User login
Dr. Maricic, what are the different types of osteopenia that primary care clinicians encounter in their practice?
DR. MARICIC: Osteopenia has several connotations, depending on the setting in which it is diagnosed. Radiologists will describe a patient as being osteopenic based on the subjective assessment that the patient has low bone density on radiography. With particular reference to osteoporosis or bone densitometry, osteopenia refers to a dual-energy X-ray absorptiometry (DEXA) T-score, which is a comparison of the bone mass of a patient to that of a young, ideal patient of the same sex and ethnicity.
DR. GALL: Is osteoporosis the only disease or are there other diseases that we may see associated with osteopenia?
DR. MARICIC: Neither osteopenia nor osteoporosis diagnosed by the DEXA score is necessarily caused by estrogen deficiency. The DEXA report tells you whether a patient has low bone density but not about the etiology. Although estrogen deficiency is a common cause of osteopenia or osteoporosis, other conditions such as primary hyperparathyroidism, multiple myeloma, vitamin D deficiency, osteomalacia and the conditions associated with it, chronic renal failure with osteitis, fibrosis cystica, and hyperparathyroidism should be considered by the primary care physician.
It’s typically recommended that all patients with low bone density diagnosed by their DEXA score have a chemistry screening done to determine the calcium and alkaline phosphatase levels, as well as 25-hydroxy-vitamin D level, in order to ensure that the patient is not vitamin D deficient. A 24-hour urine test is also recommended to ensure that the vitamin D level is not low, suggesting malabsorption, such as what we see in vitamin D deficiency or celiac disease, or that it’s not high, suggesting idiopathic hypercalciuria.
Those are the main, most common disorders that we’d like to exclude in patients with osteopenia or especially osteoporosis. We would also want to exclude secondary hyperparathyroidism; vitamin D deficiency; and, when suspected, celiac disease, idiopathic hypercalciuria, and multiple myeloma. Those are some of the conditions to be considered, especially when the T-score does not accord with the clinical history.
DR. GALL: Dr. McClung, can you please discuss the use of X-ray and DEXA scan as diagnostic tools?
DR. MCCLUNG: These 2 tools have completely different roles. We use the DEXA scan to measure bone density, primarily in the hip and the spine, in postmenopausal women and older men to obtain a T-score that is, a value comparing the patient’s bone density to the average bone density value of young adults of the same sex. A T-score of −2.5 is thought to be consistent with osteoporosis in postmenopausal women and older men, but, as Dr. Maricic pointed out, a T-score of −2.5 only tells us that the patient has low bone density. Before we conclude that the patient has osteoporosis, all of the other causes of low bone density, including osteomalacia, osteogenesis imperfecta, and any of the secondary causes that were outlined, need to be excluded.
I believe that osteopenia, which is defined as a T-score value between −1 and −2.5, is not a very useful diagnostic term for clinical purposes. We know that low bone density is one of several risk factors for fracture. Within the group of patients with osteopenia are those who are at very high risk for fracture, including older people and those who have had fractures, as well as many patients who are not at high risk for fracture. In response to this problem, the World Health Organization developed the Fracture Risk Assessment Tool (FRAX), a fracture risk assessment tool used to help distinguish patients with high or low fracture risk.1
DR. GALL: Clinicians often find the terms used in the DEXA report confusing. Could you define absolute bone mineral density (BMD) and Z-score for the clinician?
DR. MCCLUNG: The BMD test measures the bone mineral content of a specific anatomic region and the area of that region and divides those 2 numbers to get an estimate of the BMD. It is not a true bone density test, but rather a measurement of calcium content within a region of bone.
The BMD value is translated into a T-score by comparing it to the average value for healthy young adults of the same sex and is then used for diagnosis in postmenopausal women. The Z-score is obtained by comparing the patient’s BMD value with the expected average value for healthy adults of the same age and sex and is used to determine whether a low BMD value for that patient is unexpected. A low T-score for a 55-year-old woman may be surprising, whereas a low T-score for a 90-year-old woman would be expected. A Z-score lets us know how concerned we should be.
DR. GALL: Dr. Lisse, you read a lot of DEXA scans. What can give a false value? Can you tell us about that and discuss the FRAX?
DR. LISSE: Dr. McClung wrote a very nice treatise on the FRAX,2 a tool that assesses the risk of fracture in bisphosphonate-naïve patients based on the consideration of risk factors, in addition to the BMD value. The DEXA measures bone quantity, but does not assess the risk factors for osteoporosis, of which I think prior fracture and patient age are the most important.
By considering the risk factors of smoking history, advanced age, prior fracture, and family history of fracture, and by adjusting for the country and racial origin of the patient, the FRAX provides a better measure of fracture risk for the osteopenic patient compared to BMD alone. It also provides a value, the 10-year fracture risk, that’s easier for the primary doctor to interpret compared to T-scores and Z-scores, which require comparison in terms of standard deviations.
DR. GALL: How can we use the FRAX if we are interested in doing so?
DR. LISSE: The tool is available online and very easy to use. Usually, you complete the assay using the BMD value. You can actually perform the assay without a BMD value, but I think that including the BMD value improves the precision and predictive value of the results. You just plug in the information online and are given a reading. Recent literature suggests that you can use it for patients who are taking bisphosphonates, but I think that’s a little bit further down the line in our discussion.
DR. GALL: A FRAX result states that a patient has a 10-year risk of major fracture of 8%. How do I use that result? Should I start treating the patient?
DR. LISSE: Several studies that examined local socioeconomic factors concluded that using a 20% risk of major osteoporotic fracture and a 3% risk of hip fracture are cost-effective thresholds for the diagnosis of patients in the United States. Although they should not be considered absolute, they are the current thresholds, and I think physicians can use them as criteria to make treatment decisions.
DR. MCCLUNG: That description is correct. FRAX has a scientific base and is a very highly validated tool that accurately predicts fracture probability in healthy middle-aged and older adults.1 Using the tool is a good first step while considering whether osteoporosis treatment is justified. The threshold values of a 10-year probability of hip fracture of 3% and a 10-year probability of major osteoporotic fracture of 20% are specific to the United States, which is based on the United States healthcare policy and where osteoporosis fits into the United States medical priorities. Other countries have their own thresholds that are very different.
DR. GALL: Dr. Maricic, we’ve talked about the DEXA and the FRAX. What other imaging tools are available and what are their roles?
DR. LISSE: The other issue is that the FRAX uses femoral neck density, which is a good predictor; however, in some patients, especially patients taking glucocorticoids, the spine density may be lower than the hip density. A low spine T-score should also be taken into account. We must individualize patients and not become overly focused on any one tool, although the use of the FRAX is certainly a major step forward from the use of only the T-score, for which, former guidelines recommended treatment for patients with scores within the wide range of −1 and −2.5.
DR. GALL: Another issue regarding DEXA is that we often get a false high BMD in patients with fracture of the lumbar spine, osteoarthritis, or issues with alignment of the spine. In such cases, it is important to examine the image, as the presence of bone abnormalities may render the spine DEXA score and the spine T-score less important.
DR. MARICIC: The role of other modalities in diagnosing osteoporosis in the United States is limited because of the widespread availability of DEXA in most communities. A few communities in Arizona have access to only quantitative computed tomography, which, although tends to overdiagnosise osteoporosis, can be helpful if bone density is found to be low and the clinical setting is appropriate.
Likewise, quantitative ultrasound in patients older than 65 years has a very valid role in estimating risk of fracture, but because DEXA is so widely available, we do not or usually should not use ultrasound instead of a DEXA scan and ultrasound cannot be used to monitor or follow-up patients with treatment. The only modality that should be used is the DEXA scan because of its very high precision.
DR. GALL: I have seen the use of ultrasound in both remote areas and nursing homes and other areas where it is difficult for patients to visit an office at which a DEXA scan performed, but it is not as accurate as the DEXA scan.
DR. MCCLUNG: Yes, but my understanding is that you use the ultrasound to determine whether you need a DEXA scan.
DR. MARICIC: Yes, but you shouldn’t use the ultrasound to start therapy or monitor therapy.
DR. MCCLUNG: FRAX, which can be calculated without a bone density test, provides a much more accurate assessment.
DR. MARICIC: And FRAX is probably cheaper and easier.
DR. GALL: Dr. McClung, would you talk a little bit about bone markers? I once heard you speak about their role in making a decision about when to treat patients with borderline DEXA and FRAX values.
DR. MCCLUNG: Bone markers are values obtained from blood and urine tests that reflect the activity of the bone cells. Generally, high levels of bone markers reflecting high levels of bone absorption are predictive of more rapid rates of bone loss. So, when a physician is deciding whether to treat, measuring a bone marker can sometimes provide important information to help make the decision. A bone turnover rate in the low–normal range in a bisphosphonate-naïve patient indicates that his/her bone density is stable and that he/she may benefit less from treatment compared to a patient with a high rate.
You can also use bone marker values to determine whether treatment has been effective, particularly if you use antiresorptive agents such as bisphosphonates. Patients with celiac disease or those who have had a gastrectomy may not absorb oral bisphosphonates, so their markers may remain high even if they are under treatment. Although there are certain patients for whom bone markers are helpful, the use of these markers is not routine in the management of most patients with osteoporosis.
DR. GALL: I would say that bone markers are generally overused. Another area in which the use of bone marker values may be helpful is compliance. I’ve used bone biomarker values in cases in which, for example, I start a patient on a weekly bisphosphonate and the patient comes back 12 weeks later saying that he/she doesn’t need a prescription. In such cases, I may perform bone marker testing to see whether the patient has been compliant.
Is there ever a time when we need to do a bone biopsy?
DR. MARICIC: I think a bone biopsy is only helpful for patients with long-term renal failure and dialysis to separate out the various forms of renal osteodystrophy. Although we used to perform a biopsy to help us understand bone turnover or detect osteomalacia, we can now do both with a biochemical test.
