Serum osteocalcin (BGP) in tumor-associated hypercalcemia

Serum osteocalcin (BGP) is a new marker of bone turnover that reportedly evaluates bone formation. Thus, its measurement could assess the bone formation rate in tumor-associated hypercalcemia. We measured concentrations of BGP and other parameters of bone metabolism in 54 untreated hypercalcemic cancer patients as compared to 109 healthy subjects. Primary tumor sites were breast (19), lung (11), head and neck (6), multiple myeloma (3), kidney (2), and various (11) or multiple (2). Mean BGP levels were higher in the hypercalcemic subjects, 4.6 +/- 0.4 (SEM) ng/ml, than in the normal subjects, 3.6 +/- 0.1 ng/ml (p less than .05), and were normalized in the 22 patients who could be reevaluated after successful treatment of hypercalcemia with intravenous aminohydroxypropylidene diphosphonate (APD). There was no correlation of BGP levels with age, sex, or renal function. Compared with the Gaussian distribution in the normal subjects, there was a considerable scatter of the data in hypercalcemic patients, suggesting the existence of defined subgroups with abnormally low or abnormally high values. However, we found no significant relationship of BGP concentrations with tumor site or histology or with bone metastatic involvement. We found also no significant correlation between concentrations of serum BGP and total or ionized calcium, alkaline phosphatase, parameters of bone resorption, and indices of parathyroid function. In summary, serum BGP levels were slightly elevated in tumor-associated hypercalcemia and were normalized after successful treatment of hypercalcemia. More importantly, BGP concentrations varied widely even in the subgroups of patients with hypercalcemia accompanying massive bone metastatic involvement or in the patients without detectable skeletal metastases.(ABSTRACT TRUNCATED AT 250 WORDS)     

Serum levels of bone GLA protein (osteocalcin,BGP) and carboxyterminal propeptide of type I procollagen (PICP) in acromegly: Effects of long-term octreotide treatment

Summary We measured serum concentrations of bone Glaprotein (osteocalcin, BGP) and carboxyterminal propeptide of type I procollagen (PICP) in 14 patients with active acromegaly. Blood was collected at 0800 for measurement of bone Gla-protein (BGP), carboxyterminal propeptide of type I procollagen (PICP), and insulin-like growth factor I (IGF-I); growth hormone (GH) was then determined at 15-minute intervals for 3 hours and the integrated mean was calculated. The same protocol was repeated at regular intervals during treatment with the long-acting somatostatin analog, octreotide, 150–450 g/day for 6–33 months (median 15). In a case-control analysis, serum BGP concentrations recorded in the acromegalic patients were significantly elevated (14.2±4.2 g/liter versus 8.0±3.3 g/liter, P<0.001). Octreotide treatment induced a roughly parallel reduction in serum GH, IGF-I, and BGP. We found a significant positive correlation between BGP levels recorded before and during therapy and the logarithm of corresponding mean GH levels (r=0.67, P<0.001). Also IGF-I concentrations were positively correlated with BGP (r=0.66, P<0.001). On the other hand, PICP levels recorded in the acromegalics did not differ from control subjects (146±46 g/liter versus 127±44 g/liter, NS) and no correlation was found between either GH and PICP or IGF-I and PICP. To conclude, the present data are compatible with the view that GH and IGF-I play an important role in the control of BGP but not PICP production. It could be that BGP and PICP are submitted to different hormonal modulation.     

Serum osteocalcin levels are inversely associated with abdominal aortic calcification in men with type 2 diabetes mellitus

Summary

We found that serum osteocalcin (OC) and undercarboxylated OC (ucOC) levels were negatively associated with abdominal aortic calcification in type 2 diabetes mellitus (T2DM) men. This finding suggests that circulating OC and ucOC are not only related to glucose or fat metabolism but also to arteriosclerosis.

Introduction

Recent studies revealed that serum osteocalcin levels were associated with not only bone metabolism but also glucose and fat metabolism. However, the relationship between serum OC levels and arteriosclerosis remains controversial. We examined whether or not bone metabolic markers including OC are associated with abdominal aortic calcification in patients with type 2 diabetes mellitus.

