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Abstract
There is a persuasive rationale from the use of hormone replacement therapy (HRT) at the time of the menopause, but there are a number of factors which limit its widespread application for osteoporosis. These relate partly to the long-term efficacy of HRT when given for a finite duration at the time of the menopause, and long-term prospective studies are warranted to address this issue. In addition, there are problems in the acceptability of, and long-term compliance with, many HRT regimens. A further difficulty relates to the logic of targeting women at risk from osteoporosis at the time of the menopause when the benefits and risks of HRT are largely extraskeletal. There may be a case for targeting HRT much later in life provided that HRT regimens can be made acceptable to such patients. Finally, the importance of the menopause to the problems of osteoporosis has been overemphasized, and other factors are important in determining the geographic variation in hip fracture risk as well as the increase in age- and gender-specific incidence that has occurred in many countries. The causes from this are unknown, but are clearly not related to gonadal status, because these phenomena are observed both in men and in women. A plausible hypothesis is the differences in physical activity between communities and the decrease in physical activity within communities. It will be important to determine the etiology of these phenomena so that logical preventive strategies can be developed.
... Rapid postmenopausal bone loss is characterized by decrease in trabecular density and deterioration of bone architecture leading to osteoporosis [1][2][3][4]. Estrogen deficiency has been identified as causal factor for post-menopausal bone loss [5][6][7]. Ovariectomized rat is a useful model to simulate the estrogen deficient, postmenopausal human osteoporosis. This model exhibits a progressive loss of bone matrix through a process that is similar to what occurs during post-menopausal osteoporosis [8]. ...
... Osteoporosis is a disease of high prevalence with increased bone loss, substantial morbidity and mortality soon after natural or surgical menopause [2,6,28]. Physiological concentrations of estradiol have been shown to offer antioxidant protection [29,30]. ...
Methods:
Twenty four female adult rats, 90days old showing regular estrous cycles were used for the present study. The animals were divided into two groups. The Group-1 rats (n=6) were sham operated and Group-II rats were bilaterally ovariectomized (n=18) and treated with C. quadrangularis for sixty days (100mg/kg body weight and 250mg/kg body weight). After sixty days, the rats were killed, femora were dissected out, minced and homogenized in Tris-HCl buffer (pH 7.4) and the supernatant was collected and used for biochemical assays.
Results:
Ovariectomy registered a decrease (p<0.05) in the activities of SOD, GPx, GST, ALP, collagen content and increased (p<0.05) the activities of TRAP and lipid peroxidation. Simultaneous administration of C. quadrangularis maintained the enzyme activities in ovariectomized rats.
Conclusion:
C. quadrangularis, a natural herb may be used to treat the estrogen deficiency/menopause onset and ovariectomy induced oxidative stress.
... Osteoporosis is a progressive chronic disease of bone metabolism, characterized by decreased bone mass and mineral density and deterioration of bone architecture, which predisposes individuals to an increased risk of fractures. One of the most frequent causative factor is the decline in oestrogen levels, as it occurs during menopause [90]. Among the several effects on bone, oestrogen protect cells of the osteogenic lineage, including Oc, from apoptosis and senescence [91]. ...
Age-related musculoskeletal disorders, including osteoporosis, are frequent and associated with long lasting morbidity, in turn significantly impacting on healthcare system sustainability. There is therefore a compelling need to develop reliable preclinical models of disease and drug screening to validate novel drugs possibly on a personalized basis, without the need of in vivo assay. In the context of bone tissue, although the osteocyte network is a well-recognized therapeutic target, current in vitro preclinical models are unable to mimic its physiologically relevant and highly complex structure. To this purpose, several features are needed, including an osteomimetic extracellular matrix, dynamic perfusion, and mechanical cues (e.g., shear stress) combined with a 3D culture of osteocytes. Here we describe, for the first time, a high throughput microfluidic platform based on 96-miniaturized chips for large-scale preclinical evaluation to predict drug efficacy. We bioengineered a commercial microfluidic device that allows real-time visualization and equipped with multi-chips by the development and injection of a highly stiff bone-like 3D matrix, made of a blend of collagen-enriched natural hydrogels loaded with hydroxyapatite nanocrystals. The microchannel, filled with the ostemimetic matrix and osteocytes, is subjected to passive perfusion and shear stress. We used scanning electron microscopy for preliminary material characterization. Confocal microscopy and fluorescent microbeads were used after material injection into the microchannels to detect volume changes and the distribution of cell-sized objects within the hydrogel. The formation of a 3D dendritic network of osteocytes was monitored by measuring cell viability, evaluating phenotyping markers (connexin43, integrin alpha V/CD51, sclerostin), quantification of dendrites, and responsiveness to an anabolic drug. The platform is expected to accelerate the development of new drug aimed at modulating the survival and function of osteocytes.
... The first three life decades are spent creating a 'bone bank' that is used for the remainder of the life-course 31 . The female preponderance of bone loss is due to life-course variability in estrogen levels, which inhibit prolonged bone resorption 4 . The effect of menopause on bone health can be mediated through lifestyle factors and calcium supplements available to women today. ...
Remodelling is a fundamental biological process involved in the maintenance of bone physiology and function. We know that a range of health and lifestyle factors can impact this process in living and past societies, but there is a notable gap in bone remodelling data for populations from the Pacific Islands. We conducted the first examination of femoral cortical histology in 69 individuals from ca. 440–150 BP Taumako in Solomon Islands, a remote ‘Polynesian Outlier’ island in Melanesia. We tested whether bone remodelling indicators differed between age groups, and biological sex validated using ancient DNA. Bone vascular canal and osteon size, vascular porosity, and localised osteon densities, corrected by femoral robusticity indices were examined. Females had statistically significantly higher vascular porosities when compared to males, but osteon densities and ratios of canal-osteon (~ 8%) did not differ between the sexes. Our results indicate that, compared to males, localised femoral bone tissue of the Taumako females did not drastically decline with age, contrary to what is often observed in modern populations. However, our results match findings in other archaeological samples—a testament to past female bone physiology resilience, also now observed in the Pacific region.
... In women, menopause causes abnormal bone metabolism due to a decrease in female hormones, such as estrogen. 31 The delayed or inadequate healing of extraction sockets caused by the combined use of BMA and steroids has been described, and both have been reported as risk factors for ARONJ. 10 However, the interrelationship between BMA and steroids is unknown. ...
Background/purpose
Delayed healing of the extraction socket is not uncommon when tooth extraction is performed on patients taking prednisolone. This study aimed to identify specific dosage of prednisolone and factors associated with delayed healing of the extraction socket in patients taking prednisolone.
Materials and methods
This single-center retrospective study included 80 patients who underwent tooth extraction under local anesthesia and were taking prednisolone orally. Patients were divided into the nondelayed healing group (n = 50) and delayed healing group (n = 30), and their background and dosage of prednisolone were compared.
Results
The dosage of prednisolone was significantly higher in the delayed healing group than in the nondelayed healing group. A receiver operating characteristics curve analysis resulted in moderate accuracy when the cutoff value was set at 8.0, with 67% sensitivity, 76% specificity, and 0.765 area under the curve. The multivariate logistic regression analysis revealed that prednisolone dosage >8.0 mg/day (odds ratio [OR], 10.8; 95% confidence interval [CI], 2.79–41.6) and osteosclerotic changes beyond the alveolar bone around the tooth to be extracted (OR, 10.3; 95% CI, 2.81–37.8) in X-ray imaging had significant effects on delayed healing.
Conclusion
The results of this study suggested that delayed healing following tooth extractions in patients taking prednisolone was related to a dosage of 8.0 mg/day or higher and osteosclerotic changes.
... Similar to the other diseases discussed above, the effect of menopause and estrogen on bone health has been extensively researched (Kanis 1996;Melton et al. 1992;Dobbs et al. 1999). Osteoporosis is a skeletal disease that produces weakened bones and increases the risk of fractures (Beekman et al. 2019). ...
Glaucoma is a leading cause of irreversible blindness worldwide and is characterized by progressive loss of visual function and retinal ganglion cells (RGC). Current epidemiological, clinical, and basic science evidence suggest that estrogen plays a role in the aging of the optic nerve. Menopause, a major biological life event affecting all women, coincides with a decrease in circulating sex hormones, such as estrogen. While 59% of the glaucomatous population are females, sex is not considered a risk factor for developing glaucoma. In this review, we explore whether menopause is a sex-specific risk factor for glaucoma. First, we investigate how menopause is defined as a sex-specific risk factor for other pathologies, including cardiovascular disease, osteoarthritis, and bone health. Next, we discuss clinical evidence that highlights the potential role of menopause in glaucoma. We also highlight preclinical studies that demonstrate larger vision and RGC loss following surgical menopause and how estrogen is protective in models of RGC injury. Lastly, we explore how surgical menopause and estrogen signaling are related to risk factors associated with developing glaucoma (e.g., intraocular pressure, aqueous outflow resistance, and ocular biomechanics). We hypothesize that menopause potentially sets the stage to develop glaucoma and therefore is a sex-specific risk factor for this disease.
Graphical Abstract
... A variety of local shapes not straightforward to categorize as rod or plate exist in all our trabecular bone samples. formation, and thus to a lower amount of bone [3]. Lower bone mass causes reduced mechanical competence and increased fracture risk with age [4]. ...
Changes in trabecular micro-architecture are key to our understanding of osteoporosis. Previous work focusing on structure model index (SMI) measurements have concluded that disease progression entails a shift from plates to rods in trabecular bone, but SMI is heavily biased by bone volume fraction. As an alternative to SMI, we proposed the ellipsoid factor (EF) as a continuous measure of local trabecular shape between plate-like and rod-like extremes. We investigated the relationship between EF distributions, SMI and bone volume fraction of the trabecular geometry in a murine model of disuse osteoporosis as well as from human vertebrae of differing bone volume fraction. We observed a moderate shift in EF median (at later disease stages in mouse tibia) and EF mode (in the vertebral samples with low bone volume fraction) towards a more rod-like geometry, but not in EF maximum and minimum. These results support the notion that the plate to rod transition does not coincide with the onset of bone loss and is considerably more moderate, when it does occur, than SMI suggests. A variety of local shapes not straightforward to categorize as rod or plate exist in all our trabecular bone samples.
... It has been suggested that weight-bearing exercises are particularly necessary to help develop and maintain strong bones (Woolf & Akesson, 2008;Dalsky, 1987;Riggs & Melton, 1992;Kanis, 1996). Among all type of exercises, circuit training programs has been suggested enables to increase muscular strength, endurance, power and cardio respiratory endurance (Gettman & Pallock, 1998). ...
This study investigated the effects of 6 weeks combined circuit training programme and honey supplementation on bone metabolism markers in young males. Forty male participants were divided into four groups (n=10 per group): sedentary without honey supplementation control (C), sedentary with honey supplementation (H), circuit training without honey supplementation (Ex), circuit training with honey supplementation (HEx) groups. Circuit training was carried out one hour/session, 3 times/week. Participants in H and HEx consumed 300 mL of honey drink containing 20 g of Tualang honey for 7 days/week. Immediately before and after six weeks of experimental period, blood samples were taken for measuring concentrations of serum total calcium, serum alkaline phosphatase as bone formation marker and serum C-terminal telopeptide of type 1 collagen (1CTP) as bone resorption marker. There was significantly (p<0.05) greater serum alkaline phosphatase concentration in HEx at post test compared to pre test value. Meanwhile, significant (p<0.05) reduction in serum 1CTP were found in both H and HEx groups at post test compared to their pre test value respectively. Combination of circuit training and honey supplementation elicited greater effects on bone turnover markers generally compared to circuit training alone, honey supplementation alone and sedentary without honey supplementation.
