metabolic bone diseases k. bernášková. 2 bone functions body shape and movement protection of...

Metabolic bone diseases

K. Bernášková

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Bone functions

• Body shape and movement• Protection of cavities• Acid – base ballance• Erythropoesis, immunity

• Calcium homeostasis• Regulation of glucose metabolism

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Mature bone consists of:

1. Mineral component

– hydroxyapatite (Ca10(PO4)6)OH)2 (calcium and phosphate)

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Regulation of calcium homeostasisPTH Calcitriol Calcitonin Cortizol

Calcemia Bone resorption

Ca2+ reabsorption in the kidneys

(+

phosphates)

_ _

Ca2+ resorption in the gut

Indirectly

(+ phosphates

) _

Mutual influences

Activates the conversion of vitamin D inthe kidneys

level decreases PTH concentration (directly and indirectly)

PTH effect on the bone PTH

secretion, calcitriol effect in the gut

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Mature bone consists of:

1. Mineral component

2. Organic matrix (osteoid) – collagen fibers (type 1)– osteocalcin– protein S – proteoglycans, glycoproteins

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Mature bone consists of:

1. Mineral component

3. Bone cells– osteoblasts– osteocytes– osteoclasts

2. Organic matrix (osteoid)

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Osteoblasts• Derived from mesenchymal stem

cells of the bone marrow stroma

• Function: bone matrix production, bone mineralisation, control of osteoclasts maturation and function

• Rich in alkaline phosphatase• Have receptors for PTH, vitamin D, growth factors, estrogen;mechanoreceptors

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Osteocytes

• Derived from osteoblasts

• Trapped in formed bone

• Function: Calcium homeostasis, bone nutrition (?), help in bone remodelation process (sensor of bone load)

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Osteoclasts

• Derived from hemopoeticstem cells   (monocyto-makrofage series)

• Maturation and function is controlled by osteoblasts• Receptors for calcitonin• Function: bone resorption, changes of blood calcium concentration

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Osteoclast

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Structure of a long bone

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Bone remodeling

• Continuous processContinuous process

• 2 types: 2 types: targeted targeted (started by microingury, (started by microingury, ccycle lasts for 4 months)stochasticstochastic (whole skeleton) (whole skeleton)

• Resorption and formation should be in ballanceResorption and formation should be in ballance

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Bone remodeling cycle

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Importance of bone remodeling

• Maintenance of calcium and phosphate Maintenance of calcium and phosphate homeostasishomeostasis

• Maintenance of structural integrity of Maintenance of structural integrity of the bone - reparation of small the bone - reparation of small injuries (microtrauma)injuries (microtrauma)

• Adaptation of shape and bone Adaptation of shape and bone organisation to changes in organisation to changes in biomechanical forcesbiomechanical forces

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Regulation of the remodeling process

calcaemia and phosphataemia mechanical forces body metabolism hormones local factors

by

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Bone remodeling regulation 1• Systemic regulation Resorptio

nFormation

PTH ()calcitriol ()calcitonin 0cortizol

STH () ()T3, T4 ()estrogen androgen

()

()

insulin 0

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Bone remodeling regulation 2• Local factors Resorptio

nFormation

Cytokines

PRG E2

Factors from osteoblasts

, ()

Growth factors

()

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Metabolic bone diseases= due to imbalance between bone resorption and formation

= characterized by abnormal structure of the entire bony skeleton, increased fragility and pain

may reflect disturbances in the mineral phase, organic matrix, the cellular processes of remodeling and the endocrine, nutritional and other factors may be hereditary or acquired

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Types of metabolic bone diseases

1.1. OsteoporosisOsteoporosis2.2. OsteomalaciaOsteomalacia3.3. Osteitis fibrosa cysticaOsteitis fibrosa cystica4.4. Paget‘s diseasePaget‘s disease5.5. Renal osteopathyRenal osteopathy6.6. OsteopetrosisOsteopetrosis

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1. Osteoporosisis a systemic bone disease characterized by

decreased bone density, resulting in thinning and increased porosity of the bone

• bone resorption predominates (of both organic bone resorption predominates (of both organic and mineral components)and mineral components)

• the trabecular (spongiform) bone is affected the trabecular (spongiform) bone is affected moremore

• epidemiologically significant occurrence !epidemiologically significant occurrence !

• fragility of the bones increases (increases fragility of the bones increases (increases propensity to fractures)propensity to fractures)

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Osteoporotic changes in vertebrae

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The development of osteoporosis depends on:

– Colour of skin – Sex– Basal bone density (peak bone mass)– Activity (sports)– Nutrition, body weight (smoking)– Calcium and phosphate intake – Vitamin D presence– Estrogen and androgen level– Family history

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Types of osteoporosis• primary

» juvenile»postmenopausal ( estrogen bone resorption bone resorption plasmatic plasmatic

Ca2+ Ca2+ PTH PTH activation of vit D to activation of vit D to kalcitriol kalcitriol Ca2+ resorption from the gut) Ca2+ resorption from the gut)

»senile ( kalcitriol - kalcitriol - Ca2+ resorption from GIT Ca2+ resorption from GIT PTH PTH

bone resorption) bone resorption)

• secondary (many causes)

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Causes of secondary osteoporosis

Endocrine Hypogonadism ThyreotoxikosisHyperparathyreosisCushing‘s syndrome

Connective tissue diseases Osteogenesis imperfecta Marfan‘s syndrome Ehlers-Danlos‘s syndrome

MalignanciesMyeloma

Leukemia

LymfomaOsteolytiOsteolytic metastases

Other causesGastrointestinal disordersChronic kidney disease Immobilization

Diet

Drugs glucocorticoids, alcohol, warfarine, (antiepileptics)

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Signs and symptoms of osteoporosis

Osteopenia on RTG Compressing fractures and wedging of the

vertebrae Kyphotic deformity of the spine Pain Fractures of the femoral neck and distal radius

(Colles‘)

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Osteoporosis

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Osteoporosis

26- year-old manSubstituted by cortisol for a long time (hypopituitarism)

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Therapy of osteoporosis• Prevention!