Methods

We recruited 118 men and 100 postmenopausal women with T2DM. We evaluated the abdominal aortic calcification score (ACS) on a lateral lumbar radiograph and examined the association between serum OC or undercarboxylated OC levels and ACS.

Results

The ACS of 3 and greater, which corresponded well to the highest quartile, was significantly and negatively associated with serum OC and ucOC levels in men by logistic regression analyses after adjusting for age, BMI, serum levels of creatinine and LDL cholesterol, radial bone mineral density, smoking, duration of DM, hemoglobin A1c, and the index of insulin resistance [odds ratio (OR) 0.36, 95 % confidence interval (CI) 0.19–0.70, P?<?0.005, and OR 0.28, 95 % CI 0.12–0.69, P?<?0.01, per standard deviation increase in OC and ucOC, respectively]. These observations were still significant after an additional adjustment for other bone markers. In contrast, there were no significant relationships with serum OC or ucOC levels and ACS in women.

Conclusions

These findings suggest that serum OC and ucOC levels are associated with not only bone metabolism but also arteriosclerosis in men, but not in women with type 2 diabetes mellitus.     

Serum inhibin B and follicle-stimulating hormone levels as markers in the evaluation of azoospermic men: a comparison

Inhibin B is a glycoprotein hormone produced mainly by Sertoli cells of the testes in the adult male. It selectively suppresses the secretion of pituitary follicle-stimulating hormone (FSH) and has local paracrine actions in the testes. Its measurement is useful for investigating the role of inhibin B in male gonadal dysfunction. The objective of this study was to investigate the efficacy of serum inhibin B in men with nonobstructive azoospermia in comparison with FSH. Serum concentration of FSH was measured using microparticle enzyme immunoassay, inhibin B by specific solid phase sandwich enzyme-linked immunosorbent assay in men with nonobstructive azoospermia (n = 46) and control fertile men (n = 5). Mean inhibin B and FSH level was 104.6 pg ml(-1) and 4.0 mIU ml(-1) in control men whereas the value for nonobstructive azoospermic men was 17.06 pg ml(-1) and 31.1 mIU ml(-1) respectively. Inhibin B and FSH levels were significantly different in azoospermia than controls (P < 0.0001). There were six cases of nonobstructive azoospermia with normal inhibin B. Testicular histology did not find any evidence of spermatogenesis in three cases with normal inhibin B. This demonstrated that inhibin B was not a superior predictor for testicular function in our study.     

Serum osteocalcin in relation to calcaneal bone mineral density in elderly men and women: a 5-year follow-up

A 5-year follow-up study investigated serum concentrations of total (tOC) and intact (iOC) osteocalcin in relation to calcaneal bone mineral density (BMD). The study comprised two cohorts, 75- and 80-year-olds, both resident in the city of Jyv?skyl?, Finland. Baseline OC and BMD were obtained for 161 men and 233 women, of whom 83 men and 189 women participated in follow-up bone measurements. The mean concentration of tOC increased from 9.6 ± 4.3 to 13.2 ± 8.5 μg/l (P = 0.001) in men and from 11.2 ± 4.9 to 14.0 ± 6.1 μg/l (P < 0.001) in women, whereas mean iOC decreased from 6.4 ± 3.0 to 5.9 ± 3.0 μg/l (P = 0.273) and from 7.7 ± 3.7 to 6.9 ± 3.4 μg/l (P = 0.021) in men and women, respectively. TOC and iOC levels correlated inversely with BMD and change in BMD in both sexes (r ranged from −0.223 to −0.422 and P = 0.048 ≤ 0.001). When we divided the baseline tOC and iOC values into four quartiles, the decrease in BMD was significantly greater in the third tOC quartiles in women and in the fourth tOC and iOC quartiles in men when compared with the lower quartiles. During the 5-year period, 19 men and 59 women sustained at least one fracture. These individuals with fractures had significantly higher iOC values and tended to have higher tOC values compared with the nonfracture group at baseline (P = 0.038 and 0.087, respectively). Our results indicate that baseline serum tOC and iOC were associated with bone loss and predicted fracture in the two cohorts of independently living elderly men and women. Received: December 16, 2000 / Accepted: July 23, 2001     

Serum osteocalcin levels are useful as a predictor of cardiovascular events in maintenance hemodialysis patients

Backgrounds

Osteocalcin (OC) is a known bone metabolic marker and a regulator of glucose and fat metabolisms. Although bone and energy metabolisms are known risk factors for cardiovascular disease (CVD) in hemodialysis (HD) patients, few studies have examined the correlation between OC and CVD. The purpose of this study was to investigate the impact of serum OC levels on the emergence of new CVD events in HD patients.

