Daniela Merlotti

Circulating Sclerostin Levels and Bone Turnover in Type 1 and Type 2 Diabetes

CONTEXT Previous observations showed a condition of low bone turnover and decreased osteoblast activity in both type 1 and 2 diabetes mellitus (DM1 and DM2). Sclerostin is a secreted Wnt antagonist produced by osteocytes that regulates osteoblast activity and thus bone turnover. Its levels increase with age and are regulated by PTH. OBJECTIVES The aim of the present study was to evaluate circulating sclerostin levels in patients with DM1 or DM2 with normal renal function and to analyze its relationship with PTH, 25-hydroxyvitamin D, and bone turnover markers. DESIGN, AND SETTING: This was a cross-sectional study conducted at a clinical research center. PARTICIPANTS Forty DM2 and 43 DM1 patients were studied and compared with a reference control group (n = 83). RESULTS In the overall cohort, sclerostin levels were higher in males than in females and significantly increased with age in both genders. The positive correlation between sclerostin and age was maintained in DM1 but not in DM2 patients. Moreover, sclerostin levels were higher in DM2 than in controls or DM1 patients, and this difference persisted when adjustments were made for age and body mass index. Consistent with previous clinical and experimental observations, sclerostin was negatively associated with PTH in nondiabetic patients (r = -0.30; P < 0.01), independently of age and gender. Conversely, an opposite but nonsignificant trend between PTH and sclerostin was observed in both DM1 (r = 0.26; P = 0.09) and DM2 (r = 0.32; P = 0.07) cohorts. CONCLUSIONS These findings suggest that sclerostin is increased in DM2. Moreover, the transcriptional suppression of sclerostin production by PTH might be impaired in both DM1 and DM2.

Selective estrogen receptor modulators for postmenopausal osteoporosis : Current state of development

Selective estrogen receptor modulators (SERMs) are structurally different compounds that interact with intracellular estrogen receptors in target organs as estrogen receptor agonists and antagonists. These drugs have been intensively studied over the past decade and have proven to be a highly versatile group for the treatment of different conditions associated with aging, including hormone-responsive cancer and osteoporosis. Tamoxifen and toremifene are currently used to treat advanced breast cancer and also have beneficial effects on bone mineral density and serum lipids in postmenopausal women. Raloxifene is the only SERM approved worldwide for the prevention and treatment of postmenopausal osteoporosis and vertebral fractures. However, although these SERMs have many benefits, they may also be responsible for some potentially very serious adverse effects, such as thromboembolic disorders and, in the case of tamoxifen, uterine cancer. These adverse effects represent a major concern given that long-term therapy is required to prevent osteoporosis. Moreover, both preclinical and clinical reports suggest that tamoxifen, toremifene and raloxifene are considerably less potent than estrogen.The search for the ‘ideal’ SERM, which would have estrogenic effects on bone and serum lipids, neutral effects on the uterus, and antiestrogenic effects on breast tissue, but none of the adverse effects associated with current therapies, is currently under way. Ospemifene, lasofoxifene, bazedoxifene and arzoxifene, which are new SERM molecules with potential greater efficacy and potency than previous SERMs, are currently under investigation for use in the treatment and prevention of osteoporosis. These drugs have been shown to be comparably effective to conventional hormone replacement therapy in animal models of osteoporosis, with potential indications for an improved safety profile. Clinical efficacy data from ongoing phase III trials are awaited so that a true understanding of the therapeutic potential of these compounds can be obtained.

Prevalence of Paget's disease of bone in Italy

We examined the prevalence of PDB in Italy from radiological, scintigraphic, and biochemical surveys in two Italian towns. Prevalence rates varied from 0.7% to 2.4%, were higher in males than in females, and slightly differed between the two towns. Unlike previous studies in populations of British descent, no secular trend for a decreasing prevalence emerged.

