eMedicine Specialties > Rheumatology > Metabolic and Bone Disease

Hypertrophic Osteoarthropathy

Author: Richa Dhawan, MD, Faculty, Center of Excellence for Arthritis and Rheumatology, Louisiana State University Health Science Center at Shreveport
Coauthor(s): Mohammed Mubashir Ahmed, MD, Associate Professor, Department of Medicine, Division of Rheumatology, University of Toledo College of Medicine; Henri-Andre Menard, MD, Professor of Medicine, Director of Rheumatology, Department of Medicine, Division of Rheumatology, McGill University Health Center and McGill University; Director, The McGill Arthritis Center; Senior Physician, Shriner's Hospital for Crippled Children, Montreal
Contributor Information and Disclosures

Updated: Nov 7, 2008

Introduction

Background

Hypertrophic osteoarthropathy (HOA) is a syndrome characterized by excessive proliferation of skin and bone at the distal parts of extremities and by digital clubbing and periostosis of the tubular bones.1 Hippocrates first described digital clubbing 2500 years ago, hence the use of the term Hippocratic fingers.2 In approximately 1890, both Bamberger3 and Marie4 reported the association of clubbing and arthritis with chronic pulmonary and cardiac diseases. Primary hypertrophic osteoarthropathy occurs without any underlying cause, is usually familial, and usually has a chronic course. Secondary hypertrophic osteoarthropathy is associated with an underlying pulmonary, cardiac, hepatic, or intestinal disease and often has a more rapid course.

Interestingly, some patients with primary hypertrophic osteoarthropathy eventually develop diseases (eg, patent ductus arteriosus, Crohn disease, myelofibrosis) that are otherwise known to be underlying causes of secondary hypertrophic osteoarthropathy, many years after the onset of the osteoarthropathy.5

Clubbed digits

The clubbed portions of the fingers and toes consist of excessive collagen fiber deposition and accumulation of interstitial edema. Perivascular infiltrates of lymphocytes and vascular hyperplasia are responsible for thickening of the vessel walls. Electron microscopy reveals Weibel-Palade bodies and prominent Golgi complexes, confirming structural vessel wall damage.6 Vast numbers of arteriovenous anastomoses may also be seen in the nail bed.7

Periosteum

Subperiosteal, cancellous, and new bone formation exists along the distal diaphysis of tubular bones, progressing proximally over time. Initially, excessive connective tissue and subperiosteal edema elevate the periosteum; then, new osteoid matrix is deposited beneath the periosteum.8 As this mineralizes, a new layer of bone is formed, and, eventually, the distal long bones may become sheathed with a cuff of new bone.9 These pathologic changes occur at the distal ends of the metacarpus, metatarsus, tibia, fibula, radius, ulna, femur, humerus, and clavicle. The tibia is almost invariably involved.8,10

Bone

Two types of bone changes can be found in the distal phalanges, hypertrophic and osteolytic.11 Hypertrophy or bony overgrowth predominates in patients with lung cancer and hypertrophic pulmonary osteoarthropathy (HPOA), whereas acroosteolysis predominates in patients with cyanotic congenital heart disease and hypertrophic osteoarthropathy.12 The type of bone remodeling process depends on the age when clubbing develops.11 If clubbing appears in childhood, osteolysis is more prominent; however, if it develops after puberty, hypertrophic changes take place. Pineda et al hypothesize that a putative circulating growth factor destroys immature bone.11

Synovium

Synovial involvement may occur with subperiosteal changes.8 Thickening of the subsynovial blood vessels and mild lining-layer hyperplasia may occur.13,8 The edematous synovium becomes mildly infiltrated with lymphocytes, plasma cells, and occasional polymorphonuclear leukocytes, but the results from immunohistologic studies are negative. Electron-dense subendothelial deposits are present in vessel walls.14,15,16 In a study of a patient with primary hypertrophic osteoarthropathy and chronic arthritis, Lauter et al found multilayered basement laminae around small subsynovial blood vessels consistent with the late stages of vascular injury.16 Synovial fluid is usually noninflammatory with low leukocyte counts and few neutrophils.14,16

Pathophysiology

The etiology of hypertrophic osteoarthropathy is unknown. The pathological hallmark is neoangiogenesis and edema and osteoblast proliferation in distal tubular bones that leads to subperiosteal new-bone formation. One explanation involves tumor production and the release of a factor that promotes features of hypertrophic osteoarthropathy into the circulation. One candidate is vascular endothelial growth factor (VEGF). Two case reports have independently noted elevated circulating concentrations of VEGF and evidence of tumor production of VEGF associated with lung cancer.

