Aline G. Costa

Cathepsin K: its skeletal actions and role as a therapeutic target in osteoporosis

Bone remodeling consists of two phases—bone resorption and bone formation—that are normally balanced. When bone resorption exceeds bone formation, pathologic processes, such as osteoporosis, can result. Cathepsin K is a member of the papain family of cysteine proteases that is highly expressed by activated osteoclasts. Cathepsin K readily degrades type I collagen, the major component of the organic bone matrix. With such a major role in the initial process of bone resorption, cathepsin K has become a therapeutic target in osteoporosis. The antiresorptive properties of cathepsin K inhibitors have been studied in phase I and phase II clinical trials. Phase III studies are currently underway for odanacatib, a selective cathepsin K inhibitor.

Catabolic and anabolic actions of parathyroid hormone on the skeleton

PTH, an 84-amino acid peptide hormone synthesized by the parathyroid glands, is essential for the maintenance of calcium homeostasis. While in its traditional metabolic role, PTH helps to maintain the serum calcium concentration within narrow, normal limits and participates as a determinant of bone remodeling, more specific actions, described as catabolic and anabolic are also well known. Clinically, the catabolic effect of PTH is best represented by primary hyperparathyroidism (PHPT), while the osteoanabolic effect of PTH is best seen when PTH or its biological amino-terminal fragment [PTH(1–34)] is used as a therapy for osteoporosis. These dual functions of PTH are unmasked under very specific pathological (PHPT) or therapeutic conditions. At the cellular level. PTH favors bone resorption, mostly by affecting the receptor activator of nuclear factor κ-B (RANK) ligand (RANKL)-osteoprotegerin-RANK system, leading to an increase in osteoclast formation and activity. Increased bone formation due to PTH therapy is explained best by its ability to enhance osteoblastogenesis and/or osteoblast survival. The PTH-induced bone formation is mediated, in part, by a decrease in SOST/sclerostin expression in osteocytes. This review focuses on the dual anabolic and catabolic actions of PTH on bone, situations where one is enhanced over the other, and the cellular and molecular mechanisms by which these actions are mediated.

Primary hyperparathyroidism is associated with abnormal cortical and trabecular microstructure and reduced bone stiffness in postmenopausal women.

Typically, in the milder form of primary hyperparathyroidism (PHPT), now seen in most countries, bone density by dual‐energy X‐ray absorptiometry (DXA) and detailed analyses of iliac crest bone biopsies by histomorphometry and micro–computed tomography (µCT) show detrimental effects in cortical bone, whereas the trabecular site (lumbar spine by DXA) and the trabecular compartment (by bone biopsy) appear to be relatively well preserved. Despite these findings, fracture risk at both vertebral and nonvertebral sites is increased in PHPT. Emerging technologies, such as high‐resolution peripheral quantitative computed tomography (HRpQCT), may provide additional insight into microstructural features at sites such as the forearm and tibia that have heretofore not been easily accessible. Using HRpQCT, we determined cortical and trabecular microstructure at the radius and tibia in 51 postmenopausal women with PHPT and 120 controls. Individual trabecula segmentation (ITS) and micro–finite element (µFE) analyses of the HRpQCT images were also performed to further understand how the abnormalities seen by HRpQCT might translate into effects on bone strength. Women with PHPT showed, at both sites, decreased volumetric densities at trabecular and cortical compartments, thinner cortices, and more widely spaced and heterogeneously distributed trabeculae. At the radius, trabeculae were thinner and fewer in PHPT. The radius was affected to a greater extent in the trabecular compartment than the tibia. ITS analyses revealed, at both sites, that plate‐like trabeculae were depleted, with a resultant reduction in the plate/rod ratio. Microarchitectural abnormalities were evident by decreased plate‐rod and plate‐plate junctions at the radius and tibia, and rod‐rod junctions at the radius. These trabecular and cortical abnormalities resulted in decreased whole‐bone stiffness and trabecular stiffness. These results provide evidence that in PHPT, microstructural abnormalities are pervasive and not limited to the cortical compartment, which may help to account for increased global fracture risk in PHPT.

