Mechanisms of the Anabolic Effects of Teriparatide on Bone: Insight From the Treatment of a Patient With Pycnodysostosis

Abstract

Pycnodysostosis is an extremely rare genetic osteosclerosis caused by cathepsin K deficiency. We hypothesized that teriparatide, a potent anabolic agent used in the treatment of osteoporosis, might reduce skeletal fragility by activating bone turnover. We studied a typical case of pycnodysostosis in a 37-yr-old woman who exhibited short stature, skull and thorax deformities, and a history of severe fragility fractures. Cathepsin K gene sequencing was performed. Before and after 6 mo of 20 g/d teriparatide, biochemical markers of bone turnover were measured, and 3D bone structure and microarchitecture was assessed in vivo by HR-pQCT. Qualitative and quantitative analysis of transiliac bone biopsies were performed, and the degree of mineralization was evaluated by quantitative microradiography. In vitro assessment of bone resorption was performed after separation and differentiation of CD14 + monocytes from peripheral blood. Bone structure assessed by HR-pQCT on the radius and tibia showed augmentation of cortical and trabecular density. Transiliac bone biopsy showed highly increased bone mass (+63% versus age-and sex-matched controls), a decrease in bone remodeling without evidence of active osteoblasts, and a severe decrease in the dynamic parameters of bone formation (mineralizing surfaces, −90% and bone formation rate, −93% versus age-and sex-matched controls). This depressed bone turnover probably explained the increased degree of mineralization. The presence of a novel missense mutation leading to an A141V amino acid substitution confirmed a genetic defect of cathepsin K as the cause of the disease. The deficiency of active osteoclasts was confirmed by an in vitro study that showed a decreased concentration of CD14 + monocytes (the precursor of osteoclasts) in blood. These osteoclasts had low resorptive activity when incubated on bone slices. After 6 mo of teriparatide, the structure, microarchitecture, and turnover of bone-assessed by HR-pQCT, histology, and bone turnover markers-remained unchanged. Our data strongly suggest that some features of the osteoclastic phenotype-that are absent in pycnodysostosis-are a prerequisite for the anabolic effect of PTH on osteoblasts.

Advances in osteoclast biology resulting from the study of osteopetrotic mutations

“…This line is further supported by a recent case report testing the activity of parathyroid hormone (PTH) in a pycnodysostotic patient. Consistent with the distorted bone formation seen in cathepsin K deWcient individuals, PTH showed no anabolic activity (Chavassieux et al 2008), supporting the hypothesis that bone formation cannot occur in resorption pits containing high levels of collagen Wbers.…”

“…Biochemical markers of bone turnover in pycnodysostosis demonstrated that the level of the cathepsin K generated type I collagen fragment (CTX-I) was greatly reduced, whereas the MMP generated type I collagen fragment (ICTP) was present in high amounts, indicating compensation by these proteases (Nishi et al 1999) In vitro cultured cathepsin K deWcient osteoclasts showed complete absence of CTX-I release (Chavassieux et al 2008). Compensation for lack of cathepsin K activity by MMPs is also seen in cultures of human osteoclasts challenged with the cysteine proteinase inhibitor E64 Henriksen et al 2006;Sassi et al 2000), a phenomenon also seen in cathepsin K deWcient mice (Kiviranta et al 2005).…”

Translational aspects of bone quality—vertebral fractures, cortical shell, microdamage and glycation: a tribute to Pierre D. Delmas

“…Furthermore, since tissue age is a key determinant of bone's damage morphology and is, in turn, related to bone turnover, a greater emphasis has been placed on the post-translational modifications of protein components and the increase in the mean degree of tissue mineralization, or DMB. Again through a number of studies over the last decade, the group in Lyon has demonstrated that reduced bone turnover increases DMB in a number of clinical situations including, but not limited to, bisphosphonate treatment [33] and cathepsin K deficiency [34]. DMB content also increases with tissue age and is consequently higher in interstitial than in the osteonal bone compartment, but an association between DMB and microdamage morphology or between DMB and bone fracture properties has not been established.…”

Future directions for new medical entities in osteoporosis

“…Although histomorphometry shows a markedly increased bone mass, bone forming indices (e.g. mineral apposition rate and bone formation rate) have been reported to be low in individuals with a cathepsin K mutation, and quite unresponsive to intermittent PTH [40]. The experimental evidence summarized below, however, suggests differently.…”