Addition to the Web site. Thanks to John Barczyk and Bruce Jacobson for their suggestions, comments, criticisms, and work on a new page linked from the Men`s Osteoporosis Support Group Web site dedicated to men who first discover they have osteoporosis. This page is at http://www.maleosteoporosis.org/1stdiag.htm. Don`t forget that if you ever have a suggestion or idea of how we can improve the Web site or something to include in the newsletter, don`t hesitate to contact me at the e-mail address above.
Once-weekly Fosamax dosing. The FDA approved the once-weekly Fosamax dosing regimen just after I posted last quarter`s newsletter so I sent out a special e-mail notice to men in the group. This approval is great for men taking Fosamax since it is incredibly more convenient and should have their reluctant physicians now going along with the regimen. The FDA approved both the 70 mg once-weekly or 35 mg twice-weekly dose. I, however, can see no reason for taking it any way but in the 70 mg once-weekly form since it is just as effective and more convenient. Risedronate (Actonel) is also being prescribed for some men now, although it is only approved by the FDA for women, and it has only been approved by the FDA in the daily dose. Since risedronate is, for all intents and purposes, only a more potent form of alendronate, logically there is no reason to believe it won`t work just as well with the once-weekly dosing method, too. Dr. Kolba tells me that Actonel is available as a 30 mg tablet which she uses as the once-weekly dose, although it is only approved for Paget`s disease of bone.
Internet information. See Medscape`s Resource Center on Osteoporosis for a site that has links to plenty of current information on osteoporosis, with much of it directed toward women, but still valuable for men. This site requires you to sign in, but it is free.
Prostate cancer and osteoporosis. I received e-mail from a new member of the support group who also had prostate cancer. He points out that prostate cancer is rarely mentioned as a risk factor for osteoporosis, however, many treatments of the cancer can leave a man at risk for osteoporosis. I hope to produce a link to the men`s Web site with more information on this topic. For now, suffice it to say that if your prostate cancer treatment affects your testosterone levels, you are at increased risk for osteoporosis. Preventive measures are in order to preclude bone fractures, which could include calcium and vitamin D supplements, or bisphosphonates and/or calcitonin therapy. Don`t wait until osteoporosis has developed to seek therapy, prevent the bone loss in the first place.
Ask the Expert
I received an e-mail from a man recently who said that his physician would give him only testosterone injections after discovering he had osteoporosis and was hypogonadal. My assumption was that treatment would normally also include Fosamax or some other accepted therapy, and I was concerned about this for several reasons:
1. In my own case Fosamax had not yet been approved for treatment of osteoporosis when my case was diagnosed. I was placed on testosterone injections for the first year of treatment and had no improvement in bone mineral density (BMD). When Fosamax was added, there was significant improvement with each new dual-energy X-ray absorptiometry (DXA) test performed.
2. I had been told by an expert on men`s osteoporosis when I was first diagnosed not to expect more than 5% improvement in BMD using testosterone injections as the sole treatment method.
3. Logically, it would seem ideal to try to get maximum increases in BMD as soon as possible after diagnosis of osteoporosis to reduce fracture risk as quickly as possible. To wait a year or more to see whether testosterone was going to be effective could be critical for someone who suffers a debilitating fracture while waiting for those results-especially if he found no increase in BMD during that time.
Thus, I wrote Dr. Karen Kolba, our medical expert on osteoporosis for the Men`s Osteoporosis Support Group, to get her opinion of this issue. I also did a literature search to find articles that propose either testosterone as the sole treatment method or a combination therapy along with bisphosphonate, calcitonin, or other medications, as being superior to testosterone alone. Here is Dr. Kolba`s response.
