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. 1993 Dec;92(6):2577–2586. doi: 10.1172/JCI116872

The effects of 2-year treatment with the aminobisphosphonate alendronate on bone metabolism, bone histomorphometry, and bone strength in ovariectomized nonhuman primates.

R Balena 1, B C Toolan 1, M Shea 1, A Markatos 1, E R Myers 1, S C Lee 1, E E Opas 1, J G Seedor 1, H Klein 1, D Frankenfield 1, et al.
PMCID: PMC288453  PMID: 8254015

Abstract

This study examined the effect of 2 yr of treatment with the aminobisphosphonate alendronate (ALN) (0.05 or 0.25 mg/kg i.v. ALN every 2 wk) on estrogen deficiency bone loss and bone strength changes in ovariectomized (OVX) baboons (n = 7 per group) and the ALN mode of action at the tissue level. Biochemical markers of bone turnover increased in OVX animals and were maintained by ALN treatment at non-OVX levels (low dose) or below (high dose). 2 yr of treatment produced no cumulative effects on bone turnover markers. Histomorphometry showed a marked increase in cancellous bone remodeling in OVX animals. Activation frequency increased from 0.48 to 0.86 per yr (L5 vertebra), and the osteoid surfaces from 9 to 13.5% (P < 0.05). No changes were observed in eroded and osteoclast surfaces. ALN treatment decreased activation frequency and indices of bone formation to control levels (low dose) or below (high dose), did not change indices of mineralization, and increased bone mineral density (BMD) in the lumbar vertebrae (L2-L4) by 15% at 0.25 mg/kg (P < 0.05), relative to vehicle-treated animals. The mean strength of cancellous bone (L4) increased by 44% (low ALN dose) and 100% (high dose), compared with vehicle. The strength of individual bones correlated with the square of the L2-L4 BMD (r = 0.91, P < 0.0034). In conclusion, ALN treatment reversed the effects of ovariectomy on cancellous bone turnover and increased bone mass and bone strength in baboons.

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Selected References

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  1. Beardsworth L. J., Eyre D. R., Dickson I. R. Changes with age in the urinary excretion of lysyl- and hydroxylysylpyridinoline, two new markers of bone collagen turnover. J Bone Miner Res. 1990 Jul;5(7):671–676. doi: 10.1002/jbmr.5650050702. [DOI] [PubMed] [Google Scholar]
  2. Boyce R. W., Franks A. F., Jankowsky M. L., Orcutt C. M., Piacquadio A. M., White J. M., Bevan J. A. Sequential histomorphometric changes in cancellous bone from ovariohysterectomized dogs. J Bone Miner Res. 1990 Sep;5(9):947–953. doi: 10.1002/jbmr.5650050908. [DOI] [PubMed] [Google Scholar]
  3. Carter D. R., Hayes W. C. The compressive behavior of bone as a two-phase porous structure. J Bone Joint Surg Am. 1977 Oct;59(7):954–962. [PubMed] [Google Scholar]
  4. Chevalley T., Rizzoli R., Nydegger V., Slosman D., Tkatch L., Rapin C. H., Vasey H., Bonjour J. P. Preferential low bone mineral density of the femoral neck in patients with a recent fracture of the proximal femur. Osteoporos Int. 1991 Jun;1(3):147–154. doi: 10.1007/BF01625444. [DOI] [PubMed] [Google Scholar]
