Indian Journal of Orthopaedics

: 2002  |  Volume : 36  |  Issue : 4  |  Page : 225--233

Heterotopic ossification after total hip arthroplasty:A review of etiopathogenesis, risk factors and treatment modalities

ON Nagi, MS Dhillon, HS Batth 
 Department of Orthopaedics, P.G.I.M.E.R., Chandigarh, India

Correspondence Address:
O N Nagi
1027, Sector 24-B, Chandigarh

How to cite this article:
Nagi O N, Dhillon M S, Batth H S. Heterotopic ossification after total hip arthroplasty:A review of etiopathogenesis, risk factors and treatment modalities.Indian J Orthop 2002;36:225-233

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Nagi O N, Dhillon M S, Batth H S. Heterotopic ossification after total hip arthroplasty:A review of etiopathogenesis, risk factors and treatment modalities. Indian J Orthop [serial online] 2002 [cited 2020 Feb 21 ];36:225-233
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Heterotopic ossification (HO) is the formation of the mature lamellar bone in soft tissue. The reported incidence after total hip arthroplasty (THA) ranges from 0.6% to 90%. [1],[2] Although in most instances it is clinically asymptomatic, 2% to 7% of patients undergoing THA experience symptomatic HO; however less than 1% of these patients require reoperation solely due to ectopic bone. [3],[4],[5] This adds up to a substantial number of patients if one considers the ever-increasing number of THA's performed per year.

The purpose of this review is to analyse etiopathogenesis, risk factors and various prophylactic measures for the prevention of HO after THA.


The exact pathology of the heterotopic bone formation after THA is not yet completely understood. Chalmers et al [6] proposed that three ingredients were essential for heterotopic ossification: osteogenic precursor cell, inducing agents and a permissive environment. The precursor cells are pluripotent mesenchymal cell which differentiates into osteoblasts. The progeniter cells for this ectopic ossification must migrate to the site of ectopic bone formation. In case of heterotopic bone formation after THA, however, there is a unique situation that may explain both signal for and source of ectopic osteoblasts. The pluripotent mesenchymal cells in stromal tissue of bone marrow have osteogenic potential and have been termed as "Determined osteogenic precursor cells" (DOPC). These cells when released from medullary cavity and deposited into the periarticular tissues during the THA, may initiate heterotopic bone formation. [7],[8]

The signal for the mobilization and activation of stromal cells is not clearly understood. In 1965, Urist [9] discovered that demineralised bone matrix could induce bone formation ectopically and postulated a bone morphogenic protein (BMP) that would be transferred from the injured bone to surrounding soft tissues and stimulate the transformation of perivascular mesenchymal cells to osteoblasts. [9],[10] Other studies [8] postulated that fine bone dust released during the surgery permeates the highly vascular tissue around the hip. This bone dust when degraded by macrophages results in release of various factors in extra cellular fluid which regulate the proliferation and differentiation of osteoprogeniter cells. The list of factors includes insulin like growth factor, platelet derived growth factor, fibroblast growth factor etc. Recently Ho et al [11] suggested the role of prostaglandin E2 as a mediater in the differentiation of progeniter cells. The most clinically relevant piece of experimental information was the observation by Tonna and Cronkite [12] , who noted osteoblastic differentiation from primitive stem cell as early as 16 hours after experimental induced trauma to mice femora, with peak activity observed at 32 hrs. This finding has a practical clinical relevance that any prophylaxis against HO given after one week effectively has no role.

Microscopic analysis of the HO after THA indicates that the process undergoes a systematic histologic progression from initiation to maturation [Figure 1]. Osteoid is formed initially which later calcifies in four to eight weeks time. Well oriented trabecular bone forms in about six to 12 months and may or may not be associated with periosteum. [8] The key histologic features, as pointed by Ackerman [13] is the 'Zone phenomena" which includes a central cellular region and a peripheral region delimited by bone and unremarkable stroma. If allowed to mature, the entire lesion will form a lamellar bone. Quantitative histomorphometry of heterotopic bone formed after THA indicates that it is considerably more metabolically active than age matched normal bone. Various histologic parameters indicate that heterotopic tissue is 50% to 150% more active for formation of bone.

