LAUSR

Patients with dementia often fall and frequently fracture. Alzheimer’s disease (AD) is the most prevalent form of dementia, and patients with AD often have profound changes in body composition as the disease progresses, including the observed association between AD, osteoporosis, and greater fracture risk. In addition, fracture has been shown to be an independent risk factor for dementia. Although patientswith osteoporosis anddementia have increased risk formorbidity andmortality, those sufferingwith the twodiseasesmay experience evengreater consequences. For instance, the risk of hip fracture in those with dementia is increased by up to threefold, and for those with end-stage dementia who sustain a hip fracture, 6-month mortality was found to be 55% compared with 12% for cognitively intact patients (adjusted hazard ratio= 5.8). Thus dementia patients are not only at increased risk of fracture but also potentially at increased risk of mortality should they sustain a fracture. The reasons for the clinical association between dementia and osteoporosis may extend beyond their increased incidence with aging. Common risk factors apart from age include physical activity, vitamin D, and sarcopenia, and symptomatic treatments for AD can increase the risk for falls. Nevertheless, the current evidence establishing a causal link between the two diseases of aging has been limited, to a large extent, to cross-sectional studies, and there is a paucity of data implicating a common underlying biology. In this issue of JBMR, Bliuc and colleagues describe their study of the longitudinal association between cognitive decline and rate of bone loss. Their study included 1741 women and 620 men 65 years and older from the Canadian Multicentre Osteoporosis Study (CaMos) and had two aims: (i) to find the longitudinal relationship between cognitivedecline and rateof bone loss, and (ii) to determine if the rate of cognitive decline measured at the beginning of the study predicted future fracture risk. Cognitive decline was measured using Mini Mental State Examination (MMSE) scores, and the rate of bone loss was measured by the change in femoral neck dual-energy X-ray absorptiometry (DXA)-derived bone mineral density (BMD), with eachmeasure annualized based on at least twomeasurements. They conducted a 10-year studywith an additional 5 years of fracture follow-up, and models were adjusted for many covariates, including age, demographic variables, education, comorbidities, lifestyle factors, and Medical Outcome Study Short Form-36 components. The authors showed a significant association of decline in cognitive score with bone loss in women in multivariate-adjusted models with an estimated 6.5% (confidence interval [CI] 3.2–9.9%) decline in femoral neck BMD for each percentage point decline inMMSE from baseline. The association was smaller and not statistically significant in men. Additional significant covariates included age, height, activity level, prior fracture, and comorbidities. The authors thenmeasured the risk of osteoporotic fracture forwomenwith a cognitivedeclineof at least three points on theMMSE scale in the first 5 years of the study compared with women with minimal cognitive decline. Women with a three-point or more decline experienced an increased risk of osteoporotic fracture with a hazard ratio of 1.61 (95% CI 1.11–2.34) in a multivariable-adjusted model. This analysis was not performed in men because of insufficient sample size. The strong association between bone loss and dementia in women unexplained by a comprehensive set of confounders raises the possibility of an underlying biologic mechanism linking the two diseases. Estrogen exposure may be an important common factor as it has been linked to cognitive decline through either endogenous exposure (natural or surgical menopausal age) or treatment with exogenous hormone replacement therapy and has well-known associations with bone health. Indeed, studies often consider BMD as a measure of lifetime exposure to estrogen in measuring its impact on dementia and brain function. In addition to estrogen, immunological factors may contribute to both bone loss and dementia. In addition, bone-derived proteins and cells may influence AD progression, with AD progression associated with serum levels of the bone turnover markers osteopontin, osteocalcin, and sclerostin, and AD patients and patients with mild cognitive impairment (MCI) reporting higher levels of osteopontin that correlate with reduced BMD and cognitive decline. Also, AD or dementiarelated genes may impact bone or other peripheral systems. For instance, Bliuc and colleagues reference a study in which gene expression of the AD-related genes APP and BACE1 in the bone of hip fracture patients is positively associated with bone resorption and negatively associated with bone loss surrogate measures. In addition, TREM2 is mutated in Nasu-Hakola disease, causing lowbone density. This gene is also known to regulate osteoclastogenesis and is important in AD, especially in the microglia. The gene FNDC5, or Irisin, which results through cleavage of the protein precursor, has been shown to have exercise-mediated effects on bone and to have important effects in AD. Finally, the gene alpha synuclein (SNCA), which has well-known effects in Lewy body dementia and AD, has also shown effects in bone and in glucose regulation. Genetic approaches may be able to identify candidates for causal mechanisms and test causality. The shared genetic component (h) between femoral neck BMD and AD has been estimated to be 13% (standard error = 9.4%) as calculated using linkage disequilibrium (LD) score regression. In a recent genomewide association study (GWAS) of estradiol levels in men