AssessmentsBone disorders: Pathology review
USMLE® Step 1 style questions USMLE
A 9-year-old boy is brought to the pediatrician by his parents because of bone pain and an abnormal gait pattern. The patient and his family recently immigrated to the United States from India. Prior to immigrating, the patient’s diet consisted mostly of rice and salted vegetables due to food shortages. Vitals are within normal limits. He is below the 10th percentile for height and weight. Radiographic imaging reveals the following findings:
Image reproduced from Radiopedia
Which of the following set of laboratory findings will be most likely present in this patient?
Content Reviewers:Yifan Xiao, MD
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. 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 decreases 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. 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. 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. 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. 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 them. Bisphosphonates should also be used with precaution in individuals with