Advocating for a Higher Standard of Care in Bone Health
We are building a central visual-learning resource that provides education on important women’s health issues, such as bone mineral density (BMD), in a format that is both enlightening and convenient. Please peruse our video library and select a topic that interests you.
Bone Health 101
Bone Density Measurement
BMD AssessmentLearn how bone mineral density is measured
DXA of the Lumbar Spine
and the HipSee an overview of the DXA scan
Z- and T-scoresReview the difference between Z-score and T-score
Bone Mass Overview
Bone PhysiologyWatch a brief overview on bone physiology
Peak Bone MassUnderstand the definition of peak bone mass
BMD and AgeLearn how bone density changes with age
Bone Mass Factors
Factors in Peak Bone MassReview the many factors that determine peak bone mass
BMD: Gender and RaceUnderstand how gender and race influence BMD
Effect of Diseases on BMDSee examples of diseases that contribute to bone mass reduction
Effect of Medications on BMDBecome aware of the medications that reduce bone mass
Bone and Estrogen
Estrogen and Bone RemodelingReview how the presence or absence of estrogen affects bone remodeling
Estrogen Threshold HypothesisLearn about the estrogen threshold hypothesis and the therapeutic window for optimal estradiol levels, balancing bone loss and stimulation of endometriosis
Key TakeawaysSupplement your understanding with a succinct overview of all videos in this section
Hello. My name is Nelson Watts. I'm an endocrinologist by training but have been involved in osteoporosis research for a number of years. I'm currently Director of Osteoporosis and Bone Health Services at Mercy Health in Cincinnati, and I'm glad that you joined us for this overview of bone mineral density assessment. Bone mineral density is typically measured by dual-energy x-ray absorptiometry, or DEXA. On the upper left, you see what a bone density machine looks like. These are called table models, for obvious reasons. The amount of radiation is trivial: about the same as a transcontinental airline flight or spending the day at 10,000 feet elevation in the Rocky Mountains. So, it's safe for the operator to be in the room. On the upper right, you see a diagram. Under the patient is an x-ray source that generates two different wavelengths. Over the patient is a detector. How much of the generated x-ray that is known is absorbed by the patient is proportional to tissue density.
It's possible to do body composition with DEXA, but what we'll be talking about is measuring bone mineral density. In the lower left, you see a picture of the lumbar spine. People ask why we don't look at other regions of the spine, and the reason is there are other bones that get in the way. If you go higher, you have the sternum, ribs, scapula, other bones that would overlap. The results include bone mineral density, or BMD, T-scores, and Z-scores, which I'll define a little bit more in a moment. There's also a reference curve, where the patient's result is to be plotted, so you can see how they compare with women their age and with young normal values.
The measurements, as I mentioned, include the lumbar spine and the proximal femur, or hip. In the hip, we're interested in the femoral neck, which is labeled number one in the diagram. For most people, that will be the lowest T-score or Z-score of the hip sites.
We're also interested in the total hip, which includes site number two, the greater trochanter, and site number three, which is part of the femoral shaft or intertrochanteric region. The primary result of interest, BMD, is the ratio of the mineral content in grams divided by the projected two-dimensional area and centimeters squared. And in the hip, the total hip is simply adding the area of sites one, two, and three, and dividing that into the bone mineral content of those same areas to get the BMD result.
The Z-score is what is used for young people: premenopausal women. The Z-score helps answer the question: how does this person's bone density compare to what is expected? The number of standard deviations above or below the bone mineral density of an age-matched, sex-matched, and race-matched reference population. The T-score is used to define osteopetrosis, yes or no; but it should only be used in postmenopausal women.
The T-score is the number of standard deviations for the older patient compared to a young normal population peak bone mass, age 25 to 30. Z-scores and T-scores are expressed in standard deviations. On the left are Z-scores. Between plus two or minus two is the expected range. Values below zero may be of concern, but between zero and minus two is still within expected limits. For T-scores on the right, normal is minus one or above; osteoporosis is minus 2.5 or below; and between minus one and minus 2.4 is called low bone mass, or osteopenia. Although osteopenia may be a risk factor for fracture, it is not a disease. 17% of healthy young people have Z-scores between minus one and minus 2.5; and it's a range. If you're minus one, that's osteopenia; and probably at any age, that's not so bad.
