Seven Years of Treatment with Risedronate in Women with Postmenopausal Osteoporosis

The effects of 7 years of risedronate treatment were evaluated in a second 2-year extension of a 3-year vertebral fracture study in women with osteoporosis. For the first 5 years of the study, women received risedronate 5 mg/day or placebo according to the original randomization, with maintenance of blinding. All the women who entered into the 6–7 years extension study received risedronate 5 mg/day. Endpoints included vertebral and nonvertebral fracture assessments, changes in biochemical markers of bone turnover, and bone mineral density (BMD) measurements. A total of 164 women (placebo/risedronate group, 81; risedronate group, 83) entered the 6–7 years extension study and 136 (83%) completed the study. Annualized incidence of new vertebral fractures during the 6–7 years was similar between the 2 treatment groups (3.8%). The incidence of vertebral fractures did not change in the 7-year risedronate group during the 6–7 years as compared to 4–5 years, while a significant reduction was observed in the placebo group that switched to risedronate treatment during years 6–7. The incidence of nonvertebral fractures was 7.4% and 6.0% in the placebo/risedronate and risedronate groups, respectively, during years 6–7. Urinary N-telopeptide decreased from baseline by 54% and 63% at 3 months and 7 years, respectively, in the risedronate group. The increases in BMD from baseline after 5 years of risedronate treatment were maintained or increased further during years 6–7; lumbar spine BMD after 5 and 7 years of risedronate treatment increased from baseline by 8.8% and 11.5%, respectively, for this extension study population. Risedronate was well tolerated and the occurrence of upper gastrointestinal adverse events was low. After 7 years of continuous risedronate treatment there were significant increases in BMD and decreases in bone turnover to within premenopausal levels and there was no indication of any loss of anti-fracture efficacy.     

Five Years of Treatment with Risedronate and its Effects on Bone Safety in Women with Postmenopausal Osteoporosis

We have recently reported that risedronate preserves normal bone formation and decreases bone remodeling in women with postmenopausal osteoporosis after 3 years of treatment. We report now the results of a 2-year extension study. The primary objective of this study was to determine the effect of 5 years of risedronate treatment (5 mg daily) on bone quality and bone remodeling based on paired transiliac bone biopsies. There were additional measurements that included bone turnover markers and bone mineral density (BMD). Histologic evaluation of biopsy sections (placebo, n = 21; risedronate, n = 27) yielded no pathologic findings after 5 years in either treatment group. Histomorphometric assessment of paired biopsy specimens after 5 years (placebo, n =12; risedronate, n = 13) found no statistically significant differences between treatment groups in structural or resorption parameters. There was a significant reduction in osteoid (–27%) and mineralizing surfaces (–49%) from baseline values in the risedronate group that were also significantly different from placebo at 5 years. Similarly, activation frequency decreased significantly (–77%) in the risedronate group, although it was not significantly different from placebo at 5 years (0.09 vs. 0.21, respectively). Double tetracycline labels were identified in all biopsy specimens indicating continuous bone turnover. After 5 years of risedronate treatment, serum bone-specific alkaline phosphatase (bone ALP) and N-telopeptide (NTX) decreased significantly from baseline by 33.3% and 47.5%, respectively. In the placebo group, bone ALP decreased by 3.9% (P = NS), whereas NTX decreased by 27.0% (P < 0.005). Lumbar spine BMD increased significantly in the risedronate group (9.2%), whereas no significant change was seen in the placebo group (–0.26%). Risedronate was overall well tolerated; during the 2-year study extension nonvertebral fractures occurred in 7 patients in placebo and 2 patients in risedronate groups. The findings from this study are consistent with the antiremodeling effect of risedronate and support long-term bone safety and antifracture efficacy of risedronate treatment.This work was supported by grants from Procter & Gamble Pharmaceuticals, Inc., Mason, Ohio, and Aventis Pharmaceuticals, Bridgewater, New Jersey.     

