Treatment Of Postmenopausal Bone Loss Research Articles

Muramyl dipeptide alleviates estrogen deficiency-induced osteoporosis through canonical Wnt signaling.

Wnt signaling is a positive regulator of bone formation through the induction of osteoblast differentiation and down-regulation of osteoclast differentiation. We previously reported that muramyl dipeptide (MDP) increases bone volume by increasing osteoblast activity and attenuating osteoclast activity in receptor activator of nuclear factor-κBligand(RANKL)-induced osteoporotic model mice. In this study, we investigated whether MDP could alleviate post-menopausal osteoporosis through Wnt signaling regulation inan ovariectomy (OVX)-induced mouse osteoporosis model. MDP-administered OVX mice exhibited higher bone volume and bone mineral density than mice of the control group. MDP significantly increased P1NP in the serum of OVX mice, implying increased bone formation. The expression of pGSK3β and β-catenin in the distal femur of OVX mice was lower than that in the distal femur of sham-operated mice. Yet, the expression of pGSK3β and β-catenin was increased in MDP-administered OVX mice compared with OVX mice. In addition, MDP increased the expression and transcriptional activity of β-catenin in osteoblasts. MDP inhibited the proteasomal degradation of β-catenin via the down-regulation of its ubiquitination by GSK3β inactivation. When osteoblasts were pretreated with Wnt signaling inhibitors, DKK1 or IWP-2, the induction of pAKT, pGSK3β, and β-catenin was not observed. In addition, nucleotide oligomerization domain-containing protein 2-deficient osteoblasts were not sensitive to MDP. MDP-administered OVX mice exhibited fewer tartrate-resistant acid phosphatase (TRAP)-positive cells than did OVX mice, attributed to a decrease in the RANKL/OPG ratio. In conclusion, MDP alleviates estrogen deficiency-induced osteoporosis through canonical Wnt signaling and could be an effective therapeutic for the treatment of post-menopausal bone loss. © 2023 The Pathological Society of Great Britain and Ireland.

Ovariectomy induces bone loss via microbial-dependent trafficking of intestinal TNF+ T cells and Th17 cells.

Estrogen deficiency causes a gut microbiome-dependent expansion of BM Th17 cells and TNF-α-producing T cells. The resulting increased BM levels of IL-17a (IL-17) and TNF stimulate RANKL expression and activity, causing bone loss. However, the origin of BM Th17 cells and TNF+ T cells is unknown. Here, we show that ovariectomy (ovx) expanded intestinal Th17 cells and TNF+ T cells, increased their S1P receptor 1-mediated (S1PR1-mediated) egress from the intestine, and enhanced their subsequent influx into the BM through CXCR3- and CCL20-mediated mechanisms. Demonstrating the functional relevance of T cell trafficking, blockade of Th17 cell and TNF+ T cell egress from the gut or their influx into the BM prevented ovx-induced bone loss. Therefore, intestinal T cells are a proximal target of sex steroid deficiency relevant for bone loss. Blockade of intestinal T cell migration may represent a therapeutic strategy for the treatment of postmenopausal bone loss.

Potassium citrate prevents increased osteoclastogenesis resulting from acidic conditions: Implication for the treatment of postmenopausal bone loss.

The extracellular acidic milieu in bones results in activation of osteoclasts (OC) and inhibition of osteoblasts (OB) causing a net loss of calcium from the skeleton and the deterioration of bone microarchitecture. Alkalinization through supplementation with potassium citrate (K citrate) has been proposed to limit the osteopenia progression, even though its pharmacological activity in bone microenvironment is not well defined. We evaluated if K citrate was able to prevent the adverse effects that acidic milieu induces on bone cells. OC and OB were maintained in neutral (pH 7.4) versus acidic (pH 6.9) culture medium, and treated with different K citrate concentrations. We evaluated the OC differentiation at seven days, by counting of multinucleated cells expressing tartrate-resistant acid phosphatase, and the activity of mature OC at 14 days, by quantifying of collagen degradation. To evaluate the effects on OB, we analyzed proliferation, mineralization, and expression of bone-related genes. We found that the low pH increased OC differentiation and activity and decreased OB function. The osteoclastogenesis was also promoted by RANKL concentrations ineffective at pH 7.4. Non-cytotoxic K citrate concentrations were not sufficient to steadily neutralize the acidic medium, but a) inhibited the osteoclastogenesis, the collagen degradation, and the expression of genes involved in RANKL-mediated OC differentiation, b) enhanced OB proliferation and alkaline phosphatase expression, whereas it did not affect the in vitro mineralization, and c) were effective also in OC cultures resistant to alendronate, i.e. the positive control of osteoclastogenesis inhibition. In conclusion, K citrate prevents the increase in OC activity induced by the acidic microenvironment, and the effect does not depend exclusively on its alkalizing capacity. These data provide the biological basis for the use of K citrate in preventing the osteopenia progression resulting from low-grade acidosis.