  5. Civitelli R., Agnusdei D., Nardi P., Zacchei F., Avioli L. V., Gennari C. Effects of one-year treatment with estrogens on bone mass, intestinal calcium absorption, and 25-hydroxyvitamin D-1 alpha-hydroxylase reserve in postmenopausal osteoporosis. Calcif Tissue Int. 1988 Feb;42(2):77–86. doi: 10.1007/BF02556338. [DOI] [PubMed] [Google Scholar]
  6. Cleghorn D. B., Polley K. J., Bellon M. J., Chatterton J., Baghurst P. A., Nordin B. E. Fracture rates as a function of forearm mineral density in normal postmenopausal women: retrospective and prospective data. Calcif Tissue Int. 1991 Sep;49(3):161–163. doi: 10.1007/BF02556110. [DOI] [PubMed] [Google Scholar]
  7. Cummings S. R., Black D. M., Nevitt M. C., Browner W. S., Cauley J. A., Genant H. K., Mascioli S. R., Scott J. C., Seeley D. G., Steiger P. Appendicular bone density and age predict hip fracture in women. The Study of Osteoporotic Fractures Research Group. JAMA. 1990 Feb 2;263(5):665–668. [PubMed] [Google Scholar]
  8. Delmas P. D. Biochemical markers of bone turnover for the clinical assessment of metabolic bone disease. Endocrinol Metab Clin North Am. 1990 Mar;19(1):1–18. [PubMed] [Google Scholar]
  9. Delmas P. D., Schlemmer A., Gineyts E., Riis B., Christiansen C. Urinary excretion of pyridinoline crosslinks correlates with bone turnover measured on iliac crest biopsy in patients with vertebral osteoporosis. J Bone Miner Res. 1991 Jun;6(6):639–644. doi: 10.1002/jbmr.5650060615. [DOI] [PubMed] [Google Scholar]
  10. Duboeuf F., Braillon P., Chapuy M. C., Haond P., Hardouin C., Meary M. F., Delmas P. D., Meunier P. J. Bone mineral density of the hip measured with dual-energy X-ray absorptiometry in normal elderly women and in patients with hip fracture. Osteoporos Int. 1991 Sep;1(4):242–249. doi: 10.1007/BF03187468. [DOI] [PubMed] [Google Scholar]
  11. Frost H. M. The pathomechanics of osteoporoses. Clin Orthop Relat Res. 1985 Nov;(200):198–225. [PubMed] [Google Scholar]
  12. Genant H. K., Cann C. E., Ettinger B., Gordan G. S. Quantitative computed tomography of vertebral spongiosa: a sensitive method for detecting early bone loss after oophorectomy. Ann Intern Med. 1982 Nov;97(5):699–705. doi: 10.7326/0003-4819-97-5-699. [DOI] [PubMed] [Google Scholar]
  13. Grynpas M. D., Acito A., Dimitriu M., Mertz B. P., Very J. M. Changes in bone mineralization, architecture and mechanical properties due to long-term (1 year) administration of pamidronate (APD) to adult dogs. Osteoporos Int. 1992 Mar;2(2):74–81. doi: 10.1007/BF01623840. [DOI] [PubMed] [Google Scholar]
  14. Gärdsell P., Johnell O., Nilsson B. E. The predictive value of bone loss for fragility fractures in women: a longitudinal study over 15 years. Calcif Tissue Int. 1991 Aug;49(2):90–94. doi: 10.1007/BF02565127. [DOI] [PubMed] [Google Scholar]
  15. Hreshchyshyn M. M., Hopkins A., Zylstra S., Anbar M. Effects of natural menopause, hysterectomy, and oophorectomy on lumbar spine and femoral neck bone densities. Obstet Gynecol. 1988 Oct;72(4):631–638. [PubMed] [Google Scholar]
  16. Hui S. L., Slemenda C. W., Johnston C. C., Jr Baseline measurement of bone mass predicts fracture in white women. Ann Intern Med. 1989 Sep 1;111(5):355–361. doi: 10.7326/0003-4819-111-5-355. [DOI] [PubMed] [Google Scholar]
