Men`s Osteoporosis Support Group
Volume V, Issue 2	April 1, 2001

Springtime greetings

What`s new?

Pamidronate results. One of our members sent me results of his dual-energy X-ray absorptiometry (DXA) after being on I.V. pamidronate for approximately one year. He is 55 years old and was diagnosed with osteoporosis subsequent to prednisone medication (7.5-10 mg/day for 2 years) in December 1998. He was initially on nothing but calcium supplements until his second DXA indicated further bone loss. His prednisone was stopped five months after the osteoporosis diagnosis was made. After the second DXA, he started 10 mg/day Fosamax but developed gastrointestinal (GI) problems and his physician switched him to I.V. pamidronate to avoid further discomfort. However, after four treatments (one year), his physician switched him back to twice- weekly Fosamax for one month and then the once-weekly Fosamax after that. He has had no G.I. problems on the once-weekly regimen and encourages anyone who hasn`t tried that method to do so. Here are his DXA results:

12/98 Lumbar -3.89 SD Hip -2.63 SD
8/99 Lumbar -4.26 Hip -2.67 SD
9/00 Lumbar -3.64 SD Hip -2.69 SD

There was improvement in spinal BMD while on pamidronate, but no improvement in the hip, which is fairly common with bisphosphonate therapy. His physician felt his improvement will continue on the 70 mg once-weekly Fosamax, and he will avoid the trouble and discomfort of the I.V. that was needed with the pamidronate. If any other members have had experience with I.V. pamidronate or with switching to once-weekly Fosamax to relieve G.I. discomfort, please let me know so we can share your experiences with the group.

Famous folks with osteoporosis. When President Ronald Reagan fell and broke his hip I received an e-mail from Dr. Karen Kolba, our medical expert for the Men`s Osteoporosis Support Group. She felt it was a good idea to list some of the famous people who have had osteoporosis, assuming that President Reagan`s hip fracture was a result of that, too. Interestingly, I never saw any information on the Net, in newspapers, or on T.V. to indicate that his fracture was the result of osteoporosis. In fact, his orthopaedic surgeon indicated he had the bones of a much younger man. Was this the case of a very famous person simply not receiving a DXA to determine if his hip fracture was indeed from osteoporosis? Or, is there some other underlying information that we don`t know to explain his hip fracture in spite of normal BMD? Anyway, Dr. Kolba pointed out that some other famous folks with osteoporosis include the Pope, former Supreme Court Justice Brennan (died after six months in a nursing home after hip fracture), and some tough-guy actors whose name she didn`t recall. Also, the Queen Mum had a hip fracture at age 98 due to osteoporosis. Are there any other famous folks that you are aware of that we`ve missed? Let me know and I`ll mention them in a future newsletter.

Vibration and BMD. Wouldn`t it be great to just stand on a vibrating platform and automatically increase your BMD without medications or other devices? They are working on this concept at the Department of Biomedical Engineering and the Center for Biotechnology, State University of New York at Stoney Brook. See their Web site at www.bme.sunysb.edu for more details. I was apprised of the work of Dr. Clinton T. Rubin and associates at SUNY by an e-mail from an interested reader of the men`s support group newsletter. Although their work is in the early phase now with no definite time frame yet as to when a useful and FDA-approved device might be available, there is some encouraging research to date. Both in animals and in a small group of postmenopausal women, they have shown that a certain magnitude and duration of vibrations can apparently increase BMD. But, different magnitudes and duration of vibration can actually cause bone loss, so that is why the research must be exacting. So far, they have found that the application of small strains through low level vibration have the best effect on increasing BMD. There was some discussion of their work in a recent National Geographic apparently, but I don`t know exactly which issue it was.

Literature Review

NOTE: To get abstracts of articles mentioned, go to PubMed at http://www.ncbi.nlm.nih.gov/PubMed/, and enter the numeric portion only of either the UI or the PMID code into the search block. To get a copy of the article, ask your local librarian to get you a free copy from the National Library of Medicine.

