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Questions and Answers
What is a common cause of intrinsic vitamin D depletion?
What is a common cause of intrinsic vitamin D depletion?
Which of the following is considered a rare cause of phosphate deficiency?
Which of the following is considered a rare cause of phosphate deficiency?
What is the most prevalent type of phosphate depletion leading to osteomalacia in certain regions?
What is the most prevalent type of phosphate depletion leading to osteomalacia in certain regions?
Which condition is primarily associated with vitamin D deficiency?
Which condition is primarily associated with vitamin D deficiency?
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What is NOT a typical cause of vitamin D deficiency?
What is NOT a typical cause of vitamin D deficiency?
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What is the minimum daily calcium intake associated with the risk of developing calcium deficiency rickets?
What is the minimum daily calcium intake associated with the risk of developing calcium deficiency rickets?
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Which clinical manifestation is most likely to be associated with osteomalacia?
Which clinical manifestation is most likely to be associated with osteomalacia?
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What distinguishes proximal muscle weakness in osteomalacia from other muscle diseases?
What distinguishes proximal muscle weakness in osteomalacia from other muscle diseases?
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In which condition is muscle weakness most commonly observed despite normal or increased bone mass?
In which condition is muscle weakness most commonly observed despite normal or increased bone mass?
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What is a characteristic feature of calcium deficiency in children?
What is a characteristic feature of calcium deficiency in children?
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What is the main characteristic of secondary mineralization in bone tissue?
What is the main characteristic of secondary mineralization in bone tissue?
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Which condition is characterized by an osteoid surface greater than 15%?
Which condition is characterized by an osteoid surface greater than 15%?
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What is a primary symptom associated with hypovitaminosis II?
What is a primary symptom associated with hypovitaminosis II?
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Which biochemical deficiency is related to the pathogenesis of osteomalacia?
Which biochemical deficiency is related to the pathogenesis of osteomalacia?
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Which stage of hypovitaminosis D is characterized by increased bone remodeling but normal mineralization?
Which stage of hypovitaminosis D is characterized by increased bone remodeling but normal mineralization?
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What is the usual outcome when mineralization ceases in hypovitaminosis III?
What is the usual outcome when mineralization ceases in hypovitaminosis III?
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Which of the following conditions does not conform to the classical definition of osteomalacia?
Which of the following conditions does not conform to the classical definition of osteomalacia?
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What is a common effect of calcium depletion in relation to bone health?
What is a common effect of calcium depletion in relation to bone health?
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What distinguishes rickets from osteomalacia?
What distinguishes rickets from osteomalacia?
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What is the primary cause of defective mineralization in classical osteomalacia?
What is the primary cause of defective mineralization in classical osteomalacia?
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Which stage of bone mineralization occurs rapidly and accounts for 75% to 80% of maximal mineral content?
Which stage of bone mineralization occurs rapidly and accounts for 75% to 80% of maximal mineral content?
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Which of the following conditions is NOT a type of osteomalacia?
Which of the following conditions is NOT a type of osteomalacia?
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What is the primary function of FGF-23 in bone health?
What is the primary function of FGF-23 in bone health?
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What must occur for optimal mineralization of bone?
What must occur for optimal mineralization of bone?
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In which phase does the mineral content of bone matrix reach its maximum?
In which phase does the mineral content of bone matrix reach its maximum?
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How does osteomalacia manifest in adults compared to children?
How does osteomalacia manifest in adults compared to children?
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What is the most frequent biochemical abnormality seen in osteomalacia?
What is the most frequent biochemical abnormality seen in osteomalacia?
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Which of the following skeletal deformities is commonly associated with infants suffering from rickets?
Which of the following skeletal deformities is commonly associated with infants suffering from rickets?
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Which condition is distinguished by alopecia as a unique feature?
Which condition is distinguished by alopecia as a unique feature?
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Which mutation is associated with Autosomal Dominant Hypophosphatemic Rickets?
Which mutation is associated with Autosomal Dominant Hypophosphatemic Rickets?
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What is the primary treatment approach for hereditary hypophosphatemic rickets?
What is the primary treatment approach for hereditary hypophosphatemic rickets?
