Trimegestone in a low-dose, continuous-combined hormone therapy regimen prevents bone loss in osteopenic postmenopausal women

OBJECTIVE: To determine the efficacy of estrogen + progestogen therapy with 1 mg 17beta-estradiol and 0.125 mg trimegestone in the prevention of postmenopausal osteoporosis. DESIGN: For this study, 360 healthy, postmenopausal women with osteopenia [lumbar spine bone mineral density (BMD) between -1.0 and -2.5 SD of the premenopausal mean value] were enrolled in a 2-year prospective, randomized study, and 70% completed. Treatments were 1 mg 17beta-estradiol + 0.125 mg trimegestone (n = 179) or placebo (n = 181), given as daily oral therapy. All received a daily supplement of 500 mg calcium and 400 IU vitamin D. BMD measurements at the lumbar spine, total hip, and femoral neck as well as blood and urinary biochemical markers of bone turnover (serum osteocalcin), serum bone-specific alkaline phosphatase, serum CrossLaps, and urinary CrossLaps took place regularly. RESULTS: BMD increases relative to placebo were 6.3%, 3.9%, and 3.8% at the lumbar spine, total hip, and femoral neck, respectively (all P < 0.001). The biochemical markers of bone turnover were suppressed accordingly. Serum CrossLaps and urinary CrossLaps decreased rapidly, by 52% and 54%, respectively, whereas serum osteocalcin and serum bone-specific alkaline phosphatase revealed a more retarded decrease of 40% and 33%, respectively. Of the women receiving hormone therapy, 75% had amenorrhea from the first cycle, and 5% withdrew prematurely due to metrorrhagia or mastalgia. CONCLUSION: This new estrogen + progestogen therapy is efficient in increasing BMD in an osteopenic postmenopausal population. Furthermore, it is well tolerated, with few adverse events and an early bleeding control, which is likely to improve compliance to the treatment over the long term.     

Relationship between BMD, dental panoramic radiographic findings and biochemical markers of bone turnover in diagnosis of osteoporosis

OBJECTIVE: Mandibular indices, measured on panoramic radiographs, may be useful screening implements for low skeletal bone mass density (BMD). Recent studies suggest that radiographic examination of mandible may constitute an effective process for the early diagnosis of osteoporosis. Biochemical markers of bone turnover may be of value for prediction of individual bone loss and they may help in predicting risk of fracture in elderly women. In contrast to the vast information available on dental radiographic findings and BMD only scarce data exist on the relationship between panoramic mandibular indices and biochemical markers. The aim of this study was to examine the diagnostic performance of dental panoramic radiography and biochemical markers of bone turnover in relation to BMD at the spine in a group of postmenopausal women. SUBJECTS AND METHODS: An assessment of the number of lost teeth, mandibular cortical width (MCW) at the mental region and morphologic classification of mandibular inferior cortex (MIC grade) was performed on dental panoramic radiographs in a group of 141 postmenopausal women 38-81 years of age. BMD at the lumbar spine was measured by dual energy X-ray absorptiometry. BMD values were categorized as normal (T-score greater than 1.0), and as indicative of osteopenia (T-score -1.0 to -2.5) or osteoporosis (T-score less than -2.5) according to the World Health Organization classification. Serum bone alkaline phosphatase (BAP) was measured with an enzyme immunoassay. Cross-linked N-telopeptides of type I collagen (NTx) corrected for creatinine secretion, was measured with a competitive-inhibition enzyme-linked immunosorbent assay ELISA. RESULTS: In our study, a decrease in MCW by 1mm increases the likelihood of osteopenia or osteoporosis to 47% (p-value<0.05), having taken into consideration the effect of the years elapsed since menopause. The increase of alkaline phosphatase (ALP) per unit increase the likelihood of osteopenia or osteoporosis to 14% (p-value<0.05), having checked the effect of the years since menopause. A decrease in MCW by 1mm increases the likelihood of moderately or severely eroded cortex to 97% (p-value<0.001). The increase in ALP per 1 unit increases the likelihood of moderate or severe erosion per 10% (p-value<0.05), taking into account the years since menopause. CONCLUSIONS: Our results suggest that dentists have sufficient clinical and radiographic information that enables them to play a significant role in early diagnosis of osteoporosis in postmenopausal women. Panoramic radiographs and biochemical markers of bone turnover may be of value for prediction of individual bone loss and they may help in predicting risk of fracture in elderly women.     

