Hyperhomocysteinemia: a biochemical link between bone and cardiovascular system diseases?

Homocysteine (HCY) is a sulfur-containing amino acid involved in two metabolic pathways, catalized by cystathionine-B-synthase and methionine synthase, depending on vitamin (vit) B6, B12, and folate levels and enzymatic activity of methylenetetrahydrofolate. High HCY levels (HHCY) are associated with cardiovascular (CV) and bone diseases, in particular osteoporosis (OP)/hip fracture. As regards the mechanisms involved in the link between HHCY, CV diseases (CVD), and OP, it has been proposed the role of lysyl-oxydase inhibition that might interfere with collagen crosslink formation. Some studies suggested the dysregulation of the osteoprotegerin/receptor activator of nuclear factor-kappaB (RANK) ligand/RANK axis, others the involvement of oxidative stress. These mechanisms may act both on bone and CV system, but whether the common denominator is HCY itself or HCY is merely a marker, remains to be clearly established. Folate, vit B6, and B12 supplementation is associated with HCY reduction, but is unable to certainly reduce the incidence of OP/fracture and CVD, probably because, in the majority of patients, HCY is only moderately increased.

Metabolic bone diseases during long-term total parenteral nutrition.

Long-term total parenteral nutrition (TPN) is a procedure commonly applied to patients with advanced forms of intestinal malabsorption. Among TPN complications, bone metabolic diseases, such as osteoporosis and osteomalacia, are a common finding. Initially considered to be a manifestation of aluminium toxicity which followed massive contamination with the element of the solutions used in TPN, metabolic osteopathy during TPN is currently considered a multiform syndrome, with a multifactorial pathogenesis, which may manifest itself with vague or clear clinical pictures. In this review, we analyse clinical, pathogenetic, and therapeutic aspects of the most common bone metabolic diseases in patients undergoing long-term TPN.

Cyclical behavior of bone remodeling and bone loss in healthy women after menopause: results of a prospective study.

Annual changes in lumbar bone mineral density (LBMD) and bone remodeling markers were measured in 238 healthy pre- and postmenopausal women, aged 45-74 years. The subjects were divided into groups according to their menstrual status and years since menopause. The results obtained indicate that bone loss is not a constant process over time but rather exhibits cyclical damping oscillations. When the log-linear trend of LBMD decrement was transformed into a constant by considering annual percentage changes, the presence of a cyclical component of 7 years was evident. By employing a harmonic regression model, the cyclical component was also statistically significant on baseline data. The cyclical behavior of LBMD decrement corresponded to an analogous behavior of the bone remodeling markers. These results suggest that a lack of estrogen acts as a synchronizer on bone remodeling by triggering a latent cyclical rhythm of bone loss that persists throughout life after menopause. The existence of a chronobiological rhythm of bone loss starting after menopause, if confirmed, could have important clinical implications.

Annual skeletal balance and metabolic bone marker changes in healthy early postmenopausal women: results of a prospective study.

The aim of this study was to establish the duration and annual rate of menopause-related bone loss and to investigate the relationship between bone turnover and bone loss in early healthy postmenopausal women. The rate of change in bone mineral density (BMD) at the lumbar spine and in bone turnover was measured twice at the exact interval of 12 months by dual-energy X-ray absorptiometry (DXA) and by the determination of plasma alkaline phosphatase levels (ALP) and fasting urinary hydroxyproline/creatinine ratio (OHPr/Cr), respectively, in 123 healthy premenopausal and postmenopausal women 45-60 years of age. The subjects were divided into nine groups according to their menstrual status and years since menopause (YSM). Annual bone loss at the lumbar spine of women who were menopausal for 1, 2, 3, 4, and 5 years was -2.62 +/- 0.37 (95% confidence interval -3.66, -1.58), -3.87 +/- 0.96 (-6.02, -1.73), -2.50 +/- 0. 37 (-3.29, -1.70), -2.86 +/- 0.73 (-4.44, -1.27), and -1.54 +/- 0.41 (-2.42, -0.66), respectively, and was significantly less than zero. But, the annual bone loss of women who were premenopausal or menopausal for 6, 7, and 8 years was -0.76 +/- 0.60 (-2.04, +0.53), -1.16 +/- 0.68 (-2.61, +0.29), 0.24 +/- 0.48 (-0.78, +1.26), and 0. 16 +/- 0.63 (-1.18, -1.49), respectively, and was not significantly different from zero. These results demonstrate that the early hormone-dependent bone loss commences in the first year after menopause and is arrested within 6 years after the onset of menopause. The overall bone loss for this phase is estimated to be approximately 15%. Annual change in ALP and OHPr/Cr seems to indicate that bone resorption prevails on bone formation in the first 2 YSM, whereas osteoblastic activity relatively prevails from YSM 3 to YSM 5, which explains the progressive repairing of the imbalance between bone resorption and formation.

