Overview, Vol 12, Issue 3

Only doubt is certain and disbelief worth believing.
Without this courage there can be no learning.
Believe nothing.

"The quarterly journal Progress in Osteoporosis began in October 1993 as Advances in Osteoporosis 19 years ago. Its purpose was to provide readers without easy access to the literature with summaries of the most important literature. We now inhabit a virtual world. Information is instantaneously accessible to all at the tap of a keyboard; understanding is not. In the spirit captured by the anonymous author*, the purpose of this publication is to provide critical evaluation of the most important literature and so to provoke discussion. It is our intention to promote dialogue which examines the quality of information published and so its credibility. The opinions expressed are my own and do not necessarily reflect those of the International Osteoporosis Foundation."

We invite readers to comment on and discuss this journal entry at the bottom of the page.

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The Negative Bone Remodeling Balance
The Cause of Structural Decay

In young adulthood, remodeling is balanced, the volumes of bone removed and replaced during each remodeling cycle are equal so no permanent bone loss occurs (1). The first abnormality in remodeling is likely to be a reduction in the volume of bone formed by each basic multicellular unit (BMU), which is seen as a reduction in mean wall thickness (MWT) in bone biopsy specimens (2). This reduction in the volume of bone formed probably occurs around midlife, but this is not well documented. The work of Lips et al suggests there is a decline in MWT before menopause, but the data appear to be nonlinear with little diminution in MWT before menopause (2). The work of Vedi et al suggests that negative BMU balance precedes menopause, but the sample sizes were small and the reduction in MWT was modest, so that the amount of bone lost and the structural decay produced before menopause is likely to be modest given that remodeling intensity does not increase before menopause (3).

Once established, this negative balance is the necessary and sufficient cause of bone loss. Each time bone is remodeled, less bone is deposited than was removed, producing structural decay (4). Trabeculae thin and perforate, cortices become more porous and thin focally (5,6). This negative BMU balance is the ‘cause’ of structural deterioration and bone fragility, it is the target for therapeutic intervention (Figure 1).

Figure 1. The negative bone balance is the cause of structural decay and is due to a decline in both the volumes of bone deposited and resorbed by each BMU, but a greater decline in the former. Ac.F: activation frequency. (E Seeman, with permission)


After menopause, remodeling intensity increases and the negative bone balance may also worsen, resulting in accelerated structural decay. With time, trabeculae disappear and remodeling within the trabecular compartment slows down because there are no more trabeculae to remodel. In cortical bone, remodeling upon Haversian canals enlarges them focally, they coalesce, large pores appear (canals are seen as pores in cross-section), the cortices cavitate and thin from the ‘inside’ (6) (Figure 2).

Figure 2. Intracortical remodeling cavitates compact cortex thinning it from the ‘inside’. Yellow denotes trabecular bone, green cortical bone. Surface perimeter is the y-axis in the upper figure, amount of bone loss is the y-axis in the lower image. (Adapted from Zebaze et al (6))



The Surfaces of Bone
Where the Action is

Remodeling is surface dependent; for the cells of the BMU to resorb and replace bone, there must be a point upon which remodeling is initiated. This occurs upon one of the three (endocortical, intracortical, trabecular) components of the internal or endosteal surface of bone. These three components are contiguous, they are connected. The mineralized bone matrix volume is enveloped, residing ‘inside’ the periosteal surface and ‘outside’ the three components of the endosteal surface (Figure 3).

Figure 3. Mineralized bone matrix is enveloped by four ‘envelopes’. The periosteal surface is the outer envelope and the external surface of the whole bone volume. The whole bone includes the mineralized bone volume and the void volumes. The void volume comprises the medullary canal, the Haversian and Volkmann canals, and remodeling units in varying stages of excavation and refilling. (E Seeman, with permission)


Bone formation upon the periosteal envelope and upon the endocortical envelope during puberty in females or during anabolic therapy separates these surface, so cortical thickness increases. Resorptive remodeling upon the endocortical envelope during advancing age brings it closer to the periosteal envelope, thinning the cortex; while resorptive remodeling upon the Haversian canals enlarges them focally, they coalesce forming giant pores in cross-section, which fragment the cortex, particularly the inner part of the cortex adjacent to the medullary canal. This region, where the compact cortex merges with trabeculae abutting the endocortical surface, is the corticomedullary or corticotrabecular junctional region. Remodeling here is intense and fragments the cortex – it becomes ‘trabecularized’ (6,7). The fragments of cortex look like trabeculae, but they are thicker, have a chaotic architecture and are unlikely to serve to buttress the cortex, as do the true trabeculae within the medullary canal.

