Overview, Vol 10, Issue 3

Treating everyone

While the aim of treatment is to eliminate fractures as a public health problem, this goal is a formidable challenge as treatment must be safe and cost effective. Densitometry is not sensitive or specific. The BMD measurement identifies only half of all the persons who come to fracture and many people with osteoporosis do not fracture; there are many reasons for this. So there is an option – treat everyone from an early age. This would be feasible, like vaccination against small pox, provided the treatment was safe, effective, inexpensive, and easily administered. Well, treatments have not been shown to be effective in all persons. Indeed, there are many problems. Most drugs reduce vertebral fractures by only 50%; of the few drugs shown to reduce nonvertebral and hip fractures, the antifracture efficacy is about 20% for the former and 50% for the latter. Compliance is a problem and these drugs are not free from side effects or free in terms of cost. So, there are cogent arguments for not treating whole populations.

Donaldson et al estimated the proportion of older white women who would be recommended for pharmacologic treatment by the new U.S. National Osteoporosis Foundation Guidelines. The new Guidelines include recommending pharmacologic treatment based on history of hip or vertebral fracture, femoral neck (FN), or spine BMD T-scores ≤–2.5 and presence of low bone mass at the FN or spine plus a 10-yr risk of hip fracture ≥3% or of major osteoporotic fracture ≥20%. Application of NOF guidelines to SOF data estimated that at least 72% of U.S. white women ≥65 yr of age and 93% of those ≥75 yr of age would be recommended for drug treatment. J Bone Miner Res 2009;24:675-80

Advances in treatment

The search for an anabolic agent continues. While parathyroid hormone appears to confer some structural benefits, newer approaches are needed for a range of reasons. Li et al present the first clinical data supporting a role for sclerostin antibody as a new kid on the anabolic block. Scl-AbII was administered for 5 wk and increased bone formation on trabecular, periosteal, endocortical and intracortical surfaces. This not only resulted in complete reversal, at several skeletal sites, but also further increased bone mass and strength to levels greater than those found in nonovariectomized control rats. J Bone Miner Res 2009;24:578-88





 

Giant osteoclasts and bisphosphonate therapy

Cheung et al report that pamidronate therapy increased osteoclast diameter and the mean number of nuclei per osteoclast, but no structural abnormalities accompanied these changes in morphology. Indeed, a higher cancellous bone volume per tissue volume was observed in this study of children with osteogenesis imperfecta. The mechanisms responsible for the large osteoclasts and the insights this observation may provide regarding bisphosphonate action remain elusive. J Bone Miner Res 2009;24:669-74

Bisphosphonates cause fractures

Odvina et al report 13 patients who sustained atraumatic midshaft fractures, 10 were on alendronate and 3 were on risedronate therapy and other therapy as well. This is likely due to prolonged suppression of bone turnover, which could lead to accumulation of microdamage and development of hypermineralized bone. At present, the scope of this complication in the larger context of patients receiving bisphosphonate therapy is not known but appears to be small. Clin Endocrinol (Oxf) 2009;[Epub ahead of print]

Does life imitate art?

Eswaran et al report that T10 vertebral bodies from skeletally mature female beagle dogs where treated with risedronate for one year.  Stiffness of the whole vertebra and the trabecular compartment increased while the computed stiffness of the cortical shell was unaltered. Despite higher cortical thickness, maximum load taken by the shell was lower and changes in the compressive stiffness was attributable to the changes in the trabecular compartment than in the cortical shell. The authors held tissue material density constant in this calculation even though bisphosphonates increase tissue mineral density. J Biomech 2009;42:517-23

Is osteonecrosis mucosal in origin?

