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Transient Osteoporosis Associated With Hyperhomocystinemia: a Possible Role for Hyperbaric Oxygen Therapy

Posted on: Saturday, 13 November 2004, 03:00 CST

Domachevsky L, Keynan Y, Militianu D, Goldenberg I, Adir Y. Transient osteoporosis associated with hyperhomocystinemia: A possible role for hyperbaric oxygen therapy. Undersea Hyperb Med 2004; 31(2): 275-279. Transient osteoporosis of the hip is considered by some to be an early stage of avascular necrosis. Hyperbaric oxygen (HBO^sub 2^) therapy, which may be of benefit in the treatment of avascular necrosis, might therefore be used in the treatment of transient osteoporosis of the hip. We present a case of transient osteoporosis associated with elevated levels of homocysteine in a 33-year-old white male, who was treated by HBO^sub 2^. Treatment was administered at 2.5 ATA for 90 minutes once daily, five days per week. Regular follow-up examinations in the course of the HBO^sub 2^ therapy revealed improvement in the patient's complaints and the findings of the physical examination. Repeated magnetic resonance imaging (MRI) performed after 40 and 90 sessions showed decreased edema and complete resolution of the edema, respectively. Evaluation 6 months after the completion of treatment revealed complete resolution of symptoms, with a normal physical examination.

Transient osteoporosis of the hip (TOH) describes a clinical entity characterized by disabling hip pain, decreased range of motion, and a limp. Some authors (1-3) claim that TOH may be the harbinger of avascular necrosis (AVN). Predisposing factors include compromised blood flow to the bone, hypercoagulable states, metabolic and endocrinologie disturbances, orthopedic problems, dietary or environmental factors, and iatrogenic causes. Elevated levels of homocysteine may represent an additional risk, possibly due to alterations in bone growth and skeletal development, and because of the atherogenic and thrombogenic propensity of homocysteine. A number of trials have suggested benefit of hyperbaric oxygen (HBO^sub 2^) therapy in the treatment of stage 1 AVN. However, there are no reports of HB2 in the treatment of TOH. We present the case of a male who suffered from TOH associated with hyperhomocystinemia and was successfully treated by HBO^sub 2^.

CASE REPORT

A 33-year-old, previously healthy white male presented with a history of right hip pain of a few weeks duration. The pain was exacerbated by weight bearing, and had worsened gradually. At the time of presentation, the patient's sleep was disturbed by incessant pain during the night. He could not recall trauma to the affected leg. Physical examination revealed increased sensitivity to touch on the right hip and decreased range of motion. An X-ray of the hip was normal, but a technetium bone scan revealed pathological uptake in the right femoral head. Magnetic resonance imaging (MRI) of the hip disclosed a diffuse intramedullary signal abnormality: decreased signal intensity on T1-weighted images and increased signal intensity on T2-weighted images, involving the femoral head and neck and the intertrochanteric area (Figures. IA and IB). The findings were consistent with the diagnosis of transient osteoporosis of the right hip.

Fig. 1. MR images before HBO^sub 2^ therapy. A. Coronal T^sub 2^- weighted spin echo MR image, showing a diffuse high signal intensity of the bone marrow in the right proximal femur. B. Coronal T^sup 1^- weighted spin echo MR image, showing a diffuse low signal intensity of the bone marrow in the right proximal femur.

The patient was advised to use crutches to avoid weight bearing, and was prescribed Rofecoxib 12.5 mg TID. He was referred for hyperbaric oxygen therapy. Treatment was commenced at 2.5 atm abs for 90 minutes daily. The patient reported increased motion and a significant decrease in pain after the seventh hyperbaric treatment session. After the seventeenth session, the patient reported the complete disappearance of pain at rest, and he was prescribed Dipyrone 50 drops as required. Repeated MRI performed after 40 sessions showed decreased edema (Figures 2A and 2B), with complete resolution of the edema on another imaging study performed after 90 treatment sessions (Figures 3A and 3B).

