osteoporosis, osteomalasia & rickets - pharmacy427 · bone function and composition 1. the...

Osteoporosis, Osteomalasia & rickets

Bone disorders

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Bone function and composition

1. The skeleton provides structural support,

2. protects vital organs & the hematopoieticsystem,

3. and maintains homeostasis of calcium & other ions.

• The two types of bone:

1. trabecular (cancellous)

2. and cortical (compact) bone

occur in varying amounts at different anatomic sites:

• Distal radius: 75% cortical and 25% trabecular

• Lumbar spine: 34% cortical and 66% trabecular

• Femoral neck: 75% cortical and 25% trabecular

• Trochanter: 50% cortical and 50% trabecular.

Bone function & compestion

• Trabecular bone is a meshwork of struts giving it a large surface area that is in close contact with the bone marrow cavity for bone turnover and metabolic activity.

• Cortical bone is formed in layers & is highly calcified (about 80% to 90%).

• Because of these different structures & environments, trabecular bone is more metabolically active & cortical bone is more structurally strong and protective.

Bone function & composition

• Bone comprises minerals (50-70%), an organic matrix (20-40%), water (5-10%), and lipids (<3%).

• The predominant mineral is hydroxyapatite[3Ca3(PO4)2(OH)2].

• Bone contains 99% of the body’s calcium and 85% of its phosphorus.

Bone function & composition

• The organic matrix is primarily protein; 90% type I collagen & 10-15% non collagenousprotein and γ -carboxylated proteins; and cells (osteoclasts, osteoblasts, and osteocytes).

• The mineral provides strength & rigidity while the proteins provide elasticity & flexibility.

Bone remodeling and its control

• The skeleton undergoes constant remodelingthroughout life.

• Peak bone mass is achieved by age 20-30 years, long after maximum bone length has been achieved.

• Men achieve higher peak bone mass than women.

• For 5-10 years after menopause, women have accelerated bone loss, up to 3% per year.

• Age-related bone loss, about 0.5% per year, begins 10-15 years after menopause in women & in men at about age 55 years.

Bone remodeling & its control

• Bone is a dynamic tissue. • The majority of the skeleton is replaced

approximately every 7-10 years. • Remodeling repairs microfractures, prepares

bone for weight bearing, & provides access to mineral stores.

• Teams of osteoclasts & osteoblasts, termed basic multicellular units (BMUs), perform this remodeling process.

• Steps in remodeling are resorption, reversal, formation, and quiescence


• This process begins with activation of osteoclasts, causing bone resorption.

• Osteoclasts attach to bone by an integrin, αVβ3, and create a leakproof seal.

• The osteoclast’s ruffled border secretes acid and proteases, such as H+ & cathepsin K, to dissolve bone.


• Osteoclasts create tunnels in cortical bone and pits in trabecular bone.

• By-products of collagen degradation include hydroxyproline, and N-terminal and C-terminal collagen peptides, which can also serve as biomarkers of resorption.

• When excavation is complete, reversal begins by osteoclasts undergoing apoptosis or moving to a new section.

• Resorption takes 3 to 4 weeks.


• Formation begins with osteoblasts making osteoid that is mineralized over the ensuing 3 to 4 months.

• Osteoblasts then either line the bone (lining cells) or become part of the bone as osteocytes.

• Quiescence follows mineralization


• Numerous agents control mesenchymal stem cell derivation and differentiation of osteoblasts

• Osteoclasts are derived from the myeloid/monocyte cell line with derivation & differentiation also under the control of numerous agents, some of which are expressed from osteoblasts.


• A complex array and timing of cytokines and hormones control osteoblasts & osteoclasts during bone remodeling

• Intensive investigation continues to define the complete process.

• Although the triggers to begin remodeling are not completely understood, osteocytes may act as mechanosensors, reacting to bone strain & sensing fatigue and damage.

• Osteocytes communicate with lining cells via a homing signal, which is thought to summon osteoclastprecursors to initiate resorption.


• Osteoblasts regulate osteoclastic activity by secreting colony-stimulating factors (macrophage colony-stimulating factor [MCSF]; CSF-1) to promote differentiation of osteoclast precursors, receptor activator of nuclear factor κB ligand (RANKL) to promote osteoclast differentiation and maturation, and osteoprotegerin (OPG) to compete with RANKL and prevent osteoclasticdifferentiation.