Testosterone gels. Hypogonadal men with osteoporosis have historically had a couple of options to get the testosterone they needed: Injections or patches. There are some drawbacks to both of these options including discomfort and volatile hormone levels with the injections, and skin irritation and inability to keep the patch on during exercise or in warm muggy weather. There are a couple of new options that involve a testosterone gel that is simply rubbed onto the skin. The gel can be obtained in a compounded formula or as a patented prescription called AndroGel (see www.androgel.com for more information). There is an interesting recent study on this topic by Cutter CB, J Am Board Fam Pract 2001 Jan-Feb;14(1)22-32, Compounded percutaneous testosterone gel: use and effects in hypogonadal men, PMID: 11206690 that is worthy of discussion. The study involved ten hypogonadal men from age 44-77. Each man served as his own control starting out with low testosterone levels and then applying the formulation to either upper chest and under arm area or the inner thigh or scrotum. The gel was required to be in place for at least 8 hours before bathing, but no other restrictions were placed on the men. Blood tests were done at base line, then during and after the study. Androgen levels were brought into normal ranges in all men and blood lipids showed a 15% drop in all cholesterol fractions. All but one man noted considerable improvement in sexual function and overall well being and there were no adverse effects detected during the study. The author concluded, "Topically applied testosterone gels are an effective and convenient means of hormone replacement in hypogonadal men." Thus, this gel seems a desirable alternative to either injections or patches. Precautions with the gel include that you have to be careful not to have the gel come in contact with your female partner if she might be pregnant or to have it contact your young children. The effects of the testosterone on the fetus or the young child can be serious and irreversible.

From my Internet browsing, it appears that AndroGel costs from $5-6/day, and Testoderm patches about $80/month, which is certainly a consideration. The compounded gel can be purchased with a prescription from your physician for about $100/month. For cost comparison Depo-testosterone, the cypionate form of injectable testosterone would cost from about $40-120 (depending upon what part of the country you are in) for a 10 ml vial of the 200 mg/ml dose. For most men this would be about a five months supply. Assuming an average cost of about $70 for a 10 ml vial, that would be $14/month for the injections, a considerable savings compared to gels or patches. I contacted the pharmacy that Dr. Cutter used and they wrote back immediately answering all my questions. So, if you are interested in obtaining the compounded testosterone gel or need more information, contact Compounding Pharmacy of Beverly Hills at (888) 799-0202 or cpbh@pacbell.net.

Additionally, there are three other articles concerning testosterone gel that you might want to read: J Clin Endocrinol Metab 2000 Dec;85(12):4500-10, Long-term pharmacokinetics of transdermal testosterone gel in hypogonadal men. Swerdloff RS and others. PMID:11134099; J Clin Endocrinol Metab 2000 Mar;85(3):964-9, Pharmacokinetics of transdermal testosterone gel in hypogonadal men: application of gel at one site versus four sites: a General Clinical Research Center Study. Wang C and others, PMID 10720024; and J Clin Endocrinol Metab 1998 Aug;83(9):2749-57, Comparative pharmacokinetics of three doses of percutaneous dihydrotestosterone gel in healthy elderly men-a clinical research center study. Wang C and others, PMID 9709942.

Bone density and prostate cancer therapy. Androgen deprivation therapy (ADT), common therapy for prostate cancer, has been reported to increase osteoporosis and concomitant fractures. The following cross-sectional study sought to estimate the longitudinal effects of ADT on bone mineral density (BMD). See Urology 2001 Jan;57(1):127-132, Progressive decrease in bone density over 10 years androgen deprivation therapy in patients with prostate cancer. Kiratli BJ and others, PMID: 11164157. Comparing hip BMD of patients on ADT to those not on therapy showed significantly reduced BMD, 0.802 gm/cm(2) vs. 0.935 gm/cm(2). Patients at year zero had hip BMD similar to age-matched controls. There was a significant trend toward decreased hip BMD with increasing years of ADT (P=0.00008). And, when hip BMD at each time point was compared to age-matched controls, the decrease was far more dramatic (P=0.5 x 10(-16). Surgical castration showed more loss of BMD than medical ADT (P=0.08). Patients having intermittent ADT showed less loss of BMD at year 6, though not at years 2 and 4. So, this study quantifies the actual serial loss of BMD for prostate cancer patients, and indicates that intermittent medical therapy may be the least destructive therapy concerning loss of BMD. Obviously patients on this therapy should be on concomitant osteoporosis therapy (probably with bisphosphonates, calcium, and vitamin D) to try to prevent some of the destructive effects of ADT on BMD.

