Osteoporosis, Osteomalasia & rickets Bone disorders
Thank You for Your comments Voice--- Ok Lecture too long--- this is in schedule??? More interaction--- I can do that inshalla Slides are crowded--- but slides r the ref No short not in exam--- no can do Topics--- unfortunately I don t choose them More S & S--- in therapeutics (dr. hous)
Bone function and composition 1. The skeleton provides structural support, 2. protects vital organs & the hematopoietic system, 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 collagenous protein 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 remodeling throughout 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
Bone remodeling & its control 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.
Bone remodeling & its control 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.
Bone remodeling & its control 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
Bone remodeling & its control 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.
Bone remodeling & its control 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 osteoclast precursors to initiate resorption.
Bone remodeling & its control 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 osteoclastic differentiation.
Bone remodeling & its control 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), plateletderived growth factor (PDGF), insulin-like growth factor-1 (IGF-1), PTH, growth hormone, & other factors promote bone formation.
Bone remodeling & its control 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, resorption equals 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
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.
Serum Ca & Phos Regulation & Vitamin D Metabolism 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-1αhydroxylase (cytochrome P450 27B1).
Serum Ca & Phos Regulation & Vitamin D Metabolism 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.
Serum Ca & Phos Regulation & Vitamin D Metabolism 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
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).
Pathophysiology of osteoporosis 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.
Pathophysiology of osteoporosis 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.
Pathophysiology of osteoporosis 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.
Pathophysiology of osteoporosis 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 resorption more than formation. This process appears to depend on tumor necrosis factor (TNF), interleukin-1 (IL-1), interleukin-11, interleukin-6, MCSF, and prostaglandin E2, which stimulate osteoclastic activity 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 estradiol concentrations. 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 medroxyprogesterone acetate 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 osteoid mineralization. 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 hypovitaminosis D.
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 1αhydroxylase 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 oncogenic osteomalacia 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 s syndrome, 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 microsomal cytochrome 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 etidronate treatment 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.