Beta-thalassemia trait: an underrecognized risk for osteoporosis in postmenopausal women, warranting screening

Secondary Causes of Osteoporosis

To determine the prevalence of secondary causes of bone loss among patients with breast cancer with osteopenia and osteoporosis. All women referred to a bone health clinic over a 6-year period for bone evaluation were included in this retrospective study and stratified based on presence or absence of a breast cancer history. The prevalence of secondary causes of bone loss in the two groups was compared. Of the 238 women identified, 64 women had breast cancer. The non-breast cancer group (n = 174) was significantly older (P = .015), had a lower mean weight (P = .019), lower 25 hydroxy-vitamin D level (P = .019), and greater degree of bone loss in both the spine and hip (P < .001 and 0.004, respectively). The presence of at least one secondary cause of bone loss, excluding cancer-related therapies, was seen in 78% of the breast cancer patient group and in 77% of the non-breast cancer group (P = not significant). Newly diagnosed metabolic bone disorders were seen in 58% of the breast cancer population. The most common was vitamin D deficiency, seen in 38% of patients in the breast cancer group and 51% of patients in the non-breast cancer group. Idiopathic hypercalciuria was diagnosed in 15.6%, primary hyperparathyroidism in 1.6%, and normocalcemic hyperparathyroidism in 3.1% of the breast cancer population. A high prevalence of secondary causes of bone loss among patients with breast cancer supports a comprehensive evaluation in these patients, particularly those considering therapy with an aromatase inhibitor.

e11019 Background: We previously demonstrated that treatable secondary causes of bone loss (SCBL) are prevalent in breast cancer survivors (Camacho, JCO 2008). SCBL may amplify bone loss caused by aromatase inhibitors (AIs) or compromise response to bisphosphonates (BPs). Goals of our study were to determine the frequency of screening for osteoporosis and SCBL in patients (pts) enrolling onto clinical trials involving AIs or BPs, and to determine the prevalence of SCBL in this population. Methods: A retrospective chart review of pts enrolled between 2003-2009 in clinical trials involving treatment with AIs (MA-27, NSABP B-35, SWOG 0226, SOFT, MAP-3) and BPs (SWOG 0307, SWOG 0702) was conducted at a single institution. Charts were reviewed for bone density assessment with dual energy x-ray absorptiometry (DXA scan), and for SCBL including 25OH-vitamin D (25 OHD), parathyroid hormone (PTH) panel, thyroid stimulating hormone (TSH), 24 hr urine for calcium and creatinine. The WHO criteria were used to categorize pts into normal (T score ≥ -1), osteopenia, (T score <-1) and osteoporosis (T score ≤ -2.5) groups. Only MAP-3 study (9 pts) required DXA scan prior to enrollment. None of the studies required screening for SCBL. Results: Ninety-three charts were reviewed (58 on AI trials; 35 on BP trials). Overall 69/93 (74%) pts had DXA scans performed: 52/58 (88%) on AI and 17/35 (49%) on BP trials. Osteopenia was present in 26/52 (50%) pts on AI and 9/17 (53%) pts on BP trials. Ten (11%) pts had osteoporosis. 25 OHD levels were obtained in 45 (48%) pts, PTH in 30 (32%) pts, 24hr urine for calcium and creatinine in 19 (20%) pts, TSH in 29 (31%) pts. Of those pts screened, 24 (53%) had vit D deficiency, 6 (20%) had hyperparathyroidism, 2 (6%) had idiopathic hypercalciuria, and 1 (3%) had hyperthyroidism. Average time to screening for SCBL was 23 months. Conclusions: Osteopenia/porosis is common in patients enrolling onto clinical trials involving AIs and BPs. Screening for treatable SCBL occurs in the minority of patients, though the prevalence is high. Comprehensive evaluation of bone loss may be warranted prior to initiating AI or BP therapy. No significant financial relationships to disclose.

