar;41(1):295–301. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES