Mechanisms of action of antiresorptive therapies of postmenopausal osteoporosis.

In the treatment of osteoporosis, the aim of the antiresorptive therapy is to restore bone density by decreasing bone remodeling. The process of bone remodeling plays a role in plasma calcium homeostasis and serves to modify bone architecture in order to meet changing mechanical needs, to maintain osteocyte viability, and to repair microdamage in bone matrix. Estrogen deficiency results in a number of detrimental effects on bone, including suppression of osteocyte survival as well as impairment of osteoblast response to mechanical stimuli and repair of ageing bone. In this review, effects of available antiresorptive therapies on endocrine regulations of bone metabolism in postmenopausal osteoporosis are compared. The aim of antiresorptive treatment is to ensure adequate bone remodeling, reparation of microdamage of bone, and increased bone strength. Ideally, this effect should be maintained long-term. Several agents are approved for the treatment of osteoporosis. Calcitonin transiently inhibits osteoclast activity without decreasing osteoblast collagen synthesis. Aminobisphosphonates decrease bone remodeling by decreasing osteoclast activity and by inducing osteoclast apoptosis. This allows more time for secondary mineralization to proceed to completion in the existing bone tissue mass, so increasing the mechanical resistance of bone to loading. Estrogens and raloxifene (a selective estrogen receptor modulator that acts as an estrogen agonist in bone) suppress bone remodeling to the premenopausal range, maintaining the function of osteoblasts and osteocytes. In the placebo-controlled osteoporosis treatment trials, all the above treatments reduced the risk of fractures. Raloxifene therapy was also associated with a favorable or neutral effect in the cardiovascular system, and a reduced incidence of breast cancer. Selection of appropriate drug for treatment of postmenopausal osteoporosis should take into account the long-term effect of the antiresorptive agent on bone. Moreover, the effects on other tissues ++should also be considered, and this encompasses both safety concerns, as well as the potentially beneficial effects on other tissues. Further investigation is needed to evaluate the different modes of action of these agents, and their long-term effects on bone and other tissues.

Diagnostic agreement of two calcaneal ultrasound devices: the Sahara bone sonometer and the Achilles+.

Quantitative ultrasound for the assessment of skeletal status is an evolving method in the diagnosis of osteoporosis. In this cross-sectional study we investigated the diagnostic agreement between the Sahara bone sonometer and the Achilles+ with respect to broadband ultrasound attenuation (BUA), speed of sound (SOS) and stiffness/quantitative ultrasound index (QUI). 309 healthy females without diseases or medications known to influence bone metabolism (with the exception of oestrogen) were recruited at two participating centers (Erlangen and Berlin). 33% of subjects were taking oestrogens. There was no significant difference in BUA, SOS, and stiffness/QUI between oestrogen and non-oestrogen takers. In vivo precision (expressed as root mean square coefficient of variation) was calculated from two repeat measurements and analyzed in both centres. Mean values were 1.57% (BUA Achilles+), 3.64% (BUA Sahara), 0.35% (SOS Achilles+), 0.39% (SOS Sahara), 2.22% (stiffness Achilles+) and 3.04% (QUI Sahara). Between the two devices we observed a strong correlation for SOS (r=0.89, p<0.01) and stiffness/QUI (r=0.83, p<0.01), and a moderate correlation for BUA (r=0.68, p<0.01). All parameters were moderately negatively associated with age (r=-0.38 to -0.48; p<0.01 for all correlations). Kappa (kappa) scores used to report diagnostic agreement were calculated for tertiles and "equivalent T-scores". The tertiles divide the cohort on both scanners into the same number of subjects above and below a given T-score. Diagnostic agreement using tertiles was poor to moderate (kappa< or =0.51). Diagnostic agreement using equivalent T-score agreement, again, was poor to moderate for BUA but fair to good for SOS and stiffness/QUI (0.59< or =kappa< or =0.73). We conclude that diagnostic agreement between the two devices is at best comparable to the agreement of a dual X-ray absorptiometry measurement using the same densitometer at two different skeletal sites. It is therefore insufficient to compare directly two measurements of an individual patient on both ultrasound devices. Standardization of quantitative ultrasound is very much needed.