去势大鼠5种骨转换生化指标的动态变化

目的： 对去势大鼠骨质疏松动物模型形成过程中5种骨转换指标的变化及其相关性进行研究。方法: 将3月龄SD雌性大鼠分为3组：切除卵巢组(OVX)，假手术组(sham)和对照组(control)，术前和术后分别于1、1.5、2、2.5、3和4月检测血清骨钙素(OC)、碱性磷酸酶(ALP)、 骨碱性磷酸酶(BALP)、抗酒石酸酸性磷酸酶(TRAP)和羟脯氨酸(HYP)水平，并作大鼠胫骨病理切片检查。结果: OVX组血清OC、ALP、BALP、TRAP和HYP水平均明显高于sham组，其变化顺序依次为：TRAP/HYP→OC→ALP/BALP；5种指标之间呈显著正相关；术后3月OVX组大鼠胫骨小梁结构有病理改变。结论: 去势大鼠属于高转换型骨质疏松；在模型形成过程中，骨吸收指标的变化早于骨形成指标的改变；骨转换指标是反映绝经后早期骨量丢失的灵敏指标。     

Soy isoflavones for osteoporosis: an evidence-based approach

Effects of soy isoflavones on osteoporosis remain unclear. This review aimed to clarify the effect of soy isoflavones on bone mineral density (BMD) and turnover markers in menopausal women. PubMed and the Cochrane Library were searched in July 2011 for relevant meta-analyses of randomized controlled trials evaluating effects of soy isoflavones on BMD and bone turnover markers. Three meta-analyses evaluated the effects of soy isoflavones on lumbar spine, total hip, femoral neck, and trochanter BMD. Soy isoflavones significantly improved lumbar spine BMD in a moderate manner, but did not affect total hip, femoral neck, and trochanter BMD in menopausal women. Ingestion of soy isoflavones for six months appeared to be enough to exert a beneficial effect on lumbar spine BMD. Two meta-analyses evaluated the effects of soy isoflavones on a bone resorption marker (urine deoxypyridinoline) and two formation markers (serum alkaline phosphatase and osteocalcin). Soy isoflavones significantly decreased urine deoxypyridinoline in a moderate manner, but did not affect serum alkaline phosphatase and osteocalcin in menopausal women. Soy isoflavones may prevent postmenopausal osteoporosis and improve bone strength thus decreasing risk of fracture in menopausal women by increasing lumbar spine BMD and decreasing bone resorption marker urine deoxypyridinoline. Further studies are needed to address factors affecting the magnitude of the beneficial effects of soy isoflavones and to assess the possible interactions between soy isoflavones and anti-osteoporosis drugs, and to verify effects on BMD of other skeletal sites and other bone turnover markers.     

Does apolipoprotein E genotype relate to BMD and bone markers in postmenopausal women?

OBJECTIVES: Bone mineral density (BMD) and development of osteoporosis are partly determined by genetic factors. The associations between one of suggested candidate, apolipoprotein E (apo E) genotype to bone mineral density (BMD) and bone biochemical markers was studied in 464 subjects recruited from a population-based group of early postmenopausal women (n = 13100). Additionally, the influence of apo E genotype on BMD changes during a 5-year follow-up with or without hormone replacement therapy (HRT) was investigated. METHODS: Participants were randomized into two treatment groups: HRT group: Sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate with or without vitamin D3, 100-300 IU/day + calcium lactate, 500 mg/day (n = 232), and the non-HRT group: Calcium lactate, 500 mg/day alone or in combination with vitamin D3, 100-300 IU/day (n = 232). BMD was measured from the lumbar spine and proximal femur at baseline and after 5 years of treatment (n = 352). In a subgroup (n = 59), the serum concentrations of bone biochemical markers (intact osteocalcin (OC), bone-specific alkaline phosphatase (BAP) and type I collagen carboxy-terminal telopeptide (ICTP)) were measured at baseline and after 1 year of follow-up. RESULTS: At baseline, the BMDs were similar between the five apo E genotype groups (2/3, 2/4, 3/3, 3/4, 4/4). No significant differences in lumbar or femoral neck BMDs of women with the apo E4 allele were found compared with those without it. There was a statistically significant difference in 5-year BMD changes between the HRT and non-HRT groups. After 5 years, the BMD of the femoral neck had remained constant and the mean lumbar spine BMD had increased by 1.5% in the HRT group, whereas both BMDs had decreased by 4-5% in the non-HRT group. However, the apo E genotype did not modify the changes in BMD in either group. Additionally, the baseline concentrations of bone metabolic markers and their 1-year changes showed no genotype-related associations. CONCLUSIONS: The results of our population-based study indicate that apo E genotype does not modify lumbar or femoral neck BMDs or serum bone biochemical markers or their response to HRT in early postmenopausal Caucasian women.     

