Brian H. Durham

A Detailed Assessment of Alterations in Bone Turnover, Calcium Homeostasis, and Bone Density in Normal Pregnancy

The effects of pregnancy on bone turnover and the potential risk of developing an osteoporotic fracture in pregnancy are controversial. Utilizing biochemical markers of bone formation and resorption and dual‐energy X‐ray absorptiometry (DEXA), bone turnover before, during, and after pregnancy was studied in detail. Ten women (mean age 30 years; range 23–40) were recruited. Prepregnancy data were obtained and then a review was performed at 2‐week intervals, once pregnancy was confirmed, until 14 weeks of gestation and thereafter monthly until term. Bone mineral density (BMD) was estimated by DEXA scanning of hip, spine, and forearm preconception and postpartum. In addition, BMD of the forearm at 14 weeks and 28 weeks gestation was obtained. All pregnancies had a successful outcome. Urinary free pyridinium cross‐links, free pyridinoline (fPyr) and free deoxypyridinoline (fDPyr), were normal prepregnancy (mean [±SD]) 14.6 nmol/mmol (1.8) and 5.0 nmol/mmol (1.0) creat, respectively. By 14 weeks, they had increased to 20.8 nmol/mmol (4.3) and 6.1 nmol mmol (1.4) (both p < 0.02) and by 28 weeks to 26.3 nmol/mmol (5.6) and 7.4 nmol/mmol (1.6) (both p < 0.01). The ratio of fPyr to fDPyr remained constant. A similar significant increase was observed in N‐telopeptide (NTx). Bone formation was assessed by measurement of carboxy‐terminal propeptide of type 1 collagen (P1CP) and bone‐specific alkaline phosphatase (BSAP). Neither were altered significantly before 28 weeks, but subsequently mean P1CP increased from 110 μg/liter (23) to 235 μg/liter (84) at 38 weeks and mean BSAP increased from 11.1 U/liter (5.0) to 28.6 U/liter (11.1) (p < 0.01 for both variables). Lumbar spine (L1–L4) BMD decreased from a prepregnancy mean of 1.075 g/cm (0.115) to 1.054 g/cm2 (0.150) postpartum (p < 0.05). Total hip BMD decreased from a prepregnancy mean of 0.976 g/cm2 (0.089) to 0.941 g/cm2 (0.097) (p < 0.05). Forearm BMD at midradius, one‐third distal and ultradistal decreased but did not reach statistical significance. As assessed by these bone markers, in the first 2 trimesters of pregnancy, bone remodeling is uncoupled with a marked increase in bone resorption. A corresponding increase in formation markers is not observed until the third trimester. Spinal BMD exhibits a significant decrease from prepregnancy to the immediate postpartum period with a mean reduction in BMD of 3.5% in 9 months.

Plasma obestatin levels are lower in obese and post- gastrectomy subjects, but do not change in response to a meal

Objective:To investigate a potential role for obestatin in humans by examining response to a fixed energy meal.Context:A new anorectic peptide hormone, obestatin has recently been isolated from rat stomach. The significance of this peptide in humans is unknown.Study design:Case-control study.Setting:Hospital-based study.Patients:Nine healthy controls, nine morbidly obese subjects and eight post-gastrectomy subjects.Intervention:Subjects attended after an overnight fast and were given a fixed energy meal (1550 kJ).Main outcome measure:The response of obestatin to a meal in the different groups.Results:Fasting obestatin was significantly lower in obese subjects as compared to lean subjects (27.8±4 vs 17.2±2 pg/ml, P=0.03). Obestatin was also decreased in gastrectomy subjects but this did not reach statistical significance (27.8±4 vs 21.9±3 pg/ml, P=0.3). Obestatin did not change significantly from baseline in response to the meal. Lean and obese subjects had a similar obestatin/ghrelin ratio (0.04±0.003 vs 0.05±0.009, P=0.32), but this was higher in the gastrectomy group (0.04±0.003 vs 0.1±0.01, P<0.001).Conclusions:Obestatin does not vary significantly with a fixed energy meal, but is significantly lower in morbidly obese subjects as compared to lean subjects supporting a possible role for obestatin in long-term body weight regulation. Obestatin tended to be lower in gastrectomy subjects and their obestatin/ghrelin ratio differed from healthy controls. Hence, the expression of obestatin is altered following gastrectomy, suggesting other sites outside the stomach may also secrete obestatin.

The association of circulating ferritin with serum concentrations of fibroblast growth factor-23 measured by three commercial assays.

