Bone disorders: Pathology review

Definitions & Key takeaways

There are many different types of bone disorders, from common conditions such as osteoporosis to rarer diseases such as Paget's disease. Bone disorders can be caused by a variety of factors, including genetics, infection, trauma, and diet. While some bone disorders can be treated with medication or surgery, others may require more long-term care. Common bone disorders include osteoporosis, a condition in which bones become weak and brittle due to loss of bone density; rickets and osteomalacia in which bones become soft due to calcium or vitamin D deficiency; and Paget's disease of bone in which there is excessive bone resorption and disorganized bone growth that causes bones to become misshapen.

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Case Study0:00–0:52

While on your rounds, you see two individuals. First up is Jenna, a 70-year-old female who presents with left hip pain after falling while getting out of bed.
She sustained a fracture of the right hip, and preoperative chest x-ray reveals that she had pre-existing asymptomatic vertebral fractures before her fall.
She denies any other symptoms and physical examination was otherwise normal. Then you see Gerald, a 46-year-old male who presents with a mild but noticeable limp and hip pain on the right side after falling from a chair.
Examination is unremarkable. In Jenna’s case, a DEXA scan was performed, revealing a T -2.8 score.
In Gerald’s case, radiographs of the hip showed a right hip fracture and abnormally dense hip bones.Both seem to have some type of bone disorder.
But first, a bit of physiology. Bones have a hard-external layer of cortical bone and a softer internal layer of spongy bone composed of trabeculae.

Physiology0:52–3:45

The trabeculae are like a framework of beams that give structural support to the spongy bone. Now, these are replaced every few years in a process called bone remodeling.
The process has two steps: bone resorption, which is when osteoclasts break down bone by releasing hydrogen and collagenases, and bone formation, which is when osteoblasts form new bone by secreting osteoid seam.
Osteoid seam is mainly made up of collagen and it acts like a scaffold upon which hydroxyapatite, a combination of calcium and phosphate, deposits.
Bone formation requires an alkaline environment, which is why bone cells also produce alkaline phosphatase, an important marker of bone cell activity.
At a cellular level, remodeling begins when osteoblasts release receptor activator of nuclear factor κβ ligand, or RANKL for short, which binds to RANK receptors on the surface of osteoclast, activating them to begin bone matrix demineralization.
Once there’s been sufficient bone demineralization, osteoblasts secrete osteoprotegerin, which inactivates RANKL. This causes the osteoclasts to stop demineralizing the bone, and osteoblasts to secrete osteoid seam.Another high-yield concept is that osteoblasts are derived from mesenchymal stem cells in the periosteum, a membrane covering the surfaces of bones and consisting of an outer fibrous layer and an inner cellular layer.
By contrast, osteoclasts originate from hematopoietic progenitor cells, more specifically from a fusion of monocyte and macrophage precursors.
These differentiate once osteoblasts secrete RANK-L and macrophage colony-stimulating factor or M-CSF, which interact with their respective receptors on the osteoclast membrane.
Now, keep in mind that parathyroid hormone also regulates osteoclast maturation, but it does so indirectly, by stimulating RANK-L and M-CSF secretion from osteoblasts.
However, it’s action actually depends on it’s serum levels. At low, intermittent levels, the hormone exerts anabolic effects- meaning it promotes bone formation.
Conversely, chronically increased parathyroid hormone levels, like, for example, in primary hyperparathyroidism, cause catabolic effects, meaning it promotes bone resorption.
Additionally, the hormone also increases calcium levels and decrease phosphate levels by increasing its urinary excretion.Ok, now let’s talk about bone disorders, starting with osteoporosis where there’s an increased breakdown of bone mass in comparison to the formation of new bone, which results in porous and weak bones.

