Normal bone metabolism

• Normal bone metabolism

□ Calcium

• Helps prevent heterotopic ossification after THA in patients at high risk for this development

• Incidence of heterotopic ossification after THA among patients with Paget disease is approximately 50%.

  • Important in muscle and nerve function, clotting, and many other areas

  • More than 99% of the body’s calcium is stored in bones.

    • Plasma calcium is about equally free and bound (usually to albumin).

    • Approximately 400 mg of calcium is released from bone daily.

  • Absorbed in the duodenum by active transport

    • Requires ATP and calcium-binding protein

    • Regulated by 1,25(OH)2D3

  • Absorbed in the jejunum by passive diffusion

  • Kidney reabsorbs 98% of calcium (60% in proximal tubule)

    • Calcium may be excreted in stool.

  • Primary homeostatic regulators of serum calcium are PTH and 1,25(OH) 2 D 3

  • Dietary requirement for elemental calcium:

    • Approximately 600 mg/day for children

    • Approximately 1300 mg/day for adolescents and young adults (ages 10–25 years)

    • 750 mg/day for adults ages 25–50 years

    • 1200–1500 for adults over age 50 years

    • 1500 mg/day for pregnant women

    • 2000 mg/day for lactating women

    • 1500 mg/day for postmenopausal women and for the patient with a healing fracture in a long bone

  • Calcium balance is usually positive in the first three decades of life and negative after the fourth decade.

• Phosphate

  • A key component of bone mineral

    • Approximately 85% of the body’s phosphate stores are in bone.

    • Plasma phosphate is mostly unbound.

  • Also important in enzyme systems and molecular interactions as a metabolite and buffer

  • Dietary intake of phosphate is usually adequate.

  • Daily requirement is 1000–1500 mg.

• Reabsorbed by the kidney (proximal tubule)

• Phosphate may be excreted in urine.

• Parathyroid hormone

  • An 84–amino acid peptide

  • Synthesized in and secreted from chief cells of the (four) parathyroid glands

  • N-terminal fragment 1-34 is the active portion.

  • Teriparatide, the synthetic form of recombinant human PTH, contains this active sequence.

    • Used to treat some forms of osteoporosis

    • Increased risk of osteosarcoma

  • Effect of PTH mediated by the cAMP second-messenger mechanism downstream in osteocytes

     

     

    Table 1.12

     

    Regulation of Calcium and Phosphate Metabolism

     

     

    Parameter	PTH (Peptide)	1,25(OH)2D (Steroid)	Calcitonin (Peptide)
    Origin	Chief cells of parathyroid	Proximal tubule	Parafollicular cells

    	glands	of kidney	of thyroid gland
    Factors stimulating production	Decreased serum Ca2+	Elevated PTH level Decreased serum Ca2+ level Decreased serum Pi	Elevated serum Ca2+ level
    Factors inhibiting production	Elevated serum Ca2+ Elevated 1,25(OH)2D	Decreased PTH Elevated serum Ca2+ Elevated serum Pi	Decreased serum Ca2+
    Effect on end-organs for hormone action:
    Intestine	No direct effect Acts indirectly on bowel by stimulating production of 1,25(OH)2D in kidney	Strongly stimulates intestinal absorption of Ca2+ and Pi	?
    Kidney	Stimulates 25(OH)D 1α-hydroxylase in mitochondria of proximal tubular cells to convert 25(OH)D to 1,25(OH)2D Increases fractional resorption of filtered Ca2+ Promotes urinary excretion of Pi	?	?
    Bone	Stimulates osteoclastic resorption of bone Stimulates recruitment of preosteoclasts	Strongly stimulates osteoclastic resorption of bone	Inhibits osteoclastic resorption of bone ? Role in normal human physiology
    Net effect on Ca2+	Increased serum Ca2+	Increased	Decreased serum

    and Pi concentrations in extracellular fluid and serum

    level Decreased serum Pi level

    serum Ca2+ level Increased serum Pi level

    Ca2+ level (transient)

     

     

    Adapted from Netter FH: CIBA collection of medical illustrations, vol 8: Musculoskeletal system, part I: Anatomy, physiology and developmental disorders, Basel, Switzerland, 1987, CIBA, p 179.