Evaluation of Secondary Causes of Bone Loss in a Primary Care Setting

Introduction: There are limited data and consensus regarding bone mineral density (BMD) monitoring, and management of bone loss in younger women with breast cancer (BC). Adjuvant endocrine therapy for estrogen receptor positive (ER+) BC may include ovarian function suppression (OFS) plus use of aromatase inhibitors (AIs) for 5-10 years, both of which contribute to bone loss. The WHO risk prediction tool FRAX does not include BC or AI use as independent risk factors in its calculation thus underestimating risk of fracture. This study aims to evaluate current screening and management of bone health in young women with BC. Methods: A retrospective, IRB-approved chart review was performed in consecutive women ≤40 with BC diagnosed at Loyola University Chicago Medical Center between 01/01/2015 and 12/13/17. Demographic data, BC treatment, and factors contributing to secondary causes of bone loss were collected through 4/1/18. A descriptive analysis included summary values for all categorical and continuous risk factors. Results: BC ≤40yrs was identified in 136 women; 18 were excluded due to missing data. The analysis was performed on 118 patients (pts). Mean pt age was 34.6 yrs (SD 4.7). Stage at diagnosis included: stage 0 = 9 (7.6%), stage 1 = 26 (22%), stage 2 = 44 (37.3%), stage 3 = 23 (19.5%), stage 4 = 7 (5.9%), unknown = 9 (7.6%). Seventy-nine (67%) had ER+ BC; 32 (27.1%) had HER2-positive disease. The majority of pts (101, 85.6%) received chemotherapy in their treatment plan. Menopause was documented in 69 (59.0%) pts. Goserelin was used in 31 pts (44.9%), oophorectomy in 17 (24.6%), both in 5 (7.2%). Tamoxifen was used in 44 (55.7%) ER+ pts; 34 (43.0%) received an AI, and 18 (22.8%) received sequential tamoxifen and AI. 25 Hydroxy-Vitamin D (25 OHD) levels were checked in 61 (51.7%); 43 (70.5%) had levels &amp;lt;30 ng/ml; 24 (55.8%) received vitamin (vit) D supplementation. There was no difference in the 25 OHD in pre- and post-menopausal women (p=0.64). Pts with vit D deficiency had a median BMI of 26.8 vs 23.8 in those with sufficient vit D levels (exact p=.049). Secondary diagnoses contributing to low BMD were identified in 14 (11.8%). Dual energy xray absorptiometry (DXA) scans were checked in 23 pts (19.7%), 18 of whom were post-menopausal. At the femur, 0 pts had a z-score (age-matched standard deviation) of ≤-2.0, 9 pts (39.1%) had a score between 0 to -2.0. At the lumbar spine, 1 pt (4.3%) had a z-score ≤-2.0, 9 pts (39.1%) had a z-score between 0 to -2.0. No T-scores were in the osteoporosis range; 11 pts had T-scores at both femur and lumbar spine in the osteopenia range. The median 10 yr probability of a major osteoporotic fracture (FRAX score) was 1.9% (1.6-2.7%); the median 10 yr probability for hip fracture was 0.1% (0.10-0.20%). There were no differences in FRAX scores between pre- and post-menopausal women. No fractures were reported in the time period studied. Anti-resorptive therapy was used only in patients with metastatic bone disease. Conclusions: 25 OHD and DXA scans are not routinely checked in younger women diagnosed with BC. Vit D deficiency and evidence of bone loss is prevalent in those pts who do undergo testing. Further research and guidelines are necessary to address management of bone health in young women with BC to minimize future fracture risk and morbidity. Citation Format: Wendell KB, Nadeem S, Martin B, Camacho PM, Albain KS, Robinson P, Lo SS. Bone health in young women with breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-16-10.