  17. Jensen K. S., Mosekilde L., Mosekilde L. A model of vertebral trabecular bone architecture and its mechanical properties. Bone. 1990;11(6):417–423. doi: 10.1016/8756-3282(90)90137-n. [DOI] [PubMed] [Google Scholar]
  18. Jerome C. P., Kimmel D. B., McAlister J. A., Weaver D. S. Effects of ovariectomy on iliac trabecular bone in baboons (Papio anubis). Calcif Tissue Int. 1986 Sep;39(3):206–208. doi: 10.1007/BF02555119. [DOI] [PubMed] [Google Scholar]
  19. Kelly P. J., Pocock N. A., Sambrook P. N., Eisman J. A. Age and menopause-related changes in indices of bone turnover. J Clin Endocrinol Metab. 1989 Dec;69(6):1160–1165. doi: 10.1210/jcem-69-6-1160. [DOI] [PubMed] [Google Scholar]
  20. Lindsay R., Hart D. M., Forrest C., Baird C. Prevention of spinal osteoporosis in oophorectomised women. Lancet. 1980 Nov 29;2(8205):1151–1154. doi: 10.1016/s0140-6736(80)92592-1. [DOI] [PubMed] [Google Scholar]
  21. Lindsay R. Prevention and treatment of osteoporosis with ovarian hormones. Ann Chir Gynaecol. 1988;77(5-6):219–223. [PubMed] [Google Scholar]
  22. Longcope C., Hoberg L., Steuterman S., Baran D. The effect of ovariectomy on spine bone mineral density in rhesus monkeys. Bone. 1989;10(5):341–344. doi: 10.1016/8756-3282(89)90130-0. [DOI] [PubMed] [Google Scholar]
  23. Mazess B., Vetter J., Weaver D. S. Bone changes in oophorectomized monkeys: CT findings. J Comput Assist Tomogr. 1987 Mar-Apr;11(2):302–305. doi: 10.1097/00004728-198703000-00022. [DOI] [PubMed] [Google Scholar]
  24. Mazzuoli G. F., Tabolli S., Bigi F., Valtorta C., Minisola S., Diacinti D., Scarnecchia L., Bianchi G., Piolini M., Dell'Acqua S. Effects of salmon calcitonin on the bone loss induced by ovariectomy. Calcif Tissue Int. 1990 Oct;47(4):209–214. doi: 10.1007/BF02555921. [DOI] [PubMed] [Google Scholar]
  25. Mellish R. W., Ferguson-Pell M. W., Cochran G. V., Lindsay R., Dempster D. W. A new manual method for assessing two-dimensional cancellous bone structure: comparison between iliac crest and lumbar vertebra. J Bone Miner Res. 1991 Jul;6(7):689–696. doi: 10.1002/jbmr.5650060706. [DOI] [PubMed] [Google Scholar]
  26. Moore R. J., Durbridge T. C., Woods A. E., Vernon-Roberts B. Variation in histomorphometric estimates across different sites of the iliac crest. J Clin Pathol. 1989 Aug;42(8):814–816. doi: 10.1136/jcp.42.8.814. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Nordin B. E., Chatterton B. E., Walker C. J., Wishart J. The relation of forearm mineral density to peripheral fractures in postmenopausal women. Med J Aust. 1987 Mar 16;146(6):300–304. doi: 10.5694/j.1326-5377.1987.tb120266.x. [DOI] [PubMed] [Google Scholar]
  28. O'Doherty D. P., Bickerstaff D. R., McCloskey E. V., Hamdy N. A., Beneton M. N., Harris S., Mian M., Kanis J. A. Treatment of Paget's disease of bone with aminohydroxybutylidene bisphosphonate. J Bone Miner Res. 1990 May;5(5):483–491. doi: 10.1002/jbmr.5650050510. [DOI] [PubMed] [Google Scholar]
  29. Ohta H., Makita K., Suda Y., Ikeda T., Masuzawa T., Nozawa S. Influence of oophorectomy on serum levels of sex steroids and bone metabolism and assessment of bone mineral density in lumbar trabecular bone by QCT-C value. J Bone Miner Res. 1992 Jun;7(6):659–665. doi: 10.1002/jbmr.5650070610. [DOI] [PubMed] [Google Scholar]
  30. 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]
