The first Japanese case with familial combined hypolipidemia without any complications caused by loss-of function variants in ANGPTL3: Case report.

Familial combined hypolipidemia, previously known as Familial hypobetalipoproteinemia 2 (FHBL2) is considered as an extremely rare recessive disease. Here, we present the case of familial combined hypolipidemia with homozygous loss-of function (LOF) variants in angiopoietin-like protein 3 (ANGPTL3) ((NM_014495.4) c.439_442del (p.Thr146_Asn147insTer)) using panel sequencing (46 yr male whose LDL cholesterol = 34 mg/dL). The serum level of ANGPTL3 was quite low (undetectable). Despite of extreme decreasing LDL cholesterol, this case did not have any complications as hypobetalipidemia (HBL), such as steatorrhea vomiting, hematological, neuromuscular, or ophthalmological symptoms. In addition, we did not find any systemic atherosclerosis in his carotid arteries and in coronary arteries. Based on the findings suggest that inhibition of ANGPTL3 effectively reduce LDL cholesterol without any apparent side effects, although it is still unclear if he will suffer any disadvantages because of this situation in the future.

Impact of changes in Achilles tendon thickening on cardiovascular events in patients with familial hypercholesterolemia.

Background: Achilles tendon thickening (ATT) can be ameliorated by lowering low-density lipoprotein (LDL) levels in patients with familial hypercholesterolemia (FH). The Japan Atherosclerosis Society (JAS) defines ATT as ≥8.0 mm in males and ≥7.5 mm in females. We aimed to determine the clinical impact of changes in ATT on the development of major adverse cardiovascular events (MACE). Methods: Patients with clinically diagnosed heterozygous FH (HeFH) (N = 1273; 614 males, 659 females) with ATT data from X-ray were assessed. Patients were divided into four groups: patients without ATT from baseline until follow-up (group 1), patients without ATT at baseline but developed ATT at follow-up (group 2), patients with ATT at baseline but regressed at follow-up (group 3), and patients with ATT from baseline until follow-up (group 4). Cox proportional hazard models were used to assess the factors associated with MACE, including cardiovascular death and any coronary events. Results: On follow-up (median: 10.9 years), 142 MACEs were observed, and the median ATT regressed from 7.8 to 7.6 mm. Changes in ATT were significantly associated with the occurrence of MACE in all groups, when compared to group 1 (hazard ratio [HR]: 2.73; 95 % confidence interval [CI]: 1.33-4.13 [p < 0.001], HR: 2.18, 95 % CI: 1.08-3.28, [p < 0.001], HR: 6.34, 95 % CI: 3.10-9.58, [p < 0.001], in groups 2, 3, and 4, respectively). Conclusions: Assessing ATT has diagnostic value and allows for risk stratification among patients with HeFH.

A Family with Familial Hypobetalipoproteinemia Caused by a c.1468C>T in APOB.

We herein report the first family of Japanese individuals with familial hypobetalipoproteinemia caused by the c.1468C>T mutation in apolipoprotein B (APOB). A 13-year-old boy with extremely low levels of low-density lipoprotein (LDL) cholesterol (24 mg/dL) was referred to our hospital. The patient had no secondary causes of hypobetalipoproteinemia. His father and grandmother also exhibited low LDL cholesterol levels. A genetic analysis confirmed that they all had this variant in APOB (c.1468C>T). None of the patients exhibited atherosclerotic cardiovascular diseases or any other complications associated with low LDL cholesterol levels, including fatty liver, neurocognitive disorders, and cerebral hemorrhaging.

Putative Pathogenic Variants of ABCG5 and ABCG8 of Sitosterolemia in Patients With Hyper-Low-Density Lipoprotein Cholesterolemia.