... WHO defines osteoporosis as "BMD of subjects with a T-score at or below -2.5 standard deviation (SD)" while osteopenia is defined as a T-score between -1.0 and -2.5 SD below the average BMD of a young adult (Kanis 1994;Schuit et al. 2004) ( Table 2.2). Osteoporosis affects mainly women due to the fact that they have a lesser bone mass, higher bone loss and longer life expectancy compared to men (Kanis 1996). ...
Osteoporotic fractures are the clinical endpoint of osteoporosis. Previous studies have
reported that osteoporosis is associated with a delay in fracture healing but clinical
evidence is still lacking. Various factors such as transforming growth factor (TGF-β)
and oxidative stress may be considered as pathogenic factors for bone loss and
delayed fracture healing through inhibition of differentiation and induction of
apoptosis of osteoblasts. Piper sarmentosum (P.s) is a herb commonly used in
Malaysia as traditional medicine. Its extract has been reported to possess antioxidant,
anticarcinogenic and anti-inflammatory properties. It also contains a natural
scavenging antioxidant, naringenin. The aim of this study was to determine the effects
of aqueous extract of P.s on fracture healing in oestrogen deficient osteoporotic rats by
observing histological, radiological, biochemical and biomechanical changes. A pilot
study was performed prior to the main study to determine the time needed for
ovariectomy to induce osteoporosis based on bone structural histomorphometry. Forty
eight female Sprague-Dawley rats weighing 200-250gm were randomly divided into 4
groups: (i) Sham-operated (SO) group; (ii) Ovariectomised-control (OVXC) group;
(iii) Ovariectomised + oestrogen replacement therapy (OVX+ERT) (100 μg/kg /day)
group; (iv) Ovariectomised + P.s extract (OVX+P.s) (125 mg/kg) group. The right
femora of all the rats were fractured at the mid-diaphysis and K-wires were inserted
for internal fixation six weeks after ovariectomy. Following the fracture, all the rats
received the above treatment for another 6 weeks. The animals were then sacrificed
and the fractured right femora were harvested. For the pilot study, bone volume/tissue
volume (BV/TV) and trabecular number (Tb.N) reduced significantly, while
trabecular separation (Tb.Sp) increased significantly in ovariectomised rats, compared
to the control group 6 weeks post-ovariectomy (P<0.05). In the main study, the
median histological fracture healing scores (Allen’s score) for the SO, OVX+ERT and
OVXC+P.s groups were significantly higher, compared to the OVXC group. Under
radiological examination, the median fracture healing scores (Warden’s score) for the
SO, OVX+ERT and OVXC+P.s groups were significantly higher, compared to the
OVXC group, while the median callus score and the mean axial callus volume for the
SO, OVX+ERT and OVXC+P.s groups were significantly lower, compared to the
OVXC group. Under biomechanical examination, the mean flexure load, flexure stress
and Young’s modulus for the OVXC group were significantly decreased, compared to
the SO, OVX+ERT and OVXC+P.s groups. Percentage change of the plasma level of
TGF-β1 before treatment was decreased significantly in the OVXC, OVX+ERT and
OVXC+P.s groups, compared to the SO group, while after 6 weeks of treatment, the
level of TGF-β1 in the OVX+ERT group was increased significantly, compared to the
OVXC and OVXC+P.s groups (P<0.05). Treatment with P.s extract showed
improvement in biomechanical strength of the callus. Under radiological examination
there was reduction in callus volume and callus score. There was evidence of
improvement of fracture healing score as observed by histological examination.
Flavonoid compound present in P.s through its free radical-scavenging activity, may
be used effectively to improve healing of osteoporotic fractures. In conclusion,
effective supplementation of P.s extract in the oestrogen-deficient state is beneficial
for the fracture healing process.
... A marked increase has been observed in the incidence of OA and OP among postmenopausal women (33). The manner in which bone loss occurs in postmenopausal OP is determined by the differences in skeletal metabolism and architecture. ...
The aim of the present study was to observe the effect of ultrasound (US) on estradiol level, bone mineral density (BMD), bone biomechanics and matrix metalloproteinase-13 (MMP-13) expression in ovariectomized (OVX) rabbits. A total of 28 virgin New Zealand white rabbits were randomly assigned into the following groups: Control (control group), ovariectomy (OVX group), ovariectomy with ultrasound therapy (US group) and ovariectomy with estrogen replacement therapy group (ERT group). At 8 weeks after ovariectomy, the US group received ultrasound treatment while the ERT group were orally treated with conjugated estrogens, and the control and OVX groups remained untreated. The estradiol level, BMD and bone biomechanics, cartilage histology and the MMP-13 expression were analyzed after the intervention. The results indicate that the US treatment increased estradiol level, BMD and bone biomechanical function. Furthermore, the US treatment appeared to improve the recovery of cartilage morphology and decreased the expression of MMP-13 in OVX models. Furthermore, the results suggest that 10 days of US therapy was sufficient to prevent the reduction of estradiol, BMD and bone biomechanical function, to protect osteoarthritis cartilage structure, and to reduce MMP-13 transcription and expression in OVX rabbits. Therefore, US treatment may be a potential treatment for postmenopausal osteoarthritis and osteoporosis.
... It has been suggested that weight-bearing exercises such as walking, running, dancing and jumping are particularly necessary to help develop and maintain strong bones (Dalsky, 1987;Kanis, 1996;Riggs & Melton, 1992;Sinaki, 1996). Among all types of weight-bearing exercises, high-impact exercise such as jumping, which produces peak forces greater than or equal to two times the body weight (Grove & Londeree, 1992) seems to be effective in producing great osteogenic effects (Fuchs, Bauer, & Snow, 2001;Mackelvie, McKay, Khan, & Crocker, 2001;MacKelvie, McKay, Petit, Moran, & Khan, 2002;McKay et al., 2000;Petit et al., 2002;Pettersson, Nordstrom, Alfredson, Henriksson-Larsen, & Lorentzon, 2000;Witzke & Snow, 2000). ...
... 9e12 Estrogen is the dominant hormone in skeletal regulation, and its level is reduced with advancing age and during menopause. 13,14 As mentioned by Kanis, 8 Manolagas et al, 9 Syed and Khosla, 10 and Frenkel et al, 11 a decrease in bone mass is usually associated with estrogen deficiency in postmenopausal osteoporosis, in which estrogen deficiency increases bone turnover and induces an imbalance between resorption and formation, a relative deficit in bone formation, and eventually accelerates skeletal losses and increases fracture risk. ...
Little information exists about the effects of swimming exercise on bone health in ovariectomized animals with estrogen deficiency, which resembles the postmenopausal state and age-related bone loss in humans. This study investigated the effects of swimming exercise on tibia and femur bone mineral density (BMD), geometry, and microstructure in sham and ovariectomized rats. Forty 3-month-old female rats were divided into four groups: sham operated-sedentary control (Sham-control), sham operated with swimming exercise group (Sham-Swim), ovariectomy-sedentary control (OVx-control), and ovariectomy and swimming exercise (OVx-Swim) groups. Swimming sessions were performed by the rats 90 minute/day for 5 days/week for a total of 8 weeks. At the end of the study, tibial and femoral proximal volumetric total BMD, midshaft cortical volumetric BMD, cross-sectional area, and cross-sectional moment of inertia (MOI), and bone microstructural properties were measured for comparison. Data were analyzed using one-way analysis of variance (ANOVA). The Sham-Swim group exhibited significantly (p < 0.05; one-way ANOVA) greater values in bone geometry parameters, that is, tibial midshaft cortical area and MOI compared to the Sham-control group. However, no significant differences were observed in these parameters between the Ovx-Swim and Ovx-control groups. There were no significant differences in femoral BMD between the Sham-Swim and Sham-control groups. Nevertheless, the Ovx-Swim group elicited significantly (p < 0.05; one-way ANOVA) higher femoral proximal total BMD and improved bone microstructure compared to the Ovx-Sham group. In conclusion, the positive effects of swimming on bone properties in the ovariectomized rats in the present study may suggest that swimming as a non- or low-weight-bearing exercise may be beneficial for enhancing bone health in the postmenopausal population.
... It has been suggested that weight-bearing exercises such as walking, running, dancing and jumping are particularly necessary to help develop and maintain strong bones (Dalsky, 1987;Kanis, 1996;Riggs & Melton, 1992;Sinaki, 1996). Among all types of weight-bearing exercises, high-impact exercise such as jumping, which produces peak forces greater than or equal to two times the body weight (Grove & Londeree, 1992) seems to be effective in producing great osteogenic effects (Fuchs, Bauer, & Snow, 2001;Mackelvie, McKay, Khan, & Crocker, 2001;MacKelvie, McKay, Petit, Moran, & Khan, 2002;McKay et al., 2000;Petit et al., 2002;Pettersson, Nordstrom, Alfredson, Henriksson-Larsen, & Lorentzon, 2000;Witzke & Snow, 2000). ...
This study investigates the combined effects of 8 weeks of jumping exercise and honey supplementation on bone health in rats. Twelve-week old female rats were divided into four groups (n = 12 per group): sedentary without supplementation control group (C), sedentary with honey supplementation group (H), jumping exercise without honey supplementation group (J), and combined jumping exercise and honey supplementation group (JH). Jumping exercise consisted of 40 J/day for 5 days/week at a height of 40 cm. Honey supplementation was given to the rats at a dosage of 1g.kg body weight-1.rat-1.day-1 for 7 days.week-1. After 8 weeks of experimental period, the rats’ left tibia bones were harvested. Statistical analysis was performed using one-way ANOVA. JH exhibited significant (p<0.05) greater tibial mid shaft cortical area and cross-sectional moment of inertia than that in C and H. Additionally, tibial maximum force and energy values were significantly (p<0.05) greater in JH compared to C and H respectively. There were no statistical significant differences in tibial proximal total and trabecular bone mineral density among the experimental groups. Combined jumping and honey supplementation elicited more beneficial effects on tibia bone geometry and mechanical properties in general compared to jumping exercise or honey supplementation alone in rats.
... Physical activity during the growing period in children and adolescents enhances bone health (Slemenda et al., 1991;Boot et al., 1997;MacKelvie et al., 2001), and exercise during this growth period leads to long lasting adaptations in bone geometry and architecture (Kontulainen et al., 1999). Gravitational and/or mechanical loading of the skeleton is a prerequisite for developing and maintaining bone mass and strength (Dalsky, 1987;Riggs and Melton, 1992;Kanis, 1996;Sinaki, 1996). In the absence of weight bearing physical activity or other forms of mechanical stress on the skeleton, there occurs a rapid decrease in bone mineral density and strength (Dalsky, 1987;Drinkwater, 1994;Miller, 2000). ...
... It has been suggested that weight-bearing exercises such as walking, running, dancing, and jumping are particularly necessary to help develop and maintain strong bones (Dalsky, 1987;Kanis, 1996;Riggs & Melton, 1992;Sinaki, 1996). Among all types of weightbearing exercises, high-impact exercise that produces peak forces greater than or equal to two times the body weight (Grove & Londeree, 1992) seems to be effective in producing great osteogenic effects (Fuchs, Bauer, & Snow, 2001;MacKelvie, McKay, Khan, & Crocker, 2001;MacKelvie, McKay, Petit, Moran, & Khan, 2002;McKay et al., 2000;Petit et al., 2002;Petterson, Nordstrőm, Alfredson, Henriksson-Larsén, & Lorentzon, 2000;Witzke & Snow, 2000). ...
