Skeletal changes in osteoprotegerin and receptor activator of nuclear factor-kappab ligand mRNA levels in primary hyperparathyroidism: effect of parathyroidectomy and association with bone metabolism.

The effect of parathyroid hormone (PTH) on the production of osteoprotegerin (OPG) and ligand of receptor activator of NF-kappaB (RANKL) in human bone is incompletely understood. Most in vitro studies indicate that PTH decreases OPG and increases RANKL production. In primary hyperparathyroidism (PHPT), hypersecretion of PTH leads to enhanced bone resorption and formation with increased risk of fracture. Decreasing PTH levels by surgery normalizes bone metabolism, but the effects on skeletal OPG and RANKL production are unknown. In this study, 24 patients referred to our clinic for evaluation, and treatment of PHPT were included. A transiliac bone biopsy was done before (n = 24) and 12 months after parathyroidectomy (PTX) (n = 21). Biopsies were frozen in liquid nitrogen and RNA extracted using Trizol. A competitive RT-PCR assay for RANKL and OPG mRNA using artificial cDNA standards was developed and used for quantification. Results were normalized for GAPDH mRNA content. Before surgery, the RANKL/GAPDH gene expression ratio showed positive correlations with serum osteocalcin (r = 0.42, P < 0.05) and urinary NTX (r = 0.43, P < 0.05). The OPG/GAPDH mRNA levels in iliac bone before surgery correlated with serum osteocalcin (r = 0.52, P < 0.01), but not with bone resorption markers. The mRNA ratio of RANKL/OPG decreased significantly (P < 0.05) after surgery. In conclusion, RANKL and OPG gene expression within the human bone microenvironment are influenced by PTH, as the ratio RANKL/OPG decreased upon PTX. In addition, locally produced RANKL appears to affect bone turnover in the hyperparathyroid state.

Polymorphisms in the CYP19 and AR genes--relation to bone mass and longitudinal bone changes in postmenopausal women with or without hormone replacement therapy: The Danish Osteoporosis Prevention Study.

Polymorphisms in the androgen receptor ( AR) gene and genes encoding enzymes involved in synthesis of sex steroids (e.g., the CYP19 gene encoding aromatase) have recently received attention in osteoporosis research. In the Danish Osteoporosis Prevention Study, recent postmenopausal women were allocated to either hormone replacement therapy (HRT) or no treatment. We genotyped 1792 women for the CYP19 (TTTA)(n) repeat [short (TTTA)(n 7)] the CYP19 C(1558)-T, and the AR (CAG)(n) repeat polymorphism [short (CAG)(n < 22), long (CAG)(n >or= 22)], and investigated associations with bone mineral density (BMD) and 5-year change in BMD. The CYP19 polymorphisms were in strong linkage disequilibrium. Perimenopausal bone mass or bone loss in untreated women was not associated with the CYP19 polymorphisms. In hormone-treated women, BMD increase in the femoral neck was highest (+0.3%/year) for long CYP19 alleles, lowest (-0.09%/year) for short alleles, and intermediate (-0.002%/year) in heterozygous women, P = 0.015. Differences were also significant in the lumbar spine, total hip, and ultradistal forearm. The C(1558)-T T-allele was associated with a more pronounced response to HRT ( P = 0.04, total hip). AR genotype was not related to BMD, but a modifying effect of sex hormone-binding globulin (SHBG) was present. In the highest SHBG quartile (SHBG > 95 nmol/1, n = 222), AR genotype was associated with baseline BMD (femoral neck: P < 0.001, total hip: P = 0.008), but without a clear gene dosage effect. We have demonstrated that polymorphisms in the CYP19 gene are associated with the magnitude of bone gain in response to HRT and that the (CAG)(n) repeat polymorphism in the AR gene is associated with bone mass in women with high levels of SHBG. These findings emphasize the complexity of the genetics of bone mass and bone loss.

Osteoprotegerin levels in primary hyperparathyroidism: effect of parathyroidectomy and association with bone metabolism.

