No July 2002 newsletter. There will be no July 2002 issue of this newsletter. The nextt issue will be on the Web in October 2002.
Prostate cancer risk. Thanks to one of our members who emailed to remind me that, "Whenever you report some good news about PTH (parathyroid) treatment (or Calcitonin, for that matter)--as you did in the latest newsletter--you should throw up a caution flag about the possibility of increasing the risk for prostate cancer, as you have reported in a previous issue of your newsletter." See the 18th newsletter for more details on this.
One injection per year to treat osteoporosis? As reported in almost all the national media recently, intravenous (IV) injection of zoledronic acid (Zometa), combined with a daily dose of one gram of calcium, has been shown effective in increasing bone mineral density (BMD) in women with osteoporosis or osteopenia. See N Engl J Med 2002 Feb 28;346(9):653-61 Intravenous zoledronic acid in postmenopausal women with low bone mineral density. Reid IR and others, PMID 11870242. These women who entered treatment with a mean T-score of -2.9 had similar results of approximately 5% and 3% increase in spinal and femoral neck BMD, respectively, whether given the medication every three or six months, or just once yearly. And, BMD continued to increase even at the one-year end of the study, indicating the drug might be effective for even considerably longer periods. Additionally, biochemical markers of bone resorption were significantly decreased by over 50% in all treatment groups compared to placebo. These markers remained decreased after one year, too, as another indication of the very long-term effectiveness of the medication. Muscle pain and fever occurred more often in the treatment group, but treatment-related dropout rates were similar in treatment and placebo groups. Zoledronic acid has FDA approval for treatment of hypercalcemia of malignancy, but is not yet approved for treatment of osteoporosis. The results of this study should do much to help with that approval. Other bisphosphonates such as pamidronate (Aredia) have been used with IV dosing effectively in treating osteoporosis, but they must be given very slowly over a four-hour period. Interestingly, the IV Zometa can be given much quicker, with manufacturer`s recommendations of not less than 15 minutes. The study didn`t report on fracture results, so that very important end point will have to be examined in future studies. If that is positive, then this is indeed a very exciting new medication.
Our osteoporosis expert’s comments on this study. (Note: Dr. Karen Kolba is our expert advisor on osteoporosis to the Men’s Osteoporosis Support Group). Dr. Kolba says that the Reid IR and others study mentioned above was a big topic of discussion at the recent National Osteoporosis Foundation meeting in Honolulu that she attended. The FDA will definitely require a fracture study which is just starting this week, so we are probably a couple of years away from FDA approval of Zometa for osteoporosis. But, the drug is approved for treatment of other conditions, so it can be given as an off-label prescription to treat osteoporosis. Although it will be expensive ($850-900 per infusion), there is no reason to believe it won’t function like other bisphosphonates already approved for osteoporosis therapy. Actually, this cost should be comparable to what someone without prescription coverage would pay for Fosamax or Actonel–and the patient can drink coffee or have breakfast every day of the year. Thus, she will probably administer the medication in her office, especially for those who cannot take Fosamax/Actonel due to esophageal stricture. Zometa would be given in place of other bisphosphonates, and it is not at all clear if giving Forteo (PTH) during that same year will make any difference.
A reader asks for input from other readers. One of our members reported to me this quarter that since he has started taking Actonel his serum cholesterol levels have risen quite dramatically. He doesn`t know if it is a coincidence or some adverse response to the Actonel, thus he is asking for readers to report any similar findings since they started Actonel. Here are the results he reported to me:
Time
Total
cholesterol
LDL
HDL
Total/HDL
Ratio
LDL/HDL
Ratio
Before Actonel
155
105
55
2.8
1.9
1-yr later
208
130
39
5.3
3.6
6-months later
213
145
39
5.5
3.7
6-months later
226
167
41
5.5
4.1
Jan 15, 2002
223
160
43
5.2
3.7
The member reports that he was also taking Previcid during this time and that he stopped it for one month before the January 15, 2002 test was taken as he felt it could be part of the problem. He also notes that his cholesterol level has always been approximately the same as the first set of data shown in this table with the recent increase the first time that has ever occurred.
I did some checking on the Web and found that total cholesterol should be less than 200 and that 200-239 is considered borderline high. The American Heart Association (AHA) recommends that the total/HDL ratio should be below 5:1 and ideally 3.5:1. Mayo Clinic suggests that the LDL/HDL ratio should be lower than 5:1 and ideally 3:1. But, the AHA also suggest that physicians may want to just consider the separate figures as they may better suggest what type treatment is needed.