Scheper et al suggest that osteonecrosis of the jaw originates as damage to soft tissues of the oral mucosa. The authors report that human gingival fibroblast and keratinocyte cell lines exposed to zoledronic acid produced apoptosis and cell proliferation reversed using siRNA against caspase 3 or 9. Zoledronic acid rapidly and directly affected the oral mucosal tissues though the induction of a gene-regulated apoptosis. Br J Haematol 2009;144:667-76

Study structure

Brennan et al illustrate the need to study the structural basis of bone strength when therapy is used. In this animal model, pamidronate (APD), raloxifene, PTH(1-34) or vehicle were given for 16 wk. PTH induced greater maximal load than APD or raloxifene, as well as greater absorbed energy, BMD, and increased bone turnover markers. PTH increased trabecular bone volume and connectivity higher than sham. Animals treated with APD had BV/TV values higher than OVX but lower than sham, whereas raloxifene had no effect. Tissue hardness was identical in PTH-treated and OVX untreated controls. APD reversed the decline in strength, reduced bone turnover, and increased hardness. Raloxifene increased cortical hardness and elastic modulus. These results show the different mechanisms by which these drugs reduce fracture risk. PTH influences microarchitecture, whereas bisphosphonates alter material level bone properties. Raloxifene improved the material stiffness. J Bone Miner Res 2009;24:800-8

Men

Boonen et al report one of the few trials of antiresorptives in men. This multinational, 2-yr, randomized, double-blind, placebo-controlled study was conducted to determine the efficacy and safety of 35 mg once-a-week risedronate in 284 men with osteoporosis. Treatment increased spine BMD compared with placebo (4.5%; 3.5-5.6%). There was a reduction from baseline in BTMs and therapy was well tolerated and was rapidly effective as indicated by BTM decreases at month 3 and BMD increases at month 6. J Bone Miner Res 2009;24:719-25

Roles of cortical and trabecular bone in whole bone strength

Holzer et al present interesting data suggesting that trabecular bone plays a minor role in proximal femur strength in vitro. In this study, the authors removed trabecular bone from the femoral neck and report that differences between forces needed to fracture excavated and intact femurs was 7.0%, so the contribution of trabecular in respect to bone strength in the femoral neck seems to be marginal. J Bone Miner Res 2009;24:468-74

Youth is wasted on the Old

Schnitzler et al report that the structural basis of racial differences in bone fragility in adulthood originates during growth. In one of the few histomorphometric studies in children, the authors report similar increases with age in cortical thickness by race until age 15 where after it continued to increase in Blacks. Canal number was lower in Blacks. Bone 2009;44:603-11

Initiation of remodelling

The initial steps in initiation of bone remodelling remain uncertain. However, the role of osteocyte apoptotic death seems to be a potential candidate. In a very elegant study by Cardoso et al, in vivo fatigue loading of ulna in Sprague Dawley rats induced microdamage and apoptotic osteocytes colocalized with resorption in the region. Prevention of apoptotic death blocked activation of osteoclastic resorption, whereas short-term caspase inhibition was during only the first two days after fatigue. Osteocyte apoptosis is necessary to initiate intracortical remodelling in response to fatigue microdamage; a dose-response relationship exists between the two processes, and early apoptotic events after fatigue-induced microdamage may play a substantial role in determining tissue remodelling. J Bone Miner Res 2009;24:597-605

Bone loss by intracortical remodelling

Rittweger et al give new insights into immobilization-induced bone loss based on observations in 10 healthy male volunteers in whom relative losses were larger from cortical than from trabecular compartments and cortical thinning occurred from within, by trabecularization of the subendocortical layer of cortex. Bone 2009;44:612-8

Treatment and FRAX®

Kanis et al report drug efficacy in relation to fracture risk derived from FRAX® algorithms. The relationship between pre hoc 10-year fracture probabilities and efficacy of bazedoxifene was found with a 39% decrease in incident morphometric vertebral fractures and a nonsignificant 16% decrease in all clinical fractures. Hazard ratios for the effect of bazedoxifene on all clinical fractures decreased with increasing fracture probability. In patients with 10-year fracture probabilities at or above 16%, bazedoxifene decreased the risk of all clinical fractures. In patients with 10-year fracture probabilities above 6.9%, bazedoxifene decreased the risk of morphometric vertebral fractures. Bazedoxifene (20 and 40 mg doses combined) decreased the risk of all clinical fractures and morphometric vertebral fractures in women at or above a FRAX® based fracture probability threshold. Bone 2009;44:1049-54

