Biochemical Indices Of Bone Metabolism Research Articles

PS-238 Study Of Bone Biochemical Markers And The Cytokine Srankl/opg System In Children With Idiopathic Hypercalciuria

Background Idiopathic Hypercalciuria (IH) has been associated with decreased bone density up to 30% of the children. Aims To determine the concentrations of cytokines osteoprotegerin (OPG) and sRANKL and other biochemical indices of bone metabolism in children with IH. Methods In 31 children of median age 6.3 years (range 2.2–16.4) with IH OPG, sRANKL, 25(OH)D, 1,25(OH) 2 D, PTH, Ca, Pi, osteocalcin, ALP and CTx-Crosslaps were determined in serum and Ca/Cr, oxalate/Cr and citrate/Cr in urine. Times of study were at diagnosis and after 3 months of salt free and adequate Ca diet. Height and BMI z-score were assessed. Clinically healthy children (n = 35) matched for age/sex and season were used as controls (median 7.8 years, range 1.8–16.3). Results Although urinary Ca excretion (24 hCa and UCa/UCr) decreased at 3 mo (p 2 D, PTH, osteocalcin, ALP, OPG, sRANKL and sRANKL/OPG ratio in patients before and after diet or compared to controls. Only serum concentrations of CTx-Crosslaps were significantly higher in both patient samples (p Conclusion Although serum OPG/sRANKL and osteocalcin were not different in children with IH, the higher serum CTx-Crosslaps levels (bone resorption index) may suggest bone turnover uncoupling with an autocrine role of the above cytokines.

Long Term Efficacy Of Iron Chelation Therapy With Deferasirox On Endocrine Function In Thalassemia Major

Although the heart and liver have traditionally been the organs of interest for iron-related complications in Thalassemia Major (TM), endocrine disorders are common and carry significant morbidity. This is thought to result from iron accumulation in multiple organs functioning as part of endocrine systems. Deferasirox chelation therapy is well tolerated in TM and reduces iron burden effectively in the heart and liver. The impact of deferasirox on endocrine parameters remains unclear. The aim of this study was to examine the long-term efficacy of deferasirox for both the prevention of endocrine dysfunction in patients free of endocrine complications, and in improving endocrine parameters in those with pre-existing endocrine disorders.This was a multicentre retrospective cohort study of TM patients over 2 years of age receiving chelation treatment with once daily oral deferasirox monotherapy. Data on relevant clinical and laboratory parameters, including glycaemia, bone mineral density (BMD) z-scores, and testing of the pituitary, gonadal, thyroid and adrenal axes were collected at baseline and follow-up. Dosing regimens were titrated according to standard practice and only patients treated for at least 3 years were included in the present analysis. Data are presented as mean with standard deviation unless otherwise stated. Statistical comparisons were made using paired t-tests for continuous data, and chi-square test or Fisher's exact test to compare categorical data distributions.A total of 72 patients (69% female) with a mean age 26 ± 15 years were included. Mean duration of exposure to deferasirox was 6.9 ± 2.7 years with a mean daily dose of 25 ± 5 mg/kg. Myocardial T2* significantly increased from baseline to follow up (29.30 ± 10.29ms vs. 33.5 ± 13.06ms, P=0.01), signifying effective removal of iron from the heart. Among patients free of thyroid dysfunction at baseline, we observed no significant difference in mean TSH (2.10 ± 1.00 mi/u/ml vs. 2.28 ± 1.06 mi/u/ml, P=0.23 ), FT4 (6.89 ± 4.50 ng/ml vs. 7.10 ± 4.71 ng/ml, P=0.34) or FT3 (2.87 ± 1.16 pg/ml vs. 3.00 ± 0.58 pg/ml, P=0.35) during the study period. Of 9 patients with biochemical hypothyroidism at baseline, including 4 receiving thyroxine, we observed no significant change in thyroid function tests or thyroxine requirements. Two new incidences of subclinical hypothyroidism were noted. Among patients free of diabetes mellitus at baseline, we observed no significant variation in blood glucose measurements (pooled over 3 consecutive readings) at the end of treatment (88.62 ± 10.53 mg/dl vs. 88.36 ± 9.35 mg/dl, P=0.83). There was 1 incidence of type 2 diabetes during the study period. No significant difference was seen in blood sugar control or insulin requirements between baseline and end of treatment in patients with type 1 diabetes. Excluding normal pre-pubertal paediatric patients, there was no significant increase in the prevalence of hypogonadism between baseline and the end of study, 21 patients (38%) vs. 24 (44%) were diagnosed with hypogonadism respectively (P=0.56). Biochemical indices of bone metabolism showed no significant difference in calcium levels or vitamin D from baseline to follow up. BMD was improved from baseline to follow-up, with normal Z scores in 7 (20%) patients, 20 (57%) osteopenic, and 8 (23%) osteoporotic, compared with 7 (20%), 24 (69%), and 4 (11%) at end of treatment, respectively. Adverse effects were infrequent and of low grade, effecting 7 (9.7%) patients.Endocrine disorders are common sequelae of iron overload in patients with TM, and follow an insidious course of progressive dysfunction. We report infrequent development and progression of endocrine abnormalities, and significant improvement in bone density in TM patients treated with deferasirox over a 7-year follow-up period. In comparison with the incidence of complications from other studies of TM, deferasirox appears effective in reducing risk of developing endocrine disorders. Increasing myocardial T2* values confirmed effective removal of iron from the heart. Although multiple biological pathways are likely responsible, reduction in global iron alleviating siderosis of endocrine organs may be responsible for preserved function and bone mineral metabolism. Our study suggests that chelation therapy with deferasirox may prevent endocrine complications in patients with TM and prevent progression in those with established abnormalities Disclosures:Silverio:Novartis: Consultancy, Research Funding.

