EFFECTS OF BISPHOSPHONATES ON THE MECHANICAL COMPETENCE OF NORMAL ANDOSTEOPENIC SKELETONS

Bone mechanical competence (stiffness, strength) at organ level is det ermined by mechanical quality (intrinsic stiffness) and spatial distri bution (macro-architecture) of bone material in cortical tissue (in ev ery bone) and trabecular network (in vertebral bodies). These properti es are interrelated and controlled according to mechanical usage by a feed-back mechanism known as mechanostat. Therefore, the effects on bo ne fragility of any treatment should be evaluated concerning the way t hey 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 methodologie s (as peripheral quantitative computed tomography, pQCT) are being dev eloped to complement or even substitute SPA, DPA or DXA determinations . Bisphosphonate (BP) effects on bone biomechanics have been studied o nly in animal models. Many sources of variation of results (type of co mpound, dose, mode of administration, species, race, sex, age, age sin ce menopause, type of bone, remodeling ability of the skeleton, endocr ine-metabolic status, interactions with other treatments, etc.) have b een reported. In general terms, BPs are beneficial concerning cortical bone strength in purely modeling species (rodents) and trabecular str ength in remodeling mammals (dogs, baboons). This positive action at o rgan level depends on independent improvements in bone macro-architect ure (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 ov ariectomy (OX), steroid-or disuse-induced osteopenic) animals. On the other, bone material quality has been improved in the latter but not i n the former. Mechanostatic interrelationships have been differently a ffected according to the compound employed. Results reported by ours a nd other laboratories concerning the three derivatives available nowad ays in Argentina were reviewed and summarized. Pamidronate improved sm all rodents' cortical bone strength and geometric properties at low do ses but impaired mineralization, material properties and strength at t oxic doses. In normal, remodeling animals it improved mechanical prope rties 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 mechano static interrelationships. Olpadronate exerted positive effects on lon g-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 deformabilit y, body weight, and mechanical usage of the limb as an evidence of an anabolic interaction induced on bone modeling and mechanostatic interr elationships. This compound also prevented the OX- or disuse-induced i mpairment in rat cortical long-bone strength and recovered rat cortica l bone when given since 3 months after OX by improving only bone mater ial quality. No interaction with bone mechanostat was detected in thes e studies. Alendronate effects on bone biomechanics in normal rats and dogs were positive only in long treatments. They were highly dependen t on body weight of the animals, hence a positive interaction with bon e mechanostat should be hypothesized. It also prevented the negative i mpact of OX in rat femurs by improving cortical material quality with no effect on cross-sectional properties, i.e., exerting an anti-catabo lic interaction with bone mechanostat. The effects of all the three co mpounds were found positive for bone health, yet their mechanisms of a ction varied with type of bone and subject condition. A striking disso ciation between (positive) effects on bone strength and (variable) eff ects on bone stiffness was repeatedly observed in these studies. Also an enlargement of the plastic-strain (i.e., irreversible, microfractur e-dependent deformation) component of long-bone strength in bending wa s produced in many instances. This may be interpreted as an evidence a gainst the potentiality of the analyzed BPs to enhance microfracture a ccumulation into bone matrix because of an excessive inhibition of bon e remodeling. Nevertheless, large amounts of non-reabsorbed, calcified cartilage were found in femur metaphyses from very young rats treated with high doses of olpadronate. These BP effects, together with their demonstrated potentiation when administered in combination with anabo lic agents like hPTH, prostaglandin-E2 or IGF-I (that improve bone mod eling and whose durability depends largely on bone remodeling rate), s upport pure or combined BP treatment of bone-weakening diseases. Altho ugh there is no convincing evidence on microfracture accumulation duri ng BP treatment, it should be advisable to avoid an excessive inhibiti on of bone remodeling, especially in young individuals.