PTH and CatK

Yamane et al report that mice treated with cathepsin K inhibitor, alendronate with or without PTH (1-34) have differing responses. CatK inhibitor and alendronate increased the BMD and the bone volume. CatK inhibitor augmented PTH while alendronate had the same effect on the BMD and bone volume only at the primary spongiosa. CatK inhibitor did not decrease serum osteocalcin while alendronate did. CatK inhibitor did not decrease osteoclast number or bone formation rate with or without PTH, while alendronate decreased those values and increased osteoclast apoptosis. PTH and CatK inhibitor together increased alkaline phosphatase-positive CFU-F formation and c-fos, osterix, and osteocalcin mRNA expressions of bone marrow cells as well as PTH alone, while PTH and alendronate decreased those values. Alendronate enhances the anabolic action of PTH at the primary spongiosa, but blunts it in the remodelling trabecular bone, while CatK inhibitor enhances the action at both sites. Bone 2009;44:1055-62

Strontium and bone formation

Atkins et al report that adult human primary osteoblasts exposed to strontium ranelate (SR) increased osteoblast replication, induced an osteocyte-like phenotype, and increased in vitro mineralization. mRNA levels of dentin matrix protein (DMP)-1 and sclerostin suggest the presence of osteocytes. SR also increased the OPG/RANKL ratio throughout the culture period. This study suggests that SR can promote osteoblast maturation and an osteocyte-like phenotype. Osteoporos Int 2009;20:653-64

Remodelling and drug therapy

Diab et al report histomorphometric results in trabecular bone of the femoral neck and lumbar vertebrae from mature beagles treated with alendronate, which resulted in similar absolute levels of bone turnover, although the femoral neck had 33% lower pretreatment remodelling rate. The high and low dose suppressed turnover to similar absolute levels suggesting that sites of low pretreatment remodelling rate are not more susceptible to oversuppression. Osteoporos Int 2009;20:647-52

Nonenzymatic glycation with risedronate or alendronate

Tang et al report alendronate or risedronate for 1-yr accumulated AGEs at high doses but not at doses equivalent to those used for the treatment of postmenopausal osteoporosis. Postyield work-to-fracture of the tissue was reduced at these high doses. AGE accumulation inversely correlated with postyield work-to-fracture (r2=0.45; p<0.001). Osteoporos Int 2009;20:887-94

Meta-analysis and fracture risk reduction with vitamin D

Bischoff-Ferrari et al report a meta-analysis of 12 double-blind randomized controlled trials (RCTs) for nonvertebral fractures (n=42,279) and 8 RCTs for hip fractures (n=40,886). To incorporate adherence, the authors multiplied the dose by the percentage of adherence to estimate the mean received dose for each trial. The pooled relative risk (RR) was 0.86 (0.77-0.96) for nonvertebral fractures and 0.91 (0.78-1.05) for hip fractures. Including all trials, antifracture efficacy increased with a higher dose and higher achieved 25-D for both endpoints. Pooling trials with a higher dose of more than 400 IU/d resolved heterogeneity. For the higher dose, the pooled RR was 0.80 (0.72-0.89; n=33,265 subjects, 9 trials) for nonvertebral fractures and 0.82 (0.69-0.97; n=31,872 subjects, 5 trials) for hip fractures. The higher dose reduced nonvertebral fractures in community-dwelling individuals (-29%) and institutionalized older individuals (-15%). Arch Intern Med. 2009;169:551-61

 

Note from the Editor

The purpose of Progress in Osteoporosis is to provide the reader with a summary of the most important literature published in the preceding three to four months in the field of osteoporosis. Most reviews and original research are cited. In addition, summaries and figures are provided for readers who may not have easy access to all the specialist literature. The summaries are based on the contents of abstracts, which have been abbreviated to concisely convey the main theme. The contents of the abstracts and figures should be used only as a means of directing the reader to the original literature and should not be quoted verbatim or cited as a reference. The opinions expressed in the Overview are my own and do not necessarily reflect those of the International Osteoporosis Foundation.