Effect of raloxifene and clodronate on bone density in postmenopausal osteoporotic women

The aim of the present study was to determine the safety and efficacy of combined therapy with raloxifene (RLX) and clodronate (CLD) in postmenopausal women. We enrolled 45 women with postmenopausal osteoporosis. The patients were randomly assigned to two different therapeutic groups: RLX 60 mg/day (n = 23) and RLX 60 mg/day plus CLD 100 mg intramuscularly (i.m.) once every 10 days (n = 22); 1 g of calcium and 800 IU of vitamin D3 were also given daily to both groups. Lumbar and femoral bone mineral density (BMD) were assessed at baseline and after 12 months of therapy using the dual X-ray absorptiometry technique (Norland XR36). We measured the bone turnover markers NTx and CTx, bone alkaline phosphatase (BAP) and osteocalcin at baseline and after 12 months of therapy. Our data demonstrate that 1 year of combined RLX+CLD therapy induced a higher increase in lumbar BMD than treatment with RLX alone as well as a major decrease in bone resorption markers, suggesting an additive effect of CLD on bone mass and inhibition of bone turnover. Furthermore, after 1 year of therapy levels of bone formation markers (osteocalcin and BAP) had increased in both groups, but the increase in osteocalcin and BAP was significantly higher in the RLX+CLD treated group, suggesting that, in addition to its inhibitory effects on resorption, CLD might also have stimulatory effects on mature osteoblast activity.     

Bone metabolism during the perimenopausal transition: a prospective study.

OBJECTIVE: Changes in biochemical markers of bone formation and resorption were followed over the course of 1 year in premenopausal, perimenopausal and early postmenopausal women. METHODS: Sixty-four subjects were analyzed, grouped according to their menstrual pattern, menopausal complaints and endocrinological parameters to be premenopausal (n=20), perimenopausal (n=24) or early postmenopausal (n=20). The parameters studied at four visits during the 12-month study period were the urinary pyridinium cross-links pyridinoline (PYD) and deoxypyridinoline (DPD), and N-terminal telopeptide (NTX) as bone resorption markers, as well as osteocalcin (OC) and bone-specific alkaline phosphatase (BAP) in serum, representing bone formation. The longitudinal changes over time as well as intergroup differences were analyzed using generalized estimating equations (GEE) in connection with Wald statistics. RESULTS: Over the course of 1 year BAP levels decreased in the late premenopausal group (P<0.05). The perimenopausal group exhibited significant changes of PYD, DPD and OC (P<0.01), NTX levels were higher than in premenopause. Postmenopausal subjects had elevated NTX values, while PYD and DPD levels remained close to the perimenopausal range. Only for OC a time effect was seen during postmenopause. CONCLUSIONS: Changes in bone turnover already begin in late premenopause, when decreased bone formation may precede increased bone resorption. The rise of NTX from late premenopause through early postmenopause indicates diagnostic sensitivity of this parameter to changes in bone metabolism induced by estrogen withdrawal. PYD and DPD do not follow this pattern, but change significantly with time during perimenopause to then remain largely unchanged in early postmenopause.     

Impact on uterine bleeding and endometrial thickness: tibolone compared with continuous combined estradiol and norethisterone acetate replacement therapy

Objective: To evaluate endometrial thickness and the incidence of uterine bleeding in postmenopausal women using either tibolone 2.5 mg or continuous combined 2 mg estradiol and 1 mg norethisterone acetate (E+NETA) daily as hormone replacement therapy. DESIGN: We compared diary records of self-reported uterine bleeding and measurements of endometrial thickness, area, and volume by transvaginal sonography at baseline and after 1, 3, 6, and 12 months in a 1-year, prospective, randomized, double-blind, single-center trial of 100 postmenopausal women aged 46-69 years. Bleeding frequencies and endometrial thickness were assessed by Chi-square tests and analysis of covariance, respectively. RESULTS: Self-reported bleeding was significantly less in the tibolone group. Bleeding episodes were reported by 27.7% of women in the tibolone group and by 59.2% in the E+NETA group. The mean number of days with bleeding was 5.8 +/- 27.0 in the tibolone group and 35.6 +/- 58.6 in the E+NETA group. Six women in the tibolone group and seven in the E+NETA group discontinued the study; three in the E+NETA group because of bleeding. The mean endometrial thickness at baseline was 2.56 +/- 0.81 mm in the tibolone group and 2.58 +/- 1.04 mm in the E+NETA group. After 1 year, the corresponding figures were 3.32 +/- 1.58 mm and 3.07 +/- 1.68 mm. Thus, 86% of women in the tibolone group and 93% in the E+NETA group had an endometrial thickness of less than 5 mm. CONCLUSIONS: Use of tibolone 2.5 mg daily for 1 year was associated with significantly less bleeding and spotting compared with daily continuous combined 2 mg estradiol and 1 mg norethisterone acetate in postmenopausal women in the presence of both minimal and nonprogressive increase of endometrial thickness associated with the two regimens.     

