Effects of sequential osteoporosis treatments on trabecular bone in adult rats with low bone mass.
We used an osteopenic adult ovariectomized (OVX) rat model to evaluate various sequential treatments for osteoporosis, using FDA-approved agents with complementary tissue-level mechanisms of action. Sequential treatment for 3 months each with alendronate (Aln), followed by PTH, followed by resumption of Aln, created the highest trabecular bone mass, best microarchitecture, and highest bone strength.


BACKGROUND
Individual agents used to treat human osteoporosis reduce fracture risk by ∼ 50-60%. As agents that act with complementary mechanisms are available, sequential therapies that mix antiresorptive and anabolic agents could improve fracture risk reduction, when compared with monotherapies.


METHODS
We evaluated bone mass, bone microarchitecture, and bone strength in adult OVX, osteopenic rats, during different sequences of vehicle (Veh), parathyroid hormone (PTH), Aln, or raloxifene (Ral) in three 90-day treatment periods, over 9 months. Differences among groups were evaluated. The interrelationships of bone mass and microarchitecture endpoints and their relationship to bone strength were studied.


RESULTS
Estrogen deficiency caused bone loss. OVX rats treated with Aln monotherapy had significantly better bone mass, microarchitecture, and bone strength than untreated OVX rats. Rats treated with an Aln drug holiday had bone mass and microarchitecture similar to the Aln monotherapy group but with significantly lower bone strength. PTH-treated rats had markedly higher bone endpoints, but all were lost after PTH withdrawal without follow-up treatment. Rats treated with PTH followed by Aln had better bone endpoints than those treated with Aln monotherapy, PTH monotherapy, or an Aln holiday. Rats treated initially with Aln or Ral, then switched to PTH, also had better bone endpoints, than monotherapy treatment. Rats treated with Aln, then PTH, and returned to Aln had the highest values for all endpoints.


CONCLUSIONS
Our data indicate that antiresorptive therapy can be coupled with an anabolic agent, to produce and maintain better bone mass, microarchitecture, and strength than can be achieved with any monotherapy.
Center for Musculoskeletal Health and Department of Medicine, University of California Davis Medical Center, 4625 2nd Avenue, Suite 1002, Sacramento, CA, 95817, USA.
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Amugongo
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Yao
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Jia
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Lay
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Dai
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Jiang
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Walsh
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Li
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Dave
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Olivera
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Panganiban
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Ritchie
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Lane
D019386:Alendronate / Q000627:therapeutic use; D000818:Animals; D015519:Bone Density / Q000187:drug effects*; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004359:Drug Therapy, Combination; D005260:Female; D005269:Femur / Q000503:physiopathology; D020249:Hormone Replacement Therapy / Q000379:methods; D008159:Lumbar Vertebrae / Q000503:physiopathology; D010024:Osteoporosis / Q000188:drug therapy* / Q000503:physiopathology; D058866:Osteoporotic Fractures / Q000503:physiopathology / Q000517:prevention & control; D010052:Ovariectomy; D010281:Parathyroid Hormone / Q000627:therapeutic use; D020849:Raloxifene Hydrochloride / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013314:Stress, Mechanical; D016474:Weight-Bearing; D055114:X-Ray Microtomography / Q000379:methods
D050071:Bone Density Conservation Agents; D010281:Parathyroid Hormone; D020849:Raloxifene Hydrochloride; D019386:Alendronate