Weatherly's Woes

OSTEOPOROSIS

Thin bones

Osteoporosis refers to the gradual loss of bone density commonly seen in little old ladies. There is a loss of both trabecular and spongy bone mass. The underlying cause of osteoporosis is an imbalance between bone resorption and bone formation. Bone is constantly being destroyed and rebuilt. This turnover helps to keep bone “fresh.” At any given point, about 10% of your bone is being actively turned over. This recycling process is modulated in many different ways, one of the most important regulators is estrogen. Estrogen is osteoprotective. That’s why bone density typically falls after menopause (or an oophorectomy). While men can get osteoporosis, it’s comparatively rare. Other risk factors include old age, alcoholism, tobacco, being underweight (obesity is protective), lack of exercise, steroid use and proton pump inhibitor use (stomach acidity increases calcium absorption). New research in the past decade has revealed that bone is a highly metabolically active organ, with lots of very complex pathways. I won’t go into them here, but my point is that bone research and pharmacology is a booming field at the moment.

Why does osteoporosis matter? Because it increases the likelihood of a fracture. In elderly patients, a hip or back fracture carries a terrible prognosis. Once granny’s hip breaks, she loses the ability to get around on her own, she can no longer exercise, she becomes deconditioned, she gets blood clots and infections from lying around all day, etc. A hip fracture is like a needle that breaks the camel’s back.

Osteoporosis is diagnosed with a special x-ray called a DEXA scan that measures bone density. DEXA scan results are reported in terms of a “T-score,” which is a bit of a weird unit. The patient’s density is compared to the density of the average 30 year old woman. A T-score of 0 means that you’re built like a 30 year old. A T-score of 2 means that your bones are really dense! But a T-score of less than -2.5 means that you have osteoporosis. DEXA scans are recommended for all women over 65.

Treat with Bisphosphonates (Alendronate), which work like landmines. Bisphosphonates closely resemble pyrophosphate, a phosphorus-rich molecule used to construct bone. Osteoblasts inadvertently weave bisphosphonates into the bone. Eventually an osteoclast will resorb that piece of bone. Now that it’s inside the osteoclast, the bisphosphonates get to work. They have a molecular side-chain that can permanently disable the osteoclast that ate it. By reducing the activity of osteoclasts, they can decrease the body’s rate of bone loss. Note that bisphosphonates are very harsh on the GI system, especially the esophagus. If taken improperly, they can cause erosive lesions of the esophagus and stomach. Bisphosphonate pills should be taken first thing in the morning on an empty stomach, with a full glass of water, and then you should avoid laying down for at least 30 minutes. Bisphosphonates can also rarely cause avascular necrosis of the jaw and unusual “bisphosphonate fractures” of the femur (hip fracture that occurs at the sub-trochanteric region rather than the usual femoral neck). Bisphosphonates are the best drug for treating osteoporosis, by far. But there are a few other options. Teriparatide is a daily injectable PTH analog that increases osteoblast activity. Selective Estrogen Receptor Modulators (SERMs), RANKL Inhibitors (Denosumab) and Calcitonin are less popular options.

By definition, osteoporosis has normal levels of calcium and phosphorus. I speculate that the calcium and phos can adjust over time because osteoporosis is such a slow process. Despite normal levels, one of the cornerstones of treatment and prevention is calcium supplements and vitamin D supplements.

Osteopenia is mild osteoporosis. It’s defined by a T-score between -1 and -2.5.

OSTEOPOROSIS DRUGS

Boney bois

For those curious, here’s bone pharmacology. This is very low yield.

OSTEOPETROSIS

Thick bones

Osteopetrosis is the dense bone disease. Their osteoclasts don’t work. Specifically, they lack the ability to make acid to dissolve bones due to a carbonic anhydrase 2 mutation. Osteoclasts are great because they weed out unhealthy, old or brittle parts of the bone matrix. And without them, the bones get heavy (bright white bones on an x-ray), brittle (making them easy to fracture) and filled-in (leaving no room for the bone marrow, resulting in pancytopenia and extramedullary hematopoiesis). Additionally, the ossicles stop working (hearing loss) and the cranial nerves get squished in their foramina (ophthalmoplegia, etc). If the foramen magnum is squished, CSF can build up in the skull (hydrocephalus). It also tends to cause scoliosis in younger patients. Since carbonic anhydrase is defective, patients can also get renal tubular acidosis (non-anion gap metabolic acidosis), but the point I really want to emphasize is that dense bones fracture easily. The treatment for osteopetrosis is really cool. You give a bone marrow transplant, with the hope of replacing their broken osteoclasts, since osteoclasts are descended from macrophages. Note that the alkaline phosphatase level is increased.