"I think there is room for a difference of opinion on the approach. First of all, a lot depends on the gentleman`s age, whether he has already had fractures, and any other factors that could increase his risk for fall. Also, remember that osteoporosis is not a medical emergency-it took a long time to happen and will take a long time to fix. In general, without a fall there is no fracture, although spinal compression fractures can and do occur without falls or other trauma. That said, there COULD be merit in this physician`s approach. That is, to see how much of a gain with hormones (and calcium and vitamin D) occurs, then adding bisphosphonate if needed. If this person is under age 60, and not suffering from peripheral neuropathy (diabetes), Parkinson`s disease, etc., doing things one at a time has a certain charm. To see what changes in a year or two is no big deal really. On the other hand, if the physician wanted to be more aggressive, that could be acceptable, too."
"Just to clarify, I don`t doubt the efficacy of combined testosterone and Fosamax, and use it when ever I can get away with it. Still, the risk of fracture is not dependent only on bone density. I see lots of folks in their 50s, 40s, and even 30s who are just petrified to move because of the DXA results. Yet, epidemiologically, we don`t start seeing (serious) fractures until folks are in their late 60s and 70s for the most part, even at these terribly low levels."
"As to whether to seek another opinion, I would see if this gentleman feels comfortable with the physician. That is, does he like him/her, feel he/she knows something about osteoporosis, and is kind and caring, etc. If the answers are positive, why risk messing that up? After all, the next physician may NOT be an improvement!"
Dr. Kolba`s excellent comments notwithstanding, I`ve been in contact with several men who are in their 40s or 50s who did suffer debilitating fractures from osteoporosis. This prejudices me toward liberal use of any and all medications that might increase BMD at the earliest diagnosis of osteoporosis. But, I wanted to see if that prejudice is justified by the literature. Here are my findings.
As with most of the literature on osteoporosis, you are forced to examine studies done on women and hope that extrapolation of those results to men is acceptable. A very pertinent paper is by Wimalawansa SJ, J Clin Densitom 2000 Summer;3(2):187-201. Prevention and treatment of osteoporosis: efficacy of combination of hormone replacement therapy with other antiresorptive agents. UI:20332377. This is a review of nine studies that compared hormone replacement therapy (HRT) either alone or with either bisphosphonate, calcitonin, or fluoride therapy. All nine studies found significant increases in BMD when the other medication was added to HRT. In a representative study comparing three methods, the reviewer notes, "Study 1 was designed to assess the efficacy of combined HRT and bisphosphonate in preventing osteoporosis during the early stages of menopause. This combined therapy increased the lumbar spine BMD by 10.9% and the femoral BMD by 7.3% over 4 yr, compared with 6.8 and 4.0% with HRT alone, and 6.8 and 1.2% with bisphosphonate alone." The author notes a very similar result in another study conducted on postmenopausal women with established osteoporosis. The very important figure that stands out when I examine these results is the increase in femoral BMD when the HRT and bisphonate are combined-especially compared to bisphosphonate alone-but also showing improvement compared to HRT alone. Another recent review paper on men`s osteoporosis is by Sambrook PN and Eisman JA in the Med J Aust 2000 Mar 6;172(5):226-9, Osteoporosis prevention and treatment, UI: 20238695. The authors state, " For men with osteoporosis, if hypogonadism is present, it should be treated with testosterone replacement therapy. Despite limited data, a bisphosphonate should then be considered in conjunction with calcium." To my knowledge there are no studies in men yet to show if this combination drug therapy would be as effective for them. But, logically there is nothing to make similar results improbable.