• Regulation of osteoblast secretion of CSF 1, RANKL, and OPG is complex, involving parathyroid hormone (PTH), 1α-25-dihydroxyvitamin D, leptin, estrogen, and other agents.

• Transforming growth factor-β (TGF-β), platelet-derived growth factor (PDGF), insulin-like growth factor-1 (IGF-1), PTH, growth hormone, & other factors promote bone formation.


• Bone mineral density peaks between the ages of 20 & 30 in men and women.

• Peak bone mass and rate of bone loss is controlled partly by genetics.

• Under normal conditions in adults, resorptionequals formation for no net loss or gain of bone mass.

• Aging, menopause, & certain diseases & drugs can create an imbalance between formation & resorption & result in bone loss.

Serum Ca & Phos Regulation & Vitamin D Metabolism


• Vitamin D and PTH maintain calcium homeostasis .

• The sun converts 7-dehydrocholesterol in the skin to vitamin D3.

• Sunscreens inhibit vitamin D skin production.

• Although a few foods naturally contain vitamin D3 (e.g.,cholecalciferol from fish oils) or vitamin D2 (e.g., ergocalciferol from plants), most dietary intake is from foods fortified with vitamin D.


• Because both vitamin D3 & D2 work similarly in the body, they are referred to here as vitamin D.

• Vitamin D undergoes hepatic conversion to 25(OH) vitamin D (calcidiol) via D-25-hydroxylase(cytochrome P450 27A1).

• PTH stimulates renal conversion of 25-hydroxyvitamin D to the active form, 1α-25-dihydroxyvitamin D (calcitriol), via 25(OH)D-1α-hydroxylase (cytochrome P450 27B1).


• Decreased serum calcium concentrations lead to increased serum PTH concentrations, which lead to elevated calcitriol concentrations

• Calcitriol promotes intestinal calcium absorption, & calcitriol & PTH work together to release calcium from bone to restore homeostasis.


• Vitamin D receptors are found in many tissues, such as bone, intestine, brain, heart, stomach, pancreas, lymphocytes, skin, and gonads.

• Serum phosphorus is less tightly regulated than serum calcium.

• Excess ingested phosphorus is absorbed and adjusted by the kidney.

• PTH also controls the kidney “set point” and decreases renal phosphorus reabsorption.

Pathophysiology of osteoporosis


• Osteoporosis is “characterized by low bone mass and microarchitectural deterioration of bone tissue leading to enhanced bone fragility and a consequent increase in fracture risk.

• Bone loss results when resorption exceeds formation.

• TheWorld Health Organization classifies bone mass based on T-score (number of standard deviations from the mean compared to bone mass of average young women).


• Normal bone mass is defined as a T-score greater than –1, osteopenia as a Tscore of –1 to –2.5, and osteoporosis as a T-score of less than –2.5.

• In addition to low BMD, high bone turnover, poor bone strength, & impaired bone architecture result in the bone’s increased susceptibility to fracture.


• Women with osteopenia have a 1.8-fold increase in fracture rate, & women with osteoporosis have a fourfold increase in fracture rate, compared to women with normal BMD.


• Clinically, osteoporosis is categorized as postmenopausal, age related, or secondary.

• Postmenopausal osteoporosis affects primarily trabecular bone in the decade following menopause, with fractures occurring predominantly at vertebral & distal forearm sites.

• Within a few years after peak BMD is attained, usually in the mid- to late-30s, bone loss slowly begins.


• The cumulative effect over time can translate into age-related osteoporosis that affects both cortical and trabecular bone & leads to vertebral, hip, & wrist fractures.

• Secondary osteoporosis is caused by either diseases or medications & afflicts both bone types.

• Secondary causes can be found in 11-31% of women & 30-54% of men.

Postmenaposal

• The rate of bone loss commonly accelerates at menopause due to a decline in trophic sex hormone production, especially when a bone healthy lifestyle is not practiced.

• In older studies, approximately 10-25% of bone loss was documented in the decade after menopause.

• Bone loss then slows to 8-12% per decade, a rate that was similar to that of older men.

