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Diagnosis and treatment of osteoporosis
Paul Lips
Endocrine Section
Department of Internal Medicine,
VU University Medical Center
Amsterdam
The Netherlands
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Disclosures
Lecture fee Abiogen
Chair 18th Vitamin D Workshop Delft 2015
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Anatomical lesson of Dr Sebastiaen Egbertsz De Vrijpainted by Thomas de Keyser 1619
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Diagnosis and treatment of osteoporosis
• Diagnosis of osteoporosis, criteria, secondary osteoporosis
• Treatment: lifestyle, calcium vitamin D
• Specific treatment: inhibition of bone resorption
• Stimulation of bone formation: anabolic treatment
• Design of new drugs interfering with bone cells
• Summary and conclusion
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Significance of the clinical problem
• Fractures are very common in patients above 50 yearsabout 45 % of women will experience a fractureabout 20 % of men will experience a fracture
• Hip fractures cause considerable morbidity and mortality25 % dies within one year, 25 % goes to nursing home
• Vertebral fractures cause pain, loss of quality of life, and are associated with morbidity and mortality
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Diagnosis of osteoporosis
• According to World Health Organization: T-score lower than – 2.5 in femoral neck or lumbar spine measured by DXA
• About 50 % of patients with hip fracture or vertebral fracture have T-score between -1 and -2.5
• Treatment of patients with osteoporotic fractures decreases the risk of new fractures
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Dual X-ray Absorptiometry and Instant Vertebral assessment
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The osteoporosis paradox:most fractures occur with T-score -1 to -2.5
Siris E. et al Arch Intern Med 2004; 164: 1108
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Fracture Calculation Tool (FRAX)
Lalmohamed A, et al. Osteoporos Int Epub
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Multifactorial etiology of osteoporosis
Causes of secondary osteoporosis
cytokines,
growth factors
Endocrine diseaseHyperthyroidism,
Hyperparathyroidism,
Cushing syndrome,
Hypogonadism
Nutritioncalcium, vit. D, protein,
vit B12, folic acid
Immobilisation
Chronic diseaseChronic renal disease
Reumatoid arthritis,
Crohn’s disease
Myeloma
Heredity:
Parent hip
fractureCol IA1, VDR
APO E4, LRP5/6
SOST
Bone resorption > bone formation
low bone mass
osteoporosis
Lab check• TSH, (T4)• Calcium, (PTH)• (24 hr urine free cortisol)• Creatinine• alkaline phosphatase• (protein immunoelectrophoresis)• 25-hydroxyvitamin D• Testosteron in men• (celiac disease serology)
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Lifestyle intervention
• Stop smoking, decrease alcohol consumption
• Increase weightbearing activity, such as walking, aerobics, TaiChi
• Moderate sun exposure
• Increase calcium intake
• Increase vitamin D intake, vitamin D supplement
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Effect of vitamin D3 800 IU/d and calcium 1200 mg/d vs placebo on fracture incidence in 3270 French nursing home residents (mean age 84 yr)
MC Chapuy et al. N Engl J Med 1992; 327: 1637-42
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Osteoporosis: Calcium and vitamin D
Calcium
• Increase dietary calcium intake to 1000 mg/d 1 glass of milk, yoghurt = 200-300 mg50 gram cheese = 200-400 mg
• If not possible: one or two calcium tablets, containing 500 mg of calcium
Vitamin D
• Vitamin D3 800 IU/d (20 μg/d)
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Proportion of women with various fracture types during alendronate vs placebo treatment
Black DM et al J Clin Endocrinol Metab 2000;85:4118-4124
Non-vertebral fracture
Hip fracture
Any fractureClinical
vertebral fracture
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Zoledronic acid 5 mg per year in patients with hip fracture; prevention of new clinical fractures A study in 2127 men and women of 74.5 yr
Lyles et al NEJM 2007; 357: 1799-1809
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Bisphosphonates: side effects
• Short term side effects
Oral: alendronate, risedronate may cause gastrointestinal problems (5-10%), bone, joint or muscle pain, headache
Intravenous: zoledronate causes acute phase reaction, i.e. fever, flu-like symptoms
• Long term side effects
Osteonecrosis of the jaw
Atypical femoral shaft fractures
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Alternative antiresorptive treatment
• Selective estrogen receptor modulator (SERM) raloxifene, bazedoxifene, prevent vertebral fractures, safe in women 50-60 years;
Side effects: menopausal symptoms, edema, leg cramps, thrombo-embolic events
• Strontium ranelate may prevent different fracture types, but safety profile is uncertain.
Side effects: nausea and diarrhea, mouth ulcers, thrombo-embolism, heart diasease
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Denosumab: mechanism of action
Hanley et al Int J Clin Pract 2012; 66: 1139-46
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New antiresorptive drug: denosumab
• RANK-L antagonist: interferes with stimulation of osteoclast by osteoblast
• Denosumab is given by subcutaneous injection 60 mg once in 6 months
• Denosumab may be prescribed to patients with chronic renal failure.
