Effect of sequential treatments with alendronate, parathyroid hormone (1–34) and raloxifene on cortical bone mass and strength in ovariectomized rats

Abstract

Anti-resorptive and anabolic agents are often prescribed for the treatment of osteoporosis continuously or sequentially for many years. However their impact on cortical bone quality and bone strength is not clear. Methods Six-month old female rats were either sham operated or ovariectomized (OVX). OVX rats were left untreated for two months and then were treated with vehicle (Veh), hPTH (1-34) (PTH), alendronate (Aln), or raloxifene (Ral) sequentially for three month intervals, for a total of three periods. Mid-tibial cortical bone architecture, mass, mineralization, and strength were measured on necropsy samples obtained after each period. Bone indentation properties were measured on proximal femur necropsy samples. Results Eight or more months of estrogen deficiency in rats resulted in decreased cortical bone area and thickness. Treatment with PTH for 3 months caused the deposition of endocortical lamellar bone that increased cortical bone area, thickness, and strength. These improvements were lost when PTH was withdrawn without followup treatment, but were maintained for the maximum times tested, six months with Ral and three months with Aln. Pre-treatment with anti-resorptives was also somewhat successful in ultimately preserving the additional endocortical lamellar bone formed under PTH treatment. These treatments did not affect bone indentation properties. Summary Sequential therapy that involved both PTH and anti-resorptive agents was required to achieve lasting improvements in cortical area, thickness, and strength in OVX rats. Anti-resorptive therapy, either prior to or following PTH, was required to preserve gains attributable to an anabolic agent.

Raloxifene Improves Bone Mechanical Properties in Mice Previously Treated with Zoledronate

“…Most studies have combined anti-resorptive (mainly bisphosphonates) and anabolic (mainly PTH) treatments due to their distinctly different mechanisms of action. One clinical study and a few preclinical studies have combined bisphosphonates with raloxifene, although they have done so as co-administration of drugs [37–39]. Results have mainly focused on BMD and biomarkers, with modest benefits of combination treatment.…”

PDGFB-based stem cell gene therapy increases bone strength in the mouse

“…It also avoided adverse effects, such as osteomalacia, and led to a 45% increase in bone strength (maximal load to failure). In this respect, no traditional monotherapy for osteoporosis has shown long-term beneficial effect on the bone strength of the treated bone (16). Moreover, our therapy uniquely produced a 20-fold increase in trabecular connectivity and substantial reduction in cortical porosity, both of which are relevant to the bone mechanical performance.…”

Safety issues and adverse reactions with osteoporosis management

“…This limited duration of treatment was later found to be ideal also in terms of efficacy, since a more extended treatment course is likely to be associated with loss of efficacy. The efficacy of TPD is likely to be resumed after a treatment holiday, even though the opportunity to repeat a second course of treatment remains poorly investigated and still off-label [71]. …”