Overview, Vol 14, Issue 1

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

"The quarterly journal Progress in Osteoporosis began in October 1993 as Advances in Osteoporosis. 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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I dedicate this issue of Progress in Osteoporosis to my mother whose journey through life ascended through the last glass darkly. She was magnificent in her silent and defiant stare into eternity without a good bye. But we never say goodbye. Those we love are with us always, even before we meet.


Antiresorptives

Water, raloxifene and bone strength

Two fascinating papers were published recently. Samuel et al report that water affects mechanical behavior of bone by interacting with the mineral and organic phases through hydrogen bonding and polar interactions (1). The authors soaked dehydrated bone in water, heavy water (D2O), ethylene glycol (EG), dimethylformamide (DMF), and carbon tetrachloride (CCl4), compounds of different polarity, hydrogen bonding capability and molecular size. Of the matrix water in bone, 22.3% was replaced by CCl4, 71.8% by DMF, 85.5% by EG and ~100% by D2O and H2O. CCl4 soaked specimens showed similar mechanical properties as dehydrated ones. Despite great differences in replacing water, only slight differences were observed in the mechanical behavior of EG and DMF compared with dehydrated bone samples. D2O preserved the mechanical properties. About 15% water in matrix spaces (into which molecules larger than 4.0 Å cannot enter) contributes to mechanical behavior.

Gallant et al machined bone beams from canine and human donors (2). Specimens were depleted of living cells and exposed to raloxifene ex vivo which improved intrinsic toughness by increasing matrix bound water due to its hydroxyl groups. Raloxifene alters the distribution of load between the collagen and mineral crystals, placing lower strains on the mineral allowing greater deformation prior failure. This drug has not been shown to reduce nonvertebral fractures, an important limitation given that 80% of all fractures in the community are nonvertebral. Studies examining raloxifene plus bisphosphonates (which may reduce toughness) have not been done.

Figure 1. Raloxifene (a) increases canine cortical toughness dose-dependently without or (b) with fetal calf serum and does so (c) in human bone (d) without change in BMC (e) and increases energy absorption in post yield portion of curve (f) shows force displacement curves in dog and human bone, (g) toughness increases with raloxifene, or raloxifene followed by PBS compared to PBS. Reproduced from Bone, 61:191-200, Copyright (2014), with permission from Elsevier.

Denosumab

Zebaze et al report that postmenopausal women mean age 61 years (range 50-70) were randomized double blind to placebo (n=82), alendronate (ALN) 70 mg/week (n=82), or denosumab 60 mg/6 monthly (n=83) during 12 months (3). Denosumab reduced remodeling more rapidly and completely than ALN, reduced porosity at 6 months and more so by 12 months and 1.5- to 2-fold more so than ALN. By contrast, ALN reduced porosity at 6 months but no further at 12 months apart from porosity of the inner transitional zone (ITZ). So, by 12 months, compact cortex (CC) porosity was not different to baseline or controls, outer transitional zone (OTZ) and ITZ porosity was reduced relative to baseline. Each treatment increased trabecular BV/TV similarly.

Figure 2. Both ALN and denosumab reduce cortical porosity at 6 months, but denosumab further reduces porosity by 12 months. No further reduction in porosity occurs in the second 6 months in the ALN treated group and porosity is no longer significantly reduced relative to controls. The increase in trabecular density is similar with both drugs, perhaps because the accessibility to trabecular remodeling is similar. Reproduced from Bone, 59:173-9, Copyright (2014), with permission from Elsevier.

The greater reduction in porosity of the cortex by denosumab may be due to greater inhibition of intracortical remodeling. ALN is tightly bound to matrix and may not access deeper intracortical remodeling. While this remains theoretical there is evidence based on histomorphometry in primates that ibandronate does not reduce Haversian canal remodeling more than controls while suppression of endocortical and trabecular remodeling is suppressed more than controls (4).

Figure 3. In cortical bone, Haversian canal remodeling is not suppressed relative to controls and there is no change in ultimate load. By contrast, remodeling upon the endocortical surface lining the medullary canal and the trabecular surfaces is suppressed and ultimate load is increased in trabecular bone reflecting the greater accessibility of this bisphosphonate to these surfaces and the higher concentration of the drug in trabecular rich spine than cortical bone of the tibia. Adapted from Bone, 31:45-55, Copyright (2003), with permission from Elsevier.

If denosumab has better access to intracortical remodeling than bisphosphonates, then the real test is whether it reduces nonvertebral fractures more greatly than denosumab. This requires a comparator trial. None have been done using fractures as an outcome. Nakamura et al report a phase 3 randomized, double-blind, placebo-controlled trial with an open-label active-comparator fracture study of 1262 Japanese women and men with osteoporosis aged 50 years or older, who had 1-4 prevalent vertebral fractures (5). Subjects were randomly assigned to denosumab 60 mg sc 6 monthly (n=500), placebo (n=511), or oral ALN 35 mg weekly (n=251). Denosumab reduced the risk of vertebral fracture by 65.7% with incidences of 3.6% in denosumab and 10.3% in placebo at 24 months (HR=0.343; 0.194-0.606, p<0.0001). No difference in adverse events was found between denosumab and placebo. Regrettably, the antifracture efficacy of denosumab vs. open label ALN was not reported.

