QuickConsultCAST—Leading Experts Respond
to Frequently Asked Questions (FAQs) About Osteoporosis

Commercial Support Disclosure: The following questions were posed in oral or written form by physicians participating in a live symposium series titled, Screen and Intervene: Critical Challenges in Osteoporosis—Year 2006 Update. The symposium was supported by an independent educational grant from Roche Laboratories Inc. and jointly sponsored by the University of Massachusetts Medical School, Office of Continuing Education.

Conflict of Interest Faculty Disclosure:

The following questions were answered by  Ronald Emkey, MD, Director of Metabolic Bone Disease Arthritis and Osteoporosis Clinic, Wyomissing, PA

Dr. Emkey discloses that he has participated as a consultant for Merck, P&G, GSK, Roche, Amgen, and that he is on the Speakers’ Bureau of Merck, GSK, Roche, Amgen.

The answers provided by experts to ConsultCAST—Experts Answer Frequently Asked Questions reflect the opinions, output, and analyses of specifically cited experts, investigators, educators, and clinicians participating in commercially supported CME activities.

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Questions and Answers:

Question 1:

Is a patient ever too old for bisphosphonate therapy? 

QuickConsult: No. We are currently treating people in their 90’s with bisphosphonates and seeing appropriate changes in bone density and markers as well.  Additional studies will help clarify the precise role pharmacologic agents in the old elderly population.

Question 2:

Is a patient ever too old to start calcitonin or PTH? 

QuickConsult: No.  Calcitonin may be particularly useful as a bone analgesic for an elderly patient who sustains a compression fracture.  In terms of PTH, elderly subjects, both men and women, who have severe osteoporosis with multiple compression fractures could certainly be treated with PTH as the clinical situation dictates.

Question 3:

What is the approach to beginning prevention-oriented therapy in patients who are in the 70s and 80s age group?

QuickConsult: In general, a patient with a T-score in the osteopenic or osteoporotic range would have an elevated risk of fracture commensurate with the age.  For example, a patient who is 50 years of age with a T-score of -2.4 and is otherwise healthy is probably at minimal risk for fracture, whereas a patient in the 70-80 year olr range with a T-score of -2.4 is at much higher risk for fracture. 

Scoliosis can produce artifactual elevations in bone density and one may have to rely on the hip area scores in this age group to enhance one’s clinical decision capability.  In general, I am much more aggressive about beginning prevention-oriented therapy in the 70+ age group than I am in the 50+ age group for the risk issue cited above. Additionally, falls are more common in this age group than they are in the younger subjects. 

Question 4:

Should one always start therapy, regardless of age, at time of recognition and confirmation of osteoporosis, if the T-scores support therapy? 

QuickConsult: If the T-scores suggest the presence of osteoporosis, I would begin therapy whether the patient is 50 or 80, unless there is a definite contraindication to treatment.  On the other hand, if the patient is in the 50 to 60 year age group and is mildly osteopenic without risk factors, I might tend to watch this individual and repeat bone densities.  If the trend demonstrates continued loss of bone, my inclination would be to treat, as prevention is certainly better than treatment.  On the other hand, if the person is in her 50’s and has a significant risk factor, I would begin treatment, even with mild osteopenia.  In the elderly group, I treat patients whether it is osteopenia or osteoporosis, as they are certainly at much higher risk for fracture.

Question 5:

Do you treat premenopausal women with bisphosphonates?  With osteopenia?  With osteoporosis? 

QuickConsult: In general, I do not treat premenopausal women with bisphosphonates, because this is not an approved indication for these agents.  The only instance in which I have utilized bisphosphonates in the premenopausal state are patients who are on high doses of glucocorticoids for prolonged periods of time. Specific clinical situations leading to premenopausal osteoporosis require a very thorough evaluation and careful consideration that weighs the possible value of treatment versus anticipated or possible risks in premenopausal women, must be undertaken. This is especially important with regard to pregnancy and potential effects on the fetus, which are to date undefined.  Moreover, it should be stressed that, in general, young patients with osteopenia, as well as osteoporosis, are much less likely to fracture than are older patients.  As a result, it is unusual to treat a premenopausal woman who has osteopenia with bisphosphonates.

Question 6:

Are there any studies or guidelines for treatment of younger, premenopausal women with osteopenia or osteoporosis based on T-scores and/or having two or more risk factors? 