Following tumor resection, the concentrations of VEGF markedly decline, which also correlates with clinical improvement. VEGF is a platelet-derived factor; its action is induced by hypoxia. It is a potent angiogenic and permeability-enhancing factor, as well as a bone-forming agent. Diverse types of cancer growths produce VEGF as a mechanism of tumor dissemination. Abnormal expression of VEGF is known to occur in diseases associated with hypertrophic osteoarthropathy, such as mesothelioma, Graves disease, and inflammatory bowel disease. These diseases are characterized by prominent endothelial cell involvement, leading to overproduction of VEGF and thus acropachy.

Interestingly, the anatomic distribution of vagal nerve fibers correlates to the area of clubbing. Vagotomy and sympatholytic drugs have been reported to reverse or to improve hypertrophic osteoarthropathy, suggesting a role for reflex vagal stimulation.17 Bazaar and Yun proposed that sympathetic override of the normal protective function of vagal innervation is the basis of hypertrophic osteoarthropathy.18 Sympathetic activity has been noted to induce cytokine changes consistent with inflammation.

Among these, epinephrine has been shown to induce production of interleukin-11 (IL-11) in human osteoblasts. Recombinant IL-11 has been shown to cause reversible symmetric periostitis in the extremities. In diseased states, autonomic stimulation may occur as a result of chemoreceptor activation in response to acidosis, hypoxia, or hypercapnia. Examples include sleep apnea, congestive heart failure, renal failure, and tumor-induced hypoxia. Removal of the associated lung neoplasm or correction of a cyanotic heart malformation has similar effects, suggesting that alteration of lung function plays an important role.19

Paraneoplastic growth factors;19 neurologic, hormonal,20 and immune mechanisms;14 and vascular thrombi caused by platelets and antiphospholipid antibodies21 have all been proposed as possible etiologies.8 A popular current theory involves the interaction between activated platelets and the endothelium.19,21,22 Hypertrophic osteoarthropathy can be associated with pregnancy and aging secondary to platelet abnormalities, hormonal disturbances, and cytokine dysfunction.

Most illnesses associated with hypertrophic osteoarthropathy involve alterations of lung function in which intrapulmonary shunting of blood may be prominent. For example, in patients with patent ductus arteriosus complicated by pulmonary hypertension and a right-to-left shunt, hypertrophic osteoarthropathy is evident only in the limbs that receive unsaturated blood. Hypertrophic osteoarthropathy has been induced in dogs by surgically producing right-to-left shunts.23,24 Hence, hypertrophic osteoarthropathy has been suggested to be due to factors that are normally removed or inactivated in the lung.22

Normally, platelets are fragmented in the pulmonary microvasculature before they reach the general circulation. Patients with cyanotic heart diseases have large circulating platelets with abnormal and, at times, bizarre morphology. Those macrothrombocytes are responsible for the aberrant platelet volume distribution curves.25,21

Having escaped fragmentation in the lung microvasculature and reached the systemic circulation, their impaction at distal sites may lead to local endothelial cell activation through the release of growth factors (ie, platelet-derived growth factor, transforming growth factor, VEGF) stored in the platelet alpha-granules. This initiates finger clubbing by inducing connective-tissue matrix synthesis.21,22 VEGF receptors are expressed in subperiosteal bone-forming cells. In keeping with this hypothesis, Matucci-Cerinic et al have shown elevated von Willebrand factor antigen (vWF:Ag) levels in persons with primary hypertrophic osteoarthropathy and in persons with hypertrophic osteoarthropathy secondary to cyanotic heart disease.21

vWF:Ag is a surrogate marker of endothelial activation and damage because high plasma levels of vWF:Ag are also found in the vasculitides, myocardial infarction, diabetic microangiopathy, and scleroderma.21 Thus, a common pathogenetic pathway for hypertrophic osteoarthropathy possibly involves localized activation of endothelial cells by an abnormal platelet population. Macrothrombocyte and endothelial cell activation can also be present in cases of hypertrophic osteoarthropathy associated with other disease entities such as liver cirrhosis, in which a prominent intrapulmonary shunting of blood occurs.22