Objective: Sitosterolemia is a rare autosomal recessive disease caused by the deleterious variants of adenosine 5'-triphosphate (ATP)-binding cassette sub-family G member 5 (ABCG5) or ATP-binding cassette sub-family G member 8 (ABCG8). There are only few data on the pathogenicity of ABCG5 and ABCG8. This study aimed to propose a scheme for determining variant pathogenicity and to catalog the putative pathogenic variants in sitosterolemia. Methods: This study enrolled 377 consecutive Japanese patients with hyper-low-density lipoprotein cholesterolemia (mean age: 46.5±19.8 years, with 192 men) who have targeted-sequenced data on ABCG5 or ABCG8 (among 21 Mendelian lipid genes for any dyslipidemias) and serum sitosterol levels at Kanazawa University Hospital from 2016 to 2021. Serum sitosterol levels were divided by 0.79 in patients treated with ezetimibe, accounting for the average reduction with this drug. ABCG5 or ABCG8 variants were defined as putative pathogenic if associated with serum sitosterol levels ≥5 µg/mL or homozygous if associated with serum sitosterol levels ≥10 µg/mL. Results: Twenty-three ABCG5 or ABCG8 variants (16 missense, 2 nonsense, 2 frameshift, 2 deletion, and 1 splice mutation) were identified. Based on our definition, 11 putative pathogenic variants (median sitosterol level: 10.1 [6.5-17.1] µg/mL) were found in 36 individuals and 12 benign variants (median sitosterol: 3.5 [2.5-4.1] µg/mL) in 14 individuals. Conclusion: The scheme proposed for assessing the pathogenicity of genetic variations (ABCG5 and ABCG8) is useful. Using this scheme, 11 putative pathogenic, and 12 benign variants in ABCG5 or ABCG were classified.

Coronary artery calcium among patients with heterozygous familial hypercholesterolaemia.

Aims: We aimed to determine if coronary artery calcium (CAC) is associated with cardiovascular disease (CVD) events, defined as CVD-related death, unstable angina, myocardial infarction, or staged revascularization among patients with heterozygous familial hypercholesterolaemia (HeFH) under primary prevention settings. Methods and results: Data of patients with FH admitted to Kanazawa University Hospital between 2000 and 2020, who underwent CAC measurement and were followed up (n = 622, male = 306, mean age = 54 years), were retrospectively reviewed. Risk factors for CVD events were determined using the Cox proportional hazard model. The median follow-up duration was 13.2 years (interquartile range: 9.8-18.4 years). We observed 132 CVD events during the follow-up period. The event rate per 1000 person-years for CAC scores of 0 [n = 283 (45.5%)], 1-100 [n = 260 (41.8%)], and >100 [n = 79 (12.7%)] was 1.2, 17.0, and 78.8, respectively. Log (CAC score + 1) was a significant predictor of the occurrence of CVD events (hazard ratio: 3.24; 95% confidence interval: 1.68-4.80; P < 0.0001) in the multivariate Cox regression analysis, independent of other factors. The risk discrimination of CVD events was enhanced by adding CAC information to other conventional risk factors (C-statistics: 0.833-0.934; P < 0.0001). Conclusion: The CAC score helps in further risk stratification in patients with HeFH.

Impact of Healthy Lifestyle in Patients With Familial Hypercholesterolemia.

Background: Pathogenic mutations are associated with poor outcomes in patients with familial hypercholesterolemia (FH). However, data on the effects of a healthy lifestyle on FH phenotypes are limited. Objectives: The authors investigated the interaction between a healthy lifestyle and FH mutation with prognosis in patients with FH. Methods: We investigated the associations of the interaction between genotypes and lifestyle, with the occurrence of major adverse cardiac events (MACE), such as cardiovascular-related mortality, myocardial infarction, unstable angina, and coronary artery revascularization, in patients with FH. We assessed their lifestyle based on 4 questionnaires (healthy dietary pattern, regular exercise, not smoking, and absence of obesity). The Cox proportional hazards model was used to assess the risk for MACE. Results: The median follow-up duration was 12.6 (IQR: 9.5-17.9) years. During the follow-up duration, 179 MACE were observed. Independent of classic risk factors, FH mutation and lifestyle score were significantly associated with MACE (HR: 2.73; 95% CI: 1.03-4.43; P = 0.02; and HR: 0.69, 95% CI: 0.40-0.98, P = 0.033, respectively). The estimated risk of coronary artery disease by 75 years of age varied according to lifestyle, ranging from 21.0% among noncarriers with a favorable lifestyle to 32.1% among noncarriers with an unfavorable lifestyle and ranging from 29.0% among carriers with a favorable lifestyle to 55.4% among carriers with an unfavorable lifestyle. Conclusions: A healthy lifestyle was associated with reduced risk for MACE among patients with FH with or without genetic diagnosis.

Early diagnosis and treatments in childhood are associated with better prognosis in patients with familial hypercholesterolemia.

