The Prevention of Osteoporosis Using Sequential Low-Dose Hormone Replacement Therapy with Estradiol-17β and Dydrogesterone

Low-dose hormone replacement therapy (HRT) in postmenopausal women may produce fewer side-effects but its efficacy in the prevention of bone loss and osteoporosis is not established. To address this we compared the effect of 1 mg estradiol-17β with a 2 mg dose, in combination with cyclical dydrogesterone, in the prevention of postmenopausal bone loss. We conducted a multicenter double-masked prospective randomized, placebo-controlled study in 595 apparently healthy postmenopausal women randomized to either placebo, or continuous oral estradiol-17β 1 mg or 2 mg with sequential dydrogesterone for 2 years. The primary endpoint was the percentage change from baseline in bone mineral density (BMD) in the lumbar spine (LS) and femoral neck (FN) of actively treated groups compared with placebo. Women taking either 1 mg or 2 mg estradiol-17β showed a significant increase in BMD of the LS (mean ± SD, 5.2 ± 3.8% and 6.7 ± 4.0% respectively, both p <0.001) whilst BMD in the placebo group decreased (–1.9 ± 4.0%). Increases were also observed in FN BMD in both treated groups (2.7 ± 4.2% and 2.5 ± 5.2% respectively, both p <0.001) in contrast to the placebo group (–1.8 ± 4.8%). The oldest women showed the greatest treatment response. One milligram estradiol-17β in combination with dydrogesterone is effective in conserving LS and proximal femur bone mass, both of which are clinically important sites of osteoporotic fracture, and is as effective as 2 mg in preventing FN bone. The lower dose of estradiol-17β is a particularly suitable treatment for osteoporosis management in older women since it should minimize side-effects and improve the acceptability of HRT. Received: 19 June 2000 / Accepted: 26 October 2000     

Parathyroid Hormone(1–84) Treatment of Postmenopausal Women with Low Bone Mass Receiving Hormone Replacement Therapy

Treatment of postmenopausal osteoporosis (PMO) is based primarily on antiresorptive agents, including hormone replacement therapy (HT). To evaluate whether anabolic therapy together with HT provides additional benefits in the treatment of PMO, we evaluated the effects of parathyroid hormone (PTH) 1-84 in postmenopausal women with low bone mineral density (BMD) who were receiving chronic (>/=6 months) HT. Subjects were randomized to receive 100 mug PTH(1-84) or placebo injections daily for 24 months (n = 90/group). The primary efficacy outcome was change from baseline in lumbar spine BMD. Secondary end points included changes in hip and distal radius BMD, bone turnover markers, and fracture incidence. The study was terminated early following recommendations regarding HT for PMO. At 18 months, the mean increase in lumbar spine BMD was 7.9% for PTH(1-84) subjects vs. 1.5% for those receiving HT alone; between-group differences were significant at 6 months and persisted throughout the study. Lumbar spine BMD increased in 94% of women receiving PTH(1-84) compared to 59% for HT alone. Femoral neck BMD and bone turnover markers were significantly higher in PTH(1-84)-treated subjects, but the changes in total hip and distal radius BMD were not significant. PTH(1-84) treatment was generally well-tolerated, with hypercalciuria, hypercalcemia, nausea, vomiting, and dizziness reported more frequently in the HT + PTH(1-84) group. In conclusion, addition of PTH(1-84) to stable HT produced marked increases in lumbar spine BMD and may represent an additional approach to the treatment of PMO women receiving HT.     

Polymorphisms in the CYP19 and AR Genes—Relation to Bone Mass and Longitudinal Bone Changes in Postmenopausal Women With or Without Hormone Replacement Therapy: The Danish Osteoporosis Prevention Study

