The document discusses bone mineral homeostasis and the roles of parathyroid hormone (PTH), vitamin D, and calcitonin in regulating calcium and phosphate levels. It notes that 99% of calcium and 85% of phosphate in the body are stored in bone. PTH increases blood calcium by stimulating bone resorption and renal reabsorption of calcium. Vitamin D increases intestinal absorption of calcium and phosphate. Calcitonin decreases blood calcium by inhibiting bone resorption and renal reabsorption. Together these hormones tightly control bone remodeling and mineral levels through effects on osteoclasts and osteoblasts.

1. Bone –Mineral Homeostasis Dr. Mohamed Khedr Prof. of Clinical Pharmacology Faculty of Medicine-Beirut Arab University

2. Calcium homeostasis refers to the regulation of the concentration of calcium ions in the extracellular fluid [Ca ++ ] ECF . Calcium Homeostasis

3. Bone Ca ++ 99% PO4 ¯ 85% (1-2Kg/ body wt.) ( 1 Kg/ body wt.) ↓ Major source of Serum Ca ++ & Phosphate ↓ Free ionized Ca ++ only ( 50% of blood level )  .Blood coagulation. .Normal cardiac function. .Normal skeletal m. contraction. .Release of neurotransmitters.

4. Bone Mass ↓ Continuous Remodeling ->Bone building. Bone loss. young->↑ building. Old ->↑ loss. controlled by Osteoblasts Osteoclasts (Bone matrix forming (Bone matrix destructing cells) cells) Balance Remodeling

5. Schematic representation of bone remodeling. The cycle of bone remodeling is carried out by the basic multicellular unit (BMU), comprising a group of osteoclasts and osteoblasts. In cortical bone, the BMUs tunnel through the tissue, whereas in cancellous bone, they move across the trabecular surface. The process of bone remodeling is initiated by contraction of the lining cells and the recruitment of osteoclast precursors. These precursors fuse to form multinucleated, active osteoclasts that mediate bone resorption. Osteoclasts adhere to bone and subsequently remove it by acidification and proteolytic digestion. As the BMU advances, osteoclasts leave the resorption site and osteoblasts move in to cover the excavated area and begin the process of new bone formation by secreting osteoid, which is eventually mineralized into new bone. After osteoid mineralization, osteoblasts flatten and form a layer of lining cells over new bone. Schematic representation of bone remodeling. The cycle of bone remodeling is carried out by the basic multicellular unit (BMU), comprising a group of osteoclasts and osteoblasts. In cortical bone, the BMUs tunnel through the tissue, whereas in cancellous bone, they move across the trabecular surface. The process of bone remodeling is initiated by contraction of the lining cells and the recruitment of osteoclast precursors. These precursors fuse to form multinucleated, active osteoclasts that mediate bone resorption. Osteoclasts adhere to bone and subsequently remove it by acidification and proteolytic digestion. As the BMU advances, osteoclasts leave the resorption site and osteoblasts move in to cover the excavated area and begin the process of new bone formation by secreting osteoid, which is eventually mineralized into new bone. After osteoid mineralization, osteoblasts flatten and form a layer of lining cells over new bone. Schematic representation of bone remodeling. The cycle of bone remodeling is carried out by the basic multicellular unit (BMU), comprising a group of osteoclasts and osteoblasts. In cortical bone, the BMUs tunnel through the tissue, whereas in cancellous bone, they move across the trabecular surface. The process of bone remodeling is initiated by contraction of the lining cells and the recruitment of osteoclast precursors. These precursors fuse to form multinucleated, active osteoclasts that mediate bone resorption. Osteoclasts adhere to bone and subsequently remove it by acidification and proteolytic digestion. As the BMU advances, osteoclasts leave the resorption site and osteoblasts move in to cover the excavated area and begin the process of new bone formation by secreting osteoid, which is eventually mineralized into new bone. After osteoid mineralization, osteoblasts flatten and form a layer of lining cells over new bone. Schematic representation of bone remodeling. The cycle of bone remodeling is carried out by the basic multicellular unit (BMU), comprising a group of osteoclasts and osteoblasts. In cortical bone, the BMUs tunnel through the tissue, whereas in cancellous bone, they move across the trabecular surface. The process of bone remodeling is initiated by contraction of the lining cells and the recruitment of osteoclast precursors. These precursors fuse to form multinucleated, active osteoclasts that mediate bone resorption. Osteoclasts adhere to bone and subsequently remove it by acidification and proteolytic digestion. As the BMU advances, osteoclasts leave the resorption site and osteoblasts move in to cover the excavated area and begin the process of new bone formation by secreting osteoid, which is eventually mineralized into new bone. After osteoid mineralization, osteoblasts flatten and form a layer of lining cells over new bone. Schematic representation of bone remodeling. The cycle of bone remodeling is carried out by the basic multicellular unit (BMU), comprising a group of osteoclasts and osteoblasts. In cortical bone, the BMUs tunnel through the tissue, whereas in cancellous bone, they move across the trabecular surface. The process of bone remodeling is initiated by contraction of the lining cells and the recruitment of osteoclast precursors. These precursors fuse to form multinucleated, active osteoclasts that mediate bone resorption. Osteoclasts adhere to bone and subsequently remove it by acidification and proteolytic digestion. As the BMU advances, osteoclasts leave the resorption site and osteoblasts move in to cover the excavated area and begin the process of new bone formation by secreting osteoid, which is eventually mineralized into new bone. After osteoid mineralization, osteoblasts flatten and form a layer of lining cells over new bone.

