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PDQ®  Complementary/Alternative Medicine

Cartilage

Table of Contents

OVERVIEW
GENERAL INFORMATION
HISTORY
      Bovine
      Shark
LABORATORY/ANIMAL/PRECLINICAL STUDIES
HUMAN/CLINICAL STUDIES
ADVERSE EFFECTS
FOR MORE INFORMATION
REFERENCES
LEVELS OF EVIDENCE

Overview

This complementary and alternative medicine information summary is an overview of the uses of cartilage products in the United States. The summary includes a brief history of cartilage research, results of clinical trials, and possible side effects of cartilage use. Citations that appear in bold type have a level of evidence designation that indicates the degree of scientific validity of the study. A table with information about the level of evidence for these citations can be accessed by clicking on the bold reference number in the text.

General Information

Cartilage products are widely used in the United States for the treatment of medical conditions such as cancer, arthritis, and psoriasis. It is estimated that more than 50,000 Americans used shark cartilage in 1992,[1] and with media attention increasing, this number is likely to have grown substantially. In 1995 more than 40 brand names of shark cartilage products were being sold in the United States.[1] Most purchases are made over the counter. Use of these products is not limited to humans. Products containing shark and bovine (cattle) cartilage for both human and veterinary use have been marketed and sold throughout the world.

Cartilage compounds are marketed as dietary supplements that do not require Food and Drug Administration (FDA) pre-marketing evaluation or approval, and no specific quality control requirements or good manufacturing process (GMP) for dietary supplements exist at this time. This lack of regulation means there is no guarantee that claims stated on labels are accurate, that the contents of the package actually contain cartilage or one of its active ingredients, or that the product is pure and safe to use. However, before researchers can conduct clinical drug research in the United States, they must file an Investigational New Drug (IND) application; the FDA so far has granted IND status to 3 groups of investigators studying the use of cartilage as a cancer treatment.[1]

The major components of shark cartilage are proteins (approximately 40%), glycosaminoglycans (GAGs, approximately 5%-20%), and calcium salts.[2] Chondroitin sulfate, one of the most plentiful glycosaminoglycans found in cartilage, is under investigation to determine if it is one of the active ingredients.[2, 3, 4] Cartilage reportedly has been sold in many forms and is given in many ways. It can be taken orally as a pill, powder, or liquid extract; given as a topical agent, an enema, or an intravenous (i.v.) infusion; or administered as a subcutaneous (under the skin), intraperitoneal (into the lining of the abdomen), or intramuscular (into the muscle) injection.[5, 6, 7] Administration schedules and the length of treatment in animal models and in humans vary widely.

History

Various types of cartilage, including pig, sheep, chicken, bovine, and shark, have been under scientific investigation for more than 30 years. Studies to test the effectiveness of cartilage as an anti-inflammatory and analgesic (pain reliever) for arthritis [8, 9, 10, 11] and to determine if cartilage can facilitate wound healing in conditions such as psoriasis [4, 11, 12] have been conducted. In vitro (test tube) and in vivo (in a living body) tests were performed on murine (mice and rat) models, and several randomized, double-blind studies were conducted in Europe with osteoarthritis patients. The European studies demonstrated that chondroitin sulfate, an ingredient found in cartilage, improves joint mobility and reduces pain. [13, 14, 15]

During the mid 1970s, several published studies reported that the cartilage, serum, and liver of sharks may have antineoplastic (anticancer) properties against lung cancer and leukemia in a murine model.[16, 17] Research continued during the 1980s. However, many results from these early studies generated additional questions about the possible mechanism(s) of action of these compounds and provided few definitive answers.[18, 19, 20, 21, 22]

