Promising future breakthroughs|
Cathepsin, integrins, sclerostin, nitrogylcerin
Medications that are probably effective
Thiazides, Strontium ranelate
Possibly effective drugs
Bicarbonate, Vitamin K
Statins, Growth Hormone, Vitamin D metabolites, Magnesium
Fluoride, Progesterone, Phytoestrogens, Boron
Cathepsin K is secreted by osteoclasts to break down collagen. Inhibitors have been studied in animals and show effective anti-resorptive properties. Phase 2 human studies also show benefiical effects.
Integrins are needed for osteoclasts to recognize and attach to the bone matrix. Inhibitors have been studied in humans and show the classical effects of anti-resorptive drugs with decreased markers of bone resorption and formation with increased bone density. However, several years after a phase 2 study which looked positive, there have been no reports about these drugs.
An abstract on the effects of Lasofoxifene on fractures and breast cancer was presented at the 2008 ASBMR meeting. The abstract presented 3 year data and the oral presentation included a 2 year extension. This was another large, multicenter study of a new SERM, enrolling 8556 women with osteoporosis aged 59-80. 77% completed the study, 64% remained on the drug. The 0.5mg dose gave best results. RESULTS (5 years): Vertebral fractured decreased 42%, nonvertebral fractures decreased 24%, hip fractures non-significant (35 placebo vs 27 Laso.) Breast cancer showed 81% reduction, all from estrogen positive cancers; the hazard ratio for cardiovascular endpoints was 0.68 which was significant. There were more cases of venous thromboembolism. Hot flashes were increased. Thus, lasofoxifene had beneficial effects on fractures, breast cancer, and cardiovascular disease without an increase in strokes.
Although the scientific advisory committee to the FDA recommended approval, this medicine was not approved. There was an increase in overall mortality with the lower dose studied, but not with the higher dose. Most experts felt this was a chance occurrence, especially since there were a variety of causes of mortality and they were not related to any known actions of the drug.
Several of the small proteins in the Wnt-signalling pathway can be inhibited. Currently the most promising are the inhibitors of inhibitors - ie, drugs that block Dickkopf or GSK or sclerostin. The latter is most promising because it is found almost exclusively in osteocytes and so therapy would be targeted to the bone.
A small study of 243 women who did not have osteoporosis found improved bone density with topical nitroglycerin after 2 years. 35% of the women in the treatment arm experienced headaches, compared to 5% in the placebo group. There were only 4 fractures (2 in each group). One intriguing finding is that the markers for bone formation increased whereas the markers for bone resorption decreased, so this therapy potentially improves osteoblast function as it inhibits osteoclasts. (Jamal SA). However, another 3-year study in women after menopause did not find a beneficial effect on bone density. (Wimalawansa SJ).
There have been over 20 epidemiological studies that measure the risk of fractures in patients taking thiazides, and the great majority show a reduction in risk. The largest recent pharmaco-epidemiological studies show 10 to 20% reduction in those taking the medication. Bone density is also higher in patients who use thiazides. Clinical trials have shown small but significant improvements in the bone density. Nobody has done a large enough clinical trial with a fracture endpoint (it would have to be a long-term trial which would be expensive and drug companies are not interested in low-cost drugs. Therefore, these drugs are not on the "recommended" list, even though there is a great deal of evidence that they would probably be beneficial as a drug to use in patients with mildly low bone density who need to prevent bone loss so they will be better prepared to meet the age of fracture.
There have been several studies that show increased bone density, and one large study in Europe found reduction in osteoporotic fractures in patients treated with strontium. The drug has been approved for use in many countries but not in the USA. The mechanism of action is uncertain.
I have not seen any clinical trials showing benefit from over-the-counter forms such as strontium citrate, and none are listed on Clinical Trials.gov. Thus, I recommend that this form should be avoided unless it is shown to be both effective and safe.
Elderly persons may have mild cases of renal tubular acidosis which is buffered by bone. This would increase loss of bone mass. Balance studies showed that potassium bicarbonate reversed calcium balance from negative to positive. Further clinical trials of bicarbonate are needed.
Nutritional surveys have found positive skeletal effects in persons who eat foods containing vitamin K. Decarboxlyated osteocalcin, an indicator of poor vitamin K status, is associated with more fractures. But there haven't been any clinical trials.