Osteoporosis3:45–6:24

Factors that accelerate mass loss and increase the risk of osteoporosis are low estrogen levels, as in menopause, and hypocalcemia.
However, something high-yield to know is that the most important factor that influences bone mass is genetics, which explains why some individuals develop osteoporosis earlier than others.
Genetics is also the reason why Caucasians have lower bone densities than those of African descent. Additional risk factors include low weight, alcohol consumption, smoking, drugs like corticosteroids, which can decrease calcium absorption from the gut through antagonism of vitamin D, and medications like heparin, L-thyroxine, and anticonvulsants.
Physical inactivity can also lead to osteoporosis because it causes bone deposition to decrease due to a lack of stimulation, while resorption increases.
And finally, some diseases that can lead to osteoporosis include Turner syndrome, hyperprolactinemia, Klinefelter syndrome, hyperparathyroidism, multiple myeloma, diabetes mellitus, and malabsorption syndromes.
Now, the two most common types of osteoporosis are Type I or postmenopausal osteoporosis, and Type II or senile osteoporosis.
In postmenopausal osteoporosis, decreased estrogen levels lead to to increased cycles of remodeling and bone resorption.
This is because, normally, estrogen inhibits apoptosis in bone-forming osteoblasts and induces apoptosis in bone-resorbing osteoclasts.
With senile osteoporosis, it’s believed that osteoblasts just gradually lose the ability to form bone, while the osteoclasts keep doing their thing unabated.
In both cases, bone resorption usually overtakes bone formation despite normal bone mineralization and lab values for serum calcium and phosphate, causing both cortical and spongy bone loss, as well as widening of the Haversian canals, which are the canals through which blood vessels and nerves travel throughout the bone.
The result is porous bones that have an increased risk of fractures. In osteoporosis, most fractures are fragility or pathologic fractures because they typically occur after minimal trauma, like falling from a chair.People with osteoporosis don’t usually have symptoms until a fracture occurs, usually vertebral fractures, which are also known as compression fractures.

Osteoporosis Symptoms6:24–6:52

These cause back pain, height loss, and a hunched posture. Colles’ fractures, which is a type of fracture of the distal forearm, femoral neck fractures, and hip fractures can also occur, and they’re often associated with postmenopausal osteoporosis, and can cause limping and localized pain.Osteoporosis is usually diagnosed with a dual-energy X-ray absorptiometry or DEXA scan, which tests for bone density.

Osteoporosis Diagnosis6:52–7:57

The test compares the individual's total lumbar spine, hip, and femoral neck bone density to that of the average score of people of similar age, which yields the result, or the T score.
A T score less than or equal to -2.5 standard deviations is diagnostic of osteoporosis. A score between -1.0 and -2.5 means the individual has low bone density, or osteopenia.
Moving on, diagnosis can also be established by a fragility fracture at the hip or vertebra in the absence of other metabolic bone disorders.
One time screening by DEXA scan is recommended in all females 65 years old and above and in younger females with risk factors.
And a high yield fact to remember! lab values like calcium and phosphate are typically normal in osteoporosis.
Treatment for osteoporosis is high-yield and it relies on bisphosphonate drugs like alendronate and risedronate. These are pyrophosphate analogs, an important component of hydroxyapatite, which help bind hydroxyapatite in bone and inhibit osteoclast activity.