Possible new drug therapy. Osteoprotegerin (OPG) is a recently discovered regulator of bone resorption. It is a natural protein with potent ability to prevent osteoclasts from functioning to resorb bone. There is a recent study showing the capability of OPG to block bone resorption. See J Bone Miner Res 2001 Feb;16(2):348-60, The effect of a single dose of osteoprotegerin in postmenopausal women. Bekker PJ and others, PMID: 11204435. Postmenopausal women were given either a placebo injection or OPG to determine the effect of a single subcutaneous dose of OPG on bone resorption as shown by biochemical markers N-telopeptide (NTX) and deoxypyridinoline (DPG). These are stable collagen degradation products that would be decreased if bone resorption was decreased. The authors found, "At the highest doses administered (3.0 mg/kg), a mean percent decrease in NTX of approximately 80% was observed 4 days after dosing. Six weeks after dosing a mean decrease of 14% in NTX was observed." Additionally, there was no increase in markers of bone formation for 3 weeks after the dose of OPG, however, there was a decrease after that reaching about 30% at the sixth week. Thus the OPG acted on osteoclasts to decrease bone resorption. The injections were well tolerated. The authors conclude, "This study, for the first time, indicates that a single subcutaneous injection of OPG is effective in rapidly and profoundly reducing bone turnover for a sustained period and that OPG therefore may be effective in treatment of bone disease characterized by increased bone resorption such as osteoporosis." This looks like an exciting new osteoporosis therapy. Hopefully further studies will confirm its effectiveness and safety, and that it works equally well for men. For a thorough discussion of this topic on the Web go to Medscape, which is free but you`ll need to sign up first. Note that Medscape often removes Web pages after a certain period, so this URL may eventually become inactive.

Glucocorticosteroids and BMD. There are three studies concerning the effects of glucocorticosteroids on BMD. The first concerns asthma and inhaled steroids: Ann Allergy Asthma Immunol 2000 Dec;85( 6 pt 1):495-500. Bone mineral density in women with asthma on long-term inhaled corticosteroid (ICS) therapy. Bonala SB and others, PMID 11152172. Fifty-six women who had used glucocorticosteroid inhalers long term had bone density testing done and results were correlated to length of inhaler use and steroid dosage. BMD decreased from 5% in the low-dose group to 50% in the high-dose group. The authors noted, "There were significant linear trends of decline by dose in mean BMD of the hip (P<.001) and the lumbar spine (P<.002). Women who received medium or high doses of ICS had significantly greater bone loss than those receiving low doses." So, if possible the dose of ICS should be lowered, and patients on all doses should receive appropriate preventive therapy for osteoporosis. The next study involved managing glucosteroid-induced osteoporosis in male veterans. See Ann Pharmacother 2000 Dec;34(12):1380-4. Management of glucocorticoid-induced osteoporosis in male veterans. Elliott ME and others, PMID 11144692. The authors wanted to determine if the American College of Rheumatology (ACT) guidelines were being followed when male veterans were started on glucocorticoid therapy. These guidelines include: initial BMD determination for long-term therapy with prednisone > or =7.5 mg/day, provision of hormone replacement therapy as needed, calcium and vitamin D supplementation as necessary, and antiresorptive therapy as needed. The authors found, "Seventy-two men met study criteria. They had been receiving oral prednisone treatment for a median of 30 months (range 6-74); mean daily dosage during the six-month study period was 12.6 mg (range 7.5-37.5). Extensive record review revealed that only six patients (8%) received recommended calcium and vitamin D, and only 43 (60%) had a BMD determination. Of those 43 men, 32 had T-scores below -1, therefore meeting ACR criteria for recommended antiresorptive therapy. However, only 12 of these 32 patients were prescribed antiresorptive therapy." The authors noted an apparent better compliance in rheumatology clinics than other clinics, which has been noted in other studies I`ve reviewed of this nature. The bottom line is there is a lot of room for improvement in the prevention of BMD loss for patients being placed on prednisone therapy. And, the last study on this topic involves fracture risk. See Rheumatology (Oxford) 2000 Dec;39(12):1383-9. Oral corticosteroids and fracture risk: relationship to daily and cumulative doses. van Staa TP and others, PMID: 11136882. The authors looked at a huge General Practice Research Database of corticosteroid users` medical records who had been seen by general practitioners in England and Wales. They found that patients taking 7.5 mg/day of prednisolone or equivalent had significantly increased fracture risk at all sites compared to patients taking only 2.5 mg/day. They concluded, "These findings suggest that the adverse skeletal effects of oral corticosteroids manifest rapidly and are related to daily dose. The level of previous exposure to oral corticosteroids was not a strong determinant of the risk of fracture. Preventive measures against corticosteroid-induced osteoporosis should therefore be instituted as soon after the commencement of glucocorticoid therapy as possible." So, people starting oral corticosteroid therapy need osteoporosis preventive therapy immediately to reduce the risk of bone fracture later.

