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C OPYRIGHT 2013

BY

T HE J OURNAL

OF

B ONE

AND J OINT

S URGERY, I NCORPORATED

Current Concepts Review

Primary Osteoarthritis of the Hip: A Genetic

Disease Caused by European Genetic Variants
Franklin T. Hoaglund, MD

Primary osteoarthritis of the hip is a separate phenotype that occurs at a rate of 3% to 6% in the populations of the
world with European ancestry.

In all non-European populations, there is a consistent rarity of primary osteoarthritis that suggests a different
etiology for these few patients.

Family, sibling, and twin studies prove primary osteoarthritis to be a genetic disease with a 50% heritability caused
by European genetic variants.

The genetic basis is reinforced by the lower rate of primary osteoarthritis in American minorities consistent with
their degree of European gene admixture.

Whether the mechanism of degeneration of primary osteoarthritis may be secondary through a morphologic
deformity, such as femoroacetabular impingement, remains unknown.

The virtual absence of the disease in non-Europeans indicates that the European gene component is necessary for
the expression of this separate phenotype of osteoarthritis.

The most common form of hip osteoarthritis in Europeans and

in Americans of European descent has been known and reported
as primary osteoarthritis. The concept of primary osteoarthritis
has been challenged as a secondary disease, secondary osteoarthritis, because of the presence of preexisting anatomical findings, such as developmental dysplasia of the hip and slipped
capital femoral epiphysis1,2. The more recent identification of
femoroacetabular impingement, which is being operatively
corrected in young people, is now also proposed as an anatomical
predisposition to osteoarthritis in young and middle-aged adults3.
While the primary or secondary osteoarthritis argument is not
moot, it is less important with the knowledge that the etiology of
osteoarthritis of the hip in the older European and European
American population is well established as a disease with a genetic etiology. In this review of the worldwide epidemiology of
osteoarthritis of the hip, supportive genetic and gene admixture
data are cited to reinforce the concept that the genetic basis for

primary osteoarthritis lies in gene variants found in individuals

with European ancestry.
Definition of Primary Osteoarthritis
Primary osteoarthritis of the hip is a disease that occurs in
patients after the age of fifty-five years and is characterized by
degeneration of articular cartilage, which leads to loss of joint
space. Concomitant changes occur in all tissues of the hip joint,
including fibrocartilage, synovium, capsule, and bone4,5. Primary osteoarthritis is a diagnosis of exclusion after ruling out
other conditions such as osteonecrosis, trauma, sepsis, Paget
disease, rheumatoid arthritis, and childhood hip diseases such
as developmental dysplasia of the hip and slipped capital femoral
epiphysis. Osteoarthritic changes may start in the early years
because of childhood and young adult hip abnormalities such
as developmental dysplasia of the hip, Legg-Calve -Perthes disease, slipped capital femoral epiphysis, or femoroacetabular

Disclosure: The author did not receive payments or services, either directly or indirectly (i.e., via his institution), from a third party in support of any aspect
of this work. He, or his institution, has had a financial relationship, in the thirty-six months prior to submission of this work, with an entity in the biomedical
arena that could be perceived to influence or have the potential to influence what is written in this work. The author has not had any other relationships, or
engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete
Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.

J Bone Joint Surg Am. 2013;95:463-8

http://dx.doi.org/10.2106/JBJS.L.00077

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impingement. Such osteoarthritic changes occurring in the