The right answers require the right questions. The living bone is the cellular activity upon these surfaces. Instead of asking what is the effect of growth, ageing, exercise, disease and drug therapy on bone mineral density (BMD), the right question is what are the effects of each of these factors on the cellular activity upon these surfaces, and so the movement of these surfaces relative to each other and hence the three dimensional architecture of the bone.

Antiresorptives Reduce Remodeling Intensity

For therapeutic agents to stop bone loss, they must correct the negative bone balance by either reducing the volume of bone resorbed by the osteoclasts of the BMU, or by increasing the volume of bone formed by the osteoblasts of the BMU, or both. If the negative bone balance is made less negative, then treatment must reduce the intensity of bone remodeling to slow the loss of bone. Antiresorptive agents reduce the intensity of bone remodelling – the number of sites appearing on a bone surface at any time decreases, but they probably do not correct the negative BMU balance. So each time the fewer number remove bone, they then deposit less producing a net loss of bone and more structural decay, but this proceeds more slowly.

This is important, if the negative balance remains unchanged and fewer remodeling sites remove more bone than they deposit, structural decay will continue, albeit at a slower rate, despite compliance with treatment. This is not detectable using bone densitometry because secondary mineralization of the much larger volume of mineralized bone matrix not being remodeled progresses in completeness of secondary mineralization. The crystals enlarge and more of the bone volume has a higher and higher density, so BMD continues to rise. This is not ‘seen’ by the BMD machine because the rise in BMD produced by the increasingly complete secondary mineralization is occurring in a much larger volume of bone than the small volume being removed from it. So BMD rises in a progressively smaller and smaller total volume of bone (Figure 4).

Figure 4. When an antiresorptive is administered, resorption sites excavated before treatment refill (green) while fewer new remodeling sites (blue) are excavated. Areal BMD increases (green and white line) also because secondary mineralization of bone is no longer removed. If remodeling continues albeit more slowly, and the negative BMU balance persists, then total mineralized bone volume will decrease (dashed line), but its density will increase perhaps making bone more brittle. (E Seeman, with permission)

The decision to use a drug partly depends on the remodeling status of the skeleton. If potent remodeling suppressants are used and remodeling is fully suppressed, structural deterioration will be prevented, perhaps at the price of compromising the material composition of bone, particularly in persons with low baseline remodeling. It makes little sense treating someone with low bone remodeling with the most potent remodeling suppressants. Using a less potent remodeling suppressant may result in continued structural deterioration with preservation of the material composition of bone. What is worse ‒ allowing structural deterioration or allowing some compromise in the material composition of bone? The answer to this is not clear, I suspect it is worse to allow structural decay.

If antiresorptive agents abolish the negative BMU balance, remodeling will not produce further permanent structural decay. If treatment makes remodeling balance positive by reducing the volume of bone resorbed and increasing the volume of bone deposited, then it makes sense to increase remodeling intensity because each remodeling event will deposit a small moiety of bone, reconstructing the skeleton focally.

Access to Remodeling Sites
Are all Antiresorptives Equal?

Several recent publications signal the importance of access to remodeling in cortical and trabecular bone as one explanation for differences in efficacy of treatments in suppressing remodeling. Most antiresorptive agents reduce the intensity of bone remodeling by about 50% as measured by circulating remodeling markers. Why 50%? One reason may be that remodeling upon Haversian canals within cortical bone may be less accessible to bisphosphonates than remodeling upon the endocortical and trabecular surfaces. Trabecular bone consists of flattened plates with a low mineralized bone matrix volume and a large surface area – they have a large surface area/bone matrix volume configuration (Figure 5).

Figure 5. Left panel shows graph adapted from Weiss et al. Note the higher concentration of bisphosphonate in vertebrae than cortical sites. (Right panel) Trabecular plates are thin and have a large surface area. Adsorbed bisphosphonate (green) penetrates the smaller bone matrix volume so osteoclasts will encounter and engulf drug preventing further resorption. (E Seeman with permission)

Bisphosphonates bind to bone mineral and those with higher affinity for mineral cannot penetrate deeply into matrix. This is not a problem in trabecular bone because of its high surface/volume ratio. However, in cortical bone with its low surface to volume ratio, access to the deeper matrix is limited, so that drugs binding with high affinity, like alendronate, may be unable to reach and concentrate within the deeper interstitial bone or at the periphery of osteons; so remodeling initiated at points on Haversian canals may excavate mineralized bone matrix that does not contain bisphosphonate, and so osteoclasts continue to excavate matrix (Figure 6).