The association of bone mineral density and parathyroid hormone with serum magnesium in adult patients with sickle-cell anaemia

IntroductionBone disorders including osteopenia and osteoporosis are a frequent cause of morbidity in sickle-cell disease (SCD). Magnesium (Mg) regulates some biological processes important in bone remodelling. We aimed to investigate whether serum Mg levels (sMg) may have an impact on bone mineral density (BMD) in sickle-cell anaemia (SCA).Material and methodsSixty adults with SCA in steady-state and 20 age- and race-matched healthy blood donors were included in the study. The BMD was evaluated with respect to minerals and biochemical indices of bone metabolism. Multivariate analysis was performed to determine the factors influencing BMD.ResultsThe mean sMg concentration was 0.64 ±0.06 (reference range 0.7-1.2 mmol/l) for 34% of the population, and 0.86 ±0.08 mmol/l for 66%. There were significant differences between Mg groups and controls in BMD, phosphorus (PO4), parathyroid hormone (PTH) (p = 0.011, p = 0.011 and p = 0.0001 respectively) and osteocalcin (OC) (p = 0.030) levels. The sMg was found to be associated positively with serum calcium (Ca), PTH and OC (r = 0.585; r = 0.436; r = 0.351 respectively, all at p < 0.05), and negatively with PO4 (r = –0.312; p < 0.05). Multivariate analysis demonstrated that only PTH (p < 0.05) was an independent factor for BMD. Moreover, it identified sMg, OC, and CTX as independent factors for PTH (all p < 0.05).ConclusionsThese results indicate that serum Mg may be a co-contributing factor in causing low BMD. However, other possible aetiologies including decreased PTH and increased bone turnover certainly play a role. Based on the present data, it is prudent to monitor sMg routinely in this patient population and treat the condition whenever possible.

Changes in biochemical indices of bone metabolism in post‐menopausal women following a dietary intervention with fortified dairy products

In southern Europe, calcium supplementation alone is a common practice for osteoporosis prevention. The present study aimed to examine whether calcium supplementation alone could be as effective in achieving favourable changes on bone metabolism indices of Greek post-menopausal women as a holistic dietary approach combining consumption of dairy products fortified with calcium and vitamin D(3) and nutrition counselling sessions for five winter months. A sample of 101 post-menopausal women was randomised to a dairy intervention group (IG: n = 39), receiving approximately 1200 mg of calcium and 7.5 microg of vitamin D(3) per day via fortified dairy products and attending biweekly nutrition counselling sessions; a calcium-supplemented group (SG: n = 26) receiving a total of 1200 mg calcium per day; and a control group (CG: n = 36). Regarding insulin-like growth factor (IGF)-I, a higher increase was observed for the IG compared to the changes in the CG and the SG (P = 0.049). Regarding serum parathyroid hormone (PTH) levels, the increase observed in the CG was higher than the changes observed in the other two groups but the differences were of marginal significance (P = 0.055). No significant differences were observed among groups regarding the changes in serum osteocalcin and type I collagen cross-linked C-telopeptide levels. The application of a holistic intervention approach combining nutrition counselling and consumption of fortified dairy products for five winter months induced some more favourable changes in IGF-I and PTH levels compared to calcium supplementation alone. Intervention periods longer than 5 months might be required to achieve significant differences among groups for bone remodelling biomarkers as well.