As can be seen, the change in both total cholesterol and ratios is quite dramatic for this member. If anyone has any similar results to report either related to starting Actonel or any other medication once they were diagnosed with osteoporosis, would they please email me to explain the results. Or, if anyone has any other ideas or suggestions regarding this dramatic change in cholesterol totals and ratios, please let me know.
Lunar News update. I have mentioned the Lunar News in many previous newsletters. GE Medical Systems has taken over the publication of this newsletter and it is now strictly on line as eLunarNews and dedicated to bone densitometry rather than a total overview of osteoporosis.
A member`s book review. A member emailed me recently with his summary after reading The Osteoporosis Solution: New Therapies for Prevention and Treatment, by Carl Germano, R.D., C.N.S., L.D.N. with William Cabot, M.D. and a forward by Ronald Hoffman, M.D., published by Kensington Health, NY. I checked www.amazon.com and found that it is available with prices from $11.20 for new and $6.11 for used books. It was available in hardback under ISBN 1575663910 and in paperback but the ISBN was not specified. I noted that some of the book is available to read online at Amazon.com, too. The member reviewer noted, "Suffice it to say that I found this book most enlightening because it outlined what the disease is and provided much information about various studies, including how the disease affects men as well as women. I would say that the book is balanced, but it also provided good information about various types of treatments available, including what the author indicated was a breakthrough with a new approach, but this seemed to be mostly for women since it involves what I would call `artificial` estrogen. This approach is one of prevention and treatment, including dietary supplement ipriflavone (IP) and various studies."
Editor`s comment. Since this newsletter is dedicated to men with osteoporosis, I seldom mention women`s osteoporosis issues, but I will briefly here. Since this book that was reviewed seems directed to the use of IP in treating female osteoporosis, I wanted to do a very brief PubMed search to see if any controlled studies had looked at IP, a soy product, for treating osteoporosis. I just want to inform the readers of this book that IP may not be a sure-fire effective treatment for female osteoporosis based upon that research and for them to examine the issue carefully. The first abstract is from a recent study by Katase, K and others, Effects of ipriflavone on bone loss following a bilateral ovariectomy and menopause: a randomized placebo-controlled study. Calcif Tissue Int. 2001 Aug;69(2):73-7, PMID: 11683426, indicated that IP didn`t increase BMD although it did slow early rapid bone loss compared to placebo in premenopausal women after undergoing ovariectomy. In women in late-stage menopause, there was a 1.4% increase in BMD compared to women in the placebo group who had 3.9% decrease in BMD after 18 months of therapy. The second abstract from a March 2001 study by Alexandersen P and others, Ipriflavone in the treatment of postmenopausal osteoporosis: a randomized controlled trial. JAMA 2001 Mar 21;285(11):1482-8, PMID 11255425, noted, "IP does not prevent bone loss or affect biochemical markers of bone metabolism. Additionally, IP induced lymphocytopenia in a significant number of women." I think we would all like to have a magical natural remedy for all our ailments, but look for good controlled clinical trials of these natural remedies, too. Whether the product is natural or man-made, it should be shown effective in published clinical trials in quality journals. There appears to be at least some question of the effectiveness of IP, so female readers should examine this issue carefully before considering IP as an alternative to other therapies.
Literature review
Finding articles mentioned. To see abstracts of these articles, go to PubMed at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi and enter the numeric portion o>nly of the PMID into the search block and click on Go or hit the enter key.
Usefulness of bone densitometry after vertebral fracture. This study is reported in Ann Rheum Dis 2002 Jan;61(1):73-5, Usefulness of bone densitometry in postmenopausal women with clinically diagnosed vertebral fractures, Nolla JM and others, PMID 11779765. This is another study involving only women, so whether the results pertain to men is not discussed, but probable. The objective was to see if BMD assessment is required in postmenopausal women presenting with low-trauma vertebral fractures. All women seen with vertebral fractures who subsequently had dual-energy X-ray absorptiometry (DXA) during a 10-year period were included in the study. Those with high-energy trauma, malignancies, or other metabolic bone disease were excluded, leaving 215 patients. The results showed a mean age of 65.9 years and BMD at the spine of -2.94 and at the hip of -2.22. The BMD of these patients was significantly lower than that of the general population at both sites. When looking at the lowest value of the two sites examined, 3% of women had normal BMD, 23.5% had osteopenia, and 73.5% had osteoporosis. The authors conclude that, "These results indicate that bone densitometry is not required in postmenopausal women with clinically diagnosed vertebral fractures if it is performed only to confirm the existence of low BMD." This is a very interesting conclusion, with considerable potential significance. And, actually it coincides with published recommendations concerning diagnostic criteria for osteoporosis: A bone density of -2.5 SD from the normal young adult or a vertebral fracture. I interpret it as meaning that when someone presents with a vertebral fracture, they have low BMD. If a DXA is done it would only be to quantify just how low that BMD actually is, not to determine if treatment for the low BMD is needed. The fact that a fracture occurs indicates that without further studies. It is unfortunate that this study only looked at spinal fractures. I would expect the same results if hip or wrist fractures were examined. Two studies indicating the importance of this study follow.