• Side effects; infections (urinary, respiratory, skin), hypocalcemia, (limb pain)
• Long term side effects: osteonecrosis of the jaw, atypical femoral fractures
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Effect of denosumab on BMD in 6 years: FREEDOM Trial
Bone H et al J Clin Endocrinol Metab 2013; 98: 4483-92
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Bone loss after stopping denosumab:immediate fast bone loss
Hanley et al Int J Clin Pract 2012; 66: 1139-46
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Denosumab: effect on vertebral fractures
Papapoulos S et al J Bone Miner Res 2012; 27: 694-701
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Anabolic effect of teriparatide
Continuous PTH
• Stimulates RANK-L
• Suppresses OPG
• Activates osteoclasts
• Downregulation PTHR1,
IGF-1
• Decreased bone formation
Catabolic action on bone
Intermittent PTH
• Stimulates adenylate cyclase and osteoblast proliferation
• Stimulates osteoblast function through IGF-1 and FGF-2
• Increased bone formation
Anabolic action on bone
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Effect of teriparatide on bone biopsies using micro CT
Eriksen EF et al . Bone 2014; 67: 246-56
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Effect of teriparatide on fracture incidence
Neer et al N Engl J Med 2001; 344: 1434-41
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Teriparatide: dose, contraindication, side effects
• Dose: 20 μg per day by subcutaneous injection
• Contraindication: hypercalcemia, renal disease, liver disease, Paget’s disease, irradiation to the skeleton, cancer with risk for bone metastasis.
• Side effects: pain in arms or legs, nausea, headache, dizziness, local irritation on injection site.
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PTHrP analogue Abaloparatide compared with Teriparatide and Placebo
Miller P et al JAMA 2016
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Abaloparatide: effect on fracture incidence
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New drug design interfering with bone cell metabolism: from inborn error to new drug
• Pycnodysostosis: disease of osteoclast: lack of cathepsin K results in sclerotic bone disease and short stature. Cathepsin K antagonist is developed for osteoporosis
• Sclerosteosis: disease of osteocyte: lack of sclerostin results in severe sclerosis of all bones. Antibody against sclerostin is developed for osteoporosis.
Toulouse-Lautrec
Sclerosteosis
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Bone resorption by the osteoclast
therapeutic aim: cathepsin K antagonist
therapeutic aim
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Effect of odanacatib 50 mg/week on BMD in postmenopausal women
Langdahl et al J Bone Miner Res 2012; 27:2251-8
Cerebrovascular side effects!
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Sclerosteosis: mainly in South Africadue to mutation in the SOST gene, recessive disease
leading to very low sclerostin levels and severe osteosclerosis
Hamersma et al. The natural history of sclerosteosis. Clin Genet 2003; 63: 192-7
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Osteocytes stained for sclerostin Sclerostin suppresses bone formation in osteon
Poole et al 2006
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Sclerostin antibody in Cynomolgus monkeys: bone formation in vertebrae
Ominsky MS et al JBMR 2010 DOI 10.1002/jbmr.307
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Effects of romosozumab on BMD compared with alendronate and teriparatide
McClung M et al N Engl J Med 2014; 370: 412-20
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Romosozumab vs alendronate for fracture prevention
Saag et al N Engl J Med 2017; 377: 1417-27
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Relative efficacy of drugs on non-vertebral fracture and hip fracture
Russell RGG. Curr Opinion Pharmacol 2015; 22 115-130
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Specific treatment flow diagram
• T-score < -2.5 or vertebral fracture or high risk (FRAX) start bisphosphonate
• + Renal function impairment (GFR < 30 ml/min)start denosumab
• Vertebral fractures during bisphosphonate treatmentstart teriparatide
• Second choice in women<60 yr: SERM (raloxifene),
• Future: sclerostin antibody (romosozumab)PTH related peptide analog (abaloparatide)
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Summary
• Diagnosis of osteoporosis (T-score < -2.5) or vertebral fracture(s) or high fracture risk.
• Exclude or treat secondary causes
• Lifestyle intervention, exercise, calcium, vitamin D
• Specific treatment in case of T-score lower than -2.5 and/or vertebral fracture(s) and/or high fracture risk (FRAX score)
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Summary (2)
• The first choice treatment is an oral bisphosphonate. In case of gastro-intestinal side effects, intravenous bisphosphonates may be given.
• When renal function is impaired, the RANK-L antagonist denosumab can be prescribed.
• In postmenopausal women of 50-60 years a SERM can be considered.
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Summary (3)
• In case of fractures during bisphosphonate treatment or multiple vertebral fractures, an anabolic e.g. teriparatide can be prescribed during 2 years followed by bisphosphonate treatment.
• Combination therapy with denosumab and teriparatide is very effective in severe osteoporosis.
• Promising future treatment is an anti-sclerostin antibody.