Polyarticular heterotopic ossification complicating critical illness
J. W. G. Jacobs,
P. B. J. De Sonnaville2,
H. M. J. Hulsmans,
A. C. van Rinsum1 and
J. W. J. Bijlsma
Department of Rheumatology & Clinical Immunology,
1 Department of Orthopaedic Surgery, University Medical Centre, PO Box 85500, 3508 GA Utrecht and
2 Hospital `Oosterschelde', 's Gravenpolderseweg 114, 4462 RA Goes, The Netherlands
Correspondence to:
J. W. G. Jacobs.
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Abstract
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A patient with generalized heterotopic ossification (HO) complicating critical illness due to necrotizing pancreatitis is described; data on two other cases with HO are briefly presented. The clinical features, prevention and therapy of HO are discussed. The effect of surgical therapy of the HO in our three patients was good.
KEY WORDS: Heterotopic ossification, Heterotopic/ectopic bone formation, Pancreatitis, Abdominal surgery, Mechanical ventilation, Prevention, NSAIDs, Bisphosphonates, Therapy.
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Introduction
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Local heterotopic bone formation, or heterotopic ossification (HO), is not an unusual complication of orthopaedic surgery and burns. Generalized HO near joints is known to occur after head and spinal injuries or a period of treatment in an intensive care unit. The most commonly involved joints are shoulders, hips and knees; the aetiology is unknown. We were consulted in a late phase by a patient with generalized HO, which developed during a period with critical illness due to necrotizing pancreatitis.
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Case report
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A 52-yr-old woman (patient 1 in Table 1
) with a history of appendectomy and hysterectomy underwent first cholecystectomy and then endoscopic retrograde cholangiopancreatography because of suspected choledocholithiasis. Necrotizing pancreatitis and sepsis complicated the procedure. She was admitted to the intensive care unit, where in the course of 5 weeks she underwent several laparotomies and mechanical ventilation. During recovery, she complained of pain in her shoulder, elbow, hand, hip and knee joints. At physical examination, severe functional impairment of the hip and knee joints was found, and some limitation of the shoulder and finger joints. There were no signs of arthritis, except for mild warmth of the knees; the left knee exhibited bony enlargement (Fig. 1
). Laboratory investigations during this late recovery phase revealed a normal erythrocyte sedimentation rate (ESR), as well as a normal haemoglobin concentration and white cell and platelet counts. Ionized serum calcium as well as the inorganic phosphorus and acid phosphatase levels were normal.
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TABLE 1. Clinical characteristics of three patients with generalized HO after sepsis, requiring mechanical ventilation
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FIG. 1. Both knees exhibit flexion contracture, most obvious in the left knee joint. There is bony enlargement of the left knee.
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When she had fully recovered from the abdominal complications, she could barely walkeven with a walking framebecause of limited mobility of the hip and knee joints. Maximum flexion of the right hip was 45°, that of the left hip 60°; there were slight flexion contractures of both hip joints. Rotation of both hip joints was severely limited: 10° in total. The left knee showed a flexion contracture of 25°, the right knee of 40°; some further flexion (10°) of the right knee was possible. Except for slight limitation of both shoulder joints, the other joints exhibited no abnormalities. X-rays revealed heterotopic bone formation of both the hip and knee joints, especially the left knee, with subchondral bone resorption in the condyles of the femur (Fig. 2
). Therapy was surgical: excision of the heterotopic bone, with non-steroidal anti-inflammatory drugs (NSAIDs) and bisphosphonates administered after surgery to prevent recurrence. The effect of therapy after 1 yr was good: improved, albeit not normal, range of motion, good effect on disability; also a beneficial long-term effect of surgery was seen in two other patients with generalized HO after severe sepsis, requiring mechanical ventilation (see Table 1
).

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FIG. 2. X-ray of the left knee shows bridging HO with subchondral bone resorption ( ) in the condyles of the femur.