Risk factors

The exact cause of the ectopic bone formation has yet to be identified. The background is possibly multifactoral, and a number of factors have been proposed, some of them patient related and some related to operative procedure or post operative events. Individual factors have been difficult to identify and there may be multiple predisposing factors.

Patient - related risk factors

Individual predisposition is most important factor for development of HO. There is increased tendency for bilateral HO to occur after surgery of the hip joint if the ectopic bone has formed around the first treated hip. [4],[14],[15],[16] Delee et al [17] reported a probability of more than 90% in these cases; however the amount of ossification may not necessarily correspond with the heterotopic bone formed in the first hip. Quantitatively, males have greater tendency of developing HO than females. [17],[18] A correlation between advanced age and presence of HO was reported by Merton et al [19] ; others however have found a positive association with increasing age but only among females. Ectopic bone formed less in those patients who preoperatively had minimal physical activity and systemic disease. These observations are in accordance with findings that patients with HO had greater strength in hip flexion and extension postoperatively around the operated lip and also around healthy non-operated side, compared to patients without HO. [20] Revision surgery, hypertrophic OA and THA for femoral neck fractures have displayed a high incidence of HO. [21],[22],[23]

The form of underlying hip symptom is also of significance. A high incidence of HO is noted in patients with diffuse idiopathic skeletal hyperostosis (DISH) and Pagets disease. [24],[25] There are contradictory results regarding ankylosing spondylitis as a risk factor, with few studies reporting a higher incidence of HO, while others found no such increase. [26],[27] This discrepancy could be due to medication given for inflammation control and because of the fact that ankylosing spondylitis occurs in both ossifying and non­ossifying forms.

Surgery - related risk factors

The occurrence of HO depends in part on surgical technique and local tissue trauma. A higher incidence is reported in technically difficult cases, long duration of surgery, extraction of femoral head in fragmented state and per-operative removal of osteophytes in the vicinity of the joint. [23],[28] Deposition of the bone marrow especially from femoral shaft and stripping of capsule from acetabulum have also been implicated as a possible cause for ectopic bone.

Some authors have reported a high prevalence rate of HO in cemented THA while others have reported a high prevalence in uncemented THA. [29],[30] However recent trends indicate that the choice of cemented or non-cemented prosthesis does not seem to influence the rate of HO. [31],[32] Nayak et al [33] in a prospective randomized controlled trial also reported no significant differences in the prevalence of HO between cemented and non cemented THA.

Some reports attempt to correlate bone formation with the operative approach employed. Rosendahl et al [2] reported the highest incidence of HO to date in 63 of 70 patients (90%) who underwent Moore's operation after femoral neck fracture. The predisposing cause according to them was the anterolateral incision by Mcfarland Osborne approach, in which the gluteus medius is stripped from greater trochanter in continuity with the periosteum and vastus lateralis muscle. Hamblen et al [34] , however reported a higher incidence of HO occurring with the anterior Smith-Peterson approach than with the lateral approach. They postulated that muscle ischemia, caused by pressure from retractors, might be a risk factor in HO formation. Specimens from gluteus medius muscle were taken at the beginning and end of surgery, and were analyzed with respect to intracellular metabolities (lactate, phospho-creatinine). Despite the finding that around 40% of patients showed evidence of preoperative ischemia and 77% patients developed HO, no association between these two entities was found. Morrey et al [35] and Hanslik et al [36] found no significant difference between the use of anterolateral, transtrochanteric and posterior approach. In our experience, the use of modified Watson Jones approach in more than 1000 THAs has not given a higher than reported incidence of HO.