In animals, statins given parenterally increased the bone density. Several cohort studies were then analyzed for fracture risk in patients taking statins. Some found slight benefit. The large Women's Health Initiative found no benefit on fractures. A study of men in VA hospitals did find a benefit. Randomized trials of statins in patients with high cholesterol have not been able to demonstrate fracture benefit. Both statins and bisphosphonates inhibit the mevalonate pathway (at different places) so theoretically these drugs should be able to inhibit bone resorption. The doses used for cholesterol treatment may not be effective for bones. Also, most of the drugs are metabolized in the liver so oral doses do not achieve good circulating concentrations. Transdermal routes are being explored.
Growth hormone has been studied as a method of increasing bone density in elderly persons. The results are mixed. Biochemical markers of bone formation and resorption increase, and in some cases bone density increases modestly. Side effects are seen, however, which limit potential use. Patients with adult-onset pituitary deficiency may have osteoporosis. These patients also have hypogonadism which is known to decrease bone density. In these cases growth hormone may improve bone density beyond that seen with sex hormone replacement. Adults who had childhood onset growth hormone deficiency do not necessarily have osteoporosis. They have short stature, but the volumetric density of the bone is normal. Thus, the physiological role of growth hormone in maintaining adult bone density is uncertain.
Calcitriol has been studied in different countries with different results; some of this might be related to the usual intake of vitamin D and calcium in the subjects. For example, in Japan the drug was beneficial and the dietary intake of calcium is so low (about 300mg/day) that hypercalcemia or hypercalciuria are not a problem. In the USA the drug did not significantly improve bone density or fracture rates.
Newer metabolites of vitamin D are being developed.
This is heavily advertised but the actual data about magnesium and fractures is very scant. The Women's Health Initiative found that women who took magnesium supplements had significantly more forearm fractures than those who did not take them. A recent trial suggests that magnesium increases bone density, but there were not enough subjects to look at fractures.
from Abraham Verghese, MD, from the Stanford Medicine magazine, Summer 2008:
"An unstudied remedy, particulary if it's labeled "natural' or comes from the rain forests of the Amazon, has a special charm . . . A loophole in our laws allows potent drugs and potentially toxic substances to escape all scrutiny from the FDA as long as they don't make claims to treat or cure disease. . . If you dispense hope in a pill, the evidence is good that we will buy it and swallow it --- hook, line and sinker."
Fluoride was first used as a treatment for osteoporosis in 1966. It had been known that communities with naturally high fluoride levels in the drinking water had a high incidence of bone deformities. Further evaluation showed this was osteomalacia with increased bone formation rates. Researchers thought that a lower dose would be able to enhance the bone formation rate, thus increasing the bone density, without causing the osteomalacia. Fluoride definitely increased the bone formation rate as well as the bone density. However, osteomalacia still resulted. In a large well-designed randomized, blinded clinical trial, women who used fluoride for four years had increased fracture rates compared to placebo controls. The bone density of the spine increased by 32%, but the hip did not show increased density and the rate of hip fractures was nearly three times as high in the fluoride group. After this study was published, investigators wondered if even lower doses of fluoride might reduce fracture risk. A relatively small study of low-dose, slow-release fluoride has suggested a reduction in fracture risk, but many of the subjects had not taken the fluoride for more than two years. There was no osteomalacia seen in those subjects who had bone biopsies. However, another group measured the mechanical strength of bone in patients receiving low dose fluoride for five years, and found it was significantly more fragile than bone from control patients.
Newer studies show that fluoride increased the bone density but decreases the BONE QUALITY. It is the best example demonstrating why it is so important to consider fractures as an endpoint, and not bone density.
Two recent NIH-funded studies of soy isoflavones showed no difference in bone density changes, compared with placebo. (Alekel DL), (Levis S. Reported at 2009 ASBMR meeting, not yet published).
Many articles and even some books advocate this as an alternate to estrogen. The only reason to take progesterone is to protect the uterus from cancer. In one random clinical trial, progesterone did cause increased bone density at some skeletal sites in comparison to placebo, but it did not add to estrogen therapy and was definitely not as beneficial as estrogen. In young women taking injectable medroxyprogesterone acetate (Depo-provera) for contraception, the bone density is lower than in control women. This is a situation where the high progesterone clearly is NOT beneficial. We have shown that Depo-provera is associated with lower bone density, especially in young women. New information suggests that postmenopausal use of progesterone increases the risk of breast cancer.
Boron has not actually been shown to harm the skeleton, but there is so little evidence that it has any effect on the bones that I am putting it in the category of not effective.Updated 3/29/11