Genome-Wide Association Meta-Analysis of Cortical Bone Mineral Density Unravels Allelic Heterogeneity at the RANKL Locus and Potential Pleiotropic Effects on Bone

Previous genome-wide association (GWA) studies have identified SNPs associated with areal bone mineral density (aBMD). However, this measure is influenced by several different skeletal parameters, such as periosteal expansion, cortical bone mineral density (BMDC) cortical thickness, trabecular number, and trabecular thickness, which may be under distinct biological and genetic control. We have carried out a GWA and replication study of BMDC, as measured by peripheral quantitative computed tomography (pQCT), a more homogenous and valid measure of actual volumetric bone density. After initial GWA meta-analysis of two cohorts (ALSPAC n = 999, aged ∼15 years and GOOD n = 935, aged ∼19 years), we attempted to replicate the BMDC associations that had p<1×10−5 in an independent sample of ALSPAC children (n = 2803) and in a cohort of elderly men (MrOS Sweden, n = 1052). The rs1021188 SNP (near RANKL) was associated with BMDC in all cohorts (overall p = 2×10−14, n = 5739). Each minor allele was associated with a decrease in BMDC of ∼0.14SD. There was also evidence for an interaction between this variant and sex (p = 0.01), with a stronger effect in males than females (at age 15, males −6.77mg/cm3 per C allele, p = 2×10−6; females −2.79 mg/cm3 per C allele, p = 0.004). Furthermore, in a preliminary analysis, the rs1021188 minor C allele was associated with higher circulating levels of sRANKL (p<0.005). We show this variant to be independent from the previously aBMD associated SNP (rs9594738) and possibly from a third variant in the same RANKL region, which demonstrates important allelic heterogeneity at this locus. Associations with skeletal parameters reflecting bone dimensions were either not found or were much less pronounced. This finding implicates RANKL as a locus containing variation associated with volumetric bone density and provides further insight into the mechanism by which the RANK/RANKL/OPG pathway may be involved in skeletal development

Osteoporosis in Men

Produženjem očekivanog trajanja života osteoporoza je postala rastući problem u većini razvijenih zemalja svijeta. U radu se raspravlja o učestalosti, patogenezi, dijagnostičkim kriterijima i mogućnostima liječenja osteoporoze u muškaraca. Svaki treći prijelom kuka događa se u muškaraca, a više od 11 % muškaraca starijih od 50 godina doživi ovaj prijelom. Dijagnoza idiopatske osteoporoze primjenjuje se za muškarce mlađe od 60 godina u kojih nema drugih mogućih uzroka bolesti. U njih je niska mineralna gustoća kosti (BMD) najvećim dijelom posljedica niske vršne koštane mase. U oko 30 % muškaraca nalazi se sekundarna osteoporoza, a involucijska osteoporoza nastaje u muškaraca starijih od 60 godina, kao rezultat smanjenja koncentracije testosterona i IGF-1. S obzirom na rezultate istraživanja koja su pokazala da vrijednost BMD-a u oba spola pruža slične informacije o riziku prijeloma, čini se da se postojeći kriteriji za dijagnozu osteoporoze u žena mogu iskoristiti i za muškarce. U liječenju, bisfosfonati i teriparatid dokazano i značajno povećavaju BMD u muškaraca. Primjena androgena pokazala se učinkovitom u muškaraca s hipogonadizmom, no opravdanost njihove primjene u eugonada još uvijek je predmet rasprava. Povećanjem znanja o metabolizmu kosti i koštanoj pregradnji u novije vrijeme otvorila su se vrata čitavom nizu molekula koje bi u budućnosti mogle postati temelj liječenja osteoporoze u muškaraca.With the prolongation of life expectancy, osteoporosis has become an increasing problem in the majority of developed countries worldwide. The paper discusses the frequency, pathogenesis, diagnostic criteria and treatment options for osteoporosis in men. Every third hip fracture occurs in men, and more than 11 % of the male population over the age of 50 years suffer the fracture. Diagnostic tests for idiopathic osteoporosis are performed in men under 60 years of age without other potential risk factors of developing the disease. In the majority of cases, their low bone mineral density (BMD) is caused by a low peak bone mass. Secondary osteoporosis occurs in about 30 % of men, and involutionary osteoporosis developed in men over 60 years of age results from their decreased testosterone and IGF-1 levels. The study results showing that BMD levels in both sexes provide similar fracture risk information suggest that the existing diagnostic criteria for female osteoporosis can also be employed in men. It has been proved that biphosphonate and teriparitide therapy significantly increase BMD levels in men. The administration of androgens has been shown to be effective in men with hypogonadism, although their validity for patients with eugonadism has not yet been discussed. An improved knowledge of the bone metabolism and bone remodelling has recently opened the door to an extensive series of molecules that may play a key role in the treatment of male osteoporosis in the future

The effect of osteoprotegerin administration on the intra-tibial growth of the osteoblastic LuCaP 23.1 prostate cancer xenograft

Osteoprotegerin (OPG) plays a central role in controlling bone resorption. Exogenous administration of OPG has been shown to be effective in preventing osteolysis and limiting the growth of osteolytic metastasis. The objective of this study was to investigate the effects of OPG on osteoblastic prostate cancer (CaP) metastases in an animal model. LuCaP 23.1 cells were injected intra-tibially and Fc-OPG (6.0 mg/kg) was administered subcutaneously three times a week starting either 24 hours prior to cell injection (prevention regimen) or at 4 weeks post-injection (treatment regimen). Changes in bone mineral density at the tumor site were determined by dual x-ray absorptiometry. Tumor growth was monitored by evaluating serum prostate specific antigen (PSA). Fc-OPG did not inhibit establishment of osteoblastic bone lesions of LuCaP 23.1, but it decreased growth of the tumor cells, as determined by decreases in serum PSA levels of 73.0 ± 44.3% ( P < 0.001) and 78.3 ± 25.3% ( P < 0.001) under the treatment and prevention regimens, respectively, compared to the untreated tumor-bearing animals. Administration of Fc-OPG decreased the proliferative index by 35.0% ( P = 0.1838) in the treatment group, and 75.2% ( P = 0.0358) in the prevention group. The results of this study suggest a potential role for OPG in the treatment of established osteoblastic CaP bone metastases.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42587/1/10585_2004_Article_2869.pd