Metabolic Bone Diseases Flashcards
(33 cards)
What are the 3 synergistic substances
3 synergistic substances; serum mineral levels, parathyroid hormone (PTH) and 1,25(OH)2 VitD.
Discuss the Regulation of mineral metabolism
- Renal Handling of Calcium & Phosphate: Of the about 10 g or approximately 250 mmol of Ca filtered by the kidneys each day, majority is reabsorbed in the renal tubules. PTH enhances Ca reabsorption.
In contrast to the Ca-conserving effect of PTH on the kidneys, PTH increases renal phosphate excretion at the proximal tubule by directly lowering the renal phosphate threshold. - Intestinal Absorption of Calcium & Phosphate: PTH increases intestinal Ca absorption by increasing 1,25(OH)2 VitD. Ca is absorbed by passive diffusion and by an active transport system. Passive diffusion accounts for absorption of about 10% of ingested Ca per day. Active Ca absorption is under the control of 1,25(OH)2D.
Approximately 60 to 70% of dietary phosphate intake is absorbed. As with Ca, both passive and active transport systems exist; 1,25(OH)2 VitD is the principal regulator of the active transport of phosphate. PTH-stimulated synthesis of 1,25(OH)2 VitD thus offsets the phosphaturic effect of PTH. Hypophosphatemia stimulates formation of 1,25(OH)2 VitD by the kidneys. - Effect on Bone: PTH has an acute effect on the skeleton. Acutely, PTH decreases collagen synthesis in osteoblasts, but osteoclastic bone resorption is increased, with a net increase in mineral (Ca & P) release from bone into the ECF.
What is bone made up of
When is peak bone mass attained and when does it decrease?
Bone is a special connective tissue hardened by mineralization with calcium phosphate in the form of hydroxyapatite [Ca5(PO4)3(OH)2]. It is composed of approximately 70% inorganic matter (minerals) and 30% organic matter (osteoid).
Bone is a dynamic structure undergoing constant remodeling (turnover). This allows the bone tissue to repair itself and to adapt to forces placed on it. During childhood, bone turnover is very high and formation outweighs resorption. In young adulthood, formation and resorption are in equilibrium, but after age 40, there is a net loss. In order for the strength of the bone to be maintained, bone turnover is carefully regulated.
Peak bone mass attained by 30 years and begins to decrease slowly by 40 years.
Function of bone
- Structural support (provides rigidity & shape, protection & support for body structures, and aids locomotion)
- It houses haematopoetic bone marrow.
- Metabolic regulation of calcium and phosphate.
- Buffer system (release of phosphate buffer in chronic metabolic acidosis).
What regulates bone metabolism?
Bone metabolism is regulated via central mechanisms (hormones) and the local control of the osteoblasts, osteocytes & osteoclasts.
Osteoblast: derived from mesenchymal cells, differentiate to osteocytes & synthesize and deposit the bone matrix
Osteocyte: Osteoblasts, encased by the matrix that they themselves synthesize become osteocytes. Osteocytes communicate through protoplasmic extensions via lacuno-canaliculi with neighboring cells. These processes may have the potential to stimulate bone resorption. They act as mechanosensory cells and are responsible for the maintenance of bone structure and mass.
Osteoclast: are large end-differentiated multi-nucleated cells derived from bone marrow macrophages of the hematopoietic lineage. The unique function is resorbing bone matrix.
The osteoclastic bone resorption is important for modeling and remodeling the bone and for Ca homeostasis.
Normal bone physiology depends on the interaction of osteoblasts and osteoclasts. There are, however, diseases in which this interaction is disrupted; the MBDs
What is the Sequence of bone remodeling?
- Resting bone with lining cells that contain osteocytes.
- The lining cells recede and the underlying membrane is removed by metalloproteinases.
- Osteoclasts are recruited and activated followed by fusion to become multi nucleated osteoclasts.
- Osteoclasts digest the underlying bone forming a resorption cavity.
- Osteoblasts are recruited to the cavity.
- Osteoblasts lay down new osteoid, which is then calcified.
Discuss Bone turnover- Hormonal modulation of bone metabolism
1. Why does remodeling occur?
2. Which hormones are involved?
During adulthood, bone is remodeled in order to adapt acute changes in Ca homeostasis, bio-mechanical demands plus renewal and repair old bone substance and osseous micro fractures.
Hormones that systemically affect the bone metabolism are primarily parathyroid hormone (PTH) and calcitriol (1,25(OH)2 VitD).
Others include growth hormone/IGF-1, estrogens and testosterone, glucocorticoids, thyroid hormones, and calcitonin.
What are the Markers of Bone Resorption?
- Products of the degradation of type I collagen.
- Specimen: Urine, Serum
Type I Collagen Telopeptides: production of NTX molecules is mediated by osteoclasts and the urinary concentrations are directly related to the extent of bone resorption.