Changes in body composition during post-menopausal hormone therapy: a 2 year prospective study

BACKGROUND: Post-menopausal hormone therapy (pHT) induces changes in both body composition and bone mineral density (BMD). METHODS: In 109 post-menopausal women beginning either tibolone 2.5 mg (n=29), tibolone 1.25 mg (n=42) or estradiol 2 mg plus norethisterone acetate 1 mg (E2 + NETA) (n=38), we assessed body composition, total and regional BMD by dual energy X-ray absorptiometry, and the serum bone alkaline phosphatase (BAP), osteocalcin and the urinary excretion to type I collagen C-telopeptide (CTX) at baseline and after 2 years. RESULTS: At baseline, BMD at all sites correlated negatively with age and years since menopause, and positively with lean mass and fat mass (r=0.42, P<0.001 and r=0.26, P=0.006 at the total femur). During treatment, BMD increased at all sites (P<0.001), and serum BAP, osteocalcin, and urinary CTX decreased in all groups (P<0.001). Lean mass increased whereas android fat and android obesity index decreased. The increase in BMD at all sites correlated positively with changes of lean mass at 2 years. CONCLUSIONS: Both fat mass and lean mass are related to BMD in post-menopausal women, the relationship being strongest with lean mass; an increase in lean mass and a change in distribution of body fat are observed during treatment with E2 + NETA and tibolone.     

Changes in bone turnover markers after calcium-enriched milk supplementation in healthy postmenopausal women: a randomized, double-blind, prospective clinical trial

OBJECTIVE: To assess the effect of calcium, phosphorus, lactose, and vitamin D fortified skimmed milk on biomarkers of bone turnover in healthy postmenopausal women. DESIGN: The design was of a prospective, double-blind, randomized, 6 months study. Eighty postmenopausal women (aged 49-71 y) were allocated in two groups receiving 750 mL/day of a fortified skimmed milk containing 1,200 mg of calcium and 5.7 microg of vitamin D (group A) or 900 mg of calcium and 5.7 microg of vitamin D (group B). Ultrasound bone mass measurements and biochemical markers of bone formation, serum bone-specific alkaline phosphatase (AP), and carboxi-terminal propeptide of type I procollagen (PICP) and of bone resorption, urinary excretion of pyridinoline (Pyr), deoxypyridinoline (D-Pyr), and urinary type I collagen cross-linked N-telopeptide (NTx) were performed at baseline and after 10 weeks and 6 months of follow-up. RESULTS: PICP levels showed a significant reduction during the study, but no differences were observed between groups (-18.47 +/- 11.4 group A vs -14.42 +/- 12.5 group B). Pyr levels decreased in group A (P < 0.001), whereas no changes were detected in group B. At the end of the study, a significant difference (P < 0.01) was detected between groups in Pyr (-23.66 +/- 5.7 group Avs 3.465 +/- 7.1 group B) and D-Pyr (-16.64 +/- 1.6 group Avs 2.955 +/- 2.1 group B). At the 6th month, serum 25OH vitamin D increased in group A and decreased in group B (P = 0.007). Additionally, no differences were observed between groups in bone mass and in the other bone markers. Body weight was unchanged for group A, whereas a significant increase was observed in group B. CONCLUSIONS: The daily intake of 750 mL of enriched skimmed milk containing 1,200 mg of calcium appears to be a useful, safe, and acceptable measure to calcium supplementation in healthy elderly postmenopausal women.     

