JBJS | From Oranges and Lemons to Glucosamine and Chondroitin Sulfate: Clinical Observations Stimulate Basic Research

The Journal of Bone & Joint Surgery, Volume 83, Issue 8

The Orthopaedic Forum | August 01, 2001

From Oranges and Lemons to Glucosamine and Chondroitin Sulfate: Clinical Observations Stimulate Basic Research

Joseph A. Buckwalter, MD; John J. Callaghan, MD; Randy N. Rosier, MD, PhD

Joseph A. Buckwalter, MD
John J. Callaghan, MD
Department of Orthopaedic Surgery, University of Iowa College of Medicine, 01008 Pappajohn Pavilion, Iowa City, IA 52242. E-mail address for J.A. Buckwalter: joseph-buckwalter@uiowa.edu

Randy N. Rosier, MD, PhD
Department of Orthopaedics, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, P.O. Box 665, Rochester, NY 14642

The authors did not receive grants or outside funding in support of their research or preparation of this manuscript. They did not receive payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

The Journal of Bone & Joint Surgery. 2001; 83:1266-1268

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Introduction

Introduction | References

Over the long history of the medical profession, physicians seeking answers to questions raised by their clinical observations have had a central role in stimulating research that has improved the prevention and treatment of disease¹. In the last fifty years, the increasing cost and complexity of scientific investigation have helped to make basic biomedical research an enterprise of its own, increasingly separated from physicians who are skilled and experienced in medical practice. This change has occurred to the extent that expert clinicians who participate in basic scientific investigations have become scarce². Some outstanding scientists currently believe that biomedical science has advanced to the point that there is little need for investing in basic research that is stimulated or guided by clinical observations or for testing the value of basic research against clinical experience. At the same time, some prominent clinicians believe that asking fundamental questions about their clinical practice accomplishes little and that they can rely on pharmaceutical, medical-implant, and technology companies to provide the information and innovations that improve patient care. Should these views go unchallenged?

A little more than 250 years ago, James Lind (1716-1794), a British naval surgeon, designed and conducted the first controlled, prospective clinical experiment^1,3,4. Like other naval surgeons, he observed that debilitating and often fatal scurvy occurred only during long voyages. Eighteenth-century physicians used a variety of methods to prevent and treat the disease, but Lind, on the basis of his clinical experience, believed that eating oranges and lemons produced the best results. On May 20, 1747, while serving as the HMS Salisbury’s senior surgeon, Lind selected twelve sailors suffering from advanced scurvy, choosing them so that "their cases were as similar as I could have them. They all in general had putrid gums, the spots and lassitude, with weakness of their knees."⁴ He divided the twelve men into six groups of two and made sure that all twelve stayed in the same quarters and ate the same food. The first five groups received five different accepted treatments: a quart of cider per day; twenty-five drops of oil of vitriol three times per day; two spoonfuls of vinegar three times per day; a teaspoon of an electuary (a medicinal paste) containing garlic, mustard seed, radish root, and other ingredients once a day; and a half-pint of seawater per day. The experimental group of two sailors received one lemon and two oranges per day. Six days later, the ten sailors in the first five groups had grown weaker, but the two who had been given oranges and lemons were fit for duty and caring for the others.

Lind lacked a scientific rationale to explain these results, and, given the unsophisticated design of his experiment, it is surprising that the outcome was so clear. He assumed that citrus fruits cured patients with scurvy by relieving blockage of "insensible perspiration," an assumption based on the humoral theory of disease that was first proposed by the Hippocratic physicians^1,3. Because they lacked an understanding of metabolism and dietary deficiencies, Lind and the best scientists of his day could not improve on the humoral theory as an explanation for the effects of oranges and lemons. Lind’s experimental design would not meet current standards for clinical trials, but his results stimulated others to look for a better explanation of how lemons and oranges cure scurvy. In the late 1920s and early 1930s, Albert Szent-Györgyi (1893-1986) ended this search when he isolated and synthesized vitamin C and he and others showed how it prevented scurvy.