Risedronate Rapidly Reduces the Risk for Nonvertebral Fractures in Women with Postmenopausal Osteoporosis

Prevention of nonvertebral fractures, which account for a substantial proportion of osteoporotic fractures, is an important goal of osteoporosis treatment. Risedronate, a pyridinyl bisphosphonate, significantly reduces clinical vertebral fracture incidence within 6 months. To determine the effect of risedronate on osteoporosis-related nonvertebral fractures, data from four large, randomized, double-blind, placebo-controlled, Phase III studies were pooled and analyzed. The population analyzed consisted of postmenopausal women, with and without vertebral fractures, who had low bone mineral density (lumbar spine T-score <–2.5). Patients received placebo (N = 608) or risedronate 5 mg daily (N = 564) for 1 to 3 years. At baseline, 58% had at least one prevalent vertebral fracture, and the mean lumbar spine T-score was –3.4. Among placebo-treated patients, the presence of prevalent vertebral fractures did not increase the risk of incident nonvertebral fractures overall, although fractures of the humerus and hip and pelvis were more common in patients who had prevalent vertebral fractures than in those who did not. Risedronate 5 mg significantly reduced the incidence of nonvertebral fractures within 6 months compared with control. After 1 year, nonvertebral fracture incidence was reduced by 74% compared with control (P = 0.001), and after 3 years, the incidence was reduced by 59% (P = 0.002). The results indicate that risedronate significantly reduces the incidence of osteoporosis-related nonvertebral fractures within 6 months.     

The Effects of Strontium Ranelate in Asian Women with Postmenopausal Osteoporosis

The aim of this study was to assess the efficacy and safety of strontium ranelate in the treatment of postmenopausal women with osteoporosis in Taiwan. In this 12-month multicenter, randomized, double-blind, placebo-controlled study, 125 women with osteoporosis were randomly given either strontium ranelate 2 g daily or placebo. Lumbar spine, femoral neck, and total-hip bone mineral density (BMD) and biochemical markers of bone turnover were measured; adverse events and tolerability were recorded and assessed. Subjects treated with strontium ranelate showed significant increases in BMD of 5.9% at the lumbar spine, 2.6% at the femoral neck, and 2.7% at the total hip, while the placebo group exhibited no significant change at 12 months. Serum level of a formation marker (bone-specific alkaline phosphatase) was also significantly increased at 6 and 12 months. Thus, although the sample size and the treatment duration of this study could not show its effect of reducing osteoprotic fractures, strontium ranelate showed bone protection effects by increasing BMD and concentrations of a bone formation marker. Safety assessment revealed adverse events were mild and not significantly different from placebo. An erratum to this article can be found at     

Randomized Trial of the Effects of Risedronate on Vertebral Fractures in Women with Established Postmenopausal Osteoporosis

The purpose of this randomized, double-masked, placebo-controlled study was to determine the efficacy and safety of risedronate in the prevention of vertebral fractures in postmenopausal women with established osteoporosis. The study was conducted at 80 study centers in Europe and Australia. Postmenopausal women (n= 1226) with two or more prevalent vertebral fractures received risedronate 2.5 or 5 mg/day or placebo; all subjects also received elemental calcium 1000 mg/day, and up to 500 IU/day vitamin D if baseline levels were low. The study duration was 3 years; however, the 2.5 mg group was discontinued by protocol amendment after 2 years. Lateral spinal radiographs were taken annually for assessment of vertebral fractures, and bone mineral density was measured by dual-energy X-ray absorptiometry at 6-month intervals. Risedronate 5 mg reduced the risk of new vertebral fractures by 49% over 3 years compared with control (p<0.001). A significant reduction of 61% was seen within the first year (p= 0.001). The fracture reduction with risedronate 2.5 mg was similar to that in the 5 mg group over 2 years. The risk of nonvertebral fractures was reduced by 33% compared with control over 3 years (p= 0.06). Risedronate significantly increased bone mineral density at the spine and hip within 6 months. The adverse-event profile of risedronate, including gastrointestinal adverse events, was similar to that of control. Risedronate 5 mg provides effective and well-tolerated therapy for severe postmenopausal osteoporosis, reducing the incidence of vertebral fractures and improving bone density in women with established disease. Received: 29 September 1999 / Accepted: 10 November 1999     

Risedronate Preserves Bone Architecture in Early Postmenopausal Women In 1 Year as Measured by Three-Dimensional Microcomputed Tomography

