piperidines and Bone-Diseases--Metabolic

The causative link between circulating glucocorticoid excess and osteoporosis is well-established. The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which increases local cortisol production, is expressed in human osteoblasts and its activity increases with age.. We hypothesized that local 11β-HSD1 might mediate an age-related decrease in bone formation and that selective 11β-HSD1 inhibition may enhance bone formation.. A dual-center, phase II, randomized, double-blind, placebo-controlled trial of 90 days' treatment with AZD4017 (a selective 11β-HSD1 inhibitor) was conducted in 55 postmenopausal women with osteopenia. Participants received 400 mg oral AZD4017 twice daily vs matched placebo over 90 days. The primary outcome measure was the impact on the bone formation marker osteocalcin. Secondary objectives included correlation with 11β-HSD1 activity.. At 90 days, osteocalcin levels did not differ between treatment groups: active (mean 22.3 [SD 8.6] ng/mL, n = 22) and placebo (21.7 [SD 9.2] ng/mL, n = 24), with a baseline-adjusted treatment effect of 0.95 (95% CI: -2.69, 4.60). The results from the urinary [THF + alloTHF]/THE ratio (index of 11β-HSD1 activity) and the urinary cortisol/cortisone ratio (index of 11β-HSD2 activity) confirmed a > 90% inhibition of 11β-HSD1 but no change in activity of 11β-HSD2.. This trial demonstrates that AZD4017 selectively inhibits 11β-HSD1 activity in vivo in a safe and reversible manner. Following 90 days of treatment, there is no effect on bone formation, indicating that the relative impairment of bone mineral density in postmenopausal women is not mediated by local intracellular production of cortisol under normal physiological concentrations.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; 11-beta-Hydroxysteroid Dehydrogenase Type 2; Bone Diseases, Metabolic; Bone Remodeling; Female; Glucocorticoids; Humans; Hydrocortisone; Niacinamide; Osteocalcin; Piperidines; Postmenopause

Securinine (Sec) is a naturally derived compound separated from the roots of Securinega suffruticosa, which has long been used as a herbal medicine. Sec is widely known as a GABA receptor antagonist, it is also known as an innate immune cell agonist and has been reported to increase macrophage activity and promote monocyte maturation. On the basis of these studies, we investigated the effect of Sec on osteoclast differentiation and bone resorbing function. We have found that Sec inhibits RANKL-induced osteoclast differentiation, fusion, actin ring formation, and bone resorbing function by the inhibition of gene expression associated with each stage. Moreover, Sec significantly suppressed osteoclastogenesis by decreasing the phosphorylation of p38, Akt, JNK, IκB, and PLCγ2, in pathways involved in early osteoclastogenesis as well as through the subsequent suppression of c-Fos and NFATc1. Finally, Sec effectively protected bone loss induced by the excessive inflammatory responses and activity of osteoclasts in vivo by a micro-CT and histological analysis. In conclusion, our findings suggest that Sec may be a promising drug for bone metabolic diseases such as osteoporosis, which is associated with the excessive activity of osteoclasts.

Topics: Animals; Azepines; Bone Diseases, Metabolic; Cell Differentiation; Herbal Medicine; Heterocyclic Compounds, Bridged-Ring; Humans; Lactones; Mice; Osteogenesis; Piperidines

A series of new 6H-benzofuro[3, 2-c]chromenes (BFC, pterocarpans) with structure-activity relationships were investigated for their potential use in osteoporosis treatment. One of the BFCs 3-piperidylethoxypterocarpan 20 promotes osteoblast differentiation and mineralization at a dose as low as 1 pM via activation of ER/P38MAPK/BMP-2 pathway. When evaluated for in-vivo osteogenic activity in female Sprague-Dawley rats, BFC 20 increased bone mineral density and new bone formation, compared with control at 1.0 and 10.0 mg/kg/body weight by oral gavage for 30 days. The compound was devoid of any uterotrophic effect and led to the new bone formation in adult ovariectomized osteopenic rats. BFC 20 compound also inhibited bone resorption by reducing Ovx induced increase in urinary CTx, thus exhibiting both bone anabolic and anti-catabolic action. Finally, BFC 20 treatment to Ovx rats led to improved trabecular microarchitectural restoration and exhibited therapeutic potential as a dual acting anti-osteoporotic agent for the management of osteoporosis.