Frequency

United States

No systematic prevalence studies have been performed for secondary hypertrophic osteoarthropathy, but hypertrophic osteoarthropathy is associated with many illnesses. Primary hypertrophic osteoarthropathy is a rare condition. A hereditary sex-linked (male) predisposition exists, but the exact type of inheritance is unknown.26

International

Hypertrophic osteoarthropathy likely has the same incidence and prevalence around the world.

Mortality/Morbidity

The mortality and morbidity of hypertrophic osteoarthropathy vary with the associated illness.

Race

Hypertrophic osteoarthropathy affects persons of all races.

Sex

Primary hypertrophic osteoarthropathy has a male-to-female ratio of 9:1.26 Secondary hypertrophic osteoarthropathy has the same sex ratio as the associated illnesses.

Age

Primary hypertrophic osteoarthropathy has a bimodal peak of onset that occurs in patients younger than 1 year and in patients who are around puberty, ie, approximately age 15 years.26

Clinical

History

The clinical presentation of hypertrophic osteoarthropathy (HOA) varies according to the rapidity of onset and the evolution of the underlying disease.

  • In primary hypertrophic osteoarthropathy or in the slowly progressing chronic secondary forms, hypertrophic osteoarthropathy is insidious and essentially asymptomatic.
    • Such patients rarely voluntarily report symptoms because the clubbing and skin manifestations (see Physical) have progressively become part of the patient's body image over many years, and the patient usually considers them more or less normal.
    • Because patients initially seek medical help for minor pains in the shoulders and hands or recurrent swelling of a mechanical nature in the knees (hydrarthrosis) or ankles (osteoarthritis), they are sometimes surprised by the physician’s interest in their fingers.
  • When hypertrophic osteoarthropathy occurs in the presence of neoplastic or inflammatory pulmonary conditions, the patient reports pain and swelling in joints and long bones.
    • These rheumatic symptoms have a mechanical diurnal pattern, but they are definitely signs of inflammation, even if the synovial fluid is noninflammatory.
    • This picture can precede the appearance of constitutional symptoms (eg, fatigue, fever, weight loss) or respiratory symptoms (eg, cough, hemoptysis, chest pain, dyspnea) by several months.

Physical

The diagnostic criteria for hypertrophic osteoarthropathy include clubbing and periostosis of the tubular bones.1 Three incomplete forms of hypertrophic osteoarthropathy are described. These include (1) clubbing alone, (2) periostosis without clubbing in the setting of an illness known to be associated with hypertrophic osteoarthropathy, and (3) pachydermia associated with minor manifestations (eg, synovial effusion, seborrhea, folliculitis, hyperhidrosis, hypertrophic gastropathy, acroosteolysis).