Effects of Atorvastatin on Bone in Postmenopausal Women with Dyslipidemia: A Double-Blind, Placebo-Controlled, Dose-Ranging Trial

In preclinical models, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase have been shown to positively affect bone remodeling balance. Observational studies and secondary analyses from lipid-lowering trials have yielded inconsistent results regarding the effect of these agents on bone mineral density and fracture risk. Our objective was to determine whether clinically significant skeletal benefits result from hydroxymethylglutaryl-coenzyme A reductase inhibition in postmenopausal women. We conducted a prospective, randomized, double-blind, placebo-controlled, dose-ranging comparative clinical trial at 62 sites in the United States. Participants included 626 postmenopausal women with low-density lipoprotein cholesterol levels of at least 130 mg/dl (3.4 mmol/liter) and less than 190 mg/dl (4.9 mmol/liter), and lumbar (L1-L4) spine bone mineral density T-score between 0.0 and -2.5. Once-daily placebo or 10, 20, 40, or 80 mg atorvastatin was administered. We assessed percent change from baseline in lumbar (L1-L4) spine bone mineral density with each dose of atorvastatin compared with placebo. At 52 wk, there was no significant difference between each atorvastatin and placebo group or change from baseline at any tested dose of atorvastatin or placebo in lumbar (L1-L4) spine bone mineral density. Nor did atorvastatin produce a significant change in bone mineral density at any other site. Changes in biochemical markers of bone turnover did not differ significantly between each atorvastatin and placebo group. All doses of atorvastatin were generally well tolerated, with similar incidences of adverse events across all dose groups and placebo. Clinically relevant doses of atorvastatin that lower lipid levels had no effect on bone mineral density or biochemical indices of bone metabolism in this study, suggesting that such oral agents are not useful in the prevention or treatment of osteoporosis.

Calcium and phosphate balance in adolescents on home nocturnal haemodialysis

Studies in adults show superior serum phosphate and parathyroid hormone (PTH) control on slow nocturnal haemodialysis (NHD) compared with conventional haemodialysis. We studied the progress of four children aged 12, 13, 14 and 16 years after they had been initiated on NHD. The follow-up period ranged from 6 months to 20 months. Biochemical indices of bone metabolism were collected prospectively. All four children were initially dialysed against a 1.5 mmol/l calcium bath. In two patients, owing to biochemical hypocalcaemic episodes, the dialysate calcium concentration was increased to 1.75 mmol/l. One patient became hypercalcaemic and received calcitonin for bone pain secondary to osteoporosis and was dialysed against a 1.0 mmol/l calcium bath. Including an evaluation of dietary intake, all four patients had a net positive calcium balance, ranging from 5.1 mmol/m2 body surface area (BSA) per day to 24.3 mmol/m2 BSA per day. A significant reduction in the pre-dialysis phosphate level was observed in all four patients, such that none required dietary restrictions or phosphate binders, and dialysate phosphate supplements of 0.8-2.03 mmol/l were employed to prevent hypophosphataemia. The (CaxPO4) dropped below 4.4 mmol(2) l(-2) in all four patients. Concurrently, significant reductions in intact PTH levels were seen in all four patients, but the level dropped to below normal range in two. In our cohort of patients, NHD rapidly lowered plasma phosphate and PTH levels, and additional dialysate phosphate and possibly calcium may be necessary to prevent bone demineralisation due to chronic losses and to prevent oversuppression of PTH.