Methods

We designed a longitudinal, observational cohort study in which the study patients were divided into low- and high-serum OC groups based on a median serum OC level of 71.5 ng/ml.

Results

Cardiovascular disease events were observed in 29 of 126 patients (23.0 %). The number of cumulative CVD events in the low-serum OC group was significantly higher than that in the high-serum OC group, as evaluated by the Kaplan–Meier method (p = 0.0021, log-rank test). Multivariate Cox proportional hazards analysis demonstrated that a low level of serum OC is a significant predictor of a higher incidence of CVD events [hazard ratio, 2.925; 95 % confidence interval, 1.048–9.066; p = 0.0401] after adjustment.

Conclusion

Serum OC level is a significant, independent prognostic factor for CVD events in maintenance HD patients. OC may be useful in predicting new CVD events in HD patients.     

Serum undercarboxylated osteocalcin levels are inversely associated with glycemic status and insulin resistance in an elderly Japanese male population: Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) Study

Summary

Recent animal studies have demonstrated that undercarboxylated osteocalcin upregulates insulin secretion via osteoblast-insulin signaling. However, it remains unclear whether such a pathway exists in humans. This study showed that serum undercarboxylated osteocalcin levels were inversely associated with fasting plasma glucose, hemoglobin A_1c, and homeostasis model assessment of insulin resistance (HOMA-IR) levels in community-dwelling elderly Japanese men.

Introduction

Undercarboxylated osteocalcin (ucOC) was reported to increase insulin secretion and improve glucose tolerance via osteoblast-insulin signaling in animal-based studies. Whether this pathway also exists in humans is unknown. We aimed to clarify whether serum ucOC levels are associated with glycemic status and insulin resistance in the general Japanese population.

Methods

We included 2,174 Japanese men (??65?years) who were able to walk without aid from others and lived at home in four cities of Nara Prefecture. We excluded participants with a history of diseases or medications that affect bone metabolism, other than type 2 diabetes mellitus (T2DM). Fasting plasma glucose, glycated hemoglobin A_1c, and HOMA-IR levels were determined as outcome measures.

Results

Of the 1,597 participants included in the analysis, both intact OC (iOC) and ucOC levels showed significant inverse correlations with all outcome measures, even after adjusting for potential confounders. Mean values of outcome measures showed a significant decreasing trend with higher quintiles of iOC or ucOC after adjusting for confounders. This trend remained significant for ucOC quintiles after further adjustment for iOC levels, but was not significant for iOC quintiles after adjusting for ucOC levels. These results were attenuated, but still apparent, after excluding participants receiving drug therapy for T2DM.

Conclusions

Levels of ucOC, but not iOC, were inversely associated with glycemic index and insulin resistance in a population of Japanese men. These findings will need to be confirmed with longitudinal studies.     

Serum osteocalcin levels before and after 1,25 dihydroxy-vitamin D stimulation in a family with hypophosphatasia.

Because defective bone mineralization occurs in hypophosphatasia (HP) and the source of bone alkaline phosphatase is the osteoblast, we investigated another marker of osteoblast activity, namely the production of osteocalcin in an HP family and controls. The mean basal osteocalcin levels in the two affected young adults and their parents (the apparent heterozygotes) were 3.4 ng/ml (range 2.5-4.6) and were not different from the levels in age- and sex-matched controls (3.6 ng/ml; range 2.5-4.6). Furthermore, the ratio of carboxylated to total osteocalcin was normal. The rise in osteocalcin after 1,25-dihydroxycholecalciferol stimulation (2 micrograms daily for one week) was slightly greater in the controls than in the HP family. These results support the concept that there is no global defect in osteoblast function in this family with HP.     

