Postmenopausal osteoporosis is traditionally attributed to declining estrogen levels. However, a recent study showed that follicle-stimulating hormone (FSH), the secretion of which is under estrogenic feedback, directly enhances osteoclast formation and function. The deletion of one of its subunits protects against bone loss despite severe hypogonadism. This finding suggests that elevated FSH contributes to the genesis of postmenopausal osteoporosis.
However, hypogonadal bone loss is accompanied by alterations in bone and bone marrow, notably enhanced bone formation, increased T lymphocyte production, and macrophage activation. The alterations in immune function have been attributed to an increase in TNFα production that is thought to arise from estrogen deficiency.

Ablation of the TNFα gene in mice abrogates gonadectomy-induced bone loss, osteoclast and osteoblast activation, and the accompanying immune cell alterations. TNFα may therefore be essential for, and downstream of, FSH action on bone. Moreover, there is direct evidence that FSH enhances TNF receptor and TNFα expression.

Iqbal et al. [1] explored whether FSH mediates the production of TNFα and whether the abrogation of bone loss in FSH-deficient mice arises in part from decreased TNFα production. They show that FSH-deficient mice have low circulating TNFα, that FSH directly stimulates TNFα production from bone marrow granulocytes and macrophages, and that TNFα stimulates osteoclast precursor expansion and osteoblast differentiation. They show that high-turnover bone loss is due to an expanded osteoclast precursor pool, together with enhanced osteoblast formation.

They propose that hypogonadal bone loss is caused, at least in part, by enhanced FSH secretion, which in turn increases TNF production by bone marrow macrophages and granulocytes to expand the number of bone marrow osteoclast precursors.

1. Iqbal J et al. Proc Natl Acad Sci USA. 2006;103:14925-14930.