ECCEO 7 | PORTO | PORTUGAL | Daily news march 30th

HIGHLIGHTS OF THE MEETING

The Seventh ECCEO meeting, here in Porto, is the largest meeting in Europe in the field of osteoporosis and osteoarthritis, with about 4000 attendees seeking information on the epidemiology, pathogenesis, prevention, and treatment of osteoporosis and osteoarthritis. Over 500 abstracts were submitted addressing all these topics.

The meeting started on Wednesday March 28 with the well-organized Welcome Reception in the splendid Palacio da Bolsa. However, even after such a nice evening, the attendance was huge to assist, on Thursday, at the first plenary session of the ECCEO 7 meeting dealing with the epidemiology and the clinical management of osteoporosis.

The first session began with the plenary lecture of Professor Seeman, from Australia, reviewing the mechanisms of bone fragility that leads to fracture(1). He reminds us that normal bone is stiff, able to resist bending so loading can occur without cracking, yet flexible, able to absorb energy by deforming without cracking. Bon achieves these contradictory properties through its material composition and structural design. The cellular machinery of bone modeling and remodelling are responsible for the assembly of the material and structural determinants of bone strength during growth and the maintenance of its strength in accord with the loading circumstances during adulthood. After completion of longitudinal growth and the attainment of peak bone size and shape, abnormalities in the cellular machinery such altered rate of bone remodelling and an imbalance in the volumes of bone formed and resorbed in each remodelling unit produce loss of tissue stiffness, cortical thinning and porosity, trabecular thinning and loss of connectedness, features that predispose to fracture in a growing elderly population.

FRACTURES ARE ASSOCIATED WITH A HIGH MORTALITY RATE

These fractures are a major cause of pain and disability, and are associated with a high mortality rate, particularly in elderly people who have suffered hip fractures. Haentjens and Boonen, from Belgium, showed during the first plenary session of the meeting, that a white woman, when sustaining a hip fracture at age 70, has an excess mortality of 3%, 4%, 7%, and 13% at 1, 2, 5, and 10 years after injury, respectively(2). However, they also showed that excess mortality among postmenopausal women and ageing men having sustained a hip fracture depends largely on age. At any given age, however, the excess mortality after hip fracture is always higher among ageing men than among postmenopausal women. The authors concluded that the impact of a hip fracture on excess mortality continues for up to 10 years after injury, both among postmenopausal women and ageing men.

SPINE FRACTURES ARE ASSOCIATED WITH LOWER LONG TERM QUALITY OF LIFE LEVELS

There are few prospective studies investigating the consequences of fractures in terms of health outcomes. A large prospective Swedish study (KOFOR) assessing quality of life related to fractures of the hip, spine, wrist on the period 13-18 months after fracture was also presented yesterday, Thursday March 29, during the first plenary session(3). The authors showed that there are persistent quality of life losses associated with osteoporotic fractures. They also showed that spine fractures are associated with lower long-term quality of life levels than previously assumed, and the loss from a spine fracture is twice greater than of a hip fracture.

During the previous ECCEO meetings, it has been shown that falls and low bone mineral density are main determinants of low trauma fractures in the elderly. However, in contrast to women, few studies concern the relationship between falls and fracture risk in elderly men. Interestingly, a prospective 10-year study presented by Szulc and Delmas(4), from France, showed that men who sustained at least one fall during the year preceeding the recruitment had higher incidence of non-vertebral fractures compared to men who did not fall.

The authors concluded that prevalent falls are independent predictors of non-vertebral fractures in elderly men.

CLINICAL MANAGEMENT OF OSTEOPOROSIS

During the two plenary sessions of Thursday March 29, seven oral communications were related to the clinical management of osteoporosis. The first one relates to the prospective, controlled, randomized EUROFORS trial(5). This trial was designed to compare 3 sequential treatment regimens of teriparatide in postmenopausal women with established osteoporosis. The authors distinguished treatment-naïve women, adequate and inadequate responders to prior antiresorptive therapy. Inadequate response was defined as (a) >1 new clinical fragility fracture(s) after >12 months, (b) a T-score< 3 SD or (c) a bone mineral density decrease >3.5% after >24 months of previous antiresorptives, at either spine, hip, or femoral neck. The authors concluded that treatment with teriparatide for 24 months is associated with statistically significant increases of bone mineral density at all 3 measurement sites, regardless of prior antiresorptive treatment and the patient’s individual response to it.

