Bone metabolic abnormalities associated with well-controlled type 1 diabetes (IDDM) in young adult women: a disease complication often ignored or neglected.

OBJECTIVES: This investigation on a homogenous cohort of young adult Caucasian type 1 diabetic (IDDM) patients (1) aimed at studying the occurrence of low bone mineral density (BMD) at an early stage prior to menopause (i.e., during the first decade after peak bone mass) and (2) elucidating the possible mechanisms underlying IDDM-induced bone complication. METHODS: Twenty-seven female patients with insulin-treated and well-controlled diabetes, without renal complications, and 32 well-matched healthy controls, aged between 30 and 40 years and fulfilling rigorous inclusion criteria to minimize bone-confounding factors, were enrolled. Areal BMD was evaluated by dual energy X-ray absorptiometry at axial (lumbar spine) and appendicular (femur) sites, using diagnostic WHO reference (T-scores). Osteoblast functions, bone metabolism, related key minerals, and 2 osteoclast-stimulating calciotropic hormones regulating their serum levels were assessed biochemically. RESULTS: The number of cases with low BMD (T-score below -1.1 SD) was almost 2-fold greater (p < 0.01) in the IDDM group. BMD was significantly lower in this group for 3 lumbar sites (p < 0.01) and femur Ward's triangle (p < 0.05). Bone formation was reduced, as evidenced by the suppressions of osteocalcin (OC; p < 0.01) and IGF-I (p < 0.001). However, bone alkaline phosphatase (bALP) was induced (p < 0.01), in contrast to what is usually observed in cases of reduced bone formation. Correlated total ALP activity was also significantly increased. There was no change in the specific marker of bone resorption (urinary deoxypyridinoline). Serum calcium was significantly elevated, particularly after adjustment for albumin (p < 0.001), despite lower 1,25(OH)(2)D(3) (p < 0.001) and no elevation of PTH. All significant bone-related biochemical changes were significantly correlated with glycosylated hemoglobin, a clinical indicator of long-term glycemic control, indicating a direct effect of the disease. CONCLUSIONS: Bone loss in the IDDM group results from a decrease in bone formation rather than an increase of bone resorption. The induction of bALP is indicative of impaired osteoblast differentiation and maturation, which delayed (down-regulated) later stages of matrix mineralization, as evidenced by lower OC and BMD.

Coexistence of osteoporosis and cardiovascular disease risk factors in apparently healthy, untreated postmenopausal women.

This study aimed to determine whether apparently healthy, untreated postmenopausal women at risk of osteoporosis relative to nonmenopausal women are concomitantly at risk of cardiovascular disease (CVD) in terms of various aspects of lifestyle, personality, body shape and composition, and blood chemistry. Two homogeneous groups of 30 women having reached menopause for 3-5 years and 30 nonmenopausal controls, all non-estrogen users without apparent CVD risk factors, were compared in a cross-sectional design. Data related to physical activity, dietary intakes, personality type, anthropometry, and skinfold-thickness were collected. Plasma insulin-like growth factor (IGF-1) and serum lipids were measured and used as biochemical predictors of osteoporosis and CVD, respectively. Compared to nonmenopausal controls, postmenopausal women were at greater risk of bone loss given their lower plasma IGF-1, lower physical activity level, and even given their higher serum lipids, as recent literature suggests. Moreover, their dietary calcium intake fulfilled only 70% of the current recommendation, which may reduce protection against osteoporosis and CVD (particularly hypertension) as well. The two groups did not differ regarding energy intake, body weight and frame size, body mass index (BMI), waist circumference, and waist-hip ratio (WHR). However, postmenopausal subjects had more adipose tissue and differed in terms of lifestyle factors (lower dietary lipids and greater alcohol consumption). While neither group was at particular risk of CVD according to waist circumference, WHR, and serum triglycerides, postmenopausal women were at risk according to percent body adiposity and serum cholesterol. This study shows that several risk factors for osteoporosis and CVD can coexist in apparently healthy postmenopausal women after a few years of natural menopause. It emphasizes the need for a timely screening that would stress both heart and bone risk factors.

Chemical and biomechanical characterization of hyperhomocysteinemic bone disease in an animal model.

