Overview, Vol 11, Issue 3

Targeting remodelling intensity using drug therapy

Therapeutic agents influence bone material composition and bone microstructure by regulating tissue level remodelling and by changing cell (BMU) level remodelling. Most antiresorptives (but not all) reduce the surface extent or intensity of remodelling. In the face of a negative BMU balance, this reduces the progression of structural decay – porosity in cortical bone continues to appear but less so than before treatment, cortical thinning is less and loss of trabecular structure slows. However, as the name implies, a remodelling suppressant should only slow the loss of bone but not restore it. This is not the case. Antiresorptives do partly restore bone structure, but they do this by perturbing steady state remodelling – shifting it from a higher to lower remodelling intensity. This shift contracts the transient remodelling space, which is the result of the normal delay between completion of bone resorption that takes about 3 weeks, and completion of bone formation which follows but takes 3 months or more.

By acutely suppressing the appearance of new BMUs, those already present at the time of starting treatment complete their formation phase. Porosity decreases in cortical bone and excavated cavities up the trabecular surfaces and the endocortical surface partly refill. This is one reason BMD increases. The second reason is osteons that were formed months before complete secondary mineralization (which is part of the remodelling transient), so more and more of the osteons that would have been removed by the high remodelling are not and become more fully mineralized.

BMD rises but remodelling continues albeit at a lower intensity. This slower rate of remodelling slows the appearance of porosity and structural decay. The tempo of remodelling depends on the potency of the drug in suppressing remodelling. If remodelling is minimally suppressed, as occurs say with calcium supplements, when steady state remodelling reappears at about 80% of the pretreatment intensity, bone loss resumes but only slightly more slowly than prior starting calcium supplements. With more potent agents remodelling continues but more slowly, so again bone loss and structural decay continue but at a much slower rate.

Accessibility to matrix as part of drug potency in suppressing remodelling

One aspect of the remodelling suppression ‘potency’ of a drug is how accessible it is to sites undergoing remodelling. In the case of the bisphosphonates, this depends on the binding characteristics to hydroxyapatite. Risedronate is less tightly bound and so, when adsorbed onto bone matrix, it penetrates more deeply, and hence sites undergoing remodelling upon trabecular and cortical surfaces may be more accessible remodelling suppression.

Allen et al studied New Zealand white rabbits treated with RIS or ALN. By the third week, vertebral trabecular bone formation rate was suppressed with RIS compared to VEH and ALN. By the fourth week, turnover rates in RIS-treated animals remained lower than in VEH-treated and ALN groups; ALN was lower than VEH. There was no reduction in intracortical remodelling in the tibial mid-diaphysis for either RIS or ALN. This greater effect on remodelling suppression with RIS early in treatment compared to ALN is likely the result of both risedronate's greater potency on osteoclast inhibition and its lower binding affinity. Bone 2011;49:128-32

Denosumab does not bind to bone and circulates in the extracellular fluid. It suppresses bone remodelling rapidly and almost completely initially but does so reversibly. The accessibility and its potency in suppressing the activity and lifespan of existing osteoclasts, as well as the birth of new osteoclasts, results in a rapid reduction in intracortical porosity as pores present at the time of treatment refill while new remodelling sites are suppressed until the month prior with the need for the next parenteral administration. Kostenuik et al report that an OVX cynomolgus treated with denosumab for 16 months reduced remodelling, trabecular eroded surfaces, cortical porosity (28-72% lower), and tissue level bone formation (81-100% lower). Denosumab treated animals with the lowest levels of fluorescent labelling exhibited the greatest structural strength. Bone 2011;49:151-61

Subtrochanteric fractures and bisphosphonates

While remodelling suppression can partly reverse and then slow progression of structural decay, there is a potential for adverse effects. As remodelling is the cellular machinery responsible for detecting and removing damaged matrix, remodelling suppression may compromise material composition. With prolonged suppression of remodelling, osteons proceed with secondary mineralization and so may become more completely mineralized. When this occurs extensively, the heterogeneity in bone material composition decreases – adjacent regions of bone matrix become more similarly and homogeneously densely mineralized predisposing to microdamage propagation. When a crack occurs in bone, its progression through bone is limited by the heterogeneity of bone structure – larger numbers of osteons reduce the ability of a crack to travel through the interstitial bone between osteons; the cement line offers an obstruction to progression and within osteons, the lamellae with differing directions of the mineralized collagen fibrils also offer an obstruction to progression of damage (an energy requiring process).