Effects of treatment on endocrine function in patients with epilepsy

Antiepileptic drug (AED) treatment is associated with multiple short- and long-term side effects. Effects on endocrine function, including weight change, reproductive function, thyroid function, and bone health are examples of these side effects. Some AEDs affect weight, resulting in weight gain or loss. Levetiracetam and lamotrigine are weight-neutral agents, whereas valproate is associated with weight gain. Reproductive dysfunction is reported in women and men with epilepsy treated with AEDs. In women, the most common symptoms are hyperandrogenism, menstrual disorders with ovulatory failure, polycystic ovary-appearing ovaries or polycystic ovary syndrome, and hyperinsulinemia. These symptoms may be secondary to epilepsy or to AED treatment, particularly with valproate. In men, effects on sperm quality and motility, delayed sexual development, and small testicular size have been described in association with AED treatment. Carbamazepine reduces testosterone levels, whereas valproate increases androgen levels. Oxcarbazepine is not associated with changes in testosterone levels. Treatment with all of these agents can result in changes in sperm, including concentration, morphology, and motility. Enzyme-inducing AEDs are known to result in decreased thyroid hormones. Recent studies found reduced serum thyroid hormone concentrations in men and young girls treated with carbamazepine and oxcarbazepine. However, all patients were clinically euthyroid, and these changes were reversible after AED withdrawal. Persons with epilepsy treated with AEDs are at increased risk for fracture. Not only is this increased because of seizure activity, but also because of treatment with AEDs. AED treatment results in decreased bone mineral density, the most sensitive predictor of fracture and changes in biochemical indices of bone metabolism, including calcium, vitamin D, and markers of bone formation and resorption. Identifying each of these endocrine abnormalities is important because it may be necessary and beneficial to change AED treatment. In addition, multiple therapies exist for the treatment of polycystic ovary syndrome, infertility, and decreased bone mineral density.

Long‐term effects of intravenous high dose methylprednisolone pulses on bone mineral density in patients with multiple sclerosis

To determine the effects of high dose methylprednisolone (HDMP) pulses on bone mineral density (BMD) in patients with multiple sclerosis (MS), we studied 25 MS patients who received regular pulses of HDMP as well as pulses of HDMP for relapses, 18 MS patients who received HDMP at the same dose schedule only for relapses, and 61 healthy controls. We measured BMDs at lumbar spine and femoral neck and we assessed biochemical markers of bone metabolism and turnover. The average lifetime dosage of MP was 75.4 (SD 11.9) g in the pulsed HDMP group and 28.6 (SD 18.3) g in the HDMP for relapses group (P < 0.0001). Two MS patients (4.7%) and four controls (6.6%) had osteoporosis (P = NS), whereas 25 patients with MS (58.1%) and 21 controls (34.4%) had osteopenia (P = 0.016). BMDs measured at lumbar spine and femoral neck and biochemical indices of bone metabolism did not differ in MS patients and controls. BMD measures were not associated with lifetime methylprednisolone dosage. In partial correlation analysis, controlling for age, gender and menopausal status there was a significant inverse correlation between BMD at femoral neck and Expanded Disability Status Scale (EDSS) score (r = -0.31, P = 0.05). In conclusion, treatment with repeated HDMP pulses was not associated with osteoporosis in patients with MS who participated in a trial of methylprednisolone. However, osteopenia was observed more frequently in MS patients than healthy controls. Our data are reassuring, as them suggest that repeated pulses of methylprednisolone do not result in substantially increased risk of osteoporosis in MS patients. Moreover, osteopenia was found only in patients treated for relapses, who had a significantly higher EDSS score than patients in the HDMP group, suggesting that decreased mobility may contribute to bone loss more than corticosteroid use. BMD should be monitored in patients with MS, regardless of the use of methylprednisolone.

Clinical Experiences Calcium and phosphate balance in children on home nocturnal hemodialysis (NHD)

