Joop van den Bergh, internist-endocrinoloog

Maastricht UMC & VieCuri Medisch Centrum Noord-Limburg

ASBMR 2011

Lipotoxicity

Bone

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

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.

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

The amazing osteocyte

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

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

Mechanotransduction

Osteocyte cell death

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

Factors that protect against induced cell death

Mechanical loading protects against cell death / apoptosis

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

normal bone

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

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%).

Fracture repair

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

•  PTH

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

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.

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

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

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]

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.

27 prospective population-based cohorts from more than 25 countries [1036 Johansson]

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.

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

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.

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

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

Approaches to secondary fracture prevention

•  FLS (fracture liaison service) McLellan Glasgow •  Kaiser Permanente California

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.

Fig. 2 Anti-osteoporosis treatment, men and women

Osteoporos Int (2011) 22 (Suppl 3):S457

Fracture liaison services for the evaluation and management of patients with osteoporotic fracture

McLellan et al. Osteoporos Int (2011) 22:2083–2098

•  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

Mortality

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

Vitamin D

•  The IOM position and cutoff of 50 nmol/l •  Musculoskeletal health and the cutoff of 75 nmol/l

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

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)

Musculoskeletal health and the cutoff of 75 nmol/l

Relationship between serum 25-hydroxyvitamin D (25[OH]D) and serum intact parathyroid hormone (PTH

Clinical Endocrinology, 2010: 73, 277–285

Fall prevention with supplemental and active forms of vitamin D > 60 nmol/l or > 700 U D3

Bischof-Ferrari BMJ 2009;339:b3692

Non vertebral fracture prevention > 75 nmol/l or 700 U D3

Bischoff-Ferrari. Arch Intern Med 2009, 169(6):551-561