Figure 6. Cortical bone has a large volume and is enveloped with a relatively smaller surface area, so bisphosphonates (green dots) adsorbed upon the surface cannot access remodeling deep within cortical bone around Haversian canals to remove deep cracks in interstitial bone (green). Remodeling may be less inhibited, especially by bisphosphonates avidly bound to matrix beneath the endosteal envelope. (E Seeman, with permission)

Weiss et al report that the concentration of labeled zoledronic acid is higher in trabecular sites containing large amounts of trabecular bone like the vertebrae compared with the femur, a predominent cortical site (8). As reported in experiments by Allen et al, risedronate is a drug that has a lower binding affintity to matrix and penetrates more deeply beneath the surface.

Figure 7. (Left panel) Bisphosphonate is bound beneath the bone surface to matrix and cannot penenetrate deeply. (Right panel) Risedronate binds less avidly to mineral than alendronate. Remodeling is more rapidly and more greatly suppressed by risdronate as reflected in the greater reduction in the surface extent of bone formation. (Adapted from Allen et al (9))


In another experiment by Turek et al, mature female rabbits were injected with both low- and high-affinity bisphosphonate analogs bound to different fluorophores (10). Staining intensity ratios between osteocytes within rib osteons or within vertebral trabecular hemiosteons were compared to osteocytes outside the cement line and was greater for the high-affinity than the low-affinity compound which distributes across the cement line, while the high-affinity compound concentrates mostly near surfaces. The affinity of bisphosphonates for the bone determines the reach of the drugs in cortical and cancellous bone (Figure 8).

Figure 8. Turek et al. report the high affinity (blue) is concentrated around vessels and does not penetrate matrix. In right panel there is greater penetration of low affinity (red) with matrix staining of osteocytes (10).


Roelofs et al also published a study examining the effects of differing drug affinities for bone mineral and the effect on the distribution on mineral surfaces (11). Fluorescent conjugates of risedronate and its lower-affinity analogues deoxy-risedronate and 3-PEHPC were used (Figure 9). In growing rats, all compounds preferentially bound to forming endocortical surfaces in cortical bone. At forming surfaces, penetration into the mineralizing osteoid inversely correlated with mineral affinity. Lower-affinity compounds also showed a higher degree of labeling of osteocyte lacunar walls and labeled lacunae deeper within cortical bone, indicating increased penetration into the osteocyte canalicular network. These findings indicate that the bone mineral affinity of bisphosphonates is likely to influence their distribution within the skeleton.

Figure 9. Roelofs et al report penetration into the mineralizing osteoid is inversely correlated with mineral affinity (11). Lower-affinity florescent-psuedocoloured compounds show a higher degree of labeling of osteocyte lacunar walls and labeled lacunae deeper within cortical bone indicating increased penetration into the osteocyte canalicular network.

So, what might this mean in terms of bone morphology and bone strength? In a wonderful paper laiden with many interesting observations, Ohishi et al reported that osteoprotegerin (OPG), which does not bind to matrix and has a wide matrix distribution, reduced porosity in the mouse model of high turnover and porosity (12). Zoledronic acid and alendronate reduced porosity but no differently to vehicle treated mice, yet preservation of trabecular bone was similar with all three treatments so that this is not simple a dose effect (Figure 10).

Figure 10. Ohishi et al report that OPG, which does not bind to matrix, reduced porosity in the mouse model (12). Zoledronic acid and alendronate reduced porosity but no differently to vehicle treated mice. Trabecular bone was equally preserved by all treatments so the greater benefit in cortical bone of OPG is not a dose specific effect.


Does a CAT Have 9 Lives?

Remodeling inhibitors capitalise on reducing the size of the remodeling transient. That’s how they increase BMD. The Parfittian treatise on this subject is essential reading (13). The remodeling transient is the result of the normal delay between the completion of bone resorption, which takes about 3 weeks, and the completion of bone formation, which takes about 3 months. Because of this time lag, at any time, there will be a reversible and transient deficit in bone volume that is the sum of the volume of the newly excavated cavities, the volume of the newly unmineralized osteoid just deposited by other BMUs, the volume of the osteoid that has undergone primary but not secondary mineralization (now called ‘bone’), and the volume of bone that is undergoing secondary mineralization, which does not reach completion for about a year, if not longer; secondary mineralization is also part of the transient remodeling space deficit.