younger age group are characterized by their cause. The overwhelming majority of osteoarthritic hips is seen in the older
age group and accounts for most total hip replacements done
in Europe, the United States, and other concentrated areas
around the world with a population of European ancestry.
Osteoarthritis of the hip occurs in approximately 3% to 6%
of this population and is virtually absent in the rest of the
world6.
The original challenge to the concept of primary osteoarthritis came from the British radiologist, Ronald Murray, in 19651.
Murray described up to 90% of osteoarthritic hips in elderly
patients as being caused by prior childhood hip diseases, such
as developmental dysplasia of the hip or slipped capital femoral epiphysis. Over the years, many investigators, including
Solomon7 and Harris2 (who described the radiographic sign of
pistol grip deformity as a residual of slipped capital femoral
epiphysis), have concurred. Dissenting studies have found few
dysplastic hips8,9 or have related the radiographic findings to
remodeling10. The discussion continues today with attempts
to establish that femoroacetabular impingement causes what I
have noted is primary osteoarthritis.
Worldwide Epidemiology
The possibility that primary osteoarthritis of the hip is a genetic
disease dates to the broad search for the cause of osteoarthritis
sixty years ago, which was stimulated by the work of Kellgren
and Moore11. This led to systematic radiographic surveys of
specific joints in >12,000 people in Europe, America, and
Africa by multiple investigators12. Surveys found primary osteoarthritis of the hip in only two per 500 patients (0.4%) in
Hong Kong13, one per 199 patients (0.5%) in South Africa14,
and fifty-one per 51,777 patients (0.1%) in India15. In comparison, the difference was tenfold greater in the United Kingdom,
with primary osteoarthritis found in fifty-eight (7.0%) of 829
patients and twenty-nine (4.0%) of 718 European patients12,
which indicated racial differences as a possible cause. Additional data from Jamaican16, black African, and American Indian
populations12 have shown a 2% rate of moderate and severe
primary osteoarthritis (six per 304 blacks and twelve per 509
American Indians), which is half the rate of Europeans. The
Chinese in Beijing17 and Koreans18 have been reported to have
1% rates of primary osteoarthritis.
With the advent of total hip arthroplasty, the reporting of
patients having total hip replacements and the reason for the
procedure has confirmed the rarity of primary osteoarthritis in
non-European-based populations, including those of India19,
Pakistan20, Saudi Arabia21,22, Kuwait23, Iran24, Malawi25, Nigeria26,
Togo27, Singapore28, and Japan29. All non-European data, whether
direct surveys of disease, clinic data of symptomatic patients, or
comparative international rates of total hip replacement, have
consistently shown the infrequency of primary osteoarthritis in
these populations. This is in contrast to the knee, for which
there are many reports of osteoarthritis from these countries,
showing a rate of primary osteoarthritis that is many times that
of hip osteoarthritis15,21,23.

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Differences in the rates of primary osteoarthritis by race

that might be explained on the basis of different environmental
factors are negated by the low rates of osteoarthritis among Asian
Americans and African Americans living in the same environment as whites30-32. Chinese, African Americans, and Hispanics
residing in San Francisco31 and the large Japanese American populations living in Hawaii30 have low rates of total hip replacement
for primary osteoarthritis compared with whites but similar
rates of other causes of hip disease (an exception being the
higher incidence of osteonecrosis in African Americans).
Primary Osteoarthritis: A Genetic Disease
The genetic basis of primary osteoarthritis is well established in
Europeans and Americans of European descent. In Sweden and
the United Kingdom, first degree relatives of patients with
osteoarthritis of the hip were found to have more hip osteoarthritis than did control subjects33-35. In a comparison of the
concordance of disease in monozygotic and dizygotic twins, a
United Kingdom twin study of females and a U.S. twin registry
of males both revealed a 50% heritability of primary osteoarthritis of the hip36,37 (50% of the cause was attributed to genetic
factors and the remainder to environmental factors; primary
osteoarthritis is a complex genetic disease).
Numerous studies have indicated the interplay of obesity,
joint injury, excessive occupational joint load, and sports activity
as environmental factors in patients with hip osteoarthritis38.
The virtual absence of this genetic disease in the continents
of Africa and Asia (where heavy physical activity is a way of life)
indicates one cannot acquire the disease without the European
genetic predisposition.
Gene Admixture Influencing the Prevalence
of Osteoarthritis
Hip osteoarthritis data of African Americans have shown the
role of genetic mixing in raising their rate of primary osteoarthritis above that of African blacks. Medicare data for 2006
showed that the total hip replacement rate for African Americans was at 53% of that for whites39. African Americans have a
20% component of European DNA consistent with EuropeanAfrican intermarriage. Combining the higher primary osteoarthritis rate from the European genetic admixture and the
higher rate of osteonecrosis may explain the total hip replacement rate for African Americans.
Total hip replacement rates for primary osteoarthritis
among Hispanics show the effect of intermarriage between
American Indians and Europeans. Hispanics in the southwestern
U.S. are mainly Mexican American and have a 50% European
DNA component40. Their total hip replacement rate for primary
osteoarthritis varies from about one-seventh to one-half that
of whites31,41. The variations in studies may have to do with
difficulties in how Hispanics are identified. The use of Spanish
surnames may include other subgroups such as Filipinos and
may include non-Hispanic married white women. In contrast
to Hispanics and African Americans, Asians living in the United
States and Australia have retained their genetic protection against
primary osteoarthritis.