• This accelerated loss has not been demonstrated in most of the placebo groups who were taking calcium and vitamin D supplements in recently conducted randomized controlled trials.

Postmenaposal

• Estrogen deficiency increases bone resorptionmore than formation.

• This process appears to depend on tumornecrosis factor (TNF), interleukin-1 (IL-1), interleukin-11, interleukin-6, MCSF, and prostaglandin E2, which stimulate osteoclasticactivity through the OPG/RANK/RANKL system.

Postmenaposal

• Reduced TGF-β, associated with estrogen loss, enhances osteoclast action through decreased apoptosis.

• Osteocytes also may play a role.

• Normally, with more weight bearing, osteocytes trigger increased BMD.

• With menopause, osteocyte apoptosis blunts this response.

Age-related

• Bone resorption increases with age, but changes in bone formation are not observed consistently.

• Increased osteocyte apoptosis may decrease responses to mechanical strain & hinder bone repair.

• Cortical porosity from years of remodeling & decreased trabecular connectivity, particularly of horizontal struts, promotes microarchitectural deterioration of bone that is not always reflected in BMD.

• Aging also increases fracture risk in other ways that are independent of BMD.

Age-related

• Comorbid conditions, cognitive impairment, medications, & deconditioning can increase falls.

• Inadequate calcium, vitamin D, & nutritional intake also contribute to bone loss & fractures.

• Vitamin D insufficiency results from poor sun exposure, decreased cutaneous production, insufficient dietary intake, & decreased absorption.

• Calcium & vitamin D insufficiency promotes secondary hyperparathyroidism & associated bone loss .

Men

• For many reasons, men experience fewer osteoporosis-related fractures than women.

• Men comprise only approximately 20% of all persons with osteoporosis.

• This is likely attributable to men attaining a 20-40% higher peak BMD than women & losing BMD at a slower rate after the peak.

• Men’s bones also have a mechanical advantage because the larger bone diameter makes them more fracture resistant.

Men

• Finally, men have a shorter life expectancy and experience fewer falls than women.

• Male osteoporosis remains an under recognized problem.

• Although fewer men than women have osteoporosis, men still suffer up to 30% of all hip fractures and are more likely than women to die within 1 year after fracture.

Men

• Hypogonadism, secondary to age-related decreased testosterone and increased sex hormone–binding globulin (SHBG), endocrine dysfunction, or androgen ablation, can also cause bone loss.

• Estrogen, synthesized from testosterone by the enzyme aromatase, appears more important than testosterone in men for bone maintenance, with greater bone density seen in men with higher estradiolconcentrations.

• Secondary causes often contribute to male osteoporosis.

Secondary causes

• Numerous diseases and drugs can decrease bone mass. • Secondary causes are suspected when osteoporosis occurs

in premenopausal women, men younger than age 70, those with no risk factors, multiple low trauma fractures (especially at a young age), or bone loss despite adequate drug treatment & calcium supplementation.

• Patients suspected of having secondary causes should undergo careful evaluation that includes a comprehensive physical exam and laboratory assessment.

• Both the osteoporosis & contributing disorders should be treated.

Drug induced

• Unfortunately, several medications can cause bone loss by a variety of mechanisms.

• Examples include systemic glucocorticoids, thyroid hormone replacement, some antiepileptic drugs, and heparin use.

• Thyroid dose adjustment is needed to keep the thyroid-stimulating hormone (TSH) in the upper half of the normal range to minimize bone loss.

• Some anticonvulsants, like phenobarbital & phenytoin, hasten vitamin D metabolism & the resultant effects can lead to osteomalacia.

Drug induced

• Those at higher risk include people who take multiple anticonvulsants, are institutionalized, or have multiple comorbidities.

• Heparin therapy, in excess of 15,000 to 30,000 units daily for greater than 3 to 6 months, is associated with bone loss and vertebral fractures.

• Low-molecular-weight heparins such as enoxaparin may pose less risk of bone loss.

Drug induced

• A black-box warning has been added to the product labeling of medroxyprogesteroneacetate injectable contraceptive warning that it significantly decreases bone loss that increases with longer durations of therapy.

• Thus, this contraceptive product should be used only when other medications prove inadequate.