When an antiresorptive is administered, there is inhibition of the appearance of new resorption cavities and so the refilling of cavities (which remains incomplete because of the negative bone balance) excavated prior starting therapy occurs without being offset by the appearance of new resorption cavities. The higher the baseline remodeling, the larger the remodeling transient and so the greater the BMD response to a given inhibitor of remodeling. As discussed above, the rapid rise in BMD is due to the refilling of excavated cavities, the completion of primary and secondary mineralization in tissue that would otherwise have been removed had remodeling intensity not been reduced. BMD then rises more slowly and as a result of secondary mineralization.

The cathepsin K (CAT K) inhibitors do not appear to reduce remodeling intensity, but the evidence for this is not robust and may be species specific. Bone et al reported no reduction in activation frequency, the percent mineralizing surface, bone formation rate or eroded surface; each a measure of the intensity of remodeling upon the bone surface (14). The numbers of biopsies available were limited so the data is not robust, but if remodeling intensity is not slowed so that sites excavated before treatment refill but with the appearance of the same number of new sites, how can BMD increase?

One explanation is a reduction in the depth of resorption sites without a change in their numbers. There is evidence supporting this notion (15). Perturbing steady state by allowing partial refilling of sites present before treatment while the same number of resorption sites appear, but each is half the depth should increase BMD to about the same degree as partial refilling of sites present before treatment with appearance of half the number of new sites of the same depth (Figure 11).

Figure 11. Antiresorptives like the bisphosphonates and densosumab reduce the intensity of remodeling as reflected in histomorphometric measures and bone remodeling markers. This is not the case with CAT K inhibitors.


This might explain the similar rise in BMD in patients treated with alendronate and odanocatib. However, if the volume of bone deposited remains unchanged, then the negative BMU balance will lessen; more shallow resorption pits are likely to refill more completely. So when steady state is restored at the same rate of remodeling but they are more shallow and more fully refilled, bone loss will lessen but will continue unless the negative BMU balance is abolished. If the volume of bone formed increases, as suggested by several authors, then bone loss may stop, but bone mass will not increase unless the negative BMU balance is made positive. BMD will rise in the two scenarios (lessening or stopping bone loss even though the mass or volume of bone does not rise) because the bone not removed (because pits are more shallow) undergoes more complete secondary mineralization. In addition, as remodeling sites are more shallow, interstitial bone (bone between osteons) may increase in relative and absolute terms and undergo more complete mineralization contributing to the rise in BMD. Moreover, if there is relatively more interstitial bone than osteonal bone, this may compromise bone strength as interstitial bone is usually more densely mineralized than osteonal bone, has higher pentosidine content, has fewer osteocytes and is a common site of microdamage (5).

Bone resorption markers decrease following treatment with this class of drugs ‒ a puzzling observation if remodeling intensity does not decrease. But this may be the result of a decrease in the depth of the same number of remodeling sites. Remodeling markers tend to drift back up after initial suppression despite continued treatment. This might reflect the continued remodeling taking place when remodeling returns to its new steady state. Remodeling now continues, perhaps at the same intensity, but now the remodeling cavities excavated are smaller and appear at the same rate as the smaller cavities being refilled.

Bone ‘formation’ markers appear to decline less than bone ‘resorption’ markers, suggesting that osteoclasts (which remain or increase in numbers) may signal bone formation to continue (16). However, the notion that there is continued or increased bone formation by the BMUs in the presence of reduced resorption by each of them is difficult to demonstrate convincingly for several reasons.

For example, inferring circulating markers of bone remodeling are surrogates of bone resorption and formation at the morphological level is problematic. There are very few studies comparing levels of remodeling markers and volumes of bone formed or resorbed and at best the correlations are ~0.5 or less. Moreover, it remains unclear whether remodeling markers reflect remodeling intensity at the tissue level, at the cellular level, and whether they arise due to remodeling at cortical bone or trabecular bone or indeed differently at different sites of the skeleton.

Comparing markers is frought with difficulty. The variance in resorption and formation markers differ and markers are not normally distributed. Thus, a 50% reduction in a ‘resorption’ marker is not necessarily ‘less’ than a 25% reduction in a ‘formation’ marker. In addition, CAT K inhibitors prevent degradation of some markers, leaving the levels higher giving the impression that remodeling, or worse, that bone ‘formation’ is continuing.

