Osteoporosis and metabolic bone disease Flashcards
Describe the process of bone remodeling
Bone remodeling, in brief, is the process by which osteoclasts eat old bone and stimulate osteoblasts to make new bone.
The activity of osteoblasts is easy to comprehend: make bone where needed. Osteoclasts are bit trickier: why resorb bone?
The process of resorption exists for two reasons:
first, to liberate calcium and other ions; and
second, to clear out worn out pieces of the skeleton and promote the deposition of newer, better material.
Osteoclastic resorption occurs by secretion of acid and proteolytic enzymes which digest the bone matrix; Ca2+ and PO43- are then taken up by the osteoclasts and released into the circulation.
Bone formation occurs by osteoblasts secreting an organic matrix (osteoid) and then mineralizing the matrix.
When the remodeling process is skewed such that, over time, there is more eating than replenishing, you get osteoporosis.
When the remodeling process is aborted, say in avascular necrosis, bad bone accumulates. (Seen here as density). This can lead to collapse and failure of the subchondral (“under the cartilage”) bone thus can lead to arthritis.
When the remodeling process just can’t keep up with (new) mechanical demands, like over-exercising, you get a stress fracture
as shown on the bone scan to the right (xrays do not detect this)
When you get a long bone fracture, bone remodeling kicks in to literally remodel the callus and lay down new bone (not scar). This is the final step of the fracture healing cascade, shown to the lower left And to be sure, when the bone needs to liberate calcium and other ions, it employs osteoclasts and invokes the process of bone remodeling; as such the invocation of the bone remodeling program is a key feature of metabolic bone disease (such as hyperparathyroidism).
Bone resorption occurs from osteoclastic breakdown of trabecular bone via the secretion of hydrolytic enzymes. This process occurs throughout life and is tightly regulated by several factors: serum vitamin D, serum calcium, growth hormone, PTH (increase resorption), and calcitonin (increase bone formation) levels, to name a few.
Two things to recall:
you cannot "de-mineralize" the bone as you would in this party trick. . You have to "de-bone" the bone, as Dr Fred Kaplan termed it: you cannot simply dissolve out some ions when you need them and replenish the bone later; you must break down the matrix to get the mineral out. Thus, even if the body needs calcium 'only for a minute', it takes a while get the skeleton restored. Think of it as having to get a home equity load if you wanted to borrow even a small amount; it's a much bigger hassle than a credit card overdraft! Implication: if you have a state of high mineral flux, there will be lots of immature bone, as every instance of mineral withdrawal necessitated some 'de-boning'. Metabolic needs trump skeletal needs. This makes sense: calcium is needed for cardiac contractility and nerve transmission. Thus, in metabolic diseases or states of nutritional deficiency, the skeletal system can be harmed.
There are three tasks of bone: skeletal homeostasis, mineral homeostasis and hematopoesis. How can problems related to these latter two non-structural tasks lead to fracture?
Mineral homeostasis involves maintaining the correct serum levels of calcium, phosphate and magnesium and other ions. PTH increases serum calcium levels by increasing GI calcium absorption, renal phosphate and calcium resorption and releasing calcium from the skeleton by de-boning the bone
As shown here (and don’t memorize this for this class!) bone is only one of the actors, and plays a relatively subservient role
Hyperparathyroidism, to name one disease of aberrant mineral homeostasis, will increase osteoclast activity and therefore weaken the bone. Vitamin D deficiency in adults, to name another process, can cause defective bone mineralization, and will might lead to pathologic fractures.
In general, if the body needs minerals it will take them from the bones. You need the right level of Calcium to have a heart beat. You need a skeleton (in evolutionary terms) only to get to food and mate(s). Despite what you may recall of the vicissitudes of adolescence, cardiac contractility is more important, at least on a minute to minute basis, than finding food or mates.
Recall that Calcium is critical for nerve transmission.
