Verslag ASBMR 2011, deel 1. Presentatie van Dr. J.P.W. van den Bergh op 5 oktober 2011 voor de Stichting IWO.

1. ASBMR 2011
Joop van den Bergh, internist-endocrinoloog
Maastricht UMC & VieCuri Medisch Centrum Noord-Limburg

2. Lipotoxicity

7. Bone

8. Hyperlipidemia Induces Resistance to PTH Bone
Anabolism in Mice via Oxidized Lipids
Sage et al. JBMR 2011,1197–1206
• In hyperlipidemia, oxidized lipids accumulate in vascular tissues and
trigger atherosclerosis
• Such lipids also deposit in bone tissues, where they may promote
osteoporosis
• We found that oxidized lipids attenuate osteogenesis and that
parathyroid hormone
• (PTH) bone anabolism is blunted in hyperlipidemic mice

9. Regulatory factors in vascular calcification. The Venn diagram illustrates
overlap between the three categories of factors regulating vascular
calcification
The importance of oxidized lipids (OxL) and hyperphosphatemia is
reflected by their inclusion in each category.
Nat Rev Cardiol. 2010 Sep;7(9):528-36
Regulatory mechanisms in vascular calcification.

10. Teleologically
• Soft-tissue calcification might serve to create a wall of
bone to sequester noxious foci such as chronic infections,
parasites, and foreign bodies
• In bone softening of tissue might enable to eliminate
noxious foci such as chronic infections, parasites, and
foreign bodies

11. The amazing osteocyte

12. The osteocyte appears to be the descendant of the matrix-producing
osteoblast, which is a descendant of the mesenchymal stem cell

13. osteocyte lacuna sending canaliculi to the bone surface. Note the rough surfaces of canaliculi toward the
bone surface and the smooth surface of canaliculi that project away from the bone surface, suggesting a
difference between forming and formed canaliculi. Both sets of images demonstrate the complexity of this
network and the interface of osteocytes with the bone surface

14. Mechanotransduction

17. Osteocyte cell death

18. Causes of various forms of osteocyte cell death
• Glucocoritcoids
• Cytokines (IL-1, TNF)
• Pathological overload
• Lack of viability
– Lack of E2 (postmenopausal)
– Lack of oxygen and nutrients in immobilization

19. Factors that protect against induced cell death

20. Mechanical loading protects against cell
death / apoptosis

21. The Wnt/b-catenin pathway plays an important role in
osteocyte function and viability and the maintenance of
normal bone

22. Osteocytes can undergo a process of self-
preservation called autophagy
• During autophagy, parts of the cytoplasm and intracellular organelles
are localized within autophagic vacuoles for delivery to lysosomes for
degradation.
• Autophagy can preserve viability or, alternatively, can be a self-
destructive process that leads to cell death
• Preserve until favorable conditions return

23. Weekly teriparatide
[1201, nakamura et al. Japan]
• Weekly subcutaneous injection of 200 units of teriparatide (56.5 ug) in
Japanese patients (65-95 years old) with primary osteoporosis
• 578 patients with 1-5 prevalent vertebral fractures and low BMD (L2-4
BMD ,80% of young adult mean) with calcium and vitamin D, vs
placebo during 72 weeks
• teriparatide reduced the risk of new vertebral fractures, with a
cumulative incidence of 3.1% in the teriparatide group, versus 14.5%
in the placebo group (p,0.0001), and a relative risk reduction of 79.9%
(95% confidence interval, 54.7-91.1%).

24. Fracture repair
• Why accelerate repair?
– Reduce pain and discomfort
– Earlier employment and household function
– Try to fix what cannot be fixed
• PTH

25. Parathyroid Hormone 1-84 Accelerates Fracture Healing
in Pubic Bones of Elderly Osteoporotic Women
[1199]
• In 21 patients (82.8 years) treated with PTH 1-84 pelvic fractures were
healed at a mean of 7.8 weeks, whereas in patients with no PTH
treatment fractures had healed after 12.6 weeks (p<0.001)
• At week 8 all fractures in the treatment group were healed and four
fractures in the control group (healing rate 100% versus 9.1%
(p<0.001)
• Both the pain VAS and Time up and go test improved statistically
significant (p<0.001) compared to control
JBJS 2011 sept

26. Treatment of Non-Healing Fractures with
Parathyroid -Hormone (1-34)
• 8 patients: age 49 - 74 y; gender: 4 male, 4 female, fracture site: femur
(1x), proximal tibia (3x) and distal-tibial (4x), time duration of non -
unions: 9 - 32 months
• 2 months administration of 20 µg recombinant parathyroid hormone 1
- 34 seems to induce stable consolidation of the bone in non-unions
and delayed healing of bone fractures despite inconsistent changes in
bone turnover markers. Therefore PTH could be an alternative option
in the treatment of non healing fractures of long bones.

27. New delivery systems PTH
• PTHrP(1-36)
– Post-menopausal women with osteoporosis will subcutaneously
administer PTHrP 400 micrograms daily for three months
compared to PTH 1-34. (clinicaltrials.gov)
• Transdermal (SA 417)
– Daily doses of 30-, 50-, or 80-ug TD TPTD, applied to the upper
arm either by subjects or site personnel and kept on for 12 hr, or a
daily dose of 20-ug SC TPTD were given for 28 days
• Weekly

29. Fine tuning of FRAX
• 1031
– Heart Failure Is a Clinically and Densitometrically Independent and Novel Risk Factor
for Major Osteoporotic Fractures
• 1036
– High Body Mass Index, Adjusted for BMD, Is a Risk Factor for Fracture in Women
• 1091
– FRAX® Underestimates Fracture Risk in Patients with Diabetes
• 1243
– The addition of comorbidity, medication and behavioral factors to FRAX can
substantially improve the ability to identify men at high risk of fracture
• MO0377
– Effect of Co-Morbidities on Fracture Risk: Findings from The Global
Longitudinal Study of Osteoporosis in Women

30. Heart Failure Is a Clinically and Densitometrically Independent and Novel Risk Factor for
Major Osteoporotic Fractures: Population-Based Cohort Study of 45,509 Subjects in
Canada (Leslie) [1031]

31. 27 prospective population-based cohorts from more than 25 countries
[1036 Johansson]
Our results demonstrate that at a population level, obesity is protective for
fracture in women and this protection is mediated by effects on BMD. At a
given BMD, obesity appears to be a weak risk factor for fracture.