Male hip fractures and osteoporosis. This study was performed in a Veterans Affairs Medical Center in Wisconsin and is a review of medical charts of men admitted with hip fracture from 1993 to 1999. The goal was to see what secondary prevention strategies were suggested to these men after the fractures. See Ann Pharmacother 2002 Jan;36(1):17-23. Outcomes and secondary prevention strategies for male hip fractures, Riley RL and others. PMID 11816248. Medical charts were available for 43 of 53 male patients admitted for hip fracture during the study period. High-impact trauma patients were excluded. The mean age was 72 years (range 43-91) and mean length of hospitalization was 16 days (range 3-108 days). Thirty-two (82%) were discharged to a nursing home. Eleven (26%) died within 12 months after fracture. Twelve (28%) had fractured previously and 4 (10%) subsequently had another fracture. Three patients received a bone mass measurement within six months of fracture. No patient`s record included a diagnosis of osteoporosis either before or within six months after fracture. One-third of the patients had documentation of calcium or multivitamin supplementation at discharge and one patient was receiving calcitonin at the time of fracture and continued that therapy afterwards. No other patients were prescribed antiresorptive therapy at the time of discharge. The authors concluded: "Male veterans with hip fractures received inadequate evaluation and treatment for osteoporosis, although a substantial portion had documentation of recurrent fractures. Education of clinicians and creation of algorithms for management of established osteoporosis may improve outcomes for these individuals." Editor`s comment: Assuming the results of Nolla`s study above apply to men and that low-trauma fracture in the hip is as indicative of low BMD as is low-trauma fracture of the spine, these results are frightening. In summary, medical doctors failed to diagnose or treat 42 cases of osteoporosis in men attending a VA hospital. DXA results would have been indicative of the exact level of BMD, but really weren`t needed to show that antiresorptive therapy was needed for these men. What is really frightening is that three men did receive a DXA and still didn`t get therapy for osteoporosis.
Missing a therapeutic window of opportunity. This is a similar Australian study that included both men and women seen at a tertiary teaching hospital between the age of 40 and 85 with either hip or wrist fracture in the preceding 24-30 months where fracture information was obtained from hospital computer records. Patients were queried via telephone about potential osteoporosis risk factors and subsequent fractures. Additionally, people were asked whether DXA was done and if they had received information about or prescriptions to treat osteoporosis. See J Rheumatol 2001 Nov, 28(11):2504-8. Missing a therapeutic window of opportunity: an audit of patients attending a tertiary teaching hospital with potentially osteoporosis hip and wrist fractures. Smith MD, Ross W, and Ahern MJ, PMID 11708425. There was a total of 218 people interviewed with 78% being female. Thirty-two percent had subsequent DXA and 39% were offered treatment for osteoporosis. But, note that 51% of this "treatment" was nothing more than calcium supplements. There are too many results reported in this study to include them all here. Some notable ones included: 59% had a previous fracture and 84% had been given no information about osteoporosis by their physician at the time of fracture. The authors conclude, "Most patients with a potentially osteoporotic fracture will be seen at some stage by accident or emergency and/or orthopedic medical staff or a general practitioner. It is particularly important that these health professionals are aware of the need to recognize the possibility of osteoporosis, and implement an investigation and treatment plan to avoid missing this window of opportunity in the management of osteoporosis." So, the total implication of these three studies is that low-trauma fractures indicate the need to rule out osteoporosis, and to treat it if found. Physicians should view such fractures as a flashing red light indicating they need to investigate and probably treat the patient for osteoporosis to avoid future fractures. An alarming number of fracture patients are apparently not currently receiving post-fracture osteoporosis diagnostic testing or treatment by the physicians they see for fracture treatment.