Exercise and BMD. The following study involving exercise and BMD was conducted on women, so don`t assume the results would apply equally to men and particularly to men with moderate or severe osteoporosis. See J Bone Miner Res 2001 Jan;16(1):17581. Resistance training over 2 years increases bone mass in calcium-replete postmenopausal women. Kerry D and others, PMID: 11149482. This study included giving 600 mg calcium to women placed in one of three groups: Strength (S), fitness (F), or control (C). The two test groups did the same nine exercises in three sets and three times a week. But, the S group increased the loading, while the F group had additional stationary bicycle riding with minimal increase in loading. During the two years the BMD was measured every six months. There was no difference in BMD in the whole body, forearm, or lumbar spine. There was, however, a significant effect for those in the strength program at the hip. Since the hip is a difficult bone to increase BMD in with other therapies, this indicates that strength training can be an important adjunct to medications and other exercise programs. Note that men with diagnosed osteoporosis should consult their physician and/or physical therapist if desiring to follow such a program.

Diet, nutrition, and osteoporosis. There are two recent studies with somewhat conflicting results concerning animal protein intake and BMD. The first is in J Bone Miner Res 2000 Dec;15(12):2504-12, Effect of dietary protein on bone loss in elderly men and women: the Framingham Osteoporosis Study. Hannan MT and others, PMID: 11127216. This study involved 381 women and 224 men in the Framingham Osteoporosis Study and compared BMD to dietary protein intake in this elderly group. They found that, "Lower protein intake was significantly related to bone loss at the femoral and spine sites (P < or = +0.04) with effects similar to 10 lb of weight." Additionally, they noted, "Further, higher intake of animal protein does not appear to affect the skeleton adversely in this elderly population." Now contrast these results with the study in Am J Clin Nutr 2001 Jan;73(1):181-22, A high ratio of dietary animal to vegetable protein increases the rate of bone loss and the risk of fracture in postmenopausal women. Study of Osteoporotic Fractures Research Group. Sellmeyer DE and others. PMID: 11124760. This study compared protein intake to BMD and fracture risk on 1053 community-dwelling white women aged >65 years. They were followed for approximately seven years and had DXA to test for the effect of protein intake on BMD. They authors found, "Bone mineral density was not significantly associated with the ratio of animal to vegetable protein intake. Women with a high ratio had a higher rate of bone loss at the femoral neck than did those with a low ratio (P=0.02) and a greater risk of hip fracture (relative risk=3.7, P=0.04). So, although BMD was not significantly different between high and low animal protein groups, the rate of bone loss at the hip was greater and hip fracture risk was greater in the high animal protein intake group. As the authors suggest, these results will need to be confirmed in prospective studies and tested in a randomized trial. For a very thorough discussion of nutrition as it concerns bone health, see the following article. J Am Coll Nutr 2000 Nov-Dec;19(6):715-37. Nutrition in Bone Health Revisited: A story beyond Calcium. Ilich JZ and Kerstetter JE. PMID: 11194525. This is the kind of article to have on hand to answer questions you may have about the effect of various nutrients on bone health. It discusses such components as calcium protein, magnesium, zinc, copper, iron, fluoride, vitamins D, A, C, and K, etc.

