Commentary & Perspective

Commentary & Perspective on
"The Use of Alendronate to Prevent Early Collapse of the Femoral Head in Patients with Nontraumatic Osteonecrosis: A Randomized Clinical Study"
by Kuo-An Lai, MD, et al.

Commentary & Perspective by
Thomas A. Einhorn, MD*,
Boston Medical Center, Boston, Massachusetts

This is one of the most interesting articles I have read this year. It suggests that alendronate, a drug known to be safe and effective in the treatment of several bone diseases, can be used to prevent the clinical progression of osteonecrosis, a disease currently believed to be untreatable by medications. This concept is based on the premise that necrotic bone, although nonviable, provides mechanical support for the hip joint; it is not until a sufficient amount is resorbed that the subchondral plate loses mechanical support and collapses. As osteoclasts are the cells that mediate bone resorption, a potent drug that inhibits osteoclastic activity might prevent this clinical outcome. In this study, alendronate, a nitrogen-containing bisphosphonate known to inhibit osteoclasts, was used according to a protocol commonly employed in the treatment of osteoporosis. The results, which showed a statistically significant reduction in the incidence of femoral head collapse in patients with advanced osteonecrosis, are impressive.

Osteonecrosis of the femoral head accounts for approximately 10% of the primary total hip arthroplasties that are performed in the United States and is the most common diagnosis leading to the need for total hip arthroplasty in patients who are less than fifty years of age1. The prevalence varies among races and nationalities and, in Taiwan, where this study was performed, it accounts for approximately 45% of primary total hip arthroplasties2. Unfortunately, although a variety of joint-preserving treatments have been proposed, none has been shown to be universally successful and those showing greater success are fairly invasive (vascularized or nonvascularized bone grafting, angular or rotational osteotomy). Currently, there is no noninvasive medical or pharmacological treatment available to treat or slow the progression of this disease.

In their article, Lai et al. randomized forty patients with nontraumatic osteonecrosis of the femoral head to either a nonplacebo control group or a group that was treated with 70 mg of alendronate, administered orally, once a week for twenty-five weeks. All patients had a diagnosis of Steinberg stage-II or III disease with a necrotic area of >30%. Patients were observed for a minimum of twenty-four months, and Harris hip scores, plain radiographs, and magnetic resonance images were obtained. The results showed that only two of twenty-nine femoral heads in the alendronate group and nineteen of twenty-five femoral heads in the control group went on to collapse. Only one hip in the alendronate group had total hip arthroplasty compared with sixteen hips in the control group. One potential concern relating to the experimental design is that the control patients did not receive a placebo medication. This, however, does not trouble me. First, given that there is no medication thought to be useful to prevent the progression of osteonecrosis, there is no logical basis for a placebo medication and no ethical reason to ask patients to take an unnecessary drug. Second, while the lack of a placebo group prevents blinding of the patients and investigators, radiographic evidence of collapse is both obvious and measurable and not likely to be influenced by investigator bias.

Bisphosphonates are metabolically stable analogs of inorganic pyrophosphate in which the P-O-P bond has been replaced with a nonhydrolyzable P-C-P bond. The three-dimensional structure of the molecule allows it to bind divalent ions such as calcium and is the basis for its bone-targeting property. Two pharmacological classes of bisphosphonates exist: nitrogen-containing and non-nitrogen-containing compounds. The nitrogen-containing group, of which alendronate is a member, exerts its effect by inhibiting components of the intracellular mevalonate pathway, the biosynthetic pathway responsible for cholesterol production. Although this pathway is fairly complex, the end result of its inhibition is to prevent prenylation of certain intracellular proteins, and when this occurs within osteoclasts, it prevents their ability to resorb bone3. Because osteoclastic resorption of necrotic subchondral bone may lead to a mechanical weakening of the femoral head resulting in collapse, a down-regulation of osteoclastic activity has been suggested to attenuate or prevent the progression of osteonecrosis. Little et al.4, using a model of atraumatic osteonecrosis induced in young rats, found preservation of femoral head architecture six weeks after treatment with an extremely potent nitrogen-containing bisphosphonate, zoledronic acid. A more recent study of pigs treated with ibandronate demonstrated similar findings with preservation of the femoral head epiphyseal quotient (height divided by diameter)5. These investigations in animals provide a scientific basis for the use of bisphosphonates in the prevention of progression of osteonecrosis and may explain the findings reported by Lai et al. in patients.

