Klinefelter Bone Microarchitecture Evolution with Testosterone Replacement Therapy.

Klinefelter Syndrome (KS) patients, defined by a 47 XXY karyotype, have increased risk of fragility fractures. We have assessed bone microarchitecture by high resolution peripheral quantitative CT (HR-pQCT) at the radius and tibia in young KS patients, naïve from testosterone replacement therapy (TRT). Areal bone mineral density (BMD) and body composition were assessed by dual X-ray absorptiometry (DXA). Total testosterone (tT) was measured at baseline. Bone measurements have been repeated after 30 months of TRT. We enrolled 24 KS patients and 72 age-matched controls. KS patients were (mean ± SD) 23.7 ± 7.8 year-old. KS patients had significantly lower relative appendicular lean mass index (RALM) and lower aBMD at spine and hip than controls. Ten patients (42%) had low tT level (≤ 10.4 nmol/L). At baseline, we observed at radius a marked cortical (Ct) impairment reflected by lower Ct.area, Ct.perimeter, and Ct.vBMD than controls. At tibia, in addition to cortical fragility, we also found significant alterations of trabecular (Tb) compartment with lower trabecular bone volume (BV/TV) and Tb.vBMD as compared to controls. After 30 months of TRT, 18 (75%) KS patients were reassessed. Spine aBMD and RALM significantly increased. At radius, both cortical (Ct.Pm, Ct.Ar, Ct.vBMD, Ct.Th) and trabecular (Tb.vBMD) parameters significantly improved. At tibia, the improvement was found only in the cortical compartment. Young TRT naïve KS patients have inadequate bone microarchitecture at both the radius and tibia, which can improve on TRT.

Bone health in childhood cancer: review of the literature and recommendations for the management of bone health in childhood cancer survivors.

In the past decades, new cancer treatment approaches for children and adolescents have led to a decrease in recurrence rates and an increase in long-term survival. Recent studies have focused on the evaluation of the late effects on bone of pediatric cancer-related treatments, such as chemotherapy, radiation and surgery. Treatment of childhood cancer can impair the attainment of peak bone mass, predisposing to premature onset of low bone mineral density, or causing other bone side-effects, such as bone quality impairment or avascular necrosis of bone. Lower bone mineral density and microarchitectural deterioration can persist during adulthood, thereby increasing fracture risk. Overall, long-term follow-up of childhood cancer survivors is essential to define specific groups at higher risk of long-term bone complications, identify unrecognized long-term adverse effects, and improve patient care. Children and adolescents with a cancer history should be carefully monitored, and patients should be informed of possible late complications of their previous medical treatment. The International Osteoporosis Foundation convened a working group to review the bone complications of pediatric cancer survivors, outlining recommendations for the management of bone health, in order to prevent and treat these complications.

Anti-osteoporotic treatments in France: initiation, persistence and switches over 6 years of follow-up.

Limited information is available on anti-osteoporotic treatment initiation patterns in France. In 2006-2013, the most frequently prescribed first-line treatment class for osteoporosis was represented by bisphosphonates (alendronic acid and risedronic acid), followed by strontium ranelate. Persistence with anti-osteoporotic treatment was low, with high proportions of treatment discontinuations and switches. INTRODUCTION: This epidemiological, longitudinal study described first-line treatment initiation, persistence, switches to second-line treatment, and medical care consumption in osteoporotic patients in France during the 2007-2013 period. METHODS: Patients aged ≥50 years, who were recorded in a French claims database and did not die during the observation period, were included if they met ≥1 inclusion criteria for osteoporosis in 2007 (≥1 reimbursement for anti-osteoporotic treatment, hospitalisation for osteoporotic fracture (spine, hip, femur, forearm bones, humerus, wrist), or ≥1 reimbursement for long-term osteoporosis-associated status). We collected data on consumption of anti-osteoporotic treatment (alendronic acid, ibandronic acid, risedronic acid, zoledronic acid, raloxifene, strontium ranelate, teriparatide) and of osteoporosis-related medical care after the date of first reimbursement for anti-osteoporotic treatment. RESULTS: We obtained 2219 patients with a 6-year follow-up and 1387 who initiated an anti-osteoporotic treatment in 2007 and who can be selected for the treatment regimen analysis. The most frequently used first-line treatments were alendronic acid (32.7 %), risedronic acid (22.4 %), strontium ranelate (19.3 %), ibandronic acid (13.1 %) and raloxifene (12.2 %). Among patients who received these treatments, the highest persistence after 6 years was observed for raloxifene (37.3 %), alendronic acid (35.1 %) and risedronic acid (32.3 %). Treatment discontinuations were reported for 35.5 % (raloxifene) to 53.4 % (strontium ranelate) and treatment switches for 27.4 % (alendronic acid) to 56.6 % (ibandronic acid) of these patients. CONCLUSIONS: This study showed that persistence with anti-osteoporotic treatment was relatively low in France, with high proportions of treatment discontinuations and switches, and that patients with osteoporosis were insufficiently monitored by bone specialists.