  31. Parfitt A. M., Mathews C. H., Villanueva A. R., Kleerekoper M., Frame B., Rao D. S. Relationships between surface, volume, and thickness of iliac trabecular bone in aging and in osteoporosis. Implications for the microanatomic and cellular mechanisms of bone loss. J Clin Invest. 1983 Oct;72(4):1396–1409. doi: 10.1172/JCI111096. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Passeri M., Baroni M. C., Pedrazzoni M., Pioli G., Barbagallo M., Costi D., Biondi M., Girasole G., Arlunno B., Palummeri E. Intermittent treatment with intravenous 4-amino-1-hydroxybutylidene-1,1-bisphosphonate (AHBuBP) in the therapy of postmenopausal osteoporosis. Bone Miner. 1991 Dec;15(3):237–247. doi: 10.1016/0169-6009(91)90129-n. [DOI] [PubMed] [Google Scholar]
  33. Reeve J. Bone turnover and trabecular plate survival after artificial menopause. Br Med J (Clin Res Ed) 1987 Sep 26;295(6601):757–760. doi: 10.1136/bmj.295.6601.757. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Reginster J. Y., Lecart M. P., Deroisy R., Sarlet N., Denis D., Ethgen D., Collette J., Franchimont P. Prevention of postmenopausal bone loss by tiludronate. Lancet. 1989 Dec 23;2(8678-8679):1469–1471. doi: 10.1016/s0140-6736(89)92927-9. [DOI] [PubMed] [Google Scholar]
  35. 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]
  36. Schenk R., Eggli P., Fleisch H., Rosini S. Quantitative morphometric evaluation of the inhibitory activity of new aminobisphosphonates on bone resorption in the rat. Calcif Tissue Int. 1986 Jun;38(6):342–349. doi: 10.1007/BF02555748. [DOI] [PubMed] [Google Scholar]
  37. Seedor J. G., Quartuccio H. A., Thompson D. D. The bisphosphonate alendronate (MK-217) inhibits bone loss due to ovariectomy in rats. J Bone Miner Res. 1991 Apr;6(4):339–346. doi: 10.1002/jbmr.5650060405. [DOI] [PubMed] [Google Scholar]
  38. Smith M. L., Fogelman I., Hart D. M., Scott E., Bevan J., Leggate I. Effect of etidronate disodium on bone turnover following surgical menopause. Calcif Tissue Int. 1989 Feb;44(2):74–79. doi: 10.1007/BF02556464. [DOI] [PubMed] [Google Scholar]
  39. Steiniche T., Hasling C., Charles P., Eriksen E. F., Mosekilde L., Melsen F. A randomized study on the effects of estrogen/gestagen or high dose oral calcium on trabecular bone remodeling in postmenopausal osteoporosis. Bone. 1989;10(5):313–320. doi: 10.1016/8756-3282(89)90126-9. [DOI] [PubMed] [Google Scholar]
  40. Stepán J. J., Pospíchal J., Presl J., Pacovský V. Bone loss and biochemical indices of bone remodeling in surgically induced postmenopausal women. Bone. 1987;8(5):279–284. doi: 10.1016/8756-3282(87)90002-0. [DOI] [PubMed] [Google Scholar]
  41. Stepán J. J., Pospíchal J., Schreiber V., Kanka J., Mensík J., Presl J., Pacovský V. The application of plasma tartrate-resistant acid phosphatase to assess changes in bone resorption in response to artificial menopause and its treatment with estrogen or norethisterone. Calcif Tissue Int. 1989 Nov;45(5):273–280. doi: 10.1007/BF02556018. [DOI] [PubMed] [Google Scholar]
  42. Storm T., Steiniche T., Thamsborg G., Melsen F. Changes in bone histomorphometry after long-term treatment with intermittent, cyclic etidronate for postmenopausal osteoporosis. J Bone Miner Res. 1993 Feb;8(2):199–208. doi: 10.1002/jbmr.5650080211. [DOI] [PubMed] [Google Scholar]
