Overview, Vol 13, 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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Subtrochanteric Fractures

Most persons at risk for fracture are not treated, even when they have a prevalent fracture. Indeed, fewer women and men are being treated despite efforts to establish capture the fracture programs. One reason may be concern about the occurrence of atypical subtrochanteric fractures. The risk of subtrochanteric fractures needs to be kept in perspective because stopping treatment to avert rare events may result in more fractures. Stopping treatment results in an increase in the intensity of remodelling to its pretreatment state eventually. As each remodelling event removes more bone than it deposits, structural decay will recur increasing fracture risk.

Dell et al identified all femur fractures from January 1, 2007 until December 31, 2011 in 1,835,116 patients older than 45 enrolled in the Healthy Bones Program at Kaiser Southern California. Among these, 188,814 patients used bisphosphonates. Of 142 patients with atypical fractures 128 had bisphosphonate exposure. The age-adjusted incidence per 100,000 persons per year for atypical fracture with exposure from 0.1-1.9 years was 1.78, and 113.1 with exposure from 8-9.9 years (~1/1000 patients). (1)

Figure 1. Left panel: Incidence of atypical femoral fractures age adjusted (darker bar) and unadjusted by duration of bisphosphonate exposure (±95% CI). Right panel: Age at fracture versus duration of bisphosphonate exposure. Reproduced from J Bone Miner Res 2012;27:2544-50 with permission of the American Society of Bone and Mineral Research.

Patients with subtrochanteric fractures are reported to have thicker cortices. While tenting is seen in the vicinity of the cortical fracture, there is no basis for the cortices to be thicker; bisphosphonates do not increase endocortical or periosteal apposition. Bisphosphonates reduce remodelling intensity so that bone matrix that would have been resorbed undergoes more complete secondary mineralization which produces greater photon attenuation. Bone edges are more readily detected by including edge voxels that now attenuate photons above the level designated by the thresholding as being a ‘bone’. This results is an apparent thicker cortex. Similar problems arise measuring trabecular density. Claims that bisphosphonates or strontium ranelate increase trabecular number have no basis. Existing trabeculae that are more fully mineralized or contain strontium, which has twice the atomic number of calcium, attenuate photons making it seem like trabecular number or thickness has increased.

Koeppen et al report that in 59 women with an atypical fracture, femoral cortical thickness index (thickness/femoral diameter) was not increased compared with the 218 patients with ordinary fractures. There was no difference in cortical thickness between patients with or without bisphosphonate treatment or between the ipsilateral and contralateral femurs in patients with an atypical fracture. (2)

Figure 2. Cortical thickness as a function of age. There is no difference in cortical thickness in cases with atypical fracture relative to controls. Reproduced from Osteoporos Int 2012;23:2893-6 with permission from Springer.











 


Osteosarcoma and PTH Administration

Andrews et al  report that at the 7th year of the 15-year Osteosarcoma Surveillance Study, 1448 cases were identified; 549 patients or proxies were interviewed. Age of those interviewed was 61 years, 46% were female, 86% were white, and 77% were alive when the case was reported to the study investigators. There were no patients with osteosarcoma who received teriparatide. (3)


Zoledronic Acid and Vertebral Fracture Risk Reduction
in Men

There are very few randomized placebo controlled trials examining the antifracture efficacy of any drug in men. Most of the studies are small, brief in duration and so the credibility of the studies is not strong. This has changed. Boonen et al report that 1199 men aged 50-85 years with primary or hypogonadism-associated osteoporosis received an intravenous infusion of zoledronic acid (5 mg) or placebo at baseline and at 12 months. After 24 months the incidence of any new morphometric vertebral fracture was 1.6% compared with 4.9% in controls; a 67% risk reduction (RR 0.33; 95% CI 0.16-0.70). BMD was higher and bone turnover markers were lower in treated patients. Results were similar in men with low serum levels of total testosterone. The zoledronic acid and placebo groups did not differ with respect to the incidence of death (2.6% and 2.9%, respectively) or serious adverse events (25.3% and 25.2%). There was no detectable group differences in nonvertebral or hip fracture risk. (4)













Figures 3-4. Incidence of vertebral fractures at 12 and 24 months in men treated with zoledronic acid and controls. Changes in BMD and bone remodeling markers. From N Engl J Med, Steven Boonen, Jean-Yves Reginster, Jean-Marc Kaufman, et al., Fracture Risk and Zoledronic Acid Therapy in Men with Osteoporosis, Volume 367, Page 1714. Copyright © (2012) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.