Relationship between serum albumin and bone mineral density in postmenopausal women and in patients with hypoalbuminemia.

Some discrepancies exist about the relationship between serum albumin level and the pathogenesis of osteoporosis; moreover, most of the studies available have especially concerned patients with osteoporosis, often associated with fractures. Our study, therefore, aims to investigate the presence of a relationship between serum albumin level and bone mineral density in a group of healthy women (n=650; mean age 59.0 +/- 7.4 years) who voluntarily underwent screening for osteoporosis only because they were menopausal (11.2 +/- 7.4 years since menopause) and, for comparison, in a group of outpatients (n = 44; mean age 57.6 +/- 7.0 years; 9.1 +/- 6.7 years since menopause) with hypoalbuminemia associated with diseases. The results show a lack of any relationship in healthy women between serum albumin value and bone mineral density; the lack of correlation was also shown when the postmenopausal women were down into normal, osteopenic and osteoporotic (WHO criteria) or in hypo, normal and hyperalbuminemic. The only significant parameters associated with lower bone mineral density, in fact, were age and years since menopause (p<0.0001 and p<0.0001 respectively at lumbar spine and p<0.02 and p<0.001 at femoral neck level). In the group of patients with hypoalbuminemia associated with diseases, on the other hand, a relationship between reduced bone mineral density and hypoalbuminemia was found (p<0.01 and p<0.05 respectively at lumbar spine and femoral neck). In conclusion, in healthy postmenopausal women the serum albumin level does not play a significant role in the pathogenesis of bone density reduction, which is mainly due to the number of years since menopause and advancing age. The hypoalbuminemia may be related to the reduction of bone mass only in the subjects affected by diseases associated with a significant albumin reduction.

Calcium homeostasis during oral glucose load in healthy women.

It has been demonstrated that in healthy subjects during oral glucose tolerance test, serum calcium declines, while urinary calcium excretion increases, even if there is not a general agreement in this regard. The study was carried out in order to evaluate the effects of glucose oral load on calcium homeostasis in eight healthy adult women, also considering ionized calcium, plasma insulin and parathyroid hormone changes. The results showed a decline of total and ionized serum calcium (p < 0.05 and p < 0.01, respectively; maximum of the decrease at time 120'), in parallel with the increase of urinary calcium/ creatinine ratio (p < 0.05). Serum glucose and insulin increase (p < 0.0001 and p < 0.0005 respectively; maximum value at time 60'), while the parathyroid hormone level decreases (maximum decline at time 120', p < 0.01). No changes were observed in fasting control subjects for all parameters considered. The changes of these parameters with time suggest that the effects of glucose oral load on calcium metabolism in healthy adult women may be the consequence of parathyroid hormone suppression induced by acute hyperglycemia/hyperinsulinemia. The results confirm in vivo the PTH behaviour in vitro, on cultured bovine parathyroid cells, with high glucose concentration.

Clinical and prognostic significance of hyperfibrinogenemia in cerebral ischemia.

In order to evaluate the clinical and prognostic significance of early hyperfibrinogenemia in patients with transient ischemic attack (TIA) and ischemic cerebral infarction (ICI), we analyzed the relationships between plasma fibrinogen, brain damage severity, clinical status on admission and intra-hospital mortality. Vascular damage severity was estimated by measuring the necrotic area by computed axial tomography (CT) and indirectly by means of changes in some plasma enzymes (CK, LDH, GPT/ALT, and GOT/AST). Plasma fibrinogen levels were statistically higher in ICI than in TIA and control subjects (p < 0.0005; analysis of variance). Moreover, plasma fibrinogen was directly related to the extension of the necrotic area at CT scan (p < 0.05) and in ICI patients was positively correlated with CK (r = 0.50, p < 0.01), LDH (r = 0.41, p < 0.05) and GOT/AST (r = 0.42, p < 0.05) serum levels, but not with GPT/ALT. A higher plasma fibrinogen value was observed in patients with stupor or coma compared with those with alert consciousness (p < 0.05). In patients who died during hospitalization, fibrinogen levels were higher than those of subjects who were discharged (p < 0.005). The results indicate that in the early phase of cerebral ischemia, plasma fibrinogen levels are related to the severity of the clinical status and to the extension of the brain vascular damage, thus representing a negative clinical and prognostic factor of the disease.

Relationship between spine bone mineral density and vertebral body heights.