Postoperative period - Risk factors

A few conditions and complications occurring after surgery have been associated with the formation of HO. Azcarate et al [37] reported ectopic bone formation in six of seven patients with dislocations of the prosthesis during first postoperative week, but not when dislocation occurred later. In four patients having bilateral THA, HO occurred only on the side dislocating earlier. Other post operative conditions associated with HO include post operative fever more than five days, prolonged sterile discharge, superficial wound infection and post-operative hematoma. [3],[19],[23]


Clinical Features Charnley [40] considered the occurrence of HO to be "almost a matter of academic interest", even though the hip score was lower than in patients without HO mainly due to small arc of mobility. Small amounts of HO do not cause functional deficit, but several reports [3],[17],[28],[35] indicate reduced mobility in cases of significant HO and such a restriction may pose problems when climbing stairs, sitting in chairs or dressing. When HO becomes widespread, it may surround the prosthesis completely and hip joint may become ankylosed. Nollen and Slooff [4] reported impaired hip function with HO, which was proportional to the amount of HO.

Pain is the most common symptom of HO [41] . Although pain may be experienced during the formation of HO, it is not a constant finding when the process of ossification is completed. Hierton et al [19] however, reported significantly higher incidence of pain among patients with HO. In another study, general joint pain was found to be associated with HO, but pain localized to the lateral joint (trochanteric pain) was found to be negatively associated; patients with HO seemed to have less pain in trochanteric region compared to patients without HO. Other clinical features include swelling, palpable mass, low grade fever and erythema. However, these symptoms occur late and take around 8 to 10 weeks to manifest. The differential diagnosis of infection and thrombophlebitis needs to be considered.

Biochemical features

A transient depression in the calcium has been noted to occur at one week after the surgery in the patients who ultimately developed HO [42] . This is followed by an acute rise of in serum alkaline phosphatase levels at 2 weeks, which remain elevated for average of 5 months [43] . It does not however correlate with peak activity, or extent of HO lesions and has been shown to be of little clinical value when used as a routine screening test. The erythrocyte sedimentation rate (ESR) is sensitive to septic as well as aseptic inflammatory diseases. Therefore, in the uncomplicated THA's (no infection), the rise of ESR in post operative period has some predictive value for heterotopic bone formation. It's generally agreed that inflammatory process takes place during the early development of ectopic bone and various studies have shown a correlation between the elevated ESR and HO formation. Several factors nevertheless affect ESR levels after surgery; this elevation however normalizes in about 6 to 12 weeks after surgery. Moreover, post operative treatment with anti-inflammatory drugs depresses the elevated ESR. [44],[45],[46],[46],[47]

Serum C-reactive protein (CRP) is an acute phase protein, synthesized in the liver, which increases dramatically in response to infection, trauma or inflammation [48] . It reaches peak levels on third postoperative day and in uncomplicated cases drops to normal ( [49] in a prospective study in 95 patients reported a significantly higher CRP levels after THA in those patients who eventually developed HO as compared with those who did not. This significant rise in CRP was noted on the 1st post operative day and rose further at 5th post operative day. He stressed that the postoperative rise of CRP levels should be recorded as a risk factor for the formation of HO since its recording at such an early stage (1 st postoperative day) allows for the timely initiation of prophylatic treatment.


Radiographic evidence of ectopic bone appears at 4 to 6 weeks after the surgery when osteoid mineralization occurs [Figure 2]. The commonest radiographic classifications of HO have been those of Hamblen et al [34] and Brookers et al [21] [Figure 3]. Kjaersgaard - Andersen et Al [50] , however introduced a simple classification comprising only two grades: Grade I - no ossification, or HO occupying less than two-thirds of distance between the femur and pelvis; and Grade II - ossification occupying more than two-thirds of the distance between the femur and the pelvis, including apparent osseous ankylosis. This is consistent with the clinical finding that there is a limited range of motion only in patients who have the most severe grades of heterotopic bone.

Kjaersgaasel - Anderson et al [51] recognized two different patterns of HO occurring after THA. Central bone formation (perifemoral neck HO) is located around neck of the femoral component with the lateral limitation being an imaginary line between the most proximal part of greater trochanter and lateral edge of acetabular roof. Lateral bone formation (Abductor HO) is located lateral to the greater trochanter. It occurs after THA and ORIF of acetabular and trochanteric fractures. It is probably a form of myositis ossificans occurring because of the local trauma to the glutei during surgical approach and it does not respond to standard prophylatic measures. In contrast, the etiology of central ossification is obscure and as no muscles are located close to neck of femoral component where majority of central ossifications are located, it obviously can not be traumatic myositis ossifications. It is probably the true form of HO and responds to established standard prophylatic measures. [41],[51]