Normal pelvis x-ray

Osteopetrosis pelvis x-ray

OSTEOGENESIS IMPERFECTA

Broken type 1 collagen

Osteogenesis Imperfecta is a disease where there is an inability to make Type 1 Collagen, which leads to poopy bones. Specifically, patients lack the ability to form the triple helix of collagen. It’s usually due to an autosomal dominant mutation in COL1A1 or COL1A2 (COL1 is short for Collagen 1). Type One Collagen is found in bones and tendones. In bones, osteoblasts synthesize type 1 collagen and bundle it together into something called Osteoid.

Bones - broken bones and deformities. Give bisphosphonates to prevent fractures

I (eye) - blue sclera. The whites of their eyes are thin, exposing the underlying blue choroidal veins

Teeth - translucent, opalescent and fragile teeth that lack dentin

Ears - hearing loss due to ossicle deformities

Skeletal deformities

Blue sclera

EHLERS-DANLOS SYNDROME

Flexible collagen disease

Ehlers-Danlos Syndrome (EDS) is a genetic disease that impairs collagen synthesis. There are 13 different subtypes involving over 19 genes. Whew! Most patients are quite flexible, as collagen is found in cartilage, bones and tendons. Here are the most important subtypes.

Classical EDS (cEDS) causes hypermobile joints (flexible), hyperelastic skin (stretchy skin) and frequent bruising. Joining subluxations and dislocations are common. It’s caused by a defect in type 5 collagen.

Hypermobile EDS (hEDS) is quite similar to cEDS, but unlike the other 12 subtypes, we haven’t found a causative genetic mutation for hEDS. That means that the diagnosis rests on subjective clinical symptoms, like the degree of skin stretchiness. This is by far the most common type of EDS. It’s also the most controversial!

Vascular EDS (vEDS) is due to a defect in type 3 collagen, which comprises the reticular fibers found in the walls of blood vessels and other organs. They have fragile vessels! It can result in aortic dissection, berry aneurysms and popped organs (e.g., pneumothorax or uterine rupture).

Hyperelastic skin

Hypermobile joints

MARFAN SYNDROME

Lanky Bois

Marfan Syndrome is an autosomal dominant defect in fibrillin (FBN1 gene on c15). Fibrillin is a glycoprotein that forms a sheath around elastin. Elastin is an ingredient of bones, big blood vessels and eyes. Marfan's causes problems with the musculoskeletal and cardiovascular systems.

Homocystinuria is a genetic condition with symptoms that are very similar to Marfans. The differences are that their eyes sublux downward plus there is often intellectual disability. The underlying cause is an inherited defect in homocysteine metabolism (cystathionine beta synthase enzyme).

PAGET DISEASE OF BONE

Osteitis Deformans

Paget Disease of Bone is where bone growth is disorganized. “Disorganized” is such a broad term, and I think it’s horribly overused in medical texts, but in this case it’s appropriate - here’s why. I’m going to break this down in three different phases.

Phase 1 (Osteoclast hyperactivity) - In the first phase, some unknown trigger makes a group (localized symptoms) of osteoclasts turn berserk (they stop obeying RANKL / OPG messages from the osteoblasts), and they start to dissolve too much bone.

Phase 2 (Mixed hyperactivity) - In the second phase, the osteoblasts pick up the pace to match the clasts (this osteoblast proliferation increases the risk for osteosarcoma). Note that the Alk Phos will be high, since the blasts are busy, but the other lab values should be pretty normal. Paget’s is the most common cause of an isolated high alk phos in an elderly adult! This frantic pace results in sloppy craftsmanship. The bone is of poor quality -- it’s thick, sclerotic and fractures easily (painful “chalk-stick” microfractures are common). The most common symptom of Paget’s is bone pain. Although the blasts are making a lot of bone, they don’t have time to seal their new bone together (seen on histology as a “mosaic pattern” with cement lines, aka puzzle piece bone). Many of the bones will enlarge. In the face, this can result in a “lion-like” facies and an enlarging hat size. The ossicles can also be affected, resulting in hearing loss. Fun fact, this is believed to be the cause of Beethovan’s deafness.The skull foramina may close shut, causing cranial nerve lesions. The bone becomes a bustling hub of activity, requiring the formation of many new blood vessels -- so much so that it can create an AV shunt, which may lead to high output heart failure!

Phase 3 (Osteoblast hyperactivity) - In the third phase, eventually the osteoclasts tire out, leading to a brief period of osteoblast dominance (sclerotic phase).

Phase 4 (Quiescent phase) - Finally, the blasts chill out. In some individuals the disease process stops, but in others fibrosis replaces their bone marrow.

Treat Paget with things that directly inhibit osteoclasts, like Bisphosphonates. Drugs that only work by modulating OPG or RANK (SERMs, PTH, etc) will not work, since the clasts are autonomous in this condition. Treatment is rather complicated in real life, but we aren’t expected to know the details.

