Christine Brot

Hormonal replacement therapy reduces forearm fracture incidence in recent postmenopausal women — results of the Danish Osteoporosis Prevention Study

OBJECTIVESnTo study the fracture reducing potential of hormonal replacement therapy (HRT) in recent postmenopausal women in a primary preventive scenario.nnnMETHODSnProspective controlled comprehensive cohort trial: 2016 healthy women aged 45-58 years, from three to 24 months past last menstrual bleeding were recruited from a random sample of the background population. Mean age was 50. 8+/-2.8 years, and the number of person years followed was 9335.3. There were two main study arms: a randomised arm (randomised to HRT; n=502, or not; n=504) and a non-randomised arm (on HRT; n=221, or not; n=789 by own choice). First line HRT was oral sequential oestradiol/norethisterone in women with intact uterus and oral continuous oestradiol in hysterectomised women.nnnRESULTSnAfter five years, a total of 156 fractures were sustained by 140 women. There were 51 forearm fractures in 51 women. By intention-to-treat analysis (n=2016), overall fracture risk was borderline statistically significantly reduced (RR=0.73, 95% CI: 0.50-1.05), and forearm fracture risk was significantly reduced (RR=0.45, 95% CI: 0.22-0.90) with HRT. Restricting the analysis to women who had adhered to their initial allocation of either HRT (n=395) or no HRT (n=977) showed a significant reduction in both the overall fracture risk (RR=0.61, 95% CI: 0.39-0.97) and the risk of forearm fractures (RR=0.24, 95% CI: 0.09-0.69). Compliance with HRT was 65% after five years.nnnCONCLUSIONSnIt is possible to reduce the number of forearm fractures and possibly the total number of fractures in recent postmenopausal women by use of HRT as primary prevention.

Human osteoblastic cells propagate intercellular calcium signals by two different mechanisms.

Effective bone remodeling requires the coordination of bone matrix deposition by osteoblastic cells, which may occur via soluble mediators or via direct intercellular communication. We have previously identified two mechanisms by which rat osteoblastic cell lines coordinate calcium signaling among cells: autocrine activation of P2 (purinergic) receptors leading to release of intracellular calcium stores, and gap junction‐mediated communication resulting in influx of extracellular calcium. In the current work we asked whether human osteoblastic cells (HOB) were capable of mechanically induced intercellular calcium signaling, and if so, by which mechanisms. Upon mechanical stimulation, human osteoblasts propagated fast intercellular calcium waves, which required activation of P2 receptors and release of intracellular calcium stores but did not require calcium influx or gap junctional communication. After the fast intercellular calcium waves were blocked, we observed slower calcium waves that were dependent on gap junctional communication and influx of extracellular calcium. These results show that human osteoblastic cells can propagate calcium signals from cell to cell by two markedly different mechanisms and suggest that these two pathways may serve different purposes in coordinating osteoblast functions.

Early changes in muscle strength after total knee arthroplasty : A 6-month follow-up of 30 knees

We studied 30 patients with arthrosis in one knee operated on with a cemented (n 26) or an uncemented total knee arthroplasty (TKA) (n 4). Full weight-bearing from the first postoperative day was allowed in all patients, and they received standard postoperative physiotherapy. 1 week prior to surgery, and after 3 and 6 months, isokinetic and isometric muscle strength in both legs were measured, using a Cybex 6000 dynamometer. Isokinetic tests showed a bilateral, significant, and progressive increase (30-53%) in flexor muscle strength most pronounced in the operated legs. Isokinetic extensor strength increased significantly (14-18%) in the operated legs, while in the contralateral legs, a limited increase was found. Isometric flexion strength significantly decreased in the operated knees (17%). Isometric extension strength showed a temporary decrease at 3 months, which returned to the preoperative level. No significant change in isometric strength was observed in the contralateral legs. The knee pain during the muscle strength measurements decreased significantly from the preoperative level, which may indicate that the substantial pain relief within 3 months after a TKA is an important factor for evaluation of muscle strength.