Polymorphisms in the androgen receptor (AR) gene and genes encoding enzymes involved in synthesis of sex steroids (e.g., the CYP19 gene encoding aromatase) have recently received attention in osteoporosis research. In the Danish Osteoporosis Prevention Study, recent postmenopausal women were allocated to either hormone replacement therapy (HRT) or no treatment. We genotyped 1792 women for the CYP19 (TTTA)_n repeat [short (TTTA)_{n 7} or long (TTTA)_{n > 7}] the CYP19 C¹⁵⁵⁸-T, and the AR (CAG)_n repeat polymorphism [short (CAG)_{n < 22}, long (CAG)_{n 22}], and investigated associations with bone mineral density (BMD) and 5-year change in BMD. The CYP19 polymorphisms were in strong linkage disequilibrium. Perimenopausal bone mass or bone loss in untreated women was not associated with the CYP19 polymorphisms. In hormone-treated women, BMD increase in the femoral neck was highest (+0.3%/year) for long CYP19 alleles, lowest (–0.09%/year) for short alleles, and intermediate (–0.002%/year) in heterozygous women, P = 0.015. Differences were also significant in the lumbar spine, total hip, and ultradistal forearm. The C¹⁵⁵⁸-T T-allele was associated with a more pronounced response to HRT (P = 0.04, total hip). AR genotype was not related to BMD, but a modifying effect of sex hormone-binding globulin (SHBG) was present. In the highest SHBG quartile (SHBG > 95 nmol/1, n = 222), AR genotype was associated with baseline BMD (femoral neck: P < 0.001, total hip: P = 0.008), but without a clear gene dosage effect. We have demonstrated that polymorphisms in the CYP19 gene are associated with the magnitude of bone gain in response to HRT and that the (CAG)_n repeat polymorphism in the AR gene is associated with bone mass in women with high levels of SHBG. These findings emphasize the complexity of the genetics of bone mass and bone loss. Data was presented in part at the 30th European Symposium on Calcified Tissues, Rome, Italy, May 2003.     

Polymorphisms in the CYP19 and AR Genes—Relation to Bone Mass and Longitudinal Bone Changes in Postmenopausal Women With or Without Hormone Replacement Therapy: The Danish Osteoporosis Prevention Study

Polymorphisms in the androgen receptor ( AR) gene and genes encoding enzymes involved in synthesis of sex steroids (e.g., the CYP19 gene encoding aromatase) have recently received attention in osteoporosis research. In the Danish Osteoporosis Prevention Study, recent postmenopausal women were allocated to either hormone replacement therapy (HRT) or no treatment. We genotyped 1792 women for the CYP19 (TTTA)(n) repeat [short (TTTA)(n 7)] the CYP19 C(1558)-T, and the AR (CAG)(n) repeat polymorphism [short (CAG)(n < 22), long (CAG)(n >or= 22)], and investigated associations with bone mineral density (BMD) and 5-year change in BMD. The CYP19 polymorphisms were in strong linkage disequilibrium. Perimenopausal bone mass or bone loss in untreated women was not associated with the CYP19 polymorphisms. In hormone-treated women, BMD increase in the femoral neck was highest (+0.3%/year) for long CYP19 alleles, lowest (-0.09%/year) for short alleles, and intermediate (-0.002%/year) in heterozygous women, P = 0.015. Differences were also significant in the lumbar spine, total hip, and ultradistal forearm. The C(1558)-T T-allele was associated with a more pronounced response to HRT ( P = 0.04, total hip). AR genotype was not related to BMD, but a modifying effect of sex hormone-binding globulin (SHBG) was present. In the highest SHBG quartile (SHBG > 95 nmol/1, n = 222), AR genotype was associated with baseline BMD (femoral neck: P < 0.001, total hip: P = 0.008), but without a clear gene dosage effect. We have demonstrated that polymorphisms in the CYP19 gene are associated with the magnitude of bone gain in response to HRT and that the (CAG)(n) repeat polymorphism in the AR gene is associated with bone mass in women with high levels of SHBG. These findings emphasize the complexity of the genetics of bone mass and bone loss.     

Matrix Delivery Transdermal 17β-Estradiol for the Prevention of Bone Loss in Postmenopausal Women

A total of 277 early postmenopausal women were enrolled in this placebo-controlled 2-year study to examine the efficacy of a matrix transdermal 17β-estradiol system, at three different dosages (25, 50 and 75 mg/day) combined with sequential oral dydrogesterone 20 mg/day, in preventing bone loss. At 2 years, the difference from placebo in percentage change from baseline of L1–4 lumbar spine bone mineral density (BMD) (assessed by dual-energy X-ray absorptiometry) was 4.7%± 0.7% with estradiol 25 mg/day, 7.3%± 0.7% with estradiol 50 mg/day and 8.7%± 0.7% with estradiol 75 mg/day (all values mean ± SEM). There were also significant increases in femoral neck, trochanter and total hip BMD with all doses of estradiol compared with placebo. Additionally, most patients had a significant gain (increase greater than 2.08%) in lumbar spine bone mass compared with placebo. Patients who received estradiol also experienced clinically significant and dose-related decreases in total serum osteocalcin, serum bone alkaline phosphatase and urinary C-telopeptide, with all three markers of bone turnover returning to premenopausal levels. Estradiol was well tolerated during the 2-year treatment period. Transdermal estradiol is effective and well tolerated at dosages between 25–75 mg/day in the prevention of bone loss in postmenopausal women; 25 mg/day offers an effective option for those women who cannot tolerate higher doses. Received: 30 June 1998 / Accepted: 22 September 1998     

