Pathogenesis of osteoporosis

Metabolic bone disease categorized by histology :

Osteoporosis Osteomalacia

Decrease in matrix Bone matrix intact

and mineral. reduced mineral.

Osteoporosis defintion by NIH Consensus

Conference, 2000: Skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture.

Bone strength= Bone density + Bone quality1

Definition:

Regulation of bone remodeling.

Canalis E et al. N Engl J Med 2007;357:905-916

Signals that determine thedifferentiation, function, and death of these cells and theirprogenitors determine how many units are activated over time,how active and well-balanced the basic multicellular unit is,and whether, at the end of the cycle, bone mass will be gained,lost, or stable4

• Parathyroid hormone - is the most important regulator of calcium homeostasis. It maintains serum

calcium concentrations by:

Stimulating bone resorption

Increasing renal tubular calcium reabsorption

Increasing renal calcitriol production.

PTH stimulates bone formation when given intermittently, but inhibits collagen synthesis at high concentrations 26,27. It stimulates osteoclast mediated bone resorption when given (or secreted) continuously. It also stimulates gene expression and increases the production of several local factors, including IL-6, IGF-1 and an IGF-binding protein, IGF-BP-5, and prostaglandins. 28,37.

Systemic hormones involved:

Canalis E et al. N Engl J Med 2007;357:905-916

Calcitriol : increases intestinal calcium and phosphorus absorption, thereby promoting bone

mineralization. At high concentrations, under conditions of calcium and phosphate deficiency, it also stimulates bone resorption, thereby helping to maintain the supply of these ions to other tissues.

Calcitonin : inhibits osteoclasts and therefore bone resorption in pharmacologic doses. However,

its physiologic role is minimal in the adult skeleton. Its effects are transient, probably because of receptor downregulation.

Growth hormone and IGFs : The GH/IGF-1 system and IGF-2 are important for skeletal

growth, especially growth at the cartilaginous end plates and endochondral bone formation.

Osteoporotic bone showing loss of bone with larger spaces decreasing its strength .2

Clinical risk factors:

Ebeling P. N Engl J Med 2008;358:1474-1482

Raisz L. N Engl J Med 2005;353:164-171

BMD measurement:

1. Dual-Energy X-Ray Absorptiometry:Results expressed as• T-SCORE is the number of SD the measurement is above or below the YOUNG-NORMAL MEAN BMD.

• Z-SCORE is the number of SD the measurement is above or below the AGE-MATCHED MEAN BMD.

Sites used for measurement per WHO criteria:•Total proximal femur•Femoral neck•Lumbar spine•33percent(1/3rd)radius if e/o OA or surgery at other 3 sites.

Peripheral skeletal sites predict global # risk, however not used in WHO/FRAX criteria therefore limited value. Changes to therapy at these sites are slow.

WHO diagnostic categories of BMD

Ebeling P. N Engl J Med 2008;358:1474-1482

Initial laboratory tests :• Complete chemistry profile (including alkaline phosphatase) • CBC• Calcium, phosphorus • 25 hydroxyvitamin D • Urinary calcium excretion

Additional laboratory tests if indicated(clinical features/ low Z-score)• 24 hour urine for free cortisol• Estradiol, FSH, LH, Prolactin , TSH• Magnesium • 1,25 dihydroxyvitamin D ,Intact PTH • Celiac screen • SPEP/UPEP• ESR, Rheumatoid Factor• Serum tryptase and histamine levels • Homocysteine• Skin biopsy for connective tissue disorders • COL1A genetic testing for osteogenesis imperfecta• Serum and urine markers of bone turnover

Other lab tests:

Thank You.

IN THE INTESTINE

It facilitates intestinal absorption of calcium, as well as stimulates absorption of phosphate and magnesium ions.

In the absence of vitamin D, dietary calcium is not absorbed at all efficiently.

Vitamin D stimulates the expression of a number of proteins involved in transporting calcium from the lumen of the intestine, across the epithelial cells and into blood.

The vitamin D form, 1,25-dihydroxcholecalciferol

[1,25(OH)2D3],

• 1. stimulates the synthesis of the epithelial calcium

channels in the plasma membrane calcium pumps , and

• 2. induces the formation of the calbindins.

Calcitriol Raises Blood

Calcium in 3 Ways:

1. Increases Ca++ absorption by the small intestine.

2. Increases Calcium (and Phosphate ) resorption from the skeleton. It binds to hematopoietic stem cells and causes differentiation of osteoclasts.

3. Weakly promotes the reabsorption of Calcium ions by the kidney cells (less calcium excreted)

Vitamin D has also been shown to play an

important part in regulating the proliferation and differentiation of both types of bone remodeling cells - those responsible for bone breakdown and those that reform the bone anew…and more.

•

Parathyroid Gland Anatomy

• Four Parathyroid glands are usually found posterior to the thyroid gland

• Total weight of parathyroid tissue is about 150mg

• Parathyroid hormone (PTH) is made by these glands

Low Blood Calcium

Parathyroid gland releases parathyroid hormone

Stimulates osteoclasts to resorb Ca++

Blood calcium rises

Promotes the final step of Calcitriol synthesis by

kidneys

Feedback Inhibition

High Blood Calcium

Inhibits parathyroid gland