Oxytocin, a new determinant of bone mineral density in post-menopausal women: analysis of the OPUS cohort.
Oxytocin (OT), a neurohypophysial hormone regulated by estrogen and leptin, may play a role in bone metabolism in humans as suggested by animal studies. This study assessed the relationship between OT and bone status in a large population of postmenopausal women.
Subjects were included in the Osteoporosis and Ultrasound study, a 6-year prospective study in a population-based cohort. Final visit data were used for this cross-sectional study. OT, leptin, and estradiol serum levels were measured in 1097 postmenopausal women and compared with bone mineral density (BMD), fractures, and the bone turnover markers (BTMs) procollagen type 1 N-terminal propeptide, bone alkaline phosphatase, and C-telopeptide of type 1 collagen.
The median age was 70.8 years, 16% were osteoporotic, 48% were osteopenic, and 29% had at least one fracture. The OT serum level was related to spine (r = +0.12, P = .0002) and total hip BMD (r = +0.21, P < .0001) and with BTM (procollagen type 1 N-terminal propeptide: r = -0.13, P < .0001, bone alkaline phosphatase: r = -0.07, P = .02, C-telopeptide of type 1 collagen: r = -0.18, P < .0001). The relationship of OT with BMD was independent of BTM. After adjustment for confounding factors, the correlation between OT serum level and BMD remains significant at the hip in women with unmeasurable estradiol or leptin above the median value. There was no significant relationship between OT serum levels and fractures.
High OT levels are associated with high BMD, especially at the hip in women with low estradiol or high leptin serum levels. The mechanism may be explained by the effect of OT on bone turnover.
Breuil V, Panaia-Ferrari P, Fontas E, Roux C…
J. Clin. Endocrinol. Metab. Apr 2014
Oxytocin and bone remodelling: relationships with neuropituitary hormones, bone status and body composition.
There is growing evidence that oxytocin, which regulates appetite, plays a role in bone remodelling and improves osteoporosis. We previously showed a significant decrease in circulating oxytocin levels in postmenopausal osteoporotic women compared to healthy controls. However, factors involved in the pathophysiology of osteoporosis, such as estrogens and leptin, are known to regulate oxytocin secretion. Herein, we evaluated the relationships between oxytocin and other hormonal factors known to regulate bone remodeling and body composition in postmenopausal osteoporotic women, compared to healthy controls.
In 20 postmenopausal women with severe osteoporosis compared to 16 healthy controls, we measured serum levels of oxytocin, high sensitive estradiol, testosterone, FSH, LH, SHBG, TSH, osteocalcin, serum type I collagen carboxy-terminal telopeptide, leptin. Bone mineral density and body composition were also measured with DXA.
Osteoporotic women had significantly lower oxytocin, leptin and LH serum levels and higher CTX and SHBG; all other biological parameters were similar in both groups. Fat mass and lean mass were significantly decreased in osteoporotic women. Oxytocin serum levels were significantly correlated to bone mineral density but not to any other measured parameter, including leptin, estradiol and age. In a logistic regression analysis, osteoporosis remained significantly correlated to oxytocin, regardless of age.
Low oxytocin serum levels appeared to be associated with severe osteoporosis, independently of other factors associated with osteoporosis or known to regulate oxytocin serum levels, such as estradiol or leptin, reinforcing the concept that oxytocin may be involved in the pathophysiology of postmenopausal osteoporosis.
Breuil V, Amri EZ, Panaia-Ferrari P, Testa J…
Joint Bone Spine Dec 2011
Oxytocin controls differentiation of human mesenchymal stem cells and reverses osteoporosis.