This study investigates the effects of combined aerobic dance exercise and honey supplementation on bone turnover markers in young females. Forty young female subjects were divided into four groups, with 10 subjects per group: sedentary without honey supplementation control (C), sedentary with honey supplementation (H), aerobic dance exercise without honey supplementation (Ex), aerobic dance exercise with honey supplementation (HEx) groups. Aerobic dance exercise consisted of 1 hour per session, 3 sessions per week for 6 weeks. H and HEx groups consumed honey drink, in a dosage of 20g of Gelam honey diluted in 300ml of plain water, at 7 days per week for a total of 6 weeks. Subjects in HEx group consumed honey drink 30 min before performing exercise on the exercise days. Concentrations of serum alkaline phosphatase (ALP) as bone formation markers, C-terminal telopeptide of type 1 collagen (1CTP) as bone resorption marker were measured. After 6 weeks of study, HEx group exhibited highest percentage increment in serum ALP (+31.79%), among the groups. There was no statistical difference in 1CTP between pretests and posttests in all the groups. The present study suggests that combination of aerobic dance exercise and honey supplement may elicit more beneficial effects on increasing bone formation marker compared to aerobic dance exercise or honey supplementation alone.
... The authors suggested that although the age-associated decline in testosterone occurs in both men and women, this decline does not arise to the same extent in both sexes, suggesting a possible differential impact on frailty according to sex. Adverse effects of menopause on bones are well known (Kanis, 1996); less obvious are effects of " andropause " on bones (Ferrari et al., 2005). The uncertainties of the roles of major sex hormones in muscle and in bones are illustrated inFigure 1. ...
Musculoskeletal aging is detrimental to multiple bodily functions and starts early, probably in the fourth decade of an individual's life. Sarcopenia is a health problem that is expected to only increase as a greater portion of the population lives longer; prevalence of the related musculoskeletal diseases is similarly expected to increase. Unraveling the biological and biomechanical associations and molecular mechanisms underlying these diseases represents a formidable challenge. There are two major problems making disentangling the biological complexity of musculoskeletal aging difficult: (a) it is a systemic, rather than “compartmental,” problem, which should be approached accordingly, and (b) the aging per se is neither well defined nor reliably measurable. A unique challenge of studying any age-related condition is a need of distinguishing between the “norm” and “pathology,” which are interwoven throughout the aging organism. We argue that detecting genes with pleiotropic functions in musculoskeletal aging is needed to provide insights into the potential biological mechanisms underlying inter-individual differences insusceptibility to the musculoskeletal diseases. However, exploring pleiotropic relationships among the system's components is challenging both methodologically and conceptually. We aimed to focus on genetic aspects of the cross-talk between muscle and its “neighboring” tissues and organs (tendon, bone, and cartilage), and to explore the role of genetics to find the new molecular links between skeletal muscle and other parts of the “musculoskeleton.” Identification of significant genetic variants underlying the musculoskeletal system's aging is now possible more than ever due to the currently available advanced genomic technologies. In summary, a “holistic” genetic approach is needed to study the systems's normal functioning and the disease predisposition in order to improve musculoskeletal health.
... 237 Patients who used HRT had higher BMD. 237,248 The duration of HRT was longer in controls than in psoriasis patients. Within the psoriasis group, the duration of HRT was longer in patients with normal BMD. ...
... The importance of this phenomenon is underlined by the smaller but significant effect of premenopausal serum on the fate of the adipocyte/osteoblast progenitor cell. Bone turnover is known to increase with estrogen deficiency (due to an increase in all elements of bone remodeling [52]), but trabecular bone formation during each remodeling cycle does not match the volume of bone resorbed. The reduction in bone formation may result from a proportionately smaller increase in the number of osteoblasts. ...
A consistent observation in osteoporosis is bone volume reduction accompanied by increased marrow adipose tissue. No single
cause linking the two phenomena has yet been identified. In a human progenitor cell clone (hOP 7) derived from bone marrow,
however, we have demonstrated that rabbit serum can direct differentiation away from an osteoblast lineage to one of adipocytes.
We now report on whether human serum has a similar effect. Serum was collected from 10 pre- and 10 postmenopausal women and
from the 10 postmenopausal women before and following 6-week hormone replacement therapy (HRT). hOP 7 cells were cultured
with the various sera, and after 7-14 days adipocytogenesis was determined by oil red O staining and lipoprotein lipase (LPL)
and glycerol 3-phosphate dehydrogenase (G3PDH) expression. Incubation with 10% premenopausal serum led to labeling of 10.9%
of cells (P<0.05) with oil red O, whereas application of 10% postmenopausal serum led to a much larger effect, 43.5% labeling (P<0.001 with respect to premenopausal serum). Oil red O positivity was accompanied by loss of type I collagen expression
and increased LPL and G3PDH expression. HRT did not reverse the adipocytogenic effect of postmenopausal serum. In conclusion,
serum from postmenopausal women contains factors that steer hOP 7 bone progenitor cells toward an adipocytic phenotype, irrespective
of HRT. The study suggests a role for serum factors in the development of fatty marrow in postmenopausal osteoporosis.
... The disproportionate increase in risk of injury attributable to fall among women may be related to higher prevalence of osteoporosis in women after menopause compared with men. 34 Based on a large, representative cohort that was prospectively studied over several years, this study emphasizes the importance of falls as one of the most frequent complications in chronic stroke survivors. The frequency of this complication mandates fall prevention in every neurorehabilitative program. ...
Stroke survivors are at high risk for falling. Identifying physical, clinical, and social factors that predispose stroke patients to falls may reduce further disability and life-threatening complications, and improve overall quality of life.
We used 5 biennial waves (1998-2006) from the Health and Retirement Study to assess risk factors associated with falling accidents and fall-related injuries among stroke survivors. We abstracted demographic data, living status, self-evaluated general health, and comorbid conditions. We analyzed the rate ratio (RR) of falling and the OR of injury within 2 follow-up years using a multivariate random effects model.
We identified 1174 stroke survivors (mean age+/-SD, 74.4+/-7.2 years; 53% female). The 2-year risks of falling, subsequent injury, and broken hip attributable to fall were 46%, 15%, and 2.1% among the subjects, respectively. Factors associated with an increased frequency of falling were living with spouse as compared to living alone (RR, 1.4), poor general health (RR, 1.1), time from first stroke (RR, 1.2), psychiatric problems (RR, 1.7), urinary incontinence (RR, 1.4), pain (RR, 1.4), motor impairment (RR, 1.2), and past frequency of > or = 3 falls (RR, 1.3). Risk factors associated with fall-related injury were female gender (OR, 1.5), poor general health (OR, 1.2), past injury from fall (OR, 3.2), past frequency of > or = 3 falls (OR, 3.1), psychiatric problems (OR, 1.4), urinary incontinence (OR, 1.4), impaired hearing (OR, 1.6), pain (OR, 1.8), motor impairment (OR, 1.3), and presence of multiple strokes (OR, 3.2).
This study demonstrates the high prevalence of falls and fall-related injuries in stroke survivors, and identifies factors that increase the risk. Modifying these factors may prevent falls, which could lead to improved quality of life and less caregiver burden and cost in this population.
... The reduction in fracture risk by oestrogen exceeds that expected based on bone density alone. 12 Oestrogen must be continued indefinitely; 10 years after it had been stopped, bone density and fracture risk were similar in women who had used oestrogen and those who had not. 13 In clinical trials, oestrogen reduces bone turnover and increases bone density in postmenopausal women of all ages, in part because it improves calcium homeostasis. ...
... Recent surveys have indicated that only 3 to 8% of women with natural menopause are receiving HRT [12] [13]. Other agents such as bisphosphonate family and calcitonin appear to induce small incremental increases in bone mass over one or two years of treatment [14] [15]. Like HRT, these agents decrease bone turnover but do not correct the imbalance between the total amount of bone resorbed and bone formed. ...
Ovarian hormone deficiency is a major risk factor for osteoporosis. Current therapies emphasize the use of antiresorptive agents, such as estrogen, calcitonin, and bisphosphonates. These therapies are associated with certain risks and side effects making compliance a major obstacle. Recent findings suggest that a class of synthetic and naturally occurring compounds, selective estrogen receptor modulators, e.g. raloxifene and soy isoflavones can offer attractive alternatives. Evidence for bone-sparing effects of isoflavones relies mainly on animal findings supported by a limited number of human studies. These observations suggest that isoflavones exert their effects on bone by stimulating bone formation and at the same time suppressing bone resorption. However, the precise osteoprotective mechanism of isoflavones remains uncertain and awaiting further clarification. From a clinical point of view, larger and longer duration studies are warranted to enable us to draw clear conclusions in regards to the role of isoflavones on bone.
Background: Population-based studies have indicated an increase in bone turnover in hyperthyroidism with a subsequent decrease in bone mineral density and an increased risk of fractures, especially in postmenopausal women. However, heterogeneity between studies prevents a definitive conclusion. Graves' disease (GD) is an autoimmune disease, and it is the most common cause of hyperthyroidism. The aim of this study was to investigate fracture risk in patients with GD. Methods: A total of 2134 patients with incident GD and 21,261 age, sex- and county-matched controls were included 16-18 years after diagnosis in a retrospective cohort study. Drug and patient national registries in Sweden were used to assess the risk of developing skeletal complications. Up to 10 years of age, sex- and county-matched controls per patient were selected from databases from the National Board of Health and Welfare and Statistics Sweden. Cox proportional hazards models were fitted to estimate hazard ratios (HR) and confidence intervals [CI]. Results: There were no significant differences in fracture rates between GD and controls but after adjustment for comorbidities, the data showed higher vertebral fracture rates in male GD patients aged >52 years compared to male controls, HR = 2.83 [CI 1.05-7.64]. The rates of osteoporosis treatments as well as treatment with corticosteroids were higher in patients with GD. However, HR for the association between GD and fractures remained largely unchanged after adjustment for osteoporosis treatments and treatments with corticosteroids. Conclusions: There were no significant differences in total fracture rate between GD and the general population. However, men older than 52 years had a higher vertebral fracture rate. This study also shows that patients with treated GD receive more osteoporosis treatments compared to the general population.
This study examined whether the use of SRIs is associated with an increased risk of bone loss using a nested case–control design with a nationwide population–based cohort in Korea. Using the Korean National Health Screening Cohort, subjects newly diagnosed with osteoporosis or osteopenia (n = 55,799) were matched with controls (n = 278,995) at a ratio of 1:5. We stratified the participants by their time-dependent use of SRIs and sex and controlled for various confounders, including lifestyle habits, laboratory data, and comorbidities. Conditional logistic regression showed that both recent and former users of SRIs had an increased risk of subsequent bone loss compared with non-users: men [recent users: odds ratio (OR) 1.35, 95% confidential interval (CI) 1.20, 1.53; former-users: OR 1.10, 95% CI 1.01, 1.20]; women (recent users: OR 1.38, 95% CI 1.28–1.48; former-users: OR 1.07, 95% CI 1.02, 1.21). The use of SRIs was associated with an increased risk of bone loss in both men and women. In particular, the association was stronger in recent users. These findings provide population-level evidence for the risk of bone loss associated with SRI exposure and highlight the importance of monitoring the bone health of SRI users.
The study presents a fragment of pilot studies showing the reconstruction of the transverse arch of the foot using a specially constructed orthosis for this purpose. It involves the mechanical reinforcement of the effect by an orthosis, which pushes down the I, IV, and V metatarsal bones while elevating or blocking the fall of the near-immobile II and III metatarsal bones according to the “three-force” rule. The correction of the transverse arch of the foot runs simultaneously with the correction of hallux valgus (HV). As a result, the significant correction of HV and associated toe deformities was achieved. In stage I foot deformity, the reduction of HV was reduced from 19.1° before to 15.1° after putting on orthosis (p = 0.024). In stage II, the reduction was from 20.1° (before) to 16.2° (after; p = 0.032). Equally satisfactory results were obtained for the remaining angles of the metatarsal bones. In the future, the method can be suitable for patients undergoing preparation for corrective HV surgery and for maintaining postoperative HV results. It can be used preventively, for example, by women who frequently wear high-heeled shoes and by those who need to remain standing for prolonged periods of time.