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The lowered use of total hip replacement by African

Americans who have been reported to have an equal or an even
greater prevalence of osteoarthritis of the hip than whites
continues to get attention as a health-care disparity38,42. The rate
of hip osteoarthritis in African Americans as equal to the rate in
whites is not consistent with current knowledge of genetic admixture43 and worldwide epidemiology. Since African Americans are getting equivalent operative care for hip fracture44, it is
unlikely that only one-half of African Americans in the Medicare
age group are being treated for primary osteoarthritis as documented in the Dartmouth Atlas of Health Care data39. The misreported equality of rates of primary osteoarthritis with whites
comes down to three reports. It started with the National Health
and Nutrition Examination Survey (NHANES) study in 1975 and
was reported for African Americans in North Carolina45,46. The
most recent report describing the rate of hip osteoarthritis in
African Americans in the U.S. military as greater than that in whites
is not valid since the data were not based on routine radiographs
and there was no information or even mention of osteonecrosis,
which produces similar symptoms to osteoarthritis on clinical
examination of the hip47. In the NHANES study, there were
fewer than five African American patients with moderate to
severe hip osteoarthritis, with no mention of nontraumatic
osteonecrosis48.
As primary osteoarthritis of the hip, a genetic disease, is
virtually absent in black Africans, the 20% European DNA
additions in African Americans should only increase primary
osteoarthritis rates for African Americans proportionately and
not to an equal prevalence with whites. There is no current
evidence or reason to suspect some as yet unidentified environmental factor for such an increase in disease prevalence in
African Americans. Medicare data on rates of primary osteoarthritis appear to correlate with rates of intermarriage. Total hip
replacement rates are lowest for Asians, higher for blacks, and
higher still for Hispanics, which is comparable with their European DNA ethnic distributions in America41.
Rates of osteoarthritis of the hip and total hip replacement for primary osteoarthritis vary in different European
communities. The highest rates of total hip replacement for
primary osteoarthritis are in northern Europe, Sweden, Norway,
Iceland, and France49. Southern Europe, including Spain, Italy,
and Greece, has lower rates50. A difference in the primary osteoarthritis rates is compatible with variations in the frequency
of European disease gene variants modified by environmental
factors.
Other Causes of Osteoarthritis in Various Populations
In populations with European ancestry, 87% of total hip replacements are for primary osteoarthritis after the exclusion of
fractures51,52. The remaining diagnoses include rheumatoid disease, osteonecrosis, and the osteoarthritic sequelae of childhood
hip disease. In non-European populations, there is considerable
variation in these other diseases. Developmental dysplasia of the
hip is the main cause of osteoarthritis in the Japanese population29. Osteonecrosis is much more frequent in the Asian and
African populations25,53.

