Abaloparatide is a peptide analog of parathyroid hormone-related protein (PTHrP 1-34) and was approved in 2017 as the second osteoanabolic peptide for treating osteoporosis. We previously showed that intermittent abaloparatide is equally as effective as PTH (1-34). This study was designed to compare the catabolic effects of PTH (1-34) and abaloparatide on bone in young female wild-type mice. Two-month-old C57Bl/6J female mice were continuously infused with human PTH (1-34) or abaloparatide at 80 μg/kg BW/day or vehicle for 2 weeks. At euthanasia, DEXA-PIXImus was performed to assess bone mineral density (BMD) in the whole body, femurs, tibiae, and vertebrae. Bone turnover marker levels were measured in sera, femurs were harvested for micro-computer tomography (μCT) analyses and histomorphometry, and tibiae were separated into cortical and trabecular fractions for gene expression analyses. Our results demonstrated that the infusion of abaloparatide resulted in a similar decrease in BMD as infused PTH (1-34) at all sites. μCT and histomorphometry analyses showed similar decreases in cortical bone thickness and BMD associated with an increase in bone turnover from the increased bone formation rate found by in vivo double labeling and serum P1NP and increased bone resorption as shown by osteoclast numbers and serum cross-linked C-telopeptide. Trabecular bone did not show major changes with either treatment. Osteoblastic gene expression analyses of trabecular and cortical bone revealed that infusion of PTH (1-34) or abaloparatide led to similar and different actions in genes of osteoblast differentiation and activity. As with intermittent and in vitro treatment, both infused PTH (1-34) and abaloparatide similarly regulated downstream genes of the PTHR1/SIK/HDAC4 pathway such as Sost and Mmp13 but differed for those of the PTHR1/SIK/CRTC pathway. Taken together, at the same dose, infused abaloparatide causes the same high bone turnover as infused PTH (1-34) with a net resorption in female wild-type mice. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Fluoride (F) exposure can cause osteosclerosis, which is characterised by a high bone mass, but its mechanism is not fully illustrated. Here, we aimed to evaluate the effects of excessive F exposure on the bone lesion by treating female Sprague-Dawley rats with different concentrations of sodium fluoride (NaF) (0, 55, 110 and 221 mg/L) for 90 days and the corresponding concentrations of fluorine ion (0, 25, 50 and 100 mg/L, respectively). Histopathological results showed that excessive F exposure caused the enlargement of trabeculae and their integration into one large piece, growth plate thickening, articular cartilage impairment and bone collagen abnormality. Meanwhile, F promoted calcium deposition and bone mineralisation, and induced abnormal osteogenesis increased. The results of micro-computed tomography also confirmed that excessive F destroyed the bone microstructure and induced a high-bone-mass phenotype, consistent with the results of pathomorphology. Mechanistically, excessive amounts of F led to angiogenesis inhibition and HIF-1α signalling enhancement. Subsequently, F induced autophagy and canonical Wnt/β-catenin signalling pathway activation. Collectively, these results manifested that F enhanced the hypoxia inducible factor-1α signalling, which in turn triggered autophagy and canonical Wnt/β-catenin signalling activation, ultimately leading to osteosclerosis in the rats.

Tumor-induced osteomalacia (TIO) is an ultrarare disorder that is caused by renal phosphate wasting due to uncontrolled tumoral production of fibroblast growth factor 23 (FGF23) from phosphaturic mesenchymal tumors. Surgical removal of the tumor is curative. There is limited information on the biochemical changes in mineral metabolism and bone remodeling activity after surgery, but it is reported that surgery is followed by a hungry bone syndrome (HBS) with hypocalcemia and secondary hyperparathyroidism. We report the biochemical response to surgery in two patients, who presented with severe TIO, as manifested by proximal myopathy, multiple stress fractures, high FGF23, low serum phosphate, low maximum renal phosphate reabsorption threshold (TmP/GFR), and low 1,25-dihydroxy-vitamin D (1,25(OH)2D). Prior to surgery, both patients developed secondary hyperparathyroidism and one case had progressed to tertiary hyperparathyroidism. After surgery there was normalization of FGF23, TmP/GFR, and phosphate. High 1,25(OH)2D was recorded. One patient had hypocalcaemia and worsening secondary hyperparathyroidism consistent with HBS; the other patient did not have hypocalcemia but had worsening tertiary hyperparathyroidism that only resolved with cinacalcet. There was a marked increase in bone remodeling markers, both resorption and formation, consistent with a high bone turnover state. There was a different pattern of change in bone specific alkaline phosphatase, reflecting healing of osteomalacia. Biochemical monitoring in the post-surgical management of TIO is warranted for guiding adjustments in medical intervention, both short-term and long-term. Future use of burosumab prior to surgery for TIO may ameliorate the immediate post-surgery effects.