As a result of Lind’s work and that of others who demonstrated that dietary deficiencies cause a variety of diseases, the concept of preventing and treating disease with use of dietary supplements has become generally accepted. A particularly interesting manifestation of this concept is the belief that eating cartilage or its component molecules rebuilds damaged joints and prevents arthritis. Most knowledgeable scientists initially rejected this idea for good reasons; however, during the last twenty-five years, reports of the ability of oral glucosamine and chondroitin sulfate to relieve pain in patients with osteoarthritis have attracted increasing attention from the public. These reports have also attracted criticism from physicians and scientists⁵. The criticism is understandable. Many of the studies have been funded by companies with a financial interest in promoting glucosamine and chondroitin sulfate, and most have lacked scientific rigor⁵. More importantly, although proponents of the use of oral glucosamine and chondroitin sulfate for the treatment of osteoarthritis have suggested that ingestion of these substances by humans stimulates proteoglycan synthesis in articular cartilage and hyaluronan synthesis in synovial tissue and that it suppresses proteoglycan degradation in articular cartilage and synovial inflammation, these contentions have not been proven, and even the most enthusiastic advocates of these substances have not presented scientifically documented explanations of their purported effects in humans. For these reasons, many have speculated that the clinical benefits of glucosamine and chondroitin sulfate will eventually be better explained by the study of psychology than by the study of physiology.

Two recent reports have made it harder to argue that the placebo effect combined with skilled marketing explains the reported effects of glucosamine and chondroitin sulfate in patients with osteoarthritis. McAlindon et al. assessed the scientific quality of controlled clinical studies on the effects of chondroitin sulfate and glucosamine in patients with osteoarthritis and performed a meta-analysis of fifteen studies that met specific criteria⁶. They concluded that glucosamine and chondroitin sulfate improve function and relieve pain more effectively than placebos do but noted that the magnitude of the effects is uncertain. They also noted that none of the investigators reported having received funding from governmental agencies or nonprofit foundations, that most of the studies were supported at least in part by manufacturers of chondroitin sulfate and glucosamine, that only one study involved the use of intention-to-treat analysis, and that none of the investigators reported adequate allocation concealment. More recently, Reginster et al. reported the results of a randomized, double-blind, placebo-controlled trial that was performed to assess the effects of oral glucosamine on the progression of knee osteoarthritis in 212 patients during a three-year period⁷. Symptoms and function, measured with use of the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index, worsened in the patients treated with the placebo and improved in those treated with glucosamine; these findings are similar to those reported by other authors^6,8-10. Their more remarkable observation was that, while the patients treated with the placebo had progressive loss of knee articular cartilage, those treated with glucosamine had maintenance of the articular cartilage thickness. Although none of the authors of the published studies claimed that glucosamine and chondroitin sulfate could cure osteoarthritis, these studies, taken together, suggest that these substances have beneficial effects in patients with osteoarthritis.

Nevertheless, these studies leave important questions unanswered. Does ingestion of glucosamine and chondroitin sulfate affect synovial joints and relieve pain by stimulating proteoglycan synthesis, by suppressing proteoglycan degradation, by suppressing inflammation, or by mechanisms that have not yet been considered^5-12? Do these substances have any long-term adverse effect? What are the optimal doses? How do the clinical effects of oral glucosamine and chondroitin sulfate compare with other nonoperative treatments of osteoarthritis, including oral analgesics and anti-inflammatory drugs and intra-articular injections of hyaluronan? Should patients with underlying medical disorders, including diabetes, liver disease, and excess body mass, avoid use of these substances? Will future clinical studies show that the effects of oral glucosamine and chondroitin sulfate are inconsistent and of minimal clinical value for most patients? Or will they prove that these substances can decrease pain, improve function, and slow progression of joint degeneration for tens of millions of people? If so, will this proof come before basic scientific investigations provide an explanation of these effects? Answering these questions will require integration of new knowledge from basic scientific studies with clinical experience and research. That these questions have been raised by clinical observations and research shows that physicians who ask thoughtful questions based on their clinical experience still have a central role in stimulating and guiding basic biomedical research that will improve the prevention and treatment of disease.