In some cases, we want to perform a bone marrow biopsy to look for marrow-based diseases such as mastocytosis or myeloma.
DR. GALL: I’d now like to discuss the prevention of osteoporosis and the risk factors that indicate testing and treatment of patients who are not postmenopausal.
DR. LISSE: There are risk factors that are nonmodifiable, including family history and genetics; modifiable risk factors, including level of exercise, especially weight-bearing exercise, which can be decreased; smoking, which can be discontinued or at least attenuated; and alcohol intake, which can be decreased. I think the role of caffeine is still controversial, although I’d love to hear from the other members of the panel about that.
I think we have overemphasized the importance of calcium and vitamin D supplementation. However, I measure the serum 25-hydroxy-vitamin D level, which according to me, is becoming more and more popular, and I try to keep it at around 30 ng/mL. I think all female patients should obtain some calcium supplementation, especially if their dietary intake is not adequate.
It was surprising to know that there’s probably a higher prevalence of vitamin D insufficiency in Arizona than in Minnesota in spite of the abundance of sunshine in the former.
DR. GALL: I consider patients who are thin, have poor bone stock, are malnourished, did not drink milk in their childhood, and have a family history of hip fracture in a close relative to be at higher risk, and I tend to test them early and consider either preventative treatment or just treatment for them.
I think an appropriate target for daily intake of calcium is between 800 and 1 200 mg, including that obtained from diet. The appropriate target for vitamin D intake in the absence of regular sun exposure is between 600 and 2 000 units per day.
DR. LISSE: Most recommendations that I’ve seen for calcium are about 800 mg, but they vary widely.
DR. MCCLUNG: Let’s get back to the management of premenopausal women with risk factors for low bone mass such as small body size, family history of osteoporosis, and medical problems that may lead to impaired bone health such as amenorrhea during early adolescence. For these women, maintaining adequate nutrition and physical activity and avoiding harmful lifestyle factors should be encouraged, but bone density testing is rarely necessary. If premenopausal women are estrogen replete, even if they have low bone density, treatment with osteoporosis drugs is not recommended. Individuals with risk factors for low bone density should be screened at the time of menopause to decide whether aggressive prevention of the rapid bone loss that occurs at that particularly important time is warranted.
DR. GALL: Dr. Maricic, there are 2 topics I’d like you to discuss. The first is comorbidities, specifically conditions such as thyroid disease, that we need to pay attention to, and the second is hormone replacement therapy and its current role.
DR. MARICIC: The NOF guidelines for the diagnosis and treatment of osteoporosis5 list a number of comorbid disorders and medications that may be responsible for a patient’s low bone density. We should consider the potential for osteoporosis in all men and women over the age of 50 years, especially if they have other disorders or medications known to affect bone mineral metabolism.
The NOF guidelines list about 30 diseases implicated in low bone density, including type 2 diabetes, hemochromatosis, and androgen- and estrogen-deficiency hypogonadism. Low bone density should be considered in patients with gastrointestinal (GI) disorders, of which celiac disease is the most important and common; those who have undergone GI bypass or other types of GI surgery; and those with hematological disorders such as mastocytosis and myeloma. Because chronic inflammatory production of cytokines and calcium immobilization lead to accelerated bone loss, low bone density should be considered in patients with rheumatic disorders, including systemic lupus; ankylosing spondylitis; and especially, rheumatoid arthritis, which FRAX identifies as a major risk factor for accelerated bone loss. Finally, low bone density should be considered in patients with a number of miscellaneous conditions, including chronic obstructive pulmonary disease, emphysema, chronic asthma, and sarcoidosis.
Regarding medications, the agents most commonly associated with low bone density are glucocorticoids. Low bone density should also be considered in patients taking certain anticonvulsants, especially phenobarbital and phenytoin, which can lead to accelerated degradation of 25-hydroxy-vitamin D and very low vitamin D levels and consequent osteomalacia, and in those taking aromatase inhibitors, which are now very important in the treatment of breast cancer.
DR. GALL: I’d just like to mention again the association between low bone density and both thyroid disease and overmedication in thyroid replacement therapy.
DR. MCCLUNG: We should probably also include proton pump inhibitors and selective serotonin reuptake inhibitors, which have been correlated with increased rates of fracture, although the mechanism underlying that correlation is unclear.
DR. LISSE: Do you mean that their wide use poses a concern?
DR. MCCLUNG: Yes, but their effect does not seem to be reflected in bone density testing. So, while recognizing their use as an independent risk factor for fracture is important, it is still unclear whether it should be considered while deciding whether to treat with an osteoporosis drug.
DR. MARICIC: Regarding hormone replacement therapy, we must first distinguish between hormone replacement, which is a combination of estrogen and progesterone for women with an intact uterus, and estrogen replacement or estrogen therapy, which is estrogen alone for women who have undergone a hysterectomy. Definitely, there are differences in the potential for adverse effects between these 2 groups.
I believe the data from the Women’s Health Initiative (WHI) suggested that increased risk of thrombosis and breast cancer is more commonly seen with hormone therapy and may be due more to progesterone than to estrogen replacement.6 There are also some differences in the risk with regard to the age of starting hormone therapy in our patients.
From the WHI, we know that hormone therapy prevents bone loss and reduces the risk of hip and other fractures. I think hormone therapy, especially estrogen therapy for women with an intact uterus, is an option to protect the skeleton in women with low bone density, especially those who are perimenopausal or early postmenopausal.
I personally avoid starting hormone therapy in patients above the age of 70 years and sometimes even above 65 years, but I believe it can be an option for women between the ages of 50 and 60 years with low bone density and no contraindications. For women with a strong family history of breast cancer, I usually recommend raloxifene. We’re now trying to limit the lifetime exposure of women to bisphosphonates, so I tend to reserve them for older women at very high risk of fracture, and almost never administer them to women aged 50 to 60 years.
I think that hormone therapy is the first option for women between 50 and 60 years with no strong family history of breast cancer. If there is, I start them on Evista, when possible.
DR. LISSE: I think that bisphosphonate therapy has been the primary choice of osteoporosis therapy since at least 2 000, which is when alendronate came into the market under its brand name. These drugs have been shown to reliably decrease fracture and improve the quality of life. Some drugs, particularly zoledronic acid, actually decrease mortality in patients with hip fracture.7
There are some differences among them. The first one on the market obviously was alendronate, so there’s probably the most data on it. Risedronate, alendronate, zoledronic acid, denosumab, and teriparatide have been shown to reduce vertebral and nonvertebral fracture; ibandronate, to reduce spinal but not nonvertebral fracture; alendronate, risedronate, denosumab, and zoledronic acid, to prevent hip fracture in postmenopausal women; and risedronate, to decrease vertebral and nonvertebral fracture in men.7
The original studies on the effect of many of these drugs on fracture risk were conducted with daily dosing, and equivalent dosing in weekly and monthly regimens has been used and approved, sometimes without fracture data. The drugs work, their safety-to-risk ratio is quite good, and we have long-term experience with them. I think it’s not surprising that a small percentage of patients who have been on them for a decade or more have issues and side effects. There are risks to taking these drugs, as there are with any other drug.
Probably, the most common risk is GI complications, ranging from irritation to esophageal perforation, which surfaced shortly after alendronate came on the market. To prevent GI complications, strict regimens have been developed for oral bisphosphonate use. To some extent, I think that they limit our patient population because many cannot or will not comply with the requirement of taking the drug first thing in the morning on an empty stomach with approximately 230 mL of water and remain upright for 30 to 60 minutes, depending on the medication, to realize any benefit.
Gastrointestinal complications, including those affecting the esophagus, are, by far, the most common issues observed with bisphosphonate therapy. Gastric ulcerations in certain patients, especially in those who use risedronate in coated form, have also been observed.
There are other probably less common but controversial issues, including a possible association with atrial fibrillation, which was identified in the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) study.8 An association with alendronate was also suspected, but a recent meta-analysis does not support this association.9
An association with esophageal cancer has been anecdotally described in several populations, but I think that the data are mixed at this point. Then, there is the association with osteonecrosis of the jaw and atypical fracture, both of which are quite rare and occur in between 1 in 10 000 to 1 in 100 000 patients.10 I think that the wide coverage of this association in the lay press may have caused many patients who probably shouldn’t have gone off bisphosphonates, to go off them.
A positive byproduct of these associations being reported could be increased research into whether there should be a time or exposure limit to bisphosphonate use and whether a drug holiday from them is warranted.
DR. GALL: Dr. McClung, could you please describe how you monitor a patient after initiation of bisphosphonate therapy and then discuss an atypical fracture?
DR. MCCLUNG: Treatment with any osteoporosis drug is generally monitored by measuring BMD 2 years after the patient has started therapy. The changes in BMD with treatment are quite modest, so we expect to see either a modest increase or at least stability. If a clear decrease in BMD is observed, we consider noncompliance, secondary causes of bone loss, and other reasons for treatment failure.
In theory, biochemical testing of bone turnover should be useful in monitoring therapy. However, because of limitations in the quality and the reproducibility of the assays in the clinical setting, it is difficult to use the results. I think that marker measurement is not ready for use in the everyday clinic, although it has been very valuable in our research.