Peripheral quantitative computed tomography (pQCT) is useful for monitoring bone mineral density of the patients who receive hormone replacement therapy

OBJECTIVE: A forearm fracture (Colles' fracture) is often the first sign of osteoporosis and should alert the patient and physician to the possibility of underlying skeletal fragility. Therefore, the establishment of a more accurate and reliable method for the measurement of bone mineral density (BMD) at the distal radius would be beneficial for the patients who suffer from osteoporosis. The objective of the present study was to evaluate the usefulness of peripheral quantitative computed tomography (pQCT) to assess the change of BMD at the distal radius in early postmenopausal women who receive hormone replacement therapy (HRT). METHODS: Twenty healthy early postmenopausal women who were diagnosed as osteoporosis or osteopenia were randomized to either HRT or placebo treatment. We analyzed BMD of the distal radius by pQCT, lumbar spine by dual-energy X-ray absorptiometry (DXA) and the biochemical markers of bone turn over (osteocalcin, deoxypyridinoline) every 6 months. RESULTS: The placebo group showed a significant decrease from the baseline in the trabecular BMD of the radius at 12 months (7.4+/-2.5%) (p<0.05), whereas the HRT group showed a slight increase (0.7+/-2.2%). The changes in the trabecular BMD of the radius between the HRT and placebo groups were statistically different at 12 months (p<0.05). On the other hand, in the cortical BMD of the radius, no significant differences were seen between the changes of bone densities in the HRT and control groups after 1 year of treatment. pQCT could detect a significant loss of BMD of the radius in early postmenopausal women after 1 year and HRT prevented its loss. CONCLUSION: Our preliminary clinical trial showed that pQCT might be useful for the early detection of bone loss in early postmenopausal women and for the monitoring BMD of the patients who receive HRT.     

糖尿病微血管病患者骨密度及骨钙素测定的意义

目的：探讨糖尿病微血管病变对骨密度及骨钙素水平的影响。方法：选择2型糖尿病患者60例，按其是否合并糖尿病微血管病(眼病、肾病、神经病变)分为两组，合并微血管病(1组)33例，不合并微血管病(2组)27例。用生化法测定两组的空腹血糖(FBG）、果糖胺(GSP)、血清总碱性磷酸酶(TALP)及血钙(Ca^2 )，RIA测定骨钙素(BGP)，DEXA法测定腰椎和髋部骨密度(BMC)；按其身高、体重计算体重指数(BMI)。结果：两组BBMI、GSP、TALP及Ca^2 均未见明显差异；1组血清BGP水平明显低于2组，有显著性差异；1组第2—4腰椎（L2-4)、股骨颈、Ward’s三角区及股骨大转子的BMD均低于2组，差异有显著性。结论：骨密度及骨钙素与糖尿病微血管病变关系密切。认为糖尿病微血管病可能降低骨形成，加重骨质疏松。     

Multiparameter analysis of serum levels of C-telopeptide crosslaps,bone-specific alkaline phosphatase,cathepsin K,osteoprotegerin and receptor activator of nuclear factor κB ligand in the diagnosis of osteoporosis

ObjectivesC-telopeptide crosslaps (CTX) and bone-specific alkaline phosphatase (BAP) do not provide sufficient sensitivity and specificity for diagnosis of osteoporosis. Cathepsin K (CatK), osteoprotegerin (OPG), and receptor activator of nuclear factor κB ligand (total (t) and soluble (s) RANKL) play an important role in bone metabolism. Thus serum levels of biochemical markers, each or in combination, may be useful in diagnosis of osteoporosis.Study DesignIn total, 121 healthy women, 27 premenopausal women aged between 20 and 45 years, and 94 postmenopausal women aged 59–81 years, all free of known skeletal disorders were included. They underwent bone density measurement and measurement of biochemical markers.Main Outcome MeasuresBased on WHO criteria, women were stratified in four groups (premenopausal: healthy; postmenopausal: healthy, osteopenia, osteoporosis), and their levels of CatK, OPG, RANKL, CTX and BAP were analyzed.ResultsUsing WHO criteria 21 postmenopausal women had normal bone mineral density (BMD), 49 had osteopenia and 24 had osteoporosis. There were no significant correlations of CatK, OPG and RANKL with BMD (T-score) in age-adjusted analysis, but for BAP and CTX. ROC analyses resulted in poor diagnostic validity of all parameters. The best result – also confirmed by discriminant analysis – was yielded by BAP (AUC = 0.646 [0.510; 0.781]). A combination of variables did not significantly improve the diagnostic power.ConclusionsBaseline serum levels of BAP, CTX, CatK, OPG, sRANKL or tRANKL alone or in combination are not suitable to distinguish osteoporotic from non-osteoporotic postmenopausal women with sufficient accuracy.     