Risedronate reduces the risk of vertebral fractures by up to 70% within the first year of treatment. Increases in bone mineral density or decreases in bone turnover markers explain only a portion of the anti-fracture effect, suggesting that other factors, such as changes in trabecular bone architecture, also play a role. Our objective was to determine the effects of risedronate on bone architecture by analyzing iliac crest bone biopsy specimens using three-dimensional microcomputed tomography (3-D µCT). Biopsy specimens were obtained at baseline and after 1 year of treatment from women enrolled in a double-blind, placebo-controlled study of risedronate 5 mg daily for the prevention of early postmenopausal bone loss. Trabecular architecture deteriorated in the placebo group (n = 12), as indicated by a 20.3% decrease in bone volume (25.1% vs. 20.0%, P = 0.034), a 13.5% decrease in trabecular number (1.649 vs. 1.426 mm^–1, P = 0.052), a 13.1% increase in trabecular separation (605 vs. 684 µm, P = 0.056), and an 86.2% increase in marrow star volume (3.251 vs. 6.053 mm³, P = 0.040) compared with baseline values. These changes in architectural parameters occurred in the presence of a concomitant decrease from baseline in lumbar spine bone mineral density (–3.3%, P = 0.002), as measured by dual energy x-ray absorptiometry. There was no statistically significant (P < 0.05) deterioration in the risedronate-treated group (n = 14) over the 1-year treatment period. Comparing the actual changes between the two groups, the placebo group experienced decreases in bone volume (placebo, –5.1%; risedronate, +3.5%; P = 0.011), trabecular thickness (placebo, –20 µm; risedronate, +23 µm; P = 0.032), and trabecular number (placebo, –0.223 mm^–1; risedronate, +0.099 mm^–1; P = 0.010), and increases in percent plate (placebo, +2.79%; risedronate, –3.23%; P = 0.018), trabecular separation (placebo, +79 µm; risedronate, –46 µm; P = 0.010) and marrow star volume (placebo, +2.80 mm³ ; risedronate, –2.08mm³; P = 0.036), compared with the risedronate group. These data demonstrate that trabecular architecture deteriorated significantly in this cohort of early postmenopausal women, and that this deterioration was prevented by risedronate. Although there is no direct link in this study between fracture and preservation of architecture, it is reasonable to infer that the preservation of bone architecture may play a role in risedronates anti-fracture efficacy.     

Coronary Calcification and Osteoporosis in Men and Postmenopausal Women Are Independent Processes Associated with Aging

The objective of this study was to investigate whether low bone mass is directly associated with the severity of coronary atherosclerosis in men and postmenopausal women self-referred for evaluation of coronary atherosclerosis and osteoporosis. Low bone mass was evaluated by measurement of bone mineral density (BMD) using quantitative computerized tomography (QCT). Coronary atherosclerosis was evaluated by measurement of coronary calcium (CC) burden using electron beam computerized tomography (EBCT). Using a cross-sectional design, we tested the hypothesis that osteoporosis and coronary atherosclerosis are correlated, age-dependent processes. Study variables were BMD, CC scores, and other known risk factors for osteoporosis and atherosclerosis. Qualifying for the study were 313 postmenopausal women and 167 men. Men had higher baseline CC scores and higher body mass indexes compared to women. In females, those patients with coronary calcification were older and had significantly lower BMD compared to those without calcification. In males, those patients with coronary calcification were older. By univariate correlation analysis, the degree of coronary calcification was inversely associated with BMD in postmenopausal women (P < 0.0001) but not in men. However, after controlling for age, this association was absent for both men and postmenopausal women. Using multivariate logistic regression analysis in women and men separately, age was the only significant predictor of positive CC status and low BMD. Our study suggests that in postmenopausal women and in men, after controlling for age, osteoporosis and coronary atherosclerosis are independent processes.     