Sclerostin: Therapeutic Horizons Based Upon Its Actions

Inactivating mutations of the SOST gene cause a reduction in sclerostin levels and are associated with high bone mass. The clinical phenotypes, sclerosteosis and van Buchem’s disease, were described in 1950s. Much later, it was learned that both diseases are due to loss-of-function mutations in the SOST gene. As a regulator of an important osteoanabolic pathway, Wnt, inactivation of SOST leads to a stimulation of the pathway it regulates. The high bone mass in patients with either sclerosteosis or van Buchem’s disease is associated with unusual skeletal strength; they do not fracture. Knowledge of this molecule and its actions led rather quickly to the development of anti-sclerostin antibodies that lead to marked increases in bone mass in both animals and human subjects. Blocking sclerostin action with anti-sclerostin antibodies is a promising new therapeutic approach to osteoanabolic therapy of osteoporosis.

Circulating Sclerostin in Disorders of Parathyroid Gland Function

CONTEXT Sclerostin, a protein encoded by the SOST gene in osteocytes and an antagonist of the Wnt signaling pathway, is down-regulated by PTH administration. Disorders of parathyroid function are useful clinical settings to study this relationship. OBJECTIVE The objective of the study was to evaluate sclerostin in two different disorders of parathyroid function, primary hyperparathyroidism and hypoparathyroidism, and to analyze the relationship between sclerostin and PTH, bone markers, and bone mineral density. DESIGN This is a cross-sectional study. SETTING The study was conducted at a clinical research center. PATIENTS Twenty hypoparathyroid and 20 hyperparathyroid patients were studied and compared to a reference control group. RESULTS Serum sclerostin was significantly higher in hypoparathyroid subjects than in hyperparathyroid subjects (P < 0.0001) and controls (P < 0.0001). PTH was negatively associated with sclerostin, achieving statistical significance in hypoparathyroidism (r = -0.545; P = 0.02). The bone turnover markers, cross-linked C-telopeptide of type I collagen (CTX) and amino-terminal propeptide of type I collagen (P1NP), were differently associated with sclerostin according to the parathyroid disorder. In primary hyperparathyroidism, bone turnover markers were associated negatively with sclerostin (for P1NP, r = -0.490; P = 0.03). In hypoparathyroidism, bone turnover markers were associated positively with sclerostin (for CTX, r = +0.571; P = 0.01). Although there was no significant correlation between bone mineral density and sclerostin in either parathyroid disorder, there was a significant positive relationship between sclerostin and bone mineral content in hypoparathyroidism. CONCLUSIONS The results are consistent with the hypothesis that PTH is a regulator of sclerostin in human disorders of parathyroid function. In addition, the results suggest that bone mineral content may be another factor that influences sclerostin.

Presentation of Hypoparathyroidism: Etiologies and Clinical Features

CONTEXT Understanding the etiology, diagnosis, and symptoms of hypoparathyroidism may help to improve quality of life and long-term disease outcomes. This paper summarizes the results of the findings and recommendations of the Working Group on Presentation of Hypoparathyroidism. EVIDENCE ACQUISITION Experts convened in Florence, Italy, in May 2015 and evaluated the literature and recent data on the presentation and long-term outcomes of patients with hypoparathyroidism. EVIDENCE SYNTHESIS The most frequent etiology is surgical removal or loss of viability of parathyroid glands. Despite precautions and expertise, about 20-30% of patients develop transient and 1-7% develop permanent postsurgical hypoparathyroidism after total thyroidectomy. Autoimmune destruction is the main reason for nonsurgical hypoparathyroidism. Severe magnesium deficiency is an uncommon but correctable cause of hypoparathyroidism. Several genetic etiologies can result in the loss of parathyroid function or action causing isolated hypoparathyroidism or a complex syndrome with other symptoms apart from those of hypoparathyroidism or pseudohypoparathyroidism. Neuromuscular signs or symptoms due to hypocalcemia are the main characteristics of the disease. Hyperphosphatemia can contribute to major long-term complications such as ectopic calcifications in the kidney, brain, eye, or vasculature. Bone turnover is decreased, and bone mass is increased. Reduced quality of life and higher risk of renal stones, renal calcifications, and renal failure are seen. The risk of seizures and silent or symptomatic calcifications of basal ganglia is also increased. CONCLUSIONS Increased awareness of the etiology and presentation of the disease and new research efforts addressing specific questions formulated during the meeting should improve the diagnosis, care, and long-term outcome for patients.