The upper GI safety of once-weekly Fosamax. As most of you know, daily Fosamax therapy has been implicated as causing upper gastrointestinal (GI) problems since it first came on the market even though large clinical trials found it generally equal to placebo in this relationship. The once-weekly 70-mg Fosamax dose was not only more convenient than the daily dose, but logically should be less irritating. A recent study has shown this logic to be correct. See Am J Gastroenterol 2002 Jan;97(1):58-64, The upper GI safety and tolerability of oral alendronate at a dose of 70 milligrams once weekly: a placebo-controlled endoscopy study, Lanza F and others. PMID 11808969. This study involved 90 men and 187 women who were randomized to receive either alendronate (70 mg once weekly) for 10 weeks, placebo (once weekly) for 10 weeks, or placebo (once weekly) for 10 weeks followed by aspirin (650 mg four times daily) for the last week as the positive control. Endoscopy of the esophagus and duodenum was done 5 to 7 days after completing therapy. Results showed the mean gastric erosion scores (Lanza scale) were similar in subjects given 70-mg alendronate once weekly and those given a placebo (0.32 vs. 0.35), respectively. These scores were significantly lower than in those given aspirin (3.09; p<0.001). Endoscopic gastroduodenal ulcers occurred in no alendronate, two placebo, and five aspirin subjects. The authors concluded, "Alendronate (70 mg once weekly) was not associated with any increase in endoscopic lesions in the upper GI tract relative to a placebo." These results on large numbers of subjects (126 in both the alendronate and placebo group) are very reassuring and reflect the fact that I`ve not heard many complaints from any of the men on the once-weekly alendronate regimen.
Tolerability of risedronate. The following study examined the incidence of upper GI adverse events in women who had discontinued daily therapy with alendronate. See Aging (Milano) 2002 Oct;13(5):347-54, Tolerability of risedronate in postmenopausal women intolerant of alendronate, Adachi JD and others. PMID 11820707. It included 63 women who had previously discontinued treatment with alendronate 10 mg/day because of upper GI adverse events. Thirty-one of them were given placebo and 35 were given 5 mg risedronate (Actonel) daily for 3 months. The primary outcome of the study was discontinuation due to upper gastrointestinal adverse events with 5/31 (16%) in the placebo group and 4/35 (11.4%) in the risedronate group stopping therapy. The study tracked all upper GI events and noted 19.4% occurred with risedronate and 20% with placebo. The authors state, "Overall, risedronate 5 mg/day for 3 months was as well tolerated as placebo in patients who could not tolerate alendronate 10 mg." Once again Actonel has shown that it is well tolerated, even in those who couldn`t tolerate Fosamax. It is interesting that over 16% of the people discontinued therapy with the placebo due to upper GI problems. I wonder if they got relief? The authors didn`t mention that, but it would have been educational to know.
Shorter more frequent exercise to increase BMD? Although I prefer to cite studies involving humans, occasionally there is one using lab animals that is interesting enough to discuss. This one has implications for men with osteoporosis who exercise to improve BMD if the results in lab rats apply to humans, too. See Med Sci Sports Exerc 2002 Feb;34(2):196-202. Shorter, more frequent mechanical loading sessions enhance bone mass, Robling AG and others, PMID 11828225. The authors point out that the beneficial effects of exercise on bone mass result from the sensitivity of bone cells to mechanical stimuli-a very short-lived effect. The study tested whether the osteogenic response to a simulated high-impact exercise program lasting 4 months could be enhanced by dividing the daily protocol into brief session of loading separated by recovery periods. The right forelimbs of adult rats were subjected to 360 load cycles a day for 3 days per week for a total of 16 weeks. On each loading day, one group received all 360 cycles in one single uninterrupted session while the other group received four bouts of 90 cycles in separate sessions each 4 hours apart. The authors found that both of the loading regimens improved all of the several bone density factors tested compared to the left (unstimulated) forelimb. They also found that the 4-cycle regimen improved all BMD factors compared to the single-cycle regimen. If future studies in humans can verify these results, it might be better to do exercises in shorter sessions multiple times a day if increased BMD is your goal. This may make the exercise program seem less daunting, too.
A better way to give human parathyroid hormone therapy? Here`s another interesting animal study with possible important implications for humans. See J Pharm Sci 2002 Feb;91(2):350-61 by Suzuki Y and others. Prevention of bone loss in ovariectomized rats by pulsatile transdermal iontophoretic administration of human PTH(1-34), PMID 11835195. As reported in several recent newsletters, human parathyroid hormone therapy (PTH) is an exciting new way to increase BMD since it actually stimulates bone formation. One drawback to PTH therapy is that it must be given via daily subcutaneous injections. In this study the authors found that three 30-minute applications of iontophoretic pulses given three times weekly through a patch containing proper doses of PTH was equally effective as daily subcutaneous injections of PTH in Sprague Dawley rats. The iontophoretic patch might allow self-medication of PTH and thus be a useful advance in the treatment of osteoporosis. (See the 18th newsletter for possible prostate cancer implications of PTH therapy).
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.