     

    • PTH helps regulate plasma calcium.

      • Decreased calcium levels in extracellular fluid stimulate β2 adrenoreceptors to release PTH, which acts at the intestines, kidneys, and bones (Table 1.12).

  • PTH directly activates osteoblasts.

  • PTH modulates renal phosphate filtration.

  • PTH may accentuate bone loss in elderly persons.

  • PTH-related protein and its receptor have been implicated in metaphyseal dysplasia.

• Vitamin D

  • Naturally occurring steroid

  • Activated by ultraviolet radiation from sunlight or utilized from dietary intake (Fig. 1.15)

  • Hydroxylated to 25(OH)D3 in the liver and hydroxylated a

    second time in the kidney to one of the following:

    • 1,25(OH)2D3, the active hormone

    • 24,25(OH)2D3, the inactive form (Fig. 1.16)

  • 1,25(OH)2D3 works at the intestines, kidneys, and bones (see

    Table 1.12).

  • Phenytoin (Dilantin) impairs metabolism of vitamin D.

• Calcitonin

  • A 32–amino acid peptide hormone produced by clear cells in the parafollicles of the thyroid gland

  • Limited role in calcium regulation (see Table 1.12)

  • Increased extracellular calcium levels cause secretion of calcitonin.

    • Controlled by a β2 receptor

  • Inhibits osteoclastic bone resorption

    • Osteoclasts have calcitonin receptors.

    • Calcitonin decreases osteoclast number and activity.

  • Decreases serum calcium level

    • May also have a role in fracture healing and in reducing vertebral compression fractures in high-turnover osteoporosis

• Other hormones affecting bone metabolism

  • Estrogen

    • Prevents bone loss by inhibiting bone resorption

      • Decrease in urinary pyridinoline cross-links

    • Because bone formation and resorption are coupled, estrogen therapy also decreases bone formation.

    • Supplementation is helpful in postmenopausal women only if started within 5–10 years after onset of menopause.

      • Risk of endometrial cancer is reduced when estrogen therapy is combined with cyclic progestin therapy.

    • Certain regimens of hormone replacement therapy may increase risks of heart disease and breast cancer.

    • Other postmenopausal pharmacologic interventions (alendronate, raloxifene) should be strongly considered.

  • Corticosteroids

    • Increase bone loss

      • Decrease gut

        absorption of calcium by decreasing binding proteins

      • Decrease bone formation (cancellous more than cortical) by inhibiting collagen synthesis and osteoblast productivity

         

  • Thyroid hormones

• Do not affect mineralization

• Alternate-day therapy may reduce the effects.

  • Affect bone resorption more than bone formation

    • Large (thyroid-suppressive) doses of thyroxine can lead to osteoporosis.

  • Regulates skeletal growth at the physis

    • Stimulates chondrocyte growth, type X collagen synthesis, and alkaline phosphatase activity

    • Growth hormone

      • Causes positive calcium balance by increasing gut absorption of calcium more than it increases urinary excretion

         

         

        FIG. 1.15 Vitamin D metabolism. DBP, vitamin D–binding protein; OHase, 1α-hydroxylase; Pi, inorganic phosphate.

        From Kumar V et al, editors: Robbins and Cotran pathologic basis of disease, Philadelphia, 2010, Saunders.

         

      • Insulin and somatomedins participate in this effect.

    • Growth factors

      • Transforming growth factor β (TGF-β), platelet-derived growth factor (PDGF), monokines, and lymphokines have roles in bone and cartilage repair.

• Peak bone mass

  • Believed to occur between 16 and 25 years of age

  • Higher in men and in African Americans

  • After peak, bone loss occurs at a rate of 0.3%–0.5% per year

  • Rate of bone loss is 2%–3% per year in untreated women during the sixth through tenth years after menopause.

    • Affects trabecular more than cortical bone

      • Increase in trabecular rods results in increased anisotropy.

         

         

        FIG. 1.16 Vitamin D metabolism in the renal tubular cell.

