Osteonecrosis. Prognosis and Prevention of the Consequences of Osteonecrosis

Abstract: Abstract

Background
Osteonecrosis (ON) is defined by the in situ death of bone cells, osteocytes, hematopoietic and fatty marrow precursor cells. Events and risk factors known to be associated with ON are femoral neck fracture, hip dislocation, slipped capital femoral epiphysis in children, humeral head fracture and insufficiency fractures in load-bearing joints. The etiology of non-traumatic ON is less well understood. Factors associated with non-traumatic ON are corticoid steroid use, alcohol abuse and systemic lupus erythematosus. If factors related to the osteonecrotic lesion cannot be found, the lesion is defined as “spontaneous”. Regardless of the cause, vascular compromise is however the final pathway which leads to cellular death. Ingrowing blood vessels invade the necrotic bone and remodeling starts with simultaneous coupled bone resorption and formation. The changes resemble what happens in fracture healing and bone graft incorporation. The mechanical strength of the remodeling bone might temporarily be decreased due to either the resorption of the necrotic bone or a fatigue stress fracture in necrotic bone not yet revitalized. If the necrosis occurs in subchondral load bearing bone, partial joint collapse and secondary osteoarthritis may be the final consequence.

Methods
In paper 1, a 1-4 year follow-up study was performed of 17 patients with spontaneous osteonecrosis of the knee (SPONK), who were treated with bisphosphonates and evaluated regarding secondary degenerative changes. These 17 treated patients were compared to a previously untreated control group (paper 2).
In paper 2, an almost life long follow-up of 40 SPONK patients was conducted. The patients were matched with the Swedish Knee Arhtroplasty Register (SKAR) to evaluate the frequency of major knee surgery.
In paper 3 the risk of ON and secondary degenerative changes after cervical hip fracture was studied in children and younger adults. Radiographs performed at follow-up minimum of 12 months after the fracture were correlated with the scintigraphic examinations evaluating the remaining femoral head circulation made directly post-operatively.
In paper 4, the remodeling of non-vascularized bone grafts under high load was studied in a specially designed bone chamber in rats. Bone chambers with bone grafts were implanted in the proximal tibial bone. Half of the rats were administered bisphosphonates and the other half were not. The lengths of the grafts, before surgery and after harvest, were compared to assess whether bisphosphonates decreased the compression of the graft during remodeling.

Results
Paper 1. The 17 patients who were treated with bisphosphonate had a significantly (p<0,05) lower risk of developing secondary degenerative changes at the follow-up, compared to the untreated control group.
Paper 2. 75% of the patients developed secondary degenerative changes in this almost life long follow-up study with SPONK patients. 17/40 patients have had major knee surgery with arthroplasty or high tibial osteotomy. Younger patients and patients with small ON lesions were at lower risk of major knee surgery (p<0,001).
Paper 3. 3/3 children or young adults with cervical hip fracture and normal postoperative circulation had normal radiographs at follow up, as had 3/4 with partial remaining circulation. 1/3 patients with absent postoperative circulation in the scintigraphic investigations had a joint collapse, in spite of treatment with bisphosphonates and prolonged restricted weight-bearing. 1 patient had secondary radiological changes but no joint collapse and 1 patient in this group had normal radiographs at follow up.
Paper 4. Bone grafts implanted in loaded bone chambers in rats were less compressed (p<0,05) when treated with bisphosphonates compared to the grafts in untreated rats.

Discussion
Morbidity after untreated ON in subchondral bone in load bearing joint is substantial with a high risk of osteoarthritis and need for secondary joint prosthesis. Evaluating the postoperative circulation in the femoral head after cervical neck fracture helps predict the outcome in children and young adults. Bisphosphonates may reduce the risk of collapse of the necrotic bone during remodelling and thereby reduce the risk for secondary degenerative changes in the affected joint. Randomized clinical series are warranted to further define the role of bisphosphonates or other bone-acting drugs like receptor activator of NF-kB ligands (RANKL) antibodies and parathyroid hormone (PTH).