Metabolic disorders Z. Rozkydal Metabolic disorders- osteopathy •Osteoporosis •Osteomalatia •Primary hyperparathyreoidisms •Secondary hyperparathyreoidisms: • - renal osteodystrophy • - gastrointestinal osteodystrophy • Composition of bone 50 % anorganic material (hydroxyapatit crystals) 25 % organic bone matrix (osteoid): 90 % collagen type I 10 % other proteins (osteocalcin, osteonectin, proteoglycans, enzymes) 25 % water binding on collagen and proteoglycans Skeleton Weight 5 kg Cortical bone 4 kg Trabecular bone 1 kg Kostra Kosti Cortical bone Trabecular bone Osteo- haverský systém Cortical bone- Haversian system Osteo- haverský systém2 Osteo- spongioza1 Osteo- spongioza2 Trabecular bone BP - kost kortikální a trabekulární jpg Trabecular bone: - 20% of the skeleton - 80% of remodelling Cortical bone: - 80% of the skeleton - 20% of remodelling Collagen type I. Osteoblasts: They produce osteoid- organic part of matrix They provide mineralisation of bone They produce alcaline phosphatase – indicator of the synthesis of proteins Remodelace kosti schéma Osteoclasts: Large multinuclear cells They are localised in Howship lacunes on the surface od bone They produce acid phosphatase and lytic enzymes They dissolve hydroxyapatite crystals and bone matrix Remodelace kosti schéma Osteocytes They lie in lacunes of corticals and trabecular bone They are connected wit canaliculi They maintain metabolism of bone Remodelace kosti schéma BP- bone remodeling Remodelling of bone Resorption is finished in 2 weeks Mineralisation up to six months Osteoporosis is a systemic disorder of the skeleton •Diminished strength of bone •Low bone density •Impaired microarchitecture •Tendency to fractures •Loss of organic and anorganic bone Osteoporotická kost Osteoporosis •primary: • idiopathic • postmenopausal - type I. • involutional (senile) - type II. •secondary - type III. BP- graf BMD Peak bone mass – at 30 years of age Bone loss: Before menopause 0,3 % / year After menopause 3 % / year Clinical symptoms •Back ache •Diminished ability to work •Problems with walking • and standing •Problems with lifting heavy objects •Sharp pain- in a case of fracture Eliška- OP 1 Examination •Tenderness on spinous process •Limited movements of the spine •Paravertebral spasm •Thoracis kyphosis •Widow´s hump •Lower lenghth of the stature Vdovský hrb klin Fosa-skelet Postmenopausal osteoporosis •80% of all cases •25 % of female are involved •Between 50- 65 years •Loss of estrogens- high activity of osteoclasts •Trabecular bone most often affected Fosa-kyfóza Over 70 years, ratio female: male = 2 : 1 The cause: no production of osteoblasts in bone marrow Cortical and trabecular bone Senile osteoporosis Secondary osteoporosis •Corticosteroids •Hyperthyreosis •Malabsorption •Alcoholisms •After trnsplantations Osteoporosis in men • •Primary • •Hypogonadism • Risk factors •Low stature •White and yellow ethnics •Low physical activity •Low nutrition with calcium Risk factors •Higher age •Low BMI •Occurence in family • Hypogonadal conditions •premature amenorhoea •surgery of ovaria •oligomenorhoea, amenorhoea •nullipara •low endogen estrogen •mental anorexia Risk factors- drugs • •corticosteroids •anticonvulsives •diuretics •heparin Risk factors •malabsorption •chronic disorders of liver •chronic disorders of kidney •alcohol Diagnostic tools •DEXA •QCT •FRAX •Imaging methods •Laboratory tests • •X- ray shows bone loss of • 30 % or more • • Vdovský hrb rtg DXA – Dual Energy Absorptiometry BMD v g/cm2 T score Z score Change Eliška OP 2 Eliška OP 3 L1-L4 Hip Total Hip neck Wrist Eliška OP 4 Fosa-dexa FRAX FRAX – fracture risk assessment tool 10 year risk of a majer fracture Age Sex Weight Height Sustained fractures Fracture in parents Smoking Alkohol 3 or more units/day Corticosteroids Rheumatoid artritis Secondary osteoporosis Clinical data Combination DXA + FRAX HR- pQCT Pair biopsies- histology, histomorfometry 2 D micro CT, microindentation SEM Finite element analysis Raman microspectroscopy