BACKGROUND: Our previous studies demonstrated that a high bone turnover state under osteoporotic changes decreased the threshold of skeletal pain. Recent studies reported that the incidence of joint pain due to osteoarthritis (OA) in postmenopausal women was higher than that in males even with the same radiographic OA grade. The aim of this study was to evaluate whether a high bone turnover state affects the induction of pain-like behaviors in mild OA model mice.
METHODS: We established mild OA model mice with accompanying osteoporotic changes by monosodium iodoacetate injection after ovariectomy. We assessed pain-like behaviors by von Frey test and paw-flick test; histological changes in OA joints; the expression of Runx2, Osterix, Osteocalcin, and Rankl; bone micro-architecture by μCT and measured serum tartrate-resistant acid-phosphatase 5b levels in the model mice.
RESULTS: Pain-like behaviors in mice with OA and osteoporotic changes were significantly increased in comparison with those in OA mice without osteoporotic changes. The severity of histological OA changes did not differ significantly between the OA mice with and without osteoporotic changes. Bisphosphonate significantly improved pain-like behaviors accompanied with improvement in the high bone turnover state in the OA mice with osteoporosis, while it had no significant effect on pain-like behaviors in the OA mice without osteoporosis. In addition, the improvement was maintained for more than 4 weeks even after the discontinuation of bisphosphonate treatment.
CONCLUSIONS: These results indicated that a high bone turnover state under osteoporotic changes could affect the induction of pain-like behaviors in mild OA model mice.

Denosumab is a fully human monoclonal antibody against the receptor activator of nuclear factor-κB ligand (RANKL) that is used for the treatment of osteoporosis. Denosumab-induced hypocalcemia is a rare but important adverse event, which is usually asymptomatic in patients with osteoporosis. It is also known that hypocalcemia is common in patients with bone metastases and severe renal impairment. Here we report a case of symptomatic hypocalcemia following administration of 60 mg of denosumab in a patient with high bone turnover and no renal impairment (estimated glomerular filtration rate [eGFR], 71 mL/min), despite prophylactic oral vitamin D administration. This report supports our observation that there is a risk of protracted and marked denosumab-induced hypocalcemia in patients with high bone turnover, irrespective of their degree of renal impairment.

Chronic kidney disease (CKD) causes dysregulation of mineral metabolism, vascular calcification and renal osteodystrophy, an entity called \'CKD-Mineral and Bone Disorder\' (CKD-MBD). Here we determine whether metformin, an anti-diabetic drug, exerts favorable effects on progressive, severe CKD and concomitant mineral metabolism disturbances. Rats with CKD-MBD, induced by a 0.25% adenine diet for eight weeks, were treated with 200 mg/kg/day metformin or vehicle from one week after CKD induction onward. Severe, stable CKD along with marked hyperphosphatemia and hypocalcemia developed in these rats which led to arterial calcification and high bone turnover disease. Metformin protected from development toward severe CKD. Metformin-treated rats did not develop hyperphosphatemia or hypocalcemia and this prevented the development of vascular calcification and inhibited the progression toward high bone turnover disease. Kidneys of the metformin group showed significantly less cellular infiltration, fibrosis and inflammation. To study a possible direct effect of metformin on the development of vascular calcification, independent of its effect on renal function, metformin (200 mg/kg/day) or vehicle was dosed for ten weeks to rats with warfarin-induced vascular calcification. The drug did not reduce aorta or small vessel calcification in this animal model. Thus, metformin protected against the development of severe CKD and preserved calcium phosphorus homeostasis. As a result of its beneficial impact on renal function, associated comorbidities such as vascular calcification and high bone turnover disease were also prevented.