Colles' Fracture of the Wrist as an Indicator of Underlying Osteoporosis in Postmenopausal Women: A Prospective Study of Bone Mineral Density and Bone Turnover Rate

Colles' fracture has been shown to be associated with an increased risk of hip fracture. The incidence of low bone mineral density (BMD) and high bone turnover in such patients is uncertain. The aim of this study was to prospectively assess BMD and bone turnover in a cohort of consecutive postmenopausal Colles' fracture patients. BMD (spine, hip and contra-lateral radius) was measured by dual-energy X-ray absorptiometry (DXA) within 2 weeks of fracture. Bone turnover was assessed within 4 days by measurement of serum osteocalcin, total alkaline phosphatase (TALP), bone-specific alkaline phosphatase (BSAP) and urine hydroxyproline. We recruited 106 (71%) of 149 consecutive patients. Fifty-one per cent of subjects had a history of previous fracture, and 25% a past history of wrist, hip or vertebral body fracture. The incidence of osteoporosis was 21%, 42% and 22% at the spine, hip and radius respectively. Fifty per cent of subjects had osteoporosis of at least one of these sites. When compared with the values expected for their age the patients were found to have higher BMD than expected at the spine, and slightly lower BMD at the hip and distal radius. Patients aged 65 years or less had lower hip BMD than expected from the age-matched normal range (p < 0.01). Osteocalcin and TALP levels did not differ from the normal ranges, but BSAP and hydroxyproline levels were significantly elevated (p < 0.001), within 37% and 25% of patients having levels above the respective normal ranges. We conclude that osteoporosis is common in patients with Colles' fracture; however, in older patients BMD is not lower than would be expected in the normal population. In patients aged 65 years or less BMD is lower than expected at the hip. Bone turnover rate is high in many such patients. Intervention to prevent future fracture would be appropriate in women aged 65 years or less with Colles' fracture.     

Treatment of Postmenopausal Women with Osteoporosis or Low Bone Density with Raloxifene

Raloxifene, a selective estrogen receptor modulator (SERM), has been shown to improved bone mineral density (BMD) and serum lipid profiles in healthy postmenopausal women. The objective of this study was to examine the effects of raloxifene on BMD, biochemical markers of bone metabolism and serum lipids in postmenopausal women with low bone density or osteoporosis. This Phase II, multicenter, 24-month, double-masked study assessed the efficacy and safety of raloxifene in 129 postmenopausal women (mean age ± SD: 60.2 ± 6.7 years) with osteoporosis or low bone density (baseline mean lumbar spine BMD T-score: −2.8). Women were randomly assigned to one of three treatment groups: placebo, 60 mg/day raloxifene-HCl (RLX 60) or 150 mg/day raloxifene-HCl (RLX 150) and concomitantly received 1000 mg/day calcium and 300 U/day vitamin D₃. At 24 months, BMD was significantly increased in the lumbar spine (+3.2%), femoral neck (+2.1%), trochanter (+2.7%) and total hip (+1.6%) in the RLX 60 group compared with the placebo group (p<0.05). The RLX 150 group had increases in BMD similar to those observed with RLX 60. A greater percentage of raloxifene-treated patients, compared with those receiving placebo, had increased BMD (p<0.05). Serum bone-specific alkaline phosphatase activity, serum osteocalcin, and urinary type I collagen:creatinine ratio were significantly decreased in the RLX-treated groups, compared with the placebo group (p<0.01). RLX 60 treatment significantly decreased serum levels of triglycerides, and total- and LDL-cholesterol levels (p<0.01). The rates of patient discontinuation and adverse events were not significantly different among groups. In this study, raloxifene increased bone density, decreased bone turnover, and improved the serum lipid profile with minimal adverse events, and may be a safe and effective treatment for postmenopausal women with osteoporosis or low bone density. Received: 26 December 1998 / Accepted: 31 March 1999     

强骨胶囊与利塞膦酸钠治疗绝经后骨质疏松症的对比研究

目的评价中药强骨胶囊对比二膦酸盐类药物治疗绝经后骨质疏松症的临床疗效及安全性。方法90例绝经后骨质疏松症患者随机分为A强骨胶囊组、B利塞膦酸钠组及C对照组,治疗12个月,比较腰椎及髋部骨密度(BMD)在治疗前后的变化,并检测血钙(Ca)、磷(P)、碱性磷酸酶(ALP)和骨钙素(BPG)及尿Ⅰ型胶原交联氨基末端肽与肌酐比值(NTXCr),观察临床症状改善情况及不良反应。结果86例患者完成研究,A、B两组临床疗效较C组有显著差异,且A组起效更快;腰椎(L2-4)BMD12月时A、B两组分别增加(3.62±0.87)%,(4.45±1.53)%而C组为(-0.34±0.16)%(P<0.01),但A、B两组间差异不明显;股骨颈、大转子和wards三角区骨密度改变3组之间差异无统计学意义;ALP和BGP在12月时与治疗前比较A组升高,而B组降低,且与C组比较均有显著性差异。A、B两组NTXCr在12月时较治疗前显著降低(P<0.05)。结论与利塞膦酸钠相比,强骨胶囊对绝经后骨质疏松症亦疗效显著,改善肌无力、肌肉酸痛等临床症状起效更快,不良反应更少。     