Objective: To evaluate and describe biochemical indices of bone metabolism in 4 children on NHD. Method:The children, aged 12, 13, 14, and 16 yrs, have been treated exclusively on NHD for 6, 9, 9, and 15 mos. Subsequently, Pt 1 converted to a hybrid program of 4 nights on home nocturnal plus 1 session of in center conventional HD per week. Biochemical indices of bone metabolism have been collected prospectively. Results:All baseline pre‐dialysis calcium levels were within normal ranges and each patient was started on a dialysis calcium concentration of 3.0 mEq/L. However, over time the number of asymptomatic biochemical hypocalcaemic episodes increased. The dialysate calcium concentration was increased to 3.5 mEq/L in one and decreased to 2.0 mEq/L in another who was hypercalcemic and receiving concurrent calcitonin for bone pain related to osteoporosis. In Pt 1, the dialysate calcium was increased to 3.5 mEq/L during nocturnal and continued on hybrid therapy. Including an evaluation of dietary intake, all 4 patients had a net positive calcium balance, ranging between 9.8 to 23.5 mmol (393–942 mg). A significant reduction in the predialysis phosphate level was observed in all 4 patients, and none required dietary restrictions or the use of phosphate binders within 2 months or vitamin D within 6 months of HND. In addition, phosphate was added to provide a dialysate concentration of 2.4–6.1 mEq/L to prevent hypophosphatemia. This is reflected by significant reductions in intact PTH levels to the desired range (twice the normal range) in all 4, but the level continued to drop to the normal range and below in 2. In Pt 1, after introduction of hybrid therapy, both levels of phosphate and PTH rose, necessitating recommencement of phosphate binders and vitamin D. Likewise, the (Ca × PO4) dropped and remained &lt;55 in all 4 patients exclusively on NHD, but started to climb in Pt 1 during hybrid therapy. Conclusion:In our cohort of patients, NHD rapidly lowered plasma phosphate and PTH levels. With NHD, additional dialysate phosphate and possibly calcium may be necessary to prevent chronic losses and development of renal osteodystrophy, and caution is required to prevent either oversuppression of PTH and extraskeletal calcification.

Calorie restriction and skeletal mass in rhesus monkeys (Macaca mulatta): evidence for an effect mediated through changes in body size.

Little is known regarding the effects of prolonged calorie restriction (CR) on skeletal health. We investigated long-term (11 years) and short-term (12 months) effects of moderate CR on bone mass and biochemical indices of bone metabolism in male rhesus monkeys across a range of ages. A lower bone mass in long-term CR monkeys was accounted for by adjusting for age and body weight differences. A further analysis indicated that lean mass, but not fat mass, was a strong predictor of bone mass in both CR and control monkeys. No effect of short-term CR on bone mass was observed in older monkeys (mean age, 19 years), although young monkeys (4 years) subjected to short-term CR exhibited slower gains in total body bone density and content than age-matched controls. Neither biochemical markers of bone turnover nor hormonal regulators of bone metabolism were affected by long-term CR. Although osteocalcin concentrations were significantly lower in young restricted males after 1 month on 30% CR in the short-term study, they were no longer different from control values by 6 months on 30% CR.

Chronic idiopathic neutropenia of adults is associated with decreased bone mineral density and alterations in bone turnover biochemical markers.

The aim of this study was to assess bone mineral density (BMD) and biochemical indices of bone metabolism in patients with chronic idiopathic neutropenia of adults (CINA) and define the relationships, if any, between these parameters and serum levels of interleukin-1beta (IL-1beta) and tumour necrosis factor-alpha (TNF-alpha), two cytokines normally involved in bone metabolism. Femoral neck BMD, serum osteocalcin (OC), bone-specific alkaline phosphatase (BAP) and type I procollagen carboxy-terminal propeptide (PICP), as well as urine-free deoxypyridoline (Dpd) cross-links, N-telopeptide (NTx) and C-telopeptide (CTx) cross-links of type I of collagen were measured in 45 CINA patients and 36 normal subjects. Patients were arbitrarily classified in two groups, A and B, as having mild (neutrophils 1700-2500/microl) or 'pronounced' (neutrophils<1700/microl) neutropenia, respectively. BMD values were found significantly reduced in both groups of patients, compared to controls, and they strongly correlated with the number of circulating neutrophils. Serum OC and urinary NTx were significantly increased in patients of group B. Both serum OC and urinary NTx correlated inversely with the number of circulating neutrophils. Serum BAP and PICP and urine Dpd and CTx were within normal range. Serum IL-1beta and TNF-alpha were elevated in both groups of patients and correlated inversely with the number of circulating neutrophils and the values of BMD. In addition, TNF-alpha, but not IL-1beta, inversely correlated with OC and NTx. These findings indicate that CINA patients have biochemical evidence of increased bone turnover which leads to decreased BMD. The elevated serum IL-1beta and TNF-alpha concentrations, suggestive of an underlying chronic inflammatory process in these patients, may be part of a mechanism accelerating bone turnover which, if prolonged, causes lowering of BMD.