  • Clubbing
    • Clubbing usually progresses through 4 phases.8
      1. Fluctuation and softening of the nail bed, with a rocking sensation upon palpation due to increased edema and soft tissue
      2. Loss of the normal 15° angle (Lovibond angle27 ) between the nail and cuticle
      3. Accentuation of the convexity of the nails and clubbed appearance of the fingertips, with warmth and sweating
      4. Shiny or glossy change in the nail and adjacent skin, with disappearance of the normal creases and appearance of longitudinal striation of the nail
    • Clubbing can be classified into 3 topographical groups.28,29
      • Symmetrical: All the fingers and toes are involved (see Image 1).
      • Unilateral: The fingers or toes of 1 hand or foot are involved.
      • Unidigital: Only 1 finger or toe is involved.
    • Clubbing can also be classified into 3 color groups (personal observations).
      • Normal skin color: This is an insidious onset of mildly symptomatic clubbing, evolving over years, that is usually associated with chronic low-grade inflammatory and infectious diseases or primary hypertrophic osteoarthropathy.
      • Red skin color: This is of recent onset with rapid progression and fairly severe bone and joint symptoms that are usually associated with malignant diseases or chronic severe infections, such as miliary tuberculosis.
      • Blue skin color: This is chronic clubbing associated with cyanotic cardiopulmonary conditions.
    • Four clinical signs can be used to describe clubbing.
      • The profile sign: On lateral views, a loss of the normal 15° angle between the nail bed and the cuticle is visible. The hyponychial angle can also be measured.
      • The nail sign (rocking): The base of the nail bed can be palpated for sponginess.
      • The apposition sign: The distal interphalangeal (DIP) joints and the nail bed of the right and left index finger are placed in apposition. Normally, an oblong diamond-shaped aperture is visible between the 2 juxtaposed nail beds. With clubbing, this space is obliterated.
      • The digital index: The circumference of each finger at the nail bed and DIP joint are measured. The mean ratio of the nail bed circumference to the DIP joint circumference should be less than 1. Alternatively, the ratio of each finger's nail bed and DIP joint can be added. If the sum is greater than 10, clubbing is present; if the sum is greater than 11, advanced clubbing is present.30,22
  • Bone and joint symptoms
    • Periostosis may be asymptomatic or may cause a severe burning and deep-seated pain in the distal extremities. This pain is aggravated with dependency and relieved with elevation.8 In some cases, dysesthesia of the fingers is present, with accompanying heat, sweating, clumsiness, and stiffness of the hands.8 Adults with primary hypertrophic osteoarthropathy are asymptomatic.26
    • Joint symptoms range from mild to severe arthralgias that involve the metacarpal joints, wrists, elbows, knees, and ankles.8 The range of motion of affected joints may be slightly decreased. When effusions are present, they usually involve the large joints, eg, knees, ankles, and wrists (see Image 2).31 Arthrocentesis reveals a very thick noninflammatory fluid, with a cell count of less than 500 cells/µL.14 The effusions are more likely a sympathetic reaction to nearby periostosis.
  • Cutaneous symptoms
    • They are more prominent in, but not exclusive to, primary hypertrophic osteoarthropathy.
    • Cutaneous gland dysfunction occurs, resulting in acne, hyperhydrosis, or seborrhea.26
    • Hypertrophy of soft tissues occurs, resulting in coarse facial features, cylindrical calves (elephant feet), ptosis of the lids, and cutis verticis gyrata or prominent frontal cerebroid wrinkles.

Causes

Clubbing and hypertrophic osteoarthropathy likely represent different stages of the same disease process. Hypertrophic osteoarthropathy can be classified as either primary or secondary.