CTX useful for monitoring anti-resorptive therapies
N-telopeptide (NTX)
C-telopeptide (CTX)
C-telopeptide of Type I Collagen (ICTP)
Immunoassays*
Pyridinium Cross-links:
Free deoxypyridinoline (DPD)
Free deoxypyridinoline (DPD) & pyridinoline (PYD)
Total deoxypyridinoline & pyridinoline: component of collagen which is released and excreted in the urine during bone resorption
Hydroxyproline:
Chromatography*
Osteoclast-derived enzyme (Serum)
Tartrate-Resistant Acid Phosphatase (TRACP5b)
What are the Biochemical markers of Bone formation?
- Products of the osteoblast
- Specimen: serum
Propeptides of type I procollagen
Procollagen Type 1 N-terminal propeptide (P1NP) Procollagen Type 1 C-terminal propeptide (PCP)
ELISA
Bone alkaline phosphatase (BALP)
ELISA*
Osteocalcin (OC)
ELISA*
What is MBD?
A group of diseases united by a common feature of an abnormal bone chemical milieu characterized by an imbalance between bone formation & resorption with abnormalities of minerals (Ca, P) & hormones (Vit D, PTH) leading to defective skeleton & bone abnormalities.
What are the types of MBDs?
Osteoporosis
Osteomalacia & Rickets
Paget’s disease
Renal Osteodystrophy
Bone metastases
What are Other MBDs?
Hyperparathyroidism
Hypoparathyroidism
Pseudohypoparathyroidism
Fibrous dysplasia
Osteogenesis imperfecta (brittle bone disease)
Osteopetrosis (marble bone disease)
Vitamin D resistant rickets
Fanconi’s syndrome
Hypophosphatasia, etc.
This list is not exhaustive!
What is osteoporosis & osteopenia?
Definition: a progressive reduction in bone
mineral density (BMD) with abnormal micro-
architecture of bone tissue giving rise to
weak, fracture-prone bone. Esp in post
menopausal women. Most common MBD.
Not a primary disorder of Ca metabolism.
Female at more risk than Male.
Osteopenia: descriptive term for a loss of BMD observed radiologically. It may be local (as in disuse atrophy of an immobilized limb) or generalized osteopenia. Generalized osteopenia can be caused by osteoporosis unrelated to other diseases, endocrinopathies, deficiency states, neoplastic diseases, chronic diseases, drugs, & hereditary diseases.
What is the pathogenesis of osteoporosis?
- The rate of formation is usually normal but the rate of resorption is increased.
- Increased osteoclast activity relative to osteoblast activity with a greater loss of trabecular bone than compact bone.
- In women, the decrease in sex steroids at menopause accelerates bone loss to about 2% per year from 0.5% per year.
- There is equal loss of osteoid and mineral resulting in decreased BMD
In the early stage it is asymptomatic but as the disease progresses bone pain (e.g., severe backache), spontaneous fractures and collapse of vertebrae, and fractures of the ribs and hips with minimal trauma occur.
Discuss the aetiology of osteoporosis:
What are the types?
What are they caused by and what type of bone do they affect?
What type of fractures are they associated with?
PRIMARY OSTEOPOROSIS:
Type I:
* occurs as a result of oestrogen deficiency,
* mostly affects trabecular bone
* often gives rise to vertebral body collapse.
* aka Post menopausal osteoporosis
Type II
* occurs as a result of the natural loss of bone with age
* affects trabecular and cortical bone
* often associated with femoral neck fractures. (Senile osteoporosis)
SECONDARY OSTEOPOROSIS:
* Endocrine causes: Hyperthyroidism/Thyrotoxicosis, Cushing’s Syn, Hypogonadism, 10 hyperparathyroidism, DM
- Unhealthy lifestyle: smoking, alcohol abuse, poor nutrition (Ca def)
- Drugs: chronic alcoholism (No 1 cause in men), Glucocorticoids (Asthmatics, RA), corticosteroids, heparin, anticonvulsants
- GIT: malabsorption, anorexia nervosa.
- Haematologic: Multiple myeloma
- Others: immobilization, weightlessness (as in astronauts)
What are the clinical features and biochemical findings of Osteoporosis?
What are the common fracture locations?
What bone scanner is used to diagnose osteoporosis?
How to the bone markers respond to therapy?
CFs: Many mild vertebral fractures may be clinically silent when they occur, only to manifest much later as an incidental finding on an X-ray.
Fractures of the vertebrae, hip, distal radius (Colle’s #, forearm) & femoral neck occur most often.
Biochemical findings:
* Ca, phosphate and ALP are usually normal.
- Other biochemical tests may, however, be of use in detecting the underlying causes of secondaty osteoporosis.
- The diagnosis of osteoporosis is determined by the bone mineral density (measured by dual-energy X-ray absorptiometry).
- Bone markers are principally used to assess the bone turnover state prior to commencement of therapy and to monitor therapeutic response.
- Markers of bone resorption should decrease with antiresorptive therapy whereas markers of formation would increase with PTH therapy.
Treatment of Osteoporosis
Pry Goal is prevention => adequate nutrition (Ca, Vit D, protein) + regular exercise; +/- HRT in women
Definitive Rx
Antiresorptive therapy: Bisphosphonates, Calcitonin, Strontium ranelate (dual action)
HRT = Oestrogen Replacement Therapy or Raloxifen
Recombinant PTH analogues (Intermittent increase and decrease of PTH results in an anabolic effect on bone)
Therapy depends on cause in 20 Osteoporosis.