Effects of alendronate and hormone replacement therapy, alone or in combination, on bone mass in postmenopausal women with osteoporosis: a prospective, randomized study

The effectiveness of hormone replacement therapy (HRT) and alendronate, alone and in combination, was evaluated in 120 postmenopausal patients with osteoporosis with bone mineral density (BMD) measurements at least 2 SD below the mean value for young premenopausal subjects. They had no contra-indications to HRT or alendronate use and were randomized to three different treatment groups. Group I was treated with micronized 17 beta-oestradiol 2 mg and norethisterone acetate 1 mg/day per os, group II received alendronate 10 mg/day per os and group III received micronized 17 beta-oestradiol 2 mg, norethisterone acetate 1 mg/day per os and alendronate 10 mg/day per os for 1 year. Elementary calcium 1500 mg/day was supplied to patients in all three groups. Spinal and femoral neck BMD and markers of bone mineral metabolism were measured on each patient before treatment and 6 and 12 months after treatment in 95 patients. At the end of the 12th month, significant increases in spinal and femoral neck BMD were found in all groups. Increases in spinal BMD were significantly higher in patients treated with alendronate and alendronate with HRT when compared with patients treated with HRT only. No significant difference was found in femoral neck BMD changes between the groups. Significant decreases in bone resorption and markers of bone formation were observed in all groups. Alendronate was found to be more effective than HRT and could have a very beneficial effect when added to the HRT regimen in patients with postmenopausal osteoporosis. Alendronate might also be used in postmenopausal patients with osteoporosis when HRT is contra-indicated or when there is reluctance to use hormonal treatment.     

Comparison of the Effects of Alendronate and Alfacalcidol on Hip Bone Mineral Density and Bone Turnover in Japanese Men Having Osteoporosis or Osteopenia with Clinical Risk Factors for Fractures

Purpose

The comparative effects of alendronate and alfacalcidol on bone mineral density (BMD) and bone turnover have already been established in postmenopausal women with osteoporosis. An open-labeled prospective study was conducted to compare the treatment effects of alendronate and alfacalcidol on hip BMD and bone turnover in Japanese men with osteoporosis or osteopenia with clinical risk factors for fractures.

Materials and Methods

One hundred twelve men with osteoporosis or osteopenia with clinical risk factors for fractures (mean age: 71.4 years) were randomly divided into two groups of 56 patients each: the alendronate (5 mg daily) and alfacalcidol (1 µg daily) groups. The BMD of the total hip, urinary level of cross-linked N-terminal telopeptides of type I collagen (NTX), and serum levels of bone-specific alkaline phosphatase (BSAP) were measured during the 12-month-treatment period.

Results

Forty-five patients in the alendronate group and 42 patients in the alfacalcidol group completed the trial. Alendronate increased BMD (+2.3% at 12 months) following reductions in the urinary level of NTX (-46.4% at 3 months) and serum level of BSAP (-34.1% at 12 months), while alfacalcidol sustained BMD (-1.9% at 12 months) as well as the urinary level of NTX (+13.2% at 3 months) and serum level of BSAP (+1.8% at 12 months).

Conclusion

The present study confirmed that alendronate has better efficacy than alfacalcidol (active control) in increasing hip BMD and reducing bone turnover in Japanese men with osteoporosis or osteopenia with clinical risk factors for fractures.     

Metabolic characteristics and prevalence of osteoporosis among women in Tae-An area.

Understanding the metabolic changes in women is one of the important ways to prevent and treat osteoporosis. To reveal the metabolic characteristics of 289 healthy women aged between 35-65 yr in Tae-An, Korea we evaluated the association between bone mass assessed by broadband ultrasound attenuation (BUA) using quantitative ultrasound 2 (QUS2) and various parameters such as age, body mass index, serum levels of alkaline phosphatase, calcium, phosphorus, parathyroid hormone, 25(OH)D, and urinary ratios of calcium/creatinine and deoxypyridinoline (Dpyd)/creatinine. Among the subjects, 3.0% were osteoporotic, and 40.9% were osteopenic. When the subjects were classified according to their years since menopause (YSM) and age, the prevalence of osteoporosis increased along with an increase of YSM and age. Bone turnover markers such as serum alkaline phosphatase and fasting urinary Dpyd/creatinine were significantly higher in the group with low bone mass than in the normal group. In summary, this study shows, by use of biochemical markers of bone turnover and QUS2, the prevalence of osteoporosis in women aged between 35-65 in Tae-An was 3.0% and the risk of low bone mass increased with the bone turnover markers.     