Osteoporosis Treatment7:57–11:47

Bisphosphonates have poor gastrointestinal absorption, so it needs to be taken while fasting. Side effects can include jaw osteonecrosis, atypical femoral stress fractures, and, if taken orally, they can cause pill-induced esophagitis, which is why people are advised to take with water and remain upright for 30 minutes after ingesting hem.
Bisphosphonates should also be used with precaution in individuals with renal failure as they are excreted unchanged in the urine.
Next, if osteoporosis is really advanced, teriparatide, a recombinant parathyroid hormone, can be used. Now, even though parathyroid hormone stimulates bone resorption, it’s been found that pulsatile injections with teriparatide activate osteoblasts more than osteoclasts, therefore increasing bone formation.
Some of its side effects include transient hypercalcemia and an increased risk of osteosarcoma, which is why they should be avoided in people with Paget disease of the bone, unexplained elevation of alkaline phosphatase, and in those with a history of cancer or radiation therapy.
Thiazide diuretics like hydrochlorothiazide can be used to treat osteoporosis, especially in those with associated congestive heart failure.
Hydrochlorothiazide boosts calcium retention in the distal convoluted tubules of the kidney and directly stimulates osteoblast differentiation, therefore decreasing mineral bone loss.
As a downside, it can cause hypokalemic metabolic alkalosis and hyponatremia. Additionally, it can also cause hyperGlycemia, hyperLipidemia, hyperUricemia, and hyperCalcemia - all of which can be remembered using the mnemonic HyperGLUC.
Finally, other medications that are commonly tested include denosumab, which is a monoclonal antibody against RANKL that inhibits osteoclasts maturation, and raloxifene, which is a selective estrogen receptor modulator that mimics natural estrogen, both of which be used for postmenopausal osteoporosis.
Although raloxifene has agonist effects in the bone, it acts as an estrogen antagonist in the breast and uterus, which means it can actually decrease the risk of estrogen-positive breast cancer.
In rare cases, calcitonin is also used to treat osteoporosis, which works by decreasing bone resorption of calcium.Prophylaxis in those with risk factors include weight-bearing exercise and adequate calcium and vitamin D intake throughout adulthood.
Hormone replacement therapy with estrogen might also be beneficial. But, because hormone replacement therapy increases the risk of endometrial cancer and of cardiovascular disease, some women might benefit from adding progesterone or progestin to the treatment.
Another thing that you might come across is that hormone replacement therapy, just like pregnancy and oral contraceptives, can increase thyroid binding globulin or TBG levels.
TBG is the protein through which thyroid hormones circulate in plasma so its increased levels also leads to increased total T4 and T3 levels.
However, because the bound form of thyroid hormone is biologically inactive and because the level of free thyroid hormones remains within normal limits, the affected individuals remain euthyroid.Next, osteopetrosis, which means “stone bone,” is a rare genetic disorder that makes bones abnormally dense due to a decrease in bone resorption.

Osteopetrosis11:47–12:24

The condition is associated with mutations in at least nine genes, like the one for carbonic anhydrase II, which impairs the ability of osteoclast to generate the acidic environment necessary for bone resorption.
Without functional osteoclasts, old bone is not broken down as new bone is formed. As a result, bones throughout the skeleton become unusually dense and structurally abnormal, making them prone to fractures.
Symptoms of osteopetrosis depend on the severity of the disease. And depending on which genes are affected, there are three types of disease that can occur: osteopetrosis tarda, the adult form which is benign and asymptomatic; osteopetrosis congenita, and marble bone disease, the infantile forms, both of which are severe.

Osteopetrosis Symptoms12:24–14:27

Osteopetrosis congenita is associated with failure to thrive and growth delay. When skull bone tissue grows excessively, it can narrow the cranial foramina, an opening on the skull base through which many cranial nerves pass, and cause symptoms like proptosis, which is protrusion of the eyeball; blindness; deafness; and hydrocephalus, which is cerebrospinal fluid accumulation within the brain ventricles.
When bone tissue begins to replace bone marrow in the medullary cavity, it can cause severe bone marrow failure, resulting in pancytopenia.
Consequently, people with severe osteopetrosis are at risk of abnormal bleeding due to thrombocytopenia, anemia, and recurrent infections caused by withe blood cell depletion.
Now, the body tries to compensate for bone marrow failure by stimulating extramedullary hematopoiesis in the liver and spleen, resulting in hepatosplenomegaly and hypersplenism.
Unfortunately, it can’t really keep up with body demands, and, as a result, these individuals die due to severe anemia, bleeding, and infections.
Marble bone disease is not characterized by bone marrow failure, but there can be renal tubular acidosis because carbonic anhydrase II is also involved in many kidney functions.
Additionally, the affected individuals might have a short stature and present with intracranial calcifications, hearing loss, dental abnormalities, seizures, and psychomotor impairment.