Here are a couple of studies that showed the results of testosterone therapy on the treatment of osteoporosis. The first is by Katznelson L and others, J Clin Endocrinol Metab 1996, Dec;81(12):4358-65. Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism. UI:97112362. The study included 36 adult men with either central or primary hypogonadism and compared them to 44 age-matched eugonadal (normal) controls. The authors found the hypogonadal men had lower BMD at the start of the study. After administering 100 mg testosterone enanthate per week for 18 months, the authors found, "Spinal BMD and trabecular BMD increased by 5 +/- 1% (P<0.001) and 14 =+/- 3% (P <0.001), respectively. " A second study is by Behre HM and others in J Clin Endocrinol Metab 1997 Aug;82(8):2386-90. Long-term effect of testosterone therapy on bone mineral density in hypogonadal men. UI:97397244. This study involved 72 hypogonadal patients (37 men with primary and 35 men with secondary hypogonadism) who had testosterone substitution therapy that continued for up to 16 years. The authors found, "The most significant increase in BMD was seen during the first year of testosterone treatment in previously untreated patients, when BMD increased from 95.2 +/- 5.9 to 120.0 +/- 6.1 mg/cm3 hydroxyapatite (mean +/- SE). Long term testosterone treatment maintained BMD in the age-dependent reference ranges in all 72 hypogonadal men, independent of the type of hypogonadism." These studies give strong evidence of desirable results from testosterone therapy when used as the sole pharmaceutical to increase BMD in hypogonadal men. There is even some evidence to indicate that giving testosterone to eugonadal (normal gonadal function) men can increase BMD. This study is by Anderson FH and others, Bone 1996 Feb;18(2):171-7. Androgen supplementation in eugonadal men with osteoporosis-effects of 6 months of treatment on bone mineral density and cardiovascular risk factors. UI:96430061. After giving men with idiopathic primary osteoporosis 250 mg testosterone ester every two weeks, the authors state, "We conclude that testosterone supplementation significantly increased bone mineral density in this heterogeneous group of men with idiopathic primary osteoporosis, without an overall adverse effect on cardiovascular risk factors." Indeed they had found a 5% rise in BMD in the spine in six months, although there was no increased BMD in the hip.
In summary, the literature appears to support either method of treatment-- testosterone alone, or a combination therapy of testosterone and a bisphosphonate-as effective for hypogonadal men with osteoporosis. The Wimalawansa study in women combining HRT and bisphosphonate might give men with particularly low BMD in the hip reason to request the combined therapy since it showed quite an increase in hip BMD compared to either form of singular therapy. Otherwise, the combined or single therapy appear to be sound treatment choices that the patient and physician should decide on a case-by-case basis as Dr. Kolba has suggested.
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.
Estradiol levels in men. Testosterone deficiency isn`t the only hormone that has an effect on male osteoporosis. Estrogen deficiency has recently been shown to be important in controlling men`s BMD. This is shown by the following study that investigated the estrogen and androgen status of 63 men admitted to a medical clinic with the diagnosis of osteoporosis over a two-year period. See Carlsen CG and others, Osteoporos Int 2000, 11(8):698-701. Prevalence of low serum estradiol levels in male osteoporosis. UI:20544282, The authors state, "In 37 of 63 patients a complete estrogen status was available. In this group 26 were classified as having primary osteoporosis. Of these, no single case of male hypogonadism was demonstrable, while 10 (38%) exhibited undetectable serum estradiol levels." They conclude, "Thus estrogen deficiency is much more prevalent than androgen deficiency in primary male osteoporosis. Future screening tests for osteoporosis in men should therefore include assessment of serum estradiol." The interesting question evolves around treatment. That is, are males with low estradiol levels treated any differently than those with normal levels, or is the estradiol concentration merely a diagnostic phenomena? A recent report noted on the IntelliHealth Professional Network on the Web, and from Reuters health, showed that treatment with estradiol may become an option for osteoporotic men. Dr. Sundeep Khosia, from the Mayo Clinic in Rochester, MN presented his findings at the 22nd annual meeting of the American Society for Bone and Mineral Research. Normal healthy males had their testosterone and estrogen temporarily chemically suppressed. They were then divided into four groups and given either nothing (control), an estradiol patch, a testosterone patch, or both patches. Urinary levels of dexoypyridinoline were tested to show levels of bone resorption. The controls had the most bone breakdown, testosterone only had slightly less bone breakdown, estradiol had a slight increase in bone breakdown compared to baseline, and the group with both patches had less bone breakdown that at baseline. The author concludes, "Even in men, estrogen is a dominant sex steroid regulating the breakdown of bone." Thus, testosterone appears to make even a smaller direct contribution to preventing bone loss than estradiol in men.