Computed tomography (CT Scan)

The precise role of CT scan as a clinical tool for diagnosis and maturation of HO is not clearly defined. It, however, definitely aids in preoperative surgical planning prior to excision. Furthermore contrast CT may define more appropriate localization of HO and its relationship to muscle, vessels and nerves. [42],[52]

Bone scan

The use of three-phase technetium 99m - methylene diphosphonate scan in the diagnosis of HO is well established, but is expensive. The first two phases (dynamic blood flow phase and blood pool phase) are most sensitive for early detection of HO and can be abnormal within two to four weeks after the injury, even though the osseous tissue uptake may be normal (phase III). The period between the positive phase I - II uptake with negative phase III may vary between two to four weeks. Likewise, phase III may be positive up to four weeks prior to radiographic appearance of HO. The majority of bone scans return to baseline within seven to twelve months. However, few scans remain positive even after a year and some may become reactivated after a quiescent period. [41],[42]

Since the uptake in HO decreases with time, it has been suggested that serial decrease or a steady state in ratio of uptake between normal and heterotopic bone is a reliable indicator for HO maturity. This is especially true if there is associated decrease in levels of serum alkaline phosphatase. [42]

Prophylatic measures

The occurrence of HO after THA is often associated with decreased hip scores and poor clinical outcome due to reduced motion range occasionally severe pain. Earlier studies advocated the use of ethylhydroxydiphosphonate (EHDP) for prophylaxis, because it inhibits the transformation of amorphous calcium phosphate into hydroxypatite and thereby the mineralisation of osteoid matix. However, when medication is discontinued the mineralization occurs. Other studies found no difference in the prevalence of HO, pain, function or hip range of motion, in patients who had been treated with EHDP compared with those who had received no treatment or who had been given a placebo [4],[50],[53],[54] . At present, the two accepted prophylaxic modalites are anti-inflammatory drugs and irradiation.

Anti-inflammatory medication

The first report dealing with the effect of anti inflammatory medication in the prevention of HO after THA was given in 1974 by Dahl [55] . Interestingly, he undertook a placebo - controlled study to evaluate the efficacy of indomethacin as an analgesic during the first week after THA and by chance it was observed that patients taking indomethacin did not develop HO. Almasbakk and Roysland [56] , Lidgren and Nordstrom [57] and Titter et al [58] were able to confirm this. Schmidt et al [59] in a randomized, double-blind, placebo controlled clinical trial, confirmed the prophylaxic value of indomethacin. No evidence of clinically important HO was found in 102 patients, who received indomethacin for first six post­operative weeks; in contrast 50% of 99 patients who received a placebo developed Grade II and Grade III (Hamblen grading) HO. Recently, the same affect has been observed with other drugs, such as ibuprofen and aspirin. [51],[60],[61]

The reason anti-inflammatory medication inhibits the formation of heterotopic ossification is unclear. However, the effect of the medication is probably exerted through an inhibition of the formation of prostaglandins and related substances, which through the inflammatory response are known to trigger local bone remodeling after trauma and experimentally induced ectopic ossification in the soft tissue. Moreover, indomethacin is known to inhibit the differentiation of the mesenchymal cells into osteogenic cells and thereby into osteoblasts reducing the formative and resorptive phase of bone remodelling.

The duration of post-operative prophylaxis that is needed with anti-inflammatory drugs remain unclear. Schmidt et al [59] found six weeks of treatment with indomethacin to be highly effective for prevention of the most severe grades of HO. In recent studies [62],[63],[64] , short term prophylaxis from 7 to 14 days has shown to have a convincing ability to decrease HO, whereas administration for only 4 days could not achieve an acceptable prevention [65] . Cella et al [66] found that severe HO could not be prevented when prophylaxis was delayed more than five days after surgery. The doses of different drugs used in the studies were indomethacin (25 mg tid) ibuprofen (400 mg tid) and asprin (1000 mg tid). However the lowest daily dosage that is necessary for preventing severe heterotopic ossification is unknown.