Osteopetrosis Diagnosis14:27–15:54

Diagnosis is established by X-ray, which most often detect abnormally dense bones and narrowed medullary cavity. Some specific signs that can appear include diffuse symmetric sclerosis causing the classic “bone-in-bone” appearance of the vertebrae and phalanges, where there’s an even radiopaque area surrounded by a trim of radiolucent tissue; and sclerosis of skull base, pelvis and vertebral end plates, giving rise to “sandwich” vertebrae where the superior and inferior margins of the vertebrae are opaque and the middle radiolucent.
Lab tests can show thrombocytopenia, anemia, decreased calcium, and elevated serum acid and alkaline phosphatase levels.
It might be good to know that alkaline phosphatase is the biochemical marker of osteoblast and osteoclast activity in the blood.
However, it can come from other sources too, like the placenta, liver, and intestine, which means it is not highly specific for bone cell activity.
In these cases, electrophoresis and monoclonal antibodies can be used to determine the source of alkaline phosphatase. And finally, in addition to the routine laboratory investigations, genetic testing should be undertaken in all individuals with suggestive symptoms of osteopetrosis.
Osteopetrosis tarda doesn’t usually warrant any treatment except for fragility fractures. Infantile osteopetrosis, on the other hand, might benefit from childhood bone marrow transplant, which is potentially curative as osteoclasts are derived from monocytes.

Osteopetrosis Treatment15:54–16:32

Symptomatic treatment can also be provided, ranging from treatment of fragility fractures and erythropoietin for any associated anemia to corticosteroids to alleviate both the anemia and stimulate bone resorption and vitamin D to stimulate dormant osteoclasts and stimulates bone resorption.
Next, Paget disease of bone or osteitis deformans is a disorder where there’s abnormal bone remodeling that happens in either some regions of a single bone or the whole skeletal system.

Paget Disease of Bone16:32–18:29

Most often, it involves the skull, lumbar vertebrae, pelvis, and the femur. Now, the exact cause of Paget disease of bone is unclear, but it can get triggered by infections, especially with measles virus, and it’s also linked to genetic mutations like the SQSTM1 mutation, which encodes a protein involved in regulating osteoclasts.Ok, so there are three main phases to the disease, which might pop up in your exams.
Phase one is the lytic phase, and that’s where osteoclasts, which in Paget disease are large and have over 100 nuclei, start to aggressively demineralize the bone up to 20 times more than normal.
Phase two is the mixed phase, and that’s where the lytic phase occurs alongside the blastic phase. In the blastic phase, there’s a rapid but relatively disorganized proliferation of new bone tissue by an unusually large number of osteoblasts.
The result is that collagen fibers are deposited in a haphazard way. Phase three is the sclerotic phase, and that’s where new bone formation exceeds bone resorption, and the final result is bone that’s structurally disorganized and therefore weaker than normal healthy bone.
At the same time vascularization of the sclerotic bone increases as well, mainly because osteoclasts seem to secrete cytokines that activate fibroblasts and endothelial cells proliferation, which induce new blood vessel formation.
Eventually, the osteoblastic activity also slows down, and there’s a dormant state in the disease, called the “burned-out state,” which is sometimes referred to as the quiescent phase.
Early on Paget disease of bone doesn’t typically cause symptoms, but over time, the misshapen bones can impinge on nerves and cause bone pain.

Paget Disease Symptoms18:29–20:02

In addition, if the skull is involved, the overgrowth of bones can make a person have a lion- like face, which is called leontiasis.
And because the skull is larger, the affected individuals often say that they need a bigger hat. The bony overgrowth can also narrow the auditory foramen and impinge on the auditory nerve, leading to hearing loss.
If the optic nerve is compressed as it passes through the optic canal, there can be vision loss. Sometimes the accelerated bony growth can lead to genetic mutations that cause a bone cancer called osteosarcoma, which in this case it’s called Paget sarcoma.
Other bony deformities from Paget disease of bone include kyphosis, which is an excessive curvature of the spine making a person face down to the ground, lower limb muscle weakness, from misshapen vertebrae compressing the spinal cord, and pelvic asymmetry.
It can even lead to bowlegs if the tibias and femurs get too weak to support a person’s weight and begin to bend over time.
If the parts of the bone that are involved in a joint are involved, it can result in arthritis. Although cardiovascular involvement is uncommon, those with widespread Paget disease and extensive hypervascularization of the bone marrow can present with an arteriovenous shunt leading to high output cardiac failure.The diagnosis of Paget disease of bone is usually made via blood tests, which can present with elevated levels of alkaline phosphatase, which gets released into the blood as bone is destroyed, with normal calcium, phosphate, and parathyroid hormone levels.