Selective estrogen receptor modulators in T cell development and T cell dependent inflammation

Lasofoxifene (las) and bazedoxifene (bza) are third generation selective estrogen receptor modulators (SERMs) with minimal estrogenic side effects, approved for treatment of postmenopausal osteoporosis. T cells are involved in the pathology of postmenopausal osteoporosis and previous studies have established an important role for 17β-estradiol (E2) in T cell development and function. E2 causes a drastic thymic atrophy, alters the composition of thymic T cell populations, and inhibits T cell dependent inflammation. In contrast, the second generation SERM raloxifene (ral) lacks these properties. Although las and bza are drugs approved for treatment of postmenopausal bone loss, it is of importance to study their effects on other biological aspects in order to extend the potential use of these compounds. Therefore, the aim of this study was to investigate if treatment with las and bza affects T lymphopoiesis and T cell dependent inflammation. C57Bl6 mice were ovariectomized (ovx) and treated with vehicle, E2, ral, las or bza. As expected, E2 reduced both thymus weight and decreased the proportion of early T cell progenitors while increasing more mature T cell populations in the thymus. E2 also suppressed the T cell dependent delayed-type hypersensitivity (DTH) reaction to oxazolone (OXA). Ral and las, but not bza, decreased thymus weight, while none of the SERMs had any effects on T cell populations in the thymus or on inflammation in DTH. In conclusion, this study shows that treatment with las or bza does not affect T lymphopoiesis or T cell dependent inflammation.

Potent inhibitory effect of Foeniculum vulgare Miller extract on osteoclast differentiation and ovariectomy-induced bone loss

Inhibition of osteoclast differentiation and bone resorption is considered an effective therapeutic approach to the treatment of postmenopausal bone loss. To find natural compounds that may inhibit osteoclastogenesis, we screened herbal extracts on bone marrow cultures. In this study, we found that an aqueous extract of Foeniculum vulgare Miller seed (FvMs) at low concentration, which has traditionally been used as a treatment for a variety of ailments, inhibits the osteoclast differentiation and bone resorptive activity of mature osteoclasts. We further investigated the effects of FvMs on ovariectomy (OVX)-induced bone loss using microcomputed tomography, biomechanical tests and serum marker assays for bone remodeling. Oral administration of FvMs (30 mg or 100 mg/kg/day) for 6 weeks had an intermediary effect on the prevention of femoral bone mineral density (BMD), bone mineral content (BMC), and other parameters compared to OVX controls. In addition, FvMs slightly decreased bone turnover markers that were accelerated by OVX. The bone-protective effects of FvMs may be due to suppression of an OVX-induced increase in bone turnover. Collectively, our findings indicate that FvMs have potential in preventing bone loss in postmenopausal osteoporosis by reducing both osteoclast differentiation and function.

Development, Reliability, and Validity of a New Preference and Satisfaction Questionnaire

Objectives Existing questionnaires that assess preference and/or satisfaction with postmenopausal bone loss treatments were reviewed and determined to be inadequate for the assessment of an oral pill versus a subcutaneous injection. The Preference and Satisfaction Questionnaire (PSQ) was developed to assess preference, satisfaction, and bother with a weekly oral tablet versus a once every 6 months subcutaneous injection for treatment of postmenopausal bone loss. Methods Questions were developed based on literature review and expert input. Content validity of the PSQ in this patient population was assessed among current or previous bisphosphonate users in group interviews, and item comprehension and readability were also evaluated. Reliability, validity, and structure of the questionnaire were assessed in two phase 3 randomized clinical trials. Results Twenty-four women participated in cognitive interviews and found the PSQ understandable and acceptable. Subsequently, 1583 trial participants took the PSQ. Interitem correlations, ranging from 0.50 to 0.97 for preference items, 0.85 to 0.94 for pill-satisfaction items, and 0.84 to 0.92 for injection-satisfaction items, and a well-fitting confirmatory factor analysis (root mean square error of approximation 0.04, nonnormed fit index 0.99, and root mean square residual 0.08) supported the structure of the instrument. Cronbach's alpha reliability values for pill satisfaction, injection satisfaction, pill bother, and injection bother were 0.93, 0.89, 0.82, and 0.61, respectively. Discriminative validity was indicated with better satisfaction and bother scores being related to adherence and the absence of adverse events. Conclusions The PSQ is a valid and reliable measure and may be a valuable tool to assess patient preference and satisfaction with a weekly oral tablet and 6-month subcutaneous injection for postmenopausal bone loss.