Treatment with the anti-inflammatory medication may induce some undesirable side effects, more so in the geriatric patients who undergo THA. The most common are gastrointestinal effects in the form of gastritis and dyspepsia. Some patients also show central nervous system disturbances or rashes. The use of antiinflammatory drugs during early post-operative period, especially in non-cemented THA, theoretically may delay or abolish the ingrowth of bone into the implanted components. However, no clinical data documenting this suspicion have been published. Trancik and Mills [67] , found that treatment with indomethacin, aspirin or ibuprofen does not effect the mechanical strength of the interface between the bone and porous coated implant in rabbit model. Other studies [42] also document no difference in the healing of trochanteric osteotomy in patients, with or without anti-inflammatory medication. Additionally the possible interaction of these drugs with dicoumarol and heparin needs to be looked at since they are frequently given as prophylaxis against DVT. However, Krinstensen [15] and associates reported a safe and simultaneous administrable of low dose Heparin and indomethacin without hemorrhagic complications.


Ionizing radiation exerts its effect by altering DNA transcription and arresting the initial step in osteoid formation, preventing differentiation of pluripotent mesenchymal cells into osteoblasts [16] . Initial studies38 advocated doses in range of 2000-3000 cGy for HO prevention. Lower doses have since been shown to be equally effective. Ayers et al [39] administered 1000 rad prior to fourth post-operative day and Hedley et al [69] administered 600 rad on third post-operative day and reported a high success rate. When comparing the single-dose radiation regimen with fractionated or multiple dose protocols, it is important to note that when a given dose of radiation is divided into increments and delivered over a period of several day, the biologic effect is less than if the same amount of radiation has been given in a single dose. For example, a single dose of 800 cGy has a higher biologic equivalance than 1000 cGy given in five fraction. [70]

Concern about the risk of the radiation induced malignant disease has prompted continued efforts towards the reduction of dosage. Kim et al [71] noted no sarcomas after the delivery of less than 3000 cGy of radiation over a three week period. Tucker et al [72] found no increased risk for the late development of sarcoma in children followed for upto 25 years after less than 1000 rad of radiation had been administered for cancer treatment. Radiation therapy has been shown to delay or inhibit the process of bony ingrowth in animal models [73] . However, various studies have reported no significant increase in bone­implant interface radiolucency or aseptic loosening when the radiation therapy is administered at recommended doses. Moreover the use of limited portals by lead shielding intended to exclude bone in growth areas has been useful. The rates of trochanteric non-union after radiation therapy have been unfavourable, with 25% reported after 1000 cGy administration. [70] This is in contrast with prevalence of trochanteric non-union of 2-15% in non-irradiated hips. Unlike NSAIDs, however radiation therapy is localized and does not increase the risk of bleeding complications when used along with anticoagulation agents like coumadins.

Surgical Excision

In a established case of HO, both NSAIDs and irradiation are of no value. Surgical excision is recommended at the maturity of heterotopic bone which is judged by the serial decreasing levels of alkaline phosphatase towards normal and serial bone scans demonstrating progressively decreasing uptake. As a rule traumatic HO may be resected after 6 months, spinal injury HO after 1 year and head injury HO at 1.5 years [41] . Its mandatory to start early post-operative prophylaxis with indomethacin and irradiation to avoid high recurrence. Two approaches are recommended for ectopic bone excision around hip: anterior approach for anterior or inferio-medial bone and postero-lateral approach for posterior or lateral heterotopic bone [74] . Excision of immature bone is not a task to be taken lightly, as it is associated with high morbidity i.e. infection, recurrence and bleeding. Transplantation of subcutaneous fat from gluteal or abdominal area to region around neck of femoral component has shown good results in terms of increased ROM, decreased pain and low incidence of recurrence. However few studies have used this method to permit any conclusion about its effectiveness. [75]

In conclusion, although the incidence of symptomatic HO is about 1% of all the THA's, the problem can be disabling in some patients. All pre-operative and post-operative precautions should be used more so in high risk patients. This subset should be put on prophylactic medication (and in some cases irradiation). Surgical excision is only indicated for the rare cases with excessive HO, with limitation of activity and pain.


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