Whith the aim of characterizing biologic risk factors present in the elderly, a prospective, cross sectional and descriptive study was carried out, with an universe of 341 patients operated for hip fracture in the Orthopedic and traumatology service at "Salvador Allende" Hospital in Havana city, during the period from April 1st 1999 to April 1st 2000. The sample was composed of 94 patients (21,6 %), older than 60 years and residents of Cerro municipality; 61,69 % of patients older than 80 prevailed, feminine sex (74,5 %) and white skin (80,9 %), osteoarthrosis (31,9 %) prevailed as a predisposing chronic disease. The 60,68 % of elders suffered for intradomiciliary fallings, related with architectonic barriers (21,23 %), physical factors responsible for fracture; and at the same time, visual inability represented 15,9 % in relation to medical causes.
As new interventions are developed to improve the care of patients with osteoporosis, nurses will play an important role in improving patients' quality of life, reducing their fear, and assisting in maintaining their independence throughout the adult life span. This article examines key issues involved in the management of patients at risk for, or diagnosed with, osteoporosis.
The work investigated the effect of milk basic protein (MBP) from cheese whey on bone metabolism of rats. Totle 80 SD female rats were used in the work. The rats were randomly separated into 10 groups by gavaging different doses of MBP. The normal low-dose, normal media-dose, and normal high-dose were applied 5.0, 10.0, and 15.0 mg/kg body weight (BW) MBP in the rat diet, respectively. The ovx low-dose, ovx media-dose, and ovx high-dose were gavaged the same dose MBP with normal groups. The normal control, ovx control, and sham-operated were fed distilled water, and positive control was fed by casein phosphopeptides (CPP). After 12 weeks, bone mineral density (BMD), the osteocalcin, and serum calcium were increased with concomitant decrease in alkaline phosphatase (ALP) activity at low-dose groups. However, it had little effect on BMD, ALP, the osteocalcin, and serum calcium at media-dose and high-dose of MBP.
Estrogen replacement therapy (ERT) is utilized as a major regime for treatment of postmenopausal osteoporosis at present. However, long-term supplement of estrogen may cause uterine hyperplasia and hypertension leading to a high risk of endometrial cancer and breast cancer. Psoralea corylifolia L. has long been used as tonic and food additives in many countries. Previous studies had found two ingredients in Psoralea corylifolia L.: bavachin and bakuchiol exhibited osteoblastic activity. The present study was designed to investigate the protective effect of bakuchiol and bavachin on ovariectomy-induced bone loss and explore the possible mechanism. In vivo, bakuchiol and bavachin could prevented estrogen deficiency-induced bone loss in ovariectomized rats without uterotrophic activity. In vitro studies suggested that bakuchiol and bavachin induced primary human osteoblast differentiation by up-regulating the Wnt signalling pathway. This study suggests that such a bone-protective role makes them a promising and safe estrogen supplement for the ERT.
Both continuous and categorical covariates are common in traditional Chinese medicine (TCM) research, especially in the clinical syndrome identification and in the risk prediction research. For groups of dummy variables which are generated by the same categorical covariate, it is important to penalize them group-wise rather than individually. In this paper, we discuss the group lasso method for a risk prediction analysis in TCM osteoporosis research. It is the first time to apply such a group-wise variable selection method in this field. It may lead to new insights of using the grouped penalization method to select appropriate covariates in the TCM research. The introduced methodology can select categorical and continuous variables, and estimate their parameters simultaneously. In our application of the osteoporosis data, four covariates (including both categorical and continuous covariates) are selected out of 52 covariates. The accuracy of the prediction model is excellent. Compared with the prediction model with different covariates, the group lasso risk prediction model can significantly decrease the error rate and help TCM doctors to identify patients with a high risk of osteoporosis in clinical practice. Simulation results show that the application of the group lasso method is reasonable for the categorical covariates selection model in this TCM osteoporosis research.
It has been well established that estrogens in any form in doses equivalent to 0.3–1.25 mg esterified estrogens per day when
administered by oral, percutaneous, or transdermal routes are effective in preventing postmenopausal bone loss [1–3]. The
results of a variety of epidemiological studies designed to analyze the effects of hormone replacement therapy (HRT) on cardiovascular
function also reveal a reduced relative risk of morbidity and mortality from cardiovascular diseases in woman taking HRT [4,5]. Despite these observations it is becoming increasingly obvious that a low prevalence of HRT use exists [6–8]. Factors which
dispose to noncompliance and/or lack of acceptance of HRT treatment in the postmenopausal female include a dislike for withdrawal
bleeding which results from cyclic estrogen/progestin therapy, breast engorgement and pain, poor compliance with progestins,
and the fear of breast cancer [9,10]. In fact, many women either never have their prescriptions filled, follow treatment either intermittently or sporadically,
or discontinue therapy completely after 21–24 months [7,8]. Although nonhormonal therapies for preventing bone loss in postmenopausal women such as the bisphosphonates have been recommended
as effective substitutes for HRT [11–13], these pharmacological agents often require rigorous dosing schedules because of
a variety of gastrointestinal complications [11]. SERM drugs which are also available to women who can not, will not, or should not utilize HRT characteristically react
with estrogen receptors with resultant transcriptional pathways unlike those identified for estrogens [14–16].
The main consequence of osteoporosis is fracture, which is due to loss of bone mass and microarchitecture upon which mechanical integrity depends. The management of osteoporosis care focuses either on preventing bone loss (and thereby preserving mechanical integrity) or targets those who have lost a significant amount of bone and have had, or are at imminent risk of, a fracture. The prevention of osteoporosis is centred on primary care where the opportunities to identify those at risk should be included in normal clinical practice. For many patients, treatment can be started in primary care without recourse to hospital referral. Hormone replacement therapy (HRT) is the mainstay of treatment. Introduction early in the menopause is good for compliance but this wanes with time and few women will take treatment for more than 10 years. Protection from osteoporosis will then decline as they reach later life when major fractures have their peak incidence. It may be that HRT or other agents like the selective estrogen receptor modulators should be introduced for the first time in later life but this will require different strategies to achieve compliance. Treatment of established bone loss also requires the identification in primary care of those most at risk in both primary prevention and treatment of osteoporosis, bone mineral density measurements are critical to the evaluation of risk. Since bone loss is an inevitable consequence of aging, osteoporosis is so common in the elderly that treatment must be directed at those most at risk of a fracture. The bisphosphonates which are potent inhibitors of bone resorption have been shown to increase bone mass and reduce major fractures and play a key role in management. Unfortunately none of the bisphosphonates, nor any of the other agents used for treating osteoporosis (HRT, vitamin D, calcitriol, calcitonin) have been directly compared in fracture prevention studies and the relative merits of these agents have to be derived from individual trials which often differ in major respects.
In recent years, dynamic mechanical loading has been shown to effectively enhance bone remodeling. The current study attempted to research the counter-effect of constrained dynamic loading on osteoporosis (OP) in ovariectomized (OVX) mice. Female Kunming (KM) mice were randomly divided into 2 groups: SHAM and OVX. The right ulnas of the OVX mice were subjected to a 4-week constrained dynamic loading protocol, and the mechanical properties, trabecular micromorphology parameters and biochemical indices of osteogenesis were evaluated. We detected higher levels of tissue alkaline phosphatase (AKP) and serum bone gamma-carboxyglutamic-acid-containing proteins (BGPs), better trabecular micromorphology parameters and ulnar mechanical properties in the loading group than in the nonloading group. In summary, constrained dynamic loading could prevent ovariectomy-induced osteoporosis by facilitating osteogenesis, improving trabecular microstructure and enhancing bone mechanical properties.
The number of women who will live half their adult lives after the menopause increases every year.1 A challenging question for doctors is how women should be counselled about postmenopausal oestrogen therapy.
Summary points
Five or more years of postmenopausal oestrogen is the standard of care for the prevention or treatment of osteoporosis; benefit requires continued use
Oestrogen increases the risk of endometrial cancer during and after use,unless it is taken with adequate progestogen
It probably increases the risk of breast cancer, but only during current use
It may reduce the risk of coronary heart disease
Routine oestrogen treatment should not be recommended until more risk:benefit data are available from clinical trials
Methods
This review is based on observations during 25 years of research into women's health, and on Medline searches on oestrogen or menopause. Only recent publications are cited. Unless otherwise stated, oestrogen therapy refers to treatment of postmenopausal women with pharmacological doses of oral oestrogen taken alone or with an oral progestogen.
Menopausal symptoms
About 75% of women in English speaking countries experience no troublesome symptoms during the menopause transition.2 Population studies have shown that symptoms are less common or different in other countries, and more common and more severe after an induced menopause. Hot flushes and night sweats are the only symptoms universally reported to respond (usually almost immediately) to oestrogen. Without treatment, hot flushes typically disappear within 1-2 years, but in some untreated women they continue for more than 20 years.
After the menopause the vaginal wall becomes thinner and less vascular, changes which may be accompanied by vaginal dryness and dyspareunia. Intravaginal oestrogen prevents and treats these symptoms and also reduces the risk of recurrent urinary tract infection, probably by modifying the vaginal flora.3 Urinary incontinence, which becomes more common with increasing age, is not usually improved …
The estrogen receptor (ER) is a ligand-regulated transcription factor whose activity as an inducer or repressor of gene transcription depends on the nature of the ligand to which it is bound. The aim of this work is to evaluate the behavior of a set of compounds (antagonist molecules), using different docking experiments, in order to understand the relationship between ERα and such new ligands. With regard to the chemical properties of the ligands analyzed, we defined a specific guideline procedure designed for docking experiments. In our approach, we propose the use of the HINT scoring function in docking methodologies as a means of assessing the consistency of a docking solution, to discriminate correctly or near-correctly docked orientations from incorrectly docked ones, thus compensating for the lack of experimental data. © 2005 Wiley Periodicals, Inc. Int J Quantum Chem, 2006
Although estrogens have proved useful in the prevention and treatment of osteoporosis, their side effects (for example, those on breast and endometrial cancer) are worrying to patients and physicians alike. Therefore, selective estrogen receptor modulator (SERM) drugs have been developed for use in their stead. The triphenylethylene drug tamoxifen proved to be protective against bone loss, but had side effects on uterus similar to those of natural estrogens. The tamoxifen derivative toremifene has less effect on bone. Further derivatives of tamoxifen (droloxifene, idoxifene) can be expected to act like tamoxifen when approved for clinical testing. The non-steroidal benzothiophene derivative, raloxifene, is the best SERM available thus far. It does not increase the incidence of endo-metrial cancer; in addition, like tamoxifen, it has the potential to prevent breast cancer, but has a better profile in its actions on bone (for example, it reduces the vertebral fracture rate more effectively than tamoxifen). Unlike estrogen, it decreases blood triglicerides as well as cholesterol.
A meta-analysis was done to determine what effect exercise has on the bone mineral density (BMD) of the lumbar spine, proximal femur, and distal radius in postmenopausal women, utilizing data from 18 studies. Treatment effects (TE) were calculated for each of the skeletal sites, aerobic and strength training, as well as methods of BMD measurement (dual energy x-ray absorptiometry and dual photon absorptiometry). The resulting TEs found exercise, in general, to significantly increase (p c 0.05) the BMD of the lumbar spine (0.73%), and the proximal femur (0.35%); however, the distal radius showed a decrease (-0.91%) in BMD. When looking for the effect of aerobic versus strength training, significant (p c 0.05) increases in BMD were found in the spine and femur. Since positive changes were not seen in all sites, the benefits of exercise may be specific to the skeletal sites which the working muscles are attached. When the % change for exercise and control groups were analyzed separately, the exercise group increased 2.31% at the lumbar spine and 0.61% at the proximal femur. However, the exercise group decreased -2.21% at the radius. The control group decreased at the lumbar spine -1.09%, and at the femur -1.1 I%, however, increased at the radius 0.36%. The BMD % changes were significantly larger for the spine and femur, therefore, vigorous exercise along with resistance training may help slow the decrease in BMD as one ages.
