Hormonal Effects on Bone

BIO 201

 

I.  Hormones are key regulators of growth and maintenance 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

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

 

II. Growth Hormone-IGF-1 Axis                   

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

n    Regulation is complicated due to binding proteins etc.

 

GH-IGF-1 and Bone Growth and Remodeling  

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

n    Leads to cartilage expansion and linear growth of growing bone

n    IGF-1 is also a growth factor for osteoblasts

n    Correlative evidence suggests IGF-1 has an effect on bone mineral density (BMD)

 

GH Deficiency: Skeletal Effects

n    GH deficiency in childhood is associated with growth failure, short stature, & low BMD

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

 

III. Sex Steroids & Skeletal Homeostasis

n    Gonadal hormones have an important impact on bone physiology

n   Sexual dimorphism

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

 

 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 inhibit resorption by stimulating osteoclast apoptosis and preventing osteoblast and osteocyte 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   Estrogen is important in closure of growth plates in both genders

n    But, males with androgen deficiency have bone loss, despite normal estrogen levels

n    Androgens will preserve bone mass in estrogen deficiency

 

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

 

IV. Calcitropic Hormones & Bone

n    The skeleton serves as an important reservoir of calcium, hence hormones that regulate plasma calcium affect skeletal status

n    The two primary calcitropic hormones are:

n   Parathyroid hormone

n   Calcitonin

n    Vitamin D (calcitriol) has hormone-like effects and is often considered a calcium regulatory hormone

 

Intestinal Absorption of Calcium

n    Net uptake averages 100-200 mg/day

n   this amount is increased several fold during growth

n    Majority of calcium absorption occurs via carrier-mediated transport

n   this process determines the overall rate of Ca transport

n   exchanged with sodium

n   active process (energy required)

n    Transport from the GI tract into the blood is largely dependent upon the active form of Vitamin D

 

Role of Kidney in Calcium Balance

n    98%-99% of the 10,000mg of calcium filtered by the glomeruli is reabsorbed by the renal tubules

n    Reabsorption of calcium in the distal portions of the nephron is under hormonal regulation

 

Parathyroid Hormone (PTH)

n     PTH is an 84 aa protein secreted by 4 parathyroid glands in response to reduced plasma calcium

n     PTH elevates plasma calcium via

n    increased skeletal resorption

n    promotion of renal reabsorption in distal tubules

n    enhanced renal activation of vitamin D

n     PTH secretion is inhibited by adequate plasma calcium (9.2 – 10.4 mg/dL)

 

Anabolic effects of PTH

n    Anabolic effects on bone known since 1929

n   Cellular/molecular mechanism not entirely worked out

n    Increases rate of remodeling – stimulates both resportion and formation, but overall, net formation

n   Intermittent treatment different from continuous infusion or hyperparathyroidism

n    Improves bone mass, architecture, and strength

n   New bone formation on trabecular, endocortical and periosteal surfaces

n   Decreases fracture risk after 12-18 mo.

 

Tx of osteoporosis with PTH

n    rhPTH(1-34) “teriparatide” approved by FDA in 2002 as a treatment for osteoporosis in men and women

n   Administered daily SQ injection

n   Expensive: ~$7,200/year

n   Oral form & full length (1-84) also in clinical trails

n    Some people are non-responders

n    Source:  Rosen, 2004

 

Vitamin D

n    Vitamin D is essential for intestinal absorption of calcium

n   Secondary effects on kidney resorption and PTH actions

n   Must be activated in liver and then kidney

n    Vitamin D deficiency can result in skeletal demineralization

n   Rickets in children

n   Osteomalacia in adults

 

Calcitonin

n     Calcitonin is secreted by the thyroid gland in response to elevated plasma calcium

n     Calcitonin lowers plasma calcium via

n    Inhibition of skeletal resorption

n    Promotion of mineral deposition

n     Calcitonin secretion is inhibited by adequate plasma calcium

n     Calcitonin effects are relatively weak compared to PTH

 

V. Glucocorticoids and Bone

n    Known since Cushing’s 1932 description that excessive cortisol leads to osteoporosis, among other problems

n    Role of endogenous GC’s in bone modeling and remodeling unclear

n    Effects of synthetic GC’s on bone known

n   Synthetic GC’s (e.g., prednisone and prednisolone) widely used to decrease inflammation in a variety of diseases

n   Glucocorticoid induced osteoporosis

n   Tx w/ bisphosphonates