Keaveny et al report that in 48 placebo and 51 denosumab treated women, compared with baseline, hip strength increased by 12 months (5.3%; p<0.0001) and through 36 months (8.6%; p<0.0001) in the denosumab group (6). In the placebo group, hip strength did not change at 12 months and decreased at 36 months (5.6%; p<0.0001). At the spine, strength increased by 18.2% at 36 months with denosumab (p<0.0001) and decreased by 4.2% with placebo (p=0.002). At 36 months, hip and spine strength increased for the denosumab group compared with the placebo group by 14.3% and 22.4%, respectively (both p<0.0001).

Cathepsin K inhibitors

The resorptive phase of remodeling by osteoclasts of a basic multicellular unit (BMU) is about 3 weeks in duration. The formation phase that follows lasts about 3 months during which osteoblasts of that BMU lay down new osteoid which then undergoes rapid primary primary mineralization. Secondary mineralization, the enlargement of calcium hydroxyapatite crystals proceeds to completion during the next two to three years. Between these two phases is the reversal phase, a phase where there are no osteoclasts or osteoblasts (7).

There is not much understood about this phase because it has not been thought about or studied comprehensively, but Jensen et al have taken the initiative and report that, compared with ALN, odanacatib (ODN) resulted in a shorter reversal phase with more rapid initiation of osteoid deposition on the eroded surfaces and higher osteoblast recruitment as a higher density of mature bone forming osteoblasts and an increased subpopulation of cuboidal osteoblasts (8). These authors suggest that an increase in the interface between osteoclasts and osteoblast lineage cells may favor the osteoclast-osteoblast interactions for bone formation.

I suspect that this initiative arises from the finding that after initiation of ODN, resorption markers decrease reflecting suppression of bone remodeling upon the trabecular and intracortical surfaces but not on the endocortical surface, at least as assessed in subhuman primates (9). Socalled bone ‘formation’ markers appear to be suppressed less and tend, with time, to return to baseline while resorption markers continue to be suppressed.

The interpretation of these two observations is difficult. The continued suppression of resorption markers may reflect both continued remodeling – similar numbers of BMUs formed upon the endocortical surface and fewer upon the intracortical and trabecular surfaces excavate smaller resorption pits than were excavated before ODN treatment account for the persisting lower resorption markers (by about 50% of baseline). How about the return to baseline of formation markers? The inference is made that signals from the resorbed matrix or from osteoclasts (that don’t resorb but still have other viable functions) continue and allow bone formation to continue. There is no evidence, that I am aware of, that the volume of bone deposited in the smaller pits increases – mean wall thickness has not been convincingly demonstrated except perhaps upon the periosteal surface but not upon the endosteal surfaces. So, from this, the formation markers should also remain suppressed, but they don’t seem to be. I don’t understand this.

It remains possible, that if the volume of bone deposited upon the more shallow pits is either the same as before treatment, then the net bone balance produced during each remodeling transaction should be lessened, or ideally made positive. In the latter situation, it becomes an advantage to keep remodeling rate high as each remodeling event will produce a net positive bone balance and so restore bone structure. A positive BMU balance could still result if the same volume of bone was deposited in a smaller resorption pit.

There is another mechanism that may account for continued bone formation. Pennypacker et al characterized the effects of ODN on the dynamics of cortical modeling of the central femur in adult OVX rhesus monkeys (10). Animals were treated with vehicle or ODN (6 or 30 mg/kg, qd, po) for 21 months. ODN increased periosteal and endocortical bone formation (BFR/BS), increased in endocortical mineralizing surface (102%, p<0.01) with the 6m g/kg dose. Both doses reduced remodeling hemiosteon numbers by 51% and 66% (p<0.05), respectively, and ODN 30 mg/kg numerically reduced activation frequency without affecting wall thickness. On the same endocortical surface, ODN increased modeling-based parameters, while reducing intracortical remodeling. ODN 30 mg/kg increased cortical thickness (CtTh, p<0.001), reduced marrow area (p<0.01) and increased femoral structural strength (p<0.001). Peak load correlated with the increases in BMC (r2=0.91) and CtTh (r2=0.69, both p<0.0001). The authors infer that reduced cortical remodeling and stimulating modeling-based bone formation, ODN improved cortical dimension and strength in OVX monkeys.