Oral administration of edible bird's nest extract (EBNE) improved bone strength and calcium concentration in the femur of ovariectomized rats. Dermal thickness was also increased by EBNE supplementation, whereas EBNE administration did not affect the serum estradiol concentration. These results suggest that EBNE is effective for the improvement of bone loss and skin aging in postmenopause all women.
Phytoestrogens and phytoestrogen-containing plants are currently being explored as potential candidates for the treatment of estrogen-related disorders. The aim of this study was to evaluate the anti-osteoporotic effect of the phytoestrogen-rich plant Phaseolus vulgaris L, commonly known as French beans.
Adult Sprague-Dawley rats were either bilaterally ovariectomized (OVX) or sham operated. OVX and sham control groups were administered vehicle, whereas the other two OVX groups were given 0.15 mg/kg estradiol and 1 g/kg methanolic extract of P vulgaris L seeds (MPV) orally for 10 weeks (10 rats per group). At autopsy, blood, urine, bones, and uteri of the animals were collected. Serum was evaluated for estradiol, calcium (Ca), phosphorus, alkaline phosphatase, tartarate resistant acid phosphatase, and urine for Ca. The bone density, ash density, mineral content, and mechanical strength of bones was evaluated. Scanning electron microscopic analysis of bones (tibia) was performed. Results were analyzed using analysis of variance and Tukey's multiple comparison test.
Compared with the OVX control, MPV (1 g/kg PO) significantly decreased serum alkaline phosphatase and reduced serum tartarate resistant acid phosphatase and urinary Ca levels. It caused an increase in bone density, ash density, and bone mechanical strength and significantly increased bone Ca. Improvement in bone microarchitecture was indicated by image analysis of scanning electron microscopic photomicrographs. No increase in weight of atrophic uterus in OVX animals was observed with MPV treatment.
Treatment with MPV prevented estrogen deficiency-induced osteopenia without affecting the uterine mass. The promising results of the study warrant further investigation of French beans as a potential candidate for the treatment of postmenopausal osteoporosis.
Soy protein, a rich source of isoflavones, fed immediately after an ovariectomy prevents bone loss in rats. Reports of the effectiveness of natural and synthetic isoflavones in preventing or treating osteoporosis led us to examine the effect of soy protein in reversing established bone loss. Seventy-two 95-d-old female Sprague-Dawley rats were assigned to 6 groups. The rats were either sham operated (SHAM; 2 groups) or ovariectomized (OVX; 4 groups) and then fed a casein-based, semipurified diet. Thirty-five days after surgery, 1 SHAM and 1 OVX group were killed to examine the occurrence of bone loss. Thereafter, the other SHAM and 1 OVX groups continued to receive the casein-based diet. Whereas the remaining 2 OVX groups received diets in which casein was replaced by soy protein with normal (OVX+SOY) or reduced (OVX+SOY-) isoflavone content for 65 days. The OVX control group had significantly lower femoral and fourth lumbar vertebral bone densities than the SHAM group. Femoral density of rats fed SOY or SOY- diets were not significantly different from SHAM or OVX controls. This suggests a slight reversal of cortical bone loss that may be partially due to higher femoral insulin-like growth factor I mRNA transcripts resulting from both the SOY and SOY- diets. The ovariectomy-induced increases in indexes of bone turnover were not ameliorated by either of the soy diets, suggesting that any positive effect of soy was achieved through enhanced bone formation rather than slowed bone resorption. Long-term consumption of soy or its isoflavones may be needed to produce small but continued increments in bone mass.
Unlabelled:
Nowadays different lines of evidence demonstrate the benefits of postmenopausal hormone replacement therapy (HRT). HRT is extremely effective in treating subjective symptoms and can really improve the quality of life of climacteric women. HRT and dementia: Estrogens are potentially relevant to the pathogenesis and treatment of Alzheimer's disease. The effects of different progestogens on cognitive functions and Alzheimer's disease are largely unknown. The prevention of Alzheimer disease might be a major indication to long term HRT. Large prospective, randomized trials will confirm these preliminary data. HRT and osteoporosis: HRT has been strongly correlated with higher bone mineral density and lower fracture incidence. Definite answers in terms of minimum effective dosages, timing and duration of HRT for fracture prevention are needed. HRT and cardiovascular disease: Different lines of evidence suggest that HRT can exert cardioprotective effects with substantial reduction of morbidity and mortality for cardiovascular disease in postmenopausal women. The effects and the role of progestogens in cardiovascular disease prevention are still debated. Prospective, randomized, controlled studies are needed to assess the impact of different HRT regimens on cardiovascular events. HRT and cancer: The major issue in the relationship between HRT and cancer is breast cancer. Long-term and current HRT use are followed by a slight, though significant increase in the risk of breast cancer. Progestogens can modify the cellular response of normal as well as cancer breasts. The possible protective effect of continuous progestogen addition is very interesting and needs further investigation. Alternative to classical HRT: Selective estrogen receptor modulators (SERM). SERMs such as raloxifene (RAL) are a new class of drugs that exert site specific estrogenic or antiestrogenic effects in different target tissues. RAL prevents bone loss and reduces serum cholesterol in postmenopausal women. In contrast to estrogen RAL does not stimulate breast or uterine tissues. In vitro RAL is highly effective at inhibiting the growth of estrogen-dependent breast adenocarcinoma cells. SERMs are expected to represent a major breakthrough for postmenopausal health.
Conclusion:
HRT can be offered either as a preventive tool or as individualized care on the basis of personal needs. New therapeutic options like the SERMs will offer a substantial medical advancement for the treatment of postmenopausal women.
FC1271a is a novel triphenylethylene compound with a tissue-selective profile of estrogen agonistic and weak antagonistic effects. It specifically binds to the estrogen receptor alpha and beta with affinity closely similar to that of toremifene and tamoxifen. To study the in vivo effects of the compound, 4-month-old rats were sham operated (sham) or ovariectomized (OVX) and treated daily for 4 weeks with various doses of FC1271a or vehicle (orally). FC1271a was able to oppose OVX-induced bone loss by maintaining the trabecular bone volume of the distal femur. Accordingly, the OVX-induced loss of bone strength was prevented at doses of 1 and 10 mg/kg. FC1271a also prevented the OVX-induced increase in serum cholesterol in a dose-dependent manner. No significant changes in uterine wet weight or morphology were observed in the OVX-rats treated with 0.1 or 1 mg/kg FC1271a, but at a dose of 10 mg/kg it had a slightly estrogenic effect. In immature rats the effect of FC1271a on uterine wet weight was less stimulatory than that of toremifene or tamoxifen, but more stimulatory than that of raloxifene or droloxifene. The appearance of the dimethylbenzanthracene (DMBA)-induced mammary tumors was inhibited by treatment of DMBA-treated rats with FC1271a in a dose-dependent manner. In human MCF-7 breast cancer cell tumors raised in nude mice in the presence of estrogen, the growth and expression of pS2 marker gene could not be maintained after estrogen withdrawal by treatment with FC1271a. No formation of DNA adducts was observed in the liver of the FC1271a-treated rats. In conclusion, the bone-sparing, antitumor, and cholesterol-lowering effects of FC1271a combined with a low uterotropic activity and lack of liver toxicity indicate that FC1271a could be an important alternative in planning antiosteoporosis therapy for estrogen deficiency.
The aim of this study was to evaluate the efficacy, safety, and tolerability of 2 years' application of an estradiol matrix transdermal system for the prevention of postmenopausal bone loss.
In this multicenter, randomized, placebo-controlled, parallel-group study, 261 surgically or naturally postmenopausal women were randomized to apply the estradiol matrix transdermal system (0.025, 0.0375, 0.05, or 0.1 mg/d) or matching placebo twice a week for 2 years. The study was double blind with respect to treatment (active vs placebo) but not to the dose levels of active treatment (because of the differing sizes and shapes of the patches). In addition to receiving the assigned treatment, the 100 nonhysterectomized women received 2.5 mg medroxyprogesterone acetate daily throughout the study.
The evaluable group (n = 259) had a mean age of 52 years and a mean duration of menopause of 32 months. Following 2 years of treatment, there were significant differences in favor of estradiol between all doses of the estradiol matrix transdermal system and placebo in terms of the percentage change from baseline in the bone mineral density (BMD) of the L1-L4 anteroposterior lumbar spine (0.1 and 0.05 mg/d, P < 0.001; 0.0375 mg/d, P = 0.024; 0.025 mg/d, P = 0.002). Percentage changes from baseline in the BMD of the femoral neck after 2 years of treatment also consistently demonstrated the efficacy of the estradiol matrix transdermal system compared with placebo (all, P < or = 0.044). The estradiol matrix transdermal system was well tolerated.
The estradiol matrix transdermal system was effective in preventing postmenopausal bone loss at dosages of 0.025 to 0.1 mg/d, and had a safety profile consistent with the known effects of estrogen/progestin.
Therapeutic strategy in osteoporosis should rely on the results of good quality randomized controlled trials. When a fracture has already occurred, first line treatments are alendronate or hormone replacement therapy. Alternatives are cyclical etidronate, or calcitonin in some countries. General measures, such as adequate nutrition and calcium and vitamin D intake, and prevention of falls should be associated to drugs. When there is no history of fracture, the decision will rely on the existence of clinical risk factors and the bone density. Women with a densitometric osteoporosis will be treated as those who have already fractured. Those who have osteopenia can receive hormone replacement therapy, alendronate or raloxifene. No treatment is indicated in women who have normal bone density.
Bone mineral density (BMD) has been shown to be different in different ethnic groups. When lifestyle and diet evolve, there is a possibility of a change in the normal reference BMD values within an ethnic group over a period of time. As the osteoporotic risk uses the T-score as the bench mark, it is pertinent to evaluate whether such changes do occur. Two measurements, 5 years apart, of the BMD of the spine and the hip were made in a cohort of Chinese women in Hong Kong. A kernel function smoothing method, a nonparametric statistical method, was employed to present the BMD data. The greatest rate of bone loss was found to occur between 50 and 59 years of age, but this rate of loss was reduced from age 60 onwards. The BMD values obtained in these two measurements were different from the previous studies in the same population and were found to be higher at the lumbar spine and neck of femur in women over 65 years of age. Even within the cohort, there seemed to be a reduction in the BMD values of the hip in a span of 5 years, although the differences were statistically insignificant. These studies suggest that BMD values could change in a population for a variety of possible reasons. Hence, the reference BMD values might need to be evaluated at regular intervals for the T-score to be meaningful.
The management of postmenopausal women has become a major focus for the medical profession. The menopause era should progress from a period of "chaos" to an orderly understanding of the many issues related to the menopause and hormone replacement therapy (HRT). Although HRT has beneficial clinical effect and positive benefit/risk ratio, understanding of the side effects and weight gain, and, especially, a fear of cancer limit compliance. New data from long-term, controlled, prospective studies on the effects of different HRT schedules on cancer, cardiovascular disease and osteoporotic fracture risk are needed. HRT should be considered either as for prevention or for individualized care since women experience menopause as individuals, care should be taken not to make inappropriate generalizations. The priority should be the administration of appropriate medication to women with the best result in order to improve health care and quality of life. New therapeutic options will offer substantial medical advancement for the treatment of postmenopausal women.
We have compared the antitumor activities of SP500263, a novel next-generation selective estrogen receptor modulator (SERM), tamoxifen, and raloxifene side-by-side in in vitro and in vivo MCF-7 breast cancer models. In vitro, SP500263 acted as an antiestrogen and potently inhibited estrogen-dependent MCF-7 proliferation with IC(50) values in the nanomolar range. SP500263 also strongly inhibited MCF-7 proliferation in the absence of estrogen at all of the concentrations tested. To investigate the antitumor activity of SP500263 in animals, athymic nude mice were implanted with MCF-7 tumor in the presence of a tumor growth-supporting sustained release estrogen pellet. Treatment was initiated after tumors were established. SP500263, administered for 28 days through daily i.p. dosing, effectively reduced estrogen-stimulated tumor growth at 3 and 30 mg/kg. SP500263 was as efficacious as tamoxifen and superior to raloxifene at the corresponding doses. Maximum efficacy was reached with the 30 mg/kg dose. The observed effects were highly significant. SP500263 represents a member of a novel series of SERMs that is structurally unrelated to SERMs currently on the market or in clinical development. The experiments described herein demonstrate that SP500263 is efficacious in the MCF-7 proliferation assay and in a murine model of breast cancer.