Figure 12. If a drug like a CAT K inhibitor reduces the depth of resorption but not remodeling intensity, then the rise in BMD should be similar to that observed by a bisphosphonate that halves the number of sites without affecting the resorption depth. However, the effects on bone morphology and material properties may differ. (E Seeman, with permission)


There are three recent papers that lend support for the notion that CAT K inhibitors reduce resorption depth and area excavated by osteoclasts, may reduce remodeling intensity in subhuman primates and increase bone strength.

Jayakar et al report that OVX odanacatib (ODN) treated nonhuman primates had increases in integral vBMD and cortical thickness at the upper distal radius and at the distal 1/3 radius compared with and OVX-Veh treated animals. Axial compression showed the OVX-ODN group had 33% greater peak stress than the OVX-Veh group (17).

Masarachia et al report that in estrogen-deficient, skeletally mature rhesus OVX monkeys treated for 21 months with vehicle or ODN, treatment suppressed markers of bone remodeling and maintained osteoclast numbers (18). ODN prevented bone loss in lumbar vertebrae and dose-dependently increased L1 to L4 BMD. Treatment also tended to increase bone strength with a correlation (R=0.838) between peak load and bone mineral content of the lumbar spine.

A most interesting paper was published by Cusick et al (19). The authors report that ODN increased femoral neck (FN) BMD and ultimate load relative to vehicle treated nonhuman primates. Histomorphometry of FN and proximal femur (PF) revealed that ODN decreased 'bone formation rate' (BFR) upon the trabecular and intracortical surfaces. This is an ambiguous term. BFR is the product of the surface extent of remodeling which reflects remodeling intensity and mineral appositional rate (MAR). BFR may increase or decrease because of change in one or both of these terms. A change in the surface extent of remodeling reflects remodeling intensity, a change in MAR reflects a change in the number and work of osteoblasts, amount of bone deposited depends on the MAR. When authors report BFR is 'increased', this does not necessarily mean there is an anabolic effect.

The authors report ODN stimulated periosteal BFR 6-fold at the FN and 3.5-fold at the PF with the 30 mg/kg dose vs. vehicle. However, examination of the figures reveals MAR increased in one location only (Figures 13-14); the “increased” BFR is therefore a function of the high surface extent of remodeling or modeling on the periosteum. The differing behaviour on each surface, reduction, increase or no change in the surface extent of remodeling, and behavior of MAR is difficult to interpret because it is inconsistent. Moreover, the claim is made that ODN increased cortical thickness at the FN by 21% (p=0.08) and PF by 19% (p<0.05) vs. vehicle after 21 months of treatment needs to be carefully interpreted as changes in edge detection by the imageing method may occur when bone tissue density increases. More studies of histomorphometry and microstructure are needed in this class of drug.



Figures 13-14. Cusick et al report effects of ODN on BFR is site specific. For PF and FN trabecular bone, BFR was reduced with both doses due to a decrease in MS/BS, MAR was reduced or unchanged. The result was the same for the intracortical (Haversian) surface but mainly seen with the larger dose. On the proximal femur endocortical surface, MS/BS increased at the lower dose but there was no effect on MAR or the net derived BFR. On the periosteal surface of the proximal femur, BFR was increased due to a higher MAR with the higher dose and with long term labeling assessment. On the periosteal surface of the femoral neck, BFR increased even though neither small increase in MS/BS and MAR were not significant.

Oldies but Goodies

Zoledronic acid – is once enough?

Boonen et al (20) report a post hoc analysis of persistence of the antifracture effect of zoledronic acid from 9355 women randomized in two placebo-controlled pivotal trials. Zoledronic acid reduced the risk of all clinical fractures at 12 months (HR=0.75, 95% CI 0.61-0.92). Year-by-year analysis showed reduced risk for all clinical fractures in each of the 3 years (year 1: OR=0.74, 95% CI 0.60-0.91; year 2: OR=0.53, 95% CI 0.42-0.66; year 3: OR=0.61, 95% CI 0.48-0.77). Year-by year data during the first 3 years of treatment are not usually shown in clinical trials. What is usually presented is years 0-1, 0-2 and 0-3, so the carry over effect of the first year influences those results.