Figure 4. ODN increased periosteal and endocortical bone formation in the central femur of OVX monkeys. Central femurs treated with: (a-c) Vehicle and (d-f) ODN 30 mg/kg. (a&d) Light microscopic images of central femoral cross sections at low magnification; Bar=500 µm. (b&e) Fluorescent images of periosteal surfaces (insets with broken lines in a&d) at higher magnification to show calcein (15-d, white arrows) labeling at month 12, and tetracycline (15-d, yellow arrows) labeling at month 21. (c&f) Images of endocortical surfaces (insets with solid lines in a&d), showing bone formation by CAL and TCY labels; Bar=200 µm. B, bone; BM, bone marrow. Reproduced from J Bone Miner Res 2014;doi:10.1002/jbmr.2211 with permission of the American Society of Bone and Mineral Research.

Figure 5. Effects of ODN on remodeling- and modeling-based hemiosteons in the endocortical surfaces of the central femur. (A) The endocortical sections were stained with toluidine B and viewed under fluorescent (a&c) or light microscopy (b&d): (a&b) remodeling hemiosteon and (c&d) modeling hemiosteon were detected by calcein (CAL) labeling (white arrows) between two cement lines (Cm, yellow arrows), and wall thickness (WTh, double white arrowheads). B, bone; BM, bone marrow; Bar=50 µm. (B) Endocortical remodeling-hemiosteons, (scalloped cement lines), were measured including (a) the number of remodeling hemiosteons, (b) wall thickness and (c) activation frequency. (C) The same parameters from endocortical modeling-based hemiosteons, evident by the smooth cement line, were measured from central femur treated with ODN 6 mg/kg and 30 mg/kg vs. Veh. *p<0.05 and **p<0.01 vs. OVX-Veh. Mean±SEM. Reproduced from J Bone Miner Res 2014;doi:10.1002/jbmr.2211 with permission of the American Society of Bone and Mineral Research.

Cheung et al conducted a randomized, double-blind, placebo-controlled trial in 214 postmenopausal women (mean age 64.0±6.8 years, and baseline lumbar spine T-score -1.81±0.83) and that oral ODN 50 mg given for two years increases total vBMD at the distal radius and tibia assessed using HR-pQCT (11). Treatment differences from placebo were also significant (3.84% and 2.63% for radius and tibia, respectively). At both sites, significant differences from placebo were also seen in trabecular vBMD, cortical vBMD, cortical thickness, cortical area and strength (failure load) estimated using finite element analysis of HR-pQCT scans (treatment differences at radius and tibia = 2.64% and 2.66%). At the distal radius, ODN improved trabecular thickness and BV/TV vs. placebo. At a more proximal radial site, treatment attenuated the increase in cortical porosity seen with placebo (treatment difference=-7.7%, p=0.066). At the distal tibia, ODN improved trabecular number, separation, and BV/TV vs. placebo.

Figure 6. Left panel: Total trabecular and cortical volumetric BMD at the distal radius. Right panel: Two-year percent changes in other HR-pQCT parameters at (A) radius, (B) tibia. The distal radius and tibia (to the left of the vertical line) were scanned for trabecular number, separation, thickness, bone volume/total volume (BV/TV) cortical area and porosity. The more proximal regions (to the right of the vertical line) were scanned for assessment of cortical porosity. LS, least squares. Reproduced from J Bone Miner Res 2014;doi:10.1002/jbmr.2194 with permission of the American Society of Bone and Mineral Research.

Nakamura et al report the efficacy and safety of ODN 10, 25, or 50 mg once weekly for 52 weeks in a double-blind, randomized, multicenter study in 286 Japanese patients with osteoporosis [94% female, mean age(SD) 68.2(7.1) years] (12). The least squares mean percent changes from baseline to week 52 in the groups receiving placebo, 10, 25 and 50 mg of ODN for spine BMD were 0.5, 4.1, 5.7, and 5.9% and for total hip BMD were -0.4, 1.3, 1.8, and 2.7 %, respectively. The changes in femoral neck and trochanter BMD were similar to those at the total hip. The effects of ODN on bone formation markers were less compared with the effects on bone resorption markers.

Figure 7. Percent change in BMD at the spine, total hip, femoral neck and trochanter. Reproduced from Osteoporos Int 2014;25:367-76 with permission from Springer.

 

 

 

 

Figure 8. Percent change in serum CTX, urine NTX/Cr, urine DPD/Cr, serum BSAP and serum P1NP. Reproduced from Osteoporos Int 2014;25:367-76 with permission from Springer.

 

 

 

 

 

Eastell et al randomized 197 postmenopausal women with osteoporosis or osteopenia with one fragility fracture to ONO-5334 50 mg twice daily, 100 mg or 300 mg once daily, ALN 70 mg once weekly or placebo (13). After 24 months, all ONO-5334 doses increased BMD at the spine, total hip, and femoral neck (p<0.001). ONO-5334 300 mg suppressed urinary (u) NTX and serum and uCTX-I throughout 24 months and to a similar extent as ALN; other resorption marker levels remained similar to placebo (fDPD for ONO-5334 300 mg qd) or increased (ICTP, TRAP5b, all ONO-5334 doses). Levels of B-ALP and PINP were suppressed in all groups (including placebo) for 6 months but then increased for ONO-5334 to near baseline by 12-24 months. On treatment cessation, there were increases above baseline in uCTX-I, uNTX, and TRAP5b, and decreases in ICTP and fDPD.