        From Simon SR, editor: Orthopaedic basic science, Rosemont, IL, 1994, American Academy of Orthopaedic Surgeons, p 165.

         

      • Cortical bone becomes thinner and intracortical porosities increase.

      • Cortical bone becomes more brittle, less strong, and less stiff.

    • Long bones have greater inner and outer diameters.

• Bone loss

  • Occurs at the onset of menopause when both bone formation and resorption are accelerated

    • A net negative change in calcium balance: menopause decreases intestinal absorption and increases urinary excretion of calcium.

  • Both urinary hydroxyproline and pyridinoline cross-links are elevated when bone resorption occurs.

  • Serum alkaline phosphatase level is elevated when bone formation is increased.

• Conditions of bone mineralization (Tables 1.13 through 1.17)

  • Hypercalcemia

    • Can manifest in a number of ways

      • Polyuria, polydipsia, and nephrolithiasis

      • Excessive bony resorption with or without fibrotic tissue replacement (osteitis fibrosa cystica)

      • CNS effects (confusion, stupor, weakness)

      • GI effects (constipation)

    • Can also cause anorexia, nausea, vomiting, dehydration, and muscle weakness

    • Primary hyperparathyroidism

      • Overproduction of PTH usually a result of a parathyroid adenoma (surgical parathyroidectomy is curative)

        • Generally affects only one

          parathyroid gland

      • Reflected in a net increase in plasma calcium and a decrease in plasma phosphate (as a result of enhanced urinary excretion)

      • Increased osteoclastic resorption and failure of repair attempts (poor mineralization as a result of low phosphate level)

      • Diagnosis:

        • Laboratory findings

          • Increased serum calcium, PTH, and urinary phosphate

          • Decreased serum phosphate

        • Bony changes

          • Osteopenia

          • Osteitis fibrosa cystica (fibrous replacement of marrow)

          • Brown tumors: increased giant cells, extravasation of RBCs, hemosiderin staining, fibrous tissue hemosiderin

          • Chondrocalcinosis

        • Radiographic findings

          • Deformed, osteopenic bones

          • Fractures

          • Shaggy trabeculae

          • Radiolucent areas (phalanges, distal clavicle, skull)

          • Destructive metaphyseal lesions

          • Calcification of soft tissues

        • Histologic changes

          • Osteoblasts and osteoclasts active on both sides of the trabeculae (as in Paget

             

    • Other causes of hypercalcemia

      • Familial syndromes

disease)

• Areas of destruction

• Wide osteoid seams

  • Pituitary adenomas associated with multiple endocrine neoplasia (MEN) types I and II

 

 

Table 1.13

 

Overview of Clinical and Radiographic Aspects of Metabol

 

 

Disease

Cause

Clinical F

Hypercalcemia

PTH Kidney sto

overproduction: hyperr

Hyperparathyroidism adenoma

PTH

overproduction: MEN/renal

Familial syndromes

Hypocalcemia

HypoparathyroidismPTH Neuromus underproduction: irritabi idiopathic

Short MC

Renal abn

Bone defor

hypoto

Total bald

↓ Renal tubular

phosphate

dependent (types I

and II) rickets

Vitamin D–

deficiency rickets

Vitamin D–

See Table 1.16

↓ Vitamin D diet; malabsorption

Rickets (osteomalacia)

Chronic renal failure: ↓ phosphate excretion

osteodystrophy

Renal

PTH receptor abnormality

syndrome

PHP/Albright

Bone defor

hypoto

 

Endocrine

abnorm

Vitamin D–resistant   (hypophosphatemic) rickets	resorption
Hypophosphatasia	↓ Alkaline phosphatase	Bone defor hypoto
Osteopenia
Osteoporosis	↓ Estrogen: ↓ bone mass	Kyphosis,
Scurvy	Vitamin C deficiency: defective collagen	Fatigue, bl effusio
Osteodensity
Paget disease of bon	e Osteoclastic abnormality: ↑ bone turnover	Deformitie fractur
Osteopetrosis	Osteoclastic abnormality: unclear	Hepatospl anemia

↓, Decreased; ↑, increased.