  • Primary hypertrophic osteoarthropathy
    • Pachydermoperiostosis,26 also called Touraine-Solente-Golé syndrome, involves digital clubbing, periostosis (revealed by radiography), and coarse facial features. It has a hereditary predisposition (although less than a third of patients have a relative who is affected) with a male predominance (male-to-female ratio of 9:1). Disease onset has a bimodal peak, with one in the first year of life and one at puberty. The activity of the illness is limited to the growth period, with adults becoming asymptomatic. Long-standing clubbing and a positive family history suggest primary hypertrophic osteoarthropathy, but excluding any associated illness is still of utmost importance. Clinical features involve the skeleton and the skin. Associated abnormalities include cranial suture defects, gynecomastia, female hair distribution, striae, bone marrow failure, and hypertrophic gastropathy.32,8
    • Most patients with congenital and familial clubbing are asymptomatic and have relatives with the same disorder. This syndrome may reflect incomplete expression of pachydermoperiostosis.33 A case report in Germany described a family with a variant form of primary hypertrophic osteoarthropathy restricted to the lower extremities without digital clubbing or cutaneous changes. Three family members had pain, swelling, and hyperhidrosis in both feet. Radiographs showed destruction and osteoproliferative changes of the metatarsal bones with periosteal hyperostosis close to the talus. All known infectious, neurologic, metabolic, and malignant diseases that affect the bone and joints were excluded.
    • Goldbloom syndrome is a rare, idiopathic, diffuse, painful, hypertrophic periostosis occurring transiently in children. Clubbing and skin involvement are usually absent. The clinical picture consists of a high fever with weight loss and severe bone pain in the mandibles and long bones. It is accompanied by a major acute-phase reaction and polyclonal hypergammaglobulinemia.34 The syndrome spontaneously resolves in 4-8 weeks, and radiographic and bone scan abnormalities return to normal within the next few years. Long-term follow-up shows normal growth thereafter, without permanent sequelae.
  • Secondary hypertrophic osteoarthropathy
    • This is also called Pierre Marie-Bamberger syndrome. In adulthood, 90% of generalized hypertrophic osteoarthropathy is associated with an intrathoracic infectious or neoplastic condition (see Image 4).10 Features include clubbing, skin hypertrophy, thickening of tubular bones, periostosis, and effusions of large joints. The disease progresses more rapidly than primary hypertrophic osteoarthropathy. The underlying disease usually appears first. However, hypertrophic osteoarthropathy occasionally precedes symptoms of the underlying disorder by more than a year.35,8 Among pulmonary neoplasms, hypertrophic osteoarthropathy is most commonly found with non–small cell lung carcinoma.36
    • In childhood, generalized hypertrophic osteoarthropathy is associated with pulmonary infections,37 cystic fibrosis,31 congenital cyanotic heart disease,38,39 and osteosarcoma with lung metastasis.8 Case reports have described an association with biliary atresia.40,41 Cyanotic heart disease is the prototype of hypertrophic osteoarthropathy because almost all patients have clubbing and more than a third of patients have the full-blown syndrome.39
    • Localized clubbing, similar to unilateral digital clubbing, has been described in association with local vascular lesions such as aneurysms; arteriovenous fistulas; and venous abnormalities of the arm, axilla, and thoracic outlet.28,29 Other causes of localized hypertrophic osteoarthropathy include hemiplegia, patent ductus arteriosus with pulmonary hypertension, infected arterial grafts, endothelial infections, and extensive endothelial injury of a limb.29 In patients with patent ductus arteriosus, pulmonary hypertension causes right-to-left shunting of blood, which may cause hypertrophic osteoarthropathy of the toes and fingers on the left side.29,22 Unilateral clubbing always suggests a condition affecting the vessels or nerves of the arm, leg, or thoracic outlet.29
    • Thomas first described thyroid acropachy in 1933.42 It is a rare condition associated with prior or active Graves disease. Thyroid acropachy is characterized by the triad of (1) clubbing; (2) noninflammatory swelling of the soft tissues of the hands and feet; and (3) asymptomatic, asymmetrical, exuberant, periosteal proliferation preferentially affecting the diaphysis of the metacarpal and metatarsal bones.43 It usually coexists with exophthalmos and pretibial myxoedema, and patients can be hypothyroid, euthyroid, or hyperthyroid.31
  • Pulmonary
    • Chronic respiratory diseases include cystic fibrosis, pulmonary fibrosis, chronic obstructive lung disease, and chronic infections.
    • Lung cancer (primary or metastatic) can include arteriovenous malformations and mesothelioma.
  • Cardiac - Congenital cyanotic heart disease and infective endocarditis
  • Hepatic - Cirrhosis, hepatocellular carcinoma, and primary liver rhabdomyosarcoma
  • Intestinal - Crohn disease, ulcerative colitis, chronic infections, laxative abuse, polyposis, and malignant tumors
  • Mediastinal - Esophageal carcinoma, thymoma, and achalasia
  • Miscellaneous - Graves disease, thalassemia, diverse malignancies, POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) syndrome, metastatic phyllodes tumor of breast, epithelioid hemangioendothelioma, nasopharyngeal carcinoma with lung metastasis, thymic carcinoma, renal cell carcinoma with lung metastasis, Osler-Weber-Rendu syndrome, and deep infections such as vascular graft infection and perianal abscess (Primary hypertrophic osteoarthropathy and POEMS syndrome overlap; both conditions are associated with digital clubbing, pachyderma, hyperhidrosis, gynecomastia, and bone proliferation.)