Clinical presentation

Osteomalycia

Introduction

• Osteomalacia results from defective osteoidmineralization.

• Defective mineralization in the infant or child produces rickets.

• In the adult, the syndrome is called osteomalacia.

Epidemiology

• The incidence of osteomalacia is not known precisely, but is lower in the United States because foods are supplemented with vitamin D.

• Osteomalacia is more prevalent in countries with little sun exposure, minimal dietary supplementation, malnutrition, or traditional clothing covering most of the skin.

• Dark-skinned individuals synthesize less vitamin D cutaneously & can be at risk for hypovitaminosisD.

Pathophysiology

• Mechanisms leading to osteomalacia include low serum calcium or phosphorus, chronic acidosis, hypophosphatemia, liver or renal disease, and drug-induced mineralization defects.

Pathophysiology

• most common cause is vitamin D deficiency secondary to inadequate intake, decreased sun exposure, malabsorption, or decreased metabolism.

• Renal disease is associated with decreased 25(OH) vitamin D 1α-hydroxylase, with consequently decreased calcitriol and poor calcium absorption.

• In vitamin D–dependent rickets type I, a genetic defect exists in 25(OH) vitamin D 1α-hydroxylase. Vitamin D–dependent rickets type II results from defects in the vitamin D receptor or its activity.

Pathophysiology

• In vitamin D–resistant rickets, renal phosphate reabsorption is defective, & 25(OH) vitamin D 1α-hydroxylase activity is inadequate.

• A genetic defect in the PHEX gene may allow inappropriate activity of an undefined inhibitor of phosphate reabsorption that also lowers serum calcitriol concentrations.

• Pancreatitis, chronic hepatobiliary disease, Crohn’s disease, gastrectomy are also risk factors for vitamin D deficiency

Pathophysiology

• Other chronic disorders cause osteomalacia.

• Phosphate depletion from low dietary intake, phosphate-binding antacids, and oncogenicosteomalacia can cause osteomalacia.

• Hypophosphatasia is an inborn error of metabolism in which deficient activity of alkaline phosphatase causes impaired mineralization of bone matrix.

• Acidosis from renal dysfunction, distal renal tubular acidosis, hypergammaglobulinemic states (e.g., multiple myeloma), and drugs (e.g., chemotherapy) compromises bone mineralization.

Pathophysiology

• Renal tubular disorders secondary to Fanconi’ssyndrome, hereditary diseases (e.g., Wilson’s disease, a defect in copper metabolism), acquired disease (e.g., myeloma), and toxins (e.g., lead) cause osteomalacia to varying degrees.

• Chronic wastage of phosphorus &/or calcium limits mineralization, which may be further compromised by acidosis & secondary hyperparathyroidism.

Drug induced

• Drugs induce osteomalacia through various mechanisms.

• Phenytoin, primidone, phenobarbital, carbamazepine, rifampin, and some hypnotic medications may cause osteomalacia, potentially through hepatic microsomalcytochrome P450 induction and increased vitamin D metabolism.

• Anticonvulsant-associated osteomalacia usually occurs only in patients living in an institution or those receiving multiple anticonvulsant drugs.

• Cholestyramine may decrease vitamin D absorption.

Drug induced

• Defective mineralization can result from continuous or intermittent etidronatetreatment or sodium fluoride.

• Aluminum accumulation in patients with severe renal impairment or in patients undergoing hemodialysis may lead to osteomalacia, potentially through insoluble complexes with phosphates and inhibition of mineral deposition.

Clinical presentation

• Adult osteomalacia often has an insidious presentation.• Diffuse skeletal pain, bony tenderness, and proximal muscle

weakness may occur. • Pain on movement and muscle weakness may result in a

characteristic waddling gait. • Hypophosphatemia and secondary hyperparathyroidism

may contribute to these symptoms. • Tetany can result from sufficiently depressed serum ionized

calcium. • Skeletal deformities (infrequent in adults) include leg

bowing, pigeon chest, scoliosis, kyphosis, and shortening of the spine.

HW 4

• Summaries the pathophysiology of osteomalacia in one page.

osteoporosis, osteomalasia & rickets - pharmacy427 · bone function and composition 1. the...

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