Decrease of bone formation in adult women with fragility fractures

Objectives: To compare bone mineral density (BMD) and some markers of bone metabolism in women with fragility fractures and in normal age-matched subjects. Methods: A 100 women with at least one vertebral deformity >25%, and 219 age-, BMI- and parity-matched healthy women, were recruited for the study. In all the patients fractures were symptomatic and occurred at least 1 year before densitometric measurement. Forearm bone mineral density (BMD) as well as biochemical assessment of some markers of bone turnover were measured in all the subjects. Results: BMD was significantly lower in the fracture than in the control group (0.326 ± 0.073 vs. 0.379 ± 0.079; P<0.001). Fractured women showed alkaline phosphatase (ALP) and osteocalcin (OC) serum levels significantly lower than controls, while no differences were found in fasting urinary calcium and hydroxyproline excretion. Women without fractures showed a significant correlation between ALP and both age and years since menopause (YSM). Such a correlation is lacking in the fracture group. Conclusions: Women with vertebral deformities likely due to a fracture had a forearm BMD and markers of bone formation lower than normal. Whether low bone density is due to a low peak of bone mass or to an increased postmenopausal bone loss sustained by an uncoupling between the two bone remodelling processes is still unclear.     

Comparison of effects of alendronate and raloxifene on lumbar bone mineral density, bone turnover, and lipid metabolism in elderly women with osteoporosis

PURPOSE: To compare the effects of alendronate and raloxifene on lumbar bone mineral density (BMD), bone turnover, and lipid metabolism in elderly women with osteoporosis. SUBJECTS AND METHODS: One hundred twenty-two postmenopausal women with osteoporosis (mean age: 69.4 years) were randomly divided into 2 groups of 61 patients: the alendronate group and the raloxifene group. BMD of the lumbar spine, urinary level of cross-linked N-terminal telopeptides of type I collagen (NTX), and serum levels of alkaline phosphatase (ALP), total cholesterol (TC), high and low density lipoprotein cholesterols (LDL-C and HDL-C, respectively), and triglycerides (TG) were measured during the 12-month-treatment period. RESULTS: The trial in 50 patients in the alendronate group and 52 patients in the raloxifene group could be completed. Both alendronate and raloxifene increased lumbar BMD (+8.0% and +2.4% at 12 months, respectively), followed by reductions of urinary NTX level and serum ALP level; however, the effects of alendronate were more pronounced than those of raloxifene. Only raloxifene reduced the serum levels of TC and LDL-C (-3.9% and -7.7% at 12 months, respectively), without any significant effect on the serum HDL-C and TG levels. CONCLUSION: The present study confirmed the efficacy of alendronate greater than raloxifene in increasing lumbar BMD through its effect on marked reduction of the bone turnover more than by raloxifene, and some beneficial effects of raloxifene on lipid metabolism in elderly women with osteoporosis.     

Levonorgestrel and 17beta-estradiol given transdermally for the prevention of postmenopausal osteoporosis

Aim: To evaluate the efficacy and safety of a new transdermal continuous combined hormone replacement therapy (HRT) for the prevention of postmenopausal osteoporosis. Methods: 212 osteopenic (lumbar spine and/or hip (femoral neck) bone mineral density (BMD) between −1.0 and −2.5 S.D. of the premenopausal mean value) postmenopausal women aged 45–65 years participated in a 2-year prospective study. Treatments were 45 μg 17β-estradiol combined with 30 (n = 69) or 40 μg (n = 72) levonorgestrel daily or placebo (n = 71) given as a 7-day patch. All received a daily supplement of 500 mg calcium. BMD at lumbar spine (L2–L4), hip and total body, as well as blood and urinary biochemical markers of bone turnover (serum osteocalcin (sOC), serum bone-specific alkaline phosphatase (sBSAP), urinary calcium (uCa) and urinary CrossLaps (uCTX)) were measured regularly. Results: BMD at the lumbar spine, hip and total body increased by 8, 6 and 3% (P < 0.001), respectively, in the hormone groups versus placebo. The bone markers all decreased accordingly (sOC: 37%, sBSAP: 34% and uCTX: 65% from baseline (all P < 0.001)), except for uCa that did not change significantly. No significant dose-related effect of levonorgestrel was found. Vaginal bleeding/spotting decreased from 48 to 25% of the HRT-treated women during the study period. Skin tolerance was good in 84% of the women with no difference between the study groups. No incidences of endometrial hyperplasia, uterine or mammary cancer occurred. Conclusion: The transdermal combination of 17β-estradiol and levonorgestrel has a positive effect on BMD in an osteopenic postmenopausal population. Furthermore, a high safety profile was observed.     