Effects of Two Administration Schemes of Intramuscular Clodronic Acid on Bone Mineral Density

Clodronic acid is a bisphosphonate used in the prevention and treatment of postmenopausal bone loss. Previous evidence suggests a direct dose-response relationship for the densitometric effect of clodronic acid. Therefore, as it is widely accepted that a reduction in the dosing frequency of bisphosphonates may improve adherence and therefore therapeutic outcomes, an increase in the interval between consecutive administrations of clodronic acid might be associated with a concomitant increase in the overall bisphosphonate dose received. However, to our knowledge, a direct comparison of the effects of intramuscular clodronic acid 100 mg once weekly with a regimen consisting of a higher dose and a longer interval between two consecutive administrations is still lacking. This study compared the increase in bone mineral density (BMD) achieved with two different administration schemes of intramuscular clodronic acid (100 mg once weekly and 200 mg every 2 weeks) in patients with postmenopausal osteoporosis. This randomized, open-label, parallel-group trial was conducted in the Osteoporosis and Instrumental Diagnosis Center 'OsteoArticolar' (University of Siena, Siena, Italy) between January 2007 and December 2009. Consecutive women aged 50-80 years with postmenopausal osteoporosis, diagnosed ≥5 years prior to inclusion in the study, were eligible for participation in this study. Patients were randomized to receive either intramuscular clodronic acid (Clasteon®) 100 mg (group A) + lidocaine (lignocaine) once weekly or intramuscular clodronic acid 100 mg + lidocaine for two consecutive days every 2 weeks (group B), for 2 years. In total, 30 patients were randomized to group A and 30 patients to group B. Significant increases in mean ± SD BMD of the lumbar spine versus baseline values were observed in both groups at 1 and 2 year(s) from treatment initiation (group A - year 1: +2.8% ± 1.7%, p < 0.05; year 2: +3.5% ± 2.2%, p < 0.01; group B - year 1: +2.7% ± 2.1%, p < 0.05; year 2: +3.9% ± 2.2%, p < 0.01). Mean ± SD BMD at the femoral neck also significantly increased versus baseline in group A at both timepoints (year 1: +2.3% ± 1.9%, p < 0.05; year 2: +2.5% ± 1.9%, p < 0.05), while the increase reported in group B was significant only after 2 years of treatment (year 1: +1.9% ± 2.2%; year 2: +2.8% ± 1.8%; p < 0.05). Significant mean ± SD increases in total femur BMD were observed only in group A at 2 years (+2.4% ± 1.9, p < 0.05). No differences between study groups were reported. Two non-traumatic vertebral fractures were observed in group A (6.6%) and three in group B (10.0%). Treatment was well tolerated; mild pain at injection site was observed in three patients (one in group A, 3.3%; two in group B, 6.6%). This randomized study suggests, for the first time to the author's knowledge, a similar effect of intramuscular clodronic acid 100 mg once weekly and 200 mg every 2 weeks (two 100 mg administrations on two consecutive days) on BMD in women with postmenopausal osteoporosis. The administration of intramuscular clodronic acid 200 mg every 2 weeks may therefore represent a new therapeutic option in the treatment of postmenopausal osteoporosis.