Engelke et al investigated the effect of 2 years of ONO-5334 in a randomized, double-blind, placebo, and active controlled parallel group study of 147 subjects (age 55-75 years) (14). Subjects were randomized to placebo; 50 mg bd (BID); 100 mg/d (qd); ONO-5334 300 mg qd; or ALN 70 mg once weekly (qw). After 24 months, ONO-5334 produced increases vs. placebo for integral, trabecular, and cortical BMD at the spine and hip measured using QCT (for ONO-5334 300 mg QD, BMD increases were 10.5%, 7.1%, and 13.4% for integral, cortical, and trabecular BMD at the spine, respectively, and 6.2%, 3.4%, and 14.6% for integral, cortical, and trabecular total femur BMD, respectively). Changes in cortical and trabecular BMD in the spine and hip were similar for ALN and ONO-5334. There was no evidence of periosteal apposition. Cortical thickness did not change for ONO-5334 in the spine or hip, with exception of a 2.1% increase after month 24 in the intertrochanter for 300 mg qd.


Bisphosphonates

Risedronate

Bala et al recruited 161 younger (Group 1, ≤55 years) and 163 older (Group 2, ≥55 years) women randomized to risedronate 35 mg/week or placebo (15). In the younger group, distal radius compact-appearing cortex porosity increased by 4.2% ± 1.6% in controls (p=0.01). This increase was prevented by risedronate. Trabecular vBMD decreased by 3.6% ± 1.4% (p=0.02) in controls and decreased by about half that, 1.6% ± 0.6% (p=0.005) with risedronate. In the older group, changes did not achieve significance apart from a reduction in compact-appearing cortex porosity in the risedronate treated group (0.9% ± 0.4%, p=0.047). Risedronate slows microstructural deterioration in younger and partly reverses it in older postmenopausal women.

The work illustrates that the effect of therapy in part depends on the pattern of remodeling. In early menopause, accelerated bone loss is due to perturbed remodeling at the surface level where many resorption cavities are excavated and this accelerated loss is slowed but not stopped with therapy. Later, when remodeling has returned to steady state at a high remodeling rate, the drug can reduce porosity, not only just lessen its continued increase.

Figure 9. In early menopause, women given placebo (yellow) had increased porosity of the compact cortex (CC) and outer transitional zone (OTZ) and a decrease in trabecular vBMD. In later menopause women also had increased porosity but no detectable fall in trabecular vBMD. Risedronate (green) reduced the rise in porosity and fall in trabecular vBMD during early menopause and reduced porosity in later menopausal women and increased trabecular vBMD. Adapted from J Bone Miner Res 2014;29:380-8 with permission of the American Society of Bone and Mineral Research.

Zoledronic acid

Grey et al report that 180 postmenopausal women with osteopenia were randomized double-blind in a 2 year placebo-controlled trial to a single dose of intravenous zoledronic acid (1, 2.5 or 5 mg), or placebo (16). The change in spine BMD was greater in the zoledronate groups than placebo; mean (95% CI) difference vs. placebo: 1 mg 4.4%; 2.5 mg 5.5%; 5 mg 5.3% (all p<0.001). Change in total hip BMD was greater in each group than the placebo 1 mg 2.6%; 2.5 mg 4.4%; 5 mg 4.7% (all p<0.001). β-CTX and P1NP were lower in the 2.5 mg and 5 mg groups than the placebo (all p<0.001). Changes were similar in the 2.5 mg and 5 mg groups, changes in the 1 mg group were smaller than in the other zoledronate groups. The study makes the important point that this potent agent is likely to be effective at lower doses. There is evidence that a single dose may be as effective in reducing fracture rates as annual administration.

Figure 10. Left panels: BMD at the spine, total hip and total body during 2 years were highter in each dose than placebo throughout the study. Right panels: CTX and P1NP during 2 years were lower using 2.5 and 5 mg zoledronic acid than placeo. The levels using 1 mg were lower up to 18 months. Reproduced from J Bone Miner Res 2014;29:166-72 with permission of the American Society of Bone and Mineral Research.