Serum fluoride and serum osteocalcin levels in response to a novel sustained-release monofluorophosphate preparation: Comparison with plain monofluorophosphate

In a previous study we found that sustained-release monofluorophosphate (MFP-SR), a novel, sustained-release MFP preparation, acutely maintained the basal therapeutic serum fluoride levels without causing the high serum peak levels associated with plain MFP administration. The objective of the present study was to determine (a) whether chronic MFP-SR administration would provide therapeutic serum fluoride levels, and (b) whether treatment with this new preparation would result in an increase in bone formation similar to that achieved with plain MFP. Bone formation was assessed by serum osteocalcin (OC) determination. We studied 17 postmenopausal women older than 60 years and suffering from primary osteoporosis. All had received a minimum of 6 months of continuous treatment with plain MFP at a dose of 152 mg/day (76 mg b.i.d.). Upon entering the study, the subjects were randomized, in a double-masked protocol, to receive either MFP-SR (76 mg b.i.d.) (n=9) or placebo (n=8) for 2 months, after which all subjects returned to the original plain MFP regimen. Serum fluoride and serum OC levels were determined monthly for 3 months. At the beginning of the study serum fluoride levels were in the accepted therapeutic range (5–10 µM) in all patients. Serum fluoride levels were maintained in the patients switched to MFP-SR. In contrast, serum fluoride levels decreased significantly (p<0.005) in the placebo-treated control subjects and returned to therapeutic levels upon switching back to plain MFP. Similarly, serum OC levels remained elevated in the subjects switched to MFP-SR but dropped significantly (p<0.001) in the placebo-treated group. Our results demonstrate that chronic MFP-SR administration, at a dose of 152 mg/day, results in maintenance of therapeutic serum fluoride levels and in stimulation of bone formation. Because we have previously reported that high, supratherapeutic post-absorptive serum fluoride levels are avoided by MFP-SR administration, this novel preparation may prevent side effects associated with plain MFP by reducing the amount of fluoride deposited in bone.     

Serum levels of osteoprotegerin increase with age in a healthy adult population

Regulation of the balance of osteoblastic and osteoclastic activity is critical for the understanding of normal cell biology and forms the basis of metabolic bone diseases. Our study reports about influences of age and gender on serum levels of osteoprotegerin (OPG) and its association to other clinical parameters of bone metabolism in a precisely determined cohort of 1134 healthy subjects at 17 Austrian outpatient bone clinics, aged between 19 and 96 years (females n = 687, 50 ± 21 years, 19–94, and males n = 447, 52 ± 13.5 years, 24–96). Mean OPG serum levels for all participants were 50.83 ± 51.47 pg/ml (n = 1134; median 36, 2–584) and we observed a sharp increase in females after 60 years and in males after 70 years of age. OPG serum levels increased significantly by age, 2.1 pg/ml in females and 1.9 pg/ml in males for every year (P < 0.0001). Correlation of OPG serum levels and several bone parameters of bone metabolism showed that OPG negatively correlated with serum iPTH (r = −0.14; P < 0.001) and with serum estradiol in females (r = −0.16, P < 0.0001). Bone mineral density measured by DXA method at the spine and at the hip did not correlate with OPG serum levels, except a borderline negative correlation at the trochanteric region (r = −0.1, P < 0.05) in females only. Our results show a significant increase of osteoprotegerin with age in healthy females and males but fluctuations do not predict bone mineral density under in vivo conditions.     

Impaired gamma carboxylation of osteocalcin in elderly women with type II diabetes mellitus: relationship between increase in undercarboxylated osteocalcin levels and low bone mineral density