Bsm I polymorphism in the vitamin D receptor gene is related to bone collagen turnover in healthy infants

We examined the vitamin D receptor genotypes (BB, Bb and bb) defined by the BsmI restriction endonuclease in relation to biochemical indices of bone metabolism in healthy Caucasian infants. We measured the serum concentrations of the carboxy-terminal propeptide of type I procollagen (PICP) and the urinary excretion of total pyridinoline, free, total and bound deoxypyridinoline, the type I collagen N-terminal and C-terminal cross-linked telopeptides. The concentrations of the urinary indices are expressed relative to creatinine. Subjects with BB genotype had the highest mean concentrations of free, total and bound deoxypyridinoline and of the N-terminal cross-linked telopeptide (PANOVA = 0.0016, 0.0004, 0.0002 and 0.0053, respectively). BB boys had a higher excretion of the C-terminal cross-linked telopeptide than the other genotypes (PANOVA = 0.0253). In a subgroup of homozygotes aged 10 (1) months, BB subjects had the highest levels of the C-terminal cross-linked telopeptide (p=0.03), and of total deoxypyridinoline (p=0.02) and pyridinoline (p=0.06) concentrations. No significant association between the vitamin D receptor genotype and PICP was found. These data suggest that there may be a contribution of the vitamin D receptor genotype to skeletal metabolism in early childhood.

RETRACTED: Menatetrenone ameliorates osteopenia in disuse-affected limbs of vitamin D- and K-deficient stroke patients

Significant reduction in bone mineral density (BMD) occurs in stroke patients on the hemiplegic and contralateral sides, correlating with the degree of paralysis and vitamin D and K deficiency due to malnutrition, and increasing the risk of hip fracture. We evaluated the efficacy of vitamin K2 (menatetrenone: menaquinone-4; MK-4) in maintaining BMD by comparing serum biochemical indices of bone metabolism between treated and untreated patients. In a random and prospective study, of 108 hemiplegic patients following stroke, 54 received 45 mg menatetrenone daily (MK-4 group, n = 54) for 12 months, and the remaining 54 (untreatment group) did not. Nine patients excluded from the study. The BMD in the second metacarpals and serum indices of bone metabolism were determined. BMD on the hemiplegic side increased by 4.3% in the MK-4 group and decreased by 4.7% in the untreated group (p < 0.0001), while BMD on the intact side decreased by 0.9% in the MK-4 group and by 2.7% in the untreated group (p < 0.0001). At baseline, patients of both groups showed vitamin D and K1 deficiencies, high serum levels of ionized calcium, pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (ICTP), and low levels of parathyroid hormones (PTH) and bone Gla proteins (BGP), indicating that immobilization-induced hypercalcemia inhibits renal synthesis of 1, 25-dihydroxyvitamin D (1, 25-[OH]2D) and compensatory PTH secretion. Both vitamins K1 and K2 increased by 97.6% and 666.9%, respectively, in the MK-4 group. Correspondingly, a significant increase in BGP and decreases in both ICTP and calcium were observed in the MK-4 group, in association with a simultaneous increase in both PTH and 1, 25-[OH]2D. One patient in the untreated group suffered from a hip fracture, compared with none in the MK-4 group. The treatment with MK-4 can increase the BMD of disused and vitamin D- and K-deficient hemiplegic bone by increasing the vitamin K concentration, and it also can decrease calcium levels through inhibition of bone resorption, resulting in an increase in 1, 25-[OH]2D concentration.

Treatment of bone loss in oophorectomized women with a combination of ipriflavone and conjugated equine estrogen

Objective: We previously reported that 0.625 mg/day of conjugated equine estrogen (CEE) could not prevent acute bone loss in the first year after oophorectomy. The effect of additional administration of ipriflavone on bone mineral density (BMD) and biochemical indices of bone remodeling were studied to investigate whether concurrent use of CEE and ipriflavone prevent acute bone loss in the early stages following surgical menopause. Methods: One-hundred and sixteen oophorectomized women were randomly divided into four groups according to treatment; group 1: placebo, n=30; group 2: CEE (0.625 mg/day), n=29; group 3: ipriflavone (600 mg/day), n=30; group 4: CEE (0.625 mg/day) plus ipriflavone (600 mg/day), n=27. Vertebral BMD was measured using dual energy X-ray absorptiometry (DEXA) and two biochemical indices of bone metabolism, urinary pyridinoline (Pyr) and serum intact human osteocalcin (hOC), were also measured before, 24 weeks, and 48 weeks after initiation of treatment. Results: BMD was reduced 48 weeks after treatment by 6.1, 3.9 and 5.1% in groups 1–3, respectively, but by only 1.2% in group 4. Pyr decreased by 49.5, 32.0 and 41.5% in groups 2–4, respectively. hOC also decreased by 45.2 and 21.6% in groups 2 and 4, but increased by 40.5% in group 3, suggesting an inhibitory action of CEE and ipriflavone on the turnover of bone metabolism and stimulatory action of ipriflavone on bone formation. Conclusion: Concomitant use of ipriflavone with CEE from an early stage after oophorectomy inhibited bone loss and was considered to be effective in maintaining bone mass after oophorectomy.