 

 

Ibandronate

Miller et al conducted a post hoc analysis using individual patient data from the 2-year monthly oral ibandronate in ladies (MOBILE, 150 mg, n=176)), the dosing intravenous administration (DIVA) studies, and the 3-year long-term extensions (LTEs, iv ibandronate every 2 months 2 mg, n=253, or quarterly 3 mg, n=263) to assess fracture risk during 5 years (17). Three-year placebo data (n=1924) were obtained from the ibandronate osteoporosis vertebral fracture trial in North America and Europe (BONE) and iv Fracture Prevention trials. Ibandronate regimens with annual cumulative exposure ≥10.8 mg were associated with a longer time to fracture for all clinical fractures, nonvertebral fractures, and clinical vertebral fractures vs. placebo (P=0.005). For all fracture types, the rate of fracture appeared stable during the 5-year treatment period. Credibility of post hoc analyses like this is difficult to evaluate.

Meier et al report that observational studies suggest beneficial effects of bisphosphonates in osteonecrosis (ON) of the knee (18). In this randomized, double-blind, placebo-controlled trial, 30 patients (mean age, 57.3±10.7 years) with ON of the knee were assigned to ibandronate (cumulative dose, 13.5 mg) or placebo intravenously (divided into five doses 12 weeks). Patients were followed for 48 weeks. After 12 weeks, mean pain score was reduced in ibandronate-treated (mean change, -2.98; 95% CI, -4.34 to -1.62) and placebo-treated (-3.59; 95% CI, -5.07 to -2.12) subjects. Except for significant decrease in bone resorption marker (CTX) in ibandronate-treated subjects (p<0.01), adjusted mean changes in all functional and radiological outcome measures were comparable between treatment groups after 24 and 48 weeks. IV ibandronate has no beneficial effect over and above anti-inflammatory medication.


Anabolic Agents

Parathyroid hormone peptides

Fujita et al report the results of a randomized, double-blind trial of 28.2 µg teriparatide vs. placebo (1.4 µg teriparatide) in 316 subjects (19). Incident vertebral fractures occurred in 3.3% of the teriparatide group and 12.6% of the placebo group during 78 weeks. Kaplan-Meier estimates of risk after 78 weeks were 7.5% and 22.2% in the teriparatide and placebo groups, respectively, with a relative risk reduction of 66.4% (P=0.008). Lumbar BMD in the teriparatide group increased by 4.4±4.7 %, higher than in the placebo (P=0.001).

Ito et al administered weekly teriparatide [human PTH (1-34)] to 29 postmenopausal women with osteoporosis (74.2±5.1 years) and placebo (n=37, 74.8±5.3 years) (20). CT data were obtained at baseline, 48 and 72 weeks. Once weekly teriparatide increased cortical thickness/cross-sectional area and total area, and improved biomechanical properties at the femoral neck and shaft, not cortical perimeter.

Figure 11. Percent changes in cortical thickness (a), cross-sectional area (CSA) (b), total CSA (c), and cortical perimeter (d) at 48 and 72 weeks. Changes at the femoral neck (FN), intertrochanter (IT), and femoral shaft (FS) are shown. Values on top of each panel indicate p values (between teriparatide and placebo group). Red and blue bars correspond to teriparatide and placebo groups, respectively. Reproduced from Osteoporos Int 2014;25:1163-72 with permission from Springer.

Figure 12. Upper panels: Percent changes in cortical vBMD (a) and total vBMD (b) at 48 and 72 weeks. Changes at the femoral neck (FN), intertrochanter (IT), and femoral shaft (FS) are shown. Red and blue bars correspond to teriparatide and placebo groups, respectively. Lower panels. Percent changes in SM (a) and BR (b) at 48 and 72 weeks. Changes at the FN, IT and FS are shown. Reproduced from Osteoporos Int 2014;25:1163-72 with permission from Springer.

Antisclerostin antibody

Ross et al report up to 54% increases in the bone volume following Scl-Ab without change in mean global matrix mineralization of trabecular or cortical bone (21). However, there was an increase in the number of pixels with a low mineralization and a decrease in the standard deviation of the distribution. Scl-Ab did not affect the mineral-to-matrix ratio, crystallinity or collagen crosslinking in the endocortical, intracortical, or trabecular compartments. There was a trend toward accelerated mineralization intracortically and a nearly 10% increase in carbonate substitution for tissue older than 2 weeks in the trabecular compartment.

Figure 13. Representative bSEM images of (a) cortical and (d) trabecular bone from primates treated for 10 weeks with either saline (controls) or Scl-Ab (scale bar=200 μm). Newly remodeled or relatively young tissue is highlighted with arrow heads. Representative normalized BMDDs of (b) cortical and (e) trabecular bone. Representative nonnormalized BMDDs of (c) cortical and (f) trabecular bone. Reproduced from J Bone Miner Res 2014;doi:10.1002/jbmr.2188 with permission of the American Society of Bone and Mineral Research.