Has sclerostin a true endocrine metabolic action complementary to osteocalcin in older men?

UNLABELLED: The reported association between sclerostin and diabetes mellitus or abdominal fat may be biased by body size and bone mass. In older men, the association between serum sclerostin levels and metabolic syndrome lost significance after adjustment for bone mass. The association between sclerostin and energy metabolism needs further clarification. INTRODUCTION: Sclerostin is associated with abdominal fat, but this relationship may be biased since both are associated with body size and bone mass. Osteocalcin is a bone-derived hormone regulating energy metabolism. We assessed the association between serum sclerostin and metabolic syndrome (MetS) accounting for whole body mineral content (BMC) and osteocalcin. METHODS: We studied 694 men aged 51-85 who had serum osteocalcin and sclerostin measurements. RESULTS: Sclerostin was higher in 216 men with MetS compared with those without MetS (p < 0.005). Average sclerostin level increased significantly across the increasing number of MetS components. In multivariable models, higher sclerostin was associated with higher odds of MetS (odds ratio (OR) = 1.24/1 standard deviation (SD) increase [95 % confidence interval (95 % CI), 1.01-1.51]; p < 0.05). After further adjustment for BMC, the association of MetS with sclerostin lost significance, whereas that with osteocalcin remained significant. Men who were simultaneously in the highest sclerostin quartile and the lowest osteocalcin quartile had higher odds of MetS (OR = 2.14 [95 % CI, 1.15-4.18]; p < 0.05) vs. men being in the three lower sclerostin quartiles and three upper osteocalcin quartiles. After adjustment for whole body BMC, the association lost significance. CONCLUSIONS: Higher sclerostin level is associated with MetS severity; however, this association may be related to higher whole body BMC. The adjustment for BMC had no impact on the association between MetS and osteocalcin. Clinical cross-sectional studies do not elucidate the potential role of sclerostin in the regulation of energy metabolism and direct experimental approach is necessary.

Serum sclerostin: the missing link in the bone-vessel cross-talk in hemodialysis patients?

UNLABELLED: We found for the first time that in maintenance hemodialysis patients, higher sclerostin serum level was associated with severe abdominal aortic calcification (AAC). In addition, cortical bone microarchitecture (density and thickness) assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT) at tibia was also independently associated with severe AAC. These results suggest that sclerostin may be involved in the association of mineral and bone disorder with vascular calcification in hemodialysis patients. INTRODUCTION: Severe abdominal aortic calcifications are predictive of high cardiovascular mortality in maintenance hemodialysis (MHD) patients. In patients with end-stage renal disease, a high aortic calcification score was associated with lower bone turnover on bone biopsies. Thus, we hypothesized that sclerostin, a Wnt pathway inhibitor mainly secreted by osteocytes and acting on osteoblasts to reduce bone formation, may be associated with vascular calcifications in MHD patients. METHODS: Fifty-three MHD patients, aged 53 years [35-63] (median [Q1-Q3]) were included. Serum was sampled before the MHD session to assay sclerostin. Framingham score was computed and the abdominal aortic calcification (AAC) score was assessed according to Kauppila method on lateral spine imaging using DEXA. Tibia bone status was evaluated by high-resolution peripheral quantitative computed tomography (HR-pQCT). Patients were distributed into two groups according to their AAC score: patients with mild or without AAC (score below 6) versus patients with severe AAC (score of 6 and above). RESULTS: In multivariate analysis, after adjustment on age, dialysis duration and diabetes, serum sclerostin and cortical thickness were independently associated with severe AAC (odds ratio (OR) = 1.43 for each 0.1 ng/mL increase [95 % confidence interval (CI) 1.10-1.83]; p = 0.006 and 0.16 for 1 SD increase [0.03-0.73]; p = 0.018, respectively). A second cardiovascular model adjusted on Framingham score and the above mentioned confounders showed similar results. CONCLUSIONS: Elevated sclerostin serum level and poorer tibia cortical bone structure by HR-pQCT were positively and independently associated with higher odds of severe AAC in MHD patients. Serum sclerostin may become a biomarker of mineral and bone disorder and vascular risk in MHD patients.

Multi-frequency shear modulus measurements discriminate tumorous from healthy tissues.