A Combination of Low Doses of 17β-Estradiol and Norethisterone Acetate Prevents Bone Loss and Normalizes Bone Turnover in Postmenopausal Women

The effects of 17β-estradiol (E₂) 1 mg combined with low doses of norethisterone acetate (NETA) on postmenopausal bone loss and turnover were investigated in a 2-year, randomized, double-masked, placebo-controlled trial. A total of 135 postmenopausal women with a lumbar spine bone mineral density (BMD) T-score between −2 and +2 were randomized to daily treatment with an oral tablet of either placebo, E₂ 1 mg/NETA 0.25 mg, or E₂ 1 mg/NETA 0.5 mg. Significant (p<0.001) increases in BMD at the lumbar spine (L1–4) were observed with E₂ 1 mg/NETA 0.25 mg (5.2%) and E₂ 1 mg/NETA 0.5 mg (5.4%) compared with placebo (−0.9%). The total hip BMD increased significantly in the E₂ 1 mg/NETA 0.25 mg (3.1%) and E₂ 1 mg/NETA 0.5 mg groups (3.3%) compared with placebo. At the femoral trochanter, the increase in BMD in the E₂ 1 mg/NETA 0.5 mg group (6.3%) was significantly different from the placebo group (0.8%), while that in the E₂ 1 mg/NETA 0.25 mg group (3.3%) was not. No statistical differences were found between the active groups and placebo for the change in BMD at the femoral neck. Significant increases in BMD at the distal radius and total body were found for both E₂ 1 mg/NETA 0.25 mg (0.9% and 2.5%, respectively) and E₂ 1 mg/NETA 0.5 mg (2.1% and 3.0%, respectively) compared with placebo (−0.7% and 0.4%, respectively).  At the end of the treatment, urinary pyridinoline type I collagen C-telopeptide had decreased by 65% and 60% in the E₂ 1 mg/NETA 0.25 mg and E₂ 1 mg/NETA 0.5 mg groups, respectively, while the mean serum concentrations of osteocalcin had decreased by 39% and 34%, bone-specific alkaline phosphatase by 32% and 29%, and C-terminal propeptide of type I collagen by 21% and 19% had decreased by 34-39%, 29-32%, and 19-21% in the E₂ 1 mg/NETA 0.25 mg and E₂ 1 mg/NETA 0.25 mg groups, respectively.  In conclusion, combinations of E₂ 1 mg and NETA 0.25 or 0.5 mg prevent bone loss in postmenopausal women at the lumbar spine, hip, distal radius and total body, and normalize bone turnover. Received: 12 March 1998 / Accepted: 31 August 1999     

Effect of Estrogen–Progestogen Hormonal Replacement Therapy on Periurethral and Bladder Vessels

This study assessed the effect of hormone replacement therapy using estrogens and/or progestogens on the number of vessels in the proximal and distal urethra, vesicourethral junction and bladder of castrated adult female rats. Forty-five virgin adult rats (Rattus norvegicus albinus) castrated for at least 30 days were used. They were assigned to five groups; group I (control) received no medication; the others received via the subcutaneous route, respectively, 17-β-estradiol (group II), medroxyprogesterone acetate (group III), a maize oil and benzyl acid solution – placebo (group IV) and 17-β-estradiol combined with medroxyprogesterone acetate (group V), for a minimum of 28 days. Increased vascularization throughout the urinary tract, except in the distal urethra, was found following estrogen replacement alone. In the group that received combined estrogens and progestogens, no increase was found. It was concluded that estrogen replacement in castrated rats significantly increased the number of vessels in the lower urinary tract.     

Early Postmenopausal Bone Loss is Prevented by Estrogen and Partially by 1α-OH-vitamin D3: Therapeutic Effects of Estrogen and/or 1α-OH-vitamin D3