Diagnostic tools HR- pQCT High resolution, peripheral, quantitative CT Noninvasive meassurement of bone morphology Virtual biopsy Assess microarchitecture up to 82 µm B Scanco 5 OP 6 Xtreme CT Assess thickness of cortical bone B Scanco 1 SCANCO Xtreme CT HR qCT B Scanco 3 Placebo 36 months PROTELOS 36 months Pair biopsies- before and after treatment P zl Histology 4 t. 8 t. Kontrola OVX a SR B histomorfo 1 Histomorfometry Povrch kosti Mineralizovaný povrch Erodovaný povrch Tloušťka trabekul Konektivita trámců Trabekulární objem Kortikální tloušťka Healthy bone FEA- finite element analysis Trabecular bone (upto 82 µm) B Scanco 2 Plates B Scanco 2 Osteoporotic bone Rods Increases after 40 years of age - begins with resorption around Havers canal Raman microspectroscopy - cortical porosity B kortika 2 Raman microspectroscopy Laboratory tests Calcium (Normal calcium 2,0 – 2,75 mmol/l) Phosphorus (Normal phosphorus 0,7- 1,5 mmol/l) ALP, bone isoemzyme of ALP Vitamin D normal level: 20-80 ng/ml Parathormon Osteocalcin CTX- C terminal peptid of collagen NTX- N terminal telopeptid of collagen Pyridinolin, deoxypyridinolin Acid phosphatase Bone formation ALP normal level 2,7 ukat/l in man and 2,3 ukat/l i woman. - indicator of osteoblasts function. Marker of bone formation. High levels in osteomalatia !! Bone isoenzyme ALP- marker of bone formation. Osteocalcin 3,4- 11,7 ng/ml u mužů, a 2,4- 10,0 ng/ml u žen. C terminal propeptid of collagen I (PICP) N terminal propeptid of collagen I (PINP) - products of collagen synthesis Bone resorption Tartrate resistent acid phosphatase – marker of bone resorption Pyridinolin and deoxypyridinolin (crosslinks) - marker of collagen degradation - CTx- (C terminal peptid of collagen I) NTx (N-terminal peptid of collagen I) - products of proteolytic resorption of collagen in bone - Vitamin D 40-80 ng/ml, under 20 ng/ml (severe hypovitaminosis) Parathormon normal level 10-65 ng/ml. Strength of bone Density from BMD predicts only 60-75 % od mechanical power of bone Quality of cortical and trabecular bone, collagen and bone mineral Cumulation of microdamage and microfractures Remodelation of bone: -permanent removal of old and damaged bone OP 4 • • Microcracks Prevention of osteoporosis •Maximal peak bone mass •Management of disorders in children •Removal of risk factors •Management of gastrointestinal disorders •Nutrition with calcium and vitamin D •Physical activity Management Analgetics Physiotherapy Nutrition (proteins, calcium) Calcium - 1300 mg/day Vitamin D - 800 I.U/day Drugs Orthesis Surgery Fosa-cvičení Physioterapy: Bone crystals are orientated according the forces Piesoelectric efect activates osteoblasts for more production of bone osteoid Nutrition BMI 23-25 Proteins 1,0 g/kg/day + 30g of proteins /day IGF-1 – insulin like growth factor Calcium 1,5 g / day Application in the evening Calcium •Calcium eff. Pharmavit 500, 1000 mg •Calcium Sandoz forte 500 mg eff. •Calcium Slovakofarma eff. •Maxi-Kalz eff tbl, 100, 500 mg. •Vitacalcin pulvis, tablety •Biomin H plv.- Ca, Mg + IGF-1. OP KombiKalz Calcium •Kombi-Kalz pulv, 1000Ca+ • 880 IU vit D. •Osteocare tbl. •Caltrate plus tbl •Calcium 500 + vit D3 eff. •Calcium D forte cps •Calcicew OP KombiKalz 7-dihydrocholesterol In the skinn -UV beams -cholekalciferol In liver conversion to 25-OH vit. D3 In kidneys conversion to 1,25 dihydroxy-vit. D3 Active agent is kalcitriol 1,25 (OH) D3. 