Prevalence of Kidney Stones and Vertebral Fractures in Primary Hyperparathyroidism Using Imaging Technology

CONTEXT The fourth International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism (PHPT) has recently suggested that skeletal and renal imaging be routinely conducted. So far, no study has systematically assessed this issue. OBJECTIVE The objective was to evaluate the prevalence of kidney stones (KS) and vertebral fractures (VFs) in a cohort of patients with PHPT utilizing noninvasive imaging technology. DESIGN This was a prospective study evaluating patients consecutively diagnosed with PHPT in a single center over a 5-year period (2009-2013). SETTING The setting was a referral center. PATIENTS There were a total of 140 patients with PHPT (127 women [18 premenopausal and 109 postmenopausal] and 13 men; mean age, 63.2 ± 11 y). MAIN OUTCOMES MEASURES Main outcome measures were the prevalence of KS by abdominal ultrasound, osteoporosis by dual-energy x-ray absorptiometry (DXA) (lumbar spine, femoral neck, total hip, and distal 1/3 radius), and VFs by vertebral spine x-ray, with attention to those categorized as symptomatic or asymptomatic. RESULTS Fifty-five percent of all subjects had KS by ultrasound, 62.9% had osteoporosis by T-score at any site, and 35.1% had VFs by x-ray. There was no difference in the incidence of VFs and densitometric osteoporosis between symptomatic and asymptomatic patients (VFs, 34.4 vs 34.7%; osteoporosis by DXA, 59.4 vs 65.8%), whereas more KS were detected in symptomatic (78%) than asymptomatic (35.5%). Twenty-two percent of patients classified as asymptomatic at baseline without osteoporosis by DXA were found to have KS and/or VFs. CONCLUSIONS Nephrolithiasis and VFs are common in asymptomatic subjects with PHPT. The results provide evidence in support of recent recommendations that a more proactive approach be taken to detect silent bone and stone disease in asymptomatic PHPT.

Update on romosozumab: a humanized monoclonal antibody to sclerostin

Introduction: Disorders with inactivating mutations of the SOST gene result in reduced or absent expression of sclerostin and are associated with high bone mass. Sclerostin is an important regulator of bone formation due to its inhibitory actions in the osteoanabolic Wnt signaling pathway. Advances in understanding the mechanisms of action of this signaling molecule have led to the development of a pharmacological inhibitor of sclerostin with potential clinical applications as an osteoanabolic drug for the treatment of osteoporosis. Areas covered: Romosozumab is the first humanized monoclonal sclerostin antibody to be tested in clinical trials. Similar to preclinical animal studies with sclerostin antibodies, initial clinical studies show that romosozumab increases bone formation and bone mineral density. Expert opinion: Blocking sclerostin action with romosozumab is a promising new therapeutic approach to osteoanabolic therapy of osteoporosis; efficacy and safety data on large controlled studies are awaited.

Circulating Sclerostin Levels and Markers of Bone Turnover in Chinese-American and White Women

CONTEXT Chinese-American women have bone microarchitectural features that confer greater bone stiffness compared to white women, but the physiology underlying these findings has not been investigated. OBJECTIVE The purpose of the study was to assess racial differences in serum sclerostin and bone turnover markers (BTMs), and to explore their associations with each other, volumetric bone mineral density (BMD), and bone microarchitecture in Chinese-American and white women. DESIGN AND SETTING We conducted a cross-sectional study at a university hospital. PARTICIPANTS We studied 138 women. RESULTS Serum osteocalcin was 19-28% lower in pre- and postmenopausal Chinese-American vs white women, respectively (both P < .01). C-Terminal telopeptide of type I collagen (CTX) level was 18-22% lower in pre- and postmenopausal Chinese-American vs white women (both P < .05). Pre- vs postmenopausal differences in osteocalcin and CTX were greater in white vs Chinese-American women. Sclerostin levels were similar in both races, but BTMs were differentially associated with sclerostin by race and menopausal status. BTMs were not correlated with sclerostin in Chinese-Americans. CTX and bone-specific alkaline phosphatase were positively associated with sclerostin (r = 0.353, r = 0.458; both P < .05) in white premenopausal women. In contrast, in postmenopausal white women, the associations of sclerostin with amino-terminal propeptide of type I procollagen, isoform 5b of tartrate-resistant acid phosphatase, and CTX were negative (all P < .05). Adjusting for covariates, sclerostin was positively associated with areal BMD in both races. CONCLUSIONS Lower BTMs in Chinese-American women and greater age-related differences in BTMs among white women provide a physiological framework to account for racial differences in BMD, microarchitecture, and fracture.

Bone markers and osteoporosis therapy

Several factors are involved in determining bone quality including bone density, bone turnover, the extent of trabecular bone connectivity, cortical porosity and geometry. Metabolically active and in a continuous process of remodeling, approximately 20% of bone tissue is renewed annually. Bone turn over markers (