Little is known of the mechanical properties of necrotic bone at sites in which it supports weight-bearing joints. Indeed, even if osteoclasts were unavailable, it is reasonable to question how well a necrotic femoral head would maintain its integrity over time. Moreover, as osteonecrotic bone is known to be denser than normal trabecular bone, the vitality of overlying articular cartilage may be compromised6.

The potential use of a widely available class of pharmacological agents in a musculoskeletal condition heretofore thought to be untreatable by nonoperative means heralds a new chapter in the management of osteonecrosis. At this time, there are seven bisphosphonates, including alendronate, that have achieved FDA approval status for the treatment of one or more metabolic bone diseases. Thus, the potential for off-label use (and misuse) of these drugs is substantial. For this reason, I would strongly urge surgeons to resist the temptation to use bisphosphonates in the treatment of osteonecrosis until more is learned about their role. For example, the optimum dosage of alendronate in osteonecrosis is not presently known. Although, in this study, the investigators used 70 mg orally once per week, which is the most commonly used dose regimen for the treatment of osteoporosis, this may not be the optimum regimen for the treatment of other conditions. Indeed, in the treatment of Paget disease, much higher doses are needed. Second, while most bisphosphonates have been shown to be safe in the management of bone diseases, recent reports have begun to suggest potential concerns relating to the impaired healing of microcracks, microfractures, and stress fractures in patients who are using these drugs7. Since these subtle fractures may be prevalent in and around osteonecrotic bone, surgeons may need to be wary of the long-term effects of bisphosphonates in these patients. Finally, several recent reports have suggested that bisphosphonates may actually cause osteonecrosis of the jaw in certain patients, particularly those who have cancer, are undergoing dental procedures, have poor dental hygiene, are undergoing corticosteroid therapy, or who have been exposed to local radiotherapy8,9.

Despite these caveats, the body of evidence suggesting a potential role for bisphosphonates in the treatment of osteonecrosis provides new opportunities for clinicians and scientists to bring this disease under control. I would encourage surgeons who have access to large groups of patients with osteonecrosis to consider prospective clinical trials, and funding agencies such as the National Institutes of Health, the Orthopaedic Research and Education Foundation, and the Arthritis Foundation to prioritize the support of these investigations. If this concept succeeds, orthopaedics will have taken a major step forward.

*The author did not receive grants or outside funding in support of his research or preparation of this manuscript. He did not receive payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the author is affiliated or associated.

References

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2. Lai KA, Shen WJ, Yang CY, Shao CJ, Hsu JT, Lin RM. The use of alendronate to prevent early collapse of the femoral head in patients with nontraumatic osteonecrosis: a randomized clinical study. J Bone Joint Surg Am. 2005;87:2155-9.
3. Morris CD, Einhorn TA. Bisphosphonates in orthopaedic surgery. J Bone Joint Surg Am. 2005;87:1609-18.
4. Little DG, Peat RA, Mcevoy A, Williams PR, Smith EJ, Baldock PA. Zoledronic acid treatment results in retention of femoral head structure after traumatic osteonecrosis in young Wistar rats. J Bone Miner Res. 2003;18:2016-22.
5. Kim H, Randall TS, Bian H, Jenkins JR, Garces A, Bauss F. Ibandronate decreases femoral head deformity following ischemic necrosis of the capital femoral epiphysis in immature pigs. Trans Orthop Res Soc. 2004;29:151.
6. Ewald FC, Poss R, Pugh J, Schiller AL, Sledge CB. Hip cartilage supported by methacrylate in canine arthroplasty. Clin Orthop Relat Res. 1982;171:273-79.
7. Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CY. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab. 2005;90:1294-301.
8. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004;62:527-34.
9. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 2003;61:1115-7.