80-90% of daily use is covered by sun radiation Vitamin D Vitamin D 60 % off seniors have hypovitamonosis of vitamin D Optimal level in blood is 80 nmol/l Hypovitaminosis - bellow 20 nmo/l Dosage: 800 IU/day Vitamin D •Infadin gtt, vit D cps., Vigantol oel, gtt •Rocaltrol cps, Vitamín D Slovakofarma cps •Calciferol inj. •1 alfa (OH) D3 – alfakalcidol - Alpha D3 •1 alfa (OH) D2 – doxercalciferol ( Hectorol) •22 oxakalcitriol (OCT) •19 nor 1,25 (OH)2 D2 – parikalcitriol (Zemplar) • Management of osteoporosis Bisphosphonates- Alendronát (Fosavance) Risedronát (Actonel) Ibandronát (Bonviva) Zolendronát (Aclasta) Denosumab (Prolia) Parathormon, teriparatid – syntetic parathormon 1-34 fragment (Forsteo) SERM- bazedoxifen Fosa-páteř Inhibition of bone resorption Stimulation of bone formation Bisphosphonates •Incorporation in HA crystals and matrix • •Inhibition of formation, agregation and dissolution of crystals • •Inhibition of bone resorption OP- Fosamax Fosamax Bisphosphonates •Reduction of activity of osteoclasts •Induction of apoptosis of osteoclasts Bisphosphonates - indications Osteoporotic fractures All forms of osteoporosis Paget ´s disease of bone Hypercalcemia in carcinomas or myeloma Pamidronate - Aredia inj. Clodronate – Bonefos inj, cps., Lodronat inj, cps. Ibandronate – Bonviva tbl., Bondronate inj. Alendronate – Fosamax 70 mg tbl., Alendros tbl. Risedronate - Actonel tbl. Zoledronate – Aclasta inj. Bisphopsphonates SERM - selective modulators of estrogen receptors •Bazedoxifen •Agonists on bone and cardiovascular apparatus •Antagonists on endometrium and breast •They bind on the same place as estrogenes • (receptors alfa, beta ) Teriparatid – synthetic parathormon 1- 34 fragment Stimulates bone formation Stimulates osteoblasts and remodelation Improves the strength of trabecular and cortical bone OP Forsteo New agents 1. Monoclonal sclerostin antibodies Romosozumab, Blosozumab Osteoformative effect Sclerostin – inhibitor of osteoblasts production from osteocytes stimulates bone resorption via RANKL 2. Inhibitors of katepsin K- inhibition of bone resorption Odanatocibe HRT no evidence of effect OP Livial Frailty syndrom 1.Loss of weight 4-5 kg/year 2.Exhaustion 3.Muscle weakness / handgrip more than 20 % 4.Lower velocity of gait less than 20 % 5.Lower physical activity less than 20 % 6. 6. 6. Frailty syndrom Subclinicaly Early frail Late frail Endstage frailty syndrom: terminal geriatric deterioration Frailty syndrom Disposition to falls Disposition to organ decompensation Worsening of cognitive functions Need for help in daily activities Sarcopenia Osteoporosis Low level of vitamin D Occurence Advanced age 7 % persons over 65 years 25 % persons over 75 years Loss of muscle power 20 % in 65-70 years Loss of muscle power 60 % in 80 years Cause: longlasting deficiency of vitamin D Risk factors of frailty syndrom Cardiovascular disease Diabetes mellitus Atherosclerosis Renal failure Neurologic disorders Obesity Hormonal dysfunction Hypovitaminosis D Prevention and treatment of frailty syndrom Frailty syndrom is reversible Nutrition and proteins 1,3 g/kg/day Vit D 800 IU/day till 2000 IU/day Vigantol 1 drop = 500 IU, alpha kalcidol 1 µg Strengthening of muscles, exercise, walking Strengthtening of stability, prevention of falls Prevention of atherosclerosis Management of other comorbidities Aleviating of pain Stop walking when talking Sarcopenia Loss of muscle substance more than 20-30 % Dysbalance between synthesis and degradation of muscles (myostatin, glucorticoids, sexual hormons, insulin, IGF-I ) Osteopenia Sedentary way of life Sarcopenia Muscle densitometry: below 2 SD – man under 7,26 kg/m2 - woman under 5,45 kg/m2 MRI Hand grip- dynamometr Flexion- extension of the knee Maximal forced breathing out Velocity of gait Test of balance Get up and go test Walking on stairs Medication Vit D 800 IU/day till 2000 IU/day Vigantol 1 drop= 500 IU Alpha kalcidol 1 µg Testosteron Ghrelin GH secretogoga Estrogens Leptin Consequenses of sarcopenia Lower physical activity (myosteatosis, sarkopenic obesity) Sarcoporosis Higher risk of falls Risk factors for developing of sarcopenia: Parkinson sy, multiple sclerosis, CVA, catarracta Management Farmacotherapy of osteoporosis diminishes risk of fragility fractures only 20-50 % + frailty syndrom + sarcopenia + osteoarthrosis + other comorbidities + prevention of falls F koubová 1 Osteoporosis with corticosteroids Condition after transplantations Cushing syndrom Hyperthyreosis Rheumatoid arthritis Osteogenesis imperfecta Fibrous osseous dysplasia Osteomyelitis Myeloma, tumors, osteolytic