More on Hypertrophic Osteoarthropathy

Overview: Hypertrophic Osteoarthropathy
Differential Diagnoses & Workup: Hypertrophic Osteoarthropathy
Treatment & Medication: Hypertrophic Osteoarthropathy
Follow-up: Hypertrophic Osteoarthropathy
Multimedia: Hypertrophic Osteoarthropathy
References
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Further Reading

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Keywords

hypertrophic osteoarthropathy, primary hypertrophic osteoarthropathy, primary HOA, HOA, secondary HOA clubbing, Hippocratic fingers, clubbed digits, pachydermoperiostosis, acroosteolysis, Touraine-Solente-Golé syndrome, Goldbloom's syndrome, Goldbloom syndrome, Pierre Marie-Bamberger's disease, Pierre Marie-Bamberger disease, osteoarthropathie hypertrophiante pneumique, hypertrophic pulmonary osteoarthropathy, HPOA, acropachy, hyperhidrosis, digital clubbing, periostosis, intrathoracic malignancy, intrathoracic infection, cyanotic cardiac disease, cyanotic heart disease, congenital clubbing, familial clubbing, osteosarcoma, thyroid acropachy, Crohn disease, Crohn's disease, polyposis, thymoma, achalasia, Graves disease, Graves' disease, thalassemia, POEMS syndrome

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Contributor Information and Disclosures

Author

Richa Dhawan, MD, Faculty, Center of Excellence for Arthritis and Rheumatology, Louisiana State University Health Science Center at Shreveport
Richa Dhawan, MD is a member of the following medical societies: American Association of Physicians of Indian Origin, American College of Physicians-American Society of Internal Medicine, and American College of Rheumatology
Disclosure: Nothing to disclose.

Coauthor(s)

Mohammed Mubashir Ahmed, MD, Associate Professor, Department of Medicine, Division of Rheumatology, University of Toledo College of Medicine
Mohammed Mubashir Ahmed, MD is a member of the following medical societies: American College of Physicians, American College of Rheumatology, and American Federation for Medical Research
Disclosure: Nothing to disclose.

Henri-Andre Menard, MD, Professor of Medicine, Director of Rheumatology, Department of Medicine, Division of Rheumatology, McGill University Health Center and McGill University; Director, The McGill Arthritis Center; Senior Physician, Shriner's Hospital for Crippled Children, Montreal
Henri-Andre Menard, MD is a member of the following medical societies: American College of Rheumatology, Canadian Medical Association, Canadian Rheumatology Association, and Quebec Medical Association
Disclosure: Nothing to disclose.

Medical Editor

Bryan L Martin, DO, Chief, Allergy Immunology Department, Walter Reed Army Medical Center; Associate Professor of Medicine and Pediatrics, Uniformed Services University of the Health Sciences; United States Army Consultant in Allergy Immunology and Immunizations
Bryan L Martin, DO is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology, American College of Osteopathic Internists, American College of Physicians, American Medical Association, and American Osteopathic Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Lawrence H Brent, MD, Associate Professor of Medicine, Thomas Jefferson University; Chair, Program Director, Department of Medicine, Division of Rheumatology, Albert Einstein Medical Center
Lawrence H Brent, MD is a member of the following medical societies: American Association of Immunologists, American College of Physicians, and American College of Rheumatology
Disclosure: Genentech Honoraria Speaking and teaching; Genentech Grant/research funds Other; Amgen Honoraria Speaking and teaching; Wyeth Honoraria Speaking and teaching; Abbott Immunology Honoraria Speaking and teaching

CME Editor

Alex J Mechaber, MD, FACP, Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine
Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine
Disclosure: Nothing to disclose.

Chief Editor

Herbert S Diamond, MD, Professor of Medicine, Temple University School of Medicine; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital
Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, American Medical Association, and Phi Beta Kappa
Disclosure: medifocus Honoraria Review panel membership; health dialogs Honoraria Consulting; Merck, Amgen, Biogen, Zimmer, Wyeth, Johnson&Johnson, Stryker, Medtronic, Zimmer.Abbott,  Ownership interest Other; West Penn Allegheny Health System Consulting fee Consulting; Alpharma Honoraria Consulting; Proctor&Gamble Grant/research funds Independent contractor

 
 
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