A total of 79 Japanese women who were within 5 years of menopause were randomly assigned 1α-hydroxyvitamin D₃ [1α(OH)D₃] 1.0 μg/day, conjugated estrogens 0.625 mg/day, a combination of both, or control (no treatment). Lumbar spine and proximal femur bone mineral density (BMD) and biochemical indices were monitored over 2 years. In the 1α(OH)D₃-treated group, there was a nonsignificant decrease in lumbar spine BMD compared with controls, and no significant loss in the femoral neck compared with controls. In the estrogen-treated group, there was a nonsignificant increase in spine BMD (+2.17% in the first year and +1.71% in the second year), and no loss in femoral neck BMD. The combination of conjugated estrogens +1α(OH)D₃ was more effective in increasing BMD in the spine (+3.68% in the first year and +3.63% in the second year) and femur (+2.56% in the first year and +4.44% in the second year) BMD. There was a significant difference in lumbar spine BMD in both the first and second years between the combination-treated group and the 1α(OH)D₃-treated and control groups (P < 0.01). Serum osteocalcin (OC) significantly decreased in the combination-treated group (−23.8% in the first year) and the estrogen-treated group (−37.6% and −41.2% at 6 and 18 months, respectively), and serum alkaline phosphatase (Alp) decreased significantly in the first year in the combination-treated (−31.5%), estrogen-treated (−27.3%), and 1α(OH)D₃-treated (−7.9%) groups, whereas serum OC increased (+45.4% in the first year) in women without treatment. The results of this study indicate that early postmenopausal bone loss in the femoral neck is prevented by conjugated estrogens, 1α(OH)D₃, or both, whereas bone loss in the spine is not prevented by 1α(OH)D₃. Estrogen proves effective in preventing early postmenopausal bone loss by markedly inhibiting bone turnover. Moreover, a synergistic bone-sparing effect can be expected when estrogen is administered concomitantly with 1α(OH)D₃ rather than when used alone. Received: 28 April 1998 / Accepted: 23 December 1998     

MRI After Patellofemoral Replacement: the Component–Bone Interface and Rotational Alignment

Background

In an earlier paper, it was shown that tailored magnetic resonance imaging (MRI) allows for reproducible analysis of the preserved knee joint structures after patellofemoral replacement (PFR).

Purposes

This pilot study investigates to what degree MRI could produce reliable assessment of the implant–bone interface of femoral and patellar components and rotational alignment following PFR.

Methods

MRI tailored for reduction of metallic artefacts was performed in seven patients who had undergone PFR. Two independent investigators evaluated the implant–bone interface at femoral and patellar components and the rotational alignment of the femoral component. They also assessed their degree of confidence in evaluation using a five-point scale. The inter-observer reliability was determined.

Results

Implant-induced MRI artefact was barely observed and there was no interference with component–bone interface evaluation. There was excellent inter-observer reliability, inter-observer agreement, and confidence for the implant–bone interface at femoral and patellar components and for rotational alignment. The applied score for the interface was found to be reliable.

Conclusion

Tailored MRI allows reproducible analysis of the implant–bone interface and of rotational alignment of the femoral component in patients who have had PFR. It might prove helpful in the assessment of painful PFR.

Electronic supplementary material

The online version of this article (doi:10.1007/s11420-013-9336-x) contains supplementary material, which is available to authorized users.     

Vertebral Bone Mineral Density, Content and Area in 8789 Normal Women Aged 33–73 Years Who Have Never Had Hormone Replacement Therapy

The vertebral bone mineral density (BMD), bone mineral content (BMC) and bone area of the lumbar spine were measured using a bone densitometer in 8789 women aged 33–73 years who had had no previous hormone replacement therapy (HRT). The overall relationship between BMD and age was analyzed on a year-by-year basis, and comprised three separate regions that could each be described by a straight line: 33–46 years (gradient = 0.00166 g cm⁻²/year), 47–63 years (gradient = 0.0121 g cm⁻²/year) and 64–73 years (gradient = 0.0045 g cm⁻²/year). Above the age of 50 years our results were higher than the BMD in most previous reports. In those 3198 women who knew the time of their last menstrual period (mean age 49.25 years, SD 4.83) bone loss was most rapid in the first 10 menopausal years. In the whole group, the relationship between BMC and age was found to be similar to that of BMD, with three distinct regions, including a rapid drop between the ages of 47 and 63 years (gradient 0.781 g/year). Bone area showed a much more gradual (though significant) decrease with age. Based on WHO definitions and using BMD as an indicator, the percentage of women with osteoporosis varied from zero in the younger age group to about 30% of women aged over 70 years; in contrast, where BMC was used, although the trend with age had a similar shape, the percentages at each year were about half those derived from the corresponding BMD values. Osteopenia derived in the same way occurred in about 50% of women over 70 years using either BMD or BMC. The results presented here provide a reliable local reference range for lumbar spine bone densitometry measurements. They also show that for this site BMD and BMC cannot be used interchangeably to define osteoporosis. Received: 13 March 1998 / Accepted: 23 September 1998     

A Retrospective Case–Control Study Assessing the Role of Trabecular Bone Score in Postmenopausal Caucasian Women with Osteopenia: Analyzing the Odds of Vertebral Fracture