The effect of parathyroid hormone (PTH) on the production of osteoprotegerin (OPG) remains controversial. Most in vitro studies indicate that PTH decreases OPG secretion by the osteoblast, but in vivo observations are conflicting. In primary hyperparathyroidism (PHPT), hypersecretion of PTH leads to enhanced bone resorption and formation with increased risk of fracture. Patients with PHPT are cured by surgery, resulting in normalization of PTH levels and bone metabolism, but the concomitant effects on OPG production are not known. The hypothesis of the present study was that the circulating level of OPG is diminished in patients with PHPT and increases with successful parathyroidectomy. We also speculated that serum OPG may determine the magnitude of bone loss up to the time of surgery. In the present study, 20 patients (17 women and 3 men, mean age 62 y) with PHPT who were candidates for surgical cure were examined before and 12 months after surgery. Bone turnover markers decreased and BMD increased significantly after surgery. Serum OPG did not correlate with PTH before surgery (r = 0.07, P = 0.77) and was not affected by parathyroidectomy (P = 0.79). After normalization of PTH, bone formation markers showed significant (P1NP) and near-significant (osteocalcin) correlations with serum OPG. In conclusion, serum OPG is not decreased in patients with PHPT, nor is serum OPG to any demonstrable extent regulated by PTH pre- or postoperatively.

Effects of the natural and artificial menstrual cycle on the production of osteoprotegerin and the bone resorptive cytokines IL-1beta and IL-6.

Bone remodelling changes within the menstrual cycle. Though the luteal phase is accompanied by decreased bone resorption, it is also paradoxically a time of increased production of bone resorptive cytokines. The present study examined the hypothesis that changes in serum osteoprotegerin (OPG) within the menstrual cycle prevent the increase in bone remodelling, which would otherwise have been the result of the luteal increase in the capacity for producing resorptive cytokines. The study population consisted of healthy female volunteers: premenopausal women (n = 11, mean age 39.4 y +/- 6.1) without cycle irregularities. Postmenopausal women (n = 11, mean age 56.8 y +/- 3.6) receiving cyclic HRT (estradiol and noretisterone acetate). Luteal and follicular phase blood samples were diluted and cultured for 24 hours with and without lipopolysaccharide (LPS). The supernatant was assayed for IL-1 beta and IL-6 by ELISA. Serum OPG was measured by ELISA. The LPS-stimulated production of IL-1 and IL-6 was significantly higher in the luteal phase. When the analysis was restricted to the natural menstrual cycle, only the increase in IL-1 production remained statistically significant. NTX excretion was similar in the two phases of HRT, but decreased nonsignificantly (p = 0.05) in the luteal phase in the premenopausal women. OPG levels did not exhibit any menstrual cycle-dependent changes. In conclusion, bone resorption is suppressed in the luteal phase through a mechanism that does not involve increases in serum OPG. An increased cytokine secretory capacity of blood cells may be an epiphenomenon particular to the luteal phase but unrelated to bone metabolism.

Discordance between changes in bone mineral density measured at different skeletal sites in perimenopausal women--implications for assessment of bone loss and response to therapy: The Danish Osteoporosis Prevention Study.

Assessing bone loss and gain is important in clinical decision-making, both in evaluating treatment and in following untreated patients. The aim of this study was to correlate changes in bone mineral density (BMD) at different skeletal sites during the first 5 years after menopause and determine if forearm measurements can substitute for dual-energy X-ray absorptiometry (DXA) of the spine and hip. BMD was measured at 0, 1, 2, 3, and 5 years using Hologic 1000/W and 2000 densitometers in 2,016 perimenopausal women participating in a national cohort study. This analysis comprises 1,422 women remaining in the study after 5 years without changes to their initial treatment (hormone-replacement therapy [HRT], n = 497, or none, n = 925). Despite correlated rates of change between forearm and spine (r2 = 0.11; p < 0.01), one-half of those who experienced a significant decrease in spine BMD at 5 years showed no significant fall in forearm BMD (sensitivity, 50%; specificity, 85%; kappa = 0.25). The total hip had significant better agreement with spine (sensitivity, 63%; specificity, 85%; kappa = 0.37; p < 0.01). Analysis of quartiles of change also showed significant better agreement with spine and whole body for the total hip than for the femoral neck or ultradistal (UD) forearm. In a logistic regression analysis for identification of group (HRT or control), the prediction was best for whole body (82.6%) and spine (80.9%), followed by total hip (78.5%) and forearm (74.7%). In conclusion, changes at the commonly measured sites are discordant, and DXA of the forearm is less useful than DXA of the hip or spine in determining the overall skeletal response to therapy or assessing bone loss in untreated women.