If you’re minus 2.4, that's osteopenia; but at an older age, that may be associated with a higher fracture risk than a T-score of minus 2.5 in a 50-year-old recently menopausal woman.
Hello. My name is Nelson Watts. I'm an endocrinologist by training but have been involved in osteoporosis research for quite a while. I'm currently Director of Osteoporosis and Bone Health Services for Mercy Health in Cincinnati and welcome you to this program on bone health sponsored by AbbVie. In this section, we'll begin with a review of basic bone physiology, examine strategies to identify patients at risk of bone loss, and clarify some of the effects of estrogen on bone. Bone is a dynamic tissue that provides structural and foundational support. It's made up of cortical bone on the outside and trabecular bone at the ends of the long bones and the centers of the vertebral bodies. Cortical, or compact bone, is the most prevalent in the skeleton, but the trabecular bone has a much greater surface area and is more metabolically active. Bone is renewed by a process called turnover, or remodeling.
At any one time, there are millions of active bone remodeling sites in the body. Triggered by activation, bone-resorbing osteoclasts resorb a packet of bone. There's a brief reversal period where cleanup occurs. Then, bone-forming osteoblasts come in, producing the protein osteoid matrix that becomes mineralized and results in new bone. The entire remodeling process at a given site takes about three months. The goal would be to have balance—that is, the same amount of bone replaced as was removed. Much has been learned about how we can view this. The gold standard is a bone biopsy, but now we can get an idea of what's happening through chemical measurement of markers of bone resorption and markers of bone formation. From bone breakdown, we can measure end products of collagen degradation, C-telopeptide, or CTX, the carboxy terminal fragment of Type I collagen that is specific for bone, as well as the amino terminal fragment, NTx.
On the bone formation side, we can measure breakdown product of newly formed collagen, P1NP, procollagen type 1 in propeptide—that's the nitrogen N cleaved off of newly formed Type 1 collagen—enzymes, such as bone-specific alkaline phosphatase, or another protein breakdown product called osteocalcin. Bone turnover markers are of limited clinical utility. I have a talk on bone turnover markers with the subtitle, “not ready for prime time.” But markers do give us insights into dynamic changes and help us understand what happens with interventions.
Peak bone mass is the maximum level reached when growth is complete and the accumulation of mineral is consolidated. It is reached at slightly different times at different skeletal sites, but you're pretty close to it by your early twenties. I hear people say, “this person's young and their bone density is low because they didn't achieve peak bone mass.” But that statement is not correct. Peak is what it is: good or bad, high or not, it's what you get.
This graph shows the changes in bone density in the spine over the lifespan.
And these are normative data for Caucasian women. Starting on the left, note the big increase that occurs with adolescence, peaking around age 20, and then a plateau when formation and resorption are evenly matched. Around age 40 or so begins a gradual decline, with age-related bone loss around half a percent to 1 percent per year. Beginning around four or five years before the last menstrual period and continuing for another four or five years, bone loss accelerates to one to two percent per year. Without intervention, the rate of loss slows, but age-related bone loss resumes. To me, the staggering thing here is that by the time a woman is 90, her bone density is pretty much back to where it was at age nine. The quality of bone is certainly different at age 90, compared with age nine. As quantity is lost, quality is lost as well, which is why we don't worry so much about fractures at age nine as we do at age 90.
Peak bone mass is primarily determined by genetics. Men have higher bone mineral density than women. Blacks have higher bone mineral density than whites. To fulfill one's genetic potential, it's important to do things right. Get enough calcium, vitamin D, stay physically active, avoid bad habits, such as cigarette smoking or excessive alcohol use, and hope to be spared any of the diseases or medications that can cause bone loss or prevent gain that may eventually lead to increased fracture risk. Diseases like rheumatoid arthritis or medication such as long-term glucocorticoid therapy may have significant long-term adverse effects. We'll look at drugs and diseases in more detail shortly. The skeleton adapts to loading, so, at least up to a point, heavier people will have higher bone mass.
Earlier, I showed this curve of spine bone density in Caucasian women over the lifespan.
