Zoledronic acid and bone health in older adults with cognitive impairment.

Fracture prevention in cognitively impaired individuals is lacking. This work highlights the benefits of zoledronic acid on bone health in cognitively impaired older adults. Demonstrating benefits of therapy may increase treatment uptake and reduce fracture risk in this group. INTRODUCTION: Osteoporosis has detrimental consequences for frail older adults. The effects on those with both osteoporosis and cognitive impairment are compounded due to increased risk of falls and changes in mobility, both of which can lead to fracture. However, there are limited data on treatment benefits for osteoporotic individuals with cognitive impairment. METHODS: This post hoc, secondary analysis of data from a randomized, double-blind, placebo-controlled clinical trial of single-dose zoledronic acid included 179 women age ≥ 65 years residing in assisted living facilities or nursing homes, 43 of whom had mild to severe cognitive impairment. We assessed bone mineral density (BMD) of the total hip, femoral neck, and lumbar spine by dual-energy x-ray absorptiometry and serum bone turnover markers (C-terminal telopeptide of type I collagen and procollagen type I N propeptide) at 6 and 12 months. RESULTS: In participants with cognitive impairment, those who received zoledronic acid had 4.3% greater BMD at the total hip (p=.005) and 5.3% greater BMD at the femoral neck (p<.001) after 12 months compared to those in the placebo group. Bone turnover markers demonstrated significant decreases at 6 months in those with cognitive impairment who received active treatment compared to the placebo group. Improvements in bone health measures with zoledronic acid were similar to those seen in participants without cognitive impairment. CONCLUSION: Zoledronic acid improves bone health in frail older women with cognitive impairment similar to those without impairment. Further studies are warranted to assess the benefit for fracture reduction in this undertreated population.

Vitamin D deficiency is associated with functional decline and falls in frail elderly women despite supplementation.

We examined the impact of daily supplementation on vitamin D deficiency, function, and falls in female long-term care residents. Initial vitamin D deficiency was associated with greater functional decline and increased fall risk despite guideline-recommended supplementation, highlighting the importance of preventing vitamin D deficiency in frail elderly. INTRODUCTION: Institute of Medicine (IOM) guidelines recommend 800 IU vitamin D daily for older adults and maintaining serum 25-hydroxyvitamin D [25(OH) D] above 20 ng/ml for optimal skeletal health. The adequacy of IOM guidelines for sustaining function and reducing falls in frail elderly is unknown. METHODS: Female long-term care residents aged ≥65 enrolled in an osteoporosis clinical trial were included in this analysis (n = 137). Participants were classified based on baseline 25(OH) D levels as deficient (<20 ng/ml, n = 26), insufficient (20-30 ng/ml, n = 40), or sufficient (>30 ng/ml, n = 71). Deficient women were provided initial vitamin D repletion (50,000 IU D3 weekly for 8 weeks). All were supplemented with 800 IU vitamin D3 daily for 24 months. Annual functional assessments included Activities of Daily Living (ADLs), Instrumental ADL (IADL), physical performance test (PPT), gait speed, cognition (SPMSQ), and mental health (PHQ-9). We used linear mixed models for analysis of functional measures and logistic regression for falls. RESULTS: Daily supplementation maintained 25(OH) D levels above 20 ng/ml in 95% of participants. All groups demonstrated functional decline. Women initially deficient had a greater decline in physical function at 12 (IADL -2.0 ± 0.4, PPT -3.1 ± 0.7, both p < 0.01) and 24 months (IADL -2.5 ± 0.6, ADL -2.5 ± 0.6, both p < 0.01), a larger increase in cognitive deficits at 12 months (1.7 ± 0.4: p = 0.01) and more fallers (88.5%, p = 0.04) compared to those sufficient at baseline, despite supplementation to sufficient levels. CONCLUSIONS: IOM guidelines may not be adequate for frail elderly. Further study of optimal 25(OH) D levels for maintaining function and preventing falls is needed.

The effect of estradiol, progesterone, and melatonin on estrous cycling and ovarian aromatase expression in intact female mice.

OBJECTIVE: Melatonin and progesterone levels decline during the perimenopause. Both hormones inhibit estrogen action and endometrial cancer, but little is known about how they act in combination. Therefore, the interplay of progesterone (P4) and melatonin was investigated in intact female mice. STUDY DESIGN: Three P4 doses, low (25mg), mid (50mg), and high (100mg), combined with 0.5mg 17ß-estradiol (E), were administered in the diet (per 1800kcal) for 30 days. Hormone therapy (HT) with the low P4 dose (estradiol/low progesterone replacement therapy (EPLRT)) was used to create an excess estrogen environment to mimic perimenopause. Half the mice were treated with melatonin (M) 15mg/L in the drinking water at night. RESULTS: The unbalanced EPLRT treatment increased estrogen-regulated responses. Specifically, mice treated with EPLRT had significantly higher levels of ovarian aromatase mRNA versus control, which was prevented in the presence of higher doses of P4 and/or the addition of melatonin. The number of days in estrus also increased in EPLRT-treated versus control mice with no change in the length or number of complete estrous cycles. Melatonin, combined with all doses of P4, increased the number of days spent in estrus, but not the length or number of estrous cycles compared to melatonin alone; however, two-way ANOVA revealed a significant interaction between melatonin and P4 dose for days in estrus and for number of cycles. Although none of the E2 and P4 combinations significantly affected uterine weight compared to control, melatonin addition to the low or mid P4 HT resulted in slightly higher uterine weights compared to melatonin-treated mice. Melatonin significantly increased uterine estrogen receptor alpha (ERα) and progesterone receptor A levels compared to control animals. HT, added in combination with melatonin, reduced ERα levels back to control levels, but PR levels remained elevated albeit intermediary to those achieved with melatonin alone. CONCLUSION: The findings that melatonin supplementation inhibits ovarian aromatase expression and increases uterine receptors in mice given an HT that mimics perimenopause may have important clinical applications for the improvement of menopause-related conditions, like menorrhagia, associated with high levels of E2 and low levels of P4.