BACKGROUND: Classical homocystinuria is an autosomal recessive disorder caused by cystathionine beta-synthase (CBS) deficiency and characterized by distinctive alterations of bone growth and skeletal development. Skeletal changes include a reduction in bone density, making it a potentially attractive model for the study of idiopathic osteoporosis. METHODS: To investigate this aspect of hyperhomocysteinemia, we supplemented developing chicks (n = 8) with 0.6% dl-homocysteine (hCySH) for the first 8 weeks of life in comparison to controls (n = 10), and studied biochemical, biomechanical and morphologic effects of this nutritional intervention. RESULTS: hCySH-fed animals grew faster and had longer tibiae at the end of the study. Plasma levels of hCySH, methionine, cystathionine, and inorganic sulfate were higher, but calcium, phosphate, and other indices of osteoblast metabolism were not different. Radiographs of the lower limbs showed generalized osteopenia and accelerated epiphyseal ossification with distinct metaphyseal and suprametaphyseal lucencies similar to those found in human homocystinurics. Although biomechanical testing of the tibiae, including maximal load to failure and bone stiffness, indicated stronger bone, strength was proportional to the increased length and cortical thickness in the hCySH-supplemented group. Bone ash weights and IR-spectroscopy of cortical bone showed no difference in mineral content, but there were higher Ca2+/PO4(3-) and lower Ca2+/CO3(2-) molar ratios than in controls. Mineral crystallization was unchanged. CONCLUSION: In this chick model, hyperhomocysteinemia causes greater radial and longitudinal bone growth, despite normal indices of bone formation. Although there is also evidence for an abnormal matrix and altered bone composition, our finding of normal biomechanical bone strength, once corrected for altered morphometry, suggests that any increase in the risk of long bone fracture in human hyperhomocysteinemic disease is small. We also conclude that the hCySH-supplemented chick is a promising model for study of the connective tissue abnormalities associated with homocystinuria and an important alternative model to the CBS knock-out mouse.

Type 1 diabetes impairs vitamin B(6) metabolism at an early stage of women's adulthood.

Vitamin B(6) (pyridoxine) metabolism in diabetes has never been investigated except for a few reports on plasma pyridoxal 5'-phosphate (PLP). These studies indicated that this most active (coenzyme) vitamer can be reduced. The present clinical investigation aimed to measure all vitamers in blood and urine by high performance liquid chromatography as well as important related factors, in women during active reproductive years. Thirty-two insulin-treated type 1 diabetic (T1D) patients, without renal complication, and 27 well-matched healthy controls, aged 30 to 40 years old, were recruited using rigorous criteria. Both groups had normal hemoglobin and serum albumin levels. Plasma PLP and pyridoxal (PL) did not differ significantly in the T1D group but alkaline phosphatase (ALP) activity was greater (p < 0.01). This produced a shift in plasma PLP-PL profile, as evidenced by a lower plasma PLP/PL ratio (p < 0.05). Enhanced ALP activity meant more PLP being dephosphorylated to PL (the membrane transfer form), with more ending up in erythrocytes to be rephosphorylated in its active form, as suggested by the significant positive correlation (p < 0.001) between plasma PL and erythrocyte PLP. More PL into blood circulation also means more oxidation of this vitamer to 4'-pyridoxic acid in kidneys, as confirmed by the positive correlation between plasma PL and urinary 4'-pyridoxic acid (p < 0.001). The positive correlation (p < 0.001) between ALP activity and glycosylated hemoglobin indicated a direct effect of the disease. The T1D-induced alteration in vitamin B(6) metabolism, consecutive to enhanced ALP activity, may put patients at greater risk of vitamin B(6) deficiency and diabetic complications.

Enhancement of calcium/vitamin d supplement efficacy by administering concomitantly three key nutrients essential to bone collagen matrix for the treatment of osteopenia in middle-aged women: a one-year follow-up.