The use of shark cartilage as a cancer treatment has drawn attention because of the popular belief that the incidence of cancer in cartilaginous fish (sharks, skates, and rays) is very rare or nonexistent.[18, 23] However, literature on cancer in fish shows this may not be true. Comprehensive lists of literature compiled in 1933, 1948, and 1969 document that a sampling of cartilaginous fish captured over the years were found to have cancer.[24, 25, 26] Although there is no way to establish the prevalence of cancer among all sharks, various types of tumors have been found in cartilaginous fish. The majority of these cancers are melanomas and soft-tissue sarcomas.[25]

Mechanisms of action proposed to explain why cartilage compounds might be useful as a cancer therapy are based on information derived from experiments using animal models and human cell cultures.[2, 16, 17, 18, 20, 27, 28, 29, 30, 31] The most frequently cited is antiangiogenesis, a process that slows or stops the growth of blood vessels that supply nutrients and oxygen to the tumor.[2, 7, 12, 22, 27, 28, 29] Other mechanisms of action include blocking the formation of certain enzymes (metalloproteinases) that tumors use to invade tissue surrounding the tumor [5, 20, 21] and stimulating the immune system. Some researchers have hypothesized that bovine and shark cartilage have different mechanisms of action.[7, 22, 32]

Bovine

While bovine cartilage reportedly has antiangiogenesis properties, it has also been proposed that the compound inhibits tumor cell growth by using mucopolysaccharides (large sugar molecules) to block cell division.[5, 7] Other proposed mechanisms of action include inhibition of protease (a chemical that can break peptide bonds in cells),[21] blocking the formation of collagenase (enzymes that break down the protein collagen),[12] and the activation of the immune system, primarily by activating macrophage (cells that kill and digest microorganisms) and cytotoxic (tumor-killing) T and B cells.[5, 32, 33, 34]

Shark

Data from laboratory studies show that antiangiogenic activity is the mechanism of action most often noted for shark cartilage, although exactly how this activity occurs is still being debated.[2, 7, 27, 28] Research is also being conducted to learn about the antimutagenic activity of shark cartilage (its ability to inactivate or reverse the effects of cancer-causing agents), and whether shark cartilage may protect cells from DNA damage by being a scavenger of free radicals.[11, 35]

Bovine cartilage reportedly was first used to treat a human with cancer in 1972.[5] Since then, results of 3 phase I/II and phase II clinical trials, 4 clinical series, and a best case series on humans using various formulations of cartilage have been reported.[5, 7, 36, 37, 38, 39] Several clinical trials evaluating the effectiveness of bovine and shark cartilage in many types of solid tumors are ongoing or have been completed. These trials include shark cartilage with nutritional support at the Simone Cancer Center in Lawrenceville, New Jersey; a phase II trial of shark cartilage for breast and prostate patients at Metabolic Associates in New Jersey; a bovine cartilage study for renal cell cancer patients at Westchester Medical Center in New York; and a phase II study for breast cancer and brain/spinal tumor patients using a shark cartilage product sponsored by Lane Labs in New Jersey.[7] Preliminary results of these studies are not available at this time.

Laboratory/Animal/Preclinical Studies

Antitumor activity of shark and bovine cartilage has been investigated in various cancer cell lines, including astrocytoma,[28] myeloma, ovarian, colon, breast,[30] and Lewis lung carcinoma.[17] Suppression of tumor growth was most pronounced in myeloma cells exposed to continuous, high doses of the compound and in lung cancer cell lines. Limited activity was noted for astrocytoma cells treated with shark cartilage, and for ovarian, breast, and colon cells treated with bovine cartilage. In vivo studies using chicken embryos, mice, and rabbits have also been conducted.[2, 10, 11, 22, 27] Data from cell lines and studies that treat implanted human cancer cells in animals with cartilage indicate some tumor regression or stabilization and/or evidence of angiogenesis inhibition in many cases.[2, 12, 16, 17, 22, 27, 28, 29, 30, 31] The results of 3 studies have been presented at scientific meetings during the past 6 years.[29, 39, 40]