The section of geriatric trauma ("AG Alterstraumatologie") of the "Deutsche Gesellschaft für Unfallchirurgie" (DGU) and the "Lohmann & Birkner Health Care Consulting GmbH" in cooperation with the health insurance funds (vdek) put the relevant data of approximately 23 million insured from the year 2002 to 2004. All data from patients over the age of 60 staying in hospital because of proximal femur fractures and without further injuries as main diagnosis were extracted from the available amount of data and then analysed. There were 68,929 (9.5%) diagnostic cases of proximal femur fractures from 724,606 treatments in hospital. There was a significant age dependent increase of incidents of proximal femur fractures with a maximum of 3000 injuries around the age of 82 years. The surgical treatment of proximal femur fractures was carried out with a preserving stabilising method (osteosynthesis - screws - "DHS" - nailing systems) in 49.5%, with endoprothesis in 48.6% as well as other methods in 1.9% of the cases. In comparison to hip replacement care shorter hospital stay could be proved with osteosynthetic methods. In comparison of the effective number of beds there was a significant increase of the treatment of proximal femur fractures in hospitals with 101 to 300 beds. There was no difference in the operative treatment of proximal femur fractures in comparison to the number of beds of the hospital. The average hospital expense for ostheosynthesis was 6000 Euro per each case and there was no difference in comparison to the different osteosynthetic procedures. The average hospital expense for hip replacement (7,036-7,201 Euro) was about 1000 Euro higher than osteosynthetic procedures. There was no difference in the average hospital expense in comparison to the age of the patients. There was a significant age dependent increase of acute hospital mortality with a maximum of 8.6% in the group of the patients older than 85 years. As a result of the demographic change fracture rates in the elderly population will rise significantly.
This article has no abstract; the first 100 words appear below.
IF measurements of bone mass are to be clinically useful, they must be safe, precise, accurate, and of reasonable cost in relation to the information provided. Since when bone mass is low the clinical outcome of concern is fracture, there must be a demonstrated relation between the measurement and the subsequent risk of fracture. The information provided must be helpful to the clinician in making a decision to intervene or not; and if a therapeutic regimen is chosen, it must have a positive influence on health (e.g., a reduction in the incidence of fractures) without an unreasonable increase in other . . .
Supported in part by grants (P01AG 5793 and AR 27065) from the National Institutes of Health.
Source Information
From the Department of Medicine, Indiana University School of Medicine, Indianapolis (C.C.J., C.W.S.); and the Department of Health Sciences Research, Mayo Clinic and Foundation, Rochester, Minn. (L.J.M.). Address reprint requests to Dr. Johnston at the Department of Medicine, Division of Endocrinology, Indiana University School of Medicine, 545 Barnhill Dr., Emerson 421, Indianapolis, IN 46202–5124.
Although fluoride increases bone mass, the newly formed bone may have reduced strength. To assess the effect of fluoride treatment on the fracture rate in osteoporosis, we conducted a four-year prospective clinical trial in 202 postmenopausal women with osteoporosis and vertebral fractures who were randomly assigned to receive sodium fluoride (75 mg per day) or placebo. All received a calcium supplement (1500 mg per day). Sixty-six women in the fluoride group and 69 women in the placebo group completed the trial. As compared with the placebo group, the treatment group had increases in median bone mineral density of 35 percent (P less than 0.0001) in the lumbar spine (predominantly cancellous bone), 12 percent (P less than 0.0001) in the femoral neck, and 10 percent (P less than 0.0001) in the femoral trochanter (sites of mixed cortical and cancellous bone), but the bone mineral density decreased by 4 percent (P less than 0.02) in the shaft of the radius (predominantly cortical bone). The number of new vertebral fractures was similar in the treatment and placebo groups (163 and 136, respectively; P not significant), but the number of nonvertebral fractures was higher in the treatment group (72 vs. 24; P less than 0.01). Fifty-four women in the fluoride group and 24 in the placebo group had side effects sufficiently severe to warrant dose reduction; the major side effects were gastrointestinal symptoms and lower-extremity pain. We conclude that fluoride therapy increases cancellous but decreases cortical bone mineral density and increases skeletal fragility. Thus, under the conditions of this study, the fluoride-calcium regimen was not effective treatment for postmenopausal osteoporosis.
Dietary calcium intake was assessed in 535 Hong Kong Chinese by the food-frequency interview method. The average calcium intake was below 600 mg/d for all age groups and decreased with age. It was about 500 mg/d in young adults and 300 mg/d in those with age above 60. About 30% of the calcium came from vegetables, and about 20% from milk and milk products. The main sources of readily absorbed calcium in Hong Kong diets were milk products, bean curd, fish and eggs. Patients with fractured neck of femur (n = 46) had significantly lower calcium intakes than matched controls (P < 10-5), while those with Colle's or spinal fractures had comparable intakes. Chinese and European diets in Hong Kong were also compared. The Chinese diets contained less fat, more carbohydrate, less calcium, less cholesterol and less energy value than European diets. Such dietary differences, particularly calcium intake, may be pertinent to the prevention and treatment of osteoporosis in Hong Kong.
Background: Lack of sex hormones is a causal factor for development of osteoporosis. Methods: In a review the connections between osteoporosis and hormone replacement therapy are analyzed. Results: Application of estrogens requires a careful explanation of effects and possible side effects to patients. Nevertheless, there may be a large amount of patients breaking off therapy. In patients with the uterus in situ additional administration of progestogens is necessary, but this has no extra effect on bone metabolism. In cases of severe osteoporosis estrogens can be combined with bisphosphonates, calcitonin or active vitamin D metabolites. A sufficient calcium supply and exercise are preconditions of successful therapy of bone metabolism. New hormone replacement compounds have got only partial estrogen-agonistic actions on bone metabolism and do not influence the endometrium any more. Conclusions: A bone protective estrogen replacement therapy will be indicated in patients with estrogen deficiency in case of a decreased bone mineral density and/or if additional risk factors for osteoporosis do exist.
In seven strains of cultured normal human osteoblast-like cells, a mean of 1615 molecules of tritium-labeled 17 beta-estradiol
per cell nucleus could be bound to specific nuclear sites. The nuclear binding of the labeled steroid was temperature-dependent,
steroid-specific, saturable, and cell type-specific. These are characteristics of biologically active estrogen receptors.
Pretreatment with 10 nanomolar estradiol in vitro increased the specific nuclear binding of progesterone in four of six cell
strains, indicating an induction of functional progesterone receptors. RNA blot analysis demonstrated the presence of messenger
RNA for the human estrogen receptor. The data suggest that estrogen acts directly on human bone cells through a classical
estrogen receptor-mediated mechanism.
We evaluated ultrasound transmission velocity at the patella as an indicator of osteoporotic fragility in 293 nonobese women. Osteoporosis was defined by atraumatic vertebral compression deformity. Ultrasound velocity averaged 1954 ±71 (±SD) m/s in premenopausal normal women and declined significantly with age after menopause, largely independently of age-related loss of spine bone mass. Postmenopausal osteoporotic women had lower velocities than normal women (-76 m/s). After allowing for slight differences in age between the groups, the difference ( - 54 m/s) was still significant. Women with velocities below 1825 m/s were about six times more likely to have one or more fractures than women with velocities above that level. By sensitivity-specificity analysis, ultrasound velocity discriminated between normal and osteoporotic women as well as direct measurement of spine bone mass. Ultrasound velocity measures both bone mass and a component of bone fragility distinct from decreased mass; it is a potentially valuable new tool for evaluating women for osteoporotic fragility.
(JAMA. 1989;261:2986-2990)
It has been shown that the amount of calcium consumed in childhood and adolescence has a role in determining the bone mass
in later life. We recently showed that the daily calcium intake among Hong Kong Chinese is only 300–500 mg, which decreases
with age. An investigation was thus made into the calcium content and other constituents of common food consumed by the local
population. Test items included vegetables, rice, cooked food, and seasoning paste. The samples were first digested to remove
organic constituent, and the mineral content was then analyzed using atomic absorption spectrophotometry. The results show
that egg, beancurd, and sesame paste contain a high calcium content and, if consumed in sufficient amount, would provide a
good source of calcium. In view of the high incidence of lactase deficiency and thus the difficulty in increasing intake of
milk and milk products, increased consumption of other types of food with high calcium would be useful in improving the daily
calcium intake.
Hormone replacement therapy (HRT) comprises oestrogen with or without progestogen.
Benefits—HRT is the most effective treatment for the relief of menopausal symptoms and for the primary prevention of postmenopausal osteoporosis. There are also possible benefits for coronary heart disease, colorectal cancer, and neurocognitive function, but these are yet to be established....
We wished to assess the predictive value of the main clinical risk factors for osteoporosis over a low vertebral bone mineral density.
A cross-sectional study was made of a cohort of peri and post-menopausal women (mean age, 54 years).
One thousand, five hundred and sixty-five normal white women were selected from among the women referred to our menopause clinic for screening and prevention of osteoporosis.
Each woman had replied to a detailed standardized questionnaire including the main clinical risk factors and had her bone density measured using dual photon absorptiometry.
The predictive value for a low vertebral bone mineral density (2 SD below the normal young adult value) was assessed for 15 historical and anthropometric variables. Among these, age, age at menarche, weight, height, menopause and its duration, were independent predictors of a low bone mineral density, in a multiple logistic regression analysis. Odds ratios were calculated for each of these variables, weight, menopause and its duration being the three most influential variables. At best this model makes it possible to correctly classify 73% of women with a low bone mineral density and 66% of those with a normal bone mineral density. If this model is used for screening, it could possibly save 25% of bone densitometry examinations.
Direct bone densitometry remains indispensable to assess osteoporosis risk, since risk factors alone are not sufficient for accurate delineation of either low or normal bone mineral density.
Osteoporosis is a prevalent disease without a curative treatment. Agents that will prevent fracture are known and bone mineral density can now be measured. Thus there is a prima-facie case for screening, which should be explored.
OSTEOPOROSIS is one of the most important disorders associated with aging.1 , 2 More than 1.5 million Americans have fractures related to osteoporosis each year, with attendant pain, deformity, and loss of independence. The annual cost to the U.S. health care system is at least $10 billion.1 , 2 Because of the aging of the population and increases over time in the incidence of fractures, these already huge costs will more than double over the next 30 years3 unless a comprehensive program of prevention and treatment is initiated soon. The most important preventable cause of fractures is low bone mass. During the course of . . .
In assessing the role of calcium, it must be stressed that calcium is not the cause of bone health but simply a necessary condition for it. It is mechanical usage that is of primary importance for bone. In just the same way iron is essential for hemoglobin synthesis and protein is essential for muscle mass, but neither is sufficient by itself. What, then, ought we to expect from a high calcium intake? Can we prevent estrogen-withdrawal bone loss? No. Calcium is not a substitute for estrogen, anymore than it is a substitute for exercise. Will calcium slow the remodeling loss that occurs with aging? Yes, to some extent; as calcium slows remodeling, it will inevitably slow remodeling-related loss. But most importantly, a high calcium intake will prevent calcium-deficiency bone loss. The only question, therefore, is the extent to which calcium deficiency loss may contribute significantly to bone fragility in various populations.