Risedronate Reduces the Risk of First Vertebral Fracture in Osteoporotic Women

Risedronate treatment reduces the risk of vertebral fracture in women with existing vertebral fractures, but its efficacy in prevention of the first vertebral fracture in women with osteoporosis but without vertebral fractures has not been determined. We examined the risk of first vertebral fracture in postmenopausal women who were enrolled in four placebo-controlled clinical trials of risedronate and who had low lumbar spine bone mineral density (BMD) (mean T-score =–3.3) and no vertebral fractures at baseline. Subjects received risedronate 5 mg (n= 328) or placebo (n= 312) daily for up to 3 years; all subjects were given calcium (1000 mg daily), as well as vitamin D supplementation (up to 500 IU daily) if baseline serum 25-hydroxyvitamin D levels were low. The incidence of first vertebral fracture was 9.4% in the women treated with placebo and 2.6% in those treated with risedronate 5 mg (risk reduction of 75%, 95% confidence interval 37% to 90%; P= 0.002). The number of patients who would need to be treated to prevent one new vertebral fracture is 15. When subjects were stratified by age, similar significant reductions were observed in patients with a mean age of 64 years (risk reduction of 70%, 95% CI 8% to 90%; P= 0.030) and in those with a mean age of 76 years (risk reduction of 80%, 95% CI 7% to 96%; P= 0.024). Risedronate treatment therefore significantly reduces the risk of first vertebral fracture in postmenopausal women with osteoporosis, with a similar magnitude of effect early and late after the menopause. Received: 12 September 2001 / Accepted: 11 December 2001     

Bone turnover markers and bone mineral density response with risedronate therapy: Relationship with fracture risk and patient adherence

Surrogate markers of fracture risk—bone turnover markers (BTMs) and bone mineral density (BMD)—can be used to monitor treatment response. We assessed whether changes in these markers greater than the least significant change (LSC) were associated with fracture risk reduction and greater adherence. This secondary analysis of the Improving Measurements of Persistence on ACtonel Treatment (IMPACT) study—a multinational prospective, open‐label, cluster‐randomized study of postmenopausal women on oral risedronate 5 mg/d for 52 weeks—assessed adherence by electronic monitors. Urinary N‐terminal cross‐linked telopeptide of type 1 collagen (uNTX) and serum C‐terminal cross‐linked telopeptide of type 1 collagen (sCTX) levels were assessed at baseline and weeks 10 and 22, and BMD at baseline and week 52. Fractures were recorded as adverse events. In 2302 women, responses beyond LSC in BTMs (uNTX and sCTX) and BMD (spine only) were associated with a reduced risk of nonvertebral fractures (NVFs) and all fractures. NVF incidence was about 50% lower in patients with 30% or more of uNTX reduction at week 22 (1.6%) than in those with less than 30% reduction (3.2%, p = .015). NVFs also were reduced in patients with more than 3% spine BMD increase at 52 weeks than those with 3% or less. Responses greater than LSC in BTMs and BMD were associated with greater adherence, but there was no association between adherence and fracture outcomes at 52 weeks. Changes greater than the LSC in BTMs and BMD reflect better treatment adherence, were associated with fracture risk reduction, and identify differences in individual responsiveness to risedronate. © 2011 American Society for Bone and Mineral Research.     