We conducted a cross-sectional examination of the role of serum vitamin K levels as they relate to bone metabolism in elderly women with type II diabetes mellitus (DM). Eighty-five elderly women with type II DM were enrolled. Three fractions of vitamin K, phylloquinone (PK), menaquinone 4 (menatetrenone; MK 4), and menaquinone 7 (MK 7), along with undercarboxylated osteocalcin (UcOC), intact osteocalcin (IOC), urinary deoxypyridinoline (udpd), urinary type I collagen N-telopeptide (NTx), and intact parathyroid hormone (IPTH) were measured. Bone mineral density was measured in the lumbar spine (LSBMD) by dual-energy X-ray absorptiometry (DXA), and T scores or Z scores were calculated. The patients were divided into two groups by T score, under –2.5 (osteoporotic group) and over –2.5 (non-osteoporotic group). UcOC levels in osteoporotics patients were significantly higher than those in the non-osteoporotic group (3.09 ± 3.94 vs 1.82 ± 1.76ng/ml, P = 0.02). The correlation between Z score and logarithmic UcOC/IOC levels in type II DM showed a negative trend (P = 0.07) and a significantly and negatively association with logarithmic NTx (r = –0.38; P = 0.001). In osteoporotic DM, the UcOC/IOC ratio was significantly correlated with the Z score (r = –0.61; P 0.05). Furthermore, logarithmic UcOC/IOC showed a negative correlation with logarithmic MK 7 (r = –0.50; P = 0.001). In conclusion, the reduction in LSBMD in elderly women with type II DM may be associated, in part, with a defect in -glutamylcarboxylation by vitamin K.     

Serum 25-hydroxyvitamin D levels and testosterone deficiency in middle-aged Korean men: a cross-sectional study

Previous studies have demonstrated that male hypogonadism is associated with a low level of vitamin D. However, no reports have investigated the effects of vitamin D on testosterone levels in Korean men. Our aim was to investigate whether testosterone levels are associated with serum vitamin D levels and whether seasonal variation exists. This cross-sectional study analyzed serum 25-hydroxyvitamin D [25(OH)D], total testosterone (TT), and free testosterone (FT) in 652 Korean men over 40 years of age who had undergone a comprehensive medical examination. The average age of the subjects was 56.7 ± 7.9 years, and the mean serum 25(OH)D, TT and FT levels were 21.23 ± 7.9 ng ml⁻¹, 4.70 ± 1.6 ng ml⁻¹, and 8.12 ± 3.3 pg ml⁻¹, respectively. In the multiple linear regression model, 25(OH)D showed positive association with TT (β =0.137, P < 0.001) and FT (β =0.103, P = 0.008). 25(OH)D and FT showed similar seasonal or monthly variation after adjustment for age. A vitamin D deficiency [25(OH)D < 20 ng ml⁻¹] was associated with an increased risk of deficiencies of TT (<2.30 ng ml⁻¹) (odds ratio [OR]: 2.65; 95% confidence interval [CI]: 1.21–5.78, P = 0.014) and FT (<6.50 pg ml⁻¹) (OR: 1.44; 95% CI: 1.01–2.06 P = 0.048) after adjusting for age, season, body mass index, body composition, chronic disease, smoking, and alcohol use. In conclusion, we demonstrated a positive correlation between 25(OH)D and testosterone, which showed similar seasonal variation in Korean men.     

Serum bone gla protein (BGP) and other markers of bone mineral metabolism in postmenopausal osteoporosis

Summary Bone gla protein, the vitamin K-dependent protein synthesized by osteoblasts and measured in blood by radioimmunoassay, has been used as an index of the rate of bone turnover. The relationship of bone gla protein with other markers of bone mineral metabolism was determined in 31 untreated postmenopausal women with the osteoporotic syndrome. In addition to serum osteocalcin (BGP) we measured parathyroid hormone (PTH) (carboxyl and mid-molecule fragments), 25(OH)D, alkaline phosphatase, estradiol (E₂), estrone (E₁), dietary calcium intake, 24 hour urinary calcium excretion, and bone mineral density by CT scan of the lumbar vertebrae. Significant osteopenia was present on CT in untreated postmenopausal osteoporotic women (bone density in 18 out of 31 was below the critical value of 60 mg/cm³). Serum BGP correlated positively with CT scan (r+0.647,P<0.001). CT and age were negatively correlated (r−0.661,P<0.001) while CT and E₂ showed a positive correlation (r+0.554,P<0.01). Unexpectedly, BGP and age revealed a significant negative correlation (r−0.421,P<0.05). These findings suggest a state of low bone turnover in this group with untreated postmenopausal osteoporosis.     

Serum levels of Cartilage Oligomeric Matrix Protein (COMP) increase temporarily after physical exercise in patients with knee osteoarthritis

Background  

COMP (Cartilage oligomeric matrix protein) is a matrix protein, which is currently studied as a potential serum marker for cartilage processes in osteoarthritis (OA). The influence of physical exercise on serum COMP is not fully elucidated.