Selective Androgen Receptor Modulators (SARMS)


The success of SERMs has raised interest in producing drugs that do the same thing for other metabolic pathways, including the androgen pathway and how it affects bone. Osteoanabolic agents called SARMs (selective androgen receptor modulators) can slow osteoporosis but none are in wide use at this time.

Androgens protect bone, but using them for osteoporosis and osteopenia has been problematic because of their side effects and because it is difficult to get them in the bloodstream from a pill. Testosterone can be injected into the bloodstream, but that is not an optimal solution. Androgen administration brings acne, enlarged prostate, and negative effects on cholesterol and triglyceride levels in the blood. Indeed, hypogonadism is considered the only condition where the benefits of testosterone exceed the downsides.

SARMS (selective androgen receptor modulators), are hoped to leave behind the androgenic (bad) side effects of steroids while keeping the anabolic (good) effects. The goal is to find a compound that has anabolic effects without androgenic effects. The anabolic effects would ideally include osteoanabolic (bone building) ones. When we think about what we want in an osteoporosis or osteopenia medicine, that’s what we want. People concerned about other conditions such as wasting syndrome and sarcopenia want a compound that has myoanabolic effects (muscle building) without negative effects on the prostate and other organs.

Bone cells have androgen receptors that respond to hormones (both the body’s own and external supplements). Unlike bisphosphonates, which inhibit osteoclast activity, androgens and SARMs increase the rate of formation of periosteal bone. It is this osteoanabolic activity that is valuable. In the body’s normal functioning, the enzyme aromatase converts testosterone to estradiol but SARMs are not subject to this reaction.

There is also interest in use of SARMs in hypogonadism, muscle wasting, and prostate diseases. There are a lot of different compounds that act as agonists to androgen receptors, and scientists are now trying to figure out which ones have therapeutic use

Are these SARMs part of the class of chemical compounds called steroids? Some are and some are not. The idea is that if we can find non-steroidal ligands for androgen receptors the resulting drugs will be more targeted for producing bone growth.

Availability

No SARMS are on the market at this time for clinical use in bone health. The pharmaceutical companies are working on developing them with an eye to the bone market and markets in oncology (cancer cachexia), AIDS (wasting syndrome), general aging (sarcopenia), and perhaps the cardiovascular health. SARMS are sometimes marketed on-line as “legal steroids” in an appeal to bodybuilders. The FDA has issued a warning>/a> about SARMS for this use - citing “Life threatening reactions, including liver toxicity” in people using SARMS that have not been approved for medical use. The world of on-line SARMS sales is murky. An investigation reported in the Journal of the American Medical Association found most products had inaccurate labels and a large percentage of pills sold as SARMS in fact contained no active SARM -

In Development

Merck was working on a medicine called enobosarm (Ostarine) but they abandoned it after poor clinical trials results. Another, smaller company (GTX) is still pursuing it. (Enobosarm has been used by athletes to build muscle.) Bristol-Myers Squib, Ligand Pharmaceuticals, Kaken Pharmaceuticals, Acadia Pharmaceuticals are attempting to develop SARMs.

A non-steroidal SARM called LGD-4033 or ligandrol has shown promise in increasing body weight in tests. Imidazolopyrazole is another SARM under development, although at a preclinical stage and the developer seems interested in other uses than bone health. It has been found to have muscle-building effects. Eli Lilly developed a SARM under the name LY2452473 and sold the rights to Transition Therapeutics which was subsequently acquired by OPKO Health, Inc. and is developing the drug under the name TT701. The diuretic Aldactone (Spironolactone) has been used for years and it might have some SARM activity. Japanese researchers have investigated S-101479 for bone building and found it might have additive effects with other osteoporosis medicines. The SARM LGD-4033 or Anabolicum or Ligandrol has been found to promote increases in lean body mass without an increase in prostate problem markers, although the research study did not specifically look at the effect on bone density.

Combination Therapy

If SARMs do enter clinical use, there is a good chance doctors will prescribe them in combination with bisphosphonates. Because the two drugs work differently and approach the loss of bone from different metabolic directions (bisphosphonates stop osteoclastic destruction, SARMs increase bone formation), the combination will hit the osteoporosis with a "one-two punch". Research in rats found that the combination of a bisphosphonate and a SARM had a synergistic effect on osteoporosis. 

Likewise, research tests have shown the SARM S-101479 in combination with a bisphosphonate has bone-building effects in laboratory animals.

See also: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039107/

Illicit Use

When you hear about athletes taking “performance enhancing drugs” those drugs are often SARMs. Competitive athletes in judged events and professional leagues may face penalties if they test positive for SARM usage, but many amateurs use them just to bulk up. They may acquire the drugs through legally shady means, without a prescription. The FDA and others try to discourage this practice. A bill called the The SARMs Control Act of 2018 was introduced to the Senate to make SARMs illegal, but it did not pass. 

 

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