Grey et al (21) report that a single dose of 5 mg zoledronic acid decreased bone turnover and increased BMD during 3 years in 50 postmenopausal women with osteopenia. After 5 years, β-CTX and P1NP were lower by 48% and 45%, respectively. BMD in the zoledronic acid group was higher by 4.2% at the spine, by 5.3% at the total hip, and by 2.7% at the total body. This is important. Is it necessary to treat patients with suppressed remodeling with further doses of zoledronic acid when remodeling remains suppressed after one injection for 1 to even 5 years? I suspect not, but what is needed are fracture endpoints because if remodeling continues and the BMU balance remains negative, then structural decay may be continuing albeit slowly, and this will remain undetectable using bone densitometry because the rise in tissue mineralization density of the whole mineralized bone volume will overwhelm and obscure the continued loss of bone with its mineral content.

The good and bad of remodeling suppression

Remodeling suppression is good because it reduces the number of new remodeling sites appearing upon bone surfaces and so reduced the structural decay that follows, as less bone is deposited than was removed. However, remodeling suppression is bad because the bone that is no longer removed undergoes more complete secondary mineralization, and so the mineral content from osteon to osteon may become more similar, and this loss of heterogeneity in tissue mineralization density is held to allow crack propagation. Reduced remodeling means reduced damage removal as well.

Donnelly et al (22) compared biopsies from the proximal femur in bisphosphonate-naive (−BIS, n=20) and bisphosphonate-treated (+BIS, n=20, duration 7±5 years) patients with intertrochanteric (IT) and subtrochanteric (ST) fractures using FTIRI. The mean FTIRI parameters were similar, but the widths of the distributions tended to be reduced in the +BIS group, the widths of the cortical collagen maturity and crystallinity were reduced in the +BIS group relative to those of the −BIS group by 28% and 17%, respectively. The cortical mineral:matrix ratio was 8% greater in tissue from patients with atypical ST fractures (n=6) than that of patients with typical fractures (n=14) (atypical 5.6±0.3 vs. typical 5.2±0.5, p=0.03).

Hofstetter et al (23) used Raman and Fourier transform infrared microspectroscopy (FTIRM) analysis to examine material properties at bone forming trabecular surfaces in iliac crest biopsies from women treated with alendronate (ALN) or risedronate (RIS). There were 33 women treated with ALN for 3-5 years [ALN-3], 35 with ALN for >5 years [ALN-5], 26 with RIS for 3-5 years [RIS-3], and 8 with RIS for >5 years [RIS-5]). In RIS-5 there was a decrease in the proteoglycan content (-5.83% compared to ALN-5). RIS-3 and RIS-5 were associated with lower mineral maturity/crystallinity (-6.78% and -13.68% vs. ALN-3 and ALN-5, respectively), and pyridinoline/divalent collagen crosslink ratio (-23.09% and -41.85% vs. ALN-3 and ALN-5, respectively). ALN and RIS exert differential effects on the intrinsic bone material properties at actively bone forming trabecular surfaces.

Abrahamsen et al (24) examined 30,606 ALN users and 122,424 controls. ALN users were more likely to have undergone recent upper endoscopy (4.1 vs. 1.7%, p<0.001). ALN users had a lower risk of incident gastric cancer [OR 0.61; 0.39-0.97) and no increased risk of esophageal cancer (OR 0.71; 0.43-1.19). Risk reductions were greater in users with 10+ prescriptions. The risk of dying of esophageal cancer was reduced in ALN users after 3 years (OR 0.45: 0.22-0.92) but not after 9 years (OR 1.01; 95% CI: 0.52-1.95).

Chiang et al (25) report the relationship between ALN and the risk of all malignancies in women with osteoporosis and age over 55 years. The study included 6906 women with osteoporosis taking ALN, and 20,697 age- and comorbidity-matched women without bisphosphonate treatment. During 4.8 years, 821 patients from the study group and 2646 patients from the control group had new cancers (11.9% vs. 12.8%, p=0.054). The person-year incidence of newly-developed cancer in ALN users and controls was 28.0 and 29.4 per 1000 person-years, respectively (adjusted HR, 1.05; 95% CI, 0.97-1.13; p=0.237).

Boonen et al (26) report a 2-year, randomized, double-blind, placebo-controlled study in men. RIS 35 mg once a week decreased BTMs and increased BMD. In the open-label extension, all patients received RIS 35 mg once a week, and 1000 mg elemental calcium and 400-500 IU vitamin D daily for up to 2 years. A total of 218 (of 284) patients enrolled in the open-label extension. RIS continued to produce increases in lumbar spine BMD from baseline (7.87%) in the group of patients who took it for 4 years. RIS produced increases in lumbar spine BMD from baseline (6.27%) in the former placebo group who took it for 2 years during the open-label extension.

