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Combination Treatment with Sclerostin and Dkk1 Antibodies Synergizes with Tibial Loading to Stimulate Bone Formation
Abstract:
Aging is associated with decreased bone formation and bone mass and increased fracture risk. Wnt pathway activation by mechanical loading is a potent strategy to improve bone mass, however, load-induced bone formation is diminished with aging. Neutralizing antibody (Ab) therapies targeting Wnt pathway inhibitors Sclerostin (Scl) and Dickkopf-related protein 1 (Dkk1) have proven successful in preclinical and clinical osteoporotic conditions. We asked whether treatment combining Scl-Ab and Dkk1-Ab can increase load-induced bone formation in a preclinical model of osteoporosis. Aged (22-month) C57BL/6N female mice underwent combination Scl-Ab plus Dkk1-Ab therapy (15 mg/kg each; subcutaneously; 2x/wk; saline control) for 2 weeks, concomitant with a mechanical loading regimen previously shown to induce modest bone formation in tibias of aged mice (-2200 με, 1200 cycles/day, 5 day/wk). Changes in bone morphology and formation were assessed by longitudinal microCT and dynamic histomorphometry, respectively. Molecular indices of bone formation and Wnt pathway activation were assessed by qPCR of cortical bone. Treatment with Scl-Ab plus Dkk1-Ab induced significant improvements in cancellous (BV/TV +50%) and cortical morphology (Ct.Th +25%) in non-loaded limbs of antibody-treated mice vs. vehicle control mice. Importantly, periosteal bone formation rate was 10-fold higher in loaded limbs of antibody versus vehicle treated mice, indicating a synergistic effect. Gene expression analysis showed that antibody treatment and loading synergistically upregulated Wnt1 expression, which may have contributed to the observed synergistic effect on bone formation. These results confirm the potent anabolic effect of combination Scl plus Dkk1 antibody treatment. Moreover, they show that antibody treatment and skeletal loading are more effective at increasing periosteal bone formation in aged mice than either treatment alone. These findings support the concept that combinatorial therapy using dual Scl and Dkk1 antibodies plus weight-bearing exercise may be an effective treatment for age-related osteoporosis.
Insights
Combination therapy with Sclerostin (Scl)-Ab and Dickkopf-related protein 1 (Dkk1)-Ab plus mechanical loading significantly boosts bone formation in aged mice, offering a promising treatment for osteoporosis.
Area of Science:
- Gerontology
- Bone Biology
- Pharmacology
Background:
- Aging reduces bone formation and increases fracture risk.
- Mechanical loading normally stimulates bone formation, but this response is blunted in aging.
- Wnt pathway inhibitors like Sclerostin (Scl) and Dickkopf-related protein 1 (Dkk1) are targets for osteoporosis treatment.
Purpose of the Study:
- To investigate if combining Scl antibody (Ab) and Dkk1 Ab therapy with mechanical loading enhances bone formation in aged mice.
- To assess the synergistic effects of dual Wnt inhibitor blockade and mechanical stimulation on bone in a preclinical osteoporosis model.
Main Methods:
- Aged mice received combination Scl-Ab and Dkk1-Ab therapy or saline control for two weeks.
- Mechanical loading was applied to tibias concurrently with antibody treatment.
- Bone morphology was analyzed using microCT, and bone formation was assessed by dynamic histomorphometry.
- Gene expression of Wnt pathway components was analyzed in cortical bone.
Main Results:
- Combination antibody therapy improved cancellous and cortical bone morphology in non-loaded limbs.
- Periosteal bone formation rate was significantly higher (10-fold) in loaded limbs of antibody-treated mice compared to controls, indicating synergy.
- Antibody treatment and loading synergistically upregulated Wnt1 gene expression, correlating with increased bone formation.
Conclusions:
- Combination Scl and Dkk1 antibody therapy is a potent anabolic treatment for bone.
- Combined antibody therapy and skeletal loading are more effective than either intervention alone for increasing periosteal bone formation in aged mice.
- This dual therapy approach holds promise for treating age-related osteoporosis when combined with weight-bearing exercise.