Problems with hematopoesis problems can also lead to fracture–indirectly. The indirect link is that because the blood-making apparatus resides in the bone, blood cell cancers that originate in the bone can cause local bony damage. Also, because the blood-making apparatus is in the bone, the bones are essentially part of the vascular system. And because bones are part of the vascular system, bad blood cells can get stuck there (for example, sickled red blood cells can muck up the circulation and lead to infarction) as can metastatic cancer cells or infectious microbes.
Define and contrast osteoporosis and osteomalacia.
Both osteoporosis and osteomalacia can cause weak bones.
In osteoporosis, there is decreased bone mass with a normal ratio of mineral to matrix.
In osteomalacia, the ratio of mineral to matrix is decreased (ie there is too much matrix relative to the amount of bone)
Osteoporosis causes decreased bone mass, with a normal ratio of bone mineral to matrix in addition to altered bone microarchitecture. The catch-phrase of osteoporosis is “normal-enough bone, but not enough of it!”
Clinical features of osteoporosis include fractures from minimal trauma, particularly in the thoracic and lumbar spine, wrist and hip.
Thoracic vertebral compression fractures can cause dorsal kyphosis (Dowager’s hump).
Plain x-rays show decreased bone density; but only once at least 30% of bone is lost. Dual-energy x-ray absorptimoetry (DEXA) is the diagnostic test for osteoporosis; it reports bone density in terms of T scores, representing deviations from the mean of normal individuals). A DEXA > 2.5 is diagnostic of osteoporosis. Lab values of serum calcium, phosphorus and alakaline phosphatase are not diagnostic.
Osteomalacia is characterized by a decreased ratio of bone mineral to matrix.
Osteomalacia when it appears in children is called rickets.
Histologically, the un-mineralized osteoid appears as a thickened layer of matrix. The disease causes characteristic symptoms of diffuse bone pain, tenderness and muscle weakness. X-rays commonly show decreased bone density with thinning of the cortex. Advanced disease can cause concavity of vertebral bodies (codfish vertebrae) and bowed legs.
In addition, fissures/cracks (so-call Looser’s zones) may appear. These are incomplete fractures, as shown below, are filled with the un-mineralized osteoid seams.
Lab findings may show low serum and urinary calcium and high serum alkaline phosphate.
How is osteoporosis diagnosed, prevented and treated?
Diagnosis:
Good: high index of suspicion in susceptible patients maintained; Dual-energy x-ray absorptiometry (DEXA) diagnostic. Bad: faded bones seen on xray (ie advanced osteoporosis as 30% loss of bone does not show up). Worst: low energy fracture sustained.
Prevention:
Primary prevention includes diet supplementation with calcium and vitamin D.
Pharmaceuticals are typically not used in prevention, but bisphosphonates and raloxifene are approved for preventative use, typically in patients with a DEXA between 2.0 and 2.5.
Weight bearing exercise also can prevent osteoporosis.
Avoiding excess alcohol (“excess” defined as “more than I drink”) and smoking cessation can also improve bone density.
Treatment:
Non-Pharmaceutical treatment includes calcium (1500mg daily) and vitamin D supplementation (800 IU daily).
First-line pharmacologic treatment includes bisphophonates such as alendronate, which inhibit osteoclasts, reducing bone resorption and turnover.
Estrogen-progestin therapy is now rarely used in postmenopausal women due to cardiovascular side effects.
Describe the relationship between menopause and hip fracture risk. Describe the relationship between body mass and hip fracture risk.
We know with certainty that hip fracture incidence is higher after menopause. The precise mechanism –or rather, the relative contribution of known mechanisms—is debated.
Menopause, with its decreased estrogen production, leads to increased osteoclast activity. Thus, at menopause, women begin to experience a 2% loss in bone mass per year as bone resorption outpaces bone formation.
A low BMI is a risk factor for hip fracture. A BMI of 20 is estimated to have a 2.0 relative risk of hip fracture compared to an individual with a BMI of 25. (Note that a really low BMI is best thought of as cachexia –and that’s a sign of general decline, bones included.)