Secondary Causes of Osteoporosis

Recent studies have suggested that hyperhomocysteinemia and low plasma folate are associated with fracture and also bone mineral density (BMD) and that they may contribute to the pathogenicity of osteoporosis in postmenopausal women. However, as plasma total homocysteine (tHcy) and plasma folate can be regarded as short-term markers when compared to a long-term variable such as BMD, in this study we tested the hypothesis that low red blood cell 5-methyltetrahydrofolate (RBC 5-MTHFR) as a long-term marker of the folate status may be a better predictor of BMD than plasma 5-MTHF, and its deficiency may contribute to the pathogenicity of osteoporosis in postmenopausal Iranian women. The BMD at the femoral neck and lumbar spine (measured by dual-energy X-ray absorptiometry, DXA) together with anthropometric and biochemical components of the homocysteine re-methylation pathway including plasma tHcy, 5-MTHF and vitamin B12, RBC 5-MTHF and creatinine were determined in 366 postmenopausal women. RBC 5-MTHF was more highly correlated with BMD at the lumbar spine (r=0.21, P=0.001) and femoral neck (r=0.19, P=0.004) than was plasma 5-MTHF (lumbar spine; r=0.14, P=0.03 and femoral neck; r=0.17, P=0.006). Stepwise multiple linear regression analyses revealed that RBC 5-MTHF was one of the predictors of BMD explaining 4.3 and 4.0% variance of BMD at the lumbar spine and femoral neck, respectively, whereas plasma 5-MTHF was excluded in the model and not determined to be a predictor of BMD at both the lumbar spine and femoral neck when adjusted for age, BMI, years since menopause and RBC 5-MTHF. This study suggests that RBC 5-MTHF is a better predictor of BMD than plasma 5-MTHFR when compared to a long-term marker such as BMD, and its deficiency is associated with low BMD that may contribute to the pathogenicity of osteoporosis in postmenopausal women.

BackgroundStudies on the association of gestational diabetes mellitus (GDM) with osteoporosis, and bone mineral density (BMD) have been inconsistent. The aim of this study was to investigate the association of a history of GDM with osteoporosis, BMD, and trabecular bone score (TBS) in postmenopausal women.MethodsPostmenopausal women from the National Health and Nutrition Examination Survey (NHANES) between 2007 and 2010, between 2013 and 2014, and between 2017 and 2018 were retrospectively included in this cross-sectional study. The logistic regression model was used to explore the relationship between GDM and osteoporosis, and a weighted linear regression model was applied to investigate the association between GDM and total femoral BMD, femoral neck BMD, and total TBS. Subgroup analysis of the association between GDM and osteoporosis was performed according to age, body mass index (BMI), and DM (yes or no).ResultsOf the 6732 women included, 253 women (3.76%) had GDM. No significant differences in total femoral BMD, femoral neck BMD, and total TBS were observed between postmenopausal women with and without a history of GDM. However, a history of GDM was associated with a higher risk of osteoporosis in postmenopausal women [odds ratio (OR): 11.18, 95% confidence intervals (CI): 3.64 to 34.27, P < 0.001]. There was no significant difference between a history of GDM and osteoporosis in postmenopausal women whom BMI is normal and overweight women. However, there was an association between a history of GDM and osteoporosis in postmenopausal obese women (OR: 26.57, 95% CI 10.23 to 68.98, P < 0.001).ConclusionA history of GDM was associated with a higher risk of osteoporosis in postmenopausal women, particularly in postmenopausal obese women.