Paget Disease Diagnosis20:02–20:58

In addition, an X-ray scan might show the mosaic pattern that’s characteristic of Paget disease of bone, which consists of radio opaque and disorganized areas of sclerosis interspersed with lucent and more normal bone.
Long bone chalk-stick fractures might also occur, which are clean fractures that look exactly like a piece of chalk broken in two.
Finally, keep in mind that a bone biopsy is usually done to exclude malignancies which can mimic some of the findings of Paget disease of bone.
Typical findings include haphazardly-orientated collagen fibers that create a mosaic pattern.Treatment of Paget disease of bone includes pain relief medication as well as antiresorptive medications like bisphosphonates, which slow down the bone lysis.
In addition, surgery can help correct bone deformities, decompress an impinged nerve, and reduce associated fractures.Now, inadequate bone mineralization manifests as rickets in children and osteomalacia in adults.

Paget Disease Treatment20:58–21:18

Inadequate bone mineralization can be due to a deficiency or impaired metabolism of vitamin D, phosphate, or calcium. When these elements are missing osteoblasts don’t have enough calcium and phosphate to deposit into the organic matrix.
In children, because the growth plates haven’t closed yet, this leads to cartilaginous growth plates, softening of the bones, impaired growth of bones, and bone malformations.

Rickets & Osteomalacia21:18–23:23

Whereas, in adults, where the epiphyseal plates have already closed, it only causes defective mineralization of osteoid, resulting in weakening and softening of bones, which makes them easier to fracture.
Ok, now vitamin D deficiency is the most common cause of both rickets and osteomalacia. Often, it occurs in those who aren’t exposed to enough UV light since UV stimulates vitamin D synthesis.
This is especially true for those who have recently immigrated from an area with a sunny climate. Other causes of vitamin D deficiency include intestinal malabsorption, which can be seen with celiac disease or Crohn's disease; and users of medications like phenytoin, an anticonvulsant that’s metabolized by the same liver and kidney hydroxylase enzymes that’s needed for the synthesis of vitamin D.
So it makes sense that another cause of vitamin D deficiency is liver and kidney disease. For example, rickets or osteomalacia can occur in chronic liver disease, due to the liver's inability to turn inactive vitamin D into 25-hydroxy-vitamin D.
The same goes for chronic kidney disease, where the kidneys can’t turn 25-hydroxy-vitamin D into 1,25-hydroxy-vitamin D.
Both conditions result in an active vitamin D deficiency, which leads to impaired bone mineralization. With both rickets and osteomalacia, symptoms include diffuse bone and joint pain, proximal muscle weakness, bone fragility, and increased risk of fragility fractures.
Because of low levels of calcium, there may also be muscle spasms and numbness. Rickets-specific symptoms include thin, soft skull bones, which is called craniotabes, delay in the closure of fontanelles, and bow legs, also known as genu varum.

R & O Symptoms23:23–24:33

There may also be an enlarged, prominent frontal bone. Additionally, rachitic rosary can be seen which are little bumps that appear along the chest wall due to the widening of the junction between the ribs and costal cartilage in front of the rib cage.
Now, those with severe vitamin D deficiency might also present with symptoms of hyperparathyroidism, like weakness, depression, confusion, and increased urination.
The parathyroid gland increases in size since it needs to secrete more parathyroid hormone as a response to low vitamin D and calcium levels..
Rickets and Osteomalacia are usually diagnosed with lab tests, which show abnormally low vitamin D levels in blood serum, low blood calcium, and elevated serum alkaline phosphatase.
As a result of low calcium, there may also be high PTH, which may also lead to low serum phosphate. Now, X-ray imaging of rickets and osteomalacia might show signs of decreased bone mineral density or osteopenia.