 

 

 

McColm et al report two clinical studies conducted to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple doses (iv and sc) of blosozumab in postmenopausal women (22). Subjects received escalating doses of blosozumab: single iv doses up to 750 mg, single sc doses of 150 mg, multiple iv doses up to 750 mg every 2 weeks (Q2W) for 8 weeks, multiple sc doses up to 270 mg Q2W for 8 weeks, or placebo. Six subjects were randomized to each dose in the single-dose study (12 to placebo) and up to 12 subjects to each arm in the multiple-dose study. Blosozumab was well tolerated. There was up to a 3.41% (p=0.002) and up to a 7.71% (p<0.001) change from baseline in lumbar spine BMD at day 85 after single or multiple administrations of blosozumab, respectively. Prior BP did not have an impact on the effects of single doses of blosozumab. Antibodies to blosozumab were detected with no effect on PD responses were identified.


PTH and Alendronate
Two is better than one

Altman et al treated 30 female rats with vehicle (Veh), ALN, PTH, or both (23). Individual trabecula segmentation (ITS)-based analyses using in vivo microcomputed tomography showed an increase in BV/TV with all treatments and the highest in the combined group. Tb.Th increased with PTH and PTH+ALN beyond that of the Veh or ALN. SMI decreased in all treatments with PTH+ALN having the greatest tendency toward platelike structures. Increased plate Tb.N and increased plate-to-rod ratio was most pronounced in the PTH+ALN group. Stiffness increased in all treatment groups with the largest increase in the PTH+ALN group. PTH+ALN increased bone formation and suppressed resorption. PTH+ALN has an additive effect on trabecular bone.

Figure 14. Changes in BV/TV, trabecular thickness, structural model index (SMI) and trabecular stiffness in each group. Reproduced from Bone, 61:149-57, Copyright (2014), with permission from Elsevier.

 

 

 

 

 

 

 

Figure 15. (A) Calcein labelling in trabecular bone in each group, (B) serum TRAP, Osteoclast number and surface, mineralizing surface, MAR and BFR. Reproduced from Bone, 61:149-57, Copyright (2014), with permission from Elsevier.

 

 

 

Ma et al analyzed the effects of 24 months teriparatide in 29 ALN-pretreated and 16 treatment niave (TN) women (24). At baseline, reduced remodeling was evident the ALN group. Following teriparatide, forming and resorbing osteons increased. Teriparatide increased MAR in the endocortical, and MS/BS% in the periosteal compartment in the ALN-pretreated group. Most indices of bone formation remained lower in the ALN-pretreated group. Endocortical wall width was increased in both groups. Cortical porosity and cortical thickness increased in the ALN-pretreated group after teriparatide. 24 months of teriparatide increases cortical bone formation and cortical turnover in patients either TN or had previous ALN therapy.

Figure 16. Cortical changes in MS/BS, BFR and MAR upon the endocortical, periosteal and intracortical surface after 24 months in mineralizing surface. Reproduced from Bone, 59:139-47, Copyright (2014), with permission from Elsevier.

 

 

 


Remodeling Independent Mechanisms
Strontium ranelate

 

Chavassieux et al report a multicenter, international, double-blind, controlled study of 387 postmenopausal women with osteoporosis having transiliac bone biopsies at baseline and after 6 or 12 months of strontium ranelate (SrRan) 2 g/day (n=256) or alendronate 70 mg/week (n=131) (25). No deleterious effect on mineralization of SrRan or ALN was observed. In the intention-to-treat (ITT) population (268 patients with paired biopsy specimens), greater changes in static and dynamic bone formation parameters were observed with ALN than SrRan. Static parameters of formation were maintained between baseline and the last value with SrRan reflecting continued remodeling upon the endosteal surface, except for osteoblast surfaces, which decreased at M6. Decreases (not increases) in the dynamic parameters of formation (mineralizing surface, bone formation rate, adjusted apposition rate, activation frequency) were noted at M6 and M12 in SrRan. Compared with ALN, the bone formation parameters at M6 and M12 were higher (p<0.001) with SrRan. ALN, not SrRan, decreased resorption parameters. Compared with the baseline, wall thickness was decreased at M6 but not at M12 and cancellous bone structure parameters (trabecular bone volume, trabecular thickness, trabecular number, number of nodes/tissue volume) were decreased at M12 with SrRan; none of these changes were different from ALN.

This study provides compelling evidence that SrRan is not an anabolic agent and indeed, it does not really have substantive effects on bone remodeling. Bone formation surfaces remains higher than alendronate precisely because remodeling is not suppressed – the statement does not mean bone formation is higher – this refers to the surface extent of bone formation; there is no evidence that the volume of bone deposited by each BMU is increased. There is less diminution of the bone remodeling with SrRan vs. ALN because SrRan does not suppress surface level remodeling, alendronate does because it is a classic antiresorptive agent.