Objective: The early diagnosis and treatment initiation for children with familial hypercholesterolemia (FH) has been recommended in guidelines. However, there is limited data on the impact of early treatments on the prognosis of children with FH. To investigate if the early initiation of lipid-lowering therapies among Japanese pediatric patients with FH reduced the occurrence of cardiovascular disease (CVD) events in them. Methods: We retrospectively investigated the occurrence of CVD events (myocardial infarction, unstable angina, or coronary artery revascularization) in patients with FH (N = 1050, male/female = 490/560), including 106 children below 20 years. We compared a variety of phenotypes, including genetic backgrounds, other complications, LDL cholesterol, medical therapies, and their prognoses between the patients' diagnoses before the age of 20 years (children, mean age = 15 years) and after that age (adults, mean age = 52 years). Overall, 290 patients (27.6%) had a history of prior CVD events. Results: The median follow-up duration was 12.6 [9.5-17.9] years. The baseline LDL cholesterol level, 239 mg/dL, dropped to 112 mg/dL with the treatments. The Achilles tendon thickness was significantly lower in children than that of adults (7.2 vs. 8.9 mm, P < 0.001). Over the follow-up duration, 119 CVD events were observed. Importantly, no CVD event was observed in children despite their median LDL cholesterol level at follow-up being significantly higher than that of adults (122 vs. 111 mg/dL, P < 0.001). Conclusion: The likelihood of CVD events in those with FH diagnosed and treated in childhood is low.

Synergistic effect of lipoprotein (a) and C-reactive protein on prognosis of familial hypercholesterolemia.

Objective: The synergistic effect of lipoprotein (a) [Lp(a)] and C-reactive protein (CRP) on major adverse cardiovascular events (MACE) among patients with familial hypercholesterolemia (FH) is unknown. This study aimed to investigate the relations between Lp(a) and CRP levels and MACE in patients with FH whose Lp(a) levels are elevated. Methods: We retrospectively investigated associations between genotypes and phenotypes, including low-density lipoprotein (LDL) cholesterol level and the occurrence of MACE among patients with FH (N = 786, male/female: 374/412). A Cox proportional hazard model was used to identify factors associated with MACE, adjusting for traditional risk factors. Patients with FH were divided into four groups, based on their Lp(a) and CRP levels, and assessed using Kaplan-Meier curves. Results: The median follow-up was 12.6 years (interquartile range [IQR], 9.5-17.9 years). During follow-up, 129 MACE were observed. Median Lp(a) and CRP levels were 21.4 (10.9-38.3) mg/dL and 0.20 (0.11-0.29) mg/dL, respectively. Under these conditions, natural log-transformed Lp(a) and CRP were not associated with MACE (hazard ratio [HR], 1.08; 95% confidence interval [CI], 0.91-1.25; P = 0.220; and HR, 1.12; CI, 0.96-1.28; P = 0.190, respectively). However, in Group 4, Lp(a) and CRP were significantly associated with MACE (HR, 2.44; CI, 1.42-3.46; P = 1.8 × 10-7). Conclusions: In patients with FH, Lp(a) was significantly associated with MACE only when the CRP level was elevated. Patients with FH whose Lp(a) and CRP levels are elevated should be treated aggressively.

Impact of variants of uncertain significance of LDL receptor on phenotypes of familial hypercholesterolemia.

BACKGROUND: Data on the effect of variants of uncertain significance (VUS) of LDL receptor (LDLR) on familial hypercholesterolemia (FH) phenotype is limited. OBJECTIVE: To investigate the associations between genotypes and phenotypes, including low-density lipoprotein (LDL) cholesterol level and occurrence of major adverse cardiac events (MACEs), in FH patients (N = 1050, male/female = 490/560). METHODS: We retrospectively assessed the data of patients with FH admitted at Kanazawa University Hospital between 1990 and 2020. Based on genotype, the patients were divided into patients without variants, with VUS of LDLR, and with pathogenic variants. Cox proportional hazard model was used to identify the factors associated with MACEs. RESULTS: The median follow-up duration was 12.6 years (interquartile range: 9.5-17.9 years). Altogether, 777 patients had FH mutation and 273 had pathogenic mutation, with 92 having VUS. Over the follow-up duration, 175 MACEs were observed. LDL cholesterol level was found to be significantly higher in patients with pathogenic variants (251 mg/dL) than in patients with VUS (225 mg/dL) and without variants (203 mg/dL). Pathogenic variants and VUS are significantly associated with MACEs (hazard ratio [HR] = 1.52, 95% confidence interval [CI] = 1.02-2.02, P = 0.033 and HR = 3.18, 95% CI = 2.00-4.36, P = 1.9 × 10-5, relative to patients without any variants, respectively), independent of classical risk factors. CONCLUSION: VUS of LDLR was significantly associated with poor outcomes in FH patients. Genetic testing is useful for the diagnosis and risk stratification of FH patients.