In Search of Place

The problem with SERMs is the lack of evidence of efficacy against nonvertebral fractures. This is a serious limitation because 80% of all fractures are nonvertebral. Eastell et al (27) describe the changes in BTMs in response to lasofoxifene in 1126 women aged 59-80 years during 5 years. Lasofoxifene decreased resorption and bone formation markers; 0.5 mg/d was similar to 0.25 mg/d. 0.5mg/d resulted in response rates for CTX (decrease from baseline >60%), P1NP (>50%), and bone ALP (>30%) of 35%, 45%, and 43% of women at month 12, respectively, compared with placebo responses of 4%, 4%, and 7%. In contrast, the increase in BMD took longer (50% responded after 36 months of lasofoxifene 0.5 mg/d) and was not as specific (15% of placebo group responded). This is difficult to explain. The data suggest that more than half of the participants do not respond. The question is why are these agents such weak remodeling suppressants?

Calcitonin: It seemed like a good idea at the time

Binkley et al (28) report results of oral calcitonin in postmenopausal osteoporosis (ORACAL) in a randomized, double-blind phase 3 study in 565 women randomized to oral recombinant salmon calcitonin (rsCT) tablets (0.2 mg/d), synthetic salmon calcitonin (ssCT) nasal spray (200 IU/d), or placebo for 48 weeks. Women randomized to oral rsCT had greater increase in lumbar spine BMD (1.5%) greater than those randomized to ssCT nasal spray (0.78%) or placebo (0.5%). Oral rsCT also resulted in greater improvements in trochanteric and total proximal femur BMD and greater reduction in those observed in ssCT nasal spray. CT is a weak remodeling suppressant, but the evidence for antifracture efficacy has never been demonstrated convincingly; and so it seems inappropriate to consider this agent as a first line treatment for fracture prevention.

Calcium Supplementation Works in Those Deficient

Calcium supplementation is a weak remodeling suppressant. In persons who are calcium replete and have a low rate of bone remodeling, the effects are difficult to demonstrate. However, in persons with a high rate of bone remodeling and a low calcium intake, the benefit of suppressing remodeling and the subsequent rise in BMD should be demonstrable. Khadilkar et al (29) report in a double-blind, matched-pair, cluster, randomization study of 1-year supplementation with calcium, multivitamin with zinc and vitamin D in 214 school-going premenarchal girls. The mean increase in TBBMC was higher in the Ca-group (22.3%) and Ca+MZ-group (20.8%) compared to control group (17.6%) (p<0.05) with no differences between Ca+MZ and Ca groups.

Lewis et al (30) reviewed randomized controlled trial evidence of adverse events. In seven studies, self-reported gastrointestinal (GI) adverse event rates were more common in participants receiving calcium. These were described as constipation, excessive abdominal cramping, bloating, upper GI events, GI disease, GI symptoms, and severe diarrhea or abdominal pain (calcium 14.1%, placebo 10.0%) (RR 1.43, 95% CI 1.28-1.59, p<0.001). Adjudicated functional GI hospitalizations in one study were calcium 6.8%, placebo 3.6% (RR 1.92, 95% CI 1.21-3.05, p = 0.006). Self-reported myocardial infarction (MI) rates of 3.6% in the calcium group and 2.1% in the placebo group. After adjudication, the MI rates were 2.4% in the calcium group and 1.6% in the placebo group (RR 1.45, 95% CI 0.88-2.45, p=0.145).

These data support the hypothesis that calcium tablets increase the incidence of adverse GI events. Read between the lines. Whether this accounts for an increase in self-reported MI in calcium treated patients but not controls is possible, but it is not the solution to the controversy which requires properly designed and executed trials with adequate sample sizes and preplanned global outcomes including cardiac events. If there is a small increase in cardiac events, it will remain undetected with sample sizes of a few hundred individuals because of lack of power, not because the truth is that calcium is safe. We just don’t know.

Little is seen in the large randomized trials because they are flawed in study design and execution. Most subjects are not calcium deficient, so how can an effect of ‘deficiency’ be detected or the benefit (or risk) of supplementation be documented? In addition, most if not all, have dropout rates of 50%, so how can credible inferences be inferred examining the results in compliers when randomization has been violated? Compliers to placebo have better outcomes than noncompliers to placebo.