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Primary Osteoarthritis in the Non-European Populations

Primary osteoarthritis surveys in non-European populations
have placed the prevalence at approximately 1%. This number
may actually be lower on the basis of the few hips with primary
osteoarthritis seen in clinical studies. In Hong Kong clinics54 in
1998, only seven patients per million were found with primary
osteoarthritis. American whites with European ancestry have
rates of sixty to 120 per million. The only current South Asian
study of total hip replacements done in one clinic found no
primary osteoarthritis in thirty patients19. In 4721 patients in a
Saudi Arabian clinic during an eighteen-month period, only
two patients had primary osteoarthritis, while 160 knees were
diagnosed with idiopathic osteoarthritis on radiographs21. In an
arthroplasty register in Malawi25, there were more patients with
hip osteonecrosis than hip osteoarthritis. There is no gradual
gradation of rates. In all non-European people, countries, or
continents, primary osteoarthritis is consistently rare.
The cause of the few cases of primary osteoarthritis in the
non-European populations is unknown. Since hip injury can cause
the disease in the absence of a causative gene, previous trauma
may be responsible. Hip injury as a cause of primary osteoarthritis has been reported in European and in Hong Kong Chinese populations54,55. European DNA variants may account for
some cases of primary osteoarthritis, especially in Africa and
India, which were colonized by Europeans. De novo mutations may be responsible. A separate phenotype cannot be
ruled out.
Femoroacetabular Impingment as a Cause
of Osteoarthritis
Femoroacetabular impingement results from a morphologic
offset between the femoral head and neck, a retroverted acetabulum, or femoral head overcoverage (coxa profunda). This
causes articular cartilage delamination and leads to degeneration of the acetabular cartilage and labrum3. The pathoanatomy
may be the result of a slipped capital femoral epiphysis, LeggCalve -Perthes disease, or less severe developmental dysplasia of
the hip and is a cause of osteoarthritis in the young and middleaged adult. Whether this is the sole or main cause of primary
osteoarthritis56 remains unanswered. Femoroacetabular impingement is found frequently in Danish patients and is not
associated with hip osteoarthritis52. Only seventeen (18%) of
ninety-six Greek patients with femoroacetabular impingement who were an average age of forty-nine years old and
were followed for nineteen years developed osteoarthritis57. In
contrast, femoroacetabular impingement is rare in Japanese
patients with osteoarthritis caused by developmental dysplasia of the hip but has been found in a few patients with primary osteoarthritis29. In a study of elderly women without
osteoarthritis, Chinese women had fewer signs of impingement than white women did58.
Siblings of patients with femoroacetabular impingement
have an increased prevalence of femoroacetabular impingement, indicating a genetic influence59. Osteoarthritis susceptibility genes have been reported to influence the association of
hip morphology and osteoarthritis60.

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The Search for the Genetic Architecture of Osteoarthritis