BACKGROUND AND OBJECTIVES:Osteoporosis is a common disease of the elderly, in which genetic and clinical factors contribute to the disease phenotype. Since the production of interleukin-1 (IL-1) has been implicated in the bone mass and skeletal disorders, we investigated whether IL-1 system gene polymorphisms are associated with the pathogenesis of osteoporosis in postmenopausal Taiwanese women.METHODS:Osteoporosis is diagnosed by dual-energy x-ray absorptiometry, which measures bone mineral density (BMD) at multiple skeletal sites. We studied the IL-1α (-889C/T), IL-1β (-511C/T) and the 86 base pair variable number tandem repeat (VNTR) in intron 2 of the IL-1 receptor antagonist (IL-1ra) gene in 117 postmenopausal women with osteoporosis and 135 control subjects without a history of symptomatic osteoporosis. These gene polymorphisms were analyzed by polymerase chain reaction and restriction fragment length polymerase. Blood sugar and other risk factors were also determined.RESULTS:The frequencies of IL-1β (-511C/T) genotypes (P=.022, odds ratio=1.972) and alleles (P=.02, odds ratio=2.909) showed a statistically significant difference between the two groups. However, we did not find any statistically significant difference in IL-1α and IL-1ra polymorphisms (P>.05). We also observed a positive relationship between osteoporosis and cholesterol and a weak inverse relationship between blood sugar and osteoporosis in postmenopausal women.CONCLUSIONS:These experimental results suggest that the pathogenesis of osteoporosis is associated with IL-1β (-511C/T) polymorphism in postmenopausal women. This polymorphism is an independent risk factor for osteoporosis.

PurposeAs an important public health problem, osteoporosis (OP) in China is also in an upward trend year by year. As a standard method for diagnosing OP, dual-energy X-ray absorptiometry (DXA) cannot analyze the pathological process but only see the results. It is difficult to evaluate the early diagnosis of OP. Our study was carried out through a serum metabolomic study of OP in Chinese postmenopausal women on untargeted gas chromatography (GC)/liquid chromatography (LC)–mass spectrometry (MS) to find possible diagnostic markers.Materials and Methods50 Chinese postmenopausal women with osteoporosis and 50 age-matched women were selected as normal controls. We first used untargeted GC/LC-MS to analyze the serum of these participants and then combined it with a large number of multivariate statistical analyses to analyze the data. Finally, based on a multidimensional analysis of the metabolites, the most critical metabolites were considered to be biomarkers of OP in postmenopausal women. Further, biomarkers identified relevant metabolic pathways, followed by a map of metabolic pathways found in the database.ResultsWe found that there may be metabolic pathway disorders like glucose metabolism, lipid metabolism, and amino acid metabolism in postmenopausal women with OP. 18 differential metabolites are considered to be potential biomarkers of OP in postmenopausal women which are a major factor in metabolism and bone physiological function.ConclusionThese findings can be applied to clinical work through further validation studies. It also shows that metabonomic analysis has great potential in the application of early diagnosis and recurrence monitoring in postmenopausal OP women.

Low vitamin D levels may contribute to hip fractures in women, although limited data are available on vitamin D levels in US women admitted with acute hip fractures. To determine whether postmenopausal women with hip fractures have low vitamin D and high parathyroid hormone levels compared with nonosteoporotic and osteoporotic women admitted for elective joint replacement. Comparative case series conducted between January 1995 and June 1998. Ninety-eight postmenopausal community-dwelling women with no secondary causes of bone loss admitted for hip replacement, of whom 30 women had acute hip fractures and 68 women were admitted for elective joint replacement. Of the women admitted for elective joint replacement, 17 had osteoporosis and 51 did not. Women with comorbid conditions or who were taking medications that affect bone density and turnover were excluded. Primary measures were levels of vitamin D and parathyroid hormone; secondary measures were body composition and markers of bone turnover. Women with hip fractures had lower levels of 25-hydroxyvitamin D than women without osteoporosis admitted for elective joint replacement (P = .02) and than women with osteoporosis admitted for elective joint replacement (P = .01) (medians, 32.4, 49.9, and 55.0 nmol/L, respectively; comparisons adjusted for age and estrogen intake). Parathyroid hormone levels were higher in women with fractures than women in the nonosteoporotic control group (P<.001) or than elective osteoporotic women (P = .001) (medians, 5.58, 3.26, and 3.79 pmol/L, respectively; comparisons adjusted for age and estrogen intake). Fifteen patients (50.0%) with hip fractures had deficient vitamin D levels (< or =30.0 nmol/L) and 11 (36.7%) had a parathyroid hormone level greater than 6.84 pmol/L. Levels of N-telopeptide, a marker of bone resorption, were greater in the women with hip fractures than in the elective nonosteoporotic controls (P = .004). Postmenopausal community-living women who presented with hip fracture showed occult vitamin D deficiency. Repletion of vitamin D and suppression of parathyroid hormone at the time of fracture may reduce future fracture risk and facilitate hip fracture repair. Because vitamin D deficiency is preventable, heightened awareness is necessary to ensure adequate vitamin D nutrition, particularly in northern latitudes.

