The Calcium-hormones

 

 

 

The calcium-hormones function like a fire brigade; when structurally little calcium is consumed, they aren't activated that much, which is good ; no fire.

When too much calcium is consumed, the calcium-hormones are very active, stimulating absorption of calcium into the bones, and subsequently deportation and excretion. And the more this processed is enhanced, the more the bones erode.

 

 

After calcium is absorbed, calcitonine (or thyrocalcitonine) inhibits deportation of calcium from the bones, whilst the calcium automatically keeps pouring in. Calcitonine also stimulates excretion of calcium through urinating.

So, calcitonine primarily lowers blood-calcium level, and absorption of calcium into the bones is one way to reach that goal. Absorbing calcium into the bones certainly is not the purpose of calcitonine, for it stimulates excretion of calcium too.

Due to the action of calcitonine, the increased blood-calcium level decreases, inhibiting calcitonine release and stimulating secretion of two other calcium-hormones; PTH and calcitriol.

 

 

Parathyroid hormone (PTH) stimulates uptake of calcium into the bones (1) (and therefore osteoblast apoptosis (2)) and deportation of calcium from the bones, and inhibits excretion of calcium, generally increasing a low blood-calcium level. Logically, elevated PTH level accelerates ageing of the bones; see hyperparathyroidism

Low levels of PTH prevent bone loss. (3)

PTH also stimulates secretion of calcitriol;

 

 

Calcitriol (1,25 dihydroxycholecalciferol = composed of vit. D); The direct influence of calcitriol is increasing the uptake of dietary calcium into the blood, but also the uptake of calcium into the bones (4) (Calcitriol therefore also increases osteoblasts apoptosis (5)) and deportation of calcium from the bones.

 

Calcitriol however also inhibits secretion of PTH. And since the stimulating effect of PTH on the uptake of calcium into the bones and the subsequent deportation, supplementary calcitriol can, per saldo, in fact strongly decrease uptake of calcium into the bones and subsequent deportation. (6) Since calcitriol also increases intestinal calcium absorption, this however also strongly increases blood-calcium level (7).

 

Too much calcium in the blood can precipitate in the arteries, joints and ligaments and kills muscle cells (since muscle cells can only contract by deporting calcium outside the muscle-cells, which is harder if the blood contains more calcium). Too much calcitriol / vitamin D can cause arteriosclerosis, bone-deformation (8), muscle cramps and fibromyalgia.

 

 

 

Estrogen

Estrogens are multi-functional hormones, and one of their functions involves the bones.

The calcium-hormones mentioned above, induce circulation of calcium; from the blood into the bones and vice versa, ‘pumping’ the calcium around. Estrogens are the brakes on this system, to minimize erosion.

 

Calcium is absorbed into the bones due to osteoblasts, which increase free phosphate level in the bones, which causes the ‘passive’ influx of calcium, to restore the calcium-phosphate ratio.

Deportation of calcium from the bones by osteoclasts is an active process.

 

Structurally, estrogen does not stimulate osteoblasts (9) , but even inhibits osteoblast activity (10) and therefore inhibits calcium influx in the bones (11) and also inhibits deportation of calcium from the bones. Thus estrogen protects the bones against excessive bone turnover, and osteoblasts against apoptosis.

Estrogen prevents death of osteoblasts in particular because osteoblasts are more sensitive to ageing phenomena than osteoclasts. (12)

 

 

In general, this protective effect of estrogen is accredited to the decrease in deportation of calcium from the bones, and is the inhibitory effect of estrogen on calcium influx ignored.

But a characteristic action of estrogens on the skeleton is inhibition of longitudinal bone growth. (13)

Some claim that estrogen increases calcium influx in the bones, but this is only the case in the first 6 days of administration. (9)

 

 

The reason why osteoporosis risk in women is higher than in men, regardless of menopause and milk consumption, is due to monthly estrogen and PTH fluctuations;

Estrogen levels in women strongly fluctuate monthly.

