Bone health and prevalent fractures in women with polycystic ovary syndrome: a meta-analysis and endocrine-context pathophysiology review

ABSTRACT

Introduction

Bone health in those with Polycystic Ovary Syndrome (PCOS) is complex, but the general consensus is that cortical areal bone mineral density (aBMD) sites will be higher in PCOS than in age- and BMI-similar controls. However, spine aBMD sites may be lower, especially in non-obese PCOS. Whether or not incident fracture risk is increased in PCOS is currently controversial; no meta-analysis has yet assessed prevalent fractures.

Areas covered

We assessed the bone effects of PCOS-related ovarian hormone alterations, e.g. androgen excess, tonically normal/higher estradiol, and lower-than-normal progesterone levels. We also highlighted evidence that common PCOS medications (e.g. combined hormonal contraceptives [CHC], metformin, and spironolactone) have important bone effects. In adolescents, meta-analysis of CHC showed significant negative aBMD changes. Inflammation has negative PCOS bone effects and is linked with CHC use.

Expert opinion

Is fracture risk altered by PCOS? Our meta-analysis showed a 25% increased risk of prevalent fracture in PCOS versus controls; this did not reach statistical significance. Future prospective research needs to collect and evaluate ovulation characteristics, progesterone exposure, and adolescent CHC use, in addition to the complex variables that may influence risks for prevalent or incident fragility fractures and/or for cortical and cancellous aBMD values in PCOS.

KEYWORDS:

• Polycystic ovary Syndrome
• areal bone mineral density
• volumetric bone mineral density
• androgen excess
• ovulatory disturbances
• combined hormonal contraceptives
• prevalent fractures
• body mass index

Article highlights

• It is controversial whether Polycystic Ovary Syndrome (PCOS) influences bone health and fracture. PCOS is a pleomorphic condition in women (persons with ovaries of reproductive age, PORA), androgenic PCOS is diagnosed in 10% of the population who usually present with androgen excess and oligomenorrhea in late adolescence.

• Studies show PCOS is associated with similar or higher areal bone mineral density (aBMD) in the hip and total body but lower spine aBMD, especially in those who are not obese.

• Decreased ovulation and progesterone exposure in PCOS have not previously been considered as a potential risk for decreased bone formation, lower aBMD and increased prevalent and incident fracture risks.

• A controlled cohort study showed higher prevalent fractures occurrence in community-dwelling women with PCOS than in population-based age- and BMI-range similar controls.

• Meta-analysis data show that increased prevalent/past fractures are 25% higher in PCOS versus (often population-based) controls, although this did not reach statistical significance. Hypotheses that require testing are that higher prevalent fractures are related to lower bone formation from less ovulation/progesterone exposure plus use of combined hormonal contraceptives during adolescence, leading to decreased peak bone mass, as non-PCOS data document.

Acknowledgments

We deeply appreciate the energy and insights of Shirin Kalyan PhD, who as an Endocrine Research Associate was instrumental in obtaining CIHR funding, collecting the data, and analyzing the results for the important study showing the key roles of inflammation in bone in women with PCOS. She pioneered expressing inflammation as the ratio of C-reactive protein (CRP) to albumen (CRP/alb) because CRP increases with inflammation, while albumen decreases. Her demanding work as Vice-President of Innovation at Q Biologics ® prevented her from having time to review and co-author this manuscript. We also thank Millan Patel, MD, MSc, a clinical geneticist and bone expert who was instrumental in the two community PCOS studies (of eye and inflammation) and who was also then a leader in the local Canadian Multicentre Osteoporosis Centre. We also thank Dharani Kalidasan, MSc, for her steadfast support in all research but specifically for assisting with figures and tables and submission of this document.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The investigation received no funding other than donations to the Centre for Menstrual Cycle and Ovulation Research at the University of British Columbia.