Endocrine Effects on Bone

EXS 490

Overview

n Hormones are integral regulators of growth and maintenance of skeletal tissue

n Hormone levels may be modified by aging, disease, nutrition and physical activity

n Because of the role of the skeleton in calcium homeostasis, skeletal status is also determined by calcium balance, and therefore, calcitropic hormones

Endocrine Regulation of Skeletal Tissue

n Several hormones are important regulators of bone mass and distribution

n Growth regulators:

n Growth Hormone: stimulates bone formation

n IGF-1: stimulates bone formation

n Gonadal Steroids: inhibit bone resorption

n Leptin: inhibits bone formation

n Calcium regulators:

n Parathyroid hormone: stimulates formation & resorption

n Calcitonin: permits formation

n Vitamin D: stimulates resorption & allows formation

Growth Hormone-IGF-1 Axis

n Growth hormone induces the production of IGF-1 in various tissues including liver, heart, kidney, muscle & bone

n Note: Also IGF-II

n IGF-1 travels in the circulation bound to proteins (IGFBP’s); however, only free IGF-1 is biologically active

n Regulation complicated – 6 IGFBP’s, also IGFBP specific proteases

GH-IGF-1 and Bone Growth (Modeling)

n Growth hormone induces IGF-1 production in differentiating chondrocytes at the epiphyseal growth plate

n Proliferating chondrocytes differentiate which in turn leads to cartilage expansion and linear growth

GH Deficiency: Skeletal Effects

n GH deficiency in childhood is associated with growth failure and short stature

n Likewise, attainment of peak bone mass is also impaired and early osteopenia is likely

n GH deficiency in adulthood is associated with reduced BMD

n Treatment with recombinant GH (rhGH) increases stature and BMD in GH-deficient children and BMD in GH-deficient adults

n However, height and BMD never fully recover

n Treatment of non-GH deficient adults does not appear to increase BMD

IGF-1 and Bone Remodeling

n IGF-1 appears to have a role in bone remodeling

n IGF-1 is present in circulation & in the marrow

n Osteoblasts and pre-OB secrete IGF-1

n Bone resorption releases stored IGF-1

n IGF-1 appears to recruit pre-OB’s to remodeling surface, is a growth factor for OB’s

n May coordinate coupling of resorption and formation

n Role with respect to osteoclasts unclear, though IGF-1 receptor is present on osteoclast

IGF-1 and loss of Bone Mineral Density

n Considerable correlative evidence that IGF-1 has a role in declining BMD with aging:

n Positive correlation between serum IGF-1 and BMD in hip, radius, lumbar spine of older women

n Low serum IGF-1 increases risk of fracture in older women (but nutrition is confounder)

n Mutation leading to low serum IGF-1 (indep of GH) correlated w/ low BMD, associated with idiopathic osteoporosis in men

n Correlation does not establish causality

Evidence from IGF-1, GH Transgenics and Mutations

See Table

n Interpreting results difficult – lethality, morbidity, compensatory (but not normal) changes etc. complicate findings

n Omitted work on IGFBP and downstream effectors of IGF-1

n Findings suggest both serum and local IGF-1 have influence on bone maturation and maintenance

n Relative importance of each currently unknown

n Findings suggest that the growth plate and periosteum are more sensitive to circulating IGF-1 than is trabecular bone

n Skeletal IGF-1 necessary for normal trabecular mass

n Findings suggest skeletal level of IGF-1 much less sensitive to GH than is serum level

Sex Steroids & Skeletal Homeostasis

n Gonadal hormones have an important impact on bone physiology

n Sexual dimorphism

n Mineral homeostasis

n Bone balance

n Key gonadal hormones are: estrogen, progesterone, and testosterone

n Insufficient levels of gonadal steroids predispose the human skeleton to bone loss and osteoporotic fractures

