High-dose estrogen induces de novo medullary bone formation in female mice

It is well recognized that, in the mouse, high-dose estrogen induces sclero sis within the shaft of long hones, an action that is largely thought to re flect increased osteoblastic cellular activity. We undertook to characteriz e this response in more detail, by performing a histologic analysis of the early changes induced by high-dose estrogen in the tibial cavity of young i ntact female mice. Female mice were sacrificed immediately before or 4, 8, 12, or 24 days after commencing subcutaneous injections of 17 beta-estradio l (500 mu g/animal/week), and longitudinal tibial sections were subsequentl y examined. Estrogen was found to cause a rapid gain in cancellous hone, wi th cancellous hone volume increasing by similar to 50% after 8 days, and by 5-fold after 24 days. Analysis of cancellous double-labeled surfaces revea led that this gain in bone reflected the emergence of new cancellous bone f ormation sites within the medullary cavity, rather than the reactivation an d extension of formation over pre-existing bone surfaces. Comparison of the time course of these changes between proximal and distal regions of the pr oximal tibial metaphysis suggested that these new cancellous formation site s appear as a rapid wave extending distally from the secondary spongiosa. A lkaline phosphatase (ALP) immunocytochemistry revealed that, by 12 days aft er estrogen administration, a population of strongly ALP positive cells had appeared throughout the marrow cavity, We conclude that, at the proximal t ibial metaphysis of female mice, estrogen-induced medullary sclerosis large ly reflects a process of de novo medullary bone formation, possibly mediate d by the generation of osteoblasts from bone marrow osteoprogenitor cells.