Abstract
This prospective, randomized, placebo-controlled study investigated whether estrogen, tamoxifen, and raloxifene protect the skeleton from the acute catabolic effects of continuous PTH(1–34) infusion. It was infused over 24 h in 25 postmenopausal women both before and while on medication for 16–20 weeks (estrogen n = 7, raloxifene n = 5, tamoxifen n = 7, placebo n = 6). Blood and urine samples were collected at baseline and every 4 h during the PTH(1–34) infusion and analyzed for calcium homeostasis, bone remodeling, and specific cytokines. Data for the premedication PTH(1–34) infusions were pooled. During the premedication PTH(1–34) infusions, serum calcium and urine phosphorus increased, while serum phosphorus and urine calcium declined. Osteocalcin decreased (mean 18%), while urine NTX increased (mean 315%). Serum IL-6 increased 260%, but there were no other cytokine changes as a result of the PTH(1–34) infusion. On medication, the mean peak change in NTX with PTH(1–34) infusion was less (77, 59, and 31 nM/mM with raloxifene, tamoxifen, and estrogen, respectively). The reduction in urine calcium excretion was prolonged with each agent but only significantly with estrogen. There was no reduction in the IL-6 elevation induced by PTH(1–34) with any medication. The differential skeletal resorption response to PTH(1–34) infusion after the treatments may reflect different potencies of these agents or variability in interaction with the estrogen receptor. Renal calcium conservation and the blunted response of bone resorption to PTH(1–34) infusion may be mechanisms by which estrogen and estrogen agonist/antagonist agents preserve bone mass.
Similar content being viewed by others
References
Albright F, Smith PH, Richardson AM (1941) Postmenopausal osteoporosis. JAMA 116:2465–2474
Aitken JM, Hart DM, Anderson JB, Lindsay R, Smith DA, Speirs CF (1973) Osteoporosis after oophorectomy for non-malignant disease. Br Med J 1:325–328
Lindsay R, Hart DM, Forrest C, Baird C (1980) Prevention of spinal osteoporosis in oophorectomised women. Lancet 2(8205):1151–1154
Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H et al (2004) Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 291(14):1701–1712
Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML et al (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):321–333
Christiansen C, Christensen MS, Jensen J, McNair P, Hagen C, Stocklund KE et al (1980) Prevention of early post-menopausal bone mineral loss. Controlled 2-year study of 315 women [in Danish]. Ugeskr Laeger 142(44):2896–2901
Steiniche T, Hasling C, Charles P, Eriksen EF, Mosekilde L, Melsen F (1989) A randomized study on the effects of estrogen/gestagen or high dose oral calcium on trabecular bone remodeling in postmenopausal osteoporosis. Bone 10(5):313–320
Riggs BL, Khosla S, Melton LJ 3rd (2002) Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev 23(3):279–302
Delmas PD, Hardy P, Garnero P, Dain M (2000) Monitoring individual response to hormone replacement therapy with bone markers. Bone 26(6):553–560
Cosman F, Shen V, Xie F, Seibel M, Ratcliffe A, Lindsay R (1993) Estrogen protection against bone resorbing effects of parathyroid hormone infusion. Assessment by use of biochemical markers. Ann Intern Med 118(5):337–343
Masiukiewicz US, Mitnick M, Gulanski BI, Insogna KL (2002) Evidence that the IL-6/IL-6 soluble receptor cytokine system plays a role in the increased skeletal sensitivity to PTH in estrogen-deficient women. J Clin Endocrinol Metab 87(6):2892–2898
Srivastava S, Toraldo G, Weitzmann MN, Cenci S, Ross FP, Pacifici R (2001) Estrogen decreases osteoclast formation by down-regulating receptor activator of NF-kappaB ligand (RANKL)-induced JNK activation. J Biol Chem 276(12):8836–8840
Vural P, Akgul C, Canbaz M (2006) Effects of hormone replacement therapy on plasma pro-inflammatory and anti-inflammatory cytokines and some bone turnover markers in postmenopausal women. Pharmacol Res 54(4):298–302
Spelsberg TC, Subramaniam M, Riggs BL, Khosla S (1999) The actions and interactions of sex steroids and growth factors/cytokines on the skeleton. Mol Endocrinol 13(6):819–828
Pfeilschifter J, Koditz R, Pfohl M, Schatz H (2002) Changes in proinflammatory cytokine activity after menopause. Endocr Rev 23(1):90–119
Teitelbaum SL (2000) Bone resorption by osteoclasts. Science 289(5484):1504–1508
Saika M, Inoue D, Kido S, Matsumoto T (2001) 17Beta-estradiol stimulates expression of osteoprotegerin by a mouse stromal cell line, ST-2, via estrogen receptor-alpha. Endocrinology 142(6):2205–2212
Cosman F, Nieves J, Horton J, Shen V, Lindsay R (1994) Effects of estrogen on response to edetic acid infusion in postmenopausal osteoporotic women. J Clin Endocrinol Metab 78(4):939–943
Marcus R, Villa ML, Cheema M, Cheema C, Newhall K, Holloway L (1992) Effects of conjugated estrogen on the calcitriol response to parathyroid hormone in postmenopausal women. J Clin Endocrinol Metab 74(2):413–418