The yellow curve shows the same for black women. At every time point, the average for black women is significantly higher than the average for white women. But note the error bars that show the expected variability. Plus or minus 20 percent would be two standard deviations. At any age, black women on the lower end of the distribution have bone mineral density actually below the average for white women. Osteoporosis is more frequent in whites than blacks because white women start with a lower peak bone mass. But osteoporosis can affect anyone, regardless of race.
This slide lists some diseases that may reduce bone mass or increase fracture risk. It's far from complete. There’s no need to go through everything in detail, but it's important to be aware of the adverse skeletal effects of certain endocrine disorders, including hypogonadism, hyperparathyroidism, hyperthyroidism, and diabetes, as well as chronic inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease.
Malabsorption, chronic liver, and chronic kidney disease can negatively affect bone mass and bone strength
There's a growing list of medications that may increase fractures. Some of them by reducing bone mass and some by other mechanisms. Long-term glucocorticoid use is by far the most common drug-related cause of bone loss in older patients. Hormonal therapies, particularly those that reduce sex steroid levels, will cause increased bone loss and higher fracture risk. Odor antiepilepsy drugs may decrease vitamin D through increased degradation. Newer antiepilepsy drugs have also been implicated as increasing fracture risk, but the mechanism is not known. Depression itself and treatment with antidepressants are both associated with increased fall risk and increased risk of fractures due to falls, but there may be other effects on bone tissue as well. Organ transplants are associated with rapid bone loss, at least early on after the transplant, and increased risk for fractures. That could be due, at least in part, to calcineurin inhibitors and other drugs that are used to prevent organ rejection.
Antiretroviral therapies for treatment of HIV/AIDS are associated with increased risk of bone loss and osteoporosis. Proton pump inhibitors are associated with an increased fracture risk, but the mechanism is not clear. I'm a little less worried about these now. Rather than a causal effect, it may be that they're prescribed to patients who were already at higher than average risk for falling and fracture. And that may be the story. It's important to get a full list of medications as part of a fracture risk assessment and to identify potential offenders.
Estrogen has important effects on bone remodeling. The big increase from childhood to adulthood coincides with puberty, which illustrates the powerful effects of estrogen on both bone formation and bone resorption. In this chart, there is a key in the left: RANKL, RANK, and OPG are molecular signals involved in regulating the osteoclast. RANK is a receptor.
On the center diagram, you can see the receptor is expressed on osteoclast precursors and also on differentiated and activated osteoclasts. RANK ligand, represented by green dots, binds with the receptor like a key and a lock. Ligand binding with receptor stimulates osteoclast formation, function, and survival. More bone is removed. OPG, or osteoprotegerin, serves as a decoy receptor to reduce binding of RANK ligand with its receptor. Estrogen reduces the number of molecules of RANK ligand and may increase the molecules of OPG, both of which help reduce the activity of bone-resorbing osteoclasts. After the osteoclast has done its job of bone resorption, it undergoes programmed cell death, or apoptosis. As estrogen levels fall with menopause, or with pharmacologic intervention, levels of RANK ligand go up, OPG goes down, and osteoclastic bone resorption increases.
Increasing levels of estradiol can stimulate growth and activity of endometriosis.
While decreasing levels of estradiol may improve the consequences of endometriosis, at some point, decreasing estradiol will increase bone turnover and worsen bone loss. There may be an optimal level of estradiol for both bone turnover and endometriosis. Plasma estradiol somewhere between 30 and 50 picograms per mil might make Goldilocks happy: not too high in terms of endometriosis and not too low in terms of bone loss.
These are the key takeaways for this section. Bone is a dynamic tissue that is continuously resorbed by bone-removing osteoclasts and replaced by bone-forming osteoblasts. An imbalance between resorption and formation can result in bone loss. Women who are lower at their peak are at higher risk of bone loss that would get them to a troublesome place later on in life, either from disease or medications or menopause. Genetics and lifestyle factors, as well as potential exposure to some diseases and medications can, directly or indirectly, affect bone health. So, history is important to assess these factors. Gonadotropin-releasing hormone analogs that induce hypogonadism are associated with reduced bone mass and, if used long term, possibly increase the risk of fractures. The estrogen threshold hypothesis suggests that there may be a potential therapeutic window, where levels of estrogen are low enough to result in atrophy of endometriosis lesions, while still high enough to maintain healthy bones. Thank you for your participation in this program.
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