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What distinguishes X-linked Hypophosphatemic Rickets from other types?
What distinguishes X-linked Hypophosphatemic Rickets from other types?
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What is a common presentation of tumor-induced osteomalacia?
What is a common presentation of tumor-induced osteomalacia?
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What is the biochemical feature of tumor-induced osteomalacia?
What is the biochemical feature of tumor-induced osteomalacia?
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What radiologic abnormality is often diagnosed in patients with osteomalacia?
What radiologic abnormality is often diagnosed in patients with osteomalacia?
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In hereditary hypophosphatemic rickets, which of the following is typically elevated?
In hereditary hypophosphatemic rickets, which of the following is typically elevated?
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Study Notes
Rickets and Osteomalacia
- Rickets is a specific bone disorder of the growing skeleton, occurring only in children and adolescents before epiphyseal fusion has occurred.
- Osteomalacia is generalized softening of the bones, regardless of age or the cause. It can occur in both children and adults.
- Defective mineralization of both pre-osseous cartilaginous and mature osseous matrix results in subnormal linear growth in rickets, a consequence of the involvement of growth plates.
- Defective mineralization of the mature lamellar bone is a characteristic of osteomalacia.
Bone Remodeling and Mineralization
- For proper and optimal mineralization of bone, two criteria must be met:
- Synthesis of lamellar bone matrix by osteoblasts
- Exposure of this matrix to optimal Ca x P product
- Classical osteomalacia has defective mineralization due to a lack of minerals.
- Hypophosphatasia is an example of an enzyme deficiency causing osteomalacia. Other causes include fibrous dysplasia, Paget's disease of the bone, fibrogenesis imperfecta ossium, and osteogenesis imperfecta.
- Normal mineralization of bone matrix occurs in two stages:
- Primary mineralization—the rapid phase, where 75% to 80% of the maximal mineral content is deposited within a few days to weeks
- Secondary mineralization—the much slower phase, where mineral content increases further, reaching about 90% to 95% over several months. Remaining bone matrix is newly formed but not yet mineralized.
- Hyperosteoidosis is characterized by an osteoid surface greater than 15% of the bone surfaces and is seen in conditions with high bone turnover, such as post-menopausal women with estrogen depletion, hyperparathyroidism, or hyperthyroidism.
Pathogenesis
- Vitamin D depletion or deficiency:
- Extrinsic deficiency: poor dietary intake decreased sunlight exposure, or defective 25-hydroxylase in the liver or 1α-hydroxylase in the kidney
- Intrinsic depletion: impaired GI absorption of vitamin D (most common cause of osteomalacia) from intestinal disease, resection, or gastric bypass (although less common)
- Phosphate depletion or deficiency
- Rare, possibly due to prolonged parenteral nutrition, iron deficiency, or phosphate binders
- Second most common cause of rickets and osteomalacia, particularly in areas where vitamin D deficiency isn't endemic.
- Calcium deficiency
- Only causes rickets, not osteomalacia in nutritional hypocalcemia without associated vitamin D deficiency
- Short latency disease - severe 2° HPT from severe calcium deficiency in children produces rickets
- Long latency disease - mild 2° HPT over a long time produces osteoporosis
Clinical Manifestations
- Common clinical manifestations of rickets and osteomalacia:
- Bone pain (diffuse, non-descript, dull, aching, deep, seated, poorly localized; often bilateral and symmetric)
- Muscle weakness and difficulty in walking, especially in the lower extremities
- Open fontanelles, dolichocephaly, frontal bossing, rachitic rosary in infants
- Harrison sulcus, horizontal line of depression in the diaphragm (due to chest muscle weakness), genu valgum, genu varum bowing of long bones, and windswept deformity when walking.
- Looser zones or pseudofractures in bones (stress fractures on radiological images) and skeletal deformities and fractures (less common in adults with osteomalacia).
Biochemical Changes
- Elevated alkaline phosphatase is the most frequent and earliest biochemical abnormality
- Hypocalcemia is a late biochemical manifestation
- Serum phosphate levels vary—they can be low, normal, or high, especially in patients with severe hypercalcemia
- Levels of vitamin D in patients with nutritional osteomalacia are usually low (<10 ng/mL), but not all patients with low vitamin D levels develop rickets or osteomalacia.