32. Men and women with diabetes (N=3,518) and non-diabetics (N=36,085)
age ≥50 y at the time of BMD testing
[1091]
Diabetes confers an increased risk of fracture that is independent of FRAX
derived with BMD. The current study suggests that diabetes might be considered
for inclusion in future iterations of FRAX.

33. Prediction of Fracture Risk in Men: A Cohort Study
[1243 Byberg]
• The Uppsala Longitudinal Study of Adult Men (ULSAM) is a population-based
cohort study
• All men born 1920-24 in January 1970 were invited and 2322 (82%) participated
• The full model combining FRAX, comorbidity, medications, and behavioral factors
had the highest R2 values at all ages both for all fractures and for hip fracture

34. Effect of Co-Morbidities on Fracture Risk: Findings from The
Global Longitudinal Study of Osteoporosis in Women
[MO0377 Compston]
• 52,960 women were recruited from the Global Longitudinal Study of
Osteoporosis in Women (GLOW). GLOW is an observational
prospective study of women aged 55 years and older recruited through
723 primary physician practices in 17 sites in 10 countries.

35. Interpretation and use of FRAX in clinical practice
• Risk factors not considered in FRAX
– Other causes of secondary osteoporosis
– Falls (Garvan)
– Bone markers
– BMD Lumbar spine and elswhere
– QUS
– Concurrent treatment
– Probability of clinical spine, humeral and forearm
fracture
Kanis et al. Osteoporos Int 2011 online

36. Interpretation and use of FRAX in clinical practice
• While FRAX does not define intervention thresholds, which depend on
countryspecific considerations, it provides a platform to assess fracture
probability
• The tool is, however, far from perfect, but better than BMD alone
• The widespread use has fuelled interest as to how models can be
improved, extended to other countries and, in particular, how the
limitations of FRAX should temper clinical judgement
• The wish list of clinicians is large, and in many instances, these wishes
cannot presently be fulfilled
• An explanation and understanding of the reasons may be helpful in
translating the information provided by FRAX into clinical practice
Kanis et al. Osteoporos Int 2011 online

37. Approaches to secondary fracture
prevention
• FLS (fracture liaison service) McLellan Glasgow
• Kaiser Permanente California

38. Fracture prevention in Kaiser Permanente
Southern California
• Focus on those patients at highest risk for a hip
fracture in the next 2 years.
• We accomplished this by identifying two groups:
– Those that already had a hip fracture
– Those 70+years old with any prior fragility fracture
• These were the “big-bang-for-the-buck” patients.

39. Fig. 2 Anti-osteoporosis treatment, men and women
Osteoporos Int (2011) 22 (Suppl 3):S457

40. Fracture liaison services for the evaluation and management
of patients with osteoporotic fracture
McLellan et al. Osteoporos Int (2011) 22:2083–2098

41. • Only 11% to 28% of patients with a fragility fracture
receive osteoporosis treatment in the UK
• A hypothetical cohort of 1,000 fragility fracture patients
(740 requiring treatment), 686 received treatment in the
FLS compared with 193 in usual care
• An estimated 18 fractures (11 hip) were prevented and
£21,000 saved per 1,000 patients
McLellan et al. Osteoporos Int (2011) 22:2083–2098

42. Mortality
Center et al. J Clin Endocrinol Metab, 2011, 1006–1014

44. Vitamin D
• The IOM position and cutoff of 50 nmol/l
• Musculoskeletal health and the cutoff of 75 nmol/l

45. IOM (institute of medicine) report
• Only bone health could be used as an indicator for DRI (daily
reference intakes)
• Evidence for extraskeletal outcomes was inadequate, inconsistent, or
insufficient to develop DRI
• The recommended dietary allowance was found to be 600 IU/d for
ages 1–70 yr, corresponding a 25OHD level >50 nmol/liter and 800
IU/d for those older than 70 yr
• An upper limit was set at 4000 IU/d for adults, corresponding to an
average 25OHD level of 125 nmol/liter.
JCEM 2011

46. Be aware of J or U shaped curves
An intake of 10,000 IU/d was supported as the NOAEL (no observed adverse event concentration).
The IOM committee considered other adverse effects of vitamin D: all cause—mortality, cardiovascular
disease, cancer, and falls and fracture. A recent review of the literature suggested higher risk for prostate,
breast, pancreas, and esophageal cancer (J Am Diet Assoc 2010;1492)

47. Musculoskeletal health and the cutoff of 75 nmol/l

48. Relationship between serum 25-hydroxyvitamin D (25[OH]D)
and serum intact parathyroid hormone (PTH
Clinical Endocrinology, 2010: 73, 277–285

49. Fall prevention with supplemental and active forms of vitamin D
> 60 nmol/l or > 700 U D3
Bischof-Ferrari BMJ 2009;339:b3692

50. Non vertebral fracture prevention
> 75 nmol/l or 700 U D3
Bischoff-Ferrari. Arch Intern Med 2009, 169(6):551-561