Osteoporosis is a major health problem in Hong Kong, affecting about 200,000 patients among a population of 6 million. To evaluate the rate of bone loss and determinants of low bone mass among the Southern Chinese, we measured the total body and regional bone mass with the XR-26 dual-energy X-ray absorptiometry in 90 normal females. The results show that the total and regional bone densities were stable before menopause, with a change of around 0.5% every year. After menopause, a rapid loss is evident for total body and regional bone mass. The rate of bone loss varies from 1.2% for the pelvis to 3.1% for the Ward's triangle per year. Thus, by the age of 70, most Southern Chinese females would have lost at least 25% of their bone. Age, body weight, and skeletal area are important determinants for the total body bone mass. Bone densities in weight-bearing regions, including hip, pelvis, spine and legs correlate strongly with each other (r = 0.68, P less than 0.001). Correlation is poor among unrelated regions, such as between head and arms (r = 0.39, P greater than 0.5). To conclude, normal Chinese women in Hong Kong lose bone rapidly after menopause at a rate of about 2% per year. This may account for the major incidence of osteoporosis-related complications in Hong Kong.
Nineteen patients with postmenopausal osteoporosis were treated with 200 u (15 nmol) synthetic salmon calcitonin (sCT) intranasally per day for 15 months. Six months after the start of the nasal administration of sCT, antibodies were recognized in 7, and after 15 months in 10 of the 19 patients studied. The half-maximal dilution of serum binding to 60 pmol/l [125I]sCT (dilution-50) ranged from 2 to 490, and half-maximal inhibition of [125I]sCT binding (60 pmol/l) from 91 to 221 pmol/l sCT. In a cultured breast cancer cell line (T47D) cAMP production was stimulated by sCT (EC50 70 pmol/l). Stimulated cAMP production by sCT (50 pmol/l) was reduced to between 4% and 23% in the presence of serum from patients with antibody dilution-50 of [125I]sCT binding exceeding 32. In patients with lower titer antibodies cAMP production was only marginally suppressed. The values of patients with postmenopausal osteoporosis were in the range of those of earlier studied patients with Paget's disease and clinical resistance to sCT. There was a linear relation between the antibody dilution-50 and the serum dilution required for half-maximal inhibition of cAMP production (P less than 0.01). In conclusion, neutralizing antibodies to sCT may contribute to the decreased responsiveness of bone mineral loss during prolonged treatment with sCT.
Osteoporosis has become a major health problem among the elderly in Hong Kong. This study compares the level of dietary calcium intake and the differences in various risk factors among elderly fracture patients and elderly without fractures. Furthermore, this study identifies the relationship between the risk factors and the amount of calcium intake; and classifies the fracture patients and the low calcium intake group. Although the design of the present study precludes testing causal hypotheses, the findings are suggestive of factors that are likely to be important in a program to reduce fractures among elderly populations.
Progressive bone loss in osteoporosis results from bone resorption in excess of bone formation. We conducted a double-blind study in 66 women with postmenopausal osteoporosis of therapy with etidronate, a diphosphonate compound that reduces bone resorption by inhibiting osteoclastic activity. The patients were randomly assigned in equal numbers to receive oral etidronate (400 mg per day) or placebo for 2 weeks, followed by a 13-week period in which no drugs were given. This sequence was repeated 10 times, for a total of 150 weeks. Daily oral supplementation with calcium and vitamin D was given throughout the study to both groups. Vertebral bone mineral content was measured by dual-photon absorptiometry; spinal radiographs were assessed to identify new vertebral fractures. Vertebral bone mineral content increased significantly (P less than 0.01) after 150 weeks of etidronate therapy (5.3 percent; 95 percent confidence interval, 2.0 to 8.6; n = 20) but decreased with placebo (-2.7 percent; 95 percent confidence interval, -7.3 to 1.9; n = 20). The difference between groups was 8.0 percentage points (P less than 0.01; 95 percent confidence interval, 2.4 to 13.6). The rates of fracture were significantly different for the period from week 60 to week 150 between the etidronate and placebo groups (6 vs. 54 fractures per 100 patient-years; P = 0.023). No adverse clinical, biochemical, or bone histomorphometric effects of treatment were observed. We conclude that at the end of nearly three years, etidronate therapy for postmenopausal osteoporosis results in significant increases in vertebral bone mineral content and, after approximately one year of treatment, a significant decrease in the rate of new vertebral fractures.
To determine the effects of etidronate (a bisphosphonate that inhibits osteoclast-mediated bone resorption) in the treatment of postmenopausal osteoporosis, we conducted a prospective, two-year, double-blind, placebo-controlled, multicenter study in 429 women who had one to four vertebral compression fractures plus radiographic evidence of osteopenia.
The patients were randomly assigned to treatment with phosphate (1.0 g) or placebo twice daily on days 1 through 3, etidronate (400 mg) or placebo daily on days 4 through 17, and supplemental calcium (500 mg) daily on days 18 through 91 (group 1, placebo and placebo; group 2, phosphate and placebo; group 3, placebo and etidronate; and group 4, phosphate and etidronate). The treatment cycles were repeated eight times. The bone density of the spine was measured by dual-photon absorptiometry, and the rates of new vertebral fractures were determined from sequential radiographs.
After two years, the patients receiving etidronate (groups 3 and 4) had significant increases in their mean (+/- SE) spinal bone density (4.2 +/- 0.8 percent and 5.2 +/- 0.7 percent, respectively; P less than 0.017). The rate of new vertebral fractures was reduced by half in the etidronate-treated patients (groups 3 and 4 combined) as compared with the patients who did not receive etidronate (groups 1 and 2 combined) (29.5 vs. 62.9 fractures per 1000 patient-years; P = 0.043); the effect of treatment was most striking in the subgroup of patients with the lowest spinal bone mineral density at base line, in whom fracture rates were reduced by two thirds (42.3 vs. 132.7 fractures per 1000 patient-years; P = 0.004). The addition of phosphate provided no apparent benefit. There were no significant adverse effects of treatment.
Intermittent cyclical therapy with etidronate for two years significantly increases spinal bone mass and reduces the incidence of new vertebral fractures in women with postmenopausal osteoporosis.
The present study includes 70 healthy, immediately postmenopausal women stratified according to future rate of bone loss. The stratification was performed by means of four parameters of bone turnover: serum alkaline phosphatase, fasting urinary calcium and hydroxyproline, and body weight, used in an equation developed in a previous study. After the stratification the women were followed without intervention for the next 24 months, with bone mass measurements every 3 months. The bone loss estimated at baseline by means of the equation correlated with the bone loss measured in the forearm (y = 0.72x - 1.52; r = 0.61; P less than 0.001). Plasma bone gla protein (BGP, osteocalcin), which is a new specific marker of bone formation, was now added to the model (replacing body weight). This increased the diagnostic validity (y = x; r = 0.76; P less than 0.001). From the present study we conclude that the postmenopausal bone loss can be predicted by means of four biochemical parameters determined in plasma and urine in women just after the menopause.
Forty women aged 64.7 +/- 5.1 yr with established postmenopausal osteoporosis were blindly allocated to 1 yr's treatment with either continuous combined estrogen/progestogen therapy (2 mg estradiol + 1 mg norethisterone acetate + 500 mg calcium daily) or placebo + 500 mg calcium daily. In the group treated with hormones bone mineral density in the spine (dual photon absorptiometry) and bone mineral content in the ultradistal forearm (single photon absorptiometry) increased highly significantly by 8-10% during the 1 yr of treatment. Bone mineral content in the mid-shaft of the forearm (single photon absorptiometry) and the total body bone mineral (dual photon absorptiometry) increased by 3-5% when compared to that in the placebo group, which showed virtually unchanged values at all measurement sites. Seven of the women treated with hormones were examined after a further year of treatment. BMC increased by another 3-6%, reaching a 12% increase in bone mineral density in the spine after 2 yr of treatment. Biochemical estimates of bone resorption (fasting urinary calcium and hydroxyproline) and bone formation (serum alkaline phosphatase and plasma osteocalcin), decreased significantly (P less than 0.001) in the group treated with hormones, but remained unchanged in the placebo group. The reduction in indices of bone resorption was more pronounced than that in bone formation after one year, indicating a positive bone balance. No further changes were seen in these bone turnover parameters during the second year of treatment. In the group treated with hormones, serum levels of triglycerides, total cholesterol, and low density lipoprotein cholesterol decreased by about 12% (P less than 0.05-P less than 0.01), whereas high density lipoprotein cholesterol decreased by about 8% (P less than 0.001). The high density lipoprotein cholesterol/low density lipoprotein cholesterol ratio was unchanged. The hormone treatment did not produce any major side effects, and only minor bleedings were experienced by a few women. The present study demonstrates that treatment with female sex hormones in this particular combination is a realistic approach to the treatment of women with established postmenopausal osteoporosis.
Osteoporosis develops in women with estrogen deficiency and amenorrhea who lose bone at an accelerated rate. It is not known to what extent bone loss differs between ovulatory women with regular menstrual cycles who are training intensely and those who are sedentary.
We measured the density of cancellous spinal bone from the 12th thoracic vertebra to the 3rd lumbar vertebra by quantitative computed tomography on two occasions one year apart in 66 premenopausal women 21 to 42 years of age. All the women had two consecutive ovulatory cycles immediately before entering the study. Twenty-one women were training for a marathon, 22 ran regularly but less intensively, and 23 had normal levels of activity. The lengths of the women's menstrual cycles and luteal phases, diet, exercise levels, and hormonal levels were also determined. We defined ovulatory disturbances as anovulatory cycles and cycles with short luteal phases.
The mean (+/- SD) spinal bone density in the 66 women decreased 3.0 +/- 4.8 mg per cubic centimeter per year (2.0 percent per year) (P less than 0.001). Amenorrhea did not develop in any woman during the year of observation (only 2.7 percent of the cycles were greater than 36 days long). Ovulatory disturbances occurred in 29 percent of all cycles, however. Bone loss was strongly associated with these disturbances (r = 0.54, 24 percent of the variance). The 13 women who had anovulatory cycles lost bone mineral at a rate of 6.4 +/- 3.8 mg per cubic centimeter per year (4.2 percent per year). The women training for a marathon had menstrual cycles similar to those of the women in the other two groups.
Decreases in spinal bone density among women with differing exercise habits correlated with asymptomatic disturbances of ovulation (without amenorrhea) and not with physical activity.
Vitamin D deficiency leads to secondary hyperparathyroidism initially and then to mild osteomalacia, both of which conditions may be aymptomatic and may predispose to bone fracture. To assess the importance of vitamin D deficiency in predisposing to fractured neck of femur, we studied the vitamin D status, dietary intake and socio-economic characteristics in 69 patients with fractured neck of femur (group A), 28 normal subjects with age above 60 (group B), and 101 normal volunteers (group C). Patients with fractured neck of femor had significantly lower levels of serum 25-hydroxy-cholecalciferol compared with subjects of groups B and C. There is no statistically significant difference in other biochemical parameters, including calcium, phosphate, and alkaline phosphatase. Patients with fractured neck of femur and with 25-hydroxycholecalciferol below 20 ng/mL were characterized by a home-bound and/or institutionalized life-style, smaller living place, and limited access to open space. To conclude, hypovitaminosis D is a common problem among elderly patients with fractured neck of femur in Hong Kong. The fact that such vitamin D deficiency is associated with muscle weakness may contribute to falls, and thus indirectly account for an increased rate of hip fractures over the normal control.
In a longitudinal study of 283 elderly subjects aged 60 years or over living in the community, 9 subjects (7 women and 2 men) developed osteoporosis-related fractures in 30 months. These subjects initially had higher random urinary hydroxyproline/creatinine and calcium/creatinine ratios, and lower plasma 25-hydroxyvitamin D concentrations. These biochemical variables may be useful predictors of osteoporosis-related fractures and may provide a suitable community screening method to identify those most at risk.