Atypical fracture is important. As mentioned earlier, there has been concern right from the time when bisphosphonate research began about the potential for skeletal consequences with long-term therapy because of the pharmacology of bisphosphonates. We know that these drugs accumulate in the skeleton over time, and there were concerns about whether we would see progressive inhibition of bone turnover with long-term therapy. Although we were pleased to observe persistent, but not progressive, reduction in bone turnover with long-term treatment, at least for up to 10 years,11 it appears that some individuals, or perhaps, a unique subset of patients, experience too much inhibition of bone metabolism for prolonged durations. When this happens, bone brittleness occurs and is manifested by atypical chalk stick-like fractures of the femur. It is clear that there is a duration-dependent increase in risk, with fractures occurring in roughly 1 in 1 000 patients who have completed at least 10 years of alendronate therapy.12 If we properly decide whom to treat and how to treat, it is important to recognize that this risk is much, much lower than the risk of important fracture, such as that of the hip and spine, in patients who are not treated with bisphosphonate therapy.13 We should reserve bisphosphonates for patients who clearly have osteoporosis or are at high risk for fracture.
DR. GALL: Dr. Maricic, can you conclude on the use of calcitonin, denosumab, and teriparatide, ie, some of the other drugs approved for the treatment of osteoporosis?
DR. MARICIC: Calcitonin is extremely safe but it isn’t very effective and has been shown to reduce spinal fracture risk by 33% and have no effect on hip fracture risk,14 so I personally haven’t prescribed it in almost 10 years.
Denosumab, a receptor activator of nuclear factor-kB (RANK)-ligand inhibitor and monoclonal antibody, is probably among the most effective medications we have. Because it bypasses the GI tract, it’s an excellent choice for patients who develop GI problems with bisphosphonates. Nevertheless, because it is a very potent osteoclast inhibitor, it must be used carefully in patients prone to hypocalcemia, with renal failure, or who are extremely vitamin D deficient. Although hypocalcemia must be considered before initiating its use, I think it is an extremely effective agent.
Teriparatide is the only anabolic agent currently approved for use in patients at high risk of fracture, and that’s for whom we mainly use it. Because its mode of action is completely different from that of bisphosphonates, we use it for patients with either very low bone density or with multiple fractures who have not responded to bisphosphonate therapy. The Food and Drug Administration (FDA) has approved teriparatide therapy for only 2 years, after which it must be followed by antiresorptive therapy. Unfortunately, I occasionally see patients who had not been given antiresorptives after 2 years of teriparatide, causing them to lose any benefit they may have derived from being on this very expensive drug for 2 years. It must always be followed up by an antiresorptive drug.
DR. MCCLUNG: Regarding a drug holiday, you can consider it if you observe a duration-dependent increase in the risk of atypical fracture.15,16 The FDA has provided us with at least a general template for when it should be considered.17 Based on the limited information we have, it is suggested that fracture risk be reassessed after 3 to 5 years of therapy. For patients with a modest risk for fracture at that point, ie, they no longer have osteoporosis according to the results of bone density testing, it is suggested that therapy be discontinued for 1 to 2 years.
For patients found to remain at high risk for fracture, especially spine fracture, continuation of therapy is recommended. The evidence for this recommendation came from 2 large extension studies of the alendronate and zoledronic acid clinical trials.18,19
If treatment is discontinued, the question of when, if ever, to restart therapy arises. The data from the clinical trials suggest that neither the measurement of bone density nor bone markers are helpful in that regard. So, in my clinic, we treat the holiday like a vacation that has a finite end.13 We take patients off alendronate for 2 or 3 years but off risedronate for only 1 year because its effects wear off more quickly. At that point, we reassess the patient. If he/she meets the criteria for treatment with an osteoporosis drug again, we decide on the best treatment option.
DR. GALL: Dr. Lisse, please describe how treating steroid-induced male osteoporosis differs from treating postmenopausal and female osteoporosis.
DR. LISSE: Before I do so, I wanted to add that a flu-like syndrome sometimes occurs with bisphosphonate use. In a corollary to what Dr. McClung just discussed, the European registries provide at least some reassuring evidence that when patients stop taking bisphosphonates, the risk of atypical fracture appears to decrease fairly rapidly, whereas bisphosphonate efficacy doesn’t seem to tail off as quickly.15 It should be reassuring that if patients stop taking a drug, they may have some protection during that period in terms of osteoporosis coverage, unlike when they stop taking estrogen or teriparatide, whose effects tail off rather rapidly.
With glucocorticoid-induced osteoporosis, the biggest issue is probably the fact that fractures tend to occur early and at a higher bone density than what we’re used to seeing with traditional postmenopausal osteoporosis. So it has thrown the old paradigm into disarray. Before the introduction of FRAX, treatment was recommended for patients with a T-score of −1. As the FRAX includes glucocorticoids as a risk factor, its use is very helpful in this regard.
FRAX does have its limitations, and there are physicians who are concerned that it does not include consideration of steroid duration or dose. I think the American College of Rheumatology’s recommendation is to measure bone density and then subdivide the patient population into low risk, moderate risk, and high risk according to the risk for major osteoporotic fracture of ≤10%, 10% to 20%, and ≥20%, respectively.20 Treatment should be considered based on the risk and dosage. Patients taking a dose of 7.5 mg or higher probably need treatment, even if they’re at low risk. Patients on lower doses probably need treatment if they remain on glucocorticoid therapy for more than 3 months.
Although most fractures due to steroid use are of the spine, not all are. I’m sure all of us on the panel are old enough to remember the old asthmatics who used to take large doses of steroids. Certainly, one of the easiest things to do is to taper patients off steroids or reduce the dose down to the lowest possible dose. The use of topical steroids is preferred to that of oral steroids or inhaled steroids.
The NOF guidelines for testing for male osteoporosis differ from those for testing female osteoporosis. Although they recommend that all women older than 65 years be tested, they do not recommend routine testing in men older than 70 years. I think that this latter recommendation, which is based on a US Preventative Health Service Task Force recommendation,21 is probably a mistake and rather confusing.
Even though there has been a study of raloxifene in men, the guidelines are more limited regarding how men who are hypogonadal should be treated. Testosterone should be measured in all men, and those found to be hypogonadal deserve testosterone replacement. Again, the backbone of therapy is the use of bisphosphonates for the most part. Teriparatide has also been approved for use in men, although it has not been proven to provide protection against hip fracture.
DR. GALL: We’ve had an extensive discussion today on low bone density diseases, focusing mostly on osteoporosis. We have discussed at some length the risk factors and the diagnostic tools that we have, particularly the DEXA scan and FRAX, to assess the risk of fracture. We then discussed the risk factors, including comorbidities; means of prevention; and the different treatment modalities, including physical therapy and several nonpharmacologic therapies, in addition to the various medical therapies, including hormone replacement, bisphosphonates, calcitonin, denosumab, and teriparatide. We’ve also briefly touched on the differences between postmenopausal osteoporosis and steroid-induced osteoporosis and male osteoporosis.
FoxP2 Media LLC is the publisher of The Medical Roundtable.
Dr. Maricic, what are the different types of osteopenia that primary care clinicians encounter in their practice?
DR. MARICIC: Osteopenia has several connotations, depending on the setting in which it is diagnosed. Radiologists will describe a patient as being osteopenic based on the subjective assessment that the patient has low bone density on radiography. With particular reference to osteoporosis or bone densitometry, osteopenia refers to a dual-energy X-ray absorptiometry (DEXA) T-score, which is a comparison of the bone mass of a patient to that of a young, ideal patient of the same sex and ethnicity.
DR. GALL: Is osteoporosis the only disease or are there other diseases that we may see associated with osteopenia?
DR. MARICIC: Neither osteopenia nor osteoporosis diagnosed by the DEXA score is necessarily caused by estrogen deficiency. The DEXA report tells you whether a patient has low bone density but not about the etiology. Although estrogen deficiency is a common cause of osteopenia or osteoporosis, other conditions such as primary hyperparathyroidism, multiple myeloma, vitamin D deficiency, osteomalacia and the conditions associated with it, chronic renal failure with osteitis, fibrosis cystica, and hyperparathyroidism should be considered by the primary care physician.
It’s typically recommended that all patients with low bone density diagnosed by their DEXA score have a chemistry screening done to determine the calcium and alkaline phosphatase levels, as well as 25-hydroxy-vitamin D level, in order to ensure that the patient is not vitamin D deficient. A 24-hour urine test is also recommended to ensure that the vitamin D level is not low, suggesting malabsorption, such as what we see in vitamin D deficiency or celiac disease, or that it’s not high, suggesting idiopathic hypercalciuria.
Those are the main, most common disorders that we’d like to exclude in patients with osteopenia or especially osteoporosis. We would also want to exclude secondary hyperparathyroidism; vitamin D deficiency; and, when suspected, celiac disease, idiopathic hypercalciuria, and multiple myeloma. Those are some of the conditions to be considered, especially when the T-score does not accord with the clinical history.
DR. GALL: Dr. McClung, can you please discuss the use of X-ray and DEXA scan as diagnostic tools?
DR. MCCLUNG: These 2 tools have completely different roles. We use the DEXA scan to measure bone density, primarily in the hip and the spine, in postmenopausal women and older men to obtain a T-score that is, a value comparing the patient’s bone density to the average bone density value of young adults of the same sex. A T-score of −2.5 is thought to be consistent with osteoporosis in postmenopausal women and older men, but, as Dr. Maricic pointed out, a T-score of −2.5 only tells us that the patient has low bone density. Before we conclude that the patient has osteoporosis, all of the other causes of low bone density, including osteomalacia, osteogenesis imperfecta, and any of the secondary causes that were outlined, need to be excluded.
I believe that osteopenia, which is defined as a T-score value between −1 and −2.5, is not a very useful diagnostic term for clinical purposes. We know that low bone density is one of several risk factors for fracture. Within the group of patients with osteopenia are those who are at very high risk for fracture, including older people and those who have had fractures, as well as many patients who are not at high risk for fracture. In response to this problem, the World Health Organization developed the Fracture Risk Assessment Tool (FRAX), a fracture risk assessment tool used to help distinguish patients with high or low fracture risk.1
DR. GALL: Clinicians often find the terms used in the DEXA report confusing. Could you define absolute bone mineral density (BMD) and Z-score for the clinician?