Premenopausal smoking and bone density in 2015 perimenopausal women

The importance of cigarette smoking in relation to bone mass remains uncertain, especially in younger women. In a recent meta‐analysis including 10 studies in premenopausal women no effect was seen in this age group. We used baseline data from a large national cohort study (Danish Osteoporosis Prevention Study [DOPS]) to study the cumulated effect of pre‐ and perimenopausal smoking on bone mineral density (BMD) measured shortly after the cessation of cyclic bleedings. Baseline observations on 2015 recently menopausal women were available. Eight hundred thirty‐two women were current smokers and 285 were exsmokers. Significant negative associations of cigarette smoking coded as current, ex‐, or never smoking were seen on bone mass in the lumbar spine (P = 0.012), femoral neck (P < 0.001), and total body (P < 0.001). Quantitatively, the differences between current smokers and never smokers were limited to 1.6, 2.9, and 1.9%, respectively. A statistical interaction was found between smoking and fat mass, indicating that women in the highest tertile of fat mass were unaffected by cigarette smoking. Serum vitamin D levels and osteocalcin were inversely related to the number of cigarettes smoked per day (r = 0.11 and P < 0.001; r = 0.17 and P = 0.04), respectively. Bone alkaline phosphatase (BALP) and urinary hydroxyproline (U‐OHP) were unaffected by current smoking. The average cumulated effect of premenopausal smoking on bone is small but biologically significant. Reduced body mass in smokers explains part of the negative effect on the skeleton and a complex interaction between smoking and fat mass on the skeleton is indicated. Serum levels of 25‐hydroxyvitamin D (25‐OHD) and osteocalcin are lower in smokers, which may effect rate of bone loss.

Relationships between bone mineral density, serum vitamin D metabolites and calcium:phosphorus intake in healthy perimenopausal women

Abstract. Brot C, Jørgensen N, Madsen OR, Jensen LB, Sørensen OH (Copenhagen Municipal Hospital, Copenhagen, Denmark). Relationships between bone mineral density, serum vitamin D metabolites and calcium:phosphorus intake in healthy perimenopausal women. J Intern Med 1999; 245: 509–516.

Improving compliance with hormonal replacement therapy in primary osteoporosis prevention

OBJECTIVESnTo evaluate whether introduction of treatment alternatives would improve compliance with hormonal replacement therapy (HRT) as primary osteoporosis prevention in women not tolerating the first line osteoporosis prevention schedule.nnnMATERIAL AND METHODSnFollow-up in four hospitals participating in the Danish Osteoporosis Prevention Study. A total of 706 peri- and postmenopausal women aged 45-57 years between 3 and 24 months from last menstrual bleeding took part, 489 women were randomised to HRT and 217 received HRT by personal choice. A total of 135 (19%) women were hysterectomised. HRT was given as oral or transdermal oestradiol supplemented with progestogen. If the initial treatment allocation was not acceptable several alternatives were available in a pragmatic approach.nnnRESULTSnCompliance with first treatment schedule was lower in women with intact uterus (at 5 years: 48.3 +/- 2.4% compliance) than in hysterectomised (64.7 +/- 5.8%, P < 0.001 in a Cox analysis) but did not differ after the introduction of HRT alternatives (67.0 +/- 2.9 vs 77.8 +/- 5.9, P = 0.12). Compliance decreased with increasing age at treatment start (RR = 1.11, P < 0.001) in women with intact uterus but not in hysterectomised women (P = 0.96). Headache/migraine was more frequent among women with intact uterus on oral sequential oestrogen plus progestogen than among hysterectomised women receiving oral continuous oestrogen (RR = 11.3, P < 0.01).nnnCONCLUSIONSnIt seems possible to maintain a high HRT compliance by a pragmatic approach including offering alternative HRT formulations to women not tolerating the primary HRT. Further research into long-term compliance with HRT and cost-benefit is warranted.