6.  Bone Mass (↑ blood Ca ++ level )  Bone Mass (↓ blood Ca ++ level ) .PTH. .Vit. D. .Corticosteroids. ㊉ osteoclasts. Θ osteoblasts. .Calcitonin. .Androgens. .Oestrogens. .G.H. .Thyroid H. ㊉ osteoblasts. Θ osteoclasts. Bisphosphonates Regulation of Bone-Mineral Homeostasis Hormonal Regulation Non-hormonal Regulation

7. Parathormone(PT) Single polypeptide H. Secreted from parathyroid gland.

8. Release -> regulated by level of blood Ca ++ & PO4¯. ↑ ➣ when -> Ca ++ ↓ & ↑ PO4¯. ↓ Through effects on Bone Kidney GIT .  rate of Resorption .  Ca ++ reabsorption. .  PO4¯ excretion by renal tubules. Action: -> Tends to  Ca ++ level in blood. Indirect ㊉ synthesis of calcitirol (active vit. D.) ➣  absorpt n of Ca ++. Parathormone (PT)

10. Uses of PT . -> Was used for hypocalcaemia, ( PT-> immunological agent )

11. 1-Hypocalcaemic tetany -> Calcium gluconate I.V. 2-Long R/ of hypo-para-thyroidism: -> Vitamin D + Calcium gluconate or Lactate . Treatment of hypocalcaemia

12. Steroid Hormone Vit.D2 -Ergocalciferol . Vit.D3 -Cholecalciferol . Human (Pro D 3 =7 dehydrocholestrol) ↓ UVR Vit.D 3 (Chole-calciferol) Kidney 25 (OH) 25(OH) Vit.D 3 Liver 1,25(OH) 2 D 3 (Calcitriol) ( Active) Complete hydroxylation Two forms: Vitamin D

13. Vitamin D synthesis and activation.

14. Action: -> ↓ Through effects on . ↑ resorption & Formation. ( Normal-> resorption.) ( Rickets-> formation.) . ↑ Ca ++ &↑ PO4¯ absorption . Tends to  Ca ++ &  Phosphates . ↑ Ca ++ &↑ PO4¯ reabsorption by renal tubules. Bone Kidney GIT

15. Uses of vit.D .Prevention & treatment of Rickets & osteomalacia. .Treatment of hypoparathyroidism. .Osteoporosis. The hypocalcemia and hypophosphatemia that accompany vitamin D deficiency result in impaired mineralization of bone matrix proteins, a condition known as osteomalacia . Osteomalacia is also a feature of long-standing hypophosphatemia, which may be a consequence of renal phosphate wasting or chronic use of etidronate or phosphate-binding antacids. This hypomineralized matrix is biomechanically inferior to normal bone; as a result, patients with vitamin D deficiency are prone to bowing of weight-bearing extremities and skeletal fractures. Vitamin D and calcium supplementation have been shown to decrease the incidence of hip fracture among ambulatory nursing home residents in France, suggesting that undermineralization of bone contributes significantly to morbidity in the elderly. Proximal myopathy is a striking feature of severe vitamin D deficiency, both in children and in adults. Rapid resolution of the myopathy is observed upon vitamin D treatment. Though vitamin D deficiency is the most common cause of rickets and osteomalacia, many disorders lead to inadequate mineralization of the growth plate and bone The hypocalcemia and hypophosphatemia that accompany vitamin D deficiency result in impaired mineralization of bone matrix proteins, a condition known as osteomalacia . Osteomalacia is also a feature of long-standing hypophosphatemia, which may be a consequence of renal phosphate wasting or chronic use of etidronate or phosphate-binding antacids. This hypomineralized matrix is biomechanically inferior to normal bone; as a result, patients with vitamin D deficiency are prone to bowing of weight-bearing extremities and skeletal fractures. Vitamin D and calcium supplementation have been shown to decrease the incidence of hip fracture among ambulatory nursing home residents in France, suggesting that undermineralization of bone contributes significantly to morbidity in the elderly. Proximal myopathy is a striking feature of severe vitamin D deficiency, both in children and in adults. Rapid resolution of the myopathy is observed upon vitamin D treatment. Though vitamin D deficiency is the most common cause of rickets and osteomalacia, many disorders lead to inadequate mineralization of the growth plate and bone .