 

 

 

Table 1.14

 

Laboratory Findings and Clinical Data Regarding Patients

 

 

Changes in Level or Concentra

Disorder

Serum Serum

Alkalin

Calcium Phosphatase Phosph

Primary

hyperparathyroidism

↑

None or ↓

None o

 

Malignancy with bony metastases	↑	None or ↑	None o
Hyperthyroidism	↑	None	None
Vitamin D intoxication	↑	None or ↑	None o

 

↓, Decreased; ↑, increased.

 

 

 

Table 1.15

 

Laboratory Findings and Clinical Data Regarding Patients

 

 

Changes in Level or Concentration
Disorder Serum Serum Alka Calcium Phosphastase Phos
Hypopara-thyroidism	↓	↑	Non
Pseudohypoparathyroidism	↓	↑	Non
Renal osteodystrophy (high-turnover bone disease resulting from renal disease [secondary hyperparathyroidism])	↓ or none	↑↑↑	↑

Renal osteodystrophy	↑ or none	None or ↑	↑
(low-turnover bone
disease due to renal
disease [aluminum
toxicity])

↓, Decreased; ↑, increased.

 

 

 

Table 1.16

 

Laboratory Findings and Clinical Data Regarding Patients

 

 

Changes in Level or Concentration
Disorder Serum Serum Alkaline PTH Calcium Phos phos
Nutritional rickets: vitamin D deficiency	↓ or none	↓	↑	↑

Nutritional rickets: calcium deficiency	↓ or none	↓	↑	↑
Nutritional rickets: phosphate deficiency	None	↓	↑	None
Hereditary vitamin D–dependent rickets type I (pseudo–vitamin D deficiency)	↓	↓	↑	↑
Hereditary vitamin D–dependent rickets type II [hereditary resistance to 1,25(OH)2D]	↓	↓	↑	↑
Hypophosphatemic rickets (also known as vitamin D–resistant rickets and phosphate diabetes; Albright syndrome is an example of a	None	↓↓↓	↑	None

hypophosphatemic syndrome)
Hypophosphatasia	↑	↑	↓↓↓	None

↓, Decreased; ↑, increased; phos, phosphatase.

 

Table 1.17

 

Differential Diagnosis of Metabolic Bone Diseases Based

 

 

Calcium Level
Increased	Decreased
Primary	Hypoparathyroidism Pseudohypoparathyr Renal osteodystrophy (high-turnover bo disease) Nutritional rickets: vi D deficiency Nutritional rickets: ca deficiency Hereditary vitamin D dependent rickets (types I and II) Malignancy with bon metastasis Malignancy without metastasis Multiple myeloma Lymphoma Hyperthyroidism Vitamin D intoxicatio Sarcoidosis Milk-alkali syndrome Severe generalized immobilization
hyperparathyroidism
Hyperthyroidism
Vitamin D intoxication
Malignancy without bony
metastasis
Malignancy with bony
metastasis
Multiple myeloma
Lymphoma
Sarcoidosis
Milk-alkali syndrome
Severe generalized
immobilization
Multiple endocrine
neoplasias
Addison disease
Steroid administration
Peptic ulcer disease
Hypophosphatasia
Pseudohypoparathyroidism
Renal osteodystrophy
Nutritional rickets: vitamin
D deficiency
Nutritional rickets: calcium
deficiency
Hereditary vitamin D–
dependent rickets (types
I and II)

• Familial hypocalciuric hypercalcemia

  • Poor renal clearance of calcium

• Malignancy (most common)

  • Can be life threatening; commonly associated with muscle weakness

  • Initial treatment should include hydration with normal saline (reverses dehydration).

