Metabolic Bone Diseases Flashcards
What is cortical bone also called and what is the opposite of it? What does it make up?
Compact bone - makes up the outside of the shafts of the long bones (diaphysis) as well as the metaphysis / diaphysis
Trabecular bone / cancellous / spongy bone - opposite of compact / cortical bone -> makes up the metaphyseal area in the middle (head of the bone) and part of the central marrow cavity of long bones
What type of bone is the axial skeleton made up of mostly? Why is this relevant?
Mostly cancellous / spongy bone -> i.e. in the vertebral bodies. There is only a thin layer of compact bone on the outside.
Spongy bone has a much higher turnover rate (25% per year) than compact bone.
What is meant by coupling and balance in one formation?
Coupling - formation of bone occurs in coupling with resorption (osteoblasts / osteoclasts are coupled together)
Balance - resorption and formation of bone should be equal
What is the function of sclerostin protein? How might this become a drug target?
When Lrp5 binds Wnt, there is osteoblastic activity.
Sclerostin interacts with Lrp5 to prevent Lrp5 from interacting with Wnt.
If sclerostin can be targeted by a drug, bone formation can be increased.
What is the mechanism of action of estrogen in preventing bone loss? What drug is this similar to?
Estrogen upregulates osteoprotegerin, which acts as a decoy receptor for RANKL on osteoblasts. Prevents binding of RANK on osteoclasts to activate them.
Denosumab is a monoclonal antibody to RANKL.
What is the usual cause of osteoporosis and what will the lab values be?
Usual due to old age and menopause.
It is distinguished by other conditions which decrease bone density because lab values are normal:
Normal serum calcium, phosphate, PTH, and alkaline phosphatase.
What is the risk of osteoporosis ultimately based on and when is this achieved? How can this value be increased?
Based on peak bone mass determined by age 30
- > increased by diet and exercise
- > somewhat determined genetically by vitamin D receptor variants
How does bone mass change over a lifetime, and how do you make an objective diagnosis of it? Describe T vs Z score?
Decreases at about 1% per year -> everyone will get osteoposis eventually
Objective diagnosis: T score
How is diagnosis of osteoporosis made clinically?
Via a fragility fracture -> i.e. vertebral or hip fracture. Weight bearing structures are broken in situations when they normally shouldn’t be (low energy activities, i.e. walking)
What are some drugs which can cause osteoporosis?
Steroids - i.e. glucocorticoids
Anticonvulsants - decrease vitamin D levels
Thyroid replacement therapy - hyperthyroidism increases bone loss
Alcohol / smoking - poor nutrition status
What are common areas for fractures in osteoporosis and what is a common clinical symptom?
Vertebrae, hip, distal radius
Common symptom - Kyphosis w/height loss (remember 1” from Drivers’ license)
What agents are commonly used to treat osteoporosis?
- Bisphosphonates
- Denosumab
- Teriparatide - PTH analog given in bursts to stimulate osteoblasts
- Estrogens
What is the spectrum of CKD-MBD?
Chronic Kidney disease Mineral and Bone Disorder
- Increased bone turnover - osteitis fibrosa cystica
- Mixed uremic osteodystrophy
- Decreased bone turnover - adynamic bone disease
Overall leads to the condition of renal osteodystrophy with subperiosteal thinning and fragility of the bones
What causes autosomal dominant hypophosphatemic rickets?
A mutation in FGF23 molecule making it resistant to inactivation by PHEX
What is vitamin D deficient vs dependent vs resistant rickets?
Deficient - malabsorption / malnutrition of vitamin D - most common form
Dependent - absence of 1-alpha-hydroxylase enzyme
Resistant - vitamin D receptor mutation, most often X-linked
Are the bones soft or brittle in osteomalacia? What lab will be elevated (other than PTH)?
They are soft -> not enough calcium. This is adult-onset rickets.
Alkaline phosphatase will be elevated -> used by osteoblasts when they try to build bone (need basic environment to build bone, and acidic environment to destroy it)
What is the general underlying pathophys of Paget disease of bone and does it happen everywhere or is it focal? Include the phases of disease.
Imbalance between osteoclast and osteoblast function -> a localized rather than systemic disease.