Quantitative ultrasound and dual-energy X-ray absorptiometry in the prediction of fragility fracture in men

Fragility fractures in men represent a major health problem, and this prompts a necessity for reliable tools for the identification of men at risk of fracture. In order to assess the ability of dual-energy X-ray absorptiometry (DXA) and quantitative ultrasound (QUS) in the prediction of fracture risk in men and whether their combination might be useful in a clinical setting, we studied 401 men (age range 45–82 years, mean 60.3±12.5), of whom 133 had osteoporotic fractures and 268 did not. In all subjects we measured bone mineral density at the lumbar spine (BMD-LS) and at the femur, calculating thereafter the standard femoral subregions: neck (BMD-FN), total hip (BMD-T), trochanter (BMD-TR), intertrochanter (BMD-ITR), and Ward’s triangle (BMD-W), by DXA. We also performed ultrasound parameters at the calcaneus: speed of sound (SOS), broadband ultrasound attenuation (BUA) and Stiffness, by Achilles plus, and at the phalanxes: amplitude dependent speed of sound (AD-SoS) and the parameters of the graphic trace: bone transmission time (BTT), fast wave amplitude (FWA), signal dynamic (SDy) and ultrasound bone profile index (UBPI), by Bone Profiler. All DXA and QUS parameters, apart from FWA, were significantly (P<0.001) lower in patients with a history of fracture. BMD at the proximal femur showed the best ability in discriminating men with or without fractures. QUS at the heel showed discriminatory ability significantly better than QUS at the fingers. By logistic regression analysis, adjusted for age and BMI, BMD-T showed the best association with fragility fracture [odds ratio (OR)=3.43, 95% confidence interval (CI)=2.47–4.77]. Among QUS parameters, the highest value of the OR was shown by stiffness (OR=3.18, CI=2.27–4.48). FWA and SDy were not associated with fragility fractures in men. If DXA and QUS were combined, the prediction of the OR of fragility fracture events in men increases; in fact Stiffness was able to increase the OR when added to BMD-LS (OR=5.44, CI=3.16–10.13) and BMD-T (OR=6.08, CI=2.63–14.27). SOS and BUA showed a similar pattern. AD-SoS improved the prediction of fracture only when combined with BMD-LS (OR=4.36, CI=1.99–9.57). If BMD-LS and BMD-FN or BMD-T were combined, the value of the OR increases (OR=4.59, CI=2.27–9.25 and OR=4.68, CI=2.24–9.76), respectively. Our study supports the effectiveness of QUS in the identification of osteoporotic fractures in men. QUS seems to play an independent and complementary role, with respect to DXA, in order to enhance the power for predicting osteoporotic fractures in men.

Mechanisms of impaired bone strength in type 1 and 2 diabetes

Diabetes and osteoporosis are common and complex disorders with an enormous health burden that can be often associated especially in middle-age and elderly individuals. Although there is raising awareness of the higher fractures rates among patients with type 1 (DM1) and 2 (DM2) diabetes, there are few data available on the pathogenetic mechanisms responsible for this increased risk. Importantly, several experimental and clinical observations suggest that bone abnormalities associated with diabetes may differ, at least in part, from those associated with senile or post-menopausal osteoporosis. This implies that specific preventive and therapeutic strategies have to be developed and tested to prevent fractures in DM1 and DM2 patients. It is also likely that shared (i.e. due to glucose-toxicity) as well as different (i.e. due to insulin levels or other hormones) mechanisms may be associated with bone fragility in DM1 and DM2. Moreover, the hypothesis of an endocrine role of the skeleton in the regulation of glucose metabolism and insulin sensitivity has been recently proposed by experimental observations. This review summarizes the recent clinical and experimental advances on glucose tolerance, bone fragility and osteoporosis associated with diabetes.

The Effects of Recombinant TSH on Bone Turnover Markers and Serum Osteoprotegerin and RANKL Levels