As estrogen level is at its lowest (around menstruation), PTH level is at its highest, increasing deportation of calcium from the bones. (14) (and uptake of calcium into the bones)

Thus lifetime bone turnover averagely is higher in women.

 

 

 

Vitamin K

Vitamin K seems to be protective for inhibiting death of osteoblasts. (15) But how exactly this happens, remains unclear; vitamin K may inhibit fractional calcium absorption and therefore prevent osteoblast apoptosis. Or vitamin K may reduce ‘unnecessary’ apoptosis of osteoblasts even without excessive calcium turnover. Vitamin K can however also increase osteoblast apoptosis. (16)

Vitamin K does not affect intestinal calcium absorption (17), but the intake of dietary vitamin K2 has a preventive effect on bone resorption caused by ovariectomie or a lack of vitamin K, and in postmenopausal women. (18)

 

 

 

Growth Factors

The hormones mentioned above influence bone-metabolism through different mediators, like growth factors.

One such a growth factor is Insulin-Like Growth Factor-1 (IGF-1). That an increased uptake of calcium increases osteoblast apoptosis, is also shown by IGF-1 influence; IGF-1 is a potent growth factor for osteoblasts (and also increases bone resorption) and induces osteoblast apoptosis. (19)

 

Other such growth factors are Fibroblast Growth Factors (FGF). FGF play a critical role in bone growth, and overexpression of FGF2 increases osteoblast apoptosis. (20)



Sources

Abstracts of most sources can be found at The National Library of Medicine

 

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(2)Stanislaus D, In vivo regulation of apoptosis in metaphyseal trabecular bone of young rats by synthetic human parathyroid hormone (1-34) fragment. Bone 2000 / 27 (2) / 209-218.

(3) Fujiyama K, et al, Attenuation of postmenopausal high turnover bone loss in patients with hypoparathyroidism. J. Clin. Endocrinol. Metab. 1995 / 80 (7) / 2135-2138.

(4) Erben RG, et al, Therapeutic efficacy of 1alpha,25-dihydroxyvitamin D3 and calcium in osteopenic ovariectomized rats: evidence for a direct anabolic effect of 1alpha,25-dihydroxyvitamin D3 on bone. Endocrinology1998 / 139 (10) / 4319-4328.

(5) Pascher E, et al, Effect of 1alpha,25(OH)2-vitamin D3 on TNF alpha-mediated apoptosis of human primary osteoblast-like cells in vitro. Horm. Metab. Res.1999 / 31 (12) / 653-656.

(6) Sairanen S, et al, Bone mass and markers of bone and calcium metabolism in postmenopausal women treated with 1,25-dihydroxyvitamin D (Calcitriol) for four years. Calcif. Tissue Int. 2000 / 67 (2) / 122-127.

(7) Sairanen S, et al, Bone mass and markers of bone and calcium metabolism in postmenopausal women treated with 1,25-dihydroxyvitamin D (Calcitriol) for four years. Calcif. Tissue Int. 2000 / 67 (2) / 122-127. , Gurlek A, et al, Comparison of calcitriol treatment with etidronate-calcitriol and calcitonin-calcitriol combinations in Turkish women with postmenopausal osteoporosis: a prospective study. Calcif. Tissue Int. 1997 / 61 (1) / 39-43.

(8) Giunta, D.L. ,Dental changes in hypervitaminosis D. Oral. Surg. Pathol. Oral. Radiol. Endod. 1998 / 85 (4) / 410-413. , Uehlinger, P. et al, Differential diagnosis of hypercalcemia - a retrospective study of 46 dogs. (duitst.) Schweiz. Arch. Tierheilkd. 1998 / 140 (5) / 188-197. , Qin, X. et al, Altered phosphorylation of a 91-kDa protein in particulate fractions of rat kidney after protracted 1,25-dihydroxyvitamin D3 or estrogen treatment. Arch. Biochem. Biophys. 1997 / 348 (2) / 239-246. , Niederhoffer, N. et al, Calcification of medical elastic fibers and aortic elasticity. Hypertension 1997 / 29 (4) / 999-1006. , Selby, P.L. et al, Vitamin D intoxication causes hypercalcemia by increased bone resorption with responds to

pamidronate. Clin. Endocrinol. (Oxf.) 1995 / 43 (5) / 531-536. , Ito, M. et al, Dietary magnesium effect on swine coronary atherosclerosis induced by hypervitaminosis D. Acta Pathol. Jpn. 1987 / 37 (6) / 955-964.