Body composition and muscle strength in women scheduled for a knee or hip replacement. A comparative study of two groups of osteoarthritic women

SummaryIt is unclear whether patients with knee osteoarthritis (OA) and hip OA differ regarding soft tissue composition and bone mineral density (BMD). A total of 42 women waiting for a replacement of the hip (n=20) or the knee (n=22) due to OA were examined. Fat mass (FM), percent body fat (%fat), lean mass (LM) and BMD were measured by dual energy X-ray absorptiometry (DEXA). Knee extensor and flexor strength was measured by an isokinetic dynamometer. No significant differences in age, height, disease duration, Lequesne score or pain scores were found between the groups. Comparing the radiographic changes of the knees with those of the hips, changes were most severe in the joints which were to be replaced. Body weight, body mass index, total and regional FM, and %fat were more than 15% higher in patients waiting for a knee replacement (p<0.001). Also lean mass tended to be higher in the knee patients. Differences in BMD did not remain statistically significant after correction for body weight. Muscle strength was similar in the two groups but was reduced by 20% in the legs in which the joint was to be replaced compared to the contralateral legs. However, the mean difference in lean mass between the two legs was only 3% (p<0.05). The scores for pain felt during strength testing were significantly higher for the involved legs than for the contralateral legs. In conclusion, fat mass values were considerably higher in patients scheduled for a knee replacement. Impaired strength performance in OA may be more strongly associated with pain than with reduced muscle mass.

Discordance Between Changes in Bone Mineral Density Measured at Different Skeletal Sites in Perimenopausal Women—Implications for Assessment of Bone Loss and Response to Therapy: The Danish Osteoporosis Prevention Study

Assessing bone loss and gain is important in clinical decision‐making, both in evaluating treatment and in following untreated patients. The aim of this study was to correlate changes in bone mineral density (BMD) at different skeletal sites during the first 5 years after menopause and determine if forearm measurements can substitute for dual‐energy X‐ray absorptiometry (DXA) of the spine and hip. BMD was measured at 0, 1, 2, 3, and 5 years using Hologic 1000/W and 2000 densitometers in 2016 perimenopausal women participating in a national cohort study. This analysis comprises 1422 women remaining in the study after 5 years without changes to their initial treatment (hormone‐replacement therapy [HRT], n = 497, or none, n = 925). Despite correlated rates of change between forearm and spine (r2 = 0.11; p < 0.01), one‐half of those who experienced a significant decrease in spine BMD at 5 years showed no significant fall in forearm BMD (sensitivity, 50%; specificity, 85%; κ = 0.25). The total hip had significant better agreement with spine (sensitivity, 63%; specificity, 85%; κ = 0.37; p < 0.01). Analysis of quartiles of change also showed significant better agreement with spine and whole body for the total hip than for the femoral neck or ultradistal (UD) forearm. In a logistic regression analysis for identification of group (HRT or control), the prediction was best for whole body (82.6%) and spine (80.9%), followed by total hip (78.5%) and forearm (74.7%). In conclusion, changes at the commonly measured sites are discordant, and DXA of the forearm is less useful than DXA of the hip or spine in determining the overall skeletal response to therapy or assessing bone loss in untreated women.

Bone mass and riks factors for bone los in perimenopausal Danish women

Abstract. Brot C, Jensen LB, Smensen OH (Copenhagen Municipal Hospital, Copenhagen, Denmark). Bone mass and risk factors for bone loss in perimenopausal Danish women

Association between alterations in body composition and bone loss in early menopause