Vitamins D, K and osteoporosis. The importance of vitamin K as a possible therapeutic agent for osteoporosis has been noted in this newsletter before. Most of the work on this area is being done in Japan, and there is another study out showing the effectiveness of this therapy. See J Orthop Sci 2000;(6):546-551. Effect of combined administration of vitamin D3 and vitamin K2 on bone mineral density of the lumbar spine in postmenopausal women with osteoporosis. Iwamoto J and others, PMID: 11180916. This study involved 92 osteoporotic women aged 55-81 who were divided into four groups: Vitamin D3 0.75 g/day (D group), vitamin K2, 45 mg/day (K group), vitamin D3 plus vitamin K2 (DK group), and calcium lactate, 2g/day (C group). Two-way ANOVA showed a significant increase in BMD in the D and K groups compared with that in the C group (P<0.05 and P<0.001, respectively), and a significant increase in BMD in the DK group compared with that in the C, D, and K groups (P<0.0001, P<0.05 and P<0.021, respectively). The authors conclude, "These findings indicate that combined administration of vitamin D3 and vitamin K2, compared with calcium administration, appears to be useful in increasing the BMD of the lumbar spine in postmenopausal women with osteoporosis. For anyone not responding adequately to other therapies, you might want to discuss the combined vitamin D and vitamin K therapy with your physician. It appears to have promise as an effective osteoporosis therapy.

Determinants of bone mineral density in older men. This study was done to determine the correlates of bone density in men using 355 men over age 60 who were recruited from three rural communities in the northwestern United States. DXA was done on the spine and hip and then related to other factors by direct measurements or a questionnaire. The authors found weight was positively associated with BMD and age was negatively associated with it. After adjustment for these two factors, alcohol intake, osteoarthritis, and thiazaide use were associated with higher bone density, while previous fractures, gastrectomy, peptic ulcer disease, rheumatoid arthritis, glucocorticoid use, hypertension, previous hyperthyroidism, height loss since age 20 years, chronic lung disease and smoking were related to lower density. Men with these habits, histories, or conditions are candidates for preventive therapy and early diagnostic procedures to diagnose or prevent osteoporosis.