metastasis Malnutrition Algoneurodystrophy Differential diagnosis Osteomalatia •Systemic disordes in adults •Bone is in a form of nonmineralised osteoid •Calcium is not layed in HA crystalls •Bone is soft •The cause: lack of vitamin D OM4 OM5 Osteomalatia RO5 Osteomalatia Symptoms •Diffuse pain in skeleton •Muscle weakness •Tendermess of bones •Deformities of bones •Thoracic kyphosis Laboratory tests •High level of alcaline phosphatase •High level of bone isoenzyme of ALP •Low level of calcium •Normal level of phophorus Radiological finding Rarefaction of skeleton Narrow cortical bone Looser´s zone of remodelling - non mineralised osteoid - Biconcave shape of vertebras coxa vara Protrusion of acetabulum Thoracic hyperkyphosis Nik_0030 Nik_0011 Nik_0016 Osteomalatia Prevention •Vitamin D - sun radiation and in food •Application of vitamin D in renal and liver disorders Therapy •Vit. D 10 000 IU per day i.m. •Calciferol inj. •Vit. D p.os 2000 IU daily •Calcium 1000 - 2000 IU daily •Food with milk, sea fish Rickets 1. Lack of vitamin D 2. Lack of phosphates Inability to calcify of matrix Bone is soft Bending of bone Wide growth plates Metaphysis is wide Deformities of bones OM3 OM1 Rickets Fatigue Entlargement of abdomen Walking ability - worsened Craniotabes Large fontanels Dentic diturbences Caput quadratum Harrison´s groove Rachitic rosary Pectus carinatum Crura et coxa vara Pedes plani OM1 Management Vitamin D 500- 1000 IU/day 10 weeks Sun radiation Milk products with vitamin D Orthesis Osteotomies Hyperparathyreoidisms - HPT • •Adenoma of parathyroid glands •Hyperplasia of parathyryoid glands •Carcinoma of parathyrdoid glands Primary HPT •Nefrolithiasis, polyuria, polydypsia •Osteodystrofia fibrosa cystica generalisata •Gastrointestical problems •Acute pancreatitis, cholelithiasis •Muscle weakness, fatique, bone pain •Chondrocalcosis, calcifications HPT 1 HPT 2 Primary HPT •High level of calcium •Hypofosfatemia •Hyperfosfaturia •High level of ALP •High level of parathormon HPT 2 Radiological finding Rarefaction in skeleton Narrow corticalis bone Resorption in phalangs Large cysts as bone tumors Kyphosis Coxa vara Fisures and complete fractures HPT 2 HPT 3 HPT 3 Nik_0002 Nik_0018 Primary HPT RO1 RO2 Renal osteodystrophy - secondary HPT in renal disorders Secondary hyperplasia of parathyroid glands RO3 Renal osteodystrophy Fatigue, bone pain Muscle weakness Fractures Th: Treatment of renal disorders vitamin D3 calcium Resection of the stomach or intestine, gall bladder problems, coeliakia, pancreatitis Pain in bones Muscle wekness Pseudofractures Deformities of bone Secondary HPT - Malabsorption of vitamin D Nik_0026 Nik_0027 Nik_0010 Secondary HPT - malabsorption of vitamin D Paget ´s disease of bone •Sir James Paget in 1876 •Chronic disease •Slow viral infection (distemper virus from • group of paramyxovirures) •GB, USA, Australia, New Zeland, France Germany, Malta. Morbus Paget •1. Osteolytic phase •2. Mixed phase •3. Osteoblastic phase Morbus Paget •Monoostotic form - 20 % •Polyostotic form • •95 % are asymptomatic •5% symptomatic Symptoms •Pain •Fatique •Deformities •Complications Nik_0014 Nik_0016 Clinical symptoms •Mild •Modrate •Severe Nik_0011 Nik_0017 Nik_0015 Nik_0020 Nik_0023 Nik_0023 Nik_0024 Nik_0010 Nik_0014 Nik_0013 Nik_0010 Nik_0015 Nik_0016 Nik_0002 Nik_0021 Nik_0019 Nik_0001 Nik_0004 Gothic arch Nik_0005 Nik_0006 Nik_0028 Nik_0026 Complications Fissures Fractures Osteoarthrosis Deafness Neuralgia n. trigeminus Basilar invagination Vertebrobasilar insuficiency Paraparesis, sciatica Dental problems Nik_0028 Hypertension Ischemic heart disease Cardiomegaly Neoplasmatic degeneration sarcoma Nefrolithiasis Calcifications Complications Management •Bisphosphonates (Fosamax 40 mg daily • three months, Pamidronate, Zoledronate •Calcium •Therapy of complications •Osteosynthesis of fx •Total knee and hip replacement Nik_0011 Charnley total hip arthroplasty Thank You for Your attention B- černá díra mléčné dráhy Black Hole of the Milky Way