Vitamin D. There is an interesting recent article about vitamin D supplementation using identical twins in the study-a nearly ideal test model. See Hunter D and others, J Bone Miner Res 2000 Nov;15(11):2276-83. A randomized controlled trial of vitamin D supplementation on preventing postmenopausal bone loss and modifying bone metabolism using identical twin pairs. UI:20540957. This was a 2-year study testing BMD to see if there would be an effect from vitamin D supplements in 47-70 year old postmenopausal females who started the study with normal vitamin D levels. The authors found, "At 24 months, no significant treatment effect was seen on BMD or calcaneal ultrasound change within pairs." They concluded, "On the basis of these results, vitamin D supplementation, on its own, cannot be recommended routinely as an osteoporosis prevention for healthy postmenopausal women with normal vitamin D levels under the age of 70 years. Assuming that men with normal vitamin D levels follow this pattern, they probably don`t benefit from vitamin D supplements either. Thus, you might not need to be overly concerned about vitamin D intake unless tests show a definite deficiency. Note that these women didn`t receive calcium supplements along with the vitamin D-which was the sole supplement.
Risedronate (Actonel). See the Summer 2000 Osteoporosis Report, Vol. 16/No. 2 from the National Osteoporosis Foundation for this excellent report by Dr. Felicia Cosman. I won`t review the entire article, but will mention some highlights: 1) Risedronate has been approved for treatment of osteoporosis in the U.S. 2) The 5 mg/day dosage was effective at reducing new fractures in a large study of postmenopausal women with previous history of fractures by 41% with similar results in two other large studies. 3) Risedronate has been shown effective in preventing bone loss during corticosteroid use. 4) It was well tolerated in patients during studies with no significant adverse G.I. events compared to placebo in any studies. 5) Since it is poorly absorbed, it must be taken on an empty stomach with a regimen similar to that used for Fosamax. Also see the recent study by Lanza FL and others, Aliment Pharmacol Ther, 2000 Dec 27;14(12):1663-1670. Placebo-controlled, randomized, evaluator-blinded endoscopy study of risedronate vs. aspirin in healthy postmenopausal women. PMID:11121916. Using endoscopy on healthy postmenopausal women, the authors found, "Risedronate 5 mg was not associated with esophageal or gastroduodenal ulcers . . ." I have seen no reports of gastric problems with Actonel, so this study would seem to confirm that it is safe if taken according to directions. For reference purposes, the study was apparently funded by Procter and Gamble Pharmaceuticals, the manufacturer of Actonel.
G.I. adverse events with Fosamax. The American College of Gastroenterology meeting in October, 2000 produced results of analyses of records of 6,459 patients in the Fracture Intervention Trial (FIT). A total of 3,236 women were treated with Fosamax and the remainder with placebo. Results showed, ". . .patients who took the osteoporosis medicine Fosamax (alendronate sodium) had an incidence of hospitalization for perforating ulcers and bleeding (PUBs) that was no greater than the incidence in those who had osteoporosis but did not take the medicine." Dr. Brian Fennerty noted, "Short-term endoscopic studies of a few weeks duration are widely used to generate hypotheses about the possible gastrointestinal effects of medicine. Although this technique has been useful, the results must be interpreted in the context of all available data with greater weight given to outcomes data." He further stated, "The clinical incidence of disease, which is what we should be concerned about, can only be demonstrated by outcomes studies such as this." Records revealed a total of 124 hospitalizations for upper G.I. events with 115 confirmed by endoscopy, radiology, or hospital discharge summaries. The incidence of hospitalization for PUBs for women treated with Fosamax was 0.5 percent as compared to an incidence of 0.6 percent for women receiving placebo. So, once again it appears that Fosamax does well in a clinical study setting concerning adverse events. Just remember to take it with a full 8-ounce glass of water, stay upright after taking it, and don`t eat for a minimum of one-half hour, longer if possible.