The incidence of subtrochanteric stress fractures is low but this fracture is often bilateral and spontaneous. The association with bisphosphonates is debated but it is likely to be causal, particularly perhaps in a subset of patients predisposed by having low baseline remodelling which is then further suppressed for a protracted period of time. Giusti et al report that of 96/906 patients (10.6%) with subtrochanteric and femoral fracture (ST/FS), 63 with low energy fractures were matched with 126 controls with hip fracture. Atypical fractures were observed in 10/63 ST/FS cases (15.9%). Compared to patients with ordinary ST/FS fractures, those with atypical fractures were using more frequently BPs (OR, 17.0; 2.6-113.3) and glucocorticoids (OR, 5.3; 0.9-28.6). Atypical femoral fractures have a low prevalence (1.1% of all femoral fractures), compared to ordinary ST/FS fractures are more frequent in bisphosphonate users, but also occur in patients never treated with bisphosphonates. Bone 2011;48:966-71

Ageing and accumulation of advanced glycation endproducts

Suppression of bone remodelling intensity is accompanied by the accumulation of AGEs which reduce the ductility of bone matrix; bone becomes more stiff. Advancing age is accompanied by accumulation of AGEs. Dong et al report cortical specimens from young (31±6 years old), middle-aged (51±3 years old) and elderly (76±4 years old) subjects indicated that the concentration of AGEs show the greatest amount in the interstitial tissue, followed by the old osteons, and the least in newly formed osteons; the younger the donor the less AGEs were accumulated in the tissue. AGEs accumulation initiated from the cement lines and spread to the other parts as the tissue aged. Bone 2011;49:174-83

Saito et al report adult female cynomolgus OVX monkeys given once weekly subcutaneous injections of hPTH(1-34) at 1.2 or 6.0 µg/kg (low- or high-PTH groups) for 18 months had increased enzymatic immature and mature crosslinks, BV/TV, and trabecular thickness, and decreased pentosidine, compared with the OVX group. BV/TV, total enzymatic crosslinks, and calcium content independently affected ultimate load (model R2=0.748, p<0.001) and breaking energy (model R2=0.702, p<0.001). BV/TV was the most powerful and enzymatic crosslink content was the second powerful determinant of both ultimate load and breaking energy. The most powerful determinant of stiffness was the enzymatic crosslink content (model R2=0.270, p<0.001). Osteoporos Int 2011;22:2373-83

Targeting BMU imbalance

While suppressing bone remodelling intensity is an important and appropriate therapeutic target, another approach to therapy is to correct the negative BMU balance between the volumes of bone resorbed and formed by each BMU as it remodels the skeleton. This negative balance is the necessary and sufficient morphological basis for bone loss. If a drug is able to reduce the volume of bone resorbed by each BMU and increase the volume deposited in the smaller excavated site, this will either reduce the negative balance, restore balance, or make balance positive. If the mechanisms are such that BMU balance is made positive then the drug should keep remodelling intensity high or increase it because each remodelling event will deposit a net positive amount of bone reconstructing the skeleton.

Cathepsin K inhibitors target this lysosomal enzyme, that is critical to the degradation of type I collagen. The drugs do not appear to reduce the intensity of bone remodelling but rather reduce the depth (not area) of the resorption pit excavated. Unlike other antiresorptive agents, there appears to be a dissociation between the surface extent of resorption and formation. Antiresorptives like the bisphosphonates and denosumab reduce the surface extent of resorption and bone formation reflecting the reduction in remodelling intensity. Cathespsin K inhibitors do not reduce the surface extent of bone formation. The reasons for this are not understood. Osteoclast numbers are not reduced and it is possible that signals for bone formation arising from the osteoclast or from the matrix (which is still resorbed but less so) may be permissive for bone formation.

Eastell et al report the results of a 12-month, randomized, double-blind, placebo- and active-controlled parallel-group study in 285 postmenopausal women randomized to placebo; 50 mg twice daily, 100 mg once daily, or 300 mg once daily of ONO-5334; or alendronate 70 mg weekly. All ONO-5334 doses and alendronate showed an increase in BMD for lumbar spine, total hip (except 100 mg once daily), and femoral neck BMD. There was little suppression of ONO-5334 on bone formation markers, although the suppressive effects on bone resorption markers were similar to that found with alendronate. J Bone Miner Res 2011;26:1303-12

Endogenous PTH as a means of influencing bone structure

PTH peptides are anabolic when administered intermittently. This property has been utilized in the hope that intermittent stimulation of endogenous secretion of PTH might also be anabolic. John et al report that ATF936, a calcilytic triggered rapid, transient spikes in endogenous PTH. Eight weeks daily oral 30 mg/kg of ATF936, aged female rats had increases in proximal tibia metaphysis BMD, cancellous bone volume and cortical and trabecular thickness. Some evidence was provided using microCT on ex vivo specimens. While the authors suggest there was a mild anabolic effect, dynamic histomorphometric data will be needed to support this statement. Bone 2011;49:233-41