Abrahamsen et al report that the European Medicines Agency (EMA) recently warned that SrRan should be avoided in patients with ischaemic heart disease (IHD), peripheral vascular disease (PVD) or cerebrovascular disease (CVD), and in patients with uncontrolled hypertension (26). Using the Danish National Prescription Database, 3252 patients aged 50+ who began SrRan and 35,606 users of other osteoporosis drugs (controls) were studied. Patients starting SrRan were older and more likely to suffer from IHD, PVD or CVD. The adjusted risk of MI: HR 1.05 (0.79-1.41, p=0.73) in women and 1.28 (0.74-2.20, p=0.38) in men. For stroke, the adjusted HR was 1.23 (0.98-1.55, p=0.07) in women and 1.64 (0.99-2.70, p=0.05) in men. All-cause mortality was higher (women: adjusted HR 1.20 [1.10-1.30, p<0.001]; men: adjusted HR 1.22 [1.03-1.45, p<0.05]). A large proportion of patients currently treated with strontium ranelate have conditions that would now be considered contraindications according to EMA.

Cooper et al report that of 112,445 women with treated postmenopausal osteoporosis, 6487 received SrRan (27). Annual incidence rates for first myocardial infarction (1352 cases), myocardial infarction with hospitalisation (1465 cases), and cardiovascular death (3619 cases) were 3.24, 6.13 and 14.66 per 1000 patient-years, respectively. Current or past use of SrRan was not associated with increased risk for first myocardial infarction (OR 1.05, 0.68-1.61 and OR 1.12, 0.79-1.58, respectively), hospitalization with myocardial infarction (OR 0.84, 0.54-1.30 and OR 1.17, 0.83-1.66), or cardiovascular death (OR 0.96, 0.76-1.21 and OR 1.16, 0.94-1.43) vs. patients who had never used SrRan.


References

1. Samuel J, Sinha D, Zhao JC, Wang X. Water residing in small ultrastructural spaces plays a critical role in the mechanical behavior of bone. Bone 2014;59:199.

2. Gallant MA, Brown DM, Hammond M, et al. Bone cell-independent benefits of raloxifene on the skeleton: A novel mechanism for improving bone material properties. Bone 2014;61:191.

3. Zebaze RM, Libanati C, Austin M, et al. Differing effects of denosumab and alendronate on cortical and trabecular bone. Bone 2014;59:173.

4. Smith SY, Recker RR, Hannan M, Muller R, Baussd F. Intermittent intravenous administration of the bisphosphonate ibandronate prevents bone loss and maintains bone strength and quality in ovariectomized cynomolgus monkeys. Bone 2003; 2:45.

5. Nakamura T, Matsumoto T, Sugimoto T, et al. Fracture risk reduction with denosumab in Japanese postmenopausal women and men with osteoporosis: Denosumab fracture Intervention RandomizEd placebo Controlled Trial (DIRECT). J Clin Endocrinol Metab 2014;doi: http://dx.doi.org/10.1210/jc.2013-4175.

6. Keaveny TM, McClung MR, Genant HK, et al. Femoral and vertebral strength improvements in postmenopausal women with osteoporosis treated with denosumab. J Bone Miner Res 2014;29:158.

7. Baron R. Importance of the intermediate phases between resorption and formation in the measurement and understanding of the bone remodeling sequence. In: Meunier PJ. Bone histomorphometry: proceedings of the second international workshop. Société de la Nouvelle Imprimerie Fournié, Toulouse 1977, 179-183.

8. Jensen PR, Andersen TL, Pennypacker BL, Duong le T, Delaisse JM. The bone resorption inhibitors odanacatib and alendronate affect post-osteoclastic events differently in ovariectomized rabbits. Calcif Tissue Int 2014;94:212.

9. Duong L, T. Therapeutic inhibition of cathepsin K-reducing bone resorption while maintaining bone formation. Bonekey Rep, 2012;1:1:67. doi: 10.1038/bonekey.2012.67.

10. Pennypacker BL, Chen CM, Zheng H, et al. Inhibition of cathepsin K increases modeling-based bone formation, and Improves cortical dimension and strength in adult ovariectomized monkeys. J Bone Miner Res 2014;doi:10.1002/jbmr.2211.

11. Cheung A, Majumdar S, Brixen K, et al. Effects of odanacatib on the radius and tibia of postmenopausal women: Improvements in bone geometry, microarchitecture and estimated bone strength. J Bone Miner Res 2014;doi:10.1002/jbmr.2194.

12. Nakamura T, Shiraki M, Fukunaga M, et al. Effect of the cathepsin K inhibitor odanacatib administered once weekly on bone mineral density in Japanese patients with osteoporosis-a double-blind, randomized, dose-finding study. Osteoporos Int 2014;25:367.

13. Eastell R, Nagase S, Small M, et al. Effect of ONO-5334 on bone mineral density and biochemical markers of bone turnover in postmenopausal osteoporosis: 2-year results from the OCEAN Study. J Bone Miner Res 2014;29:458.

14. Engelke K, Nagase S, Fuerst T, et al. The effect of the cathepsin K inhibitor ONO-5334 on trabecular and cortical bone in postmenopausal osteoporosis: The OCEAN Study. J Bone Miner Res 2014;29:629.