(9) Qu Q, et al, Estrogen enhances differentiation of osteoblasts in mouse bone marrow culture. Bone 1998 Mar;22(3):201-9.

(10) Jilka RL, et al, Loss of estrogen upregulates osteoblastogenesis in the murine bone marrow. Evidence for autonomy from factors released during bone resorption. J. Clin. Invest. 1998 / 101 (9) / 1942-1950.

(11)Bryant HU, et al, An estrogen receptor basis for raloxifene action in bone. J Steroid Biochem Mol Biol 1999 / 69 (1-6) / 37-44. , Jilka RL, et al, Loss of estrogen upregulates osteoblastogenesis in the murine bone marrow. Evidence for autonomy from factors released during bone resorption. J. Clin. Invest. 1998 / 101 (9) / 1942-1950. , Sims NA, et al, Estradiol treatment transiently increases trabecular bone volume in ovariectomized rats. Bone1996 / 19 (5) / 455-461.Smith, G.R. et al, Inhibitory action of oestrogen on calcium-induced mitosis in rat bone marrow and thymus. J. Endocrinol. 1975 / 65 (1) / 45-53.

(12) Eriksen EF, et al, The pathogenesis of osteoporosis. Horm. Res.1997 / 48 Suppl 5 / 78-82.

(13) Bryant HU, et al, An estrogen receptor basis for raloxifene action in bone. J Steroid Biochem Mol Biol 1999 / 69 (1-6) / 37-44. , Hannon R, et al, Response of biochemical markers of bone turnover to hormone replacement therapy: impact of biological variability. J. Bone Miner. Res. 1998 / 13 (7) / 1124-1133.

(14) Zittermann A, et al, Physiologic fluctuations of serum estradiol levels influence biochemical markers of bone resorption in young women. J Clin Endocrinol Metab 2000 / 85 (1) / 95-101.

(15) Urayama S, et al, Effect of vitamin K2 on osteoblast apoptosis: vitamin K2 inhibits apoptotic cell death of human osteoblasts induced by Fas, proteasome inhibitor, etoposide, and staurosporine. J. Lab. Clin. Med. 2000 / 136 (3) / 181-193.

(16) Sakagami H, et al, Apoptosis-inducing activity of vitamin C and vitamin K. Cell. Mol. Biol. (Noisy-le-grand) 2000 / 46 (1) / 129-143.

(17) Zhao X, et al, [Effect of various levels of vitamin K intake on bone metabolism of rat]. [Article in Chinese] Chung Hua Yu Fang I Hsueh Tsa Chih 1998 / 32 (6) / 359-362.

(18) Yamaguchi M, et al, J. Bone Miner. Metab. 1999 / 17 (1) / 23-29. , Zhao X, et al, [Effect of various levels of vitamin K intake on bone metabolism of rat]. [Article in Chinese] Chung Hua Yu Fang I Hsueh Tsa Chih 1998 / 32 (6) / 359-362. , Jie KS, et al, Effects of vitamin K and oral anticoagulants on urinary calcium excretion. Br. J. Haematol.1993 / 83 (1) / 100-104.

(19) Kawakami A, et al, Insulin-like growth factor I stimulates proliferation and Fas-mediated apoptosis of human osteoblasts. Biochem. Biophys. Res. Commun. 1998 / 247 (1) / 46-51.

(20) Mansukhani A, et al, Signaling by fibroblast growth factors (FGF) and fibroblast growth factor receptor 2 (FGFR2)-activating mutations blocks mineralization and induces apoptosis in osteoblasts. J. Cell. Biol.2000 / 149 (6) / 1297-1308.

                                                

 

 

 

 



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