VITABIIt e RECEPTOR (VDB) ALLELIC POLYMORPHtSMS AND BONE MASS IN FEMALES: INFLUENCE OF AGE AND CALCIUM SUPPLEi~NTATION. S. Ferr~ri, R. Rizzofi, D. Marten, D. Slosman, J. Eisman and J.-P. Bonjour. Div. el Clinical Pathophysiology, WHO Collaborating Center for Osteoporosisend Bone Disease, Dept. of Internal Medicine, University Hospllal, Geneva, S~tzedand. Background. Studies concerning an association belween bone mass in adults and VDR allelic polymorph~uns have yielded conflicting results. This prompted us to examine the relationship between VDR genotypes and bone mineral density (BMD) ~ a cohort el healthy females through prapuborty, adolescence and adulthood, as we[I as to prospectively investigate a possible interaction between VDR alle~ polymoq0hisms and calcium intal~e. Me~x/s. DNA was extracted from saliva of 369 non-poslmenopausal females aged 6.6 Io 56 yrs (meand:sd, 23.6• yrs) and VDR alleles (B/b) determined by Barn I endonuclease restriction after PCR amplification. BMD was measured at the level of ~mber spine (LS), lamoral reck (FN) and lemocal diaphysis (FS) by DXA (Holdgic QDR-2O00) in ati subjects. Among them, 128 girls aged 7.9i0.5 yrs had further 8MD measurements of ~ femoral trcohanter (FT), radial metaphysis (RMel) and diaphysis (RDia), and were then randomly assigned to a calcium supplement of 850 mg/d (n=69, total dairy calcium, 1728• rag/d) or placebo {n=59, total dalff calaum, 8904:40 rag/d) for 1 year. Results. The pravatanna of the various VDR genotypes in the whole cohort was: bb, 41%, 8b, 45% alr BB, 14%. Among 128 prepubertal girls (bb, 50, Bb, 63 and BB, 15) age-adjusted BMD was significantly lower at most skeletal sites in 8B as compared to either Ba or bb (mean Z.scoreJ:sem, -0.51• 0.12:t-0.08 and -0.07r in BB, Bb and bb, respectively, p<O.O2 (ANOVA)). By contrast, bone mass did not differ among genotypas in subjects ;t18 years (n=161). Mulliple regression analysis including calcium intake, heighl and weight (Z-scores) furl~r demonstrated that the genotype BB was significanlly associated with a de=eased BMD at the LS and FN in girls _<12 years (n=152; BB regression coelficien1195% Oil, -0.70 [-1.10; 9 0.31], p<0.001 and -0.43 [-0.86; -0.01], p<0.O5, Ior LS and FN, respectively), whereas this association declined progressively by including older adolescentS into lha analysis. In 99 gids who completed 1 year treatment, calcium supplements markedly increased BMD accumulalion (%/yr • sam) at most peripheral sites in Bb and 8B, but nol inbb: bb (n=40) Bb (n=45) BB (n=t4) Calcium Placebo Calcium Racebo Cak~um Placebo RMeI 4.0 • 3.7 • 5.7 +1.6# 2.1 +10 9.5 _+4.3 2.7 • RDia 4.6 :L~0.7 4.2 _+1.~ 5.0 +_0.6 2.2 _qk7 3.4 _+1.0 3.8 • FN 3.7 • 4.3 • 3.3 -+09 # 12 • 6.1 -+15 3.4 -+1.6 FT 4.4 • 4.4 • 5,9 -+08 26 • 6.8 -+2.0 # 17-_+1.6 FS 5.B i-0.7 6.1 _+0.6 6.8 +-0.3 5.5 -+0.5 6.9 • 4.7 -+0.5 LS 3.7 r 3.9 • 4.1 _+0.7 3.1 _+0.6 5.5 • 6.6 _+2.8 Mean 3.7 • 3.9 • 5.1 +0.4 2.0 _+0.5 6A • 3.8 +1.0 p _< 0.001 p ~ 0.01; p -< 0.05; # p -< 0.07, as compared lo placebo. Conclusions: This study shows an association of the VDR genotype BB with a decreased bone mass in prepubertal females that vanished during puberty. Moreover, there was no difference between bb and Bb at any age. Since bone mass accumulation in response to a nigh calcium intake differed among genotypes, it suggests that genetically-determined differences in bone mass could be attenuated by gane/environment interactions occurring early during skeletal growth.