- In calcium-dependent rickets, 25-hydroxy vitamin D is either normal or slightly reduced.
- 1,25-dihydroxy vitamin D levels are usually low, but not always, in hypophosphatemic rickets and osteomalacia.
- PTH levels are always elevated in nutritional vitamin D and calcium deficiency-induced rickets and osteomalacia, unless there is concomitant vitamin D deficiency.
Radiological Changes
- Generalized decrease in bone density on X-rays, often with generalized thinning of cortices in the long bones, due to PTH-mediated endocortical bone resorption
- Subperiosteal bone resorption (best seen in the radial aspect of the middle phalanges) , Cod fish vertebrae (symmetrical biconcavity of vertebrae—virtually diagnostic of osteomalacia), Fishmouth appearance of intervertebral spaces, Looser zones or pseudofractures (lucent bands perpendicular to the long axis of the bone)
- Milkman syndrome, enthesopathy, and Rugger Jersey spine.
Diagnostic Approach
- Diagnostic approach involving biochemical, radiologic, and/or histological evaluations
- The approach can be summarized as a series of questions to help identify the type and probable cause of rickets and/or osteomalacia.
Treatments
- Treatment of nutritional rickets and osteomalacia begins with symptom relief, but the speed of recovery in such cases differs significantly relative to different biochemical and/or radiological or histological features observed (e.g., those without significant abnormalities recover quickly compared with those exhibiting prolonged or severe clinical symptoms).
- The goal is not only to relieve symptoms but to achieve restoration of bone strength by mineralizing excess osteoid.
- Treatment often involves vitamin D supplementation (ergocalciferol [D2] is often the initial choice due to the short half-life of calcitriol and alpha-calcidol), potentially in high doses for those with significant malabsorption, and calcium supplementation.
- For cases of severe or refractory hyperparathyroidism (PTH > 500 pg/mL), treatment with calcitriol may be suggested.
- Treatment of secondary or resistant hyperparathyroidism requires vitamin D supplementation and frequent monitoring of serum and urine electrolytes, calcium, and/or phosphate and/or alkaline phosphatase.
Vitamin D-Dependent Rickets and Familial Hypophosphatemic Rickets
- Vitamin D-dependent rickets: Due to a defective 25-hydroxyvitamin D 1α-hydroxylase, the critical enzyme required in the final step of vitamin D biologic activation (can have alopecia).
- Hypophosphatemic Rickets: Most commonly, X-linked. Characterized by proximal renal tubular resorptive disorders (e.g., Fanconi syndrome). Two main types:
- Type 1: Mutation in FGF23 gene (Arg176, Arg 179 resistance to proteolytic processing)
- Type 2: Mutation in ENPP1 gene
- There is a distinguishing clinical manifestation in patients with XLH (i.e., enthesopathy—seen exclusively in X-linked hypophosphatemia).
Tumor-Induced Osteomalacia
- Paraneoplastic syndrome characterized by bone pain, profound muscle weakness, and fractures.
- Often caused by small mesenchymal tumors.
- Biochemical features include hypophosphatemia (< 2.5 mg/dL in ambulatory non-hospitalized fasting patients), low or normal 1,25-dihydroxyvitamin D, and elevated or inappropriately normal FGF23.
Drug-Induced Rickets and Osteomalacia
- Tenofovir and adefovir are the most common causes of drug-induced rickets, due to sporadic Fanconi syndrome with phosphate depletion.
- Symptoms can be managed with vitamin D supplementation.
Conditions that Resemble Rickets and Osteomalacia
- Primary/secondary hyperparathyroidism in children
- Paget's disease of the bone
- Fibrogenesis imperfecta ossium
- Hypophosphatasia
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Description
Test your knowledge on the bone disorders rickets and osteomalacia. This quiz covers the causes, effects on growth, and the underlying mechanisms of these conditions. Dive into the details of bone remodeling and mineralization, and understand the importance of minerals for bone health.