Medroxyprogesterone acetate with Zoladex for long-term treatment of fibroids: effects on bone density and patient acceptability

A randomized trial was carried out to investigate the effect of 12 months administration of the gonadotrophin-releasing hormone agonist (GnRHa) Zoladex in combination with either placebo or medroxyprogesterone acetate (MPA) from the third month. Bone density, markers of bone resorption, symptoms and uterine volume were monitored in 24 women with symptomatic fibroids or menstrual problems. A total of 21 women were recruited to act as controls for the assessment of bone parameters. Vasomotor side-effects were reduced significantly in the MPA-treated group. The reduction in uterine volume in women with fibroids was not impaired by the addition of MPA. The bone markers osteocalcin and alkaline phosphatase were assessed in plasma, and the cross-links pyridinoline and deoxypyridinoline measured in urine. Changes in these markers are reported which suggest increases in bone resorption during the period of observation. Bone mineral density (BMD) was assessed by dual energy X-ray absorptiometry at the spine and forearm. The net reduction in BMD at the spine in the treated groups was 4.30 +/- 0.59% at 6 months and 7.50 +/- 0.78% at 1 year, with no change in the control group. No change was seen in forearm BMD. No protective effect was observed when MPA was added. At 1 year after the completion of treatment, BMD remained significantly below baseline, and this has implications for the prolonged use of GnRHa.      

Seasonal variation of bone turnover markers in top-level female skiers

Different levels of weight-bearing activities imply different levels of anabolic effects on skeletal tissue and this can be assessed by measuring biochemical markers reflecting bone metabolism. With this study we wanted to determine how the serum levels of bone turnover markers change during different phases of annual training in elite female skiers. Fourteen top-level Caucasian athletes, from the Italian Women’s Alpine Ski Team (slalom and giant slalom), were tested at the end of the relative rest period (T1), the pre-competitive season (T2) and the competitive season (T3). Serum levels of bone-specific alkaline phosphatase (BAP) and tartrate-resistant acid phosphatase (TRAP5b) activities and of osteocalcin (OC), and crosslaps (the carboxyterminal crosslinked telopeptide of type I collagen—β-CTx), were assayed together with the determination of 25(OH)D levels. The formation markers, BAP and OC and the resorption marker TRAP5b significantly increased from T2 to T3, while crosslaps showed no significant changes. The peculiar trends of bone formation markers correlated one to each other at T2 versus T3, and this was probably linked to the highly demanding period of competitions when, in athletes performing weight-bearing exercise, bone is more stimulated by mechanical forces. 25(OH)D levels, instead, changed from T1 to T2 and from T1 to T3 and its trend do not show any correlation with that of bone markers. In conclusion, we found that both the bone formation markers and TRAP5b, marker of resorption, are significantly increased from the pre-competitive season to the competitive season.     

A randomized clinical trial of the effects of isosorbide mononitrate on bone formation and resorption in post-menopausal women: a pilot study

BACKGROUND: Nitric oxide (NO) stimulates bone formation and inhibits bone resorption in vitro. NO donors (nitrates) are inexpensive and widely available, but their value for post-menopausal osteoporosis has never been evaluated in a randomized trial. The objective of this study was to compare the effects of 5 and 20 mg of isosorbide mononitrate (ISMO) on markers of bone turnover in post-menopausal women. METHODS: A prospective randomized trial was carried out in the Department of Obstetrics & Gynecology, Ain Shams University, Egypt. The study included 50 healthy post-menopausal women with a hip bone mineral density T score between 0 and -2.5. Participants were randomly assigned to 5 or 20 mg/day of ISMO for 12 weeks. Urine N-telopeptide (NTx), a marker of bone resorption, and serum bone-specific alkaline phosphatase (BSALP), a marker of bone formation, were measured. Markers were measured immediately before randomization and after 12 weeks of treatment. The percent change in NTx and BSALP for each of the treatment groups (5 mg ISMO and 20 mg ISMO) was calculated. The main outcome measures were serum NTx and BSALP in the 5 and 20 mg ISMO groups after 12 weeks of treatment. RESULTS: Women adhering to 20 mg of ISMO had a 42.03% (95% confidence interval (CI), 20.1-73.7) reduction in NTx and a 29.05% (95% CI, 10.8-48.4) increase in BSALP, and women adhering to 5 mg of ISMO had a 31.12% (95% CI, 8.3-68.2) reduction in NTx and a 28.4% (95% CI, 4.6-52.1) increase in BSALP. CONCLUSION: ISMO, as a NO donor, may be useful for the prevention of post-menopausal osteoporosis.     

