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Regional and Hormone‐Dependent Effects of Apolipoprotein E Genotype on Changes in Bone Mineral in Perimenopausal Women *

We studied 479 perimenopausal Danish women aged 45–58 years to examine differences between APOE genotypes with respect to (1) baseline total body bone mineral density (BMD) and densities measured in five different regions (ultradistal forearm, proximal forearm, lumbar spine, femoral neck, and total hip region); (2) serum levels of alkaline phosphatase, bone isoenzyme alkaline phosphatase, osteocalcin, parathyroid hormone (PTH), 25‐hydroxyvitamin D, and urine hydroxyproline/creatinine excretion ratio; and (3) changes in bone mineral during 5 years of follow‐up. Baseline BMDs were identical, whereas serum levels of alkaline phosphatase and its bone isoenzyme were higher in women with APOE 2–2 and APOE 2–3 than in women with APOE 3–3 and APOE 3–4 and lower in women with APOE 4–4. Among women not receiving hormonal‐replacement therapy (HRT; n = 262), those with APOE 2–2 and APOE 2–3 had 30–40% lower rates of femoral neck and total hip bone mineral loss than women with APOE 3–3 and APOE 3–4, whereas the rates of mineral loss in other skeletal regions did not differ between these APOE genotypes. Women with APOE 4–4 appeared to have lower rates of bone mineral loss in all regions. Women treated with hormones throughout the follow‐up period (n = 113) gained bone mineral, and women with APOE 3–4 and APOE 4–4 gained relatively more mineral than other women. A comparison of untreated and treated women with APOE 2–3, APOE 3–3, and APOE 3–4 suggests a possible modification of the effect of APOE genotype by HRT. In conclusion, the common APOE polymorphism has a complex effect on bone metabolism in perimenopausal Danish women including possible modification by hormone use: (1) among women not receiving HRT, those with APOE2 have lower bone mineral losses in the femoral neck and hip region than other women, and (2) among women receiving HRT, those with APOE4 gain more bone mineral than other women.