15. Bala Y, Chapurlat R, Cheung AM, et al. Risedronate slows or partly reverses cortical and trabecular microarchitectural deterioration in postmenopausal women. J Bone Miner Res 2014;29:380.

16. Grey A, Bolland M, Mihov B, et al. Duration of antiresorptive effects of low-dose zoledronate in osteopenic postmenopausal women: a randomized, placebo-controlled trial. J Bone Miner Res 2014;29:166.

17. Miller PD, Recker RR, Harris S, et al. Long-term fracture rates seen with continued ibandronate treatment: Pooled analysis of DIVA and MOBILE long-term extension studies. Osteoporos Int 2014;25:349.

18. Meier C, Kraenzlin C, Friederich NF, et al. Effect of ibandronate on spontaneous osteonecrosis of the knee: a randomized, double-blind, placebo-controlled trial. Osteoporos Int 2014;25:359.

19. Fujita T, Fukunaga M, Itabashi A, Tsutani K, Nakamura T. Once-weekly injection of low-dose teriparatide (28.2 µg) reduced the risk of vertebral fracture in patients with primary osteoporosis. Calcif Tissue Int 2014;94:170.

20. Ito M, Oishi R, Fukunaga M, et al. The effects of once-weekly teriparatide on hip structure and biomechanical properties assessed by CT. Osteoporos Int 2014;25:1163.

21. Ross RD, Edwards LH, Acerbo AS, et al. Bone matrix quality following sclerostin antibody treatment. J Bone Miner Res 2014;doi:10.1002/jbmr.2188.

22. McColm J, Hu L, Womack T, Tang CC, Chiang AY. Single- and multiple-dose randomized studies of blosozumab, a monoclonal antibody against sclerostin, in healthy postmenopausal women. J Bone Miner Res 2014;29:935.

23. Altman AR, Tseng WJ, de Bakker CM, et al. A closer look at the immediate trabecula response to combined parathyroid hormone and alendronate treatment. Bone 2014;61:149.

24. Ma YL, Zeng QQ, Chiang AY, et al. Effects of teriparatide on cortical histomorphometric variables in postmenopausal women with or without prior alendronate treatment. Bone 2014;59:139.

25. Chavassieux P, Meunier PJ, Roux JP, et al. Bone histomorphometry of transiliac paired bone biopsies after 6 or 12 months of treatment with oral strontium ranelate in 387 osteoporotic women: Randomized comparison to alendronate. J Bone Miner Res 2014;29:618.

26. Abrahamsen B, Grove EL, Vestergaard P. Nationwide registry-based analysis of cardiovascular risk factors and adverse outcomes in patients treated with strontium ranelate. Osteoporos Int 2014;25:757.

27. Cooper C, Fox KM, Borer JS. Ischaemic cardiac events and use of strontium ranelate in postmenopausal osteoporosis: a nested case-control study in the CPRD. Osteoporos Int 2014;25:737.


Reviews

The fragile elderly hip: Mechanisms associated with age-related loss of strength and toughness
Reeve J, Loveridge N
Bone 2014;61:138

Osteocytes: Master orchestrators of bone
Schaffler MB, Cheung WY, Majeska R, Kennedy O
Calcif Tissue Int 2014;94:5

Osteocyte-driven bone remodeling
Bellido T
Calcif Tissue Int 2014;94:25

Talking among ourselves: Paracrine control of bone formation within the osteoblast lineage
Tonna S, Sims NA
Calcif Tissue Int 2014;94:35

Cadherin-mediated cell-cell adhesion and signaling in the skeleton
Marie PJ, Hay E, Modrowski D, Revollo L, Mbalaviele G, Civitelli R
Calcif Tissue Int 2014;94:46

Molecular mechanisms of osteoblast/osteocyte regulation by connexin43
Stains JP, Watkins MP, Grimston SK, Hebert C, Civitelli R
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Adipocytes and the regulation of bone remodeling: A balancing act
Nuttall ME, Shah F, Singh V, Thomas-Porch C, Frazier T, Gimble JM
Calcif Tissue Int 2014;94:78

Osteoclast-derived coupling factors in bone remodeling
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Calcif Tissue Int 2014;94:88

Cells of the immune system orchestrate changes in bone cell function
Wythe SE, Nicolaidou V, Horwood NJ
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Cellular complexity of the bone marrow hematopoietic stem cell niche
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Control of bone remodeling by the peripheral sympathetic nervous system
Elefteriou F, Campbell P, Ma Y
Calcif Tissue Int 2014;94:140

Bone cell senescence: Mechanisms and perspectives
Marie PJ
J Bone Miner Res 2014;doi:10.1002/jbmr.2190

Biomechanical mechanisms: Resolving the apparent conundrum of why individuals with type II diabetes show increased fracture incidence despite having normal BMD
Jepsen KJ, Schlecht SH
J Bone Miner Res 2014;29:784