Detailed analyses of periarticular osteoporosis in rheumatoid arthritis.

Periarticular osteopenia is the earliest radiographic sign of rheumatoid arthritis (RA). Recent studies using dual-energy X-ray absorptiometry (DXA) have indicated that the loss of periarticular BMD can be quantified by whole-hand bone mineral density (BMD) measurements. The aim of this study was to analyze periarticular BMD in more detail by DXA and quantitative ultrasound (QUS). In a cross-sectional study 23 women aged 30-76 years with early RA, mean disease duration 26 +/- 19 months, and 18 men aged 42-69 years, mean disease duration 24 +/- 25 months, were examined. All patients received antirheumatic therapy. The reference population consisted of 103 age-matched controls (68 females, 35 males) and young healthy controls. BMD measurements were performed using a DXA Expert XL densitometer (Lunar). BMD of the whole-hand and two subregions was determined: two subchondral regions of interest (S.CH.) were set within the trabecular bone, distal to the proximal interphalangeal joints of digits II and III excluding the dense subchondral bone of the metacarpophalangeal (MCP) joint and two metacarpal regions of interest (MCP) were set including the entire MCP joint of these fingers. QUS measurements at the proximal phalanges of digits II-V were performed using a DBM Sonic (Igea); amplitude-dependent speed of sound (Ad-SoS) was determined. In comparison with whole-hand BMD measurements, bone loss was pronounced in patients with a disease duration of 18-72 months at the subchondral regions of interest in both genders compared with age-matched controls (women: mean BMD loss S.CH. -23%, p<0.001, whole-hand -16%, p<0.001; men: mean BMD loss S.CH. -19%, p < 0.05, whole-hand -12%, p<0.05). The bone changes were also shown by QUS (women: Ad-SOS values of 1950 +/- 90 m/s in RA vs 2137 +/- 35 m/s in young healthy controls (p <0.005); men AD-SOS 1956 +/- 87 m/s in RA vs 2146 +/- 41 m/s in young healthy controls (p <0.05)). These results show that BMD and Ad-SOS values are significantly lowered in patients with early RA and indicate that periarticular osteoporosis in early RA might possibly be better detected using detailed hand scan analyses.

Ultrasound measurements at the proximal phalanges in healthy women and patients with hip fractures.

Measurements of bone mineral density (BMD) are useful for the assessment of fracture risk in osteoporosis. First prospective studies showed that quantitative ultrasound as measured at the calcaneus also predicts future hip fracture risk, independently of BMD and as accurately as BMD. The aim of this study was to compile a reference population for a new ultrasound device that determines amplitude-dependent speed of sound (AD-SOS) through the proximal phalanges of the hand and to prove its ability to distinguish between health volunteers and osteoporotic patients. In a case-control study we examined 139 healthy women aged 21-94 years and a group of 24 female patients aged 69-94 years with recent hip fractures. In the healthy reference population additional BMD measurements were performed with dual-energy X-ray absorptiometry (DXA) and quantitative ultrasound measurements at the calcaneus were carried out. In vivo precision of AD-SOS measurements through the phalanges was 0.52% CV. Simple regression analyses showed a negative correlation with age (r = -0.73, p < 0.001); modest significant correlations with BMD of the lumbar spine (r = 0.36, p < 0.001) and BMD of the femoral neck (r = 0.37, p = 0.002) as measured with DXA were shown. The comparison with another ultrasound device measuring SOS and broadband ultrasound attenuation (BUA) through the calcaneus showed correlation with SOS (r = 0.50, p < 0.001); no significant correlation was found with BUA measurements. Furthermore a dependency of AD-SOS values in anthropometric factors such as body mass index (r = 0.37, p < 0.001), height (r = 0.40, p < 0.001) and weight (r = 0.23, p < 0.05) was shown. First study results on 24 clinically diagnosed osteoporotic patients, defined as patients with recent (< 1 week) pertrochanteric or femoral neck fractures, showed a good separation between age- and sex-matched controls and osteoporotic patients (Z = -2.0 SD). Receiver operating characteristic (ROC) curves showed an area under the fitted curve of 0.83 +/- 0.06. These results are powerful for a device measuring AD-SOS through the proximal phalanges of the hand, and further prospective studies have proven the capability of phalangeal ultrasound in fracture risk assessment.

