Overview, Vol 10, Issue 1

Treatment

Saito et al treated 29 one-year-old beagles (15 males, 14 females) with incadronate at doses of 0.3 or 0.6 mg/kg/day orally for 3 years. A cortex of a rib was fractionated into low and high density portions. Calcium, phosphorus, and pentosidine contents and the ratio of mature to immature crosslinks increased with incadronate in a dose-dependent manner, but the total amount of enzymatic crosslinks was unchanged. The pentosidine content correlated inversely with cortical activation frequency. Long term suppression of bone remodelling by bisphosphonate increases degree of mineralization, collagen maturity, and nonenzymatic crosslinking. Osteoporos Int 2008;19:1343-54

Sunyecz et al report women ≥45 years of age and who filled a new bisphosphonate prescription during years 2000-2002. In 32,944 women who filled a new prescription for daily or weekly alendronate (n=26,581) or risedronate (n=6,363), at 3 years, 37% were compliant and 21% were persistent. Unadjusted total mean healthcare costs were lower for the compliant vs. noncompliant and persistent vs. nonpersistent cohorts. Total healthcare costs were reduced by 8.9% for persistent patients (p<0.001) and 3.5% for compliant patients (p=0.014). Persistence decreased the likelihood of inpatient admission by 47%. Osteoporos Int 2008;19:1421-9

Iwamoto et al report 49 female rats, 3 months of age, were randomized into five groups according to control, glucorticoid (GC), GC+vitamin K2, risedronate, or vitamin K2+risedronate. At the end of the 8 weeks, GC decreased percent cortical bone area and increased percent marrow area as a result of decreased periosteal bone formation, and increased endocortical bone erosion, and increased cortical porosity. Vitamin K2 prevented a reduction in periosteal bone formation but did not affect percent cortical bone and marrow areas. Risedronate prevented a reduction in periosteal bone formation and an increase in endocortical bone erosion, resulting in prevention of alterations in percent cortical bone and marrow areas. Both increased osteocyte density and lacunar occupancy and prevented a GC-induced increase in cortical porosity. Vitamin K2 and risedronate had additive effects on osteocyte density and lacunar occupancy and a synergistic effect on cortical porosity. Calcif Tissue Int 2008;83:121-8

Syed et al reanalysed bone biopsies from a randomized, placebo controlled trial involving 56 postmenopausal osteoporotic women (mean age, 64 years) treated with placebo (n=27) or transdermal estradiol (E) (0.1 mg/d, n=29) for one year. Adipocyte volume/tissue volume (AV/TV) and adipocyte number increased by about 20% in the placebo but was unchanged or decreased in the E group. E also prevented increases in mean adipocyte size over one year. Osteoporos Int 2008;19:1323-30

Strontium ranelate in ovariectomized rats (25 or 150 mg/kg/day) for 90 days did not increase bone formation on trabecular or periosteal bone surfaces, and failed to inhibit bone resorption of trabecular bone regardless of Ca intake. There were no improvements in bone mass, volume or strength with either dose of strontium ranelate given normal Ca. Osteoporos Int 2008;19:1331-41

Whyte et al report that prolonged bisphosphonate in children produced bone fragility. A 12-year-old boy developed osteopetrosis (OPT) receiving pamidronate.  Now 17 years of age, he had further fractures of a metacarpal, an osteosclerotic distal radius, and a dense diaphyseal ulna "chalkstick" break that remained incompletely healed after 2 years. Modelling disturbances of OPT persisted. Metaphyseal osteosclerosis had remodelled imperfectly. Newer metaphyseal bone was osteopenic, with thin cortices and a paucity of trabeculae. Femoral necks had become short and wide. A "bone-within-bone" configuration was present. In vertebrae, endplates were thin, and trabecular osteopenia was present. BMD Z-scores assessed by DXA had decreased into the normal range. J Bone Miner Res 2008;23:1698-707

Mori et al studied female cynomolgus ovariectomized monkeys and given minodronic acid which inhibited bone turnover markers and the decrease in lumbar vertebral BMD. Ultimate load on lumbar vertebral bodies and femoral neck of the OVX-control animals were reduced compared to the sham. Minodronic acid prevented and perhaps reversed some of these reductions in strength and maintained trabecular architecture. Bone 2008;43:840-8