The effects of luteolin on osteoclast differentiation, function in vitro and ovariectomy-induced bone loss

Flavonoids, a group of polyphenolic compounds abundant in plants, are known to prevent bone loss in ovariectomized (OVX) animal models. Inhibition of osteoclast differentiation and bone resorption is considered as an effective therapeutic approach in the treatment of postmenopausal bone loss. Luteolin, a plant flavonoid, has potent anti-inflammatory properties both in vivo and vitro. In this study, we found that luteolin markedly decreased the differentiation of both bone marrow mononuclear cells and Raw264.7 cells into osteoclasts. Luteolin also inhibited the bone resorptive activity of differentiated osteoclasts. We further investigated the effects of luteolin on ovariectomy-induced bone loss using micro-computed tomography, biomechanical tests and serum markers assay for bone remodeling. Oral administration of luteolin (5 and 20 mg/kg per day) to OVX mice caused significant increase in bone mineral density and bone mineral content of trabecular and cortical bones in the femur as compared to those of OVX controls, and prevented decreases of bone strength indexes induced by OVX surgery. Serum biochemical markers assays revealed that luteolin prevents OVX-induced increases in bone turnover. These data strongly suggest that luteolin has the potential for prevention of bone loss in postmenopausal osteoporosis by reducing both osteoclast differentiation and function.

Phytotherapy versus hormonal therapy for postmenopausal bone loss: a meta-analysis

This meta-analysis included 14 randomized controlled trials involving 780 patients to compare phytotherapy with hormonal therapy in the treatment of postmenopausal bone loss. Current evidence suggests that phytotherapy may possess a similar effect on bone mineral density (BMD) values but clinically is not associated with a high incidence of uterine bleeding and breast pain as is hormonal therapy. Clinical trials indicate that phytotherapy may be a potential treatment for postmenopausal osteoporosis. The objective of this meta-analysis was to compare the efficacy and safety of phytotherapy with that of hormonal therapy, to assess the quality of phytotherapy trials, and to identify herbs used commonly in the treatment of postmenopausal bone loss. A total of 43 electronic databases were searched. The quality of eligible trials was assessed using Jadad's scale. Outcome measures were BMD values and adverse events. Revman 5.0 software was used for data syntheses and meta-analyses. The database search revealed 14 randomized controlled trials involving 780 patients that met the inclusion criteria, and four trials were graded as high quality (score 3-5). There was no significant difference in lumbar, femoral or forearm BMD values between subjects treated with phytotherapy and those treated with hormonal therapy (P>0.05), but the incidence of uterine bleeding and breast pain was significantly lower in those treated with phytotherapy than in those treated with hormonal therapy (P = 0.002 and P = 0.01). The six most commonly used herbs in the included trials were identified. Phytotherapy may not show effects beyond hormonal therapy, but may be safer than hormonal therapy in the treatment of postmenopausal bone loss. Further trials with high-quality study designs should be conducted in this field.

High-intensity resistance training and postmenopausal bone loss: a meta-analysis

Conflicting evidence exists regarding the optimum exercise for postmenopausal bone loss. A systematic review and meta-analysis was undertaken to evaluate the effects of randomised controlled trials (RCTs) of progressive, high-intensity resistance training on bone mineral density (BMD) amongst postmenopausal women. Structured electronic searching of multiple databases and hand-searching of key journals and reference lists was undertaken to locate relevant studies up to December 2004. Study quality and possible publication bias were assessed using recognised methods. Primary outcomes were absolute changes in BMD at the lumbar spine (LS), femoral neck (FN) and total hip (TH). A priori defined subgroup analyses included concurrent hormonal or antiresorptive therapy or calcium supplementation during the intervention. The weighted mean difference method (WMD) was used for combining study group estimates. Random or fixed effect models were applied according to study heterogeneity observed from the I (2) statistic. At the LS, 14 RCT study groups were homogenous (I (2)=25.2%) in demonstrating a significant increase (P=0.006) in BMD of 0.006 g/cm(2) (fixed effect; 95% CI 0.002-0.011) following high-intensity resistance training. In contrast, marked heterogeneity (I (2)=88.2%) was apparent within 11 RCT study groups evaluating FN. For this comparison, a random effects model showed a positive change in FN BMD of 0.010 g/cm(2) (95% CI -0.002 to 0.021; P = 0.11). Subgroup analyses showed more anatomical variability of BMD responses to resistance training according to participants' hormone therapy use. Treatment effects for study groups increasing all participants' calcium intake showed significant positive BMD changes at TH (P=0.007). Methodological quality of all included studies was low, and a reporting bias towards studies with positive BMD outcomes was evident. These findings are relevant to the nonpharmacological treatment of postmenopausal bone loss.

