An ounce of prevention: stopping menopausal bone loss before it starts

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Summary The aphorism “an ounce of prevention is worth a pound of cure” very much applies to postmenopausal osteoporosis. Immediately following menopause, bone loss rates can reach as high as 3-4% per year. At present, there is no acceptable way to prevent this. A good prevention strategy would abrogate the increase in bone loss without over-suppressing bone turnover and without off-target effects. Estrogen replacement therapy effectively prevents menopausal bone loss, but the Women’s Health Initiative exposed the risks of ERT and it has largely been abandoned as a preventive strategy. SERMs like ERT increase the risk of DVT. The long-term use of bisphosphonates increases the risk of atypical fracture. To address this treatment gap, we propose a bold new strategy, based on the biology of Colony Stimulating Factor 1. Colony Stimulating Factor 1 (CSF1) is the principal colony stimulating factor released by osteoblasts and, in addition to RANKL, is absolutely required for osteoclast formation. There are two major isoforms of CSF1, a membrane-bound isoform (mCSF1) and a soluble, or circulating, isoform (sCSF1). The sCSF1 isoform has a unique carboxy-terminus extension. Withdrawal of estrogen selectively up-regulates sCSF1 in osteoblasts, while mCSF1 is unchanged. Importantly, an isoform-indiscriminate neutralizing antibody to CSF1 completely prevents ovariectomy (OVX)-induced bone loss in mice. However, blocking both isoforms of CSF1 is not a viable preventive strategy for estrogen-deficiency bone loss, because CSF1 is required for normal osteoclastogenesis. We found that selectively deleting sCSF1 in vivo causes no phenotype, does not change the basal rate of bone turnover, but protects mice against OVX-induced bone loss. These data point to sCSF1 as a novel therapeutic target to prevent estrogen-deficiency bone loss. This R21 will test the hypothesis that selective inhibition of the soluble isoform of CSF1 protects against estrogen-deficiency bone loss without affecting normal bone remodeling or bone quality. In Specific Aim 1, phage display antibody selection will be employed to rapidly develop an antibody that selectively inhibits sCSF1 by targeting the unique 73 amino acid c-terminus of that isoform. In Specific Aim 2, the dose and timing of neutralizing antibody administration that completely prevents bone loss in OVX wild type mice will first be determined using serial in vivo DXA bone density measurements in OVX wild type mice. OVX animals treated with estrogen and OVX-sCSF1-/- mice will serve as controls. Using the protocol that prevents a change in BMD from baseline, OVX and Sham-OVX wild type animals will be treated with neutralizing antibody or isotype matched control antibody for 4 weeks. Comprehensive BMD and body composition measurements, as well as ex vivo microCT, biochemical, biomechanical and histomorphometric analyses will be undertaken. To ensure adequate rigor, these studies will be performed in two different strains of mice. If successful, these studies will provide evidence for an entirely new way to prevent postmenopausal bone loss before it begins.