  • Can occur in the absence of extensive bone metastasis

  • Most commonly results from release of systemic growth factors and cytokines that stimulate osteoclastic bone resorption at bony sites not involved in the tumor process (RANKL pathway)

  • PTH-related protein secretion (lung carcinoma)

  • Lytic bone metastases and lesions (e.g., multiple myeloma)

• Hyperthyroidism

• Vitamin D intoxication

• Prolonged immobilization

• Addison disease

• Steroid administration

• Peptic ulcer disease (milk-alkali syndrome)

• Kidney disease

• Sarcoidosis

• Hypophosphatasia

• Treatment of hypercalcemia

  • Hydration (saline diuresis)

  • Loop diuretics

  • Dialysis (for severe cases)

  • Mobilization (prevents further bone resorption)

  • Specific drugs (bisphosphonates, mithramycin, calcitonin, and gallium nitrate)

• Hypocalcemia (Fig. 1.17)

  • Findings

    • Low plasma calcium

    • Results from low levels of PTH or vitamin D3

    • Neuromuscular irritability (tetany, seizures, Chvostek sign), cataracts, fungal nail infections, ECG changes (prolonged QT interval), and other signs and symptoms

• Hypoparathyroidism

  • Reduced PTH level causes decrease in plasma calcium level and increase in plasma phosphate level

    • Urinary excretion not enhanced because of the lack of PTH

  • Common findings:

    • Fungal nail infections

    • Hair loss

    • Blotchy skin (pigment loss, vitiligo)

  • Skull radiographs may show basal ganglia calcification.

  • Iatrogenic hypoparathyroidism most commonly follows thyroidectomy.

• Pseudohypoparathyroidism (PHP)

  • A rare genetic disorder caused by lack of effect of PTH on the target cells

  • PTH is normal or high.

  • PTH action is blocked by an abnormality at the receptor, by the cAMP system, or by a lack of required cofactors (e.g., Mg2+)

  • Defect in GNAS gene from mother

  • Albright hereditary osteodystrophy, a form of PHP

    • Short first, fourth, and fifth metacarpals (MCs) and metatarsals (MTs)

    • Brachydactyly

       

       

      FIG. 1.17 Body’s reaction to hypocalcemia, with consequent resorption of bone. When calcium level falls, PTH is secreted, which releases calcium and Pi from bone. PTH increases renal reabsorption of calcium while inhibiting phosphate reabsorption. These actions in combination restore calcium concentration. If hypocalcemia persists, PTH stimulates renal production of 1,25(OH)2D3, which increases intestinal calcium absorption.

      From Goldman L, Ausiello D, editors: Cecil medicine, ed 23, Philadelphia, 2008, Saunders Elsevier.

       

    • Exostoses

    • Obesity

    • Diminished intelligence

• Pseudo-pseudohypoparathyroidism (pseudo-PHP)

  • Normocalcemic disorder that is phenotypically similar to PHP

  • However, response to PTH is normal.

  • Renal osteodystrophy (Fig. 1.18)

    • A spectrum of bone mineral metabolism disorders in chronic renal disease.

    • Due to impaired excretion, which compromises mineral homeostasis

    • Leads to abnormalities in bone mineral metabolism

    • High-turnover renal bone disease

      • Chronically elevated serum PTH level leads to secondary hyperparathyroidism (hyperplasia of parathyroid gland chief cells).

      • Factors contributing to sustained PTH increase and secondary hyperparathyroidism include:

        • Diminished renal phosphorus excretion; phosphorus retention promotes PTH secretion by three mechanisms:

          •

          Hyperphosphatemi lowers serum calcium, stimulating PTH.

          • Phosphorus impairs renal 1α-hydroxylase activity, impairing production of 1,25(OH) 2 D 3 .

          • Phosphorus retention may directly increase the synthesis of PTH.

          • Hypocalcemia

          • Impaired renal calcitriol [1,25(OH)2D3]

          • Alterations in the control of PTH gene transcription secretion

          • Skeletal resistance to the actions of PTH

    • Low-turnover renal bone disease (adynamic lesion of bone and osteomalacia)

      • Secondary hyperparathyroidism is not characteristic with this condition.

        • Serum PTH level is normal or mildly elevated.

      • Bone formation and turnover are reduced.

      • Excess deposition of aluminum into bone (aluminum toxicity) negatively affects bone mineral metabolism.