Beta Blockage as a Protective Factor

Exposure to β-blockers (BBs) is associated with lower fracture rates. In 501,924 Korean patients (≥65 years, 65% female), the incidence of fractures per 1000 person-years in users (17.2 men, 30.5 women) was lower than in nonusers (29.3 and 48.2 per for men and women, respectively. Non-BB users had an increased risk (95% CI) of all fracture [aHR 1.56 (1.42-1.72) in men and 1.44 (1.36-1.51) in women] and hip fracture [aHR 2.17 (1.45-3.24) in men and 1.61 (1.31-1.98) in women] after adjustment. The risk of all fractures in users of α-blockers, calcium channel blockers, diuretics, and renin-angiotensin-aldosterone system blockers were higher compared to BB users (1.72, 1.77, 1.58, 1.29 in men; 2.11, 1.50, 1.46, 1.22 in women, respectively). Compared to non-BBs, β1 selective BBs showed a lower risk of fracture (39% for men and 33% for women) after adjustment. Nonselective BBs were not protective. (5)


The Osteocyte:
Conductor of remodeling symphony for two

Discussions of bone remodelling as a classical duet for osteoclasts and osteoblasts are no longer appropriate. This insight, reported by Frost in the middle of the last century is not wrong, but it is incomplete. The osteocyte is a third player, not as a third fiddle, but rather the conductor initiating the first movement of this orchestral concert. Osteocyte apoptosis initiates osteoclastic bone resorption following fatigue-induced microdamage in vivo. However, apoptotic osteocytes may not be the signal for damage repair.

Kennedy et al report that ulnae from female Sprague Dawley rats were loaded to a single fatigue level. Osteoclast expression of RANKL, OPG, VEGF genes associated with osteoclastogenesis and apoptosis were assessed. Osteocyte apoptotic (caspase 3-positive) cells were highest in the damage region and declined to control levels within several hundred microns of microdamage. Cells expressing RANKL or VEGF peaked between 100-300 μm from the damage site, then returned to control levels beyond this distance. Osteocytes in nonfatigued control bones expressed OPG. OPG staining was reduced in osteocytes immediately surrounding microdamage. (6)

Osteocyte apoptosis triggers remodeling response to microdamage, the neighbouring nonapoptotic osteocytes are the source of pro-osteoclastogenic signals. The apoptotic and osteoclast-signalling osteocyte populations are localized in a spatially and temporally restricted pattern consistent with the targeted nature of this remodelling response.

Figure 5. Gene expression of osteoclastogenic factors: RANKL, OPG, VEGF and M-CSF from osteocyte enriched segment of rat ulnar cortex at 3 and 7 days after fatigue loading (*p<0.001). Reproduced from Bone, 50:1115-22, Copyright (2012), with permission from Elsevier.

 

Figure 6. Left panel: Distance distribution showing expression of (A) Cas-3 and RANKL (B) Cas-3 and OPG (C) Cas-3 and VEGF in osteocytes as a function of distance from the damage region 3 days (left panels) and 7 days (right panels) after fatigue loading. (*p<0.01). Reproduced from Bone, 50:1115-22, Copyright (2012), with permission from Elsevier.





 


Vitamin D: A little surprise

Vitamin D has been in fashion for some time, it has a cult following, a bit like The Rocky Horror Show which plays at midnight and you better bring a raincoat. Excess blood as a cause of everything and bloodletting as a cure for everything were in the same league up to the mid-1970s. Leach farming was a big business and farmers did not declare a conflict of interest.

The first recent surprise was the randomized double blind trail from Sanders et al suggesting that large doses of vitamin D increase fracture risk. Now that can’t be correct surely, this doesn’t ‘fit’ with our preconceived ideas, it doesn’t make sense so it must be wrong (7). Recall Galileo’s words to his student, “be most worried when the data fits your hypothesis.”

Another little surprise is here. Rossini et al report that 37 elderly subjects (mean age 75 years) were randomized to a single oral bolus of 600,000, 300,000, or 100,000 IU vitamin D3. Twenty-four subjects served as controls. With 600,000 IU, a significant increase of sCTX was observed at day 1 and was sustained for 2 months. The changes in sCTX with smaller doses were less and reached significance only within the first 3 days with the 300,000 IU dose. BAP remained unchanged in patients given 300,000 and 600,000 IU. No relevant changes in markers were observed in controls. In patients given 100,000 IU sCTX rose by 15-23%. Vitamin D bolus exceeding 100,000 IU may be associated with acute increases of sCTX. (8) Is this the beginning of the end; probably not. Does more work need to be done? Of course.


PTH1-34 Reduces Vertebral and Nonvertebral Fractures
But what of hip fractures?