OBJECTIVE Recently it was found that thyrotropin (TSH) receptors are present both in osteoclast and osteoblast and that TSH can modulate bone remodeling independent of thyroid hormones. The aim of this study was, firstly, to evaluate the effects of acute administration of TSH on bone remodeling markers both in men and in women and, secondly, to evaluate if these effects are mediated by variations in serum osteoprotegerin (OPG) and receptor activator of nuclear factor-KB ligand (RANKL). DESIGN We studied 30 thyroidectomized patients (10 premenopausal and 10 postmenopausal women, 10 men) affected by thyroid carcinoma on l-thyroxine therapy. Eighty age- and sex-matched subjects were used as controls. A blood sample was drawn from each patient at baseline and 3 and 5 days after recombinant human TSH (rhTSH) administration, in preparation for (131)I whole body scan, to assess serum bone markers and serum OPG and RANKL levels. MAIN OUTCOME At baseline, postmenopausal women and men had significantly higher values of bone turnover markers and serum OPG compared to control subjects. In all thyroidectomized patients serum RANKL was lower than in controls. After rhTSH administration, serum N-terminal propeptide of type-I procollagen (PINP), a marker of bone formation, increased significantly in postmenopausal women, while serum RANKL significantly increased after 3 days in postmenopausal patients and men returning to baseline values at day 5. Serum OPG levels did not change significantly. CONCLUSIONS The low serum TSH observed in thyroidectomized patients on l-thyroxine therapy is associated with an increase of bone turnover in postmenopausal women and men that is associated with an increase of OPG and a decrease of serum RANKL levels. The acute TSH administration results in an increase of PINP, an index of osteoblastic activity, associated with an increase of serum RANKL. The lack of this response in premenopausal women suggests an influence of estrogen status on bone reactivity to TSH.

Characteristics and Familial Aggregation of Paget's Disease of Bone in Italy

This study examined the characteristics of 147 PDB cases from Italy. Our data showed a reduced clinical severity of PDB with respect to other populations and provided further support of the importance of environmental factors (rural area of residence and animal contact) in the pathogenesis of PDB. Familial aggregation was observed in 15% of cases.

Endocrine actions of osteocalcin.

Osteocalcin is the most abundant noncollagenous protein of bone matrix. Once transcribed, this protein undergoes posttranslational modifications within osteoblastic cells before its secretion, including the carboxylation of three glutamic residues in glutamic acid, which is essential for hydroxyapatite binding and deposition in the extracellular matrix of bone. Recent provocative data from experimental observations in mice showed that the circulating undercarboxylated fraction of osteocalcin increases insulin secretion and sensitivity, lowers blood glucose, and decreases visceral fat in both genders, while it enhances testosterone production by the testes in males. Moreover, both total and undercarboxylated osteocalcins increase following physical activity with potential positive effects on glucose tolerance. Despite that these evidences have been only in part confirmed in humans, further prospective investigations are needed to definitively establish the endocrine role of osteocalcin both in the general population and cohorts of patients with diabetes or other metabolic disorders.

FSHR gene polymorphisms influence bone mineral density and bone turnover in postmenopausal women

OBJECTIVE FSH, via its receptor (FSHR), influences bone remodeling and osteoclast proliferation and activity. The aim of this study was to evaluate the influence of two single nucleotide polymorphisms (SNPs) of the FSHR gene on bone mineral density (BMD) and bone turnover markers (bone alkaline phosphatase and type I collagen C-telopeptides) in postmenopausal women. METHODS Two hundred and eighty-nine unrelated postmenopausal women were genotyped for the SNPs rs1394205 and rs6166. BMD was estimated using dual-energy X-ray absorptiometry and quantitative ultrasound (QUS) methodologies. RESULTS AA rs6166 women showed a lower BMD (femoral neck and total body), lower stiffness index (calcaneal QUS), and higher serum levels of bone turnover markers compared to GG rs6166 women. The prevalence of osteoporosis was significantly higher in AA rs6166 women compared with GG rs6166 women. These results were not influenced by circulating levels of FSH and estrogens. CONCLUSION The SNP rs6166 of the FSHR gene significantly influences BMD in postmenopausal women. In particular, AA rs6166 women are at increased risk of postmenopausal osteoporosis compared with GG rs6166 women, independently of circulating levels of FSH and estrogens. Previous studies have demonstrated that this SNP influences cell and tissue response to hyperstimulation of FSHR in vivo and in vitro. Our study results appear in agreement with these experimental data and with known biological actions of FSH/FSHR system in bone homeostasis.

Comparison of Different Intravenous Bisphosphonate Regimens for Paget's Disease of Bone

This randomized study compared different intravenous bisphosphonates in PDB. Zoledronate was superior with respect to pamidronate in achieving biochemical remission, with therapeutic response maintained in most patients at 15 mo. Single neridronate and zoledronate infusion showed a similar efficacy in up to 90% of patients nonresponders to pamidronate.