[Hormone replacement therapy reduces the risk of forearm fracture in postmenopausal women. Results of the Danish Osteoporosis Prevention Study]. / Behandling med hormonsubstitutionsterapi nedsaetter risikoen for underarmsbrud hos postmenopausale kvinder. Resultater fra Danish Osteoporosis Prevention Study.

In a prospective, controlled, comprehensive cohort trial of 2,016 healthy early postmenopausal women aged 45-58 years we studied fracture prevention through the use of oestrogen. There were two main study arms: a randomised arm (randomised to HRT [n = 502] or not [n = 504]) and a non-randomised arm (on HRT [n = 221] or not [n = 789] by own choice). After five years, an intention-to-treat analysis (n = 2,016) showed a reduction in the overall fracture risk (RR = 0.73, 95% CI: 0.50-1.05) and in the forearm fracture risk (RR = 0.45, 95% CI: 0.22-0.90) with oestrogen. Restriction of the analysis to women who had adhered to their initial allocation of either oestrogen (n = 395) or no oestrogen (n = 977) showed a significant reduction in both the overall fracture risk (RR = 0.61, 95% CI: 0.39-0.97) and the risk of forearm fractures (RR = 0.24, 95% CI: 0.09-0.69). We conclude that it is possible to reduce the number of forearm fractures in early postmenopausal women by the use of oestrogen as primary prevention.

[Markers for risk of IDDM in children of Danish patients with IDDM. A population-based, historical prospective study]. / Markører for IDDM-risiko hos børn af danske IDDM-patienter. En populationsbaseret, historisk prospektiv undersøgelse.

To assess the offspring IDDM recurrence risk in a Danish population-based study and to investigate parental and offspring related biological variables that might influence this risk, we identified 2726 IDDM probands and their 2826 offspring from a background population of 1.725 million people (33% of the Danish population). Proband current age was 20-60 years and age at IDDM onset was 30 years or less. Offspring data were obtained by a questionnaire. The cumulative IDDM risk up to age 30 years was found significantly decreased in maternal offspring compared to paternal offspring (2.3 +/- 0.6% and 5.7 +/- 0.9%, RR = 2.40, 95% CI 1.30-4.47; Mantel Cox: p = 0.004) only if parents were diagnosed with IDDM before offspring birth. However, due to a low number of diabetic offspring of probands diagnosed with IDDM after offspring birth, this observation need to be confirmed in a larger population. Using the Cox proportional hazards model we found that among several biological variables tested separately on offspring of male and female probands, all diagnosed with IDDM before pregnancy, paternal age at IDDM onset was the only statistically significant predictor of IDDM risk in offspring. Our findings may be important for counselling families in which one parent has IDDM.

[Preoperative localization of parathyroid adenomas using Tc-99m-sestamibi]. / Praeoperativ lokalisation af parathyreoideaadenomer ved hjaelp af Tc-99m-sestamibi.

Over an eight month period, ten patients with primary hyperparathyroidism were preoperatively scanned with Tc-99m-Sestamibi in order to locate adenomas. An adenoma was detected in nine patients, of which four were operated and good concordance was found between the scanning and the operative findings. Of the remaining six patients two were inoperable, two refused operation and two died of other causes.