Human/Clinical Studies

Studies using bovine and shark cartilage on human subjects with cancer have been ongoing since the early 1980s.[5] However, little information exists on how treatment was administered and how patients were monitored during the study, and the long-term outcome of treatment is limited. Most reports on tumor response and survival after cartilage treatment consist of anecdotal information that provides few details.[7] Very little scientifically based data have been published on this subject. Two clinical series, one using shark cartilage with 32 breast and prostate patients and another utilizing bovine cartilage with 35 renal cell carcinoma patients, and a phase II trial of oral shark cartilage powder with 60 advanced cancer patients have been presented as abstracts at national oncology meetings.[36, 37, 38] Only 2 bovine cartilage case series and 1 phase I/II shark cartilage case series have been published in peer-reviewed, scientific journals.[5, 36, 38] The majority of studies have used bovine or shark cartilage as a treatment for advanced cancer patients, but the response rate to cartilage therapy for these patients has not been impressive. Randomized clinical trials to test whether cartilage may be effective for patients with limited disease have not been conducted.

The results of a clinical series that used intensive i.v. and oral bovine cartilage therapies for patients with advanced cancer were reported in 1985. Although the study claimed to have induced a 90% initial response rate (complete and partial responses) in a group of 31 patients, confounding factors such as concomitant treatment with chemotherapy, radiation, or surgery may be the reason for many of the positive responses.[5] The ability to generalize these data to other groups of patients is difficult. No standard dosing schedule or route of administration was used for the entire group of patients or within groups of patients with a particular type of cancer. In addition, prior treatment among patients varied widely, ranging from no prior therapy at all to heavy pretreatment. In one clinical series, a less intensive dose of bovine cartilage was administered subcutaneously to 9 patients with advanced disease who had received no chemotherapy for a month. Strict entry criteria were used and baseline staging and follow-up were performed during the study. A complete response was achieved by a patient with renal cell carcinoma, but no other patients responded to therapy.[36] Another study used oral and injectable forms of bovine cartilage with 4 different schedules of administration to treat patients with metastatic renal cell carcinoma. Of the 22 patients who could be evaluated, 3 had durable partial responses and 1 had stable disease.[37]

Two phase II clinical trials for cancer patients using shark and bovine tracheal cartilage (sponsored by Cancer Treatment Centers of America (CTCA)) and a clinical trial using shark cartilage in AIDS patients with Kaposi's sarcoma (sponsored by Lane Labs) have been conducted and are listed in the closed clinical trial section of PDQ. Results from the phase II CTCA shark cartilage study, published in November 1998, concluded that oral shark cartilage given as a single agent was ineffective in 47 patients with advanced breast, colon, lung, and prostate cancer.[38] The results of the other CTCA study and the Lane Labs study have not yet been published. A phase III double-blind, placebo-controlled, multicenter trial (sponsored by the National Cancer Institute) using a liquid shark cartilage extract with conventional chemotherapy and radiation therapy for stage IIIA/IIIB non-small cell lung cancer patients will begin in late 1999. For more information on clinical trials, call the National Cancer Institute's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237); TTY at 1-800-332-8615.

Adverse Effects

Information on side effects associated with taking cartilage preparations is limited, but cartilage therapy apparently has few side effects regardless of route of administration. Reported side effects include dysgeusia (bad taste in the mouth), fatigue, dyspepsia (problems with digestion), nausea,[37, 38, 39] fever, dizziness, hypercalcemia,[38, 39] scrotal edema (swelling of the scrotum),[37] and discomfort at the injection site.[5, 36]

For More Information

For more information on complementary and alternative therapies, contact the NIH National Center for Complementary and Alternative Medicine (NCCAM):

NCCAM Clearinghouse
Post Office Box 8218
Silver Spring, MD 20907-8218
TTY/TDY: 1-888-644-6226 (toll free)

Additional information is available in the NCI Cancer Facts sheet Questions and Answers About Complementary and Alternative Medicine in Cancer Treatment.