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Discussion
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HO is the formation of new bone within soft tissue. It is different from calcification of soft tissues: in HO, undifferentiated mesenchymal cells differentiate into osteoblasts. HO is a feature of fibrodysplasia ossificans, a rare disease [1], but generally it is idiopathic. Idiopathic local HO is seen after joint surgery, e.g. arthroplasty, especially of the hip or knee joint, and after severe burns and traumas. It also develops in abdominal wounds after abdominal surgery [2]; abdominal surgery as such does not lead to HO of joints. Generalized HO near joints is seen after spinal cord or severe head injury (in the absence of a local trauma), especially if passive rehabilitation of joints is delayed until joint contracture has already started to develop [3], or after severe illness requiring prolonged chemical paralysis and cardiorespiratory support [4, 5]. The incidence of HO after severe spinal cord or central nervous system injury is ~1020% [68], although only a minority of these cases are clinically relevant. Only 1020% of patients with HO experienced problems, especially restricted joint motion and retardation of the rehabilitation process [7, 8].
Recently, generalized HO was described in six patients with critical illnesses that required prolonged mechanical ventilation; two of these patients also had pancreatitis. It was concluded that neuromuscular blockade in the setting of adult respiratory distress syndrome is a risk factor for development of HO [5]. Pancreatitis may lead to hypocalcaemia and osteonecrosis in an early phase, and pancreatic calcification in a late chronic phase, but there are no data on an association of pancreatitis with HO in the literature. However, if it exists, an independent association of necrotizing pancreatitis with HO would be difficult to prove because necrotizing pancreatitis causes critical illness, often requiring surgery and mechanical ventilation.
Juxta-articular HO of the hip can be classified according to Brooker: class I, islands of bone within the soft tissues; class II, bone spurs from the pelvis or proximal end of the femur, leaving at least 1 cm between bone surfaces; class III, bone spurs from the pelvis or proximal end of the femur, reducing the space between opposing surfaces to <1 cm; class IV, apparent bone ankylosis of the hip [9]. If applicable for the knee, the HO classification of the left knee would yield class IV for our patient (Fig. 2
). Following total hip arthroplasty for primary coxarthrosis without therapy to prevent HO, the incidence of class I HO was 25%, class II HO 25%, class III 19% and class IV 7%; only 24% of arthroplasties were not complicated by HO [10]. However, patients with HO after total hip replacement do not necessarily have poor functional results [9]; in general, Brooker class III and IV seem to be clinically relevant.
The aetiology and pathophysiology of HO are uncertain. First, there seem to be inflammatory changes that can be visualized by ultrasonography [1113]. These changes might be based on microtraumata [11, 12]. The fact that different lateral approaches for total hip arthroplasty result in different frequencies of severe HO [14] seems to support the theory of microtraumata. The theory does not explain, however, why the incidence of local HO is much higher among patients with previous HO, e.g. after total hip replacement [9]. It is speculated that bone morphogenic proteins have a role in the aetiology [5]. This might explain a genetic propensity to HO.
Following these changes, perivascular undifferentiated mesenchymal cells differentiate into osteoblasts, which synthesize the osteoid matrix of early bone [5]. Mineralization of the osteoid leads to true bone that can be identified on radiographs. The interval between the initial injury or underlying condition and radiological diagnosis ranges from 1 to 7 months [8, 15, 16], probably depending on clinical suspicion, which will increase as the extent of the heterotopic bone formation increases.
The newly formed bone has the same high turnover rate as growing bone [17]. During the process of HO, there are hotspots on the three-phase bone scan [7, 18, 19]; in all three of our patients (Table 1
), this was the case. Often, there is an increase in serum alkaline phosphatase [1820], but serum osteocalcin does not seem to help in the diagnosis of HO [15]. Symptoms include swelling, pain, local warmth and eventually loss of motion of the afflicted joint [18]. HO in an early stage may mimic arthritis [15]. However, non-inflammatory knee joint effusion also occurs in spinal cord-injured and other paralysed patients without development of HO [21]. In addition to limited joint function, complications of HO are compression of neurovascular structures with neurological and vascular sequelae, e.g. ulnar nerve compression at the elbow [22, 23], deep venous thrombosis [23, 24] and lymphoedema [23].