R & O Diagnosis24:33–25:51

First, there’s Looser zones, which are bands of low bone density that form on the surface of the bone. And they look a bit like bone fractures, so they’re also called pseudofractures.
Looser zones frequently develop in the inferior and superior pubic rami of the pelvic bone. In rickets, an X-ray image of the wrist and long-bone metaphysis might show metaphyseal cupping and flaring.
With metaphyseal cupping, the edges of the metaphysis widen laterally like flared jeans and the metaphysis itself drops inwards, towards the diaphysis which makes it look a bit like a cup.
Another X-ray finding in rickets is metaphyseal fraying, where instead of the metaphyseal surface appearing smooth, it appears fuzzy and irregular.Treatment for both rickets and osteomalacia involves oral vitamin D supplementation and treating the underlying cause, which could be any condition affecting the organs responsible for vitamin D activation.
In addition, preventive measures include vitamin D supplementation during pregnancy, and administering vitamin D drops to neonates and infants, especially those who are breast fed.
Alright, as a quick recap, osteoporosis refers to decreased bone density due to increased bone resorption compared to bone formation, resulting in porous bone with an increased risk of fracture.

R & O Treatment25:51–26:17

There are many risk factors, including decreased estrogen levels, physical inactivity, and smoking. Osteopetrosis is a genetic disorder that causes an increase in bone density secondary to osteoclast dysfunction.
In adults, it is mostly asymptomatic but it can cause fragility fractures. In children, it can lead to bone marrow failure, nerve palsies, failure to thrive and grow, hepatosplenomegaly, and renal tubular acidosis.

Review26:17–28:02

In Paget disease of bone there’s an excessive amount of bone resorption and haphazard bone growth. There’s a lytic phase, a mixed phase, and a sclerotic phase, which result in weak and hypervascularized bones.
Paget disease of bone is usually asymptomatic, but can result in misshapen bones that cause fragility fractures and lead to nerve compression.
Rickets and osteomalacia are conditions in which bone softening occurs due to a mineral deficiency or lack of vitamin D.
Now, rickets presents in children and osteomalacia in adults, and symptoms depends on if there was growth plate closure.
Nonetheless, some key symptoms of rickets are craniotabes and bow legs. In both osteomalacia and rickets, there can be diffuse bone and joint pain, proximal muscle weakness, bone fragility, and increased risk of fractures with minimal trauma.Now back to our cases.
Jenna is the 70-year-old woman who presents with hip pain after falling while getting out of bed. She sustained a fragility fracture of the right hip and preoperative chest x-ray also reveals that she had existing asymptomatic vertebral fractures before her fall.
Based solely on the fact that Jenna is an older female who suffered a fragility fracture of the hip, we should suspect osteoporosis, although we need to rule out other metabolic diseases.
DEXA confirms our diagnosis by showing a T score of -2.8 standard deviations. Gerald, on the other hand, is the 46-year-old man who presents with a mild but noticeable limp and right hip pain after falling from a chair.

Summary28:02–29:01

Examination was unremarkable, but radiographs of the hip showed generalized sclerosis and increased radiodensity of the hip bones.
Now, based on his clinical picture, we should suspect osteopetrosis tarda, although genetic testing would be required to confirm the diagnosis.
who suffered a fragility fracture of the hip we should suspect osteoporosis Although we need to rule out other metabolic diseases Dexa confirms our diagnosis by showing a T score of negative 2.8 standard deviations Gerald on the other hand is the 46 year old man who presents with a mild but noticeable limp and right hip pain after falling from a chair Examination was unremarkable but radio graphs of the hip show Generalized Sclerosis and increased radio density of the hip bones Now based on his clinical picture we should suspect Osteopetrosis Targa although genetic testing would be required to confirm the diagnosis