Background: The measurement of the serum concentration of fibroblast growth factor-23 (FGF-23) is beginning to be used as a diagnostic tool in renal phosphate wasting disorders. Having observed an increased serum FGF-23 in three subjects with low circulating ferritin concentrations we investigated the association between low ferritin and raised serum FGF-23. Methods: We measured FGF-23 in 150 random anonymized serum samples with ferritin concentrations between <5 and 50 µg/L using three commercially available enzyme-linked immunosorbent assay (ELISA) kits. One kit, Human FGF-23[C-term] (Immutopics Inc, USA) measures total FGF-23 whereas the other two kits, Immutopics intact and FGF-23 ELISA (Kainos, Japan) are reported to measure only the biologically active intact molecule. Results: We have detected a significant inverse correlation of -0.565 (P<0.0001) between serum ferritin when <50 µg/L and FGF-23 using the C-terminal assay. This relationship is also shown with the Immutopics intact assay but is not demonstrated with the Kainos intact assay. Conclusion: The measurement of FGF-23 by both Immutopics assays is altered in the presence of low circulating concentrations of serum ferritin whereas with the Kainos intact assay this effect was not demonstrated. Serum ferritin should be measured when an elevated FGF-23 is obtained using the Immutopics C-terminal or intact FGF-23 assay to prevent misdiagnosis of the cause of this abnormality.

Parathyroid hormone secretory pattern, circulating activity, and effect on bone turnover in adult growth hormone deficiency.

Adult growth hormone deficiency (AGHD) is associated with osteoporosis. Reports have associated parathyroid hormone (PTH) circadian rhythm abnormalities with osteoporosis. Furthermore, there is evidence of relative PTH insensitivity in AGHD patients. Factors regulating PTH circadian rhythm are not fully understood. There is evidence that serum phosphate is a likely determinant of PTH rhythm. The aim of this study was to investigate PTH circadian rhythm and its circulating activity and association with bone turnover in untreated AGHD patients compared to healthy individuals. We sampled peripheral venous blood at 30-min and urine at 3-h intervals during the day over a 24-h period from 1400 h in 14 untreated AGHD patients (7 M, 7 W; mean age, 49.5 +/- 10.7 years) and 14 age (48.6 +/- 11.4 years; P = NS) and gender-matched controls. Cosinor analysis was performed to analyze rhythm parameters. Cross-correlational analysis was used to determine the relationship between variables. Serum PTH (1-84), phosphate, total calcium, urea, creatinine, albumin, type I collagen C-telopeptides (CT(x)), a bone resorption marker, and procollagen type I amino-terminal propeptide (PINP), a bone formation marker, were measured on all samples. Nephrogenous cyclic adenosine monophosphate (NcAMP), which reflects the renal activity of PTH, was calculated from plasma and urinary cAMP. Urinary calcium and phosphate were measured on all urine samples. Significant circadian rhythms were observed for serum PTH, phosphate, CT(x), and PINP in AGHD and healthy subjects (P < 0.001). No significant rhythm was observed for serum-adjusted calcium. PTH MESOR (rhythm-adjusted mean) was significantly higher (P < 0.05), whereas the MESOR values for phosphate, CT(x) (P < 0.05), and PINP (P < 0.001) were lower in AGHD patients than in controls. AGHD patients had significantly lower 24-h NcAMP (P < 0.001) and higher urinary calcium excretion (P < 0.05). Maximum cross-correlation between PTH and phosphate (r = 0.75) was observed when PTH was lagged by 1.5 h in healthy individuals, suggesting that changes in phosphate precede changes in PTH concentration. PTH/CT(x) and PTH/PINP showed maximum correlation when CT(x) (r = 0.68) and PINP (r = 0.71) were lagged by 3 h. In AGHD patients, compared to controls the maximum correlation between PTH/phosphate (r = 0.88, P = 0.007), PTH/CTx (r = 0.61, P = 0.027), and PTH/PINP (r = 0.65, P = 0.028) was observed when the lag time was reduced by 1.5 h in all variables, with changes in PTH and phosphate occurring at concurrent time points. Our data suggest decreased end-organ sensitivity to the effects of PTH in AGHD patients, resulting in a significantly lower NcAMP, low bone turnover, and higher calcium excretion in the presence of significantly higher PTH concentrations. We have also demonstrated that changes in serum phosphate precede those of PTH, which in turn precede changes in bone resorption and formation in healthy individuals. This relationship was altered in AGHD patients. These results suggest a possible role for GH in regulating PTH secretion and the bone remodeling process.

Effects of peripheral administration of synthetic human glucose-dependent insulinotropic peptide (GIP) on energy expenditure and subjective appetite sensations in healthy normal weight subjects and obese patients with type 2 diabetes

Background  Apart from their role in insulin secretion and glucose homeostasis, the incretin hormones glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic peptide (GIP) exert a number of extra‐pancreatic effects which in the case of GIP remain largely unknown.

