[PHNUTR-L] Pituitary hormone implicated in bone loss after menopause

[Kathrynne Holden, MS, RD]

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Public release date: 20-Apr-2006
http://www.eurekalert.org/pub_releases/2006-04/cp-phi041706.php

Contact: Heidi Hardman
hhardman at cell.com
617-397-2879
Cell Press

Pituitary hormone implicated in bone loss after menopause

New evidence in the April 21, 2006 Cell challenges the long-standing 
notion that declining estrogen levels alone lead to osteoporosis after 
women go through menopause. The researchers rather found that high 
levels of pituitary-derived follicle-stimulating hormone (FSH) cause 
bone loss in mice. The pituitary is a master gland found at the base of 
the brain.

What's more, the researchers reported, mice with symptoms of severe 
estrogen deficiency, lacking either the FSH hormone or its receptor, 
became resistant to bone loss.

FSH normally triggers egg development and stimulates estrogen production 
by the ovaries, the researchers explained. As women approach menopause 
and estrogen levels decline, the pituitary gland responds by releasing 
more FSH.

Treatments that prevent bone loss by blocking FSH might therefore offer 
alternative methods to treat or prevent osteoporosis without the risks 
associated with other hormone replacement therapies, said Mone Zaidi of 
Mount Sinai School of Medicine. For example, estrogen replacement 
therapy has been linked to an increased risk of breast cancer, 
especially when taken in combination with progesterone, he said.

"For the last three decades, the idea has clearly been that estrogen 
loss is responsible for the changes experienced in postmenopausal 
women--including flushing, dryness, and bone loss," Zaidi said. 
"Although FSH levels rise sharply in parallel to estrogen decline, a 
direct effect of FSH on the skeleton had never before been explored."

"We've now found that, irrespective of the nature or severity of 
estrogen deficiency, an intact pituitary and, more specifically, high 
FSH levels are prerequisites for bone loss in animals with reduced or 
absent ovarian function."

Osteoporosis affects nearly 45 million women worldwide with fracture 
rates that far exceed the combined incidence of breast cancer, stroke, 
and heart attacks, the researchers said. The disease results from a 
disruption of the fine balance between bone formation and resorption. 
After menopause, resorption exceeds new bone formation, leading to a net 
bone loss that can be slowed by estrogen therapy through mechanisms that 
have remained somewhat murky, Zaidi said.

However, emerging evidence has begun to cast some doubt on whether 
estrogen deficiency can fully explain bone loss after menopause, he 
added. For example, mice without an intact pituitary gland become 
resistant to the effects of ovary loss on bone density. FSH levels also 
show a closer correlation than estrogen levels to the rate of bone 
turnover in postmenopausal women.

The researchers now show that mice lacking FSH or its receptor become 
resistant to bone loss despite severe loss of ovarian function. In mice 
with normal ovaries and approximately half the normal concentration of 
FSH, bone mass increased due to a decline in bone resorption by cells 
known as osteoclasts, which break down bone. Indeed, they report, FSH 
stimulates receptors found on the surface of bone-degrading osteoclasts 
and their precursors, leading to the bone cells' formation and function.

The study suggests that FSH plays a role in the normal process by which 
bone is mobilized by osteoclasts before it can be replaced, Zaidi said.

"As you run or walk throughout life, microcracks develop in bone," he 
explained. "Therefore, bone remodeling and replacement with new bone is 
required to maintain skeletal integrity. Osteoclasts essentially dig 
around those cracks to clear the way for repairs."

In combination with the research group's earlier finding that 
thyroid-stimulating hormone directly regulates the skeleton, the 
findings revise the understanding of how pituitary-derived hormones 
function, Zaidi added. Scientist had thought pituitary hormones acted 
primarily through their effects on other endocrine glands.

"This should change the textbook picture of pituitary hormone 
physiology," he said.

###

The researchers include Li Sun, Yuanzhen Peng of the Mount Sinai School 
of Medicine in New York, NY; Allison C. Sharrow of the University of 
Pittsburgh in Pittsburgh, PA and the VA Medical Center in Pittsburgh, 
PA; Jameel Iqbal and Zhiyuan Zhang of the Mount Sinai School of Medicine 
in New York, NY; Dionysios J. Papachristou of the University of 
Pittsburgh in Pittsburgh, PA and the VA Medical Center in Pittsburgh, 
PA; Samir Zaidi and Ling-Ling Zhu of the Mount Sinai School of Medicine 
in New York, NY; Beatrice B. Yaroslavskiy of the University of 
Pittsburgh in Pittsburgh, PA and the VA Medical Center in Pittsburgh, 
PA; Hang Zhou of the Mount Sinai School of Medicine in New York, NY; 
Alberta Zallone of the University of Bari in Bari, Italy; M. Ram Sairam 
of the Clinical Research Institute of Montreal in Montreal, Canada; T. 
Rajendra Kumar of the University of Kansas in Kansas City, KS; Wei Bo 
and Jonathan Braun of the University of California, Los Angeles in Los 
Angeles, CA; Luis Cardoso-Landa, Mitchell B. Schaffler and Baljit S. 
Moonga of the Mount Sinai School of Medicine in New York, NY; Harry C. 
Blair of the University of Pittsburgh in Pittsburgh, PA and the VA 
Medical Center in Pittsburgh, PA; and Mone Zaidi of the Mount Sinai 
School of Medicine in New York, NY.

Sun et al.: "FSH Directly Regulates Bone Mass: Implications for 
Understanding the Pathogenesis of Osteoporosis Due to Hypogonadism." 
Publishing in Cell 125, 247-260, April 21, 2006. DOI 
10.1016/j.cell.2006.01.051 www.cell.com
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