Although recombinant human bone morphogenetic proteins (BMPs) are used locally for treating bone defects in humans, their systemic effect on bone augmentation has not been explored. We have previously demonstrated that demineralized bone (DB) from ovariectomized (OVX) rats cannot induce bone formation when implanted ectopically at the subcutaneous site. Here we showed in vitro that 17␤-estradiol (E 2 ) specifically induced expression of Bmp6 mRNA in MC3T3-E1 preosteoblastic cells and that bone extracts from OVX rats lack BMPs. Next we demonstrated that 125 I-BMP-6 administered systemically accumulated in the skeleton and also restored the osteoinductive capacity of ectopically implanted DB from OVX rats. BMP-6 applied systemically to aged OVX rats significantly increased bone volume and mechanical characteristics of both the trabecular and cortical bone, the osteoblast surface, serum osteocalcin and osteoprotegerin levels, and decreased the osteoclast surface, serum C-telopeptide, and interleukin-6. E 2 was significantly less effective, and was not synergistic with BMP-6. Animals that discontinued BMP-6 therapy maintained bone mineral density gains for another 12 weeks. BMP-6 increased in vivo the bone expression of Acvr-1, Bmpr1b, Smad5, alkaline phosphatase, and collagen type I and decreased expression of Bmp3 and BMP antagonists, chordin and cerberus. These results show, for the first time, that systemically administered BMP-6 restores the bone inductive capacity, microarchitecture, and quality of the skeleton in osteoporotic rats.Bone loss during aging and after menopause in women is known to result from an imbalance between bone formation and resorption leading to altered bone microarchitecture and excess bone fragility. Inferior bone strength and increased bone fracture rate of bone in patients with osteoporosis might be associated with decreased osteoinductive and thus self-regenerative bone capacity eventually due to the lower content of growth and differentiation factors including bone morphogenetic proteins in the bone extracellular matrix (1-4).Demineralized bone matrix (DBM) 2 induces de novo bone formation when implanted into the rat muscle (5). On the contrary, DBM from OVX animals implanted into both normal and OVX rats induces only fibrous tissues suggesting that its decreased bone inducing activity is due to abnormal composition of bone from OVX rats and not to the 17␤-estradiol (E 2 )-deficient microenvironment (1). Lack of specific signals needed for ectopic bone induction may, at least in part, explain diminished bone potency to heal fractures in osteoporotic patients (6,7). It has been demonstrated that fetal osteoblastic cell lines treated by E 2 specifically express Bmp6 mRNA, whereas gene transcripts of other members of the BMP family are unaffected (8). A functional relationship between E 2 and BMP-6 was further suggested by E 2 binding to the Bmp6 gene promotor (9) and by increased BMP-6 immunostaining in bone marrow of mice treated with E 2 (10).Although numerous studies have unequivoc...

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