Short-Term Risedronate Treatment in Postmenopausal Women: Effects on Biochemical Markers of Bone Turnover

The development of new biochemical markers has made it possible to assess the effects of therapeutic agents on bone turnover more rapidly and precisely. In this early phase II study, we analyzed the effects of short-term, high-dose treatment with risedronate, a potent pyridinyl bisphosphonate, on markers of bone resorption and formation. Resorption markers included urinary free deoxypyridinoline (D-Pyr) crosslinks, N-terminal telopeptide (NTx) and C-terminal telopeptide (CTx) type I collagen crosslinks. Bone formation markers included osteocalcin (OC), bone-specific alkaline phosphatase (BSAP) and the C-terminal peptide of type I procollagen (PICP). All three resorption markers showed rapid, significant (p<0.05) decreases from baseline following daily administration of 30 mg risedronate for 2 weeks. The mean decreases at 2 weeks were 28% for D-Pyr, 61% for NTx and 73% for CTx, respectively. Over the next 10 weeks after treatment, D-Pyr approached baseline while NTx and CTx remained well below baseline values. The markers of bone formation showed little change during therapy but decreased significantly at 4–10 weeks after therapy – an expected outcome of bisphosphonate therapy. Moreover, there was a significant correlation between the early effects on bone resorption markers and the delayed effects on formation markers. This study demonstrates that the approved dose of risedonate (30 mg/day) for Paget”s disease is effective at decreasing bone turnover after 2 weeks of treatment, as observed by the sensitive response of bone turnover markers. Received: 18 August 1999 / Accepted: 18 January 2000     

Intramuscular Neridronate in Postmenopausal Women with Low Bone Mineral Density

Compliance to osteoporosis treatment with oral bisphosphonates is very poor. Intermittent intravenous bisphosphonate is a useful alternative, but this route is not readily available. Neridronate, a nitrogen-containing bisphosphonate that can be given intramuscularly (IM), was tested in a phase 2 clinical trial in 188 postmenopausal osteoporotic women randomized to IM treatment with 25 mg neridronate every 2 weeks, neridronate 12.5 or 25 mg every 4 weeks, or placebo. All patients received calcium and vitamin D supplements. The patients were treated over 12 months with 2-year posttreatment follow-up. After 12-month treatment, all three doses were associated with significant bone mineral density (BMD) increases at both the total hip and spine. A significant dose–response relationship over the three doses was observed for the BMD changes at the total hip but not at the spine. Bone alkaline phosphatase decreased significantly by 40–55% in neridronate-treated patients, with an insignificant dose–response relationship. Serum type I collagen C-telopeptide decreased by 58–79%, with a significant dose–response relationship (P < 0.05). Two years after treatment discontinuation, BMD declined by 1–2% in each dose group, with values still significantly higher than baseline at both the spine and the total hip. Bone turnover markers progressively increased after treatment discontinuation, and on the second year of follow-up the values were significantly higher than pretreatment baseline. The results of this study indicate that IM neridronate might be of value for patients intolerant to oral bisphosphonates and unwilling or unable to undergo intravenous infusion of bisphosphonates.     

Bone Volume Fraction Explains the Variation in Strength and Stiffness of Cancellous Bone Affected by Metastatic Cancer and Osteoporosis

Preventing nontraumatic fractures in millions of patients with osteoporosis or metastatic cancer may significantly reduce the associated morbidity and reduce health-care expenditures incurred by these fractures. Predicting fracture occurrence requires an accurate understanding of the relationship between bone structure and the mechanical properties governing bone fracture that can be readily measured. The aim of this study was to test the hypothesis that a single analytic relationship with either bone tissue mineral density or bone volume fraction (BV/TV) as independent variables could predict the strength and stiffness of normal and pathologic cancellous bone affected by osteoporosis or metastatic cancer. After obtaining institutional review board approval and informed consent, 15 patients underwent excisional biopsy of metastatic prostate, breast, lung, ovarian, or colon cancer from the spine and/or femur to obtain 41 metastatic cancer specimens. In addition, 96 noncancer specimens were excised from 43 age- and site-matched cadavers. All specimens were imaged using micro-computed tomography (micro-CT) and backscatter emission imaging and tested mechanically by uniaxial compression and nanoindentation. The minimum BV/TV, measured using quantitative micro-CT, accounted for 84% of the variation in bone stiffness and strength for all cancellous bone specimens. While relationships relating bone density to strength and stiffness have been derived empirically for normal and osteoporotic bone, these relationships have not been applied to skeletal metastases. This simple analytic relationship will facilitate large-scale screening and prediction of fracture risk for normal and pathologic cancellous bone using clinical CT systems to determine the load capacity of bones altered by metastatic cancer, osteoporosis, or both.     