This case–control study assessed whether the trabecular bone score (TBS), determined from gray-level analysis of DXA images, might be of any diagnostic value, either alone or combined with bone mineral density (BMD), in the assessment of vertebral fracture risk among postmenopausal women with osteopenia. Of 243 postmenopausal Caucasian women, 50–80 years old, with BMD T-scores between –1.0 and –2.5, we identified 81 with osteoporosis-related vertebral fractures and compared them with 162 age-matched controls without fractures. Primary outcomes were BMD and TBS. For BMD, each incremental decrease in BMD was associated with an OR = 1.54 (95% CI = 1.17–2.03), and the AUC was 0.614 (0.550–0.676). For TBS, corresponding values were 2.53 (1.82–3.53) and 0.721 (0.660–0.777). The difference in the AUC for TBS vs. BMD was statistically significant (p = 0.020). The OR for (TBS + BMD) was 2.54 (1.86–3.47) and the AUC 0.732 (0.672–0.787). In conclusion, the TBS warrants a closer look to see whether it may be of clinical usefulness in the determination of fracture risk in postmenopausal osteopenic women.     

Association of a G2014A Transition in Exon 8 of the Estrogen Receptor-α Gene with Postmenopausal Osteoporosis

We report the association of a newly identified synonymous G2014A single nucleotide polymorphism (SNP) which does not alter the amino acid sequence in exon 8 of the estrogen receptor-α (ERα) gene with osteoporosis in Thai postmenopausal women. Subjects consisted of 228 postmenopausal women aged more than 55 years divided into two groups – with vertebral or femoral osteoporosis (n= 106) or without osteoporosis (n= 122) – according to bone mineral density (BMD) criteria. The exon 8 G2014A SNP, which is 6 nucleotides upstream from the end of the stop codon, was identified by PCR-RFLP. Data are expressed as the mean and 95% CI. The allele frequency of the G2014A polymorphism was 26.4% in osteoporotic subjects and was significantly higher than that in non-osteoporotic women (15.2%) (p<0.05). By stepwise logistic regression analysis, it was found that the G2014A polymorphism was related to the presence of osteoporosis (odds ratio 2.7 per A allele, 95% CI 1.49–4.76) independently of body weight (odds ratio 0.93 per kg, 95% CI 0.89–0.96) and years since menopause (odds ratio 1.12 per year, 95% CI 1.08–1.19). In a multiple linear regression model, L2–L4 BMD of osteoporotic subjects was associated with body weight (p<0.05), endogenous estradiol levels (p<0.05) and the G2014A genotype (p<0.001), while it was related only to body weight (p<0.05) and estradiol levels in non-osteoporotic women (p<0.05). We conclude that a G2014A SNP in exon 8 of ERα is associated with the presence and severity of postmenopausal osteoporosis. Linkage disequilibrium between this polymorphism and the 3′-untranslated region of the ERα gene which may participate in the regulation of ERα gene expression remains to be determined. Received: 17 October 2000 / Accepted: 11 June 2001     

A Comparison between Xenogenic Deproteinized Bone Substitute Pyrost? and Autologous Bone Graft in the Surgical Management of Simple Bone Cysts

Background: The basic principle of surgical treatment of simple bone cysts has remained unchanged over the years, with curettage followed by packing of the defect with autogenic bone graft. With the introduction of ceramic biomaterials, an alternative packing material is available, avoiding the complications associated with cancellous bone harvesting or the use of a bioceramic implant. The aim of this study was to compare bony union and recurrence rate after packing of surgically treated simple bone cysts with either Pyrost^® or autogenic spongiosa. Patients and Methods: 58 patients with simple bone cysts were treated by curettage followed by packing of the cavity with either high-porosity hydroxyapatite (Pyrost^®) inoculated with locally aspirated autogenic bone marrow (n = 26) or autogenic spongiosa (n = 32). Minimum X-ray follow-up was 36 months. Results: No recurrence of the bone cyst was seen in 44 (75.9%) patients. According to Neer's criteria, complete obliteration was observed in 43.1% and residuals were found in 53.4%. The remaining 3.4% required subsequent operation due to recurrence. Entire packing of the cavity with xenogenic deproteinized bone substitution was radiologically confirmed in 80.8%. There were no significant differences (p = 0,76) between the use of autogenic spongiosa and the xenogenic deproteinized bone substitute concerning the rate of recurrency and radiographically verified complete bone consolidation. Conclusions: Pyrost^® can be considered an alternative to conventional bone grafting in the treatment of simple bone cysts. The primary advantages of bone substitute materials ar their abundance and the avoidance of morbidity associated with bone harvesting. Questions concerning long-term biocompatibility and biomechanical aspects of the composite of unabsorbed bone substitute and bone warrant further investigation.