Bone Vol. 19, No. 3, Supplement Abstracts September 1996: 129S-169s The 7th International Congress of Bone Morphometry

155s

103 THE EFFECTS OF PTH AND FLUORIDE ON BONE QUALITY Lis Mosekilde, Dept. of Cell Biology, Inst. of Anatomy, University of AarhuS, 8000 &hus C, Denmark.

Before accepting aI’ty agent for clinical osteoporosis trials, FDA requires that its efficacy has been proven in a small animal model and also in a larger animal model with known intracortical bone remodelling. This efficacy should be proven concerning both bone mass and biomechanical competence.

In the present overview, &JO anaholic agents: PTH and fluoride will be discussed cdnterning their influence on bone mass and bone’strength. Both drugs have been followed from small animal models to large animal models and, finally, to clinical sttidies.

Fluoride has consistently shown a discrepancy between changes in bone mass and bone strength during treatment, indicating a negative influence of fluoride on bone material quality. This seems mainly caused by deleterious effects on newly formed bone tissue. On the other hand, PTH has consistently shown that the induced increase in bone mass was followed by a similar increase in bone strength - at all skeletal sites measured. This indicates that PTH induces formation of new bone of normal material quality. Furthermore, do’ sign, of cortical steal, phncxnenon was disclosed in either stir41 or’ large animal’ tidd& duping PTH treatment.

It is concluded.thht theie is a marked difference between the effects of the two an&&c agents fluoride and’PT%I, and that it is only PTH that’p<dtiuce’s bode of normal niaterial quality.

104 0sTEocnE ANb I\~(IC~~OFRACTURE LOCATION IN HUMAN LAMELLAR BONE. M.A. Muglia, G. Marotti Dipartimento di Scienze Morfologiche e Medico Legali Sezione di Anatomia umana. Modena (Italy)

The classical model of bone lamellation was not confirmed by personal PLM, SEM and TEM studies. We found that: (a) bony lamellae do not have the same structure, since collagen-poor cellular layers (loose lame/lab) alternate with collage&rich acellular layers (dense lamellae); (b) collagetl fibers are highly interwoven inside all lamellae.‘,* T& test mechanical properties of lamellae, a combined SEM and’ PLM ahalysis was carried out on cylinders (150pm thick, 400pm dihmeter) drilled from fresh human compact bone, subjected to compression perperidicular to their axis, in oid& to produce microfractures.’ Microfractures inside cross- and longitudinal-sections of bone surrotinding a femoral prbsthesis, taken from a Cadaver, were also studied. Both experimentally-induced microfractures and those in periprostheiic b&e were found to occur inside loose larnellae only, i.e. osteocytic lamellae. Asceqzi et al.,3 too, found microfractures inside longitudinal lamellae only, but longitudirial lamellae correspond to our loose ones. The occurrence of osteocyte laclinae and microfractures inside lamellae having the loose configuration in both cross- and longitudinal-sections additionally proofs thatcqllagen fibers do not follow a preferential orientation inside lamellae; if.the classical model we& ti’ue both lacufiae and microfra&rl?s should occur in lamellae showing an inverse appearance in cross- and longitudina!- section respectively. The present results demonstrate that bony lamellae also differ from the mechanical viewpoint: dense lamellae, thanks to their dense collagen texture and acellularity appear to be stronger and capable of withstanding mainly tensile strain, whereas loose /ama//ae owing to their loose structure and cellular, content seem to be less resistant. The co-localization of microfractures and osteocytes fits with the hypothesis that in vivo fatigue damage could be repaired by remodeiing processes tiiggered by dstijocytes. 1. Marotti G.. Muglia M.A., Arch. ital. Anat. Embriol. 93:163-175. 1966 2. Marotti G., Calcif. Tissue Int. 53:S47-S56 3. Ascenzi A., Bonucci E., Simkin A. J Biomechanics 6:227-235, 1973

105 OSTEOCYTE DENSITY AND ~~~RPHoMETRIc PARAMETERS IN CANCELLOUS BONE IN FIVE MAMMALIAN SPECIES

M&&$&n& R. Huiskes H. Versleyen P. Buma

Biomech. & Histomorphol. Sections, Inst. Orthop., Univ. ?%jmb&n; Ttie NMherlands

It is assumed that osteocytes are m&zhano-sensory cells, wliidh r.$ggulate bone

adaptation’. A computer model based on this hypothesis predicted thl trabecular

thickness is regulated by the range of action of osteocytes and is independent of their

density, while osteocyte density affects the rate of bone remodeling’. To validate

these predictions, we have measured histomorphometric pamme& and osteocyte

densities in trabecular bone of five different mammal> of various sizes.