Osteoporosis constitutes a major worldwide public health burden characterized by enhanced skeletal fragility. Bone metabolism is the combination of bone resorption by osteoclasts and bone formation by osteoblasts. Whereas increase in bone resorption is considered as the main contributor of bone loss that may lead to osteoporosis, this loss is accompanied by increased bone marrow adiposity. Osteoblasts and adipocytes share the same precursor cell and an inverse relationship exists between the two lineages. Therefore, identifying signaling pathways that stimulate mesenchymal stem cells osteogenesis at the expense of adipogenesis is of major importance for developing new therapeutic treatments. For this purpose, we identified by transcriptomic analysis the oxytocin receptor pathway as a potential regulator of the osteoblast/adipocyte balance of human multipotent adipose-derived stem (hMADS) cells. Both oxytocin (OT) and carbetocin (a stable OT analogue) negatively modulate adipogenesis while promoting osteogenesis in both hMADS cells and human bone marrow mesenchymal stromal cells. Consistent with these observations, ovariectomized (OVX) mice and rats, which become osteoporotic and exhibit disequilibrium of this balance, have significant decreased OT levels compared to sham-operated controls. Subcutaneous OT injection reverses bone loss in OVX mice and reduces marrow adiposity. Clinically, plasma OT levels are significantly lower in postmenopausal women developing osteoporosis than in their healthy counterparts. Taken together, these results suggest that plasma OT levels represent a novel diagnostic marker for osteoporosis and that OT administration holds promise as a potential therapy for this disease.
Elabd C, Basillais A, Beaupied H, Breuil V…
Stem Cells Sep 2008
PMID: 18583541 | Free Full Text
Oxytocin reverses osteoporosis in a sex-dependent manner.
The increase of life expectancy has led to the increase of age-related diseases such as osteoporosis. Osteoporosis is characterized by bone weakening promoting the occurrence of fractures with defective bone regeneration. Men aged over 50 have a prevalence for osteoporosis of 20%, which is related to a decline in sex hormones occurring during andropause or surgical orchidectomy. As we previously demonstrated in a mouse model for menopause in women that treatment with the neurohypophyseal peptide hormone oxytocin (OT) normalizes body weight and prevents the development of osteoporosis, herein we addressed the effects of OT in male osteoporosis. Thus, we treated orchidectomized mice, an animal model suitable for the study of male osteoporosis, for 8 weeks with OT and then analyzed trabecular and cortical bone parameters as well as fat mass using micro-computed tomography. Orchidectomized mice displayed severe bone loss, muscle atrophy accompanied by fat mass gain as expected in andropause. Interestingly, OT treatment in male mice normalized fat mass as it did in female mice. However, although OT treatment led to a normalization of bone parameters in ovariectomized mice, this did not happen in orchidectomized mice. Moreover, loss of muscle mass was not reversed in orchidectomized mice upon OT treatment. All of these observations indicate that OT acts on fat physiology in both sexes, but in a sex specific manner with regard to bone physiology.
Beranger GE, Djedaini M, Battaglia S, Roux CH…
Front Endocrinol (Lausanne) 2015
PMID: 26042090 | Free Full Text
Oxytocin reverses ovariectomy-induced osteopenia and body fat gain.
Osteoporosis and overweight/obesity constitute major worldwide public health burdens that are associated with aging. A high proportion of women develop osteoporosis and increased intraabdominal adiposity after menopause. which leads to bone fractures and metabolic disorders. There is no efficient treatment without major side effects for these 2 diseases. We previously showed that the administration of oxytocin (OT) normalizes ovariectomy-induced osteopenia and bone marrow adiposity in mice. Ovariectomized mice, used as an animal model mimicking menopause, were treated with OT or vehicle. Trabecular bone parameters and fat mass were analyzed using micro-computed tomography. Herein, we show that this effect on trabecular bone parameters was mediated through the restoration of osteoblast/osteoclast cross talk via the receptor activator of nuclear factor-κB ligand /osteoprotegerin axis. Moreover, the daily administration of OT normalized body weight and intraabdominal fat depots in ovariectomized mice. Intraabdominal fat mass is more sensitive to OT that sc fat depots, and this inhibitory effect is mediated through inhibition of adipocyte precursor’s differentiation with a tendency to lower adipocyte size. OT treatment did not affect food intake, locomotors activity, or energy expenditure, but it did promote a shift in fuel utilization favoring lipid oxidation. In addition, the decrease in fat mass resulted from the inhibition of the adipose precursor’s differentiation. Thus, OT constitutes an effective strategy for targeting osteopenia, overweight, and fat mass redistribution without any detrimental effects in a mouse model mimicking the menopause.