Topics: Alkaline Phosphatase; Anabolic Agents; Animals; Biomarkers; Bone Density; Bone Diseases, Metabolic; Bone Morphogenetic Protein 2; Bone Remodeling; Calcification, Physiologic; Cancellous Bone; Cell Differentiation; Female; Osteoblasts; Ovariectomy; Phosphorylation; Piperidines; Pterocarpans; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Receptors, Estrogen; RNA, Messenger; Signal Transduction

Vertebral fracture is the most common osteoporotic fracture, affecting quality of life and increasing mortality. Epidemiological data on incidence of vertebral fracture are scarce in Brazil and throughout Latin America. Our aim was to determine vertebral fracture incidence and risk factors in a female Brazilian population.. Postmenopausal women with low bone mass were studied from the Brazilian placebo group of Arzoxifene Generations Trial (n = 974), followed for up to 5 years. The primary endpoint was new vertebral fractures, detected by X-Ray. Experimental design defined two strata: A. Osteoporosis or previous vertebral fracture with osteopenia; B. Osteopenia without previous fracture. Previous fracture, T-score, ionized calcium, alkaline phosphatase, creatinine and glucose were analyzed at baseline. Crude and adjusted incidence rates of vertebral fractures were estimated and Poisson regression model was used.. Incidence rate was 7.7 (95% CI of 5.4 to 10.9) per 1,000 person-years (PY), increasing as a function of age. Women with new vertebral fractures had higher prevalence of previous nonvertebral fracture after menopause, were older and had lower lumbar spine (LS) T-score. Fracture risk increased by 46% for each unit reduction in LS T-score. Variables correlated with new vertebral fracture were age (p = 0.034), LS T-score, stratum A (p = 0.001 for both) and previous nonvertebral fracture after menopause (p = 0.019). In the final model, LS T-score was the strongest predictor.. Incidence rate of vertebral fracture of 7.7 per 1,000 PY. Age and previous fractures were associated with new vertebral fracture, but LS T-score was the most important predictor.

Topics: Age Distribution; Aged; Aged, 80 and over; Bone Diseases, Metabolic; Brazil; Calcium; Dietary Supplements; Female; Follow-Up Studies; Humans; Incidence; Middle Aged; Osteoporosis, Postmenopausal; Piperidines; Postmenopause; Randomized Controlled Trials as Topic; Risk Factors; Spinal Fractures; Thiophenes; Vitamin D

Adolescent idiopathic scoliosis (AIS) is a complex three dimensional spinal deformity which occurs mostly in prepubertal and pubertal girls. Although bracing and surgery have been the mainstays of treatment for AIS, because of the complications and poor compliance, many patients with this disorder continue to experience significant residual symptoms. The etiology and pathogenesis of AIS is unclear, but recent studies show the association between osteopenia and AIS and imply that osteopenia play a causative role in the development of AIS. Anti-osteoporosis treatment can improve bone strength, prevent osteoporosis and rebalance the OPG-RANK-RANKL system, which may help to prevent curve progression in AIS. This report proposes that anti-osteoporosis treatment may be an effective treatment for AIS.