Once-weekly alendronate 70 mg and raloxifene 60 mg daily in the treatment of postmenopausal osteoporosis

OBJECTIVE: To compare the efficacy and tolerability of once-weekly (OW) alendronate (ALN) 70 mg and raloxifene (RLX) 60 mg daily in the treatment of postmenopausal osteoporosis. DESIGN: This 12-month, randomized, double-blind study enrolled 456 postmenopausal women with osteoporosis (223 ALN, 233 RLX) at 52 sites in the United States. Efficacy measurements included lumbar spine (LS), total hip, and trochanter bone mineral density (BMD) at 6 and 12 months, biochemical markers of bone turnover, and percent of women who maintained or gained BMD in response to treatment. The primary endpoint was percent change from baseline in LS BMD at 12 months. Adverse experiences were recorded to assess treatment safety and tolerability. RESULTS: Over 12 months, OW ALN produced a significantly greater increase in LS BMD (4.4%, P < 0.001) than RLX (1.9%). The percentage of women with > or = 0% increase in LS BMD (ALN, 94%; RLX, 75%; P < 0.001) and > or =3% increase in LS BMD (ALN, 66%; RLX, 38%; P < 0.001) were significantly greater with ALN than RLX. Total hip and trochanter BMD increases were also significantly greater (P < or =0.001) with ALN. Greater (P < 0.001) reductions in N-telopeptide of type I collagen and bone-specific alkaline phosphatase were achieved with ALN compared with RLX at 6 and 12 months. No significant differences in the incidence of upper gastrointestinal or vasomotor adverse experiences were seen. CONCLUSION: ALN 70 mg OW produced significantly greater increases in spine and hip BMD and greater reductions in markers of bone turnover than RLX over 12 months. A greater percentage of women maintained or gained BMD on ALN than RLX. Both medications had similar safety and tolerability profiles.     

Prevention of postmenopausal bone loss with exchange for short-term HRT for 1alpha-hydroxycholecalciferol

OBJECTIVE: The present study investigated bone turnover with exchange of hormone replacement therapy (HRT) by treatment with 1alpha-hydroxycholecalciferol in early postmenopausal women. METHODS: Subjects included a total of 75 postmenopausal women between 49 and 59 years of age who visited the Department of Obstetrics and Gynecology at Osaka Medical College Hospital for regular gynecological checkups and menopausal disorder, postmenopausal osteoporosis or hyperlipidemia, and were diagnosed with menopausal disorder or osteopenia. Changes in bone turnover and vertebral bone mineral density (BMD) in 28 patients who had undergone HRT; conjugated equine estrogen 0.625 mg daily and medroxyprogesterone acetate 2.5 mg daily) for at least 2 years and then switched to 1alpha-hydroxycholecalciferol (0.5 microg orally twice daily) and in 26 patients who were observed without drug administration after discontinuation of HRT were compared with those in 37 patients who continued HRT. BMD of the lumbar spine (L2-4) was determined using Dual Energy X-ray Absorptiometry. RESULTS: While we observed a significant decrease in vertebral bone mass in the HRT-no medication group at 12 months (P=0.049) and 18 months (P=0.013), there was no significant decrease in vertebral bone mass in either the continuous HRT group or the group with change of HRT to 1alpha-hydroxycholecalciferol. In the group with change of HRT to 1alpha-hydroxycholecalciferol, although urinary pyridinoline level increased significantly from the baseline level throughout the study period (P<0.05), serum propeptide of type-1 procollagen (P1CP) level also increased significantly from the baseline level throughout this period (P<0.001). Furthermore, significant increase from the baseline value (P<0.01) was observed in serum osteocalcin level at 6, 12 and 18 months. CONCLUSIONS: These results indicate that switching to 1alpha-hydroxycholecalciferol therapy after short-term HRT increased both bone resorption and bone formation, and permitted maintenance of increase in bone mass due to HRT for at least 18 months, though this switching accelerated bone turnover. This may have occurred because stimulation of bone formation induced by HRT was maintained by 1alpha-hydroxycholecalciferol, though bone turnover was slightly promoted because of withdrawal of HRT. This method was thus found to be very effective in preventing bone loss in patients who have discontinued HRT and are considered relatively contraindicated for use of estrogen.     