Beranger GE, Pisani DF, Castel J, Djedaini M…
Endocrinology Apr 2014
Improved adherence with PTH(1-84) in an extension trial for 24 months results in enhanced BMD gains in the treatment of postmenopausal women with osteoporosis.
The purpose of this study is to examine the effect of PTH(1-84) treatment over 24 months followed by 12 months discontinuation on BMD, bone turnover markers, fractures and the impact of adherence on efficacy.
There is limited information about the effect of PTH(1-84) after 18 months and limited data about the impact of compliance on response to anabolic therapy.
Seven hundred and eighty-one subjects who received active PTH(1-84) in the Treatment of Osteoporosis with Parathyroid hormone trial for approximately 18 months were entered into a 6-month open-label extension. Thereafter, they were followed for 12 additional months after discontinuation of treatment. Endpoints examined included changes in BMD and biochemical markers.
PTH(1-84) treatment over 24 months increased BMD at the lumbar spine by 6.8% above baseline (p<0.05). The total corresponding BMD increases at the hip and femoral neck were 1.1 and 2.2% above baseline. Larger increases in spine BMD were observed in participants with ≥80% adherence to daily injections of PTH(1-84) (8.3% in adherent vs 4.9% in poorly adherent patients). Total hip BMD gains were 1.7% in adherent vs 0.6% in poorly adherent participants. Markers of bone turnover (BSAP and NTx) peaked 6 months after starting PTH(1-84) treatment and declined slowly but remained above baseline at 24 months. After discontinuation of PTH(1-84) treatment (at 24 months), bone turnover markers returned to near baseline levels by 30 months. The adherent group sustained significantly fewer fractures than the poorly adherent group.
PTH(1-84) treatment over 24 months results in continued increases in lumbar spine BMD. Adherence to treatment with PTH(1-84) for up to 24 months is also associated with greater efficacy.
Black DM, Bilezikian JP, Greenspan SL, Wüster C…
Osteoporos Int Apr 2013
Effects of a low-dose oral estrogen only treatment on bone mineral density and quantitative ultrasonometry in postmenopausal women.
The aim of this study was to evaluate an oral low-dose estrogen therapy on bone mineral density (BMD) and quantitative ultrasonometry (QUS) in osteopenic postmenopausal women.
This prospective, open-label cohort study investigated 120 postmenopausal hysterectomized women. Forty-seven women had been treated with 0.3 mg conjugated equine estrogen daily (ET). Primary end point was the change in BMD at the spine after 24 months. Secondary end points were among other changes in QUS at the os calcis and phalanges.
After matching 42 participants in the ET group, 42 controls were analyzed. The change in BMD differed significantly after 24 months (p = 0.019). Women on ET showed significant increase of spine and hip Z-score, whereas controls showed significant decreases in spine and total hip BMD. In QUS of the os calcis and the phalanges, a number of variables showed a significant improvements with ET.
Our results comprised a positive effect of an oral low-dose estrogen therapy on BMD. Limitations of the study are the small sample size and the open-label, non-randomized cohort study design. The findings are in accordance to the common literature and support the use of ET in the primary prevention of postmenopausal bone loss.
Ziller M, Herwig J, Ziller V, Kauka A…
Gynecol. Endocrinol. Dec 2012
New developments in the treatment of osteoporosis.