Changes in bone markers after once-weekly low-dose alendronate in postmenopausal women with moderate bone loss

BACKGROUND: High bone turnover, with bone resorption exceeding bone formation, is a major mechanism of postmenopausal osteoporosis. Therefore, inhibition of bone resorption is a rational approach for the prevention of bone loss. The objective of the current study was to determine the short-term efficacy of once-weekly low-dose alendronate in the prevention of bone loss, via bone turnover markers, in early postmenopausal Korean women with moderate bone loss. METHODS: This study involved a 12-week, randomized, double-blind clinical trial that compared the effects of placebo with alendronate 20mg once weekly. All subjects received supplemental calcium 600 mg and vitamin D 400IU daily. We recruited 63 postmenopausal women (ranging from 50 to 65 years of age) with the lowest lumbar spine bone mineral density (BMD) at least 2.0 S.D. below the mean value for young healthy adults. BMD was measured at baseline and serum alkaline phosphatase (ALP), osteocalcin, C-terminal telopeptide of type I collagen (CTX), and osteoprotegerin (OPG) were measured at baseline and 12 weeks after treatment. RESULTS: We randomly assigned 63 women to either placebo or alencronate 20 mg once a week for 3 months. Forty-nine women continued and completed all 3 months. After 3 months, bone resorption markers were significantly decreased in the alendronate group than in the placebo group: CTX -47.2% vs. 15% (p<0.01), ALP 1.6% vs. 25.9% (p=0.01), osteocalcin -29.2% vs. -13.6 (p=0.06). Women who received alendronate showed similar results to those who received placebo with regard to adverse events. CONCLUSION: Once-weekly low-dose alendronate may be a cost-effective and safe method of suppressing bone turnover in early postmenopausal women with moderate bone loss.     

Influence of Infliximab on Cytokines Network and Markers of Bone Remodeling in Rheumatoid Arthritis Patients

Purpose

Our aim was to determine the effects of infliximab on bone mineral metabolism in rheumatoid arthritis (RA) patients and analyze the relationship between inflammatory markers of acute phase thought to play a major role in bone remodeling.

Materials and Methods

36 patients with established RA were investigated. All patients underwent physical examination and blood and urinary analysis at baseline, 2 weeks, 14 weeks, 6 months and 12 months after the initiation of treatment. The serum levels of: tumor necrosis factor alpha (TNF-alpha), tumor necrosis factor alpha receptor 1 (TNFR1), TNFR2, interleukin 6 (IL-6), IL-17, IL-23 and markers of bone remodeling such as osteocalcin (BGP), deoxypyridynoline (Dpd), and N-telopeptide of type I collagen (NTx) were measured by ELISA.

Results

The results showed significant decrease of all the above cytokines levels in RA patients in comparison with those after 2 weeks of treatment. After 6 months, the markers of bone formation and resorption decreased compared to baseline values. We found positive correlation between the levels of NTx and the levels of IL-6, IL-17 and TNFR1, and between the levels of Dpd and IL-6 and Dpd and TNFR2, whereas negative correlation between BGP and IL-23. After 12 months the positive association was found at the BGP level and IL-6 as well as Dpd and the level of IL-6. We also observed a positive relation between Dpd and TNF-alpha and negative between BGP and TNFR1.

Conclusion

We suggest that infliximab treatment may limit the risk of osteoporosis in RA patients.     

Effects of inhaled budesonide on serum markers of bone metabolism in children with asthma.

The effects of inhaled glucocorticoids on serum markers of bone formation were evaluated in asthmatic children. Serum total alkaline phosphatase (AP), bone alkaline phosphatase (BAP), osteocalcin, and the novel marker of bone formation, carboxypropeptide of type I procollagen (PICP), were measured. In the cross-sectional part, long-term glucocorticoid users were compared with sodium cromoglycate (SCG) users. In the boys (n = 16), but not in the girls (n = 11), PICP was significantly lower in the glucocorticoid users than in the SCG users. PICP correlated positively with BAP (n = 54; groups combined, r = 0.29, p < 0.05). In the longitudinal part, the effects of inhaled budesonide or SCG, both used for the first time, were evaluated before and after 1 and 5 months of treatment. The budesonide dose was 800 micrograms/m2/day for 1 month and thereafter half of that. The SCG dose was 30 mg/day throughout the study. Only during budesonide use did osteocalcin and PICP decrease, the median osteocalcin by 8% at 1 month (p < 0.05) and by 6% at 5 months (n = 15), and PICP by 5% at 1 month (p < 0.05) and by 28% at 5 months (n = 7, p < 0.01). AP and BAP did not change significantly. Decreased PICP suggests decreased bone formation rate. PICP might be clinically useful as a marker of early adverse effects of glucocorticoids on bone.     