Topics: Adolescent; Antibodies, Monoclonal, Humanized; Bone Diseases, Metabolic; Denosumab; Female; Humans; Models, Biological; Osteoprotegerin; Piperidines; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Scoliosis

Wrist and ankle fractures are the most frequent causes of complex regional pain syndrome (CRPS type I). The current study examined the temporal development of vascular, nociceptive and bony changes after distal tibial fracture in rats and compared these changes to those observed after cast immobilization in intact normal rats. After baseline testing the right distal tibial was fractured and the hindlimb casted. A control group was simply casted without fracturing the tibia. After 4 weeks the casts were removed and the rats retested. Subsequent testing was performed at 6, 8, 10, 16, and 20 weeks after onset of treatment. Distal tibial fracture or cast immobilization alone generated chronic hindlimb warmth, edema, spontaneous protein extravasation, allodynia, and periarticular osteoporosis, changes resembling those observed in CRPS. Hindlimb warmth and allodynia resolved much more quickly after cast immobilization than after fracture. Previously we observed that the substance P receptor (NK(1)) antagonist LY303870 reversed vascular and nociceptive changes in a sciatic section rat model of CRPS type II. Postulating that facilitated substance P signaling may also contribute to the vascular and nociceptive abnormalities observed after tibial fracture or cast immobilization, we attempted to reverse these changes with LY303870. Hindpaw warmth, spontaneous extravasation, edema, and allodynia were inhibited by LY303870. Collectively, these data support the hypotheses that the distal tibial fracture model simulates CRPS, immobilization alone can generate a syndrome resembling CRPS, and substance P signaling contributes to the vascular and nociceptive changes observed in these models.

Topics: Animals; Body Temperature; Bone Diseases, Metabolic; Casts, Surgical; Disease Models, Animal; Edema; Hindlimb; Indoles; Male; Nociceptors; Piperidines; Rats; Rats, Sprague-Dawley; Reflex Sympathetic Dystrophy; Signal Transduction; Substance P; Tibial Fractures

Estrogen (E) treatment has proven to be effective in preventing bone loss after menopause with, however, some undesirable side effects. Many of these side effects are related to the hormone's actions on reproductive tissues. Raloxifene is an organ-selective estrogen agonist that prevents acute cancellous osteopenia in ovariectomized (OVX'd) growing rats. The effects of raloxifene on adult rats with established bone loss are not known. We now compare the dose response effects of 4 months of treatment with raloxifene and estrogen in 8-month-old rats that had been OVX'd 2 months before treatment. OVX resulted in increased body weight, uterine atrophy and severe cancellous bone loss. Estrogen resulted in a dose-dependent increase in uterine weight in OVX'd rats whereas raloxifene did not promote uterine growth. Both treatments reduced body weight and serum cholesterol. Raloxifene and estrogen were each effective in stabilizing cancellous bone by preventing additional cancellous bone loss, but neither treatment replaced lost bone. These findings provide further evidence that raloxifene is a much more potent estrogen agonist on the skeleton and liver than on the uterus.

Topics: Animals; Bone and Bones; Bone Diseases, Metabolic; Dose-Response Relationship, Drug; Estrogen Antagonists; Ethinyl Estradiol; Female; Ovariectomy; Piperidines; Raloxifene Hydrochloride; Rats; Rats, Sprague-Dawley

In mature female and male rats sex hormone deficiency was produced by surgical castration and by antiestrogen or antiandrogen administration. For the latter purpose we used the nonsteroidal antiestrogens tamoxifen, keoxifene (LY156758) and tetramethylhexestrol, and the steroidal antiandrogen cyproterone acetate. Dosages of 0.4 mg tamoxifen/rat/day and isomolar dosages of keoxifene and tetramethylhexestrol led to a bone mass reduction which was comparable to ovariectomized rats. Cyproterone acetate showed, at 10 mg/rat/day, a similar decrease in bone mass like orchidectomy. The often discussed intrinsic estrogen activity of the antiestrogens was present only in the highest dosage tested of tamoxifen. Keoxifene and tetramethylhexestrol showed no estrogenic effects, but this may be a dosage problem. Cyproterone acetate revealed no androgenic side-effects. These results indicate that antigonadal hormone drugs reduce bone mass to a varying extent.

Topics: Androgen Antagonists; Animals; Bone Density; Bone Diseases, Metabolic; Cyproterone; Cyproterone Acetate; Estrogen Antagonists; Female; Hexestrol; Male; Orchiectomy; Ovariectomy; Piperidines; Raloxifene Hydrochloride; Rats; Tamoxifen; Testosterone