- Lytic phase - osteoclasts overwork without the permission of osteoblasts
- Mixed phase - osteoblasts begin working to rebuild bone ASAP
- Sclerotic - osteoclasts stop, but blasts keep building and cause bone overgrowth of poor quality
What is the etiology of Paget disease and in what bones is it most severe?
Genetic in some, possible viral (measles)
Most severe in skull, pelvis, and long bones
What pattern can be seen in lamellar bone in Paget disease, histologically and on X-ray?
Histology: Mosiac or puzzle piece pattern of bone with cement lines not having been sealed properly
X-ray: Thick, sclerotic bone which fractures easily
What are common presenting symptoms of Paget disease? One of these is a lab value.
- Increasing hat size with lion-like faces -> craniofacial involvement
- Hearing loss -> impingement on cranial nerve + auditory foramen narrowing + damage to ossicles themselves sometimes
- Bone pain due to microfractures
- Isolated elevated alkaline phosphatase (no other labs abnormal).
What are possible complications of Paget disease of bone?
- High output cardiac failure -> due to AV shunts formed in poorly formed bone
- Osteosarcoma
What is the treatment for Paget disease of bone?
Bisphosphonates and calcitonin, especially early in the disease course
What is the cause of tumor induced osteomalacia?
FGF23 secreting tumor -> paraneoplastic syndrome of renal phosphate wasting and decreased vitamin D levels.
What is the cause of osteogenesis imperfecta and the usual inheritance pattern? What is the characteristic of the bone formed?
Usually autosomal dominant, due to decreased production of type I collagen.
Bones are very brittle with reduced mass, easy fractures.
What are the clinical features associated with osteogenesis imperfecta? What might it be confused with?
BITE
B = Bones - multiple fractures
I = Eye -> blue sclera from choroidal veins showing (translucent connective tissue)
T = Teeth, - abnormal dentin
E = Ears- hearing loss, due to abnormal ossicles
Confused with child abuse -> look for ITE signs
What is the pathophysiological problem is osteopetrosis?
petrosis = hard
Bones are abnormally hard and thick due to decreased resorption
-> bone fractures easily due to poor OSTEOCLAST function
What are the clinical features of osteopetrosis?
- Easy fractures
- Bone fills the marrow space -> pancytopenia, extramedullary hematopoesis “myelophthisic process”
- Vision / hearing impairment -> impingement of cranial nerves from thickening of skull
- Hydrocephalus - foramen magnum narrowing
- Poor teeth eruption
What is the most common enzyme deficiency underlying osteopetrosis and what other symptom is associated with this variant?
Carbonic anhydrase II deficiency (also used in proximal tubule)
-> needed for acid environment of Howship’s lacunae
Associated with a Type II (Proximal) renal tubular acidosis
What is the treatment for osteopetrosis?
Bone marrow transplant -> osteoclasts are derived from monocytes and can be replaced
What enzyme is deficient in hypophosphatasia? Why does this matter?
Tissue nonspecific alkaline phosphatase (TNSALP)
TNSALP is required to cleave inorganic pyrophosphate and PLP (B6) outside of cells.
If inorganic pyrophosphate is not cleaved -> accumulation inhibits hydroxyapatite -> osteomalacia
If PLP is not cleaved -> B6 cannot enter cells -> severe CNS neurotransmitter deficits
How severe is hypophosphatasia?
It’s a spectrum cuz there are over 200 TNSALPs which can be decreased and contribute to this condition.
Autosomal recessive forms -> very severe, infantile death
Autosomal dominant forms / some recessive forms -> less severe, adult onset
What are some of the characteristic symptoms of childhood and adult hypophosphatasia?
Childhood -> craniosynostosis, rickets, premature loss of deciduous (baby) teeth
Adult -> easily fracturing metatarsals, mildly decreased TNSALP.
What is the cause of autosomal dominant osteopetrosis type 1 (ADO1)? I’ll give you a hint: he’s obsessed with this pathway from earlier in the lecture.
LRP5 activating mutation -> activates the Wnt pathway, makes it immune to inactivation by interaction with sclerostin.
Remember, the Wnt pathway is involved in beta-catenin promotion of growth / bone formation in this case.
What is the phenotype of ADO1?
Dense skull base
Wide jaw
Torus palatinus -> bone growth of palate.