16. The boy pictured here has rickets, a disease resulting from a lack of calcium and/or vitamin D in the diet. Rickets weakens the long bones, so that they are not strong enough to support the body; they bend outwardly under the body’s weight .( the skeleletal and muscluar systems Gregory Stewart)

17. The hypocalcemia and hypophosphatemia that accompany vitamin D deficiency result in impaired mineralization of bone matrix proteins, a condition known as osteomalacia . Osteomalacia is also a feature of long-standing hypophosphatemia, which may be a consequence of renal phosphate wasting or chronic use of etidronate or phosphate-binding antacids. This hypomineralized matrix is biomechanically inferior to normal bone; as a result, patients with vitamin D deficiency are prone to bowing of weight-bearing extremities and skeletal fractures. Vitamin D and calcium supplementation have been shown to decrease the incidence of hip fracture among ambulatory nursing home residents in France, suggesting that undermineralization of bone contributes significantly to morbidity in the elderly. Proximal myopathy is a striking feature of severe vitamin D deficiency, both in children and in adults. Rapid resolution of the myopathy is observed upon vitamin D treatment. Though vitamin D deficiency is the most common cause of rickets and osteomalacia, many disorders lead to inadequate mineralization of the growth plate and bone The hypocalcemia and hypophosphatemia that accompany vitamin D deficiency result in impaired mineralization of bone matrix proteins, a condition known as osteomalacia . Osteomalacia is also a feature of long-standing hypophosphatemia, which may be a consequence of renal phosphate wasting or chronic use of etidronate or phosphate-binding antacids. This hypomineralized matrix is biomechanically inferior to normal bone; as a result, patients with vitamin D deficiency are prone to bowing of weight-bearing extremities and skeletal fractures. Vitamin D and calcium supplementation have been shown to decrease the incidence of hip fracture among ambulatory nursing home residents in France, suggesting that undermineralization of bone contributes significantly to morbidity in the elderly. Proximal myopathy is a striking feature of severe vitamin D deficiency, both in children and in adults. Rapid resolution of the myopathy is observed upon vitamin D treatment. Though vitamin D deficiency is the most common cause of rickets and osteomalacia, many disorders lead to inadequate mineralization of the growth plate and bone The hypocalcemia and hypophosphatemia that accompany vitamin D deficiency result in impaired mineralization of bone matrix proteins, a condition known as osteomalacia . Osteomalacia is also a feature of long-standing hypophosphatemia, which may be a consequence of renal phosphate wasting or chronic use of etidronate or phosphate-binding antacids. This hypomineralized matrix is biomechanically inferior to normal bone; as a result, patients with vitamin D deficiency are prone to bowing of weight-bearing extremities and skeletal fractures. Vitamin D and calcium supplementation have been shown to decrease the incidence of hip fracture among ambulatory nursing home residents in France, suggesting that undermineralization of bone contributes significantly to morbidity in the elderly. Proximal myopathy is a striking feature of severe vitamin D deficiency, both in children and in adults. Rapid resolution of the myopathy is observed upon vitamin D treatment. Though vitamin D deficiency is the most common cause of rickets and osteomalacia, many disorders lead to inadequate mineralization of the growth plate and bone The hypocalcemia and hypophosphatemia that accompany vitamin D deficiency result in impaired mineralization of bone matrix proteins, a condition known as osteomalacia . Osteomalacia is also a feature of long-standing hypophosphatemia, which may be a consequence of renal phosphate wasting or chronic use of etidronate or phosphate-binding antacids. This hypomineralized matrix is biomechanically inferior to normal bone; as a result, patients with vitamin D deficiency are prone to bowing of weight-bearing extremities and skeletal fractures. Vitamin D and calcium supplementation have been shown to decrease the incidence of hip fracture among ambulatory nursing home residents in France, suggesting that undermineralization of bone contributes significantly to morbidity in the elderly. Proximal myopathy is a striking feature of severe vitamin D deficiency, both in children and in adults. Rapid resolution of the myopathy is observed upon vitamin D treatment. Though vitamin D deficiency is the most common cause of rickets and osteomalacia, many disorders lead to inadequate mineralization of the growth plate and bone The hypocalcemia and hypophosphatemia that accompany vitamin D deficiency result in impaired mineralization of bone matrix proteins, a condition known as osteomalacia . Osteomalacia is also a feature of long-standing hypophosphatemia, which may be a consequence of renal phosphate wasting or chronic use of etidronate or phosphate-binding antacids. This hypomineralized matrix is biomechanically inferior to normal bone; as a result, patients with vitamin D deficiency are prone to bowing of weight-bearing extremities and skeletal fractures. Vitamin D and calcium supplementation have been shown to decrease the incidence of hip fracture among ambulatory nursing home residents in France, suggesting that undermineralization of bone contributes significantly to morbidity in the elderly. Proximal myopathy is a striking feature of severe vitamin D deficiency, both in children and in adults. Rapid resolution of the myopathy is observed upon vitamin D treatment. Though vitamin D deficiency is the most common cause of rickets and osteomalacia, many disorders lead to inadequate mineralization of the growth plate and bone Radiograph of the scapula of a 58-year-old woman with osteomalacia. The presence of a pseudofracture, or Looser's zone, is indicated by an arrow.