Gallagher et al identified 44,531 patients prescribed alendronate or risedronate; 58.3% continued bisphosphonate for >1 year and 23.6% for >5 years. The risk of hip/femur fracture (RR, 0.78; 95% CI 0.64-0.94) and osteoporotic fracture (RR, 0.85; 95% CI 0.76-0.94) were lower with current than past bisphosphonate use. The largest reduction in hip/femur and osteoporotic fracture risk was observed in patients treated for at least 6 months and no reduction in those treated for <6 months. Increased risks were found in patients with low compliance. Use of bisphosphonates was associated with fracture risk reductions after 6-12 months of treatment, but only 58% of the patients were treated for at least one year. J Bone Miner Res 2008;23:1569-75

DeMichele et al report that in a case-control study of women age 50-79 years diagnosed with endometrial cancer, of 547 cases and 1,410 controls, 3.3% cases had taken raloxifene and 6.2% had taken tamoxifen. Among controls, 6.6% had taken raloxifene and 2.4% had taken tamoxifen. The adjusted odds of endometrial cancer among raloxifene users was 50% that of nonusers (OR=0.50, 0.29-0.85); whereas tamoxifen users had three times the odds of developing endometrial cancer compared with raloxifene users (OR=3.0, 1.3-6.9). Endometrial tumors in raloxifene users had a more favorable histologic profile and were predominantly stage I and low grade. J Clin Oncol 2008;26:4151-9

Hershman et al report that zoledronic acid (4 mg intravenously every 3 months) given for one year in 101 premenopausal women prevented the decline in BMD associated with chemotherapy. Bone loss in the placebo arm was associated with decline in LS BMD at both 6 (2.4%) and 12 (4.1%) months. Similarly, total hip BMD declined by 0.8% at 6 months and 2.6% at 12 months. J Clin Oncol 2008 [Epub ahead of print]

Ellis et al report that women with hormone receptor-positive nonmetastatic breast cancer treated with adjuvant aromatase inhibitor therapy were randomly assigned to placebo (n=125) or subcutaneous denosumab 60 mg (n=127) every 6 months. At 12 and 24 months, spine BMD increased by 5.5% and 7.6%, respectively, in the denosumab group versus placebo. Increases were observed at one month and were not influenced by duration of aromatase inhibitor therapy. Increases in BMD were also observed at the cortical sites. Bone turnover markers decreased with denosumab. J Clin Oncol 2008 [Epub ahead of print]

Curtis et al studied 9,063 older women compliant with bisphosphonates ≥2 years. Hip fracture incidence in women who discontinued bisphosphonates versus those who did not was 8.43 versus 4.67 per 1000 person-years (p=0.016). The adjusted hazard ratio of hip fracture per 90 days following discontinuation was 1.2 (1.1-1.3). For women with higher compliance at 2 years (MPR ≥80%) or compliant for 3 years, there were no significant differences in risk associated with discontinuation. The rate of hip fracture was increased among women compliant with bisphosphonate therapy for 2 years who subsequently discontinued, suggesting that discontinuation is not advisable. Osteoporos Int 2008;19:1613-2

Ayukawa et al report simvastatin injected into a rat bony defect for 3 days from surgery demonstrated larger new bone area. The number of tartrate-resistant acid phosphatase-positive multinucleated cells was less than in the control and the expressions of both alkaline phosphatase and BMP2 mRNA increased. The expression of cathepsin K was suppressed. The expression of RANKL was depressed. At day 10, there were no differences among the groups in either histomorphometric or reverse transcription polymerase chain reaction analyses. New bone area increased under the influence of simvastatin; however, the effect did not continue when the administration was terminated. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008 [Epub ahead of print]

Wu et al induced osteonecrosis by low dose lipopolysaccharide and subsequent pulsed high dose methylprednisolone. Rabbits in the treated group were subjected to subcutaneous injections of G-CSF at a dose of 100 μg/kg and SCF 25 μg/kg per day for 5 days. All rabbits displayed increased osteocalcin protein expression in response to G-CSF/SCF. MRI scans showed a reactive interface between the necrotic and reparative zones after G-CSF/SCF. Quantitative analysis showed new vessel formation. The histologic and histomorphometric analysis revealed that the new bone volume was higher in the G-SCF/SCF group than in the control group at 4 weeks. J Rheumatol 2008 [Epub ahead of print]