        • Impairs differentiation of precursor cells to osteoblasts

        • Impairs proliferation of osteoblasts

        • Impairs PTH release from the parathyroid gland

        • Disrupts the mineralization process

        • Adynamic lesion: accounts for the majority of cases of low-turnover bone disease in patients with chronic renal failure

        • Osteomalacia: defects in mineralization of newly formed bone

      • Radiographs may demonstrate a rugger jersey spine (vertebral bodies appear to have increased density in the upper and lower zones in a striated appearance, like that in childhood osteopetrosis) and soft tissue calcification.

      • β2-Microglobulin may accumulate

        with long-term dialysis, leading to amyloidosis.

        • Amyloidosis may be associated with carpal tunnel syndrome, arthropathy, and

          pathologic fractures.

           

           

           

          FIG.

          1.18 Pathogenesis of bony changes in renal osteodystrophy. PTR, proximal tubule reabsorption.

          From McPherson RA, Pincus MR, editors: Henry’s clinical diagnosis and management by laboratory methods, ed 21, Philadelphia, 2007, Saunders Elsevier.

           

        • In amyloidosis, Congo red stain causes tissue material to turn pink.

      • Laboratory findings:

        • Abnormal glomerular filtration rate (GFR)

        • Increased alkaline phosphatase, blood urea nitrogen (BUN), and creatinine levels

        • Decreased venous bicarbonate level

      • Treatment directed at relieving the urologic obstruction or kidney disease

  • Rickets (osteomalacia in adults; Box 1.1)

    • Failure of mineralization leading to changes in the physis in the zone of provisional calcification (increased width and disorientation) and bone (cortical thinning, bowing)

      B ox 1 . 1 C a u s es of R i c ket s a n d O s t eoma l a c i a

       

      Nutritional Deficiency

      Vitamin D deficiency

      Dietary chelators (rare) of calcium Phytates

      Oxalates (spinach) Phosphorus Deficiency (Unusual)

      Abuse of antacids (which contain aluminum), which leads to severe dietary phosphate binding

      Gastrointestinal Absorption Defects

      Postgastrectomy (rare today)

      Biliary disease (interference with absorption of fat-soluble vitamin D)

      Enteric absorption defects Short bowel syndrome

      Rapid transit (gluten-sensitive enteropathy) syndromes

      Inflammatory bowel disease

      Crohn disease Celiac disease

      Renal Tubular Defects (Renal Phosphate Leak)

      • X-linked dominant hypophosphatemic vitamin D–resistant rickets or osteomalacia

      • Classic Albright syndrome or Fanconi syndrome type I

      • Fanconi syndrome type II

      • Phosphaturia and glycosuria

      • Fanconi syndrome type III

      • Phosphaturia, glycosuria, aminoaciduria

      • Vitamin D–dependent rickets (or osteomalacia) type I—a genetic or acquired deficiency of renal tubular 25(OH)D 1α-hydroxylase enzyme that prevents conversion of 25(OH)D to the active polar metabolite 1,25(OH)2D

      • Vitamin D–dependent rickets (or osteomalacia) type II—which

         

        represents enteric end-organ insensitivity to 1,25(OH)D and is probably caused by an abnormality in the 1,25(OH)2D nuclear receptor)

      • Renal tubular acidosis

      • Acquired: associated with many systemic diseases

      • Genetic

        • Debré–De Toni–Fanconi syndrome

        • Lignac-Fanconi syndrome (cystinosis)

        • Lowe syndrome

          Renal Osteodystrophy: Miscellaneous Causes Soft tissue tumors secreting

          putative factors Fibrous dysplasia Neurofibromatosis

          Other soft tissue and vascular mesenchymal tumors

          Anticonvulsant medication (induction of the hepatic P450 microsomal enzyme system by some anticonvulsants—e.g., phenytoin, phenobarbital, and primidone [Mysoline]—causes increased degradation of vitamin D metabolites)

          Heavy metal intoxication Hypophosphatasia

          High-dose diphosphonates

                       Sodium fluoride        

          Adapted from Simon SR, editor: Orthopaedic basic science, ed 2, Rosemont, IL, 1994, American Academy of Orthopaedic Surgeons, p 169.