References:

1. Shark Cartilage Information Sheet, Office of Special Health Issues, Food and Drug Administration, 3/27/97.

2. Davis PF, He Y, Furneaux RH, et al.: Inhibition of angiogenesis by oral ingestion of powdered shark cartilage in a rat model. Microvascular Research 54(2): 178-182, 1997.

3. Ronca G, Conte A: Metabolic fate of partially depolymerized shark chondroitin sulfate in man. International Journal of Clinical Pharmacology Research 13(suppl): 27-34, 1993.

4. Henke CA, Roongta U, Mickelson DJ, et al.: CD44-related chondroitin sulfate proteoglycan, a cell surface receptor implicated with tumor cell invasion, mediates endothelial cell migration on fibrinogen and invasion into a fibrin matrix. Journal of Clinical Investigation 97(11): 2541-2552, 1996.

5. Prudden JF: The treatment of human cancer with agents prepared from bovine cartilage. Journal of Biological Response Modifiers 4: 551-584, 1985.

6. Miller D, Midwestern Regional Medical Center: Phase II Study of the Safety and Efficacy of Shark Cartilage (Cartilade) in Patients with Advanced or Metastatic Cancer (Summary Last Modified 9/97), clinical trial, closed, 12/05/96

7. The Center for Alternative Medicine Research in Cancer at the University of Texas-Houston Health Science Center. Cartilage Summary, http://www.sph.uth.tmc.edu:8052/utcam/agents/crtlg.htm

8. Ronca F, Palmieri L, Panicucci P, et al.: Anti-inflammatory activity of chondroitin sulfate. Osteoarthritis and Cartilage 6(suppl A): 14-21, 1998.

9. Pipitone VR: Chondroprotection with chondroitin sulfate. Drugs Under Experimental and Clinical Research 17(1): 3-7, 1991.

10. Fontenele JB, Viana GS, Xavier-Filho J, et al.: Anti-inflammatory and analgesic activity of a water-soluble fraction from shark cartilage. Brazilian Journal of Medical and Biological Research 29(5): 643-646, 1996.

11. Fontenele JB, Araujo GB, de Alencar JW, et al.: The analgesic and anti-inflammatory effects of shark cartilage are due to a peptide molecule and are nitric oxide (NO) system dependent. Biological and Pharmaceutical Bulletin 20(11): 1151-1154, 1997.

12. Moses MA, Sudhalter J, Langer R: Identification of an inhibitor of neovascularization from cartilage. Science 248(4961): 1408-1410, 1990.

13. Bourgeois P, Chales G, Dehais J, et al.: Efficacy and tolerability of chondroitin sulfate 1200mg/day vs chondroitin sulfate 3 x 400 mg/day vs placebo. Osteoarthritis and Cartilage 6(suppl A): 25-30, 1998.

14. Morreale P, Manopulo R, Galati M, et al.: Comparison of the antiinflammatory efficacy of chondroitin sulfate and diclofenac sodium in patients with knee osteoarthritis. Journal of Rheumatology 23(8): 1385-1391, 1996.

15. Uebelhart D, Thonar E, Delmas PD, et al.: Effects of oral chondroitin sulfate on the progression of knee osteoarthritis: a pilot study. Osteoarthritis and Cartilage 6(suppl A): 39-46, 1998.

16. Pettit GR, Ode RH: Antineoplastic agents L: isolation and characterization of sphyrnastatins 1 and 2 from the hammerhead shark Sphyrna lewini. Journal of Pharmaceutical Sciences 66(5): 757-758, 1977.

17. Snodgrass MJ, Burke JD, Meetz, GD: Inhibitory effect of shark serum on the Lewis lung carcinoma. Journal of the National Cancer Institute 56(5): 981-983, 1976

18. Bodine AB, Luer CA, Gangjee SA, et al.: In vitro metabolism of the pro-carcinogen aflatoxin B1 by liver preparations of the calf, nurse shark and clearnose skate. Comparative Biochemistry and Physiology 94C(2): 447-453. 1989.