Discuss osteomalacia and rickets:
Aetiopathogenesis?
How can Vit Deficiency cause hypophosphatemia?
Osteomalacia refers to the softening of bones due to a defective mineralization of the bone matrix or cartilage, or both resulting in the accumulation of excess osteoid. Rickets in growing bone.
Aetiopathogenesis: The basic cause is calcium or phosphate deficiency or both.
Resorption > formation + abnormal mineralisation.
- Calcium deficiency is usually due to the vitamin D deficiency syndromes.
- Decreased absorption (malnutrition, malabsorption syndromes)
- Decreased production (insufficient exposure to sunlight, liver disease, kidney disease, anti-epileptics, etc)
- Resistance to vitamin D
↓Vit D → ↓Ca absorption → Hypocalcaemia → ↑PTH secretion → ↑ renal phosphate excretion → Hypophosphataemia
Discuss Phosphaturic rickets (phosphate deficiency) and renal tubualr acidosis type 1 in the development of osteomalacia
- Phosphaturic rickets (phosphate deficiency) is most commonly due to due to chronic renal losses (defective tubular phosphate reabsorption) e.g., familial X-linked hypophosphataemia, Fanconi’s syndrome) and phosphate malabsorption due to gut-binding by aluminium hydroxide antacids.
- In renal tubular acidosis type I (distal) there is significant loss of calcium and phosphate in the urine as the bone is mobilized to buffer the metabolic acidosis.
What are the TYPES OF Rickets?
- Nutritional (Ca, P, Vit D def)
- Non-nutritional
i. Familial hypophosphataemia (Vitamin D resistant rickets): X-linked dominant
ii. Vitamin D dependent rickets Type I: AR mutation in the gene encoding renal 1 α-hydroxylase
iii. Vitamin D dependent rickets Type II (Receptor defect rickets): AR; characterized by the absence of calcitriol receptor sites.
iv. Defective 25 hydroxylase: Rare AR mutation
v. Fanconi syndrome: 20 to generalized dysfunction of the renal proximal tubule with loss of phosphate, amino acids, bicarbonate, glucose, urate, and other molecules that are normally reabsorbed.
vi. Hypophosphatasia: rare AR disorder characterized by absence of ALP.
vii. Metaphyseal Dysplasia: AD genetic disorder of collagen
viii. RenaI Rickets: occurs in ESRD due to loss of 1 α-hydroxylase function and inadequate phosphate secretion
ix. Oncogenous Rickets: tumours of bone or CT secrete Fibroblast growth factor 23 (FGF 23) which causes loss of phosphate.
What are the Clinical features of Osteomalacia & Rickets?
Clinical features in children are bone pain, fracture, and skeletal deformities such as enlarged costochondrial joints (rachitic rosary), bow legs (genu varum), knock-knees (genu valgus), and cranial defects such as frontal bossing, and posterior skull flattening (craniotabes). Also, growth retardation and muscle weakness.
The clinical features in adults are non-specific; bone pain, muscular weakness, and fractures associated with minimal trauma.
What are the biochemical features of Osteomalacia & Rickets?
Biochemical features: ↓ Ca, ↓P, ↑ALP and ↑ serum PTH levels.
- Ca levels are usually low/N due to secondary hyperparathyroidism as the parathyroids try and mobilize Ca.
- Phosphate is often low due to the action of PTH and ALP levels are characteristically high as osteoblasts attempt to lay down new bone.
- In Vit D deficient syndromes there will be decreased serum Vit D and its metabolites.
Serum concentrations of CTX may be elevated.
What is the treatment of Osteomalacia & Rickets?
Rx - Identify causal factors and then aim to treat the underlying cause if possible.
Therapy involves Vitamin D or its hydroxylated derivatives together with Ca and P supplements.
Discuss Chronic kidney disease metabolic bone disease, CK-MBD (Renal Osteodystrophy)
What does it consist of?
Discuss the pathogenesis
A MBD consisting of variable combinations of:
1. osteitis fibrosa
2. osteomalacia
3. secondary hyperparathyroidism &
4. osteosclerosis in association with CRF.
Pathogenesis: Resorption ≤ formation with abnormal mineralization. Inability to excrete phosphate is the initiating event.
i. High phosphate suppression of α-1-hydroxylase activity together with overall loss of α-1-hydroxylase due to decreased renal mass results in 1,25(OH)2 VitD deficiency and osteomalacia with hypocalcaemia
ii. Chronic acidosis promotes bone demineralization to buffer hydrogen ions.
iii. Hyperparathyroidism due to hypocalcaemia triggers increased bone resorption to try and raise serum Ca levels; PTH induced bone disease is called osteitis fibrosa cystica.
iv.Hyperphosphataemia due to renal inability to excrete it can trigger metastatic calcification if the solubility product of Ca and P is exceeded. This is called osteosclerosis in bone.