Changes in sex hormones and bone turnover were studied longitudinally in 31 women aged 47-54 years who were approaching the menopause. Every 6 weeks for 2-3 years, hormones and biochemical estimates of the bone turnover were determined and the bone mass was measured at two forearm sites by single photon absorptiometry. Spinal bone mass was measured every 6 months. The bone turnover was normal in women aged 47-54 years with regular menstruation, whereas the estimates of bone resorption were high in the women with irregular menstruation. In nine women, who reached the menopause during the study, bone resorption increased significantly, whereas bone formation showed only a small increase. When the results of the nine women were combined with those of 50 women, who had passed a natural menopause within the preceding 3.5 years, the bone resorption indices reached their peak within the first postmenopausal year, whereas bone formation increased until 1.5-2 years after the last menstrual cycle. At the ultradistal forearm site the rate of bone loss was maximal (5% per year) immediately after the menopause and subsequently declined, which suggests that trabecular bone is more sensitive than cortical bone to changes in bone turnover. Spinal bone loss was identical in late peri- and early postmenopausal women. We conclude that bone resorption starts to increase during the last perimenopausal years, with a beginning acceleration in bone loss, which then becomes sharp after the menopause. The changes are related to the decline in oestrogens, but other mechanisms may also play a role.
To study the effect of salmon calcitonin (salcatonin) given intranasally on calcium and bone metabolism in early postmenopausal women.
Double blind, placebo controlled, randomised group comparison.
Outpatient clinic for research into osteoporosis.
52 Healthy women who had had a natural menopause two and a half to five years previously.
The 52 women were allocated randomly to two years of treatment with either salcatonin 100IU given intranasally (n = 26) or placebo (n = 26). Both groups received a calcium supplement of 500 mg daily. Seven of the women receiving salcatonin and six of those receiving placebo left the study before its end.
Bone mineral content in the spine, the total skeleton, and the forearms after two years of treatment.
Bone mineral content in the spine was significantly higher in the women who had received salcatonin than in those who had received placebo both after one year and after two years of treatment. After one year the difference was 3.8% (95% confidence interval 0.0 to 7.6%) and after two years it was 8.2% (3.8 to 12.6%). In contrast, the bone mineral content in the distal and proximal forearms and in the total skeleton declined similarly in both groups by about 2% each year, and after two years of treatment the differences between the groups were not significant. Biochemical estimates of bone turnover were not affected by salcatonin.
The results suggest that salcatonin given intranasally in the dose used prevents bone loss in the spine of early post menopausal women but does not affect the peripheral skeleton.
We evaluated ultrasound transmission velocity at the patella as an indicator of osteoporotic fragility in 293 nonobese women. Osteoporosis was defined by atraumatic vertebral compression deformity. Ultrasound velocity averaged 1954 +/- 71 (+/- SD) m/s in premenopausal normal women and declined significantly with age after menopause, largely independently of age-related loss of spine bone mass. Postmenopausal osteoporotic women had lower velocities than normal women (-76 m/s). After allowing for slight differences in age between the groups, the difference (-54 m/s) was still significant. Women with velocities below 1825 m/s were about six times more likely to have one or more fractures than women with velocities about that level. By sensitivity-specificity analysis, ultrasound velocity discriminated between normal and osteoporotic women as well as direct measurement of spine bone mass. Ultrasound velocity measures both bone mass and a component of bone fragility distinct from decreased mass; it is a potentially valuable new tool for evaluating women for osteoporotic fragility.
Spinal collapse is a painful complication of osteoporosis. In this study, the analgesic effect of salmon calcitonin, administered intranasally (200 IU per day), was assessed in 18 patients with acute collapse of one to four vertebrae. Pain was evaluated by a descriptive pain scale (ie, Keele's) as well as by the daily consumption of analgesic drugs. When compared with placebo, intranasal salmon calcitonin significantly relieved pain and occasioned a decrease in the consumption of analgesic drugs. No major side effects were reported by the patients under study.
Bone loss was determined in 178 women in the early postmenopausal period by photon absorptiometry measurement of forearm bone mineral content (BMC) every 3 months for 2 years. With a sequential cut-off technique, the results of a single determination of body fat mass, urinary calcium and hydroxyproline, and serum alkaline phosphatase, carried out at the first examination, correctly identified 79% of "fast bone losers" (bone loss greater than 3% annually) and 78% of "slow bone losers". With this simple approach the majority of women at highest risk of osteoporotic fractures in later life can be identified in the early postmenopausal period and started on prophylactic hormone replacement therapy.
To assess the effect of weight-bearing exercise training and subsequent detraining on lumbar bone mineral content in postmenopausal women.
Non-randomized, controlled, short-term (9 months) trial and long-term (22 months) exercise training and detraining (13 months).
Section of applied physiology at a university school of medicine.
Thirty-five healthy, sedentary postmenopausal women, 55 to 70 years old. All women completed the study. There was 90% compliance with exercise training.
All women were given calcium, 1500 mg daily. The exercise group did weight-bearing exercise (walking, jogging, stair climbing) at 70% to 90% of maximal oxygen uptake capacity for 50 to 60 min, 3 times weekly.
Bone mineral content increased 5.2% (95% confidence interval [CI], 2.0% to 8.4%; P = 0.0037) above baseline after short-term training whereas there was no change (-1.4%) in the control group. After 22 months of exercise, bone mineral content was 6.1% (95% CI, 3.9% to 8.3% above baseline; P = 0.0001) in the long-term training group. After 13 months of decreased activity, bone mass was 1.1% above baseline in the detraining group.
Weight-bearing exercise led to significant increases above baseline in bone mineral content which were maintained with continued training in older, postmenopausal women. With reduced weight-bearing exercise, bone mass reverted to baseline levels. Further studies are needed to determine the threshold exercise prescription that will produce significant increases in bone mass.
Prevention of osteoporosis is clearly the preferred approach, since treatment of the established disorder is less than satisfactory. However, accurate identification of those at risk for fractures is impossible at present. By judicious use of risk assessment and the addition of bone mass measurements in the postmenopausal patient, the physician can define a group of patients who will be at some increased likelihood of subsequent osteoporosis. Since estrogen therapy is the most effective single agent for prevention of bone loss, estrogens can be recommended for this group of patients, if otherwise not contraindicated. The addition of a progestogen to the regimen may add to the effect of estrogen by stimulating bone formation. Estrogen therapy may have other effects in the postmenopausal patient population that must be considered when deciding about the introduction of therapy.
This article has no abstract; the first 100 words appear below.
OSTEOPOROSIS is an enormous public health problem, responsible for at least 1.2 million fractures in the United States each year. The sites of these fractures are the vertebrae in 538,000 cases, the hip in 227,000, the distal forearm (Colles' fracture) in 172,000, and other limb sites in 283,0001 (and Melton LJ, Riggs BL: unpublished data). One third of women over 65 will have vertebral fractures (Melton LJ, Riggs BL: unpublished data). By extreme old age, one of every three women and one of every six men will have had a hip fracture.² This catastrophic type of fracture is fatal in . . .
Supported by grants (AM-27065, AM-30582, and AG-04875) from the National Institutes of Health, U.S. Public Health Service.
Source Information
From the Endocrine Research Unit, Division of Endocrinology, Metabolism, and Internal Medicine, and the Department of Medical Statistics and Epidemiology, Mayo Clinic and Mayo Foundation, Rochester, Minn. Address reprint requests to Dr. Riggs, Division of Endocrinology and Internal Medicine, Mayo Clinic, Rochester, MN 55905.
The effect of percutaneous estradiol alone and combined with natural progesterone on postmenopausal bone loss was studied. A total of 57 women who had experienced a natural menopause 6 months to 3 years previously entered the study. After an initial examination the women were allocated in a blinded pattern to treatment with 3 mg of percutaneous estradiol or placebo. The code was broken after 1 year of treatment, and the women receiving estradiol continued with a cyclic addition of progesterone, whereas those receiving placebo continued with placebo. The women were examined every 3 months during the 2 years of treatment. Measurement of the bone mineral content in the forearms (single photon absorptiometry) and the spine and total skeleton (dual photon absorptiometry) showed a significant decrease of 5% to 7% in the placebo group during the 2 years of treatment, whereas it remained constant in all bone compartments in the estradiol group. Addition of progesterone did not influence the results. Biochemical estimates of calcium metabolism changed toward a premenopausal level in the estradiol group but remained unchanged in the placebo group. We conclude that percutaneous estradiol is effective as preventive therapy of postmenopausal bone loss and that addition of progesterone does not influence bone or calcium metabolism.
Bone mass was measured prospectively in 73 women during the period immediately after menopause. By comparing the rates of loss at three skeletal sites, we assessed the protective effects of calcium supplements given alone or combined with low-dosage estrogen therapy. After 2 years of follow-up, spinal trabecular mineral content, measured by quantitative computed tomography, decreased by a mean of 9.0% (p = 0.002 compared with baseline) in untreated women and a mean of 10.5% (p = 0.0001) in women given calcium supplements alone. By contrast, women given conjugated estrogens, 0.3 mg/d, with calcium supplements showed an insignificant increase of 2.3%. Significant losses of a lesser magnitude were seen in the appendicular cortical skeleton of women not receiving therapy and in those receiving calcium alone, but no significant changes were observed in women receiving estrogen with calcium.
Calcitonin deficiency has been implicated in the pathogenesis of accelerated bone loss, especially in postmenopausal osteoporosis. To investigate this issue, we studied 25 patients with untreated postmenopausal osteoporosis, 14 age-matched and sex-matched healthy controls (spinal bone mineral density greater than or equal to age-specific and sex-specific mean), and 5 women who had undergone total thyroidectomy. Each subject received an intravenous infusion of 2 mg of elemental calcium per kilogram of body weight over 5 minutes, to test the C-cell secretory reserve. We measured calcitonin by radioimmunoassay in whole plasma and in silica-cartridge extracts of plasma, the latter method providing greatly improved sensitivity and specificity for monomeric calcitonin. Basal immunoreactive calcitonin concentrations, whether measured in whole plasma or in extracts, were significantly higher in the subjects with osteoporosis (P less than 0.01) than in the healthy controls. The calcitonin secretory reserve, as assessed by calcium stimulation, was normal in the osteoporotic group but virtually absent in the thyroidectomy group. We conclude that postmenopausal osteoporosis is not associated with and does not result from calcitonin deficiency. On the contrary, excessive skeletal calcium release may stimulate calcitonin secretion in patients with the disorder.
The effect of norethisterone on bone mineral metabolism was examined in 43 postmenopausal women. A significant decline in serum calcium, phosphate, and alkaline phosphatase in urinary calcium/creatinine ratio and in tubular maximum reabsorption of phosphate was demonstrated. There was no alteration in urinary hydroxyproline/creatinine ratio. The bone mineral content measured over two years by single photon absorptiometry was compared in 20 patients receiving norethisterone and a matched control group receiving placebo. There was significant protection against bone loss in the norethisterone group.
In man, the major function of calcitonin appears to be prevention of excessive or unwanted bone resorption. There is a striking sex difference in circulating levels, with a relative deficiency in women. Calcitonin secretion in young adults is increased by oestrogens and therefore long periods of oestrogen lack, such as after the menopause, may be associated with a more pronounced calcitonin deficiency. This exaggerated deficiency could be an important factor in the pathogenesis of postmenopausal bone loss, especially since the latter may be due to excessive bone resorption. In a study of the effects of oestrogen treatment on circulating levels of calcitonin, parathyroid hormone, and vitamin-D metabolites in postmenopausal women, the most striking change was a sharp rise in plasma-calcitonin. Oestrogens prevent postmenopausal bone loss, and it is suggested that this effect could be mediated, at least in part, through control of calcitonin secretion. Calcitonin may prove effective in the prevention of postmenopausal bone loss, and it is suggested that this effect could be mediated, at least in part, through control of calcitonin secretion. Calcitonin may prove effective in the prevention of postmenopausal bone loss. Its place in the treatment of postmenopausal osteoporosis warrants further evaluation.