Sitosterolemia.

Sitosterolemia is an inherited metabolic disorder characterized by increased levels of plant sterols, such as sitosterol. This disease is caused by loss-of-function genetic mutations in the ATP-binding cassette (ABC) subfamily G member 5 or member 8 (ABCG5 or ABCG8, respectively), both of which play important roles in the selective excretion of plant sterols from the liver and intestine, leading to a failure to excrete plant sterols. Sitosterolemia, which is currently considered a rare genetic disorder, has been described as a phenocopy of homozygous familial hypercholesterolemia (FH). Typical phenotypes of sitosterolemia, including elevated low-density lipoprotein (LDL) cholesterol, tendon xanthomas, and premature coronary artery disease, overlap those of homozygous FH; however, there are substantial differences between these two diseases in terms of treatments and prognoses. Moreover, it is of note that sitosterolemia appears to be quite underdiagnosed, although accurate diagnosis and appropriate interventions will likely to lead to better prognoses compared with homozygous FH. Unlike cases of homozygous FH, dietary counseling is quite effective in reducing the LDL cholesterol as well as sitosterol of patients with sitosterolemia. In this chapter, we summarize the current understandings of this disease and provide useful tips for the diagnosis as well as better treatment of patients with sitosterolemia.

Case Report: Myocarditis Associated With COVID-19 mRNA Vaccination Following Myocarditis Associated With Campylobacter Jejuni.

We herein present our experience with a case involving a 17-year-old Japanese boy suffering from acute myocarditis after his second coronavirus disease-2019 (COVID-19) messenger RNA (mRNA) vaccine shot. The patients had a history of myocarditis associated with Campylobacter jejuni 3 years prior. This has been the first-ever documented case of myocarditis associated with COVID-19 mRNA vaccination in a patient with a history of myocarditis. We present a series of images and blood biomarkers for different types of myocarditis that developed in this single patient.

Effects of Different Types of Pathogenic Variants on Phenotypes of Familial Hypercholesterolemia.

Objective: It has been shown that pathogenic variants are associated with poor clinical outcomes in patients with familial hypercholesterolemia (FH). However, data on the effect of different types of pathogenic variants on FH phenotype is limited. Methods: We retrospectively investigated the associations between genotypes and phenotypes, including low-density lipoprotein (LDL) cholesterol level and the occurrence of major adverse cardiac events (MACEs), defined as cardiovascular death, myocardial infarction, unstable angina, or coronary artery revascularization, in patients with FH (N = 1,050, male/female = 490/560). Based on genotype, the patients were divided into the following three groups: patients without pathogenic variants, patients with missense variants, and patients with protein-truncating variants (PTVs). Cox proportional hazard model was used to identify the factors associated with MACEs. Results: The median follow-up duration was 12.6 years (interquartile range = 9.5-17.9 years). There were 665 patients with FH-mutation (277 patients with missense variants and 388 patients with PTVs) and 385 patients without FH-mutation. Over the follow-up duration, 175 MACEs were observed. We identified 89 different pathogenic variants in the 665 patients with FH. LDL cholesterol level was found to be significantly higher in patients with PTVs (256 mg/dl) than in patients with missense variants (236 mg/dl) and patients without pathogenic variants (216 mg/dl). It was also found that PTVs and missense variants are significantly associated with MACEs (hazard ratio [HR] = 1.58, 95% confidence interval [CI] = 1.08-2.08, p = 0.0033 and HR = 3.24, 95% CI = 2.12-4.40, p = 3.9 × 10-6, respectively), independent of classical risk factors. Conclusion: Pathogenic variants, especially PTVs, are significantly associated with poor outcomes in patients with FH. Genetic testing is useful for the diagnosis and risk stratification of patients with FH.

Clinical and genetic features of sitosterolemia in Japan.