The aim of this study was to investigate the correlation between lumbar spine bone mineral density (LS-BMD) and the vertebral body heights with advancing age and years since menopause. One hundred and sixty-three women ages 39-74 years (77 normal premenopausal, ages 39-54, and 86 normal postmenopausal, ages 46-74 years) were studied. LS-BMD was measured by dual energy X-ray absorptiometry. Vertebral heights were evaluated, using morphometry, as the sum of anterior (AHs), middle (MHs), and posterior (PHs) vertebral body heights from T4 to L5. The AHs/PHs ratio at the same level was also calculated. AHs, MHs, PHs, and AHs/PHs ratio directly correlated with LS-BMD; the correlations are AHs r = 0.80, P < 0.0001, MHs r = 0.75, P < 0.0001, PHs r = 0.76, P < 0.0001, and AHs/PHs r = 0.66, P < 0.001. Both LS-BMD and AHs are inversely correlated with age, and the regressions fit with both linear and cubic curves. The statistical significance of the correlations persists while maintaining age constant. The linear regression curve of AHs with age indicates that the spine height decrement rate is 2.12 mm/year, corresponding to 7.4 cm in 35 years. AHs decreases immediately after menopause fitting with a cubic curve model, with a decrement rate of about 3 cm in the first 5 years after menopause. We conclude that the measurement of the sum of vertebral body heights could usefully integrate LS-BMD evaluation in the clinical and epidemiological investigation of osteoporosis.

Acute serum calcium changes in transient ischemic attack and cerebral infarction.

Total (T-Ca), albumin corrected (A-Ca) and ionized (Ca++) serum calcium levels were measured in patients affected by transient ischemic attack (TIA) and ischemic cerebral infarction (ICI), in order to evaluate the clinical and prognostic significance of calcemic status during the acute phase of these events. These results demonstrate that the calcium level is decreased in cerebral ischemia and that more substantial changes are observed in ICI than in TIA and controls (p < 0.0001, p < 0.02 and p < 0.0001 respectively for T-Ca, A-Ca and Ca++; analysis of variance). The mean T-Ca was significantly reduced in patients who died during hospitalization compared with values observed in survivors (p < 0.005), whereas A-Ca and Ca++ were not different. The calcium changes observed in the early phase of TIA and ICI suggest that the severity of cerebral ischemia may condition the amount of its acute decrease. The cause of hypocalcemia is unclear (primary effect or secondary epiphenomenon of cerebral ischemia?), but when A-Ca and Ca++ are considered, its in-hospital unfavorable prognostic role may be excluded.

Serum albumin level at admission: mortality and clinical outcome in geriatric patients.

We evaluated serum albumin at time of admission, within 72 hours, in 135 geriatric patients who were older than 70 years to establish its role as a predictor of death and clinical outcome at time of discharge. Serum albumin values were reduced significantly in patients who died compared with those who were discharged in unchanged/impaired and improved conditions (3.01 +/- 0.68 g/dL, 3.18 +/- 0.55 g/dL, and 3.65 +/- 0.52 g/dL respectively, P < 0.0001). A correlation between serum albumin concentration at admission and number of days elapsed from admission and death was found (r = 0.43, P < 0.05). Mortality rate was 38.6% in patients with serum albumin values < 3.3 g/dL compared with 14.1% in those with albumin values > or = 3.3 g/dL (P < 0.005). Similar results were obtained even when the main diagnostic conditions, such as cardiocerebrovascular disease and cancer, were considered. The results demonstrate that in geriatric patients the serum albumin level at admission may be a predictor of mortality and clinical outcome at discharge.

[A digital radiology method for assessing vertebral osteoporosis]. / Metodica di radiologia digitale per la valutazione dell'osteoporosi vertebrale.

The radiologic identification of vertebral fractures is usually subjective and reproducibility is poor. This paper describes a new digital radiologic method to perform vertebral morphometry, i.e. osteoradiometry (ORM). Lateral radiographs of the thoracic and lumbar spine were obtained in 50 premenopausal women and digitalized by means of a video camera. A special computer software enables to calculate the anterior (Ha), middle (Hm), and posterior (Hp) heights of vertebral bodies (T4-L5) and the morphometric indices of vertebral fractures. ORM reproducibility was assessed by comparing repeated measurements made by two radiologists: the intra- and interobserver variation coefficients (CV) were respectively 1.5% and 2.3% for Hp; 1.3% and 2% for Hm; 1.4% and 2.1% for Ha. The normal range for vertebral dimensions was therefore established. The anterior and posterior heights increased from T4 to L2, but for L3-L5 the posterior height was lower than the anterior height (Ha/Hp > 1). Vertebral heights positively correlated with the standing heights of the subjects (r = 0.2, p < 0.05). Weight and the body mass index (BMI) were not correlated with vertebral heights. These normal values, compared with those found in osteoporosis patients, will allow to assess ORM diagnostic efficacy in identifying vertebral fractures.

Aging changes in vertebral morphometry.