Randomized trial comparing low-dose hormone replacement therapy and HRT plus 1α-OH-vitamin D3 (alfacalcidol) for treatment of postmenopausal bone loss

We conducted a prospective, randomized, multicenter, open-label 2-year trial with 76 postmenopausal women aged > or =60 years with low (T-score less than -1) lumbar bone mineral density (BMD). The hormone replacement therapy (HRT) group received a low dose of conjugated estrogen (CEE) at a dose of 0.31 mg/day +/- medroxyprogesterone acetate (MPA) 2.5 mg/day. Group HRT/D received the same dose of HRT together with alfacalcidol in a daily dose of 1.0 microg/day. Changes in lumbar BMD measured by dual energy X-ray absorptiometry (DXA) were followed every 6 months for 2 years. The lumbar BMD of group HRT increased 3.37% [95% confidence interval (CI) 1.6%-5.2%], 4.00% (95%CI 1.6%-6.4%), and 2.32% (95%CI -0.7% to 5.3%) at 12, 18, and 24 months, respectively, when the baseline value was taken as 0%. Lumbar BMD of group HRT/D showed a significant increase beyond 6 months. The percent increases for this group at 6, 12, 18, and 24 months were 6.18 (95%CI 1.3%-6.6%), 6.18% (95%CI 3.9%-8.5%), 7.17% (95%CI 4.3%-10.0%), and 8.75% (95%CI 6.0%-11.5%), respectively. In addition, there was a significant difference in the changes of the lumbar BMD between the two groups at 24 months, suggesting that the combination of HRT and alfacalcidol is more effective than HRT alone in terms of the BMD effect. This study is the first prospective trial demonstrating an additive effect of alfacalcidol on lumbar BMD in postmenopausal women receiving low-dose HRT. It suggests that the combination therapy can be considered to be a promising mode of treatment for bone loss after menopause.

Prospective 10-year study of the determinants of bone density and bone loss in normal postmenopausal women, including the effect of hormone replacement therapy.

To prospectively assess bone density and the factors determining the rate of bone loss over a 10-year period of postmenopausal life. Prospective, observational study. One hundred and four normal White postmenopausal women, baseline mean age 59 years (range 47-71 years) completed the study (mean duration of follow-up 10.2 years, range 9.4-10.6 years). None had diseases or were taking medications affecting bone metabolism at entry to the study. Information was collected on medical, fracture and smoking history, alcohol use, dietary calcium intake and physical activity. Body composition and bone density were measured by dual-energy X-ray absorptiometry at baseline and at 10 years. Biochemical, haematological and hormonal analyses were performed. Twenty-four percent of the women started hormone replacement therapy (HRT) during the study period; most of these remained on therapy at follow-up. The mean duration of therapy was 6.6 years (range 2.8-10.4 years). The use of HRT was associated with significant gains in bone density (total body + 3.0%, trochanter + 4.2%, Ward's triangle + 4.4%, spine + 10.5%) and a significant reduction in vertebral fracture risk [standardized risk ratio compared with non-HRT users 0.42 (confidence interval 0.18-0.83)]. HRT use was not associated with greater weight gain than that occurring in other members of the cohort. The baseline and follow-up bone densities in the non-HRT users were highly correlated (0.82 < or = r < or = 0.91, P < or = 0.0001) and baseline bone density accounted for the majority of the variance in the 10-year results. Multivariate analyses showed that the independent correlates of rate of change of bone density were weight and fat mass (both baseline values and changes during follow-up), time after menopause, sex hormone concentrations, urinary calcium loss, PTH levels and haemoglobin concentration (which may reflect nutrition and health). Bone density is highly predictable over an extended period of time in normal postmenopausal women. Maintenance of body weight and good health reduce bone loss. HRT is effective for treating osteoporosis, with improvement in bone density and reduction in vertebral fractures. Good compliance with HRT long-term is achievable. These findings are relevant to deciding the frequency of bone density measurement, and in advising women regarding prevention and treatment of postmenopausal bone loss.