SEVERE VITAMIN D DEFICIENCY

Rickets & Osteomalacia

In a severe Vitamin D deficiency, there aren’t enough ingredients to make bone. While the osteoblasts will make plenty of excellent osteoid, there isn’t enough calcium or phosphate to mineralize that osteoid into bone. The osteoblasts sense that there are weak bones, and they (futilely) work harder, resulting in a high Alk Phos. There are a lot of causes of a severe Vitamin D deficiency. You could have poor intestinal fat absorption, since Vitamin D is a fat-soluble vitamin. Since it’s partially processed in the skin, you could get it from avoiding sunlight, which is pretty common in nursing homes. Since it’s also processed in the kidneys and liver, you could get it from kidney or liver disease. But regardless of the cause, the treatment will probably consist of Vitamin D supplements.

RICKETS occurs in children. It makes their bones soft. Kids obviously make a lot of new bone. In rickets, that new bone will be deformed. They can have a pigeon breast deformity, craniotabes (soft skull), frontal bossing (big frontal skull bone), rachitic rosary (a vertical line of lumps on the costochondral cartilage) and leg bowing (genu varum). There’s a bunch of unused osteoid laying around, which migrates and settles into weird places like the costochondral junctions (rachitic rosary). For some reason, they develop bony protuberances at their wrists, because their styloid process grows (into a “cup” or “flare” shape).

OSTEOMALACIA occurs in adults. They don’t suffer from deformities, since their epiphyseal plates are already closed. The only symptom is fragile bones, which manifests as fractures. There is one kind of fracture that is relatively specific for osteomalacia -- pseudofractures. These subtle fractures are tiny and hard to spot on an x-ray, but cause lots of bone pain.

ACHONDROPLASIA

Short Limbs

Achondroplasia is the most common form of dwarfism (70% of little people). It’s also important because it highlights the normal physiology of bone growth, specifically endochondral bone formation. Endochondral growth is responsible for long bone growth, where cartilage is transformed into bone -- it’s very active during puberty. Achondroplasia is an autosomal dominant genetic condition that stops endochondral bone formation. So patients have short limbs with a normal head and torso. Patients retain membranous ossification (which makes the chest, skull, jaw), which is why patients will have a large head and chest relative to their limbs. They have short fingers and toes, which can give rise to a trident shape (see image). Interestingly, Achondroplasia is due to an activating mutation in Fibroblast Growth Factor Receptor 3 (FGFR3), which (despite it being “activating”) turns chondrocytes off. 85% of cases are sporadic.

The legendary Jason Acuña of Jackass

AVASCULAR NECROSIS

Bone attack

Avascular Necrosis is ischemic bone death. It’s like a heart attack for bones. This is bad because (a) it hurts, (b) it can fracture and (c) it will cause arthritis down the road. It can happen anywhere, but focus on these two bones:

Scaphoid - the scaphoid is a wrist bone. It sometimes gets fractured during falls. Scaphoid fractures are very messy. That’s because the blood supply to the Scaphoid bone is very wimpy, and is often obliterated during a fracture. Scaphoid avascular necrosis is notorious for causing severe, untreatable wrist arthritis. Complicating this, Scaphoid fractures are often undetectable on x-ray, so the best way to diagnose it is by pressing on their anatomical snuffbox. If that elicits tenderness, call ortho.

Femoral Head - the femoral head has a wimpy blood supply too -- the medial circumflex femoral artery is a total joke. It anastomoses with the obturator artery on top of the femoral head. Trauma to the hip can disturb these blood vessels, resulting in a watershed infarction. But there are a lot of other causes: Steroids, Sickle Cell Disease, Lupus, the Bends (Caisson disease), Gaucher disease and Alcoholism. Legg-Calvé-Perthes disease is a rare idiopathic cause that affects young kids. While scaphoid necrosis is annoying, femoral head necrosis is permanently disabling, because it will inevitably result in a hip fracture since it’s a weight bearing joint. Hip fractures are bad news bears.

OSTEOMYELITIS

Bone infection

Osteomyelitis is a bone infection, usually bacterial. It causes bone pain and a fever. Bacteria usually reach the bone via the blood (hematogenous spread) from a distant infection, but it can also spread from overlying skin that is infected (local spread). Osteomyelitis likes to seed the metaphysis in kids and the epiphysis / vertebrae in adults. The infection creates a bubble of liquefactive necrosis (lytic focus). While x-rays can spot severe or chronic infections (look for a “dissolved” bone), the gold standard imaging choice is an MRI. Empiric antibiotic treatment includes Vancomycin and Ceftriaxone. Then get a bone biopsy to determine a more individualized antibiotic choice.

Most board questions will ask you to pair a rare organism to a risk factor.

A nasty shoulder infection