Bone Mineral Density of the Lumbar Spine is Associated with TNF Gene Polymorphisms in Early Postmenopausal Japanese Women

We investigated the relationships between tumor necrosis factor (TNF) gene polymorphism, circulating TNF-alpha (TNF-) concentrations, and bone mineral density (BMD) in the lumbar spine. TNF gene polymorphisms studied were the Nco I polymorphism within the first intron of TNF-beta (TNF-) and three single nucleotide polymorphisms in the promoter region of the TNF- gene, at positions –857, –863, and –1031. Allelic variants of the TNF gene were identified using restriction fragment length polymorphism (RFLP) analysis in 177 postmenopausal Japanese women within 10 years after menopause, aged 56.4 ± 4.5 years (mean ± SD). A significantly higher prevalence of the alleles TNF--863A (20.3% versus 9.9%) and TNF--1031C (21.3% versus 12.4%) was seen in the low BMD group (Z-score < 0, n = 91) than in the high BMD group (0 Z-score, n = 86). In genotype analysis, although difference did not reach a significant level, women with the rarest allelic variants, i.e., homozygous TNFb1, TNF--863A, and TNF--1031C, showed the lowest BMD Z-scores. Women with another rarest allelic variant, TNF--857T/T had significantly lower BMD Z-scores than did women with TNF--857C/T or –857C/C. The BMD Z-score decreased significantly with an increase in the total number of such rare alleles. Serum concentrations of TNF- did not differ significantly among groups divided by genotypes. Multiple linear regression analysis revealed that the total number of rare alleles, in addition to the body mass index and the number of years since menopause, was an independent predictor of the BMD. These presumptive functional polymorphisms of the TNF gene may be associated with the lumbar spine BMD in early postmenopausal Japanese women.     

Klotho Gene Polymorphisms are Associated with Osteocalcin Levels but not Bone Density of Aged Postmenopausal Women

Osteoporosis is known to have a strong genetic basis. It has been proposed that polymorphisms within the KL (klotho) gene have a significant effect on aging, in particular, the osteoblast defect of aging. The association between polymorphisms within this gene and biochemical markers of bone formation and resorption, bone structure, and fracture rates was studied in 1,190 postmenopausal women with a mean age of 75 years. Genotyping of these polymorphic sites was carried out using Matrix-Assisted Laser Desorption Ionization—Time of Flight (MALDI-ToF) mass spectrometry. The G allele of SNP c.1775G>A was associated with a lower osteocalcin level than the A allele (P = 0.004) in a codominant model. SNPs C-387T and IVS1+8262c>t both showed nonsignificant associations with osteocalcin (P values of 0.063 and 0.068, respectively), but a haplotype analysis of 2 of 5 haplotypes of the three SNPs with a frequency greater than 4% revealed a significant association with osteocalcin (P = 0.036). None of the individual polymorphisms or haplotypes analyzed showed any associations with a marker of bone resorption the deoxypyridinoline creatinine ratio, bone structure, or fracture data. Therefore, the G polymorphism within the c.1775G>A SNP site and a haplotype including this are associated with a reduced osteoblast product osteocalcin. These data suggest that variation in the KL gene product affects osteoblast activity independent of osteoclast activity but that this defect does not result in an effect on bone structure in this population, perhaps because of “rescue” by other genetic or environmental factors in this population.     

Treatment of Osteoporosis with Parathyroid Hormone and Teriparatide

Nowadays osteoporosis treatment is based primarily on therapy with antiresorptive agents, like the bisphosphonates. Parathyroid hormone (Preotact) and human recombinant parathyroid hormone peptide 1–34 (Teriparatide) are relatively new for the treatment of osteoporosis and belong to the group of anabolic agents. Both agents demonstrated an increase in bone mineral density and a significant reduction in vertebral fractures in postmenopausal women with osteoporosis when given for 18–24 months. Data on nonvertebral fractures are, however, not clear-cut, and so far only bisphosphonates and strontium ranelate have been demonstrated to reduce all types of fractures and therefore remain the front-line option for treatment of osteoporosis. As the safety, tolerability, and cost of the therapy also influence the choice of therapy, Preotact and Teriparatide might be useful additions to the armamentarium for (second-line) treatment of osteoporosis. An erratum to this article can be found at