Reduced mortality associated with antiresorptive treatment

There is some evidence to support the view that antiresorptive agents reduce mortality independent of any association with fracture risk reduction. This was reported in the study of zoledronic acid following hip fracture trial. Nurmi-Luthje et al report that home-discharged hip fracture patients aged 50 years or older (n=23,615), unadjusted 1-year mortality was lower in patients who purchased calcium plus vitamin D or vitamin D and antiosteoporotic drugs than those who did not (HR=0.74, 0.67-0.81). Among men, the use of calcium plus vitamin D or vitamin D supplements was associated with lower 1-year mortality (HR=0.74, 0.56-0.97). Among women, the use of antiosteoporotic drugs was associated with lower mortality (HR=0.79, 0.67-0.93). There was a tendency to even better survival if calcium plus vitamin D or vitamin D supplements and antiosteoporotic drugs were used simultaneously (HR 0.72; 0.50-1.03 in men and 0.62;0.50-0.76) in women. J Bone Miner Res 2011;26:1845-53

Errors in measurement

Duque et al report biopsies at baseline and after placebo or risedronate for 3 years (n=14 per group). Adipocyte volume/tissue volume (AV/TV), number (AD(#)), and diameter (AD(diam)) increased after 3 years (~15%) in placebo. In contrast, AD(diam) remained unchanged and AV/TV and AD(#) decreased (~20%) in the risedronate group. These changes were associated with a reduction in PPARγ2 expression in marrow of risedronate treated women. Reduction in marrow fat may increase BMD. Osteoporos Int 2011;22:1547-53

Racial differences in bone microarchitecture

Smaller bones are assembled with more bone per unit volume. Walker et al report radius CSA was 10% smaller in the Chinese American than the white group, whereas C.Th and D(comp) values were 18% and 6% greater. Tibial HR-pQCT results for cortical bone were similar to the radius, but Tb.Th was 11% greater in Chinese American vs. white women. Tibial trabecular number and spacing were 17% lower and 20% greater, respectively, in Chinese American women. Chinese American women had a greater percentage of load carried by the cortical bone compartment. Whole bone finite element analysis may indicate that the thicker, more dense cortical bone and thicker trabeculae compensate for fewer trabeculae and smaller bone size. J Bone Miner Res 2011;26:1392-8

Liu et al report Chinese American women had higher plate bone volume fraction as well as higher plate number density compared with white women. With similar rodlike characteristics, the plate-to-rod ratio was twice in Chinese American than in whites. Plate-rod junction density, a parameter indicating connectivity, was greater in Chinese American women. Orientation of the trabecular bone network was more axially aligned in Chinese American women because axial bone volume fraction was higher than in white women. J Bone Miner Res 2011;26:1783-92

High bone mass

Frost et al report that in 19 Lrp5-HBM patients Z-scores for the forearm, total hip, lumbar spine, forearm, and whole body were between 4.9-7.52 SD higher than controls. Serotonin was lowest in cases and inversely associated with tibial cortical density (r=-0.49) and directly with OC, B-ALP), and PINP) (r=0.5) in controls only. J Bone Miner Res 2011;26:1721-8

O'Brien et al report that transgenic mice expressing a PTH receptor in osteocytes have increased cortical bone area, elevated periosteal and endocortical bone formation, and increased intracortical remodelling and porosity. Crossing these mice with mice lacking LRP5, or with mice overexpressing Sost in osteocytes, reduced or abolished, respectively, the increased cortical bone area, periosteal bone formation rate, and expression of osteoblast markers and Wnt target genes exhibited by the mice. DMP1-caPTHR1 lacking LRP5 or double transgenic DMP1-caPTHR1;DMP1-Sost mice have exacerbated intracortical remodelling and increased osteoclast numbers, and decreased osteoprotegerin. Thus, Sost downregulation is required for the stimulatory effect of PTH receptor signalling on periosteal bone formation, the Wnt-independent increase in osteoclastogenesis induced by PTH receptor activation in osteocytes overrides the effect on Sost. J Bone Miner Res 2011;26:1035-46

Central control of bone mass

Bartell et al report that intracerebroventricular (ICV) leptin increased expression of genes associated with osteogenesis, whereas those associated with osteoclastogenesis, adipogenesis, and adipocyte lipid storage were decreased. Leptin decreased weight, food intake, body fat and increased muscle mass, BMD, bone area, marrow adipocyte number, and mineral apposition rate. Serum insulin decreased, whereas serum osteocalcin, IGF-1, osteoprotegerin, pyridinoline, and RANKL increased. Expression of genes in adipose tissue associated with apoptosis, lipid mobilization, insulin sensitivity, and thermogenesis was increased, whereas expression of genes associated with cell differentiation and maturation was decreased. J Bone Miner Res 2011;26:1710-20

Williams et al report leptin receptor (db/db) deficient mice at the tibia had reduced trabecular bone volume and cortical bone volume, trabecular thickness and trabecular number. In the fifth lumbar vertebral body, the trabecular thickness and cortical thickness were decreased whereas the trabecular and cortical percent bone volume and trabecular number did not reach significance. The total (endosteal and periosteal) cortical perimeter increased. Serum osteocalcin decreased in the db/db mice as did bone strength and material stiffness. J Bone Miner Res 2011;26:1698-709

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.

Ego Seeman