Osteoporotic fractures affect >1.4 million U.S. postmenopausal women annually, and contribute to loss of
independence and mortality. This study aims to establish a foundation that will ultimately allow us to address a
potentially paradigm-changing question: should we prevent fast bone mineral density (BMD) decline during the
menopause transition (MT) and early postmenopause (before substantial BMD decline has occurred) to reduce
the risk of subsequent fractures?
The MT and early postmenopause may be opportune times for early, short-term intervention because
increased bone turnover and negative balance between bone resorption and formation contribute to fast BMD
decline, damage to bone microarchitecture and risk of fracture. However, before we can test the efficacy of
early intervention, we must surmount a critical barrier: we have to be able to predict whether a woman in her
40s to 50s is at risk for fast BMD decline and fracture during the MT and early postmenopause.
The overarching objective of this study is to tackle this barrier by examining whether a novel bone balance
index (BBI) that combines individual bone resorption and formation to non-invasively estimate bone balance,
can predict fast BMD decline and fracture. We will conduct this study in the Study of Women's Health Across
the Nation (SWAN). From SWAN, we previously created a proof-of-concept BBI using bone turnover markers
that are no longer recommended for clinical research. This BBI was a stronger predictor of BMD decline than a
bone resorption marker alone.
Here, we will further develop the BBI construct, in an effort to maximize its ability to predict BMD decline
and fracture. We propose to access banked serum collected from SWAN participants during the MT and early
postmenopause to measure currently acknowledged reference bone resorption (serum collagen type I C-
telopeptide [s-CTX]) and formation (serum procollagen type I propeptide [s-PINP]) markers. We will then
recreate our BBI using s-CTX and s-PINP. Aim 1 will characterize how s-CTX, s-PINP, and BBI (created from
s-CTX and s-PINP) change during the MT and early postmenopause. Aim 2 will examine the ability of BBI and
s-CTX to predict fast BMD decline. Aim 3 will examine the ability of BBI and s-CTX to predict future fracture.
These aims will lay the foundation for developing a tool that combines BBI with clinical risk factors (similar
to adding BMD to clinical risk factors in FRAX) to identify women who may benefit from early intervention, and
thus pave the way for clinical trials testing the efficacy of early, short-term, preventive intervention. This
program of investigation could ultimately contribute to a shift in the way that we prevent fracture: targeting high-
risk women in their 40s-50s prior to substantial BMD decline.