References

Introduction | References

Buckwalter JA. Advancing the science and art of orthopaedics. Lessons from history. J Bone Joint Surg Am,2000;82: 1782-803. 821782 2000 [PubMed]

Hurwitz SR,Buckwalter JA. The orthopaedic surgeon scientist: an endangered species?. J Orthop Res,1999;17: 155-6. 17155 1999 [PubMed]

Carpenter KJ. The history of scurvy and vitamin C. New York: Cambridge University Press; 1986. p 43-74.

Lind J. A treatise of the scurvy. 1753, Edinburgh: Sands, Murray and Cochran; www.people.virginia.edu/~rjh9u/scurvy.html; www.mc.vanderbilt.edu/biolib/hc/journeys/book9.html.

Callaghan JJ, Buckwalter JA,Schenck RC Jr. Argument against use of food additives for osteoarthritis of the hip. Clin Orthop,2000; 381: 88-90. 38188 2000 [PubMed]

McAlindon TE, LaValley MP, Gulin JP,Felson DT. Glucosamine and chondroitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis. JAMA,2000; 283: 1469-75. 2831469 2000 [PubMed]

Reginster JY, Deroisy R, Rovati LC, Lee RL, Lejeune E, Bruyere O, Giacovelli G, Henrotin Y, Dacre JE,Gossett C. Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomized, placebo-controlled clinical trial. Lancet,2001;357: 251-6. 357251 2001 [PubMed]

Buckwalter JA, Stanish WD, Rosier RN, Schenck RC Jr, Dennis DA,Coutts RD. The increasing need for nonoperative treatment of patients with osteoarthritis. Clin Orthop, 2001;385: 36-45. 38536 2001 [PubMed]

Das AK,Hammad TA. Efficacy of a combination of FCNG49 glucosamine hydrochloride, TRH 122 low molecular weight sodium chondroitin sulfate and manganese ascorbate in the management of knee osteoarthritis. Osteoarthitis Cartilage,2000;8: 343-50. 8343 2000

Leffler CT, Philippi AF, Leffler SG, Mosure JC,Kim PD. Glucosamine, chondroitin, and manganese ascorbate for degenerative joint disease of the knee or low back: a randomized, double-blind, placebo-controlled pilot study. Mil Med,1999;164: 85-91. 16485 1999 [PubMed]

Fenton JI, Chlebek-Brown KA, Peters TL, Caron JP,Orth MW. Glucosamine HCL reduces equine articular cartilage degradation in explant culture. Osteoarthritis Cartilage,2000;8: 258-65. 8258 2000 [PubMed]

Patwari P, Kurz B, Sandy JD,Grodzinsky AJ. Mannosamine inhibits aggrecanase-mediated changes in the physical properties and biochemical composition of articular cartilage. Arch Biochem Biophys,2000;374: 79-85. 37479 2000 [PubMed]

Topics

Buckwalter JA. Advancing the science and art of orthopaedics. Lessons from history. J Bone Joint Surg Am,2000;82: 1782-803. 821782 2000 [PubMed]

Hurwitz SR,Buckwalter JA. The orthopaedic surgeon scientist: an endangered species?. J Orthop Res,1999;17: 155-6. 17155 1999 [PubMed]

Carpenter KJ. The history of scurvy and vitamin C. New York: Cambridge University Press; 1986. p 43-74.

Lind J. A treatise of the scurvy. 1753, Edinburgh: Sands, Murray and Cochran; www.people.virginia.edu/~rjh9u/scurvy.html; www.mc.vanderbilt.edu/biolib/hc/journeys/book9.html.

Callaghan JJ, Buckwalter JA,Schenck RC Jr. Argument against use of food additives for osteoarthritis of the hip. Clin Orthop,2000; 381: 88-90. 38188 2000 [PubMed]

Accreditation Statement

These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.

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Joseph A. Buckwalter, John J. Callaghan, Randy N. Rosier; From Oranges and Lemons to Glucosamine and Chondroitin Sulfate: Clinical Observations Stimulate Basic Research. The Journal of Bone & Joint Surgery. 2001 Aug;83(8):1266-1268.

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