18. Calcitonin From parafollicular (C) cells of thyroid glands ↓ Hypercalcaemia &  vitamin D. Action: -> Tends to ↓ Ca ++ &Phosphates ↓ Through effects on Bone Kidney Θ Osteoclast activity. Tends to  Ca ++ &Phosphates as a result of . Θ Ca ++ & PO4¯ reabsorption by renal tubules.

20. Uses of Calcitonin : -> As it Θ bone Resorption . Diseases in which active or chronic loss of bone mass : .Post menopausal osteoporosis. .Hypercalcaemia of malignancy. .Paget’s disaese . Preprations: Human calcitonin -> t½ 10 min. Calcitonin-salmon -> long t½ , more potent, (miacalcin), s.c , I.M, nasal spray.

21. PTH Vitamin D Calcitonin Bone: ↑ resorption. ↑ resorption & ↓ resorption. formation. Kidney: ↑ tubular Ca ++ ↑ tubular Ca ++ & ↓ tubular Ca ++ & reabsorption. PO 4 ¯reabsorpt n PO 4 ¯ reabsorpt n. ↑ tubular PO 4 ¯ excretion. G.I.T. Indirect through ↑ Ca ++ &PO 4 ¯ calcitriol reabsorption. (↑ Ca ++ &PO 4 ¯ reabsorption). Serum Ca ++ PO 4 ¯ -

23. Bisphosphonates Θ Bone Resorption Non-hormonal Agents affecting Bone-Mineral Homeostasis . Θ Osteoclast activity ( by Θ osteoclast proton-pump, so Θ n of dissolution of hydroxy- apatite; the ground substance matrix of bone). . ㊉ osteoclst apoptosis (cell death). . ㊉ osteoblast activity. .↓ calcitriol activity (active vit.D) -> ↓ GIT absorption of Ca ++.

24. Pharmackinetics of Bisphosphonates: Absorption: -> orally , only 10% & interfered with food. (empty stomach) Distribution -> Bone ( 50% of the dose ). Excretion -> Renal. Therapeutic Uses .Postmenopausal osteoporosis. .Paget’s disease. .Malignancy associated with hypercalcaemia.

25. Preparations .Alen-dronate ( fosamax ) Orally one tab./ w. ( patient is upright with glass of water, to prevent oesophageal ulceration). .Eti-dronate. Orally & parenterally. .Rise-dronate. Side effects G.I.T irritations Contraindications .Kidney diseases. .Peptic ulcer.

26. 1-Bisphosphonates. -> Θ Bone resorption. 2-Oestrogen. -> ↑ Bone mass ( Θ oseoclast activity). 3-Vitamin D & Ca ++ . 4-Calcitonin. -> Θ Bone resorption. ( Θ osteoclast activity). Drugs used for treatment of osteoporosis

27. Cumulative proportions of women with osteoporosis who suffered clinical fracture (vertebral, hip, or wrist) during 3 years of treatment with alendronate or placebo (FIT 1). (From DM Black et al: Lancet 348:1535, 1996.) Cumulative proportions of women with osteoporosis who suffered clinical fracture (vertebral, hip, or wrist) during 3 years of treatment with alendronate or placebo (FIT 1). (From DM Black et al: Lancet 348:1535, 1996.)