We analyzed the vertebral morphometry of healthy premenopausal women and their changes with age and menopause in order to better define the reference population for the clinical and epidemiological evaluation of vertebral fractures. Vertebral morphometry has been performed on lateral thoracic and lumbar spine films from 50 premenopausal and 76 postmenopausal normal women, age range 39-74 years. Vertebral heights and the anterior height/posterior height ratio are significantly lower in postmenopausal compared with premenopausal women. Vertebral anterior height decreases about 1.5 mm/year, whereas middle and posterior height decreases about 1.3 and 1.2/mm year, respectively. A statistically significant reduction of vertebral heights by around 1 mm/vertebra was observed in postmenopausal (n = 16) compared with premenopausal women (n = 20) of the same age (P < 0.05). The results demonstrate that vertebral heights are lower with advancing age and menopause and that the vertebral heights difference in elderly people is not only the consequence of a cohort effect. The results also contribute to better defining the reference population to be chosen for evaluating vertebral deformation.

[Calcium and bone mass at different periods of life]. / Calcio e massa ossea nelle diverse età della vita.

In this review we report some considerations on the relationships between calcium intake and bone density during life time, with particular regard to postmenopausal women. We also report some practical aspects concerning calcium salt supplementation.

Hip fracture in Italy: epidemiology and preventive efficacy of bone-active drugs.

In this paper we report the results on the epidemiology of hip fracture and the preventive efficacy of bone-active drugs in Italy, observed in men and women aged 50 years or over, recruited in the three Italian centres participating in the Mediterranean Osteoporosis Study (MEDOS), namely Parma, Rome, and Siena. The number of fractures observed was 1,437 in a catchment area population of 847,508 individuals, with a total incidence of 169.6/100,000--a female-to-male ratio of 3.5 and a doubling-time of about 5.5 years. The female excess becomes evident in the age groups over 60 years. The mean age of fractures was 77 years in females and 73 in males. From the data collected, the estimated number of fractures per year in the Italian population aged over 50 years is 32,000. The pattern of use and the preventive efficacy of bone-active drugs was examined in women. Calcitonin and calcium were the drugs mainly used; less than 3% had taken vitamin D or oestrogen and only a minor percentage had taken anabolic steroids. Fluorides were not used at all. As seen in the European sample, the protective effect of calcium and calcitonin is statistically significant even in Italy, while vitamin D is not. The use of anabolic steroids was associated with a decrease in risk. Oestrogen administration does not seem to reduce the relative risk of hip fracture in Italian women, probably due to the small sample size.

Plasma fibrinogen and platelet count in stroke.

Plasma fibrinogen levels and platelet counts were evaluated in 30 patients with acute ischemic cerebral infarction (CI) three and nine days after the onset of symptoms. Hyperfibrinogenemia (379.4 +/- 80.3 vs 327.3 +/- 48.3 mg/dL of controls, p < 0.005), a reduction of platelet count (207.133 +/- 48.388 vs 288.375 +/- 61.373 x 10(9)/L of controls, p < 0.001), and an inverse correlation (r = -0.41, p < 0.05) between the two parameters were observed on day three. On day nine, platelet counts normalized while plasma fibrinogen levels slightly increased; the inverse correlation no longer occurred. The results suggest that in the earliest phase of stroke plasma fibrinogen levels may condition the extent of platelet accumulation or consumption in the ischemic area. This confirms in vivo that the platelet aggregation process is strictly dependent on fibrinogen concentration.

Neurological state, infarct size and clinical outcome are related to early platelet count decrease in stroke.

We performed this study in order to verify the existence of a correlation between early platelet count reduction and initial neurological impairment, infarct extension and mortality or clinical outcome in an established ischemic cerebral infarction. The results demonstrate that the platelet consumption and/or accumulation in the infarct area, expressed by circulating platelet decrease, is related to the severity of neurological involvement, infarct size and poor clinical outcome.

Clinical aspects of early increase in serum gamma-glutamyl transferase in cerebral infarction.

Gamma-glutamyl transferase (GGT) serum levels were measured in 42 female patients within 72 hours, and on day 10, after an ischaemic cerebral infarction (CI) and correlated with neurological impairment at admission and with mortality during hospitalization. Mean +/- SEM GGT serum value within 72 hours after CI was significantly higher compared to the mean +/- SEM value observed in control subjects (26.7 +/- 2.5 vs 16.5 +/- 1.2 U/L, P < 0.001) and it correlated with the severity of neurological status and with mortality. A positive correlation between GGT and creatine kinase (CK) serum levels was also observed (r = 0.47, P < 0.01). On day 10 after CI, normalization of serum GGT values was found. We conclude that GGT serum level increases in CI as a consequence of brain damage and that this increment may be considered as a clinical and prognostic unfavourable index of the disease.