Two vitamins and proline (CB(6)Pro), three nutrients essential for bone collagen, were used in combination to a 1000 mg calcium/250 IU vitamin D (Ca/D) daily supplement to treat osteopenia as a preventive measure against osteoporosis later in life. Middle-aged women not using estrogen were screened for osteopenia using the WHO criteria and divided into three groups (n = 20 each): 1) placebo healthy controls with normal bone mineral density (BMD); 2) control Ca/D-treated osteopenic patients; and 3) Ca/D + CB(6)Pro-treated osteopenic patients. The three groups were comparable at baseline except for BMD. After one-year treatment, cortical diaphyseal BMD remained constant in each group, but trabecular bone loss persisted (at 5 lumbar sites) in osteopenic group 2. No further bone loss was detected in osteopenic group 3. A loss of 2% was evidenced in the placebo group at one lumbar site. Markers of bone formation (which increase in coupling to resorption) decreased significantly in both osteopenic groups. Although biomarkers of resorption did not change, hormone (PTH and 1,25(OH)(2)D(3))-induced osteoclastic activity was significantly reduced. No decline in BMD occurred at any bone site in osteopenic group 3, highlighting the importance of improving the quality of bone matrix concomitantly to mineral replacement.

Bone mineral density and metabolism at an early stage of menopause when estrogen and calcium supplement are not used and without the interference of major confounding variables.

OBJECTIVES: To measure bone mineral density (BMD) and to screen for early biochemical abnormalities in bone mineral metabolism in the first five years of natural menopause when estrogen and calcium supplement are not used and in the absence of major confounding variables. SETTING: Two homogeneous and comparable groups (n = 30) of healthy pre- and postmenopausal Caucasian women living in a northern region (latitude 46 degrees N) were recruited during the mid-Spring/Summer season in a cross-sectional design. METHODS: Volumetric apparent BMAD (g/cm(3)) was calculated from areal BMD (g/cm(2)) which was evaluated by dual energy X-ray absorptiometry (Lunar) at both axial and peripheric (femur) sites using two sets of reference values (WHO criterion expressed as T-score and absolute values of areal density) in combination to bone specific biochemical measurements. RESULTS: BMD and BM(A)D were significantly lower in postmenopausal women for all lumbar sites, but not for Ward's triangle and any other femoral sites whereas free deoxypyridinoline (Dpd), urinary biochemical marker of bone resorption, was markedly (p < 0.0001) greater. Their serum calcium and phosphate were significantly higher without a difference in 1,25(OH)(2)D(3) and PTH. The prevalence of osteopenia in pre- and postmenopausal women was about 2-fold lower in both groups (26.6 and 46.9%, respectively) when lumbar (L) spine and femur neck were combined and using the criteria based on reference values of areal density instead of T-scores. CONCLUSIONS: The present study showed that the negative effects of estrogen deficiency on BMD and bone metabolism in early menopause occurred independently of the effect of major calcitropic hormones. Bone loss affects a non negligible proportion of premenopausal women. The prevalence of osteopenia in pre- and postmenopausal women varied according to the criterion used and anatomic site.

Is serum ferritin an additional cardiovascular risk factor for all postmenopausal women?

BACKGROUND: Most of the studies on cardiovascular disease (CVD) risk factors in menopause have focused on serum lipid(lipoprotein) abnormalities and were conducted in populations which were not well controlled for several important influential factors. METHODS: Two homogenous groups of 30 apparently healthy Caucasian premenopausal women and 3-5 years postmenopausal women who were nonobese, nonsmoking and not using estrogen were compared in a well-controlled cross-sectional design. Fasting serum ferritin and plasma total homocysteine (tHcy) were evaluated concomitantly to classical serum lipid(lipoprotein) risk factors. Relationships between risk factors and the influence of other contributing variables such as diet and body weight were also examined. RESULTS: Serum total cholesterol (p < 0.01), low-density lipoproteins (LDL; p < 0.05) and triglycerides (p < 0.05) of postmenopausal women were greater than that of their menstruating counterparts, even though they ate a CVD-preventive diet, had similar body weight and body fat distribution. Their serum ferritin was almost 3-fold greater (p < 0.0001) but was still within normal limits, except for the 38.5% of postmenopausal women who exhibited values above the 80 mug/l limit that has been associated with sharp increases in the rate of heart disease in either gender. Serum ferritin was low in one third of the postmenopausal group (as low as in the premenopausal control group, whose dietary iron intake was slightly below the nutritional recommendation). The mean plasma tHcy of the postmenopausal group was almost twice as elevated (p < 0.0001). Both ferritin and tHcy were found to be linked to serum cholesterol. The correlation between tHcy and triglycerides was also significant. CONCLUSION: Early menopause is not associated with blood iron overload and CVD risk factor in an important proportion of women.