Morbidity/Mortality

It may appear too late to treat the elderly, certainly a view held by the very low use of drug therapy in this group, and the virtual lack of therapy given after hip fractures. This is not right and von Friesendorff et al demonstrate why. This instructive study shows that of women suffering a hip fracture during 1984-1985 in Malmo (n=766), mortality after one year was 7%, 21%, and 33% for <75, 75-84, and ≥85 years of age, respectively, and 95% of those ≥85 years old were dead at 10 years. 768 fractures occurred in 342 women (45%; mean, 2.3 fractures/woman; range, 1-11 fractures/woman). Of the fracture occasions, 15% occurred within the first year, 27% within the second year, and 73% within 5 years. The residual lifetime fracture risk was 45%, with a mortality-adjusted increase to 86%. The 10-year fracture risk was 40%; with a mortality-adjusted increased to 65%. Almost half of all women with a hip fracture suffer a new fracture. The message is clear – treat these patients after they sustain a fracture. J Bone Miner Res 2008;23:1832-41

Exercise

Martyn-St James et al report a meta-analysis showing regular walking has no effect on preservation of BMD at the spine in postmenopausal women, whilst significant positive effects at femoral neck were found. While meta-analyses may be regarded by some as the highest level of evidence, the authors make the point that the work is very difficult to interpret in any way given the diverse methodological and reporting discrepancies in the published trials.
Bone 2008;43:521-31

Sample et al report adaptation is neuronally regulated. Load induced responses in the left and right ulnas and humeri were determined after loading of the right ulna in male Sprague Dawley rats. Neuronal block by perineural anesthesia of the brachial plexus during loading prevented loading induces adaptive responses by bone formation. J Bone Miner Res 2008;23:1372-81

Biomechanics

Van Lenthe et al report beam theory underestimates tissue modulus. Femoral geometry and size had strong effects on beam theory-derived tissue moduli. Owing to their relatively thin cortex, underestimation was higher for B6 than C3H. Underestimation was dependent on support width in a strain-specific manner. Bone 2008;43:717-23

Lochmuller et al mechanically tested the right forearm and left distal radius of 130 human specimens to failure with the hand, elbow, ligaments, and tendons intact. BMD of the distal radius correlated (r=0.82) with failure loads. Microstructural parameters showed correlation coefficients with the failure loads of ~0.55 and did not add to DXA in predicting failure loads. Calcif Tissue Int 2008;83:293-9

Arlot et al report microdamage in cancellous bone from human lumbar (L2) vertebral bodies obtained from 23 donors 54-93 years of age related to 3D microarchitecture, as assessed by high-resolution microCT. There were no sex differences although women had a higher microcrack density (Cr.Dn) than men. Cr.Dn increased with age (r=0.65) and correlated with BV/TV (r=–0.55) trabecular number (Tb.N; r=–0.56), structure model index (SMI; r=0.59), and trabecular separation (Tb.Sp; r=0.59). SMI was the best predictor of microdamage, explaining 35% of the variance in Cr.Dn and 20% of the variance in diffuse damage accumulation. Microcrack length was greater in the highest versus lowest tertiles of SMI. J Bone Miner Res 2008;23:1613-8

Men

Mellstrom et al studied 2639 men with a mean age 75 for 3.3 years. Fracture incidence was 20.9/1000 person-years. Estradiol levels per SD decrease conferred a hazard of 1.34 (1.22-1.49), free estradiol (fE2 1.41, 1.28-1.55), testosterone (T 1.27, 1.16-1.39), and free testosterone (fT 1.32, 1.21-1.44) were all inversely, while SHBG (HR per SD increase, 1.41, 1.22-1.63) was directly related to fracture risk. fE2 and SHBG, but not fT, were associated with fracture risk. fE2 was inversely associated with clinical vertebral fractures (1.57, 1.36-1.80), nonvertebral osteoporosis fractures (1.42, 1.23-1.65), and hip fractures (1.44, 1.18-1.76). The inverse relation between serum E2 and fracture risk was nonlinear with a strong relation <16 pg/ml for E2 and 0.3 pg/ml for fE2. J Bone Miner Res 2008;23:1552-60