DR. MCCLUNG: The BMD test measures the bone mineral content of a specific anatomic region and the area of that region and divides those 2 numbers to get an estimate of the BMD. It is not a true bone density test, but rather a measurement of calcium content within a region of bone.
The BMD value is translated into a T-score by comparing it to the average value for healthy young adults of the same sex and is then used for diagnosis in postmenopausal women. The Z-score is obtained by comparing the patient’s BMD value with the expected average value for healthy adults of the same age and sex and is used to determine whether a low BMD value for that patient is unexpected. A low T-score for a 55-year-old woman may be surprising, whereas a low T-score for a 90-year-old woman would be expected. A Z-score lets us know how concerned we should be.
DR. GALL: Dr. Lisse, you read a lot of DEXA scans. What can give a false value? Can you tell us about that and discuss the FRAX?
DR. LISSE: Dr. McClung wrote a very nice treatise on the FRAX,2 a tool that assesses the risk of fracture in bisphosphonate-naïve patients based on the consideration of risk factors, in addition to the BMD value. The DEXA measures bone quantity, but does not assess the risk factors for osteoporosis, of which I think prior fracture and patient age are the most important.
By considering the risk factors of smoking history, advanced age, prior fracture, and family history of fracture, and by adjusting for the country and racial origin of the patient, the FRAX provides a better measure of fracture risk for the osteopenic patient compared to BMD alone. It also provides a value, the 10-year fracture risk, that’s easier for the primary doctor to interpret compared to T-scores and Z-scores, which require comparison in terms of standard deviations.
DR. GALL: How can we use the FRAX if we are interested in doing so?
DR. LISSE: The tool is available online and very easy to use. Usually, you complete the assay using the BMD value. You can actually perform the assay without a BMD value, but I think that including the BMD value improves the precision and predictive value of the results. You just plug in the information online and are given a reading. Recent literature suggests that you can use it for patients who are taking bisphosphonates, but I think that’s a little bit further down the line in our discussion.
DR. GALL: A FRAX result states that a patient has a 10-year risk of major fracture of 8%. How do I use that result? Should I start treating the patient?
DR. LISSE: Several studies that examined local socioeconomic factors concluded that using a 20% risk of major osteoporotic fracture and a 3% risk of hip fracture are cost-effective thresholds for the diagnosis of patients in the United States. Although they should not be considered absolute, they are the current thresholds, and I think physicians can use them as criteria to make treatment decisions.
DR. MCCLUNG: That description is correct. FRAX has a scientific base and is a very highly validated tool that accurately predicts fracture probability in healthy middle-aged and older adults.1 Using the tool is a good first step while considering whether osteoporosis treatment is justified. The threshold values of a 10-year probability of hip fracture of 3% and a 10-year probability of major osteoporotic fracture of 20% are specific to the United States, which is based on the United States healthcare policy and where osteoporosis fits into the United States medical priorities. Other countries have their own thresholds that are very different.
DR. GALL: Dr. Maricic, we’ve talked about the DEXA and the FRAX. What other imaging tools are available and what are their roles?
DR. LISSE: The other issue is that the FRAX uses femoral neck density, which is a good predictor; however, in some patients, especially patients taking glucocorticoids, the spine density may be lower than the hip density. A low spine T-score should also be taken into account. We must individualize patients and not become overly focused on any one tool, although the use of the FRAX is certainly a major step forward from the use of only the T-score, for which, former guidelines recommended treatment for patients with scores within the wide range of −1 and −2.5.
DR. GALL: Another issue regarding DEXA is that we often get a false high BMD in patients with fracture of the lumbar spine, osteoarthritis, or issues with alignment of the spine. In such cases, it is important to examine the image, as the presence of bone abnormalities may render the spine DEXA score and the spine T-score less important.
DR. MARICIC: The role of other modalities in diagnosing osteoporosis in the United States is limited because of the widespread availability of DEXA in most communities. A few communities in Arizona have access to only quantitative computed tomography, which, although tends to overdiagnosise osteoporosis, can be helpful if bone density is found to be low and the clinical setting is appropriate.
Likewise, quantitative ultrasound in patients older than 65 years has a very valid role in estimating risk of fracture, but because DEXA is so widely available, we do not or usually should not use ultrasound instead of a DEXA scan and ultrasound cannot be used to monitor or follow-up patients with treatment. The only modality that should be used is the DEXA scan because of its very high precision.
DR. GALL: I have seen the use of ultrasound in both remote areas and nursing homes and other areas where it is difficult for patients to visit an office at which a DEXA scan performed, but it is not as accurate as the DEXA scan.
DR. MCCLUNG: Yes, but my understanding is that you use the ultrasound to determine whether you need a DEXA scan.
DR. MARICIC: Yes, but you shouldn’t use the ultrasound to start therapy or monitor therapy.
DR. MCCLUNG: FRAX, which can be calculated without a bone density test, provides a much more accurate assessment.
DR. MARICIC: And FRAX is probably cheaper and easier.
DR. GALL: Dr. McClung, would you talk a little bit about bone markers? I once heard you speak about their role in making a decision about when to treat patients with borderline DEXA and FRAX values.
DR. MCCLUNG: Bone markers are values obtained from blood and urine tests that reflect the activity of the bone cells. Generally, high levels of bone markers reflecting high levels of bone absorption are predictive of more rapid rates of bone loss. So, when a physician is deciding whether to treat, measuring a bone marker can sometimes provide important information to help make the decision. A bone turnover rate in the low–normal range in a bisphosphonate-naïve patient indicates that his/her bone density is stable and that he/she may benefit less from treatment compared to a patient with a high rate.
You can also use bone marker values to determine whether treatment has been effective, particularly if you use antiresorptive agents such as bisphosphonates. Patients with celiac disease or those who have had a gastrectomy may not absorb oral bisphosphonates, so their markers may remain high even if they are under treatment. Although there are certain patients for whom bone markers are helpful, the use of these markers is not routine in the management of most patients with osteoporosis.
DR. GALL: I would say that bone markers are generally overused. Another area in which the use of bone marker values may be helpful is compliance. I’ve used bone biomarker values in cases in which, for example, I start a patient on a weekly bisphosphonate and the patient comes back 12 weeks later saying that he/she doesn’t need a prescription. In such cases, I may perform bone marker testing to see whether the patient has been compliant.
Is there ever a time when we need to do a bone biopsy?
DR. MARICIC: I think a bone biopsy is only helpful for patients with long-term renal failure and dialysis to separate out the various forms of renal osteodystrophy. Although we used to perform a biopsy to help us understand bone turnover or detect osteomalacia, we can now do both with a biochemical test.
In some cases, we want to perform a bone marrow biopsy to look for marrow-based diseases such as mastocytosis or myeloma.
DR. GALL: I’d now like to discuss the prevention of osteoporosis and the risk factors that indicate testing and treatment of patients who are not postmenopausal.
DR. LISSE: There are risk factors that are nonmodifiable, including family history and genetics; modifiable risk factors, including level of exercise, especially weight-bearing exercise, which can be decreased; smoking, which can be discontinued or at least attenuated; and alcohol intake, which can be decreased. I think the role of caffeine is still controversial, although I’d love to hear from the other members of the panel about that.
I think we have overemphasized the importance of calcium and vitamin D supplementation. However, I measure the serum 25-hydroxy-vitamin D level, which according to me, is becoming more and more popular, and I try to keep it at around 30 ng/mL. I think all female patients should obtain some calcium supplementation, especially if their dietary intake is not adequate.
It was surprising to know that there’s probably a higher prevalence of vitamin D insufficiency in Arizona than in Minnesota in spite of the abundance of sunshine in the former.
DR. GALL: I consider patients who are thin, have poor bone stock, are malnourished, did not drink milk in their childhood, and have a family history of hip fracture in a close relative to be at higher risk, and I tend to test them early and consider either preventative treatment or just treatment for them.
I think an appropriate target for daily intake of calcium is between 800 and 1 200 mg, including that obtained from diet. The appropriate target for vitamin D intake in the absence of regular sun exposure is between 600 and 2 000 units per day.
DR. LISSE: Most recommendations that I’ve seen for calcium are about 800 mg, but they vary widely.
DR. MCCLUNG: Let’s get back to the management of premenopausal women with risk factors for low bone mass such as small body size, family history of osteoporosis, and medical problems that may lead to impaired bone health such as amenorrhea during early adolescence. For these women, maintaining adequate nutrition and physical activity and avoiding harmful lifestyle factors should be encouraged, but bone density testing is rarely necessary. If premenopausal women are estrogen replete, even if they have low bone density, treatment with osteoporosis drugs is not recommended. Individuals with risk factors for low bone density should be screened at the time of menopause to decide whether aggressive prevention of the rapid bone loss that occurs at that particularly important time is warranted.
DR. GALL: Dr. Maricic, there are 2 topics I’d like you to discuss. The first is comorbidities, specifically conditions such as thyroid disease, that we need to pay attention to, and the second is hormone replacement therapy and its current role.
DR. MARICIC: The NOF guidelines for the diagnosis and treatment of osteoporosis5 list a number of comorbid disorders and medications that may be responsible for a patient’s low bone density. We should consider the potential for osteoporosis in all men and women over the age of 50 years, especially if they have other disorders or medications known to affect bone mineral metabolism.
The NOF guidelines list about 30 diseases implicated in low bone density, including type 2 diabetes, hemochromatosis, and androgen- and estrogen-deficiency hypogonadism. Low bone density should be considered in patients with gastrointestinal (GI) disorders, of which celiac disease is the most important and common; those who have undergone GI bypass or other types of GI surgery; and those with hematological disorders such as mastocytosis and myeloma. Because chronic inflammatory production of cytokines and calcium immobilization lead to accelerated bone loss, low bone density should be considered in patients with rheumatic disorders, including systemic lupus; ankylosing spondylitis; and especially, rheumatoid arthritis, which FRAX identifies as a major risk factor for accelerated bone loss. Finally, low bone density should be considered in patients with a number of miscellaneous conditions, including chronic obstructive pulmonary disease, emphysema, chronic asthma, and sarcoidosis.