A general knowledge of secondary causes of bone loss and osteoporosis is useful and necessary in the practice of densitometry. It must be remembered that the bone density study provides information on the density of the bone at that moment only. It does not, by itself, identify any magnitude of bone loss and certainly cannot be used to identify the cause of any suspected bone loss. It is a single snapshot in time, telling the physician what the bone density is that day, but not how or why it got that way. Because of this, any time that the bone density is classified as low or osteoporotic, an evaluation of the patient for secondary causes of bone loss is appropriate. This evaluation would be performed by the patient’s treating physician, and the extent of the evaluation would be guided by his or her knowledge of the patient. If the patient is well known to the physician, a review of the patient’s medical records may be all that is warranted. It is also possible that additional testing or inquiry may be necessary to exclude causes of bone loss and conditions other than postmenopausal or age-related osteoporosis, as specific interventions may be necessary for successful treatment. Even if the densitometrist is not the treating physician, he or she may still be called upon to render an opinion as to the possible differential diagnoses for suspected bone loss and any appropriate evaluations necessary to exclude those possibilities. The International Society for Clinical Densitometry (ISCD) recommended in 2003 (1) that bone density reports contain a reminder to the referring physician that a “medical evaluation for secondary causes of low BMD may be appropriate.” Specific recommendations regarding the nature of such an evaluation were considered optional. The ability to make specific recommendations, however, is desirable and often necessary in order to assist the referring physician.

SummaryIt is unknown whether there is any relationship between extremity arterial macroangiopathy and osteoporosis in type 2 diabetic mellitus (T2DM) patients. We provide evidence to show the association between lower extremity arterial calcification and the presence of osteoporosis in postmenopausal T2DM women, but not in T2DM men of similar age.PurposeTo investigate the relationship between lower extremity arterial calcification and the presence of osteoporosis in type 2 diabetic mellitus (T2DM) patients.MethodsWe performed a retrospective cross-sectional study in patients with T2DM. They were assigned into two groups (patients with or without vascular calcification) in both sexes. Clinical characteristics, presence of osteoporosis, and bone metabolic markers were compared. Arterial calcification was determined by ultrasonography examination. Osteoporosis was defined based on the measurements from dual-energy X-ray absorptiometry. The relationship between the lower extremity arterial calcification and the presence of osteoporosis was analyzed. Statistical analysis was performed in SPSS 26.0.ResultsA total of 933 T2DM patients (535 men ≥ 50 years old, and 398 postmenopausal women) were identified and analyzed. A significant association between arterial calcification and osteoporosis was only observed in women, with a higher prevalence of osteoporosis observed in women with calcification (40.8%) than in women without calcification (26.9%) (P = 0.004). Compared to women without calcification, women with calcification had lower bone mineral densities in the hip (P < 0.001) and femoral neck (P < 0.001). Ordinal logistic regression analysis showed that women with calcification had a nearly 2-fold increased risk for osteoporosis, even after adjusting for age, duration of T2DM, body mass index, pulse pressure, clearance of creatinine, glycosylated hemoglobin, and fasting C-peptide. Similar differences were not identified between men with and without calcification.ConclusionCalcification of lower extremity arteries is related with the presence of osteoporosis in postmenopausal T2DM women.

Strategies for the prevention and treatment of osteoporosis during early postmenopause

Visceral fat metabolic activity evaluated by 18F-FDG PET/CT is associated with osteoporosis in healthy postmenopausal Korean women