Fig. 2. MR images after 40 HBO^sub 2^ sessions. A. Coronal T^sub 2^-weighted spin echo MR image, showing a reduction in the intensity of the pathological signal in the right proximal femur. B. Coronal T^sub 1^-weighted spin echo MR image, showing a reduction in the intensity of the pathological signal in the right proximal femur.

Figure 3. MR after 90 HBO^sub 2^ sessions. A. Normal coronal T^sub 1^-weighted spin echo MR image. B. Normal coronal fast spin echo protein density fat sat MR image.

Physical examination at this time showed the patient to be asymptomatic. The patient used a walking stick for another month, and was gradually permitted to bear weight on the affected limb. Physical examination on follow-up 6 months later was normal, and the patient had returned to the full range of his daily activities.

In the course of the HBCO^sub 2^ sessions, visual acuity in the patient's right eye decreased from 6/6 to 6/7.5. This returned to normal one month after the completion of treatment.

The results of the laboratory tests conducted are shown in Table 1. The prothrombin and partial thromboplastin times were normal, as were renal and liver function tests. The patient was homozygous for MTHFR mutation and had low levels of folic acid and vitamin B12. Other tests for hypercoagulable states were normal. The patient was prescribed folic acid 10 mg and Vitamin B12 1000 μg daily. Five months after beginning this therapy, folic acid and Vitamin B12 were within normal limits, and the homocysteine level had fallen to 6.7mol/l.

Table 1

DISCUSSION

Transient osteoporosis of the hip (TOH) is manifested by disabling hip pain, reduced range of motion, focal loss of radiodensity, a positive bone scan, and the appearance of bone marrow edema on MRI without specific signs of avascular necrosis (AVN). The clinical course is usually characterized by an abrupt or gradual onset of pain, with functional disability increasing to a maximum within 4-8 weeks. This is followed by a period of weeks or months during which the level of pain remains stable, before a regression phase in which the pain gradually subsides. Positive bone scan and bone marrow edema are seen on MRI just a few days after the appearance of symptoms, before any radiographie changes can be found. Controversy still exists as to the etiology, pathophysiology and outcome of the disease. However, some authors have suggested that TOH may be an early phase of AVN, and that it might share the same predisposing factors (1-3). These include metabolic and endocrine disturbances, orthopedic problems, dietary or environmental factors, and iatrogenic causes. However, it is generally accepted that the final common pathway of both entities involves compromised blood flow to the bone.

Homocysteine is a sulfur-containing amino acid formed in the metabolic pathway between methionine and cysteine. Elevated levels of homocysteine can manifest as mental retardation, thromboembolic events, subluxation of the ocular lens, and skeletal abnormalities. In vitro studies have suggested that homocysteine may directly damage the endothelium, perhaps via its sulfhydryl group, leading to enhanced hydrogen peroxide formation, inhibition of prostacyclin synthesis, or impaired nitric oxide production (4,5). It has been suggested that indirect disturbances potentiated by homocysteine may include structural alteration of lipoprotein(a) to enhance apo(a) binding to fibrin, with a concomitant increase in thrombotic potential (6). In vivo studies have shown a positive association between high levels of homocysteine and elevated hemostatic factors such as beta-TG and factor VII (7). Beta-TG is a marker of platelet activation, and may indicate that damage has occurred at the level of the endothelium, whereas factor VII in an activated complex with tissue factor initiates extrinsic coagulation by activating factor X that converts prothrombin to thrombin.

Skeletal abnormalities due to elevated levels of homocysteine include accelerated skeletal growth, osteopenia, elongated appendicular skeleton, and flattening of the vertebral bodies (8,9). Some of the osseous manifestations are attributable to a disturbance in collagen cross-links, which is known as McKusick's hypothesis (10). Thus, the development of transient osteoporosis of the hip in patients with high levels of homocysteine might be partly due to both the atherogenic propensity of homocysteine and its role in skeletal abnormalities.