BACKGROUND AND AIM: Clinical manifestations and genetic backgrounds of Japanese patients with sitosterolemia have been unclear. MATERIALS AND METHODS: We searched PubMed for studies using the keywords "sitosterolemia" or "phytosterolemia" and "Japan". Moreover, we added information from the members of the Committee on Primary Dyslipidemia under the Research Program on Rare and Intractable Disease of the Ministry of Health, Labour and Welfare (MHLW) of Japan. RESULTS: We identified 36 patients with sitosterolemia caused by biallelic pathogenic mutations in the ATP-binding cassette subfamily G member 5 (ABCG5) or ATP-binding cassette subfamily G member 8 (ABCG8) from 31 families in Japan. The diagnosed age ranged from 0 to 64 years (median 13 years). The median sitosterol and LDL cholesterol levels were 100 µg/ml (IQR: 50-183), and 193 mg/dl (IQR: 108-295), respectively. All the patients exhibited cutaneous and/or tendon xanthomas, up to 9 (25%) patients exhibited premature coronary artery disease, 5 (16%) patients exhibited arthritis, and 8 (22%) patients exhibited blood abnormalities. Ezetimibe was administered to all the patients, including infantile cases, while statins, colestimide, evolocumab, probucol, and LDL apheresis were also used. CONCLUSION: We are providing a demographic overview of the clinical and genetic backgrounds of Japanese patients with sitosterolemia.

Prevalence and Impact of Apolipoprotein E7 on LDL Cholesterol Among Patients With Familial Hypercholesterolemia.

Background: It has been suggested that a rare mutant apolipoprotein E7, APOE7 (p.Glu262Lys, p.Glu263Lys), has been identified to be associated with hyperlipoproteinemia in the general population. Moreover, its prevalence has been shown to be 0.005-0.06%. However, there are no prior data regarding its prevalence and impact on serum lipids in patients with familial hypercholesterolemia (FH). Methods: We recruited 1,138 patients with clinically diagnosed FH [mean age = 48, men = 512, median low-density lipoprotein (LDL) cholesterol = 231 mg/dl]. The coding regions of three FH genes (LDLR, APOB, and PCSK9) and apolipoprotein E (APOE) gene were sequenced. We investigated the prevalence and impact of APOE7 mutant on serum lipid levels in patients with FH. Results: We identified 29 patients (2.5 %) with a mutant APOE7 (heterozygote), which is apparently much higher than that of the general population. Moreover, when we focus on those without FH mutation (n = 540), we identified 21 patients (3.9 %) with a mutant APOE7. Patients with a mutant APOE7 exhibited significantly higher median LDL cholesterol and triglyceride levels compared with those without this rare mutant (249 vs. 218 mg/dl, p < 0.05, 216 vs. 164 mg/dl, p < 0.05, respectively). Moreover, LDL cholesterol levels in the APOE7-oligogenic FH individuals, with a pathogenic mutation in FH genes and APOE7 mutant, were significantly higher than that in monogenic FH patients (265 vs. 245 mg/dl, p < 0.05). Conclusion: We identified more patients with a mutant APOE7 than expected among those diagnosed with FH clinically, especially among those without FH-causing mutation. This implies a mutant APOE7 may be one of the causes FH, especially among those without FH mutations.

Serum sitosterol level predicting ABCG5 or ABCG8 genetic mutations.

BACKGROUND: Currently, serum concentrations of sitosterol above 10 µg/ml are considered to be one of the major diagnostic criteria of sitosterolemia. METHODS: We retrospectively investigated consecutive 206 Japanese dyslipidemic subjects (mean age = 46 yr, male n = 94) with the assessments of serum sitosterol level and the presence of ABCG5 or ABCG8 genetic mutations in our institute since 2009-2018. We divided the subjects into 3 groups based on the number of pathogenic mutations in ABCG5 or ABCG8 genes. We compared serum lipids and serum sitosterol among those groups, and tried to validate the cutoff value discriminating patients of sitosterolemia with double mutations from others. RESULTS: We identified 8 individuals with sitosterolemia with double mutations (affected), 26 individuals with a single mutation (carrier), and 172 individuals without any mutations (wildtype control). Serum sitosterol level of patients with sitosterolemia with double mutations (affected) exhibited significantly higher than those of any other groups (45.2. vs. 7.9 µg/ml, p = 2.5 × 10-2, 45.2 vs. 3.1 µg/ml, p = 1.8 × 10-2). Under these conditions, a cutoff value of sitosterol 10 µg/ml could discriminate the patients with sitosterolemia with double mutations in ABCG5 or ABCG8 gene from no mutation carrier (wildtype control) perfectly, although 6 heterozygous mutation carries exhibited sitosterol level greater than 10 µg/ml. Receiver-operating characteristic (ROC) analysis predicting double mutation status showed that the best cut-off value was 14.81 µg/ml. CONCLUSION: We suggest a cutoff value of sitosterol 15 µg/ml that shows higher positive predictive value than 10 µg/ml.