Alendronate and men. Another study has been published to show the effectiveness of alendronate in men with osteoporosis. See Ho YV and others, Osteop Int 2000; 11(2):98-101. Effects of alendronate on bone density in men with primary and secondary osteoporosis. There were 23 men with primary and 18 with secondary osteoporosis in this study who took 10 mg/day doses of alendronate and who were followed for 12 months to evaluate BMD changes. At 12 months BMD in the lumbar spine increased 5.4% and 7% in primary and secondary osteoporosis groups respectively. Trochanteric BMD increased by 2.6 and 3.7% respectively. These results are about 0.5 S.D. improvement in BMD per year and correlate with other studies in men and women.
Comparison of alendronate and intranasal calcitonin. There have been studies using either alendronate or calcitonin, but few if any directly comparing them. Thus, these results should be meaningful to any physician deciding which medication to prescribe or to a patient deciding which to ask for. See Downs RW Jr and others, J Clinc Endocrinol Metab 2000 May;85(5):1783-8. Comparison of alendronate and intranasal calcitonin for treatment of osteoporosis in postmenopausal women. UI:20300138. Two hundred women who were five years postmenopausal, received either 10 mg alendronate or 200 IU calcitonin daily. Results showed, "Alendronate produced greater increases in BMD than calcitonin at 12 months at the lumbar spine (5.16% vs. 1.18%; P<0.001), trochanter (4.73% vs. 0.47%; P<0.001), and femoral neck (2.78% vs. 0.58%; P<0.001) Changes in BMD with calcitonin were greater than with placebo at the femoral neck, but were not different from placebo at either the trochanter or lumbar spine." Additionally, "Greater decreases in bone turnover were seen with alendronate than with calcitonin (serum bone-specific alkaline phosphatase, 43% vs. 9%, P<0.001), urinary N-telopeptide, 62% vs. 11%, P<0.001). These results indicate that alendronate is the drug of choice compared to calcitonin when comparing BMD and bone turn over.
Parathyroid hormone combined with alendronate therapy. I`ve reported several times previously in this newsletter that human parathyroid hormone (PTH) causes marked increase in vertebral BMD. This increase may be rapidly reversed if therapy is discontinued. So, a study was done to see if patients given alendronate after PTH could retain their gains in BMD. See Rittmaster RS and others, J Clin Endocrinol Metab 2000 Jun;85(6):2129-34. Enhancement of bone mass in osteoporotic women with parathyroid hormone followed by alendronate. UI:20309280. The authors found, "During the first year changes in BMD (mean +/- SD) in women receiving PTH (all doses combined) were 7.1% +/- 5.6% (spine), 0.3 +/- 6.2% (femoral neck), and -2.3 +/- 3.3% (total body. After switching to alendronate for 1 year in women who previously had received PTH, mean changes in BMD were 13.4 +/- 6.4% (spine), 4.4 +/- (femoral neck), and 2.6 +/- 3.1% (whole body). This combination of drugs would appear to be an excellent way to increase BMD. Unfortunately, PTH is not yet approved by the FDA for treatment of osteoporosis, and is only effective in an injectable form. It is my understanding that researchers are hoping to develop an intranasal or similar form that will be much more convenient than injections. It would be interesting to see the results of combination PTH/alendronate therapy from the beginning of treatment, too. A short-term trial in women showed that it should be effective as reported in a previous newsletter: http://www.osteoporosis.org/nl7.htm. See this excellent PTH review:
Fluoride for treatment of osteoporosis. Don`t expect to see fluoride accepted as a treatment for osteoporosis any time soon. A recent review of the effectiveness of fluoride in treating osteoporosis concludes, "Although fluoride has an ability to increase BMD at the lumbar spine, it does not result in a reduction of vertebral fractures. See Cochrane Database Syst Rev 2000;4:CD002825. Fluoride for treating osteoporosis (Cochrane Review). PMID:11034760.
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.