Regarding medications, the agents most commonly associated with low bone density are glucocorticoids. Low bone density should also be considered in patients taking certain anticonvulsants, especially phenobarbital and phenytoin, which can lead to accelerated degradation of 25-hydroxy-vitamin D and very low vitamin D levels and consequent osteomalacia, and in those taking aromatase inhibitors, which are now very important in the treatment of breast cancer.
DR. GALL: I’d just like to mention again the association between low bone density and both thyroid disease and overmedication in thyroid replacement therapy.
DR. MCCLUNG: We should probably also include proton pump inhibitors and selective serotonin reuptake inhibitors, which have been correlated with increased rates of fracture, although the mechanism underlying that correlation is unclear.
DR. LISSE: Do you mean that their wide use poses a concern?
DR. MCCLUNG: Yes, but their effect does not seem to be reflected in bone density testing. So, while recognizing their use as an independent risk factor for fracture is important, it is still unclear whether it should be considered while deciding whether to treat with an osteoporosis drug.
DR. MARICIC: Regarding hormone replacement therapy, we must first distinguish between hormone replacement, which is a combination of estrogen and progesterone for women with an intact uterus, and estrogen replacement or estrogen therapy, which is estrogen alone for women who have undergone a hysterectomy. Definitely, there are differences in the potential for adverse effects between these 2 groups.
I believe the data from the Women’s Health Initiative (WHI) suggested that increased risk of thrombosis and breast cancer is more commonly seen with hormone therapy and may be due more to progesterone than to estrogen replacement.6 There are also some differences in the risk with regard to the age of starting hormone therapy in our patients.
From the WHI, we know that hormone therapy prevents bone loss and reduces the risk of hip and other fractures. I think hormone therapy, especially estrogen therapy for women with an intact uterus, is an option to protect the skeleton in women with low bone density, especially those who are perimenopausal or early postmenopausal.
I personally avoid starting hormone therapy in patients above the age of 70 years and sometimes even above 65 years, but I believe it can be an option for women between the ages of 50 and 60 years with low bone density and no contraindications. For women with a strong family history of breast cancer, I usually recommend raloxifene. We’re now trying to limit the lifetime exposure of women to bisphosphonates, so I tend to reserve them for older women at very high risk of fracture, and almost never administer them to women aged 50 to 60 years.
I think that hormone therapy is the first option for women between 50 and 60 years with no strong family history of breast cancer. If there is, I start them on Evista, when possible.
DR. LISSE: I think that bisphosphonate therapy has been the primary choice of osteoporosis therapy since at least 2 000, which is when alendronate came into the market under its brand name. These drugs have been shown to reliably decrease fracture and improve the quality of life. Some drugs, particularly zoledronic acid, actually decrease mortality in patients with hip fracture.7
There are some differences among them. The first one on the market obviously was alendronate, so there’s probably the most data on it. Risedronate, alendronate, zoledronic acid, denosumab, and teriparatide have been shown to reduce vertebral and nonvertebral fracture; ibandronate, to reduce spinal but not nonvertebral fracture; alendronate, risedronate, denosumab, and zoledronic acid, to prevent hip fracture in postmenopausal women; and risedronate, to decrease vertebral and nonvertebral fracture in men.7
The original studies on the effect of many of these drugs on fracture risk were conducted with daily dosing, and equivalent dosing in weekly and monthly regimens has been used and approved, sometimes without fracture data. The drugs work, their safety-to-risk ratio is quite good, and we have long-term experience with them. I think it’s not surprising that a small percentage of patients who have been on them for a decade or more have issues and side effects. There are risks to taking these drugs, as there are with any other drug.
Probably, the most common risk is GI complications, ranging from irritation to esophageal perforation, which surfaced shortly after alendronate came on the market. To prevent GI complications, strict regimens have been developed for oral bisphosphonate use. To some extent, I think that they limit our patient population because many cannot or will not comply with the requirement of taking the drug first thing in the morning on an empty stomach with approximately 230 mL of water and remain upright for 30 to 60 minutes, depending on the medication, to realize any benefit.
Gastrointestinal complications, including those affecting the esophagus, are, by far, the most common issues observed with bisphosphonate therapy. Gastric ulcerations in certain patients, especially in those who use risedronate in coated form, have also been observed.
There are other probably less common but controversial issues, including a possible association with atrial fibrillation, which was identified in the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) study.8 An association with alendronate was also suspected, but a recent meta-analysis does not support this association.9
An association with esophageal cancer has been anecdotally described in several populations, but I think that the data are mixed at this point. Then, there is the association with osteonecrosis of the jaw and atypical fracture, both of which are quite rare and occur in between 1 in 10 000 to 1 in 100 000 patients.10 I think that the wide coverage of this association in the lay press may have caused many patients who probably shouldn’t have gone off bisphosphonates, to go off them.
A positive byproduct of these associations being reported could be increased research into whether there should be a time or exposure limit to bisphosphonate use and whether a drug holiday from them is warranted.
DR. GALL: Dr. McClung, could you please describe how you monitor a patient after initiation of bisphosphonate therapy and then discuss an atypical fracture?
DR. MCCLUNG: Treatment with any osteoporosis drug is generally monitored by measuring BMD 2 years after the patient has started therapy. The changes in BMD with treatment are quite modest, so we expect to see either a modest increase or at least stability. If a clear decrease in BMD is observed, we consider noncompliance, secondary causes of bone loss, and other reasons for treatment failure.
In theory, biochemical testing of bone turnover should be useful in monitoring therapy. However, because of limitations in the quality and the reproducibility of the assays in the clinical setting, it is difficult to use the results. I think that marker measurement is not ready for use in the everyday clinic, although it has been very valuable in our research.
Atypical fracture is important. As mentioned earlier, there has been concern right from the time when bisphosphonate research began about the potential for skeletal consequences with long-term therapy because of the pharmacology of bisphosphonates. We know that these drugs accumulate in the skeleton over time, and there were concerns about whether we would see progressive inhibition of bone turnover with long-term therapy. Although we were pleased to observe persistent, but not progressive, reduction in bone turnover with long-term treatment, at least for up to 10 years,11 it appears that some individuals, or perhaps, a unique subset of patients, experience too much inhibition of bone metabolism for prolonged durations. When this happens, bone brittleness occurs and is manifested by atypical chalk stick-like fractures of the femur. It is clear that there is a duration-dependent increase in risk, with fractures occurring in roughly 1 in 1 000 patients who have completed at least 10 years of alendronate therapy.12 If we properly decide whom to treat and how to treat, it is important to recognize that this risk is much, much lower than the risk of important fracture, such as that of the hip and spine, in patients who are not treated with bisphosphonate therapy.13 We should reserve bisphosphonates for patients who clearly have osteoporosis or are at high risk for fracture.
DR. GALL: Dr. Maricic, can you conclude on the use of calcitonin, denosumab, and teriparatide, ie, some of the other drugs approved for the treatment of osteoporosis?
DR. MARICIC: Calcitonin is extremely safe but it isn’t very effective and has been shown to reduce spinal fracture risk by 33% and have no effect on hip fracture risk,14 so I personally haven’t prescribed it in almost 10 years.
Denosumab, a receptor activator of nuclear factor-kB (RANK)-ligand inhibitor and monoclonal antibody, is probably among the most effective medications we have. Because it bypasses the GI tract, it’s an excellent choice for patients who develop GI problems with bisphosphonates. Nevertheless, because it is a very potent osteoclast inhibitor, it must be used carefully in patients prone to hypocalcemia, with renal failure, or who are extremely vitamin D deficient. Although hypocalcemia must be considered before initiating its use, I think it is an extremely effective agent.
Teriparatide is the only anabolic agent currently approved for use in patients at high risk of fracture, and that’s for whom we mainly use it. Because its mode of action is completely different from that of bisphosphonates, we use it for patients with either very low bone density or with multiple fractures who have not responded to bisphosphonate therapy. The Food and Drug Administration (FDA) has approved teriparatide therapy for only 2 years, after which it must be followed by antiresorptive therapy. Unfortunately, I occasionally see patients who had not been given antiresorptives after 2 years of teriparatide, causing them to lose any benefit they may have derived from being on this very expensive drug for 2 years. It must always be followed up by an antiresorptive drug.
DR. MCCLUNG: Regarding a drug holiday, you can consider it if you observe a duration-dependent increase in the risk of atypical fracture.15,16 The FDA has provided us with at least a general template for when it should be considered.17 Based on the limited information we have, it is suggested that fracture risk be reassessed after 3 to 5 years of therapy. For patients with a modest risk for fracture at that point, ie, they no longer have osteoporosis according to the results of bone density testing, it is suggested that therapy be discontinued for 1 to 2 years.
For patients found to remain at high risk for fracture, especially spine fracture, continuation of therapy is recommended. The evidence for this recommendation came from 2 large extension studies of the alendronate and zoledronic acid clinical trials.18,19
If treatment is discontinued, the question of when, if ever, to restart therapy arises. The data from the clinical trials suggest that neither the measurement of bone density nor bone markers are helpful in that regard. So, in my clinic, we treat the holiday like a vacation that has a finite end.13 We take patients off alendronate for 2 or 3 years but off risedronate for only 1 year because its effects wear off more quickly. At that point, we reassess the patient. If he/she meets the criteria for treatment with an osteoporosis drug again, we decide on the best treatment option.
DR. GALL: Dr. Lisse, please describe how treating steroid-induced male osteoporosis differs from treating postmenopausal and female osteoporosis.
DR. LISSE: Before I do so, I wanted to add that a flu-like syndrome sometimes occurs with bisphosphonate use. In a corollary to what Dr. McClung just discussed, the European registries provide at least some reassuring evidence that when patients stop taking bisphosphonates, the risk of atypical fracture appears to decrease fairly rapidly, whereas bisphosphonate efficacy doesn’t seem to tail off as quickly.15 It should be reassuring that if patients stop taking a drug, they may have some protection during that period in terms of osteoporosis coverage, unlike when they stop taking estrogen or teriparatide, whose effects tail off rather rapidly.
With glucocorticoid-induced osteoporosis, the biggest issue is probably the fact that fractures tend to occur early and at a higher bone density than what we’re used to seeing with traditional postmenopausal osteoporosis. So it has thrown the old paradigm into disarray. Before the introduction of FRAX, treatment was recommended for patients with a T-score of −1. As the FRAX includes glucocorticoids as a risk factor, its use is very helpful in this regard.
FRAX does have its limitations, and there are physicians who are concerned that it does not include consideration of steroid duration or dose. I think the American College of Rheumatology’s recommendation is to measure bone density and then subdivide the patient population into low risk, moderate risk, and high risk according to the risk for major osteoporotic fracture of ≤10%, 10% to 20%, and ≥20%, respectively.20 Treatment should be considered based on the risk and dosage. Patients taking a dose of 7.5 mg or higher probably need treatment, even if they’re at low risk. Patients on lower doses probably need treatment if they remain on glucocorticoid therapy for more than 3 months.
Although most fractures due to steroid use are of the spine, not all are. I’m sure all of us on the panel are old enough to remember the old asthmatics who used to take large doses of steroids. Certainly, one of the easiest things to do is to taper patients off steroids or reduce the dose down to the lowest possible dose. The use of topical steroids is preferred to that of oral steroids or inhaled steroids.
The NOF guidelines for testing for male osteoporosis differ from those for testing female osteoporosis. Although they recommend that all women older than 65 years be tested, they do not recommend routine testing in men older than 70 years. I think that this latter recommendation, which is based on a US Preventative Health Service Task Force recommendation,21 is probably a mistake and rather confusing.
Even though there has been a study of raloxifene in men, the guidelines are more limited regarding how men who are hypogonadal should be treated. Testosterone should be measured in all men, and those found to be hypogonadal deserve testosterone replacement. Again, the backbone of therapy is the use of bisphosphonates for the most part. Teriparatide has also been approved for use in men, although it has not been proven to provide protection against hip fracture.
DR. GALL: We’ve had an extensive discussion today on low bone density diseases, focusing mostly on osteoporosis. We have discussed at some length the risk factors and the diagnostic tools that we have, particularly the DEXA scan and FRAX, to assess the risk of fracture. We then discussed the risk factors, including comorbidities; means of prevention; and the different treatment modalities, including physical therapy and several nonpharmacologic therapies, in addition to the various medical therapies, including hormone replacement, bisphosphonates, calcitonin, denosumab, and teriparatide. We’ve also briefly touched on the differences between postmenopausal osteoporosis and steroid-induced osteoporosis and male osteoporosis.
FoxP2 Media LLC is the publisher of The Medical Roundtable.
Dr. Maricic, what are the different types of osteopenia that primary care clinicians encounter in their practice?
DR. MARICIC: Osteopenia has several connotations, depending on the setting in which it is diagnosed. Radiologists will describe a patient as being osteopenic based on the subjective assessment that the patient has low bone density on radiography. With particular reference to osteoporosis or bone densitometry, osteopenia refers to a dual-energy X-ray absorptiometry (DEXA) T-score, which is a comparison of the bone mass of a patient to that of a young, ideal patient of the same sex and ethnicity.
DR. GALL: Is osteoporosis the only disease or are there other diseases that we may see associated with osteopenia?
DR. MARICIC: Neither osteopenia nor osteoporosis diagnosed by the DEXA score is necessarily caused by estrogen deficiency. The DEXA report tells you whether a patient has low bone density but not about the etiology. Although estrogen deficiency is a common cause of osteopenia or osteoporosis, other conditions such as primary hyperparathyroidism, multiple myeloma, vitamin D deficiency, osteomalacia and the conditions associated with it, chronic renal failure with osteitis, fibrosis cystica, and hyperparathyroidism should be considered by the primary care physician.
It’s typically recommended that all patients with low bone density diagnosed by their DEXA score have a chemistry screening done to determine the calcium and alkaline phosphatase levels, as well as 25-hydroxy-vitamin D level, in order to ensure that the patient is not vitamin D deficient. A 24-hour urine test is also recommended to ensure that the vitamin D level is not low, suggesting malabsorption, such as what we see in vitamin D deficiency or celiac disease, or that it’s not high, suggesting idiopathic hypercalciuria.
Those are the main, most common disorders that we’d like to exclude in patients with osteopenia or especially osteoporosis. We would also want to exclude secondary hyperparathyroidism; vitamin D deficiency; and, when suspected, celiac disease, idiopathic hypercalciuria, and multiple myeloma. Those are some of the conditions to be considered, especially when the T-score does not accord with the clinical history.
DR. GALL: Dr. McClung, can you please discuss the use of X-ray and DEXA scan as diagnostic tools?
DR. MCCLUNG: These 2 tools have completely different roles. We use the DEXA scan to measure bone density, primarily in the hip and the spine, in postmenopausal women and older men to obtain a T-score that is, a value comparing the patient’s bone density to the average bone density value of young adults of the same sex. A T-score of −2.5 is thought to be consistent with osteoporosis in postmenopausal women and older men, but, as Dr. Maricic pointed out, a T-score of −2.5 only tells us that the patient has low bone density. Before we conclude that the patient has osteoporosis, all of the other causes of low bone density, including osteomalacia, osteogenesis imperfecta, and any of the secondary causes that were outlined, need to be excluded.
I believe that osteopenia, which is defined as a T-score value between −1 and −2.5, is not a very useful diagnostic term for clinical purposes. We know that low bone density is one of several risk factors for fracture. Within the group of patients with osteopenia are those who are at very high risk for fracture, including older people and those who have had fractures, as well as many patients who are not at high risk for fracture. In response to this problem, the World Health Organization developed the Fracture Risk Assessment Tool (FRAX), a fracture risk assessment tool used to help distinguish patients with high or low fracture risk.1
DR. GALL: Clinicians often find the terms used in the DEXA report confusing. Could you define absolute bone mineral density (BMD) and Z-score for the clinician?
DR. MCCLUNG: The BMD test measures the bone mineral content of a specific anatomic region and the area of that region and divides those 2 numbers to get an estimate of the BMD. It is not a true bone density test, but rather a measurement of calcium content within a region of bone.
The BMD value is translated into a T-score by comparing it to the average value for healthy young adults of the same sex and is then used for diagnosis in postmenopausal women. The Z-score is obtained by comparing the patient’s BMD value with the expected average value for healthy adults of the same age and sex and is used to determine whether a low BMD value for that patient is unexpected. A low T-score for a 55-year-old woman may be surprising, whereas a low T-score for a 90-year-old woman would be expected. A Z-score lets us know how concerned we should be.
DR. GALL: Dr. Lisse, you read a lot of DEXA scans. What can give a false value? Can you tell us about that and discuss the FRAX?
DR. LISSE: Dr. McClung wrote a very nice treatise on the FRAX,2 a tool that assesses the risk of fracture in bisphosphonate-naïve patients based on the consideration of risk factors, in addition to the BMD value. The DEXA measures bone quantity, but does not assess the risk factors for osteoporosis, of which I think prior fracture and patient age are the most important.
By considering the risk factors of smoking history, advanced age, prior fracture, and family history of fracture, and by adjusting for the country and racial origin of the patient, the FRAX provides a better measure of fracture risk for the osteopenic patient compared to BMD alone. It also provides a value, the 10-year fracture risk, that’s easier for the primary doctor to interpret compared to T-scores and Z-scores, which require comparison in terms of standard deviations.
DR. GALL: How can we use the FRAX if we are interested in doing so?
DR. LISSE: The tool is available online and very easy to use. Usually, you complete the assay using the BMD value. You can actually perform the assay without a BMD value, but I think that including the BMD value improves the precision and predictive value of the results. You just plug in the information online and are given a reading. Recent literature suggests that you can use it for patients who are taking bisphosphonates, but I think that’s a little bit further down the line in our discussion.
DR. GALL: A FRAX result states that a patient has a 10-year risk of major fracture of 8%. How do I use that result? Should I start treating the patient?
DR. LISSE: Several studies that examined local socioeconomic factors concluded that using a 20% risk of major osteoporotic fracture and a 3% risk of hip fracture are cost-effective thresholds for the diagnosis of patients in the United States. Although they should not be considered absolute, they are the current thresholds, and I think physicians can use them as criteria to make treatment decisions.
DR. MCCLUNG: That description is correct. FRAX has a scientific base and is a very highly validated tool that accurately predicts fracture probability in healthy middle-aged and older adults.1 Using the tool is a good first step while considering whether osteoporosis treatment is justified. The threshold values of a 10-year probability of hip fracture of 3% and a 10-year probability of major osteoporotic fracture of 20% are specific to the United States, which is based on the United States healthcare policy and where osteoporosis fits into the United States medical priorities. Other countries have their own thresholds that are very different.
DR. GALL: Dr. Maricic, we’ve talked about the DEXA and the FRAX. What other imaging tools are available and what are their roles?
DR. LISSE: The other issue is that the FRAX uses femoral neck density, which is a good predictor; however, in some patients, especially patients taking glucocorticoids, the spine density may be lower than the hip density. A low spine T-score should also be taken into account. We must individualize patients and not become overly focused on any one tool, although the use of the FRAX is certainly a major step forward from the use of only the T-score, for which, former guidelines recommended treatment for patients with scores within the wide range of −1 and −2.5.
DR. GALL: Another issue regarding DEXA is that we often get a false high BMD in patients with fracture of the lumbar spine, osteoarthritis, or issues with alignment of the spine. In such cases, it is important to examine the image, as the presence of bone abnormalities may render the spine DEXA score and the spine T-score less important.
DR. MARICIC: The role of other modalities in diagnosing osteoporosis in the United States is limited because of the widespread availability of DEXA in most communities. A few communities in Arizona have access to only quantitative computed tomography, which, although tends to overdiagnosise osteoporosis, can be helpful if bone density is found to be low and the clinical setting is appropriate.
Likewise, quantitative ultrasound in patients older than 65 years has a very valid role in estimating risk of fracture, but because DEXA is so widely available, we do not or usually should not use ultrasound instead of a DEXA scan and ultrasound cannot be used to monitor or follow-up patients with treatment. The only modality that should be used is the DEXA scan because of its very high precision.
DR. GALL: I have seen the use of ultrasound in both remote areas and nursing homes and other areas where it is difficult for patients to visit an office at which a DEXA scan performed, but it is not as accurate as the DEXA scan.
DR. MCCLUNG: Yes, but my understanding is that you use the ultrasound to determine whether you need a DEXA scan.
DR. MARICIC: Yes, but you shouldn’t use the ultrasound to start therapy or monitor therapy.
DR. MCCLUNG: FRAX, which can be calculated without a bone density test, provides a much more accurate assessment.
DR. MARICIC: And FRAX is probably cheaper and easier.
DR. GALL: Dr. McClung, would you talk a little bit about bone markers? I once heard you speak about their role in making a decision about when to treat patients with borderline DEXA and FRAX values.
DR. MCCLUNG: Bone markers are values obtained from blood and urine tests that reflect the activity of the bone cells. Generally, high levels of bone markers reflecting high levels of bone absorption are predictive of more rapid rates of bone loss. So, when a physician is deciding whether to treat, measuring a bone marker can sometimes provide important information to help make the decision. A bone turnover rate in the low–normal range in a bisphosphonate-naïve patient indicates that his/her bone density is stable and that he/she may benefit less from treatment compared to a patient with a high rate.
You can also use bone marker values to determine whether treatment has been effective, particularly if you use antiresorptive agents such as bisphosphonates. Patients with celiac disease or those who have had a gastrectomy may not absorb oral bisphosphonates, so their markers may remain high even if they are under treatment. Although there are certain patients for whom bone markers are helpful, the use of these markers is not routine in the management of most patients with osteoporosis.
DR. GALL: I would say that bone markers are generally overused. Another area in which the use of bone marker values may be helpful is compliance. I’ve used bone biomarker values in cases in which, for example, I start a patient on a weekly bisphosphonate and the patient comes back 12 weeks later saying that he/she doesn’t need a prescription. In such cases, I may perform bone marker testing to see whether the patient has been compliant.
Is there ever a time when we need to do a bone biopsy?
DR. MARICIC: I think a bone biopsy is only helpful for patients with long-term renal failure and dialysis to separate out the various forms of renal osteodystrophy. Although we used to perform a biopsy to help us understand bone turnover or detect osteomalacia, we can now do both with a biochemical test.
In some cases, we want to perform a bone marrow biopsy to look for marrow-based diseases such as mastocytosis or myeloma.
DR. GALL: I’d now like to discuss the prevention of osteoporosis and the risk factors that indicate testing and treatment of patients who are not postmenopausal.
DR. LISSE: There are risk factors that are nonmodifiable, including family history and genetics; modifiable risk factors, including level of exercise, especially weight-bearing exercise, which can be decreased; smoking, which can be discontinued or at least attenuated; and alcohol intake, which can be decreased. I think the role of caffeine is still controversial, although I’d love to hear from the other members of the panel about that.
I think we have overemphasized the importance of calcium and vitamin D supplementation. However, I measure the serum 25-hydroxy-vitamin D level, which according to me, is becoming more and more popular, and I try to keep it at around 30 ng/mL. I think all female patients should obtain some calcium supplementation, especially if their dietary intake is not adequate.
It was surprising to know that there’s probably a higher prevalence of vitamin D insufficiency in Arizona than in Minnesota in spite of the abundance of sunshine in the former.
DR. GALL: I consider patients who are thin, have poor bone stock, are malnourished, did not drink milk in their childhood, and have a family history of hip fracture in a close relative to be at higher risk, and I tend to test them early and consider either preventative treatment or just treatment for them.
I think an appropriate target for daily intake of calcium is between 800 and 1 200 mg, including that obtained from diet. The appropriate target for vitamin D intake in the absence of regular sun exposure is between 600 and 2 000 units per day.
DR. LISSE: Most recommendations that I’ve seen for calcium are about 800 mg, but they vary widely.
DR. MCCLUNG: Let’s get back to the management of premenopausal women with risk factors for low bone mass such as small body size, family history of osteoporosis, and medical problems that may lead to impaired bone health such as amenorrhea during early adolescence. For these women, maintaining adequate nutrition and physical activity and avoiding harmful lifestyle factors should be encouraged, but bone density testing is rarely necessary. If premenopausal women are estrogen replete, even if they have low bone density, treatment with osteoporosis drugs is not recommended. Individuals with risk factors for low bone density should be screened at the time of menopause to decide whether aggressive prevention of the rapid bone loss that occurs at that particularly important time is warranted.
DR. GALL: Dr. Maricic, there are 2 topics I’d like you to discuss. The first is comorbidities, specifically conditions such as thyroid disease, that we need to pay attention to, and the second is hormone replacement therapy and its current role.
DR. MARICIC: The NOF guidelines for the diagnosis and treatment of osteoporosis5 list a number of comorbid disorders and medications that may be responsible for a patient’s low bone density. We should consider the potential for osteoporosis in all men and women over the age of 50 years, especially if they have other disorders or medications known to affect bone mineral metabolism.
The NOF guidelines list about 30 diseases implicated in low bone density, including type 2 diabetes, hemochromatosis, and androgen- and estrogen-deficiency hypogonadism. Low bone density should be considered in patients with gastrointestinal (GI) disorders, of which celiac disease is the most important and common; those who have undergone GI bypass or other types of GI surgery; and those with hematological disorders such as mastocytosis and myeloma. Because chronic inflammatory production of cytokines and calcium immobilization lead to accelerated bone loss, low bone density should be considered in patients with rheumatic disorders, including systemic lupus; ankylosing spondylitis; and especially, rheumatoid arthritis, which FRAX identifies as a major risk factor for accelerated bone loss. Finally, low bone density should be considered in patients with a number of miscellaneous conditions, including chronic obstructive pulmonary disease, emphysema, chronic asthma, and sarcoidosis.
Regarding medications, the agents most commonly associated with low bone density are glucocorticoids. Low bone density should also be considered in patients taking certain anticonvulsants, especially phenobarbital and phenytoin, which can lead to accelerated degradation of 25-hydroxy-vitamin D and very low vitamin D levels and consequent osteomalacia, and in those taking aromatase inhibitors, which are now very important in the treatment of breast cancer.
DR. GALL: I’d just like to mention again the association between low bone density and both thyroid disease and overmedication in thyroid replacement therapy.
DR. MCCLUNG: We should probably also include proton pump inhibitors and selective serotonin reuptake inhibitors, which have been correlated with increased rates of fracture, although the mechanism underlying that correlation is unclear.
DR. LISSE: Do you mean that their wide use poses a concern?
DR. MCCLUNG: Yes, but their effect does not seem to be reflected in bone density testing. So, while recognizing their use as an independent risk factor for fracture is important, it is still unclear whether it should be considered while deciding whether to treat with an osteoporosis drug.
DR. MARICIC: Regarding hormone replacement therapy, we must first distinguish between hormone replacement, which is a combination of estrogen and progesterone for women with an intact uterus, and estrogen replacement or estrogen therapy, which is estrogen alone for women who have undergone a hysterectomy. Definitely, there are differences in the potential for adverse effects between these 2 groups.
I believe the data from the Women’s Health Initiative (WHI) suggested that increased risk of thrombosis and breast cancer is more commonly seen with hormone therapy and may be due more to progesterone than to estrogen replacement.6 There are also some differences in the risk with regard to the age of starting hormone therapy in our patients.
From the WHI, we know that hormone therapy prevents bone loss and reduces the risk of hip and other fractures. I think hormone therapy, especially estrogen therapy for women with an intact uterus, is an option to protect the skeleton in women with low bone density, especially those who are perimenopausal or early postmenopausal.
I personally avoid starting hormone therapy in patients above the age of 70 years and sometimes even above 65 years, but I believe it can be an option for women between the ages of 50 and 60 years with low bone density and no contraindications. For women with a strong family history of breast cancer, I usually recommend raloxifene. We’re now trying to limit the lifetime exposure of women to bisphosphonates, so I tend to reserve them for older women at very high risk of fracture, and almost never administer them to women aged 50 to 60 years.
I think that hormone therapy is the first option for women between 50 and 60 years with no strong family history of breast cancer. If there is, I start them on Evista, when possible.
DR. LISSE: I think that bisphosphonate therapy has been the primary choice of osteoporosis therapy since at least 2 000, which is when alendronate came into the market under its brand name. These drugs have been shown to reliably decrease fracture and improve the quality of life. Some drugs, particularly zoledronic acid, actually decrease mortality in patients with hip fracture.7
There are some differences among them. The first one on the market obviously was alendronate, so there’s probably the most data on it. Risedronate, alendronate, zoledronic acid, denosumab, and teriparatide have been shown to reduce vertebral and nonvertebral fracture; ibandronate, to reduce spinal but not nonvertebral fracture; alendronate, risedronate, denosumab, and zoledronic acid, to prevent hip fracture in postmenopausal women; and risedronate, to decrease vertebral and nonvertebral fracture in men.7
The original studies on the effect of many of these drugs on fracture risk were conducted with daily dosing, and equivalent dosing in weekly and monthly regimens has been used and approved, sometimes without fracture data. The drugs work, their safety-to-risk ratio is quite good, and we have long-term experience with them. I think it’s not surprising that a small percentage of patients who have been on them for a decade or more have issues and side effects. There are risks to taking these drugs, as there are with any other drug.
Probably, the most common risk is GI complications, ranging from irritation to esophageal perforation, which surfaced shortly after alendronate came on the market. To prevent GI complications, strict regimens have been developed for oral bisphosphonate use. To some extent, I think that they limit our patient population because many cannot or will not comply with the requirement of taking the drug first thing in the morning on an empty stomach with approximately 230 mL of water and remain upright for 30 to 60 minutes, depending on the medication, to realize any benefit.
Gastrointestinal complications, including those affecting the esophagus, are, by far, the most common issues observed with bisphosphonate therapy. Gastric ulcerations in certain patients, especially in those who use risedronate in coated form, have also been observed.
There are other probably less common but controversial issues, including a possible association with atrial fibrillation, which was identified in the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) study.8 An association with alendronate was also suspected, but a recent meta-analysis does not support this association.9
An association with esophageal cancer has been anecdotally described in several populations, but I think that the data are mixed at this point. Then, there is the association with osteonecrosis of the jaw and atypical fracture, both of which are quite rare and occur in between 1 in 10 000 to 1 in 100 000 patients.10 I think that the wide coverage of this association in the lay press may have caused many patients who probably shouldn’t have gone off bisphosphonates, to go off them.
A positive byproduct of these associations being reported could be increased research into whether there should be a time or exposure limit to bisphosphonate use and whether a drug holiday from them is warranted.
DR. GALL: Dr. McClung, could you please describe how you monitor a patient after initiation of bisphosphonate therapy and then discuss an atypical fracture?
DR. MCCLUNG: Treatment with any osteoporosis drug is generally monitored by measuring BMD 2 years after the patient has started therapy. The changes in BMD with treatment are quite modest, so we expect to see either a modest increase or at least stability. If a clear decrease in BMD is observed, we consider noncompliance, secondary causes of bone loss, and other reasons for treatment failure.
In theory, biochemical testing of bone turnover should be useful in monitoring therapy. However, because of limitations in the quality and the reproducibility of the assays in the clinical setting, it is difficult to use the results. I think that marker measurement is not ready for use in the everyday clinic, although it has been very valuable in our research.
Atypical fracture is important. As mentioned earlier, there has been concern right from the time when bisphosphonate research began about the potential for skeletal consequences with long-term therapy because of the pharmacology of bisphosphonates. We know that these drugs accumulate in the skeleton over time, and there were concerns about whether we would see progressive inhibition of bone turnover with long-term therapy. Although we were pleased to observe persistent, but not progressive, reduction in bone turnover with long-term treatment, at least for up to 10 years,11 it appears that some individuals, or perhaps, a unique subset of patients, experience too much inhibition of bone metabolism for prolonged durations. When this happens, bone brittleness occurs and is manifested by atypical chalk stick-like fractures of the femur. It is clear that there is a duration-dependent increase in risk, with fractures occurring in roughly 1 in 1 000 patients who have completed at least 10 years of alendronate therapy.12 If we properly decide whom to treat and how to treat, it is important to recognize that this risk is much, much lower than the risk of important fracture, such as that of the hip and spine, in patients who are not treated with bisphosphonate therapy.13 We should reserve bisphosphonates for patients who clearly have osteoporosis or are at high risk for fracture.
DR. GALL: Dr. Maricic, can you conclude on the use of calcitonin, denosumab, and teriparatide, ie, some of the other drugs approved for the treatment of osteoporosis?
DR. MARICIC: Calcitonin is extremely safe but it isn’t very effective and has been shown to reduce spinal fracture risk by 33% and have no effect on hip fracture risk,14 so I personally haven’t prescribed it in almost 10 years.
Denosumab, a receptor activator of nuclear factor-kB (RANK)-ligand inhibitor and monoclonal antibody, is probably among the most effective medications we have. Because it bypasses the GI tract, it’s an excellent choice for patients who develop GI problems with bisphosphonates. Nevertheless, because it is a very potent osteoclast inhibitor, it must be used carefully in patients prone to hypocalcemia, with renal failure, or who are extremely vitamin D deficient. Although hypocalcemia must be considered before initiating its use, I think it is an extremely effective agent.
Teriparatide is the only anabolic agent currently approved for use in patients at high risk of fracture, and that’s for whom we mainly use it. Because its mode of action is completely different from that of bisphosphonates, we use it for patients with either very low bone density or with multiple fractures who have not responded to bisphosphonate therapy. The Food and Drug Administration (FDA) has approved teriparatide therapy for only 2 years, after which it must be followed by antiresorptive therapy. Unfortunately, I occasionally see patients who had not been given antiresorptives after 2 years of teriparatide, causing them to lose any benefit they may have derived from being on this very expensive drug for 2 years. It must always be followed up by an antiresorptive drug.
DR. MCCLUNG: Regarding a drug holiday, you can consider it if you observe a duration-dependent increase in the risk of atypical fracture.15,16 The FDA has provided us with at least a general template for when it should be considered.17 Based on the limited information we have, it is suggested that fracture risk be reassessed after 3 to 5 years of therapy. For patients with a modest risk for fracture at that point, ie, they no longer have osteoporosis according to the results of bone density testing, it is suggested that therapy be discontinued for 1 to 2 years.
For patients found to remain at high risk for fracture, especially spine fracture, continuation of therapy is recommended. The evidence for this recommendation came from 2 large extension studies of the alendronate and zoledronic acid clinical trials.18,19
If treatment is discontinued, the question of when, if ever, to restart therapy arises. The data from the clinical trials suggest that neither the measurement of bone density nor bone markers are helpful in that regard. So, in my clinic, we treat the holiday like a vacation that has a finite end.13 We take patients off alendronate for 2 or 3 years but off risedronate for only 1 year because its effects wear off more quickly. At that point, we reassess the patient. If he/she meets the criteria for treatment with an osteoporosis drug again, we decide on the best treatment option.
DR. GALL: Dr. Lisse, please describe how treating steroid-induced male osteoporosis differs from treating postmenopausal and female osteoporosis.
DR. LISSE: Before I do so, I wanted to add that a flu-like syndrome sometimes occurs with bisphosphonate use. In a corollary to what Dr. McClung just discussed, the European registries provide at least some reassuring evidence that when patients stop taking bisphosphonates, the risk of atypical fracture appears to decrease fairly rapidly, whereas bisphosphonate efficacy doesn’t seem to tail off as quickly.15 It should be reassuring that if patients stop taking a drug, they may have some protection during that period in terms of osteoporosis coverage, unlike when they stop taking estrogen or teriparatide, whose effects tail off rather rapidly.
With glucocorticoid-induced osteoporosis, the biggest issue is probably the fact that fractures tend to occur early and at a higher bone density than what we’re used to seeing with traditional postmenopausal osteoporosis. So it has thrown the old paradigm into disarray. Before the introduction of FRAX, treatment was recommended for patients with a T-score of −1. As the FRAX includes glucocorticoids as a risk factor, its use is very helpful in this regard.
FRAX does have its limitations, and there are physicians who are concerned that it does not include consideration of steroid duration or dose. I think the American College of Rheumatology’s recommendation is to measure bone density and then subdivide the patient population into low risk, moderate risk, and high risk according to the risk for major osteoporotic fracture of ≤10%, 10% to 20%, and ≥20%, respectively.20 Treatment should be considered based on the risk and dosage. Patients taking a dose of 7.5 mg or higher probably need treatment, even if they’re at low risk. Patients on lower doses probably need treatment if they remain on glucocorticoid therapy for more than 3 months.
Although most fractures due to steroid use are of the spine, not all are. I’m sure all of us on the panel are old enough to remember the old asthmatics who used to take large doses of steroids. Certainly, one of the easiest things to do is to taper patients off steroids or reduce the dose down to the lowest possible dose. The use of topical steroids is preferred to that of oral steroids or inhaled steroids.
The NOF guidelines for testing for male osteoporosis differ from those for testing female osteoporosis. Although they recommend that all women older than 65 years be tested, they do not recommend routine testing in men older than 70 years. I think that this latter recommendation, which is based on a US Preventative Health Service Task Force recommendation,21 is probably a mistake and rather confusing.
Even though there has been a study of raloxifene in men, the guidelines are more limited regarding how men who are hypogonadal should be treated. Testosterone should be measured in all men, and those found to be hypogonadal deserve testosterone replacement. Again, the backbone of therapy is the use of bisphosphonates for the most part. Teriparatide has also been approved for use in men, although it has not been proven to provide protection against hip fracture.
DR. GALL: We’ve had an extensive discussion today on low bone density diseases, focusing mostly on osteoporosis. We have discussed at some length the risk factors and the diagnostic tools that we have, particularly the DEXA scan and FRAX, to assess the risk of fracture. We then discussed the risk factors, including comorbidities; means of prevention; and the different treatment modalities, including physical therapy and several nonpharmacologic therapies, in addition to the various medical therapies, including hormone replacement, bisphosphonates, calcitonin, denosumab, and teriparatide. We’ve also briefly touched on the differences between postmenopausal osteoporosis and steroid-induced osteoporosis and male osteoporosis.
FoxP2 Media LLC is the publisher of The Medical Roundtable.
FoxP2 Media LLC