Effects of Growth Hormone Administration on Bone Mineral Metabolism, PTH Sensitivity and PTH Secretory Rhythm in Postmenopausal Women With Established Osteoporosis

Introduction: Growth hormone (GH) replacement improves target organ sensitivity to PTH, PTH circadian rhythm, calcium and phosphate metabolism, bone turnover, and BMD in adult GH‐deficient (AGHD) patients. In postmenopausal women with established osteoporosis, GH and insulin like growth factor‐1 (IGF‐1) concentrations are low, and administration of GH has been shown to increase bone turnover and BMD, but the mechanisms remain unclear. We studied the effects of GH administration on PTH sensitivity, PTH circadian rhythm, and bone mineral metabolism in postmenopausal women with established osteoporosis.

The circulating concentration and ratio of total and high molecular weight adiponectin in post-menopausal women with and without osteoporosis and its association with body mass index and biochemical markers of bone metabolism

OBJECTIVES There is increasing evidence suggesting that adiponectin plays a role in the regulation of bone metabolism. DESIGN AND METHODS This was a cross-sectional study of 34 post-menopausal women with and 37 without osteoporosis. All subjects had body mass index (BMI), bone mineral density (BMD), total-, high molecular weight (HMW)-adiponectin and their ratio, osteoprotegerin (OPG), a marker of bone resorption (betaCTX) and formation (P1NP) measured. RESULTS We observed a positive correlation between BMI and BMD (r=0.44, p<0.001). When normalised for BMI, total-, HMW-adiponectin concentrations and HMW/total-adiponectin ratio were significantly lower in obese compared to lean subjects but there was no difference between those with or without osteoporosis. There were significant negative correlations between HMW/total-adiponectin ratio and BMI (r=-0.27, p=0.030) and with OPG (r=-0.44, p<0.001). CONCLUSIONS Our data suggests that there is no significant difference in the circulating concentration of fasting early morning total- or HMW-adiponectin in post-menopausal women with or without osteoporosis. The correlation between HMW/total-adiponectin ratio and OPG may indicate that adiponectin could influence bone metabolism by altering osteoblast production of OPG thereby affecting osteoclasts mediated bone resorption.

Parathyroid hormone‐related protein in the aetiology of fibrous dysplasia of bone in the McCune Albright syndrome

Fibrous dysplasia, observed in bone lesions in the McCune Albright syndrome (MAS), is thought to result from abnormalities in cells of the osteogenic lineage associated with over‐activation of the cAMP signalling pathway in affected cells. The aim of this study was to investigate the role of parathyroid hormone‐related protein (PTHrP) in the aetiology of MAS, and to determine a possible therapeutic role for 1,25‐dihydroxy vitamin D3 (1,25(OH)2D3).

PTH Circadian Rhythm and PTH Target-Organ Sensitivity Is Altered in Patients With Adult Growth Hormone Deficiency With Low BMD

AGHD is associated with osteoporosis. We examined PTH circadian rhythmicity and PTH target‐organ sensitivity in 23 patients with AGHD with low BMD and 20 patients with AGHD with normal BMD. Patients with low BMD had a blunted nocturnal rise in PTH concentration and reduced PTH target‐organ sensitivity compared with patients with normal BMD; these factors may be important in the pathogenesis of AGHD‐related osteoporosis.

Effect of Oral Phosphate and Alendronate on Bone Mineral Density When Given as Adjunctive Therapy to Growth Hormone Replacement in Adult Growth Hormone Deficiency

BACKGROUND Adult GH deficiency (AGHD) is associated with osteoporosis, which occurs as the result of reduced sensitivity of the bone and kidney to the effect of PTH. AIM The aim of the study was to examine the effect of oral phosphate and alendronate therapy on PTH sensitivity, bone turnover, and bone mineral density (BMD) in AGHD patients. METHODS Forty-four AGHD patients were hospitalized for 24 h, and half-hourly blood and 3-hourly urine samples were collected for PTH, nephrogenous cAMP (marker of renal PTH activity), procollagen type-I amino-terminal propeptide, and type-I collagen β C-telopeptide. Patients were randomized to one of six groups: patients who were previously naive to GH were randomized to receive GH replacement (GHR) alone, GHR+alendronate, or GHR+phosphate-sandoz, whereas patients already receiving GHR were randomized to continue GHR alone, GHR+alendronate, or GHR+phosphate-sandoz. Study visits were repeated after 1, 3, 6, and 12 months in the previously GH-naive group and after 12 months in the previously GH-replaced group. BMD was measured at 0 and 12 months. RESULTS Patients receiving GHR+phosphate had greater increases in nephrogenous cAMP and bone markers than patients receiving GHR alone (P < 0.01), and this was associated with greater increases in BMD (P < 0.01). In the GHR+alendronate groups, type-I collagen β C-telopeptide decreased (P < 0.001), and BMD increases were greater than in those receiving GHR alone (P < 0.05). The greatest increases in BMD were seen in patients receiving GHR+phosphate. CONCLUSIONS Phosphate and alendronate therapy given in combination with GHR confer advantage in terms of BMD increase. Phosphate appears to exert its effect by increasing PTH target-organ action, whereas alendronate acts primarily through reduction in bone resorption.