The predominant approach in the search for the genetic basis
of all forms of osteoarthritis has been by linkage analysis. This
involves the use of genetic markers, such as single nucleotide
polymorphisms, for linkage scans to specific regions of the
genome for the location of risk alleles and analysis of candidate
genes in the linkage region or elsewhere in the genome61. Of the
many candidate genes studied, only one, a single nucleotide
polymorphism of the growth and differentiation factor GDF5
gene, is associated with knee osteoarthritis62. What has only
recently been appreciated is that too few patients with osteoarthritis were enrolled in most of these studies63. The resulting
insufficient power has weakened most conclusions. However,
these studies have shown that susceptibility alleles are numerous and that each has a small effect requiring the study of a
large number of individuals with osteoarthritis.
As the technology has progressed, the recognition and
characterization of common and rare DNA variants have advanced along with faster and cheaper genotyping platforms
enabling the use of genome-wide association scans63. A genomewide association scan can compare large numbers of patients
with osteoarthritis and controls by testing a large number of
genetic variants covering the whole genome and can identify
genes for which no previous information was available. This
hypothesis-free search allows the recognition of genes that
might not be considered from our current knowledge61.
Only two other convincing associations with osteoarthritis
have been found by genome-wide association scans. A variant
in the gene MCF2L64, a nerve growth regulator, was found to
be associated with hip and knee osteoarthritis, and a region of
7q22 was found to be associated with knee and/or hand osteoarthritis65. These studies involved thousands of patients and
controls and required patient data and collaboration across
osteoarthritis genetic laboratories throughout Western Europe.
Overview
The knowledge that primary osteoarthritis of the hip occurs in
communities with European DNA may help to refine the phenotype. Its rarity in non-European populations suggests that it
is a separate phenotype in the white population. A United
Kingdom twin study of women with use of multivariate modeling has shown that primary osteoarthritis of the hip has no
common or shared genetic factors with hand or knee osteoarthritis66. Clinical data have indicated that it is independent of
osteoarthritis of the knee67. That osteoarthritis is rare in the
non-European population explains the failure of many earlier
attempts to group white and other populations to enlarge DNA
collections. It also negates studies that combine hip and knee
arthroplasty data for racial comparisons.
The difference in whether the pathophysiology of this
disease is from a growth abnormality causing mechanical wear
or is just late onset degeneration in normal structures of the
joint might aid in the search for causative alleles, i.e., growth
and development or latent degeneration. The greatest value of
defining the primary osteoarthritis phenotype as those with
European variants may be to establish Asians and Africans as

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control groups for the investigation of the presence or absence

of known or possible genetic variants thought to be associated
with primary osteoarthritis or proximal femoral morphology
variations possibly contributing to primary osteoarthritis in
whites.
Although DNA studies for primary osteoarthritis in the
last few years have not replicated most previously reported
genetic associations68, the worldwide association of primary
osteoarthritis with European and European American populations, their 50% heritability, and the absence of any dominant environmental risk factor in any population leaves
genetic investigation as still the best approach to search for
the molecular basis for initiation and progression of this
phenotype of osteoarthritis. It is now recognized that much
larger populations of patients with osteoarthritis are needed
for genome-wide association scans and all joint tissues may
need genetic and epigenetic considerations in the disease
biology69.
Primary osteoarthritis of the hip is responsible for 65%
to 70% of total hip replacements in the populations of the
world with European genes. It is virtually absent in Asia,
South Asia, and Africa on the basis of consistent surveys and
clinical studies reported for the past thirty-five years. Family
and twin studies have proven it to have a genetic basis with a
50% heritability in whites. Its rarity in non-European populations indicates that a European gene component is necessary
for the expression of the phenotype. The genetic basis of the
disease is reinforced by showing the role of gene admixture in
the varying distribution of primary osteoarthritis in American
minorities. Total hip replacement data for African Americans
are consistent with their European DNA content from twenty
generations of intermarriage between African blacks and Europeans. The same is true for Hispanics with a 50% European
component. Asian Americans with almost no intermarriage
have primary osteoarthritis rates similar to the prevalence
throughout Asia.
Whether primary osteoarthritis may be, in fact, a secondary osteoarthritis is challenged again with the recognition
of femoroacetabular impingement. Regardless of whether this
impingement is associated with late onset of osteoarthritis,
the cause of the disease is not known. Femoroacetabular impingement is seen more commonly in those of European descent. Non-European populations can provide control groups
for genetic variant or morphologic comparison for such deformity. That femoroacetabular impingement does not occur
in the face of any environmental insult in Asia or Africa emphasizes the need for continued search for the causative European
genetic variants. n
NOTE: The author thanks Lynne Steinbach, Professor of Clinical Radiology and Orthopaedic Surgery
at University of California San Francisco, for the editing of this paper.

Franklin T. Hoaglund, MD
60 Inverness Way, Hillsborough, CA 94010.
E-mail address: fhoaglund@comcast.net

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