Anabolic Agents

Calcium sensing receptor antagonists and endogenous PTH

Fisher et al (31) report that stimulating endogenous PTH may produce an anabolic effect on the skeleton. This is a nice idea killed by experimentation. The CaSR antagonist JTT-305/MK-5442 increased endogenous PTH. Daily treatment for 12 weeks increased BMD at axial and appendicular skeletal sites, but the changes did not reach significance. Histological analyses confirmed increases in mineralized surface (MS/BS), reflecting increased remodeling intensity but not necessarily new bone formation. In the presence of existing osteoclasts, endogenous PTH will increase remodeling and produce bone loss. The same observations have been made with several other drugs such as ronacalerat, which was associated with appendicular bone loss (32). With denosumab, acute suppression of remodeling reduces serum calcium within the normal range and increases endogeneous PTH, but reduced synthesis of osteoclasts and reduced activity of existing osteoclasts appears to prevent the resorptive action of the endogenous rise in PTH (33). At this time, endogenous PTH stimulators do not appear to be a viable option in the treatment of osteporosis.

Figure 15. Ronacalerat reduces serum calcium and increases endogenous PTH, but the resorptive action of the drug produces cortical bone loss.


Marsell et al (34) report glycogen synthase kinase 3β (GSK-3β) in the canonical Wnt pathway is a therapeutic target because it inhibits bone formation so that inhibitors of this kinase may produce net bone formation. A GSK-3 inhibitor, AZD2858, dose dependently increased trabecular bone mass in rats after two weeks with a maximum effect at 20 mg/kg daily (total BMC increased by 172%). An effect was also seen at cortical sites (total BMC increased by 111%). Vertebral compression strength increased by 370% and femoral diaphyseal strength increased by 115%.

Ascenzi et al (35) explored the role of orientation of type I collagen in bone strength before and after treatment with PTH. PTH increased the Haversian area by 11.9 to 12.8 mm2; decreased bright birefringence from 0.45 to 0.40, increased the average percent area of osteons with alternating birefringence from 48.15  to 66.33%, and nonsignificantly decreased the average percent area of semihomogeneous birefringent osteons and of birefringent bright osteons (4.1 vs. 2.1%,  p=0.10). Lamellar thickness increased from 3.78 to 4.47 µm for bright lamellae, and from 3.32 to 3.70  µm for extinct lamellae. This increased lamellar thickness altered the distribution of birefringence and the distribution of collagen orientation in the tissue. With PTH, a higher percent area of osteons at the initial degree of calcification was observed, relative to the intermediate-low degree of calcification (57.16 vs. 32.90%), with percentage of alternating osteons at initial stages of calcification increasing from 19.75 to 80.13. PTH increases heterogeneity of collagen orientation.

Other Agents
Mechanisms to be Determined

Strontium ranelate

Strontium ranelate reduces vertebral and nonvertebral fractures, and in post hoc analysis, reduces hip fractures as well. However, like most studies, this evidence is confined to 3-5 years of treatment. Difficulties arise in assessing antifracture effiacy for longer periods of time because of lack of controls and dropouts. Reginster et al (36) report that of the original cohort of postmenopausal osteoporotic women participating in SOTI and TROPOS for 5 years, 237 received strontium ranelate 2 g/d during a 5-year open-label extension. As there was no randomized control group, fracture rates were compared with fracture rates observed in the first 5 years in a FRAX®-matched placebo group identified in the TROPOS placebo arm. The incidence of vertebral and nonvertebral fracture in years 6-10 was comparable to the incidence between years 0-5, but was lower than the incidence in the FRAX®-matched placebo group over 5 years (P<0.05); relative risk reductions for vertebral and nonvertebral fractures were 35% and 38%, respectively. The authors infer that long-term treatment is associated with the maintenance of antifracture efficacy over 10 years. The veracity of this data is difficult to assess because randomization is violated. The lower fracture rate reported in the treated group may have nothing to do with the treatment. Sampling bias may have resulted in a group less prone to sustaining fractures with or without treatment. Over 10 years, spine BMD increased to 34.5±20.2% above baseline, the morphological basis of this large increase is not known.


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Twenty-five years of PTHrP progress: From cancer hormone to multifunctional cytokine
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J Bone Miner Res 2012;27:1231

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More bone density testing is needed, not less
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What's in a name? What constitutes the clinical diagnosis of osteoporosis?
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Osteoporos Int 2012;23:2093