Co-administration of Antiresorptive and Anabolic Agents: A Missed Opportunity

Abstract

Co-administration of antiresorptive and anabolic therapies has appeal because these treatments target the two main abnormalities in bone remodeling responsible for bone loss and microstructural deterioration. Antiresorptives reduce the number of basic multicellular units (BMUs) remodeling bone and reduce the volume of bone each BMU resorbs. Intermittent parathyroid hormone (PTH) increases the volume of bone formed by existing BMUs and those generated by PTH administration. PTH also increases bone formation by stimulating the differentiation, maturation, and longevity of osteoblast lineage cells residing upon quiescent bone surfaces. Despite these rationally targeted actions, enthusiasm for this approach waned when combined therapy blunted the increase in areal bone mineral density (aBMD) relative to that produced by PTH. Although many studies have since reported additive effects of combined therapy, whatever the aBMD result (blunting, additive, or null), these outcomes give little, if any, insight into changes in bone's material composition or microstructure and give misleading information concerning the net effects on bone strength. Combined therapy remains a potentially valuable approach to therapy. Because studies of antifracture efficacy comparing combined with single therapy are unlikely to be performed in humans, efforts should be directed toward improving methods of quantifying the net effects of combined therapy on bone's material composition, microarchitecture, and strength.

Irreversible Deterioration of Cortical and Trabecular Microstructure Associated With Breastfeeding

“…The rapid increase in cortical porosity and decrease in trabecular BV/TV are the net result of many excavated sites that appear at the same time as refilling occurs in the fewer cavities excavated pre-lactation, before remodeling becomes rapid. (35) The fewer sites excavated pre-lactation do not refill immediately. Refilling is delayed by the reversal phase, and then proceeds slowly, during 3 months, and so occurs during early lactation when rapid remodeling begins.…”

“…Refilling is delayed by the reversal phase, and then proceeds slowly, during 3 months, and so occurs during early lactation when rapid remodeling begins. (35) This delay in the initiation and slowness of the refilling phase produces a transient deficit in bone matrix and mineral. (36) If rapid remodeling was the only abnormality associated with estrogen deficiency, the increase in cortical porosity and decrease in trabecular density produced would be expected to be fully reversed because all the cavities excavated producing the transient deficit in bone matrix and mineral eventually fully reverse with cessation of lactation and restoration of estrogen production.…”

Abaloparatide Is an Anabolic, but Does It Spare Resorption?

“…(13,14) The delay in resorption marker increase after starting PTH treatment can be explained by the principles of basic multicellular unit (BMU)-based remodeling. (15)(16)(17)(18) BMUs remodeling bone are in their resorptive, reversal, or formative phases. At any time, there are more BMUs in their formation phase at various locations than there are BMUs in their resorption phase at other locations (because the duration of the formation phase is longer than the resorption phase).…”

“…(43,44) As discussed below and elsewhere, resorption and formation "markers" are not accurate surrogates of volumes of bone matrix resorbed or formed. (18,45) Whether PTHrP(1-36) and teriparatide produce a similar anabolic effect but PTHrP(1-36) produces less bone resorption than teriparatide was not evaluated; no histomorphometry was performed. However, a recent large study of iliac crest biopsies from the Miller and colleagues study (1) reported no differences in static or dynamic indices of bone formation or resorption between the two drugs.…”

“…There are formidable challenges in determining whether less bone is resorbed using abaloparatide than teriparatide when remodeling markers are used as surrogates of these cellular events. (18,45) The biochemical measurements correlate weakly with radiokinetic measurements of remodeling or the surface extent of bone remodeling determined using histomorphometry. (58,59) No correlations with measures of the volumes of bone resorbed or deposited upon a skeletal surface have been reported.…”