Differential time-related effects of conjugated equine estrogen on bone metabolism in oophorectomized women

Objective: The effects of conjugated equine estrogen (CEE) on bone mineral density (BMD) and biochemical indices of bone remodeling in oophorectomized women were studied for 3 years during estrogen replacement therapy (ERT) to investigate whether 0.625 mg/day of CEE alone prevent acute bone loss in the early stage of surgical menopause. Methods: We divided the subjects into three groups according to interval between oophorectomy and the start of ERT (group 1: less than 2 years after surgery, n = 31; group 2: 2–5 years after surgery, n = 29; and group 3: more than 5 years after surgery, n = 27). Vertebral BMD was measured using dual energy X-ray absorptiometry (DEXA). Two biochemical indices of bone metabolism, urinary deoxypyridinoline (DPyr) and serum intact human osteocalcin (hOC) were also measured. Results: In group 1, continuous ERT with 0.625 mg/day of CEE could not prevent a BMD decrease within the first year. However, by the end of the second year, BMD was restored to the pre-ERT. The same dosage of CEE significantly increased BMD in groups 2 and 3 by the end of the first year. DPyr and hOC levels both decreased dramatically in the initial 6 months of therapy and were stable thereafter. Conclusion: In the initial 2-year period after oophorectomy, 0.625 mg/day of CEE alone could not prevent acute bone loss suggesting that additional therapy for the prevention of osteoporosis may be needed.

Markers of bone and collagen metabolism-problems and perspectives in paediatrics.

This paper gives a short overview of the physiology of biochemical indices of bone metabolism, their origins, the problems of interpretation of their activities and the most important clinical applications in childhood and adolescence. Markers of bone formation are all osteoblast products that enter the circulation; alkaline phosphatase (bone isoform), osteocalcin and type I procollagen peptides. Most of the traditional and new markers for bone resorption analyse the matrix (collagen) degradation products in urine from osteoclast activity. These include urinary hydroxyproline, hydroxylysine glycosides, total or free pyridinoline cross-links and cross-linked N- or C-telopeptides. Many studies have shown that both the old and new markers of bone metabolism are useful tools for basic bone biology research, for defining physiological phenomena in clinical studies, or drug trials of growth modifying therapies (e.g. growth hormone), and for following up individual patients. For the exact interpretation of bone markers it is necessary to define the factors which may influence measurement of the markers, such as age, sex, puberty, height velocity, circadian rhythms, diet, liver function and kidney clearance rates.

Hypovitaminosis D and decreased bone mineral density in amyotrophic lateral sclerosis.

To assess the bone health of patients with amyotrophic lateral sclerosis (ALS), we evaluated the bone density and serum biochemical indices of bone metabolism in 11 ALS patients. The serum concentration of 25-hydroxyvitamin D (25-OHD) was significantly lower in patients (14.0 +/- 3.7 ng/ml) than in controls (25.2 +/- 4.0 ng/ml), at deficient levels (< 10 ng/ml) in 2, and at insufficient levels (10-20 ng/ml) in 9 patients. Serum levels of parathyroid hormone (PTH) and ionized calcium were elevated in 8 and 6 patients, respectively. Dietary intake of vitamin D was below the recommended level (100 IU) in 10 patients, and 10 patients were in a sunlight-deprived state. The metacarpal bone density (MBD) and the metacarpal index (MCI) of the second metacarpal bone were measured by computed X-ray densitometry. Z scores of the MBD and the MCI were negative in 7 and 6 patients, respectively. The serum concentration of 25-OHD was positively correlated with the Z score of the MBD (p < 0.05, r = 0.727) and negatively with the PTH level (p < 0.05, r = -0.410). The degree of dysfunction of hand grip also correlated with the Z score of the MBD (p < 0.05, r = 0.749). These data underscore the importance of hypovitaminosis D and compensatory hyperparathyroidism in the development of osteopenia in patients with ALS.