19. Langer R, Brem H, Falterman K, et al.: Isolation of a cartilage factor that inhibits tumor neovascularization. Science 193(4247): 70-72, 1976.

20. Sadove AM, Kuettner KE: Inhibition of mammary carcinoma invasiveness with cartilage-derived inhibitor. Surgical Forum 28: 499-501, 1977.

21. Pauli BU, Memoli VA, Kuettner KE: Regulation of tumor invasion by cartilage-derived anti-invasion factor in vitro. Journal of the National Cancer Institute 67(1): 65-70, 1981

22. Lee A, Langer R: Shark cartilage contains inhibitors of tumor angiogenesis. Science 221(4616): 1185-1187, 1983.

23. Ballantyne JS: Jaws: the inside story. The metabolism of elasmobranch fishes. Comparative Biochemistry and Physiology 118B(4): 703-742, 1997

24. Haddow A, Blake I: Neoplasms in fish: a report of six cases with a summary of the literature. Journal of Pathology and Bacteriology 36: 41-47, 1933.

25. Schlumberger HG, Lucke B: Tumors of fishes, amphibians, and reptiles. Cancer Research 8: 657-754, 1948.

26. Wellings SR: Neoplasia and primitive vertebrate phylogeny: echinoderms, prevertebrates, and fishes--a review. National Cancer Institute Monograph 31: 59-128, 1969

27. Oikawa T, Ashino-Fuse H, Shimamura M, et al.: A novel angiogenic inhibitor derived from Japanese shark cartilage (I): extraction and estimation of inhibitory activities toward tumor and embryonic angiogenesis. Cancer Letters, 51(3): 181-186.

28. McGuire TR, Kazakoff PW, Hoie EB, et al.: Antiproliferative activity of shark cartilage with and without tumor necrosis factor-a in human umbilical vein endothelium. Pharmacotherapy 16(2): 237-244, 1996.

29. Cataldi JM, Osborne DL: Effects of shark cartilage on mammary tumor neovascularization in vivo and cell proliferation in vitro. Federation of American Society of Experimental Biology Journal. 9(3): A135, 1995

30. Durie BG, Soehnlen B, Prudden JF: Antitumor activity of bovine cartilage extract (Catrix-S) in the human tumor stem cell assay. Journal of Biological Response Modifiers 4(6): 590-595, 1985.

31. Riviere M, Alaoui-Jamali M, Falardeau P, et al.: Neovastat: an inhibitor of angiogenesis with anti-cancer activity. Proceedings of the American Association for Cancer Research 39: A317, 1998

32. Rosen J, Sherman WT, Prudden JF, et al.: Immunoregulatory effects of Catrix. Journal of Biological Response Modifiers 7(5): 498-512, 1988.

33. McKinney EC, Haynes L, Droese AL: Macrophage-like effector of spontaneous cytotoxicity from the shark. Developmental and Comparative Immunology 10(4): 497-508, 1986.

34. McKinney EC: Shark cytotoxic macrophages interact with target membrane amino groups. Cellular Immunology 127(2): 506-513, 1990.

35. Gomes EM, Souto PR, Felzenszwalb I: Shark-cartilage containing preparation protects cells against hydrogen peroxide induced damage and mutagenesis. Mutation Research 367(4): 203-208, 1996.

36. Romano CF, Lipton A, Harvey HA, et al.: A phase II study of Catrix-S in solid tumors. Journal of Biological Response Modifiers 4(6): 585-589, 1985.

37. Puccio C, Mittelman A, Chun P, et al.: Treatment of metastatic renal cell carcinoma with catrix. Proceedings of the American Society of Clinical Oncology 13: A769, 1994.

38. Miller DR, Anderson GT, Stark JJ, et al.: Phase I/II trial of the safety and efficacy of shark cartilage in the treatment of advanced cancer. Journal of Clinical Oncology 16(11): 3649-3655, 1998.