In joint surgery, HO can be prevented by means of pre-operative or post-operative radiotherapy, and/or administration of NSAIDs such as indomethacin and/or the bisphosphonate etidronate [2528].
Bisphosphonates inhibit osteoclasts and, because of coupling between bone resorption and formation, also osteoblasts. Bisphosphonates also very efficiently inhibit experimentally induced calcification of various soft tissues such as arteries, kidneys, skin, etc.; this effect is not mediated by inhibition of osteoblasts, but most probably is explained by a physicochemical mechanism [29]. Inhibition of calcification of osteoid tissue is probably the mode of action of etidronate in HO. It is not known whether therapy with other bisphosphonates, by means of inhibition of calcification of osteoid or by decreased formation of osteoid tissue due to inhibition of osteoblasts, also results in prevention of HO. A scheme is to give etidronate 20 mg/kg body weight, starting 1 month before the operation, and to give it up to 3 months after the intervention [29]. Longer treatment should not be given because of the risk of osteomalacia; vitamin D levels must be checked and, if necessary, corrected before this therapy starts.
A preventive effect regarding HO has been described for several different NSAIDs, suggesting that NSAIDs inhibit local environmental inflammatory stimuli leading to HO; possibly radiation therapy has the same mode of action. From a prospective randomized controlled open study with review of the literature, it is advised to use for 7 days 50 mg of indomethacin b.i.d. with gastric mucoprotection as prophylaxis in all patients after total hip replacement [27]. A single irradiation of 7 Gy is recommended for patients who have developed HO after previous operations or in whom indomethacin is contraindicated [27]. For patients with a history of HO, prophylactic treatment should be considered in situations with a known association with local or generalized HO, e.g. trauma, joint surgery or mechanical ventilation.
In established HO, surgical excision is the only remedy together with prevention of recurrence of HO and extensive rehabilitation with range-of-motion exercises. As trauma is associated with HO, it is probably wise to prevent local trauma due to passive range-of-motion exercises against resistance. Theoretically, these preventive measures could be combined since they probably act at different levels: NSAIDs probably suppress early inflammatory changes, radiotherapy possibly does the same; etidronate prevents calcification of osteoid tissue and range-of-motion exercises prevent bridging of the joint by newly formed bone.
Prior to surgery, serum alkaline phosphatase should be normal [30] and bone scanning should show that the process of HO is quiescent. Stabilization of HO on bone scans may be defined as uptake ratios of
2 for patients with initial uptake ratios between 3 and 5, and uptake ratios of
3 for patients with initial ratios exceeding 5 [19]. It has been suggested that surgical timing depends on the aetiology of HO: resection of traumatic HO at 6 months, HO due to spinal cord injury at 1 yr and HO due to brain injury after 1.5 yr [8]. Our patients described in Table 1
underwent surgery with major functional improvement and, to date, no recurrence.
The development of a general preventive strategyother than by range-of-motion exercisesfor all critically ill patients to prevent (complications of) HO and preserve joint function is not easy. Ultrasonography proved to be very sensitive in detecting early HO changes [1113]; theoretically, it thus enables early secondary prevention of HO. However, the role and timing of this technique as well as bone scanning in daily practice for critically ill patients have not yet been established. The problem is that there are no clear clinical features of early HO; if there were, ultrasonography and bone scanning could be performed and prophylactic medication administered in an early phase. However, in paralysed patients, signs of deep venous thrombosis or arthritis should be considered as indicators of possible HO. In our patients, prevention should at least have consisted of passive range-of-motion exercises during the intensive care period [3].
In conclusion, a high level of clinical suspicion is the first step towards optimally preventing HO in patients at risk. Surgical therapy seems to be beneficial if the above-mentioned strategies are followed.
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Submitted 16 June 1998;
revised version accepted 30 April 1999.