Another study compared the onset of fracture reduction between risedronate and alendronate therapies( 6). The authors of this study conducted a retrospective cohort study based on claims for 2 large health care systems in the USA to assess the 6-month and 12-month incidence of nonvertebral fractures and hip fractures in 2 large cohorts of female patients (over 65 years) newly treated with risedronate and alendronate. The results showed that the risedronate cohort had a significantly lower incidence of nonvertebral fractures and of hip fractures than did the alendronate cohort after adjustment for potential confounders.

Felsenberg and collaborators presented yesterday the results of a post-hoc analysis in which structural geometry of the hip was determined for postmenopausal osteopenic or osteoporotic women treated with denosumab 60 mg 6-monthly, placebo, or open-label alendronate 70 mg once weekly for up to 24 months(7). They showed that, at 12 and 24 months, denosumab and alendronate improved bone mineral density and geometry compared with placebo at all measured sites. Moreover, Denosumab effects on bone geometry of the proximal shaft were significantly greater than with alendronate.

In 2000 the number of osteoporotic fractures was estimated at 3.79 million of which 0.89 million were hip fractures (179000 hip fractures in men and 711000 in women). The total direct costs were estimated at €31.7 billion (£21 billion) which were expected to increase to €76.7 billion (£51 billion) in 2050 based on the expected changes in the demography of Europe(8). However, the need for cost-effective treatment is of primary importance in health economics. The study of Lynch and colleagues is then of interest, showing that Ibandronate IV injection reduces fracture burden for women who are intolerant to oral bisphosphonates and is a costeffective strategy when compared to no treatment(9).

The ECCEO meeting looks also at the future of osteoporosis treatment by giving the opportunity to present results of phase I or II trials. For example, it has been shown that MK-0822, a potent cathepsin K inhibitor, results in suppression of bone resorption markers (urine NTx/Cr, serum CTx) when administered once-daily to postmenopausal women for 21 days, suggesting that the cathepsin K inhibitor MK-0822 may be developed as an effective therapeutic agent for osteoporosis(10).

INADEQUATE VITAMIN D LEVEL IS ASSOCIATED WITH SECONDARY HYPERPARATHYROIDISM, INCREASED BONE TURNOVER AND BONE LOSS

It has been previously shown, in the other ECCEO meetings, that inadequate vitamin D level is associated with secondary hyperparathyroidism, increased bone turnover and bone loss, which increase fracture risk. Moreover, vitamin D status has also been shown to be related to body sway (a measure of neuromuscular stability) and the probability of falling in the elderly. It is hypothesized that vitamin D supplementation could improve body sway and, as a consequence, could reduce the potency to fall. Lips and Colleagues have shown yesterday, in the second plenary session, that treatment with vitamin D3 8400 IU once weekly reduced body sway in subjects with elevated basal mediolateral sway, but did not affect sway in subjects with normal basal mediolateral sway(11). They also showed that baseline 25(OH)D status did not affect the effectiveness of vitamin D3 8400 IU once weekly on sway.

Results of the FREE trial were also presented in the plenary session by Boonen and Colleagues(12). The international, multicenter, randomized, controlled Fracture Reduction Evaluation (FREE) trial was initiated to compare effectiveness and safety of balloon kyphoplasty to non-surgical management for the treatment of acute painful vertebral compression fracture. Balloon kyphoplasty is a minimally invasive surgical option for the treatment of osteoporotic and cancer-related vertebral compression fracture. The authors showed that compared to non-surgical management, balloon kyphoplasty demonstrated superior shortterm pain, function and quality of life outcomes with no difference in serious adverse events for the treatment of acute, painful vertebral compression fractures. However, no long-term data are currently available.

ADVERSE EVENTS DUE TO PHARMACOLOGICAL TREATMENT

Adverse events due to pharmacological treatment have also been covered during the first day of the ECCEO meeting. For example, it has been previously suggested in animal studies that bisphosphonates could increase microdamage frequency, owing to excessively suppressed bone turnover, but there are few data in humans. Chapurlat and Colleagues, from France, measured histomorphometric parameters and microcrack frequency on iliac crest bone biopsies in 50 postmenopausal osteoporotic women who had received bisphosphonates therapy (IV pamidronate, oral alendronate and oral risedronate) for at least 4 years, and compared those variables to those found in bone biopsies performed in 12 cadavers (13). They conclude that among postmenopausal osteoporotic women on long-term bisphosphonates, microcrack frequency in the iliac bone is low, and interestingly, there was no association between microcrack frequency and the duration of bisphosphonates therapy.