Constitutive c-fos expression in osteoblastic MC3T3-E1 cells stimulates osteoclast maturation and osteoclastic bone resorption.

The effect of culture supernatants of c-fos-transfected MC3T3-E1 osteoblastic cells on osteoclastic bone resorption was studied. Human c-fos cDNA was integrated in the expression vector pH8, and the cells were transfected using the calcium phosphate precipitation technique. Osteoclastic bone resorption was quantified by the pit formation assay, and the osteoclast maturation from precursor was assessed by the generation of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells (MNC). The culture supernatants of MC3T3-E1 transfectants constitutively expressing c-fos gene enhanced osteoclast-like MNC formation from haematopoietic blast cells compared with those of control transfectants (P < 0.01). The culture supernatants also promoted osteoclastic bone resorption: the pit number, 118.7 +/- 38.5, was significantly higher than 19.0 +/- 10.1 of the control (P < 0.05). The absorption area, 12,394 +/- 3145 mm2, was significantly larger than 1646 +/- 314 mm2 of the control (P < 0.05). The culture supernatants also promoted bone resorption by purified chick osteoclasts (P < 0.05). The results show that constitutive expression of c-fos gene in osteoblastic MC3T3-E1 cells stimulates osteoclast maturation and osteoclastic bone resorption by releasing humoral mediator(s).     

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。     

Effects upon bone metabolism following total hip and total knee arthroplasty.

OBJECTIVE: In a prospective study we evaluated the course of markers for bone formation and bone resorption in patients undergoing elective total hip and total knee arthroplasty due to osteoarthritis. The aim was to evaluate which changes in bone metabolism take place in the immediate postoperative course following arthroplasty. METHODS: Serum and urine samples were obtained preoperatively and in the postoperative course from patients undergoing total arthroplasty over a 90- or 180-day period. The study included a total of 63 patients with cemented hip prostheses (n = 20), uncemented hip prostheses (n = 23) and cemented knee prostheses (n = 20). Different biochemical markers of bone metabolism were assessed including the serum markers bone-specific alkaline phosphatase, and carboxyterminal propeptide of type I procollagen, and the urine markers n-telopeptide (NTx) and deoxypyridinoline (DPD). RESULTS: For all four markers, there were changes over time which were statistically significant. Markers indicating bone formation were slightly elevated after a 3-month period. In contrast, the two markers indicating bone resorption were back to normal after a 6-month period. There were differences between the groups with cemented and uncemented total hip arthroplasty in the postoperative course with higher values of the markers indicating bone resorption in the cemented group. However, these differences were not statistically significant. CONCLUSIONS: Our results indicate that the two markers of bone resorption, NTx and DPD, are elevated during the first 6 months after hip and knee arthroplasty. Therefore, during this period they cannot be used as a marker for aseptic loosening. However, if these two markers are still elevated after this period, they may reflect an impaired bone metabolism. Further studies are required to assess the potential value of these markers for the diagnosis of aseptic loosening.     

Effect of therapeutic ultrasound on bone healing and blood bone markers in dogs with experimental tibial osteotomies

Experimental tibial osteotomy was performed in 24 dogs, fixed by either intramedullary (IMO; n?=?12) or plate and screw osteosynthesis (PLO; n?=?12). Six dogs with IMO and another six with PLO were subjected to daily therapeutic ultrasound therapy at the site of osteotomy for 10?days, starting from the first post-operative day. The other dogs served as controls. Radiological studies were performed immediately after surgery, by week?2 and months?1, 2 and 3. Blood markers of bone formation (bone alkaline phosphatase and osteocalcin) and bone resorption (tartrate-resistant acid phosphatase and C-terminal telopeptide of collagen type I) were assayed before surgery, by post-operative weeks?1 and 2 and months?1, 2 and 3. Therapeutic ultrasound had a beneficial effect on bone formation, bone union and bone resorption. Blood bone alkaline phosphatase exhibited a very high activity as early as weeks?1 and 2, statistically significant compared to controls. Osteocalcin levels were also significantly higher in periods of bone callus mineralization (month?1). From bone resorption markers, only acid phosphatase was increased in the IMO group treated with ultrasound, while C-terminal telopeptide concentrations did not change over the experimental period. It could be concluded that therapeutic ultrasound could be used as a physical adjunct to assist and stimulate early post-operative healing after osteosynthesis of long bones in dogs.     