Lasofoxifene (CP-336,156), a novel selective estrogen receptor modulator, in preclinical studies

Estrogen replacement therapy is reported to reduce the incidence of vertebral fractures in postmenopausal women, however, its compliance is limited because of side effects and safety concerns. Estrogen's side effects on breast and uterine tissues leading to the potential increased risk of uterine and breast cancer limit widespread estrogen usage. Thus, there is a significant medical need for a therapy that protects against postmenopausal bone loss but is free of estrogen's negative effects on reproductive tissues. Selective estrogen receptor modulators (SERMs) have been investigated as an alternative to hormone replacement therapy. One such compound, raloxifene, has been approved for the prevention and treatment of osteoporosis. Lasofoxifene (LAS), a new, nonsteroidal, and potent SERM, is an estrogen antagonist or agonist depending on the target tissue. LAS selectively binds with high affinity to human estrogen receptors. In ovariectomized (OVX) rat studies, LAS prevented the decrease in femoral bone mineral density, tibial and lumbar vertebral trabecular bone mass at an ED100 of about 60 μg/kg/day. LAS inhibited the activation of trabecular and endocortical bone resorption and bone turnover in tibial metaphyses and diaphyses, and lumbar vertebral body in OVX rats. In addition, LAS decreased total serum cholesterol, inhibited body weight gain and increased soleus muscle weight in OVX rats. Similarly, LAS prevented bone loss induced by orchidectomy or aging in male rats by decreasing bone resorption and bone turnover while it had no effect in the prostate. Further, LAS decreased total serum cholesterol in intact aged male rats or in orchidectomized male rats. Synergestic skeletal effects were found with LAS in combination with bone anabolic agents such as prostaglandin E2 (PGE2), parathyroid hormone (PTH) or a growth hormone secretagoue (GHS) in OVX rats. In combination with estrogen, LAS inhibited the uterine stimulating effects of estrogen but did not block the bone protective effects of estrogen. In immature and aged female rats, LAS did not affect the uterine weight and uterine histology. In OVX adult female rats, LAS slightly but significantly increased uterine weight. These results demonstrated that LAS produced effects on the skeleton indistinguishable from estrogen in female and male rats. However, unlike estrogen, LAS had little effect on uterine weight and cellular proliferation of uterus in female rats. In preclinical anti-tumor studies, LAS inhibited human breast cancer growth in mice bearing MCF7 tumors, prevented NMU-induced mammary carcinomas and possessed chemotherapeutic effects in NMU-induced carcinomas in rats. Therefore, we conclude that LAS possesses the antiestrogenic effects in breast tissue and estrogenic effects in bone and serum cholesterol, but lacks estrogen's side effects on uterine tissue. These data support the therapeutic potential of LAS for the prevention and treatment of postmenopausal bone loss and mammary carcinomas in humans.

Salmon calcitonin nasal spray

The efficacy and safety of estrogen replacement therapy (ERT) and salmon calcitonin in the treatment of postmenopausal osteoporosis are reviewed with special consideration given to patients for whom ERT, the primary antiresorptive therapy for osteoporosis, is not indicated, tolerable, or is refused. The various formulations of estrogen and salmon calcitonin, for which the nasal spray formulation was recently approved for use in the United States, are reviewed in depth with reference to dose ranges, side effects, and convenience. Data regarding increases in bone mineral density (BMD) produced by each agent are presented. Specifically, the range of increases in BMD induced by ERT and salmon calcitonin are comparable. Given the substantial public health consequences of postmenopausal osteoporosis and osteoporotic fractures, the primary care physician is increasingly faced with the need to educated and recruit postmenopausal patients to appropriate therapy with the optimal agent for that particular patient. In the many patients who are unable or unwilling to accept, initiate, and comply with prescribed ERT, alternative therapeutic options are necessary Based on the established safety profile of salmon calcitonin, ease of administration, an uncomplicated dosing regimen, no reported drug interactions, and the lack of uterine bleeding associated with ERT or gastrointestinal adverse effects of other agents used to treat osteoporosis, salmon calcitonin nasal spray is an appropriate alternative approach for the treatment of postmenopausal bone loss.

Practical Management of Postmenopausal Women with Low Bone Mineral Density

For the management of postmenopausal women with low bone mineral density (BMD), the gynecologist, as a primary care physician, should play a central role in preventing osteoporotic fracture by educating them for elimination of risk factors and for healthy life-style and by providing an appropriate drug therapy. Because the risk of fracture usually increases after BMD decreases as much as 20-30% of peak bone mass, it is practically reasonable to set this level of BMD as a criteria for the initiation of management. As for a drug treatment, it is better to combine estrogen, the first choice drug, with progestogens to counteract any neoplastic effect of unopposed estrogen on the endometrium. Bisphosphonates and calcitonin, which are inhibitors of bone resorption, provide an alternative in prevention and treatment of postmenopausal bone loss in case of contraindication for estrogen or in those women who are unwilling to take estrogen.