Boros S, Bindels RJ, Hoenderop JG (2009) Active Ca2+ reabsorption in the connecting tubule. Pflugers Arch 458(1):99–109
Civitelli R, Agnusdei D, Nardi P, Zacchei F, Avioli LV, Gennari C (1988) Effects of one-year treatment with estrogens on bone mass, intestinal calcium absorption, and 25-hydroxyvitamin D1 alpha-hydroxylase reserve in postmenopausal osteoporosis. Calcif Tissue Int 42(2):77–86
Riggs BL, Hartmann LC (2003) Selective estrogen-receptor modulators—mechanisms of action and application to clinical practice. N Engl J Med 348(7):618–629
Cosman F (2003) Selective estrogen-receptor modulators. Clin Geriatr Med 19(2):371–379
Prestwood KM, Gunness M, Muchmore DB, Lu Y, Wong M, Raisz LG (2000) A comparison of the effects of raloxifene and estrogen on bone in postmenopausal women. J Clin Endocrinol Metab 85(6):2197–2202
Cranney A, Tugwell P, Zytaruk N, Robinson V, Weaver B, Adachi J et al (2002) Meta-analyses of therapies for postmenopausal osteoporosis. IV. Meta-analysis of raloxifene for the prevention and treatment of postmenopausal osteoporosis. Endocr Rev 23(4):524–528
Siris E, Adachi JD, Lu Y, Fuerst T, Crans GG, Wong M et al (2002) Effects of raloxifene on fracture severity in postmenopausal women with osteoporosis: results from the MORE study. Multiple Outcomes of Raloxifene Evaluation. Osteoporos Int 13(11):907–913
Rogers A, Clowes JA, Pereda CA, Eastell R (2007) Different effects of raloxifene and estrogen on interleukin-1beta and interleukin-1 receptor antagonist production using in vitro and ex vivo studies. Bone 40(1):105–110
Ozmen B, Kirmaz C, Aydin K, Kafesciler SO, Guclu F, Hekimsoy Z (2007) Influence of the selective oestrogen receptor modulator (raloxifene hydrochloride) on IL-6, TNF-alpha, TGF-beta1 and bone turnover markers in the treatment of postmenopausal osteoporosis. Eur Cytokine Netw 18(3):148–153
Michael H, Harkonen PL, Kangas L, Vaananen HK, Hentunen TA (2007) Differential effects of selective oestrogen receptor modulators (SERMs) tamoxifen, ospemifene and raloxifene on human osteoclasts in vitro. Br J Pharmacol 151(3):384–395
Mendez-Davila C, Garcia-Moreno C, Turbi C, de la Piedra C (2004) Effects of 17beta-estradiol, tamoxifen and raloxifene on the protein and mRNA expression of interleukin-6, transforming growth factor-beta1 and insulin-like growth factor-1 in primary human osteoblast cultures. J Endocrinol Invest 27(10):904–912
Cosman F, Shen V, Herrington B, Lindsay R (1991) Response of the parathyroid gland to infusion of human parathyroid hormone-(1–34) [PTH-(1–34)]: demonstration of suppression of endogenous secretion using immunoradiometric intact PTH-(1–84) assay. J Clin Endocrinol Metab 73(6):1345–1351
Duncam D (1955) Multiple range and multiple F tests. Biometrics 11:1–42
McKane WR, Khosla S, Burritt MF, Kao PC, Wilson DM, Ory SJ et al (1995) Mechanism of renal calcium conservation with estrogen replacement therapy in women in early postmenopause—a clinical research center study. J Clin Endocrinol Metab 80(12):3458–3464
Masiukiewicz US, Mitnick M, Grey AB, Insogna KL (2000) Estrogen modulates parathyroid hormone-induced interleukin-6 production in vivo and in vitro. Endocrinology 141(7):2526–2531
Kumru S, Yildiz FM, Godekmerdan A, Kutlu S, Yilmaz B, Gurates B (2008) Effects of raloxifene and hormone replacement therapy on serum Th2 and Th3 type cytokine concentrations in healthy postmenopausal women: a randomised controlled trial. Arch Gynecol Obstet 277(6):489–493
Boyle WJ, Simonet WS, Lacey DL (2003) Osteoclast differentiation and activation. Nature 423(6937):337–342
Fernandez-Garcia D, Munoz-Torres M, Mezquita-Raya P, de la Higuera M, Alonso G, Reyes-Garcia R et al (2008) Effects of raloxifene therapy on circulating osteoprotegerin and RANK ligand levels in post-menopausal osteoporosis. J Endocrinol Invest 31(5):416–421
Cheung J, Mak YT, Papaioannou S, Evans BA, Fogelman I, Hampson G (2003) Interleukin-6 (IL-6), IL-1, receptor activator of nuclear factor kappaB ligand (RANKL) and osteoprotegerin production by human osteoblastic cells: comparison of the effects of 17-beta oestradiol and raloxifene. J Endocrinol 177(3):423–433
Joborn C, Ljunghall S, Larsson K, Lindh E, Naessén T, Wide L, Akerström G, Rastad J (1991) Skeletal responsiveness to parathyroid hormone in healthy females: relationship to menopause and oestrogen replacement. Clin Endocrinol 34(5):335–339
Acknowledgements
This work was supported by NIDDK 46381.
Author information
Authors and Affiliations
Corresponding author
Additional information
F. C. and R. L. are consultants, advisors, and speakers for Eli Lilly. The other authors have stated that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Kulak, C.A.M., Baz-Hecht, M., Nieves, J. et al. Responses of Urinary N-Telopeptide and Renal Calcium Handling to PTH Infusion after Treatment with Estrogen, Raloxifene, and Tamoxifen. Calcif Tissue Int 90, 263–271 (2012). https://doi.org/10.1007/s00223-012-9572-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00223-012-9572-y