As far as their mechanical properties are concerned, cancerous lesions can be confused with healthy surrounding tissues in elastography protocols if only the magnitude of moduli is considered. We show that the frequency dependence of the tissue's mechanical properties allows for discriminating the tumor from other tissues, obtaining a good contrast even when healthy and tumor tissues have shear moduli of comparable magnitude. We measured the shear modulus G*(ω) of xenograft subcutaneous tumors developed in mice using breast human cancer cells, compared with that of fat, skin and muscle harvested from the same mice. As the absolute shear modulus |G*(ω)| of tumors increases by 42% (from 5.2 to 7.4 kPa) between 0.25 and 63 Hz, it varies over the same frequency range by 77% (from 0.53 to 0.94 kPa) for the fat, by 103% (from 3.4 to 6.9 kPa) for the skin and by 120% (from 4.4 to 9.7 kPa) for the muscle. These measurements fit well to the fractional model G*(ω)=K(iω)n, yielding a coefficient K and a power-law exponent n for each sample. Tumor, skin and muscle have comparable K parameter values, that of fat being significantly lower; the p-values given by a Mann-Whitney test are above 0.14 when comparing tumor, skin and muscle between themselves, but below 0.001 when comparing fat with tumor, skin or muscle. With regards the n parameter, tumor and fat are comparable, with p-values above 0.43, whereas tumor differs from both skin and muscle, with p-values below 0.001. Tumor tissues thus significantly differs from fat, skin and muscle on account of either the K or the n parameter, i.e. of either the magnitude or the frequency-dependence of the shear modulus.

Osteoid osteoma is an osteocalcinoma affecting glucose metabolism.

Osteocalcin is a hormone secreted by osteoblasts, which regulates energy metabolism by increasing ß-cell proliferation, insulin secretion, insulin sensitivity, and energy expenditure. This has been demonstrated in mice, but to date, the evidence implicating osteocalcin in the regulation of energy metabolism in humans are indirect. To address this question more directly, we asked whether a benign osteoblastic tumor, such as osteoma osteoid in young adults, may secrete osteocalcin. The study was designed to assess the effect of surgical resection of osteoid osteoma on osteocalcin and blood glucose levels in comparison with patients undergoing knee surgery and healthy volunteers. Blood collections were performed the day of surgery and the following morning after overnight fasting. Patients and controls were recruited in the orthopedic surgery department of New York Presbiterian Hospital, NY-USA and Hospices Civils de Lyon, France. Seven young males were included in the study: two had osteoid osteoma, two underwent knee surgery, and three were healthy volunteers. After resection of the osteoid osteomas, we observed a decrease of osteocalcin by 62% and 30% from the initial levels. Simultaneously, blood glucose increased respectively by 32% and 15%. Bone turnover markers were not affected. This case study shows for the first time that osteocalcin in humans affects blood glucose level. This study also suggests that ostoid osteoma may be considered, at least in part, as an osteocalcinoma.

Systemic bone effects of biologic therapies in rheumatoid arthritis and ankylosing spondylitis.

Inflammatory joint diseases are responsible of chronic systemic inflammation, joint degradations, deformities, and altered quality of life. Patients suffering from chronic rheumatic diseases also present increased bone fragility and increased fracture risk. Registration of biologic therapies has deeply modified care in rheumatic diseases, especially in rheumatoid arthritis and ankylosing spondylitis. The available biologics are the anti proinflammatory cytokine therapies (TNFα blockers, anakinra and tocilizumab) and the biologics active on T cell activation (abatacept and rituximab). These drugs succeeded in blocking disease activity and joint degradation. They are also able to stop systemic bone loss among patients with inflammatory rheumatic diseases. In this review, we present the current understanding of the inflammatory-induced bone loss and the skeletal effects of biologic therapies in inflammatory joint diseases.

Estrogen-dependent increase in bone turnover and bone loss in postmenopausal women with breast cancer treated with anastrozole. Prevention with bisphosphonates.

Aromatase inhibitors have demonstrated their superiority to tamoxifen as adjuvant therapy for early breast cancer in postmenopausal women, but are associated with an increased risk of fractures. The aim of our study was to analyze bone loss, bone turnover and their determinants in postmenopausal women treated with anastrozole. We investigated bone loss and bone turnover markers (BTM) in a prospective open cohort study of 118 postmenopausal women treated with anastrozole for an early hormone-dependent breast cancer. Women without osteoporosis were not treated and compared with an age-matched control group of 114 healthy women. Osteoporotic patients (T-scoreor=6 courses) and a marked antiestrogenic response--defined by a level of 17beta-estradiol50% between baseline and 1 year--were associated with greater bone loss. In multivariate model, women in the highest quartile of bone loss at the spine (>5.6% at 1 year) and hip (>4.9%) had a marked antiestrogenic response with OR of 10.4 [95% C.I. 1.9-57.2] (p=0.007) and 5.7 [1.3-25] (p=0.024) respectively. Among patients in the surveillance group, those with a normal T-score at both sites (n=46) had also a significant bone loss at spine -3.3+/-0.5% [-4.3 to -2.3], p<0.0001 and at the hip -2.9+/-0.6% [-4.1 to -1.7] p<0.0001. In osteoporotic women treated simultaneously with anastrozole and risedronate, bone loss was prevented at hip, and increased at the spine (+4.1+/-0.9% [2.3 to 5.9], p=0.008), and BTM decreased (-24%, -39% for CTX, p=0.003 and 0.001 vs. changes in the untreated group). Anastrozole increases bone turnover and induces an accelerated bone loss that is significantly related to the suppression of 17beta-estradiol production induced by aromatase inhibitor. The bisphosphonate risedronate prevents anastrozole induced bone loss.