89207902 Transdermal estradiol in the treatment of postmenopausal bone loss

89207902 Transdermal estradiol in the treatment of postmenopausal bone loss

Transdermal estradiol in the treatment of postmenopausal bone loss

The effects on calcium metabolism and forearm bone mineral density of sequential transdermal estradiol (ESTRADERM TTS-50), 50 μg/day and medroxyprogesterone (10 mg/day for 12 days) was studied in a randomised controlled trial in 34 healthy females 2–4 years after the menopause. At the end of the 18 months' treatment course with transdermal estradiol, bone density was increased by 4.31% ( P < 0.01) but was decreased by 3.5% ( P < 0.01) in the control group. In the treated group, serum calcium, calcium excretion and hydroxyproline excretion significantly fell during the first 2 months with no significant changes thereafter. Serum alkaline phosphatase significantly decreased only after 4 months, it continued to fall until the fourteenth month when a plateau became apparent. Serum phosphate and tubular maximum for urinary phosphate progressively fell until the tenth month of therapy but thereafter they rose up to initial values. Serum intact parathyroid hormone did not show any significant change. In conclusion, small doses of transdermal estradiol are as effective as oral estrogens. This suggests that the bone sparing effects of estrogens may be due only to low circulating estradiol concentrations, but not to supraphysiological estrone levels. It seems also that estrogens exert both a straight inhibition of bone resorption and a partial inhibition of parathyroid responsiveness.

The aged rat model of ovarian hormone deficiency bone loss.

Three studies were carried out. First, the effects of aging on the maturation of the female skeleton were assessed. Second, the hypothesis that has linked ovarian hormone deficiency bone loss to hypercalcemic suppression of the parathyroids leading to a decrease in 1,25-dihydroxyvitamin D synthesis and gut absorption of calcium was examined. Third, the effects of ovariectomy and a combination of ovarian hormone deficiency and low dietary calcium on bone and the calcium-regulating hormones were evaluated. After 6 months, ovariectomy and a low calcium diet independently decreased the density of the ilium, the femur, and the fourth lumbar vertebra as well as the calcium content of the latter two. The effects of the two treatment regimens were additive and more marked in the vertebral bone. Ovariectomy lowered serum calcitonin only in animals fed a normal diet and had no effect on serum PTH and vitamin D metabolites, while a low calcium diet caused a significant increase in serum 1,25-dihydroxyvitamin D. In both dietary regimens ovariectomy resulted in about a 30% decrease in intestinal calcium absorption. A low calcium diet increased morphometric indices of bone formation and bone resorption as did ovariectomy, with resorption exceeding formation. The discussion of our findings led to the conclusion that the aged rat model of ovarian hormone deficiency bone loss qualifies for serious consideration as a practical convenient cost-effective animal model for exploring aspects of the pathogenesis and treatment of postmenopausal bone loss.

Is progestogen superior to estrogen for the treatment of postmenopausal bone loss

Is progestogen superior to estrogen for the treatment of postmenopausal bone loss

UNCOUPLING OF BONE FORMATION AND RESORPTION BY COMBINED OESTROGEN AND PROGESTAGEN THERAPY IN POSTMENOPAUSAL OSTEOPOROSIS

10 healthy early postmenopausal women were treated with oestrogen and progestagen for two cycles of 28 days. Serum alkaline phosphatase and bone Gla protein increased during progestagen administration, whereas urinary excretion of calcium and hydroxyproline fell significantly during treatment, independently of progestagen intake. Thus, bone formation increases when progestagen is added to oestrogen treatment, whereas bone resorption may be kept constantly low during oestrogen plus progestagen treatment, leading to a positive calcium balance. This makes possible effective treatment of postmenopausal osteoporosis—treatment of elderly postmenopausal women with substantial bone loss before their bones have fractured or when they have just started to fracture. This study design can be used for easy and rapid screening of potential drugs for the prevention and treatment of postmenopausal bone loss.