Whenever there is a need to improve tissue oxygenation, enhanced plasma oxygen delivery by HBO^sub 2^ therapy might be of benefit. HBO^sub 2^ enhances reparative processes, specifically fibrogenesis and osteogenesis, as well as resorption of necrotic bone, in a rat model of AVN (11). Reis et al. (12) and Strauss and Dvorak (13) concluded that HBO^sub 2^ therapy is effective in the treatment of the early stages of AVN. TOH, which is considered an early stage of AVN, could be treated with HBO^sub 2^, although no such cases have been recorded. We report here a case of TOH associated with hyperhomocystinemia for which HBO^sub 2^ therapy was given with good results. We suggest that the mechanisms of action of HBO^sub 2^ might enhance bone repair, thus pr\eventing the progression to AVN and shortening the clinical course of the disease.

Taking into account the diversity of etiologies that may contribute to the development of TOH, it would be reasonable to expect that more than one mode of therapy might be effective. Drugs such as biphosphonates, calcitonin, and bone sparing steroids have been effective in a number of cases in reducing the duration of TOH (14,15,16). However, these drugs are not routinely prescribed due to a lack of controlled studies establishing their role in the treatment of TOH. A conclusion about the role of HBO^sub 2^ therapy in the treatment of TOH cannot be drawn from this case report, but a rationale basis for early HBO^sub 2^ therapy and the favorable results described in this paper warrant investigation. In addition, we suggest that a laboratory test for elevated levels of homocysteine be included in the diagnostic workup of patients with TOH.

ACKNOWLEDGMENTS

The authors wish to thank Professor N.D. Reis, Department of Orthopedic Surgery, Rambam Medical Center, Haifa and Professor Jochanan H. Boss, for critical comments and suggestions.

REFERENCES

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7. Schreiner PJ, Wu KK, Malinow MR, et al. Hyperhomocyst(e)inemia and hemostatic factors: the atherosclerosis risk in communities study. Ann Epidemio12002; 12:228-236.

8. Schedewie H, Willich E, Grobe H, Schmidt H, Muller KM. Skeletal findings in homocystinuria: a collaborative study. Pediatr Radial 1973; 1:12-23.

9. Brenton DP. Skeletal abnormalities in homocystinuria. Postgrad Med J 1977; 53:488-496.

10. Pyeritz RE. Homocystinuria. In: Beighton P, ed. McKusick's heritable disorders of connective tissue, 5th ed. St. Louis, MO: Mosby, 1993:137-178.

11. Levin D, Norman D, Zinman C, et al. Treatment of experimental avascular necrosis of the femoral head with hyperbaric oxygen in rats: histological evaluation of the femoral heads during the early phase of the reparative process. Exp MolPathol 1999; 67:99-108.

12. Reis ND, Schwartz O, Militianu D, et al. Hyperbaric oxygen therapy as a treatment for stage-I avascular necrosis of the femoral head. J Bone Joint SurgBr 2003; 85:371-375.

13. Strauss M, Dvorak T. Femoral head necrosis and hyperbaric oxygen therapy. In: Kindwall EP, Whelan HT, eds. Hyperbaric medicine practice, 2nd ed. Flagstaff, AZ: Best Publishing Co., 1999:909-927.

14. Carmona-Ortells L, Carvajal-Mendez I, Garcia-Vadillo JA, Alvaro-Gracia JM, Gonzalez-Alvaro I. Transient osteoporosis of the hip: successful response to deflazacort. Clin Exp Rheumatol 1995; 13:653-655.

15. Varenna M, Zucchi F, Binelli L, Failoni S, Gallazzi M, Sinigaglia L. Intravenous pamidronate in the treatment of transient osteoporosis of the hip. Bone 2002; 31:96-l01.

16. Arayssi TK, Tawbi HA, Usta IM, Hourani MH. Calcitonin in the treatment of transient osteoporosis of the hip. Semin Arthritis Rheum 2003; 32:388-397.

L. DOMACHEVSKY1, Y. KEYNAN1, D. MILITIANU2, I. GOLDENBERG1, and Y. ADIR1

1 Israel Naval Medical Institute, Israel Defense Forces Medical Corps, P. O. Box 8040, 31 080 Haifa, Israel

2 Department of Diagnostic Radiology, Rambam Medical Center, Haifa, Israel

Copyright Undersea & Hyperbaric Medical Society Fall 2004

Source: Undersea & Hyperbaric Medicine

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