Placebo-controlled multicenter study of oral alendronate in postmenopausal osteoporotic women. FOSIT-Study-Group. Fosamax International Trial.

OBJECTIVES: To evaluate effects on bone mineral density (BMD), safety, and tolerability of a single daily dose of alendronate (10 mg), administered for 1 year to postmenopausal women with osteoporosis. METHODS: This interim analysis includes the first approximately 20% of patients to complete treatment in a large, placebo-controlled study (the Fosamax International Trial (Fosit)), which enrolled 1908 patients from 34 countries. Patients < or = 85-year-old with osteoporosis (lumbar spinal BMD > or = 2 S.D. below mean for mature premenopausal Caucasian women) were randomly assigned to treatment with alendronate or placebo once daily in the morning; all patients received supplemental calcium (500 mg/day). Dual-Energy X-ray Absorptiometry (DXA) was used to measure BMD in spine and proximal femur. RESULTS: A total of 297 patients had BMD data available for analysis. Patients treated with alendronate showed progressive increase of BMD during treatment. At 12 months, mean BMD had increased significantly (P < 0.001) at the lumbar spine (5.6%), trochanter (3.6%), and femoral neck (2.6%) in the alendronate group. Increases in BMD were significantly (P < 0.001) greater than in the placebo group at all sites. Among 442 patients assessed for safety, there were no statistically or clinically significant differences between treatment groups in the incidence of adverse events, including upper gastrointestinal adverse events, or laboratory abnormalities. CONCLUSIONS: Results of this multinational study show that oral alendronate, administered as 10 mg once daily for 1 year, is generally well tolerated and produces significant, progressive increases in BMD at the lumbar spine and proximal femur of postmenopausal women with osteoporosis.

Ultrasound velocity of the tibia in normal German women and hip fracture patients.

One of the latest developments in quantitative ultrasound (QUS) is the measurement of the speed of sound (SOS) of cortical bone of the midtibia. To determine the diagnostic validity of this method we measured 150 healthy women aged 22-94 years. Additionally, we report on first results of patients with hip fracture. Precision in vivo of the tibial QUS expressed as the percentage coefficient of variation (CV) was 0.39% for the first day and 0.45% after repositioning the second day (mean CV = 0.42%). No significant dependency of tibial SOS was found with weight, height, and body mass index in pre- and postmenopausal women. There was a significant decline of SOS with age in postmenopausal women (SOS = 4225 - 5.3 age, r = -0.46, P < 0. 001), whereas premenopausal women showed no decline (SOS = 3906 + 1. 3 age, r = 0.13, ns) Mean SOS values of premenopausal women were significantly higher than those of postmenopausal women (3960 +/- 78.7 m/second and 3898 +/- 120 m/second, respectively, P < 0.001). Postmenopausal women on estrogen substitution had significantly higher mean tibial SOS values than age-comparable postmenopausal women without estrogen substitution (3980 +/- 99 m/second and 3869 +/- 100 m/second, respectively, P < 0.001). Significant difference between age-matched healthy women, n = 11, and hip fracture patients, n = 13, expressed as z-score of -1.4 SD was found. In conclusion, tibial QUS declines with age and detects higher values in premenopausal women and postmenopausal women on estrogen substitution and lower values in hip fracture patients. Further prospective studies are needed to clarify its role in fracture risk assessment.