Another potential serious adverse effect of biphosponates is the osteonecrosis of the jaw. A German initiative, with the objective to produce an exhaustive register to explore the development of osteonecrosis of the jaw as a serious adverse event of bisphosphonate treatment, has been presented in the second plenary session(14). Focus of the register was placed on the patient’s primary disease, dental status, co-medication, bisphosphonate single and cumulative dosage, and the diagnosis and treatment of osteonecrosis of the jaw. So far, 352 cases were registered.
Analyses of the data confirm that osteonecrosis of the jaw under bisphosphonate therapy is a serious adverse event that almost exclusively affects patients with malignant disease and pathological dental status. The authors also pointed that osteonecrosis of the jaw presents a variety of clinical, histological and radiological findings.

The first day of the ECCEO meeting has then been a great success due to the high scientific quality of the researches presented either in oral or in poster communication.

REFERENCES

1. Why do bones break? A reappraisal of mechanisms of bone fragility. E. Seeman
2. Excess mortality after hip fracture among postmenopausal women and ageing men: evidence from data searches and lifetable analyses for gender related differences in absolute risk of death after hip fracture. P. Haentjens, S. Boonen
3. Long term quality of life related to osteoporotic fractures. 13–18 months after fracture. O. Ström, F. Borgström, N. Zethraeus, O. Johnell, B. Jönsson
4. Prevalent falls predict incident non-vertebral fractures in elderly men – prospective minos study. P. Szulc, P.D. Delmas
5. Bone mineral density response to 2 years of coninuous treatment with teriparatide: final results from the EUROFORS study. P. Hadji, T. Nickelsen, F.
Marin, J. Farrerons, E.V. McCloskey, M. Audran, S. Boonen, A. Anastasilakis, C. Barker
6. Risedronate and alendronate for the reduction of nonvertebral fractures, a retrospective cohort study. P.D. Delmas, S. L. Silverman, N.B. Watts, J.L. Lange, R. Lindsay
7. Hip structural analysis of the proximal femur in postmenopausal women with low bone mass treated with denosumab. D. Felsenberg, P.D. Miller, EM. Lewiecki, C. Libanati, Y. Liu, T.J. Beck
8. Internet: www.iofbonehealth.org/
9. Cost-effectiveness of ibandronate injection IV in the treatment of UK women with postmenopausal osteoporosis who are intolerant to oral bisphosphonates. N.O. Lynch, S.R. Earnshaw, C.N. Graham, H. Middelhoven
10. Effect of cathepsin K inhibition on bone resorption markers in healthy postmenopausal women. S.A. Stoch, D.L. Miller, K. Van Dyck, B. Jin, D. Panebianco, Q. Liu, J. Stone, K.M. Gottesdiener, L.E. Wehren, J.A. Wagner
11. Treatment effects of vitamin D3 8400 IU once weekly on body sway of elderly subjects with vitamin D insufficiency. P. Lips, M. Pfeifer, J. Walliser, A. Holst, N. Binkley, R. Recker, K. Krohn, M. Liu, D. Cohn, L.E. Wehren, D.A. Papanicolaou
12. International multicenter randomized comparison of balloon kyphoplasty and nonsurgical management in patients with acute vertebral body compression fractures. S. Boonen, D. Wardlaw, L. Bastian, P. Lips, J. Van Meirhaeghe, S. Cummings
13. Effect of long-term bisphosphonates on bone turnover and microdamage in osteoporotic women: a bone biopsy study. R.D. Chapurlat, M. Arlot, B. Burt Pichat, P. Chavassieux, J.P. Roux, N. Portero-Muzy, P.D. Delmas
14. Osteonecrosis of the jaw under bisphosphonate therapy – a German register for patients with osteonecrosis of the jaw. T. I. Jung, J. von der Gablentz, D. Felsenberg, B. Hoffmeister, S. Mundlos, M. Amling, P. Fratzl, M. J. Seibel

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