Effects of bisphosphonates on the mechanical efficiency of normal and osteopenic bones

: Bone mechanical competence (stiffness, strength) at organ level is determined by mechanical quality (intrinsic stiffness) and spatial distribution (macro-architecture) of bone material in cortical tissue (in every bone) and trabecular network (in vertebral bodies). These properties are inter-related and controlled according to mechanical usage by a feed-back mechanism known as mechanostat. Therefore, the effects on bone fragility of any treatment should be evaluated concerning the way they may have affected bone material or geometric properties as well as the mechanostatical interactions between them. Standard densitometry does not provide the necessary data, but some alternative methodologies (as peripheral quantitative computed tomography, pQCT) are being developed to complement or even substitute SPA, DPA or DXA determinations. Bisphosphonate (BP) effects on bone biomechanics have been studied only in animal models. Many sources of variation of results (type of compound, dose, mode of administration, species, race, sex, age, age since menopause, type of bone, remodeling ability of the skeleton, endocrine-metabolic status, interactions with other treatments, etc.) have been reported. In general terms, BPs are beneficial concerning cortical bone strength in purely modeling species (rodents) and trabecular strength in remodeling mammals (dogs, baboons). This positive action at organ level depends on independent improvements in bone macro-architecture (mainly affected by bone modeling) and material stiffness (chiefly affected by bone composition and remodeling). On one hand, bone macro-architecture has been positively affected by BPs in normal (not in ovariectomy (OX), steroid- or disuse-induced osteopenic) animals. On the other, bone material quality has been improved in the latter but not in the former. Mechanostatic interrelationships have been differently affected according to the compound employed. Results reported by ours and other laboratories concerning the three derivatives available nowadays in Argentina were reviewed and summarized. Pamidronate improved small rodents' cortical bone strength and geometric properties at low doses but impaired mineralization, material properties and strength at toxic doses. In normal, remodeling animals it improved mechanical properties in vertebral bodies but not in long bones. It also prevented the negative impact of OX-, steroid- or disuse-induced osteopenia in rats by improving bone material properties without affecting normal mechanostatic interrelationships. Olpadronate exerted positive effects on long-bone strength at any dose in normal rats and mice by improving cross-sectional properties and preserving both mineralization and material properties. These effects were highly dependent upon bone deformability, body weight, and mechanical usage of the limb as an evidence of an anabolic interaction induced on bone modeling and mechanostatic interrelationships. This compound also prevented the OX- or disuse-induced impairment in rat cortical long-bone strength and recovered rat cortical bone when given since 3 months after OX by improving only bone material quality. No interaction with bone mechanostat was detected in these studies. Alendronate effects on bone biomechanics in normal rats and dogs were positive only in long treatments. They were highly dependent on body weight of the animals, hence a positive interaction with bone mechanostat should be hypothesized. It also prevented the negative impact of OX in rat femurs by improving cortical material quality with no effect on cross-sectional properties, i.e., exerting an anti-catabolic interaction with bone mechanostat. The effects of all the three compounds were found positive for bone health, yet their mechanisms of action varied with type of bone and subject condition. A striking dissociation between (positive) effects on bone strength and (variable) effects on bone stiffness was repeatedly observed in these studies. Also an enla