A 12-month, phase III, randomized, multicenter, double-blind, placebo-controlled trial with BMD as a primary endpoint was conducted in Japanese subjects. A meta-analysis was carried out in 3 studies in which fracture data were available from prospectively scheduled spinal radiographs. Odds ratios (95% CI) were 0.29 (0.20, 0.43) for vertebral fracture and 0.53 (0.32, 0.86) for nonvertebral fracture. There was also a consistent effect of teriparatide to increase BMD. Furthermore, teriparatide-mediated increases in spine BMD accounted for 25–32% of the reduction in vertebral fracture risk in the combined Caucasian and Japanese patients. (9)


The Burden of Nonvertebral Fractures

The incidence of hip, spine, major NHNV (pelvis/leg, shoulder/arm) and minor NHNV (wrist/hand, ankle/foot, rib/clavicle) fractures was assessed among women in GLOW. Health-related quality of life (HRQoL) was analysed using the EuroQol EQ-5D tool and the SF-36 health survey. Among 50,461 women, there were 1822 fractures (57% minor NHNV, 26% major NHNV, 10% spine, 7% hip) over one year. Spine fractures had the greatest detrimental effect on EQ-5D summary scores, followed by major NHNV and hip fractures. The number of women with mobility problems increased most for those with major NHNV and spine fractures (both +8%); spine fractures were associated with the largest increases in problems with selfcare (+11%), activities (+14%), and pain/discomfort (+12%). Decreases in physical function and health status were greatest for those with spine or hip fractures. EQ-5D reduction was greatest for spine fractures, followed by hip and major/minor NHNV. Statistically significant reductions in SF-36 physical function were found for spine fractures, and were borderline significant for major NHNV fractures. NHNV fractures have a detrimental effect on HRQoL. (10)

Figure 7. Left panel: 1-year incidence of fractures in GLOW by age group. Right panel: Distribution of incident fracture types. Major NHNV pelvis, upper leg, lower leg, shoulder, upper arm, knee, and elbow; minor NHNV wrist, hand, ankle, foot, rib, and clavicle. Reproduced from Osteoporos Int 2012;23:2863-71 with permission from Springer.


References

1. Dell RM, Adams AL, Greene DF, et al. Incidence of atypical nontraumatic diaphyseal fractures of the femur. J Bone Miner Res 2012;27:2544.

2. Koeppen VA, Schilcher J, Aspenberg P. Atypical fractures do not have a thicker cortex. Osteoporos Int 2012;23:2893.

3. Andrews EB, Gilsenan AW, Midkiff K, et al. The US postmarketing surveillance study of adult osteosarcoma and teriparatide: Study design and findings from the first 7 years. J Bone Miner Res 2012;27:2429.

4. Boonen S, Reginster JY, Kaufman JM, et al. Fracture risk and zoledronic acid therapy in men with osteoporosis. N Engl J Med 2012;367:1714.

5. Song HJ, Lee J, Kim YJ, et al. Beta 1 selectivity of beta-blockers and reduced risk of fractures in elderly hypertension patients. Bone 2012;51:1008.

6. Kennedy, OD, Herman BC, Laudier DM, et al. Activation of resorption in fatigue-loaded bone involves both apoptosis and active pro-osteoclastogenic signaling by distinct osteocyte populations. Bone 2012; 50:1115.

7. Sanders KM, Stuart AL, Williamson EJ, et al. Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA 2010;303:1815.

8. Rossini M, Adami S, Viapiana O, et al. Dose-dependent short-term effects of single high doses of oral vitamin D3 on bone turnover markers. Calcif Tissue Int 2012;91:365.

9. Nakamura T, Tsujimoto M, Hamaya E, Sowa H, Chen P. Consistency of fracture risk reduction in Japanese and Caucasian osteoporosis patients treated with teriparatide: A meta-analysis. J Bone Miner Metab 2012;30:321.

10. Roux C, Wyman A, Hooven FH, et al. Burden of non-hip, non-vertebral fractures on quality of life in postmenopausal women: The Global Longitudinal study of Osteoporosis in Women (GLOW). Osteoporos Int 2012;23:2863.


Reviews

Treatment failure in osteoporosis
Diez-Perez A, Adachi JD, Agnusdei D, Bilezikian JP, Compston JE, Cummings SR, Eastell R, Eriksen EF, Gonzalez-Macias J, Liberman UA, Wahl DA, Seeman E, Kanis JA, Cooper C.
Osteoporos Int 2012;23:2769

Safety of osteoanabolic therapy: A decade of experience
Capriani C, Irani D, Bilezikian JP
J Bone Miner Res 2012;27:2419

Sclerostin and Dickkopf-1 as therapeutic targets in bone diseases
Ke HZ, Richards WG, Li X, Ominsky MS
Endocr Rev 2012;33:747

TGF-β and BMP signaling in osteoblast differentiation and bone formation
Chen G, Deng C, Li YP
Int J Biol Sci 2012;8:272

The nanometre-scale physiology of bone: Steric modelling and scanning transmission electron microscopy of collagen-mineral structure
Alexander B, Daulton TL, Genin GM, Lipner J, Pasteris JD, Wopenka B 
 Thomopoulos S
J R Soc Interface 2012;9:1774