High prevalence of vitamin D deficiency and reduced bone mass in multiple sclerosis

Female patients with multiple sclerosis (MS) are at risk for osteoporosis because of gender, immobility, and corticosteroid use. Bone mineral density (BMD) was measured by dual x-ray absorptiometry in 80 female MS patients admitted to a tertiary care hospital. All patients completed a questionnaire that included measurements of dietary intake and sunlight exposure. Biochemical indices of bone metabolism and turnover were measured in a random sample of 52 patients. BMD of the lumbar spine and femoral neck was 1 to 2 SDs lower in MS women compared with a healthy reference population. BMD was lower in patients with more severe MS. The mean 25(OH)D level of the sample population (43 nmol/l) was in the insufficient range, and 12 patients (23%) had frank vitamin D deficiency (< 25 nmol/l). BMD and age-related BMD (z scores) at all skeletal sites measured were lowest when 25(OH)D levels were deficient. Parathyroid hormone (PTH) was frankly elevated in 13% of patients. PTH levels were negatively correlated with 25(OH)D levels and with BMD. Dietary intake of vitamin D was below the recommended level in 80% of patients, and 40% reported no weekly sunlight exposure. After controlling for age, cumulative steroid use was not a determinant of BMD. BMD was significantly reduced in female MS patients, which might increase fracture risk two- to threefold. Vitamin D deficiency with secondary hyperparathyroidism is prevalent and is probably a significant cause of low BMD in this population. Vitamin D deficiency in the female MS patient might be safely and inexpensively corrected by the routine use of vitamin D supplements.

The early effects of radioiodine therapy for hyperthyroidism on biochemical indices of bone turnover.

We investigated the early changes following radioiodine therapy for hyperthyroidism, in biochemical indices of bone synthesis and degradation, and their relationship to circulating thyroid hormone concentrations. Prospective follow-up over the first 12 weeks after radioiodine therapy. Six women with clinical and biochemical evidence of hyperthyroidism. Serum concentrations of T4, free T3 and osteocalcin, and urinary excretion of the pyridinium cross-links, pyridinaline and deoxypyridinaline, measured before and weekly for 12 weeks after administration of radioiodine therapy. Biochemical indices of bone metabolism were elevated prior to treatment. There was a brisk reduction in circulating thyroid hormones levels paralleled by a similar fall in pyridinium cross-link excretion, which had returned to normal in five patients by the end of the study. There was a positive correlation between pyridinium cross-link excretion and thyroid hormone concentrations. There was no significant change in serum osteocalcin. Treatment of hyperthyroidism results in prompt correction of the associated increased rate of bone collagen degradation suggesting that effective early correction of hyperthyroidism is desirable to limit its detrimental effect on skeletal mass.

Subcutaneous injection or infusion of gonadotropin releasing-hormone agonist buserelin in the treatment of enlarged uteri harboring leiomyomata

Thirteen women with symptomatic enlarged leiomyomatous uteri completed 6 months treatment with the gonadotropin releasing-hormone agonist (GnRH-a) buserelin, 600 μg daily subcutaneously (s.c.). Seven patients received injections (200 μg thrice daily, I-group) and six infusion by pump (50 μg · min −1 · 2 h −1, P-group). Residual uterine volumes after 6 months therapy were comparable in both study groups (I-group median 37%, range 23 to 74%; P-group median 49%, range 30 to 69%), as were estradiol levels. Symptoms were well controlled within short time. Six months posttreatment follow-up revealed uterine regrowth to pretreatment dimensions in all but 1 patient with recurrence of symptoms in most women. During therapy, several biochemical indices of bone metabolism were significantly elevated, reflecting an increased bone resorption; they were restored within 3 months after cessation of therapy, except for alkaline phosphatase. Triglycerides and HDL-cholesterol did not change during study; cholesterol was slightly, but significantly elevated after 6 months therapy. GnRH-a buserelin, 600 μg daily by s.c. injection or infusion is equally effective in reducing enlarged leiomyomatous uteri. Discontinuation of therapy is followed by uterine regrowth with recurrence of symptoms in most women. The present mode of therapy seems to be beneficial as an adjunct before myomectomy, or in advancing menopause in symptomatic, climacteric women.