Major causes of impractical brachytherapy in elderly patients with uterine cervical cancer.

AIM: Incomplete brachytherapy is a major risk factor for recurrence. However, high-dose-rate intracavitary brachytherapy has not been assessed adequately in elderly patients with invasive cervical cancer. The present study investigated the clinical importance of intracavitary brachytherapy and risk factors of incomplete intracavitary brachytherapy in elderly patients with cervical cancer. MATERIAL AND METHODS: Subjects were 76 patients aged 70-89 years old with invasive cervical cancer. All subjects were recruited between January 1997 and September 2010, and were planning to receive external beam radiation therapy followed by high-dose-rate intracavitary brachytherapy. Survival rates and the incidence of complications were compared between the 70s and 80s age groups. Risk factors for recurrence in elderly patients were evaluated using multivariate analysis, and risk factors for impractical intracavitary brachytherapy were also estimated. RESULTS: No significant differences were observed in 3-year progression-free survival rates or the incidence of complications in the two age groups. Cox multivariate analysis showed that histology (non-squamous cell carcinoma), incomplete intracavitary brachytherapy, and lymph node swelling were significant prognostic factors for recurrence. Impractical application was the major reason for incomplete treatment. Multiple logistic regression analysis revealed that a previous history without vaginal births (P = 0.016) was an independent risk factor for the impractical application, independent of tumor diameter ≥ 4 cm (P = 0.007). CONCLUSIONS: Incomplete intracavitary brachytherapy decreased the survival rates of elderly patients. Larger tumors and patients without a history of vaginal births were the two major causes of impractical intracavitary brachytherapy, which may be fatal, especially in elderly patients with bulky tumors.

Clinical usefulness of Mohs' paste for genital bleeding from the uterine cervix or vaginal stump in gynecologic cancer.

BACKGROUND: Atypical genital bleeding due to gynecologic cancer not only impairs patients' quality of life (QOL), but also becomes a major causative factor of death. We report the clinical usefulness of Mohs' paste for genital bleeding from the uterine cervix or vaginal stump in patients with recurrent gynecologic cancer. METHOD AND RESULTS: Eight patients with gynecologic cancer were enrolled between January 2010 and March 2012. Mohs' paste was directly applied to the bleeding tumor. In patients with recurrent genital bleeding after the application of Mohs' paste, the technique was repeated. The effect of this procedure continued for 4 days to 1 year. The effect of Mohs' paste continued for 3 months or more in three patients. None of the eight patients have died of genital bleeding. CONCLUSIONS: The use of Mohs' paste is safe and convenient for massive genital bleeding from the uterine cervix or vaginal stump due to recurrent gynecologic cancer. However, our study does have some limitations including the small number of enrolled subjects and heterogeneous cancer types.

Cross-sectional study of the effects of parturition and lactation on bone mineral density later in life.

OBJECTIVE: The present cross-sectional study investigated the effects of parturition and lactation on bone mineral density (BMD) later in life. METHODS: The subjects were 456 premenopausal and 713 postmenopausal Japanese women aged 40-69 years old. They were classified into six subgroups at 5-year increments. Age, height, weight, menopausal status, age at menopause (in postmenopausal women), years since menopause (in postmenopausal women), parity, and total lactation period were recorded. Lumbar spine BMD (L2-4) was measured by dual-energy X-ray absorptiometry (DEXA). In each subgroup, correlations of parturition and lactation with BMD were investigated using Pearson's correlation test and multiple regression analyses. RESULTS: In premenopausal women aged 40-44 years old (n=143), total lactation period was inversely correlated with BMD (r= -0.293, P<0.01). This relationship remained significant after adjusting for age, height, weight, and parity (P<0.05). Although the total lactation period was inversely correlated with BMD in the group aged 60-64 years old (r= -0.194, P<0.05, n=218), this relationship disappeared after adjusting for age, YSM, height, weight, and parity. However, in the other subgroups, there were no significant correlations between total lactation period and BMD. There were no significant correlations observed between parity and BMD in any groups. CONCLUSION: Reproductive history of lactation and parity does not seem to be a major determinant of BMD later in life.