IFN-gamma enhances osteoclast generation in cultures of peripheral blood from osteopetrotic patients and normalizes superoxide production.

Interferon-gamma (IFN-gamma) treatment increases osteoclastic bone resorption in vivo in patients with malignant osteopetrosis (OP). The treatment effect was studied in vitro in osteoclasts generated by culturing peripheral white blood cells (PWBC) from OP patients and normal human control subjects. Osteoclasts were treated with or without IFN-gamma prior to the end of the culture period. Osteoclasts from normal subjects were large in size (161 +/- 18 microm in diameter) with >10 nuclei per osteoclast. These cells showed intense staining for tartrate-resistant acid phosphatase (TRAP), expressed abundant calcitonin receptors (CTR), and formed numerous resorption pits on bovine bone slices, indicative of authentic osteoclasts. In contrast, similarly cultured osteoclasts from OP patients were smaller in size (18 +/- 3 microm in diameter), with 2-3 nuclei per osteoclast, and stained lightly for TRAP. However, IFN-gamma treatment of osteoclasts from OP patients resulted in the formation of larger osteoclasts (171 +/- 33 microm in diameter) with >10 nuclei per cell, similar in appearance to osteoclasts from normal subjects. IFN-gamma stimulation increased the intensity of TRAP staining (p < 0.0001) to levels near that of the normal osteoclasts. Unstimulated osteoclasts from 6 OP patients had a significantly lower baseline level of superoxide production, as measured by nitroblue tetrazolium reduction (p < 0.0001), compared with normal osteoclasts. IFN-gamma markedly increased (p < 0.0001) superoxide production. Whereas there was a 3-fold increase in superoxide generation in OP patients' osteoclasts, osteoclasts from control subjects had only a small and insignificant increase in superoxide production after IFN-gamma treatment.     

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.     

Estrogen receptor alpha gene polymorphisms are associated with changes in bone remodeling markers and treatment response to estrogen

OBJECTIVES: Association studies between estrogen receptor alpha (ERalpha) gene polymorphisms and bone mineral density (BMD) have yielded inconsistent results. In the present study we evaluated the influence of XbaI and PvuII ERalpha gene polymorphisms on BMD, biochemical markers, rates of bone loss and the response to estrogen/hormone therapy (ET/HT) in elderly postmenopausal women. METHODS: At baseline, we measured the association between ERalpha genotypes and BMD and biochemical markers in 489 elderly women, mean age 71 +/- 3 years. In the longitudinal study, the changes in the same measures were determined in 96 women on placebo and in 79 women receiving the ET/HT for 3 years. The XbaI and PvuII ERalpha polymorphisms were determined by polymerase chain reaction (PCR). BMD measurements for spine, femoral neck and total body were performed by DEXA, and biochemical indices were measured by standard methods. RESULTS: Neither the PvuII nor the XbaI ERalpha gene polymorphisms were associated with baseline BMD and biochemical indices. In the longitudinal study, there were trends for higher bone loss in the placebo group in the genotypes pp or xx compared to PP or XX genotypes, but the changes were not significant. However, the changes in the bone markers were significantly (p < 0.05) higher in genotype group pp compared to PP (serum osteocalcin, 4.9 +/- 7.0% versus -13.4 +/- 6.7%; urine NTx:Cr ratio, 32.3+/-10.3% versus -2.5 +/- 10.3%) or xx compared to XX (serum osteocalcin, 7.5 +/- 6.4% versus -15.6+/-7.3%; urine NTx:Cr ratio, 39.4 +/- 9.2% versus -8.84+/-10.7%). At the end of 3 years, the mean urine NTx:Cr ratio was 78.7 +/- 9.0 versus 44.6 +/- 4.9 in pp versus PP (p < 0.05) and 75.5 +/- 10.7 versus 48.7 +/- 5.4 in xx versus XX (p < 0.05) genotypes. The response in total body BMD to ET/HT treatment was significantly higher in women with the PP genotype compared to pp genotype (2.48 +/- 0.55% versus 0.66 +/- 0.46%). Similar trends were seen at other skeletal sites for both XX and PP compared to pp and xx genotypes. CONCLUSION: Women with ERalpha, PP and XX genotypes have lower bone remodeling, lower rates of bone loss and benefit more from hormone therapy.     