• Estrogen; selective modulators of estrogen receptors in bones (tamoxifen); (androgen)

• Calcium• Vitamin D• Bisfosfonates (fosamax)• Sodium fluorid • PTH, calcitonin, (leptin) • Vitamin K

Resorption

Formation

PTH ()calcitriol ()calcitonin

0

cortizol

STH () ()T3, T4 ()estrogen androgen

()

()

insulin 0

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2. Osteomalatia/rickets• Due to invalide

mineralisation of bone (late or missing)

• in children called ricketts (seraph disease)

• not so rare as affirmed

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Pathophysiology of osteomalatia

vitamin D hypocalcaemia PTH calcaemia , but phosphataemia

calcium – phosphate disproportion doesn‘t allow normal mineralisation

wide osteoid border, decreased bone formation

• changes in both spongiform and compact bone

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Causes of osteomalatia • vitamin D deficit

(diet; malabsorption; disorders of vitamin D metabolism in skin, liver or kidneys; receptor disease)

• phosphate deficit disorder of phosphate reuptake in kidneys (phosphate diabetes, Fanconi‘s sy)

• deficit of alcalic phosphatase in osteoblasts• toxic substances

(fluorid, aluminium, antacid‘s binding phospate)

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Signs and symptoms of osteomalatia

• diffuse bone pain (predominantly hip region) • muscle weakness• fractures due to minimal forces• biochemistry:

hypocalcaemia, hypophosphataemia, slightly PTH

• in children growth retardation, bone deformities

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Signs of ricketts

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Ricketts

Deformation of long bones

Enlarged epiphysis at wrist

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Ricketts

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Rickets

• tetany, convulsions• failure to thrive• apathy

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3. Osteitis fibrosa cystica

= complication of advanced hyperparathyreosis (very rare recently)

= extensive activity of osteoclasts bone resorption and fibrous replacement,

fibrous degeneration of bone marrow, cystic or tumor-like lesions (brown tumours)

• Softened bones of the entire skeleton deformations

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Osteitis fibrosa cystica

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Osteitis fibrosa cystica

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4. Paget‘s disease

• the second most common metabolic bone disease

• bone cells increase their volume, number and activity

• local damage

• metabolic turnover of bone increases up to 40x

= osteitis deformans

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4. Paget‘s disease (osteitis deformans)

• Cause unknown (viruses?)

• Abnormal activity of osteoclasts bizarre and irregular pattern of resorption

• Increased osteoblastic response irregular bone formation

So called „Woven bone“

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Sign‘s, symptoms and complications of Paget‘s disease

Signs and symptoms: often asymptomatic; pain, fracture, warmth feeling

Complications: Bone deformation (bowing long bones, deformation of hip, „growing“ of the head) Nerve compression palsies ( deafness, weakness and paresthesias in lower extremities) Fractures Left heart failure (rare) Neoplastic transformation of affected bone

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Paget‘sdisease

- bowing long bones

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Paget‘s disease

Massy (1513): Portrait of an old woman

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5. Renal osteopathy

• Bone damage due to chronic renal failure

• Multifactorial

• Combination of osteoporosis, osteosclerosis, osteomalatia, osteitis fibrosa

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Renal osteopathy

Aluminium toxicity

amount of nephrons

biosyntethic activity

calcitriol formation

Ca and P resorption in GIT

kidney excretory functions

Retention of toxic metabolits

Metabolic acidosis

phosphataemia

calcaemia

PTH secretion

Osteitis fibrosa

Remodeling of bone Osteosclerosis

Metastatic calcifications

Calcium –phosphate disbalance(bone -buffer)

Osteoporosis

Protein-caloric malnutrition

Growth disturbance in children

bone senzitivity to calcitriol

Osteomalatia

Drugs

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6. Osteopetrosis

• Rare hereditary disease• Heterogenous

pathophysiology ( quantity or activity of osteoclasts)

• Bone resorption failure thickening of bones x incresed fragility

• Dg RTG skull changes: „Alien“

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Thank you for your attention

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Literature:

• http://depts.washington.edu/bonebio/ASBMRed/diseases.html

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Calcium – phosphate relationships phosphate + calcium primary hyperparathyreosis

PTHrp

+ N calcium Phosphaturia Secondary hyperparathyreosis in vitamin D deficiency

+ calcium D hypovitaminosis Vitamin D receptor insensitivity

phosphate + calcium Terciary or quartery hyperparathyreosis in failing kidneys Vitamin D excess Sarcoidosis Increased bone resorption (myeloma, lymphoma, bone metastases, bone tumours)

+ N calcium Increased phosphate intake (laxatives) Transiently in secondary hyperparathyreosis due to kidney failure

+ calcium Decreased PTH Phosphate retention in chronic kidney failure + metastatic calcification