A Perspective on Postmenopausal Bone Loss with Aging

Low bone mineral density (BMD) is a major risk factor for hip, spine, and other osteoporotic fractures. Therefore, BMD testing using dual-energy X-ray absorptiometry (DXA) is recommended as part of fracture risk assessment in postmenopausal women aged 65 years and older in most treatment guidelines, including the National Osteoporosis Foundation (NOF), the Endocrine Society, the International Society for Clinical Densitometry (ISCD), Associations of Clinical Endocrinologists (AACE), and United States Preventive Services Task Force (USPSTF). Greater postmenopausal bone loss more quickly leads to osteoporotic BMD and so screening with serial DXA is important. However, the optimal interval for repeating DXA scans to reassess BMD and fracture risk is uncertain, and this should be informed by the expected change in BMD over time. In this issue of the JBMR, Moilanen and colleagues attempt to fill this evidence gap by examining the long-term changes in femoral neck BMD after menopause in 2695 women from the Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE) study. Baseline mean age was 53 years. Participants had DXA scans at baseline and every 5 years for a duration of up to 25 years— the longest timeframe reported in the literature. Baseline femoral neck BMD was normal. Careful cross-calibrations were performed between DXA scans over time to account for changes in densitometers. Self-reported risk factors and health conditions were also obtained by questionnaires at 5-year intervals. Although follow-up was fairly complete over the first 15 years, about 50% of women were lost to follow-up by 20 years and 75% by 25 years. Mortality and long-term care institutionalization account for 35% of all dropouts. The study reported a mean femoral neck bone loss of 10% (0.4%/year), which was constant over the 25 years. Notably, menopausal hormone therapy (HT) along with larger weight gain were protective of bone loss. The Study of Women’s Health Across the Nation (SWAN) has shown that bone loss begins 1 year before the final menstrual period, accelerates over the next 2 years, and continues at a slightly reduced rate over the next 5 years. In various studies including SWAN, the rate of femoral neck bone loss appears largely steady up to 15 years after menopause. However, the degree of bone loss with aging, particularly after age 65 years, is less certain. A study by Ensrud and colleagues, which included 5689women over 65 years of age with longitudinal BMD measurements by DXA over an average of 3.6 years, found that annual rate of loss in hip BMD almost tripled between ages 65 and 69 years ( 0.35%/year) and ages over 85 years ( 1.00%/year). Other studies have also shown similar accelerations in rates of bone loss with aging after age 65 years. Various processes likely contribute to the accelerated bone loss including decreased physical activity, comorbidities, and lower metabolic functions. This acceleration in femoral neck bone loss is consistent with the exponential increase in hip and spine fracture risk after age 65 years. Although Moilanen and colleagues found an overall linear trend in femoral neck BMD loss over 25 years, there was a slightly higher loss between 15 and 25 years after baseline ( 6.0%) than the first 10 years from baseline ( 4.7%), which is consistent with the study by Ensrud and colleagues. The study by Moilanen and colleagues is unique in having 25 years of follow-up, whereas most other studies have had only as much as 3 to 5 years of follow up. The only other long-term study was by Zhai and colleagues, which followed a cohort of 1003 women from Chingford, UK, with a mean enrollment age of 55 years for 15 years. Both studies found that BMD loss at the hip continues with age, although Zhai and colleagues found a somewhat larger loss in femoral neck BMD in the Chingford cohort at 1.7%/year ( 0.8% after covariate adjustment) over the 15 years. The disparity could likely be explained by the differences in two study populations such as diet, exercise, body mass index (BMI), use of HT, and other medications. Furthermore, there are several aspects of the study by Moilanen and colleagues that may have led to an underestimate of the rate of bone loss. A major limitation of the 25-year longitudinal data was that a near 75% of the women initially recruited were lost to follow-up. The most common reasons mentioned by the authors included death, relocation to long-term care facilities, and age-related reasons for withdrawal. Assuming that bone loss would be higher in older women, a substantial participant loss among older women would result in an underestimate of the true bone loss rate. Another potential reason for an underestimate of bone loss is the lack of accounting for use of osteoporosis medications, such as bisphosphonates. The first aminobisphosphonates (alendronate and soon after risedronate) became available in 1996, which was about 7 years into the 25-year follow-up, and it would seem very likely that among this cohort, with frequent BMD measurements, those with lower BMDwould have adopted treatment. Moilanen and colleagues did not account for these medications, which would result in a lower rate of bone loss compared to what would have been observed if no women were treated. In addition, the large proportion of women taking HT (23.8%) in the study by Moilanen and colleagues might also have decreased the apparent bone loss from a treatment naïve population. These factors might not only account for the lower rate of bone loss compared to the Chingford cohort but may also have masked an acceleration in bone loss with aging. Nevertheless, Moilanen and colleagues confirmed an essential observation that bone loss at the hip continues with age.