The efficacy of two dosages of a continuous combined hormone replacement regimen

OBJECTIVES: To evaluate the efficacy of a low-dose combination of estradiol (E2) and norethisterone acetate (NETA) on bone markers, lipid and bleeding profiles and menopausal symptoms. METHOD: Ninety-six healthy Chinese postmenopausal women were allocated randomly to receive 1 mg E2/0.5 mg NETA (low-dose hormone replacement therapy (HRT)) or 2 mg E2/1 mg NETA (high-dose HRT) for 6 months. RESULTS: Bone resorption markers (collagen I N-terminal telopeptides (NTX) and deoxypyridinoline (dPyr)) were significantly reduced; -66 and -32%, respectively, in high-dose HRT versus -55 and -24%, respectively, in low-dose HRT. Bone-specific alkaline phosphatase remained unchanged with either combination of hormones. Total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) levels were decreased significantly (-12 and -13%, respectively, in high-dose HRT vs. -7 and -8% in low-dose HRT). High density lipoprotein cholesterol (HDL-C) was decreased to a lesser extent in low-dose HRT and triglycerides (TG) levels remained unchanged. Both the low and high-dose HRT were effective in alleviating menopausal symptoms. After 6 months of treatment, 2% of women in the low-dose HRT were bleeding compared with 23% in the high-dose HRT. Breast pain occurred in 2% of women in low-dose HRT compared with 15% in high-dose HRT. The endometrium in the majority of the women remained normal. CONCLUSION: Menopausal symptoms were reduced effectively in postmenopausal women on either low-dose or high-dose HRT. TC, LDL-C levels and bone resorption markers were reduced in a dose-dependent manner. Low-dose HRT provided a better bleeding profile and the incidence of breast pain was low.     

Bone formation is suppressed with multi-stressor military training

Purpose

To determine the effects of US Army Ranger Training, an 8-week, physically demanding program (energy expenditure of 2,500–4,500 kcal/day) with energy restriction (deficit of 1,000–4,000 kcal/day) and sleep deprivation (<4 h sleep/night) on bone metabolism.

Methods

Blood was collected from 22 men (age 24 ± 4 years) before and after training. Follow-up measurements were made in a subset of 8 subjects between 2 and 6 weeks after training. Serum was analyzed for bone formation biomarkers [bone alkaline phosphatase (BAP) and osteocalcin (OCN)], bone resorption biomarkers [C-telopeptide cross-links of type I collagen (CTX) and tartrate-resistant acid phosphatase (TRAP5b)], calcium, parathyroid hormone (PTH), and vitamin D (25(OH)D). Data were analyzed using a paired t test to compare baseline to immediate post-training measures. A repeated-measures ANOVA with time as the only factor was used to analyze data on the subset of 8 subjects who completed follow-up data collection.

Results

BAP and OCN significantly decreased by 22.8 ± 15.5 % (pre 41.9 ± 10.1; post 31.7 ± 7.8 ng/ml) and 21.0 ± 23.3 % (pre 15.0 ± 3.5; post 11.3 ± 2.1 ng/ml), respectively, with training, suggesting suppressed bone formation. OCN returned to baseline, while BAP remained suppressed 2–6 weeks post-training. TRAP5b significantly increased by 57.5 ± 51.6 % (pre 3.0 ± 0.9; post 4.6 ± 1.4 ng/ml) from pre- to post-training, suggesting increased bone resorption, and returned to baseline 2–6 weeks post-training. PTH Increased significantly by 37.3 ± 45.2 % with training. No changes in CTX, calcium, or PTH were detected.

Conclusions

These data indicate that multi-stressor military training results in increased bone resorption and suppressed bone formation, with recovery of bone metabolism 2–6 weeks after completion of training.