We highly appreciate Drs. Hill and Richarson’s letter regarding our recent review article entitled “Osteocyte-derived sclerostin inhibits bone formation: its role in bone morphogenetic protein and Wnt signaling"(1).

One important factor that promotes bone loss at the peri-implant site is the wear debris-mediated activation of osteoclasts(2). However, whereas short-term improvements have been reported with the osteoclast inhibiting bisphosphonates, these agents may not prevent peri-prosthetic bone loss in the long term(2, 3). These results not only indicate that other factors are at play (for example. those that may compromise the activity of bone forming osteoblasts) but also the need to find solutions for this clinical problem.

Stress shielding of bone by relatively stiff metallic prostheses has been attributed as another determinant that promotes bone loss(4). As pointed out by Hill and Richardson, sclerostin is an important sensor that regulates osteoblast activity and bone mass in response to changes in mechanical stress(5), and therefore its expression may well be increased at bone sites surrounding the prosthetic components that are subjected to stress shielding. If so, the increased sclerostin expression may lead to decreased bone formation by osteoblasts, and make sclerostin a target for therapeutic intervention.

We, therefore, fully agree with Drs. Hill and Richarson that there is an exiting therapeutic potential for sclerostin antagonists alone (or in combination with bisphosphonates) in the prevention of peri-prosthetic bone loss induced by stress shielding.

References:

1. ten Dijke P, Krause C, de Gorter DJ, Löwik CW, van Bezooijen RL. Osteocyte-derived sclerostin inhibits bone formation: its role in bone morphogenetic protein and Wnt signaling. J Bone Joint Surg Am. 2008;90 Suppl 1:31-5.

2. Tsiridis E, Gamie Z, Conaghan PG, Giannoudis PV. Biological options to enhance periprosthetic bone mass. Injury. 2007; 38:704-13.

3. von Knoch F, Eckhardt C, Alabre CI, Schneider E, Rubash HE, Shanbhag AS. Anabolic effects of bisphosphonates on peri-implant bone stock. Biomaterials. 2007;28:3549-59.

4. Huiskes R, Weinans H, van Rietbergen B. The relationship between stress shielding and bone resorption around total hip stems and the effects of flexible materials. Clin Orthop Relat Res. 1992:124-34.

5. Robling AG, Niziolek PJ, Baldridge LA, Condon KW, Allen MR, Alam I, Mantila SM, Gluhak-Heinrich J, Bellido TM, Harris SE, Turner CH. Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J Biol Chem. 2008;283:5866-75.

To The Editor:

We read with interest the review by Dijke et al. regarding the role of Sclerostin in bone formation(1). The authors suggest that further knowledge of the mechanism of action of Sclerostin may enable inhibition of the molecule to be exploited for the treatment of osteoporosis. Indeed, a monoclonal antibody to Sclerostin (AMG-785), currently in clinical trials, has been reported to increase markers of bone formation in post-menopausal women(2).

We propose two additional lines of investigation, namely the possible role for Sclerostin inhibitors in the prevention of peri-prosthetic bone loss, and in promoting osseo-integration.

Peri-prosthetic bone loss represents a significant complication of joint arthroplasty(3); as an epidemic of degenerative joint disease affects our aging populations, and in the absence of appropriate alternative means of treatment, peri-prosthetic bone-loss and implant loosening warrant the development of mechanobiological management strategies. A number of biological mediators are under investigation for their potential role in ameliorating this problem(4).

Bone loss occurs as a response to the discrepancy in stiffness between prosthetic components and surrounding bone, and consequently, stress shielding of peri-prosthetic bone. That is, reduced mechanotransduction in peri-prosthetic bone leads to a net reduction in bone formation.

As Dijke et al. mention, Sclerostin production is reduced by mechanical stimulation(5). Crucially, the primary inhibitive target of Sclerostin, osteoblast membrane receptor LRP5, appears to be pivotal in the osteogenic response to mechanotransduction(6). Therefore, we suggest that long-term inhibition of Sclerostin in peri-prosthetic bone may reduce antagonism of LRP5 in that area, with the net effect of lowering the threshold for stress transduction required to maintain bone density. Sclerostin inhibitors may, therefore, skew the balance of bone remodeling towards net formation, protecting peri-prosthetic bone stock without necessitating changes in current stress-shielding prosthetic designs.

Furthermore, shorter-term inhibition of Sclerostin to promote bone formation could be used in conjunction with osseo-conductive and –inductive prosetheses to engender osseo-integration.

In both cases, there appears to be significant potential for Sclerostin inhibition to provide additional benefit over existing techniques in the field of joint arthroplasty, and this avenue is one we suggest is worthy of exploration.

The authors did not receive any outside funding or grants in support of their research for or preparation of this work. Neither they nor a member of their immediate families received 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, division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, are affiliated or associated.

References:

1. ten Dijke P, Krause C, de Gorter DJJ et al. Osteocyte-Derived Sclerostin Inhibits Bone Formation: Its Role in Bone Morphogenic Protein and Wnt Signalling. J Bone Joint Surg Am. 2008;90:31-35.

2. Padhi D, Stouch B, Jang G et al. Anti-Sclerostin Antibody Increases Markers of Bone Formation in Healthy Postmenopausal Women. Am Soc Bone Miner Res. 2007;S37:abs 1129.

3. Tsiridis E, Haddad FS. Gie GA The management of periprosthetic femoral fractures around hip replacements. Injury 2003;34:95-105.

4. Tsiridis E, Gamie Z, Conaghan PG et al. Biological options to enhance periprosthetic bone mass. Injury. 2007; Jun;38(6):704-13.

5. Robling AG, Niziolek PJ, Baldridge LA et al. Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J Biol Chem. 2007;Dec 17.

6. Sawakami K, Robling AG, Ai M et al. The Wnt co-receptor LRP5 is essential for skeletal mechanotransduction but not for the anabolic bone response to parathyroid hormone treatment. J Biol Chem. 2006 Aug 18;281(33):23:698-711.