Gastric problems and bisphosphonates. There are three articles on this topic in the recent literature. The first found that the combination of naproxen and alendronate can cause gastric ulcers. See Arch Intern Med 2001 Jan 8;161(1):107-10, Alendronate and naproxen are synergistic for development of gastric ulcers. The study involved 18 women and 8 men who were healthy with no stomach damage before the test. Endoscopy was done after taking either alendronate, naproxen, or the combination of the two for 10 days with a 1-4 week washout between evaluations. Two subjects got ulcers from alendronate, 3 from naproxen and 10 from the combination of the two. The authors conclude, "The combination appears synergistic. Alendronate should be used with caution in those who simultaneously require nonsteroidal anti-inflammatory drugs." I wonder if these results would be applicable with the once-weekly dosage of alendronate, my guess is probably not? The second study is an elegant test of whether or not alendronate causes clinical upper gastrointestinal (UGI) problems. See Clin Ther 2000 Dec;22(12):1433-42, Rechallenge of patients who had discontinued alendronate therapy because of upper gastrointestinal symptoms. Miller PD and others, PMID: 11192135. Large-scale clinical placebo-controlled trials have consistently failed to find significant UGI problems with alendronate, in spite of the fact that it can cause esophageal erosion if taken incorrectly, and as shown in tests using endoscopy. This study was a multicenter, double-blind trial with postmenopausal women who had previously discontinued alendronate therapy because of UGI adverse experiences. They were put into two groups, one taking 10 mg alendronate and one taking placebo daily for 8 weeks. The authors found, "On rechallenge, 14.8% (13/88) of patients in the alendronate group and 16.7% (14/84) in the placebo group discontinued treatment because of UGI adverse experiences." They conclude, "The results of this study suggest that many UGI adverse experiences reported during therapy with alendronate may reflect a high background incidence of UGI complaints and an increased sensitivity to detection of such complaints, rather than a causal relationship to therapy." So, once again, under carefully controlled conditions, there is no significant difference between alendronate and placebo as concerns UGI complaints, even in patients who previously stopped therapy because of those complaints. The third study involves endoscopy after risedronate (Actonel). See Aliment Pharmacol Ther 2000 Dec;14(12):1663-70. Placebo-controlled, randomized, evaluator-blinded endoscopy study of risedronate vs. aspirin in healthy postmenopausal women. Lanza FL and others. PMID 11121916. Comparing 5 mg/day Actonel to 2600 mg aspirin, or placebo, the authors found no gastric or esophageal erosions or ulcers in the Actonel group using endoscopy after 14 days of therapy. This study lends credence to the prevailing notion that Actonel has minimal tendency to cause gastric problems. If it can`t cause problems when used daily, it is hard to imagine any problems when used on a once-weekly basis. Actonel is not approved for once-weekly dosing yet, but virtually certainly will work as well that way and should eventually be approved for that method. It will be interesting to see how alendronate and risedronate compare long term as concerns UGI complaints.

Biochemical markers of bone turnover. There is an excellent review article that is the result of a renowned consensus panel on the use of biochemical markers of bone turnover in J Clin Densitometry 1999 Fall 2(3):323-342. Practical clinical application of Biochemical Markers of Bone Turnover. Miller PD and others. PMID:10548827. The article is directed entirely toward postmenopausal women with osteoporosis, but I assume that men could benefit from judicial and appropriate use of biochemical markers, too. In summary, the authors found biochemical markers to be useful when used at baseline to detect the rate of bone loss and to predict future fracture risk. Additionally, they can help with the differential diagnosis since bone turnover rate is helpful in separating some causes of osteoporosis from others. And, the third use is in monitoring therapy effectiveness. Three to six months after instituting osteoporosis therapy, biochemical markers can tell if therapy is working. This is much quicker than using a DXA. This may allow starting another therapy and may prevent fractures that would occur otherwise if waiting for other tests to determine effectiveness. For instance, last month I discussed the use of testosterone either as a sole therapy or in conjunction with bisphosphonates. Using biochemical markers, the physician could tell fairly rapidly if bone turnover had returned to normal levels on , e.g., testosterone therapy alone. If not, then a bisphosphonate could be added immediately rather than waiting for a year or more to have a repeat DXA that would show no improvement or additional loss of BMD. In summary, the authors state: "Biochemical markers of bone turnover are extremely useful for management of osteoporosis because they provide information that is different and complementary to bone mass measurement." My guess is that biochemical markers are under used and that you may have to ask to have them done if you think they will help in your case. Read this information yourself, or refer your physician to this article for an excellent review of the topic.

Disclaimer. Diagnosis and treatment of osteoporosis are the responsibility of the patient and his or her physician. Nothing in this newsletter is to be interpreted as a recommendation for treatment or to change treatment that your physician has prescribed. Although we attempt to assure that information in this newsletter is factual, errors will occur. It is the responsibility of the reader to verify that information they are acting on is factual. There is no relationship between this newsletter and any national osteoporosis group, including the National Osteoporosis Foundation. All references to any such groups are for informational purposes only.

EDITOR

Jerome C. Donnelly
Email