Femurs were obtained from adult mammals (6 Wistar rats, 6 New Zealand white

rabbits, 7 Rhesus monkeys, 6 pigs, 5 cows). Morphometric parameters’were measured

in the right femoral heads by digital analysis. Bone volumk fraction, bone surface per

bone volume, mean trabecular thickness, separation and number were calculated’.

Ostcocyte nuclei were counted in trabecular bone of the left femoral’heads, using a

microscope and a digital image analysis system. Means (i SD) of all p&ram&en were

determined per group. Differences between groups were tested using ANOVA.

Trabecular thickness and separation were lower and trabecular number was larger

in rats than in the other species (p<O.Ol). The opposite was true, for these parameters

in the cow (p<O.Ol, trabecular thickness in cow did not differ from rabbit). The

morphometric parameters of rabbit, monkey and pig were not different, only

trabecular separation was higher in pig than in monkey (p<O.Ol). The.nu&bers of

osteocyte nuclei per bone area were similar for animals of the saitia species, but

differed between all species (p<O.Ol), except between pig and monkey. The values

decreased with increasing animal size from 943/mm* (rat) to 295iinm’ (Crm):

The smaller trabecular thickness in the rat may he due to the pres&ce‘ of growth

plates in adult rats, which causes a different regulatory and mtchanitil enCironm&t hi the o&&‘s’@cies, the relative range of wriation’of trabe’culti thi&ne& was small,

indicating t!iitt’,the domain regulated by the individual ostebcyta is of similsi size in

these speciei Conversely, osteocyte density in trabedular bone varie? wldkly between

species, and is’inversely related to species size. As metab6lic rate ,is also ihversely

related to bdd$‘si&, this agrees with the prediction that osteocyte density affects the rate of bone ttimover. The relationships with species are different for osteocyte

density than for morphometric parameters, which supports our hydothesis that

osteocyte density is not directly related lo the macroscopic tr~a+ulai architecture. I. Mullender MG, Huiskes R, JOrrhop Res 13: 503-12, 1995; 2. Spaargaren OH, Acra

Biorheor42: 263-9, 1994; 3. Partitt AM et al, J Bone Min Res 2: 595-610. 1987.

106 THE CALClMiMETlC COtiPOtJND NPS R-j66 H’AS Ati ANAti.OLIC-LIKE A’cl+iON’ IN THE BONES dF tJREMi% RATS WITH A LOW TURNOVER BONE LESION’ N. Nagano, M. Wada, Y. Furaya, H. Ishii, E.F. Nemeth, m Pharmaceutical Research Laboratory. Kirin Brewery, Takasaki (Japan); NPS Pharmaceuticals, Salt Lake City, UT (USA)

The parathyroid cell-surface C$+ receptor (CaR) plays a key role in sensing changes iv the co?centration of extracellular Ca*+ and regulating PTH secretion. NPS R-568 is a calcimlm&ic cotipound that acts as an agonist at the CaR and suppresses PTH releasd. We have tested the’ effects of NPS’R-568 administration on the bones of male rats with hyperparathyroidism secondary to chronjc~ renal inSufficiency (CRI) induced by i.v. injections of adriamycin (ADR; 3 and 2 m&kg giveri at an Interval of 3 weeks). Four months after the first ADR injection, the C@I rats were d[vided into 4 matched groups and NPS R-568,tias-given either by daily gavage (10 mg/kg) or by S.C. infusion (0.9 or 4.4 rng/kp da9 by osmotic minipump) for 57 days. Saline-injected normal and control CRI rats received a S.C. infusion of vehicle. In the CR1 - Vehiclb group, serum creatiliine ahd PTH levtils increasid Q-fold, tiheteas 1,25’(0@,Ds, alkaline phosphatase and urinary deox@yridinbiine. I&&Is w&e- significantly Ibwer. Bone mineral density (BMD) was’ red&c&d’& 18% in the distal femur. In the proximal tibia1 metaphysis, c&ce!lous‘bone volume (BVITV) and trabeculqr thickness (Tb.Th.) were 67 and 30% lower, respectively, with a >5O% decrease in BFR‘ and a! increase in osteoid volume (OV/EV r 15%). This-indidates’tha! ADR-injeCt&l Gel rats produce a low-turnover bdne With osteotialacia. NPS’R-568 suppressed PTH levels-in a pulsatile mannei when adminiiterbd orally, but in a sustained fashion when infused. Oral, but not S.C. administered NPS R-568 led lb; significant’iricieases in BUD in the distal fern&, aqd in BFR, BVm/ and Tb.Th. in the proximal tibia1 metaphy$iq. T$s,, these results demonstrate that the daily oral administratidn of NPS R-568 ‘has a beneficial effect in rats tiith CRI and low-turnover bone-by incr&sing, BFR and bone mass. In conclusion,-jntermitti?nt suppreSsion of the elevated PTH levels in rats with CRI appeared to mimic the anabolic effects on bone of exogenously administered PTH that is seen in‘rats with normal renal function.