Efficacy of a soy rich diet in preventing postmenopausal osteoporosis: the Menfis randomized trial

Objectives: To compare the effect of a soy rich diet and hormone replacement therapy (HRT) on the main biomarkers of bone turnover and bone mineral density (BMD) at postmenopausal age. Methods: 187 healthy asymptomatic postmenopausal women, aged 39–60, were recruited and randomized into a soy rich diet group, a HRT group, and a control group. Bone biomarkers and BMD were evaluated at baseline and after 6 months at the end of the study. Results: Diet is not as effective as HRT in reducing the postmenopausal turnover; however diet stimulates bone osteoblastic activity, as evidenced by significant increase in osteocalcin concentrations. BMD decreases significantly only in the control group, but not in the intervention groups. Conclusions: Our data suggest that soy products could be effective in reducing the risk of osteoporosis in asymptomatic postmenopausal women, but our findings should be confirmed before recommending the diet as a valid alternative to HRT.     

Bisphosphonates for prevention of postmenopausal osteoporosis

Our studies showed that 5 mg alendronate per day was the lowest, most effective dose that persistently prevented bone loss in recently postmenopausal women with normal bone mass. The effect on bone mass and biochemical markers was found comparable to that of commonly recommended regimens of postmenopausal HRT, and 5 mg alendronate per day is suggested as a new option for prevention of postmenopausal osteoporosis. HRT must, however, still be considered the first choice for this indication because of additional beneficial effects on other organ systems. The effect of alendronate was unaffected by bone or fat mass status, but increased with increasing postmenopausal age. The implications were that alendronate stabilized bone mass to a comparable extent in women at particular risk of osteoporosis because of thin body habitus or low bone mass and in healthy postmenopausal women with normal bone mass. Calcium supplementation was insufficient to prevent bone loss and did not add an effect on bone metabolism when combined with alendronate treatment in recently postmenopausal women. The gastrointestinal risk and adverse event profile of 5 mg alendronate per day was comparable to that of placebo, and this dose of alendronate appeared safe for long-term use. Bone loss resumed at a normal postmenopausal rate promptly after withdrawal of alendronate in early postmenopausal women consistent with a substantial underlying natural bone loss during early menopause. Oral ibandronate increased bone mass at all skeletal regions in elderly postmenopausal women with low bone mass, and 2.5 mg ibandronate per day was the lowest dose with this effect. The results are indicative of ibandronate as an option for secondary prevention of postmenopausal osteoporosis, but longer-term phase III trials should be performed before ibandronate can be recommended for this indication. The study showed that 2.5 mg ibandronate per day was efficient for prevention of bone loss and increment in bone mass in a population of women at particular risk of osteoporosis because of low bone mass. There were no differences between 2.5 mg ibandronate per day and placebo in terms of side effects, including complaints from the gastrointestinal tract, and ibandronate appeared safe for longer-term use in this dosing. Bone loss resumed at a normal postmenopausal rate when treatment was withdrawn. The response in bone mass and biochemical markers indicated that 2.5 mg ibandronate per day is equivalent to 10 mg alendronate per day in postmenopausal women. Our studies of two recently developed biochemical markers, urine CTX and serum total OC, showed that bone turnover was lowest in the premenopausal period, where these biochemical markers furthermore revealed a negative association with bone mass. It indicated that increased bone turnover contributes to a small premenopausal bone loss and resulting lowered bone mass. In consistence, a small premenopausal bone loss was observed in some regions of the hip. The biochemical markers increased at the time of menopause, consistent with initiation of the postmenopausal bone loss, and became gradually more negatively associated with bone mass as time past the menopause increased. The biochemical markers were furthermore higher in postmenopausal women with low bone mass, consistent with the characterization of postmenopausal osteoporosis as a condition with increased bone turnover. Our results consistently indicated a central role of increased bone turnover for development of low bone mass and osteoporosis. It is, however, also important to stress that the associations between biochemical markers and bone mass were too weak to allow for a valid individual estimation of bone mass based on biochemical markers. In contrast, the biochemical markers were shown as valid tools for monitoring and prediction of treatment effect of bisphosphonates. CTX, NTX, and total OC revealed the best performance characteristics in this respect. Six months after start of treatment, the level of suppression of these biochemical markers of bone resorption and formation accurately reflected the size of the 1-2 year response in bone mass in groups of women treated with bisphosphonate. This was a clear advance over bone densitometry, which has a precision error in the area of the anticipated yearly bone mass response during bisphosphonate therapy. The relationship was consistent during treatment with alendronate or ibandronate and in younger or elderly postmenopausal women. In individual patients, cut-off values of an about 40% decrease in urine CTX or NTX and an about 20% decrease in total OC validly predicted long-term prevention of bone loss. The sensitivity of prediction was high, but the specificity low. This implicated that the biochemical markers could be used as an exact method to detect "responders" to therapy, whereas "non-responders" to bisphosphonate treatment should be detected with bone densitometry in patients who do not reveal a decrease below the cut-off value in the biochemical marker during treatment. However, before such approach can be generally recommended the cut-off values of the biochemical markers should be validated in future clinical trials of bisphosphonate. Postmenopausal osteoporosis develops slowly over many years and mainly becomes a significant individual and socio-economic health problem 1-3 decades after the menopause. Prevention of postmenopausal osteoporosis by bisphosphonates is therefore likely to imply a treatment regimen of at least a decade, as presently recommended for HRT (Consensus Development Statement 1997). However, future cost-effectiveness studies should reveal when bisphosphonate treatment should ideally be initiated. Our studies showed that the bisphosphonates were effective over the range from general recommendation (recently postmenopausal women with normal bone mass) to a reservation for women at particular risk of osteoporosis (elderly women, thin women, or women with osteopenia). Presently available biochemical markers could be used for groupwise and individual monitoring and prediction of treatment response. Most presently available biochemical markers, however, have the drawback of a low specificity. Recent studies of CTX measured in serum are promising, and indicate that this new biochemical marker might have overcome these drawbacks due to a pronounced response to treatment and a low long-term biological variation (Christgau et al. 1998b, Rosen et al. 1998, and 2000).     