Mechanism of Sex Steroid Action

n Estrogen, progesterone, and testosterone are steroid hormones

n Lipid soluble

n Intracellular or intranuclear receptors

n Steroid hormones act upon tissues by altering rates of gene expression

Mechanism of Sex Steroid Action, Part 2

n Recent evidence suggests that intramembrane receptors exist in caveolae (invaginations of cell membrane) of bone cells, thereby allowing for non-genotypic responses to hormonal stimulation

n Act via second messengers to alter bone cell apoptosis and thus bone remodeling activity

n Estrogen increases IGF-1 expression, probably via second messengers

Sex Steroids in Non-Reproductive Tissues

n The density of receptors for sex steroids on non-reproductive tissue is much lower compared to reproductive tissues

n Similar levels of estrogen and androgen receptors in bone cells of males and females, some possibility that the receptors are indiscriminant and will bind either

Sex Steroid Effects on Remodeling

n Sex steroids play an important role in maintaining adult bone mass by suppressing spongy bone remodeling

n Sex steroids attenuate the maturation of both osteoclasts and osteoblasts

n Sex steroids inhibit resorption by stimulating osteoclastic apoptosis and preventing osteoblastic and osteocytic apoptosis

n Thus, loss of sex steroids can accelerate osteoclast activity

n Result is a remodeling imbalance which favors resorption

Estrogens vs. Androgens

n It is still unclear which sex steroid is the key regulator of bone tissue

n Early evidence suggested that estrogen was the dominant hormone in skeletal regulation

n Both T & E decline with advancing age in men

n Serum bioavailable estrogen has been the most consistent predictor of BMD in males (Khosla 1998)

n Men w/ non-functional estrogen receptor or aromatase deficiency exhibited normal mineral status, but delayed closure of growth plates

n Estrogen is important in closure of growth plates in both genders

n Both estrogen depleted women and hypogonadic men demonstrate reduced bone mass

n Males with androgen insufficiency display reduced bone mass despite normal estrogen levels

n Androgens appear to prevent bone loss during estrogen insufficiency

Sex steroid deficiency & bone

n Sex steroid deficiency may result from:

n Hormone deficiency and/or receptor malfunction

n Ovariectomy

n Menopause

n Excessive exercise

n Poor nutrition

n Low dietary fat

n Low energy

BMD of Amenorrheic Athletes as % BMD of Sedentary Women

Hypogonadic men

n Reductions in circulating androgens and estrogens in men is also associated with reduced BMD

n Males with delayed puberty (>15 years) exhibit BMD 1 SD lower than those males with a normal onset of puberty

n These reductions persist into adulthood

n Male athletes who participate in endurance activities and maintain low body weight may also be at risk although likely not to the same extent as their female counterparts

Effects of HRT on Bone

n The rate of bone loss following cessation of ovarian function accelerates to 2-5%/yr

n Hormone replacement therapy can halt or even reverse the loss by inhibiting resorption

n Most effective with early intervention

n Osteoporotic fractures may be reduced by 50%

n But HRT also has drawbacks – no longer recommended for majority of women

n Partial agonists (selective estrogen receptor modulators (SERM’s)) may also prove effective

Leptin – central regulation of Bone Mass

n Obervations:

n Estrogen depletion (as with menopause or OVX) leads to increased osteoclast activity and net bone resorption

n Obesity appears to lower risk of osteoporosis

n Leptin known to be involved in regulation of body adiposity, lead to idea that leptin was involved in regulation of bone

Leptin, body weight, and bone mass

n Leptin is produced by adipocytes, receptors located in hypothalamus

n Ob/Ob mice lack leptin and are extremely obese, as well as hypogonadal

n Mice with leptin receptor defect (db/db) also obese

n Both mice strains have ~40% greater bone mass than normal, despite hypogonadism

n Not due to obesity per se

n Leptin repletion via infusion into the brain decreases bone mass in ob/ob and normal mice

n High bone mass due to increased formation of both cortical and trabecular bone

Link between leptin and bone cells

n Leptin induces catecholamine secretion from the hypothalamus

n Osteoblasts express beta-adrenergic receptors

n Isoproterenol (B-ad receptor agonist) reduces bone mass in ob/ob and normal mice

n Propranolol (B-ad receptor antagonist) increased bone mass in normal mice and prevented bone loss post-OVX

n CCN: Leptin inhibits bone formation via the sympathetic nervous system, Beta-2 receptor

n Source: Takeda, 2005