There are two schools of thought why low BMI leads to fracture, both centered on the role of fat.
Fat is a substrate for the synthesis of estrogen and thus is an indirect osteoclast inhibitor. More fat = more estrogen = more bone. Fat provides soft tissue padding. The energy absorbed by the bone in a fall is equal to the energy generated by the fall, minus the energy absorbed by other tissues. Hence, More fat = more energy absorbed by soft tissues = less energy absorbed by bone = lower risk of fracture. What is the practical distinction between the two? Basically, it's the question of whether low energy fractures are an intrinsic bone problem or an extrinsic, medical problem and in turn, whether the best plan to decrease fractures is to optimize the bone or minimize the energy to which the bone is exposed at the time of falling.
What are the three fractures typically associated with osteoporosis? Which is the worst? Why is this fracture so deadly?
The three areas typically subjected to fragility fracture with osteoporosis are:
wrist (distal radius)
vertebral body compression
hip (femoral neck shown and intertrochanteric).
Hip fractures are the worst: there is a ~30% mortality within the first year of fracture. That may be because of its effect on mobility, or maybe because getting a fracture in the first place is a sign of the dwindles…
And don’t forget: a low energy wrist fracture is a sign suggestive of underlying osteoporosis—a wrist fracture from a fall should be the initiator of an osteoporosis work up, or empiric treatment.
What else besides intrinsic bone problems could cause hip fracture?
As the figure below shows (with a lot of artistic license), osteoporosis makes the bone intrinsically weak, simply by offering less structural mass.
But there is more Old people get the dwindles. They fall more and when they fall, the risk of fracture is higher because they can’t catch themselves. A risk of falls (from caused such as bad vision, say, or a neurological disease) is an independent risk factor for a hip fracture.
The key point to know and recall is that the amount of energy needed to break a hip is only a fraction of the energy available from a typical fall. That most falls do not cause fracture is a testament to the normally present energy-absorbing processes (catching yourself, basically).
So if you fall frequently and if you can’t catch yourself as you fall, you are going to break bones even if those bones are intrinsically healthy.
A related point: that’s why patients falling off the OR table is such a potential disaster: sleeping patients can’t catch themselves! (and anecdotally, some of the worst fractures I have seen are in the inebriated.)
What is Pagets disease of the bone?
Paget’s Disease of the Bone is a disorder where resorption of bone by hyperactive osteoclasts outpaces the ability of osteoblasts to keep up (ie, laying down strong organized bone).
This results in focal lytic lesions affecting one or many bones, as well as areas of proliferation of soft, disorganized bone.
This xray of the pelvis shows earlier signs of Paget’s disease: thickening of the femoral neck and diffuse sclerosis of bone.
The disease runs in families and though the etiology is not entirely clear, it is commonly thought to have both a genetic and a viral component. It is a disease of older patients; those younger than 40 years are rarely affected, with incidence increasing thereafter with age. It is also more common among people of European descent and has a slight predilection for males over females.
Aching bone pain is the most common presenting symptom, but patients are often asymptomatic early in disease, and frequently picked up by incidental radiographic findings or due to blood work that reveals an elevated alkaline phosphatase.
A bone scan will be “hot” because of the increased remodeling activity
Mr. Smith is right to be happy that cancer hasn’t been found. (Paget’s Disease of the Nipple, a rare form of breast cancer, is unrelated except by name.) Nonetheless, Paget’s is associated with increased risk of bone malignancy, affecting about 1% of people with disease and with osteosarcomas of the pelvis, femur, humerus and skull seen most frequently.
Additionally, he should not be dancing for joy (or anything else for that matter!) too aggressively because in addition to accelerated OA, another complication of Paget’s is increased fracture risk.
Fortunately for him, remission (understood as normalizing of x-ray findings, serum alk phos and relief of pain–not “cure”) can be achieved in more than 90% of patients via IV bisphosphonate therapy. He’ll need good follow up and continued monitoring for recurrence or malignancy going forward.