The last 25 years have seen the development of a plethora of new, effective agents for the treatment of osteoporosis. These agents reduce the risk of spine fractures by up to 70%, hip fractures by 40-50% and non-vertebral fractures by up to 50-80%. Amino-bisphosphonates, taken orally or intravenously, remain the dominant treatment modalities for osteoporosis. These so-called anti-resorptive or anti-catabolic agents stabilize the skeleton and reduce fracture risk in osteoporotic as well as osteopenic individuals. A monoclonal antibody against receptor activator of nuclear factor κB ligand, Denosumab, constitutes a new anti-resorptive agent recently approved worldwide. In younger postmenopausal women, low-dose estrogen or estrogen/progestin still has a place for short-term (up to 5 years) preservation of bone mass, especially in women with menopausal symptoms. Likewise, selective estrogen receptor modulators should be considered in younger postmenopausal women, especially those at increased risk of breast cancer. Anabolic (bone forming) regimens, of which parathyroid hormone is the only agent currently available, aid in the build up of new bone, increase bone mass and improve bone architecture. In cancellous bone, 30-60% increases of bone mass have been documented, but cortical bone thickness also increases. These improvements lead to profound reduction in fracture rates in both the axial and appendicular skeleton. Owing to cost and the need for parenteral administration, in most countries these agents are reserved for severe osteoporosis with multiple fractures.
Eriksen EF, Halse J, Moen MH
Acta Obstet Gynecol Scand Jun 2013
Melatonin promotes angiogenesis during repair of bone defects: a radiological and histomorphometric study in rabbit tibiae.
The pineal gland hormone, melatonin, is an immunomodulator and neuroendocrine hormone; it also stimulates monocyte, cytokine and fibroblast proliferations, which influence angiogenesis. The aim of this study was to investigate the effects of melatonin on angiogenesis during bone defect repair by means of radiological and histomorphometric evaluations of bone response to melatonin implants.
Twenty New Zealand rabbits weighing 3,900-4,500 g were used. Twenty melatonin implants were inserted in the proximal metaphyseal area of the animals’ right tibia and 20 control areas were located in the left proximal metaphyseal area. Following implantation, the animals were sacrificed in groups of five, after 1, 2, 3 and 4 weeks, respectively. Anteroposterior and lateral radiographs were taken, and radiographic thermal imaging analysis was performed for all groups at different time stages following implant insertion. Samples were sectioned at 5 μm and stained using Hematoxylin-Eosin and Masson’s trichrome, supplementing radiographic findings with histomorphometric analysis.
After 4 weeks, radiological images showed complete repair of the bone defects. No healed or residual bone alterations attributable to the presence of the melatonin implant were observed. Histomorphometric analysis at 4 weeks showed the presence of a higher density newly formed bone. There were statistically significant differences in the length of cortical formation between the melatonin group and the control group during the first weeks of the study; there were also statistically significant differences in the number of vessels observed in the melatonin groups at the first two study stages.
Melatonin may have potential beneficial effects on bone defect repair.
Ramírez-Fernández MP, Calvo-Guirado JL, de-Val JE, Delgado-Ruiz RA…
Clin Oral Investig Jan 2013
Melatonin regulates human bone sialoprotein gene transcription.
Melatonin is produced by the pineal gland and regulates various physiological processes including osteoblast differentiation and bone formation. Bone sialoprotein (BSP) is a mineralized connective tissue-specific protein expressed in the early stage of cementum and bone mineralization. To elucidate the effects of melatonin on human BSP gene expression, we utilized human Saos2 osteoblast-like cells. Melatonin (100 nM) increased the level of BSP mRNA at 3 h, and the level became maximal at 12 and 24 h. We then investigated the melatonin-induced transcriptional activity of luciferase constructs (between -84LUC and -868LUC) including different lengths of the human BSP gene promoter transfected into Saos2 cells. The effects of melatonin abrogated in constructs included 2-bp mutations in the two cAMP response elements (CRE1 and CRE2). The effects of melatonin were suppressed by protein kinase A, tyrosine kinase, ERK1/2 and phosphatidylinositol 3-kinase inhibitors. Gel mobility shift assays showed that melatonin increased the binding of nuclear proteins to CRE1 and CRE2, and antibodies against CRE binding protein 1 (CREB1), phospho-CREB1, c-Fos, c-Jun, JunD and Fra2 disrupted CRE1 and CRE2 protein complex formation. These data indicate that melatonin induces BSP transcription via the CRE1 and CRE2 elements in the human BSP gene promoter.
Matsumura H, Ogata Y
J Oral Sci 2014
PMID: 24739710 | Free Full Text