  43. Thompson D. D., Seedor J. G., Quartuccio H., Solomon H., Fioravanti C., Davidson J., Klein H., Jackson R., Clair J., Frankenfield D. The bisphosphonate, alendronate, prevents bone loss in ovariectomized baboons. J Bone Miner Res. 1992 Aug;7(8):951–960. doi: 10.1002/jbmr.5650070812. [DOI] [PubMed] [Google Scholar]
  44. Thompson D. D., Seedor J. G., Weinreb M., Rosini S., Rodan G. A. Aminohydroxybutane bisphosphonate inhibits bone loss due to immobilization in rats. J Bone Miner Res. 1990 Mar;5(3):279–286. doi: 10.1002/jbmr.5650050312. [DOI] [PubMed] [Google Scholar]
  45. Turner R. T., Vandersteenhoven J. J., Bell N. H. The effects of ovariectomy and 17 beta-estradiol on cortical bone histomorphometry in growing rats. J Bone Miner Res. 1987 Apr;2(2):115–122. doi: 10.1002/jbmr.5650020206. [DOI] [PubMed] [Google Scholar]
  46. Uebelhart D., Gineyts E., Chapuy M. C., Delmas P. D. Urinary excretion of pyridinium crosslinks: a new marker of bone resorption in metabolic bone disease. Bone Miner. 1990 Jan;8(1):87–96. doi: 10.1016/0169-6009(91)90143-n. [DOI] [PubMed] [Google Scholar]
  47. Uebelhart D., Schlemmer A., Johansen J. S., Gineyts E., Christiansen C., Delmas P. D. Effect of menopause and hormone replacement therapy on the urinary excretion of pyridinium cross-links. J Clin Endocrinol Metab. 1991 Feb;72(2):367–373. doi: 10.1210/jcem-72-2-367. [DOI] [PubMed] [Google Scholar]
  48. Valkema R., Vismans F. J., Papapoulos S. E., Pauwels E. K., Bijvoet O. L. Maintained improvement in calcium balance and bone mineral content in patients with osteoporosis treated with the bisphosphonate APD. Bone Miner. 1989 Jan;5(2):183–192. doi: 10.1016/0169-6009(89)90095-0. [DOI] [PubMed] [Google Scholar]
  49. Wasnich R. D., Ross P. D., Davis J. W., Vogel J. M. A comparison of single and multi-site BMC measurements for assessment of spine fracture probability. J Nucl Med. 1989 Jul;30(7):1166–1171. [PubMed] [Google Scholar]
  50. Watts N. B., Harris S. T., Genant H. K., Wasnich R. D., Miller P. D., Jackson R. D., Licata A. A., Ross P., Woodson G. C., 3rd, Yanover M. J. Intermittent cyclical etidronate treatment of postmenopausal osteoporosis. N Engl J Med. 1990 Jul 12;323(2):73–79. doi: 10.1056/NEJM199007123230201. [DOI] [PubMed] [Google Scholar]
  51. Weinreb M., Rodan G. A., Thompson D. D. Osteopenia in the immobilized rat hind limb is associated with increased bone resorption and decreased bone formation. Bone. 1989;10(3):187–194. doi: 10.1016/8756-3282(89)90052-5. [DOI] [PubMed] [Google Scholar]
  52. Wronski T. J., Cintrón M., Dann L. M. Temporal relationship between bone loss and increased bone turnover in ovariectomized rats. Calcif Tissue Int. 1988 Sep;43(3):179–183. doi: 10.1007/BF02571317. [DOI] [PubMed] [Google Scholar]
  53. Zysset E., Ammann P., Jenzer A., Gertz B. J., Portmann L., Rizzoli R., Jaquet-Müller F., Pryor-Tillotson S., Bonjour J. P., Burckhardt P. Comparison of a rapid (2-h) versus a slow (24-h) infusion of alendronate in the treatment of hypercalcemia of malignancy. Bone Miner. 1992 Sep;18(3):237–249. doi: 10.1016/0169-6009(92)90810-z. [DOI] [PubMed] [Google Scholar]

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