39. Leitner SP, Rothkopf MM, Haverstick L, et al.: Two phase II studies of oral dry shark cartilage powder (SCP) in patients (pts) with either metastatic breast or prostate cancer refractory to standard treatment. Proceedings of the American Society of Clinical Oncology 17: A240, 1998.

40. Fossel E, Albright T, Zanella C. Trimethylamine oxide, a component of shark blood, exhibits chemopreventive properties. Proceedings of the American Association for Cancer Research 34: A3281, 1993.

Levels of Evidence and Endpoints for Complementary and Alternative Cancer Studies

The following table characterizes some of the references cited in the text on the basis of the statistical strength and scientific validity of the findings in the study to help the reader judge the strength of evidence of the reported results of the studies. A detailed explanation of the significance of the levels of evidence that are assigned follows.

Note: An asterisk (*) following the level of evidence designation for a cited article indicates that the study gave no uniform criteria for therapeutic response.

Levels of Evidence

In reviewing the findings of a human study, an alphanumeric rating system is used to represent the statistical strength and the scientific validity of the study. Statistical strength is measured on a numeric scale of 1-3; 1 refers to the statistically strongest study design, 2 is less strong, and 3 is the weakest. The scientific validity of the findings of a study is determined by the endpoints that are measured in the study and are expressed in terms of an alphabetic scale. The letter A refers to the strongest endpoint that can be measured and D refers to the weakest. These are referred to as the "levels of evidence" for a study. Results from a study with a level of evidence of 1iA have the strongest scientific validity, while, results from a study with a level of evidence of 3iiiDiii have the least scientific validity. The following section provides an explanation of the specific alphanumeric criteria that are used in assigning a level of evidence to references in the complementary and alternative medicine information summaries on CancerNet.

Statistical Strength of Study Design

The various types of study design are described below in descending order of strength.

Randomized controlled clinical trials: Studies in which participants are assigned by chance to separate groups that compare different treatments. It is the patient's choice to be in a randomized trial but neither the researcher nor the patient can choose the group in which he or she will be placed. Using chance to assign people means that the groups will be similar and that the treatments they receive can be compared. At the time of the trial, there is no way for the researchers to know which of the treatments is best. These trials can be double-blinded or nonblinded.

i) Double-blinded ­ Neither the patients nor the researcher(s) know which patients are receiving a placebo or the therapy under study.
ii) Nonblinded ­ The researcher(s) and the patients know what therapy is being given.

Nonrandomized controlled clinical trials: Studies in which participants are assigned based on criteria that may be known to the investigators, such as birth date, chart number, or day of appointment.

Case series: Studies in which participants are grouped in an order determined by the researcher. These studies are the weakest in design.

Population-based consecutive series: A specific population is studied by race, age, and other factors in the order in which they present to the researcher.

i) Consecutive cases ­ Not population-based, a series of cases.
ii) Nonconsecutive cases ­ Includes best case series or cases that have the best results.

Strength of Endpoints

A variety of endpoints may be measured and reported in studies. They are listed below in descending order of strength.

Total mortality: Overall survival from a defined point in time. This is the most easily defined and objective endpoint.

Cause specific mortality: Mortality from a specified cause for a defined population, for example, deaths from cancer vs. deaths from side effects of therapy vs. other causes. This is a more subjective endpoint than total mortality.

Carefully assessed quality of life: Although a more subjective endpoint, quality of life is an extremely important endpoint to patients. The strength of the assessment of the quality of life depends on the validity of the instruments used to assess it.

Indirect surrogates: These are measures that substitute for actual health outcomes and are subject to investigator interpretation. These surrogates include the following:

i) Disease-free survival ­ Length of time no cancer was detected after treatment.
ii) Progression-free survival ­ Length of time disease was stable or did not get worse after treatment.
iii) Tumor response rate ­ How quickly and to what degree the tumor responded to treatment.

Date Last Modified: 07/99