Effect of physical activity on bone turnover in young boys

AIMS: To evaluate the effect of the physical activity on bone turnover in young male soccer players at the Tanner's stage of 1-2. MATERIAL AND METHODS: 61 young soccer players (13,4 +/- 0,3 years old) who actively participated in soccer since 3,7 +/- 0,7 years were compared to 60 age and sex- matched non active subjects. Bone mineral density (BMD) of whole body, and in specific skeleton sites, fatty body mass (FBM) and lean body mass (LBM) were determined by a dual energy X-ray absorptiometry (DXA). Total plasma alkaline phosphatase (ALP) and plasma bone alkaline phosphatase (BALP), plasma osteocalcin (OC) and plasma collagen type I cross-linked C-telopeptide (CTX) were measured. RESULTS: BMD of the whole body and at the lumbar spine (L2-L4), femoral, lower limbs and LBM were significantly higher in young soccer players than in controls. The biochemical markers of bone turnover: ALP (6,7%), BALP (8,9%), OC (3%) and CTX (3,1%) were not significantly higher in sportsmen than in controls. The calcium was significantly higher in sportsmen than in controls. CONCLUSION: These results suggest that soccer practice induced an increase of bone mass in boys. The increase in the level of bone turnover evaluated by the new biochemical markers was not significant in the sportsmen.     

Biochemical markers of bone turnover : clinical usefulness in osteoporosis

The recent development of specific and sensitive biochemical markers reflecting the overall rate of bone formation and bone resorption, has markedly improved the non invasive assessment of bone turnover in various metabolic bone diseases, especially for osteoporosis. The immunoassay of human osteocalcin recognizing the intact molecule and its major proteolytic fragment, assays for bone alkaline phosphatase and the intact form of the N-terminal extension propeptide of type I collagen are currently the most sensitive markers to assess bone formation. The best indices of bone resorption are the new immunoassays for the pyridinoline crosslinks and type I collagen related peptides in urine, but also very recently available in serum. Using these new markers, several studies have shown that bone turnover increases markedly after the menopause and remains elevated in late postmenopausal and elderly women. An increased bone turnover rate is related to a fast rate of bone loss in postmenopausal women and to a decreased bone mass in elderly women. Recent data suggest that some of the new immunoassays for pyridinoline crosslinks and related peptides could predict the subsequent risk of hip fracture in elderly women. Thus, bone markers might be used in combination with bone mass measurement to improve the prognostic assessment of postmenopausal women, i.e. their risk of developing osteoporosis and ultimately fractures. Treatment of postmenopausal women with antiresorptive drugs such as estrogens, bisphosphonates and calcitonin is followed by rapid decrease of the levels of bone markers that is correlated with the long term increase of bone mass as assessed by dual-energy X ray absorptiometry measurement. Thus, bone markers should be useful in monitoring treatment efficacy in patients with osteoporosis. Appropriate combination of the most efficient markers of bone formation and resorption will probably provide a powerful tool in the clinical investigation of osteoporosis.