QuickConsult: In general, I am not aware of specific guidelines for treating younger premenopausal women with osteopenia or osteoporosis based upon T-scores or fracture risks.  However, in adolescents and in a premenopausal state, one should rely on the Z-score rather than the T-score. The possibility of treatment should be considered in individuals with a Z-score of less than -2.  In the premenopausal state, if a patient has significant bone loss, one should certainly look for specific secondary causes of bone loss, which could be appropriately treated and may result in improvement in bone density.  Additional factors, such as nutrition, additional calcium and vitamin D intake, and especially, good resistive exercise programs, may be very helpful in treating these patients.  In general, if these patients’ hormonal status is normal, they may well have suppressed levels of bone markers, rendering additional antiresorptive therapy less meaningful.  The only caveat to this would be in when considering patients who are on high doses of glucocorticoid treatment. Several case studies have demonstrated the usefulness of additive calcium, vitamin D, and bisphosphonate therapy while the patients are on chronic glucocorticoid therapy, generally above 6mg per day of Prednisone or equivalent.

Question 7:

Please comment on the interpretation of DEXA scan results in adolescents and young adults. 

QuickConsult: In adolescents and young adults, specifically in the premenopausal age, interpretation of DEXA scans should be assessed in terms of Z-scores and not T-scores.  A Z-score of -2 or lower can be defined as “below the expected range for age” and a Z-score of above -2 is “within the expected range for age.”  Generally speaking, this is the level which would trigger an investigation into secondary causes and, if indicated, appropriate treatment.  In my experience with evaluating prepubertal children, it is prudent to have them evaluated at a center that specializes in children’s issues, as I believe, in this age group the interpretation of these data requires the expertise clinicians who have specialty training and experience in pre-adolescent densitometry and metabolic bone disease.

Question 8:

Please comment on safety and efficacy of use of meds for osteoporosis in young women with eating disorders, female athlete triad. 

QuickConsult: Definite recommendations with regard to medications for eating disorders and the female athlete triad are wanting.  They are very complex and in many ways, related to disorders including sex steroid deficiency, marked malnutrition, low body mass, increased levels of endogenous cortisol secretion, and low IGF-I.  Most studies have shown that there is a response to enhancing nutrition and weight gain with appropriate rises in the levels of several of these compounds and increases in bone density.  In the case of the female athlete, this generally correlates with some reduction in activity levels to return menstruation to a normal range.  Studies, both with DHEA and HRT, have shown variable, but generally positive results with regard to increases of BMD at the hip, etc.  There are no “approved” medical therapies directed at anorexia nervosa and/or the female athlete triad.  It may make sense some day to consider bisphosphonates in patients who have low hormone levels and high bone markers, although this is not always the case and does require appropriate study before making specific recommendations.

Question 9:

A recent study suggested that Ca++ supplementation did not help prevent fracture.Should we continue to recommend Ca++ to our patients?

QuickConsult: A recent study that suggested calcium supplementation did not help prevent fracture involved many essentially healthy women, a significant percentage of whom had been on calcium supplementation prior to the onset of the study.  However, several other studies have shown a reduction in fractures, both in the United States, as well as Europe, particularly in patients who are somewhat insufficient in their daily calcium and vitamin D intake prior to the onset of the study.  Most of the clinical trials performed in this country have involved the utilization of calcium and/or vitamin D as the placebo control.  Looking carefully at these trials, one notices an increase in bone density and reduction in bone markers in patients taking calcium and vitamin D, both of which are surrogates for a reduction in fracture risk.  I believe it is imperative that we continue to recommend calcium and vitamin D to our patients.

Question 10:

What are the effects of bisphosphonates on fracture healing?  If there is an effect, how long do you recommend waiting prior to starting a bisphosphonate? 

QuickConsult: There are no data to suggest that bisphosphonates interfere with fracture healing.  In fact, I believe the opposite is true, that is, following hospitalization of a hip fracture, very few patients leave the hospital on appropriate treatment to prevent a subsequent fracture.  I think it is critical that following a hip fracture, all patients are evaluated with a densitometry, appropriate laboratory work, and then, if indicated,  placed on appropriate therapy to prevent an additional fracture.

Question 11:

Is there any evidence of decreased calcium absorption with the long-term use of PPI (proton pump inhibitor) drugs? 

QuickConsult: In general, if one is going to utilize a PPI drug, there is the assumption that the hydrochloric acid production is reduced and the gastric pH is increased.  In this scenario, calcium citrate has been shown to be absorbed more efficiently than calcium carbonate, and thus the suggestion would be to use that type of calcium preparation in patients with achlorhydria, whether it is disease-induced, i.e. pernicious anemia, or via a medication, i.e. PPI drugs.  I am not aware of any long-term data, however, with regard to follow-up bone densities, fracture rates, as it relates to this strategy.

Question 12:

Did ibandronate show a hip fracture reduction in any of its studies? 

QuickConsult: Ibandronate did not reveal a hip fracture reduction in any of its studies, as none of the studies with ibandronate were powered to look at hip fracture reduction. The BONE study was powered to provide evidence that there would be a reduction in vertebral fractures, which is the FDA requirement, and ibandronate did reduce vertebral fractures. However, in a post-hoc analysis of the BONE study, it was found that in patients with a T-score of -3 or greater (i.e. – 3.5, -4.0, etc), which represents a higher risk population, there was a 69% reduction in non-vertebral fractures. Ibandronate does not carry an indication for reduction of non-vertebral hip fracture.

Question 13:

Can you compare, contrast, and differentiate amone SERMs
(Selective Estrogen Receptor Modulators) vs. bisphosphonates? 

QuickConsult: SERMs and bisphosphonates are quite different.  Although the SERM studies reveal a reduction in the incidence of vertebral fractures, there has been no evidence of reduction in non-vertebral hip fractures with SERMs.  This may be related to the fact that with SERMs  produce comparatively small increase in bone density and a small reduction in bone markers.  Bisphosphonates, however, have been shown to reduce hip and non-vertebral fractures.  In some studies, there appears to be a significant correlation between the extent of bone density increase and decrease in bone markers, and the risk reduction for non-vertebral fractures.  Generally, bisphosphonates produce a greater increase in BMD and reduction in bone markers than is observed with SERMs. 

Question 14:

What is the mechanism causing osteonecrosis of the jaw with bisphosphonates? 

QuickConsult: There mechanistic relationship between bisphosphonates and osteonecrosis of the jaw is still being clarified and is under investigation. No precise mechanisms have been confirmed. In short, the entity of osteonecrosis of the jaw is not well defined and, therefore, its pathogenesis is not clear.  There appears to be a higher incidence of this entity in patients with metastatic malignant disease, particularly multiple myeloma and breast cancer, who are undergoing chemotherapy with or without glucocorticoids and concomitant bisphosphonates.  However, there are very few case reports in otherwise healthy patients with osteoporosis who are taking oral bisphosphonates.  Additionally, this entity also has been seen in patients who are not taking bisphosphonates. Although, inhibition of osteoporotic resorption of bone and inhibition of angiogenesis factors and endothelial proliferation have been discussed as potential causes, until the entity osteonecrosis of the jaw is more well-defined and its pathogenesis has been elucidated, the mechanisms are largely conjecture and speculative at this point.

Question 15:

What is the mechanism of injury responsible for GI toxicity with bisphosphonates? 

QuickConsult: The postulated mechanisms that have been considered for GI toxicity associated with bisphosphonates have been developed from the observation in laboratory animals that continual exposure with these agents to the esophageal mucosa is necessary for erosive damage.  Initial studies suggested that patients with esophageal reflux and an acid milieu of approximately pH2, in combination with a bisphosphonate, may potentially create erosions as is noted in dog pouch studies. 

In the case of alendronate at pH values of less than 2, the drug is in the free acid form, which is known to be more irritating than the sodium salt form.  It is proposed that this drug would also convert to free acid when exposed to the stomach in which the pH is generally between 1 and 2.  If the patient, for example, would lie down immediately after taking the tablet and has gastroesophageal reflux, the acid drug mixture can reflux into the esophagus and expose it to free acid from the drug and potential irritation. 

Studies suggest that the reflux-mediated esophageal irritation can occur with all the  bisphosphonates, although the mechanisms may differ slightly.  Another factor to consider is that much of the esophagus is covered with a keratinized tissue, the upper surfaces of which are covered by stratified squamous epithelium.  When the mucosa is subjected to continuous exposure to a bisphosphonate, the keratinocyte growth in culture is inhibited.  Thus, the process of tissue repair in response to insults, such as regurgitated acid, may be inhibited as well.  When the bisphosphonate is removed in these circumstances, normal proliferation resumes.  Because the esophageal mucosal turnover is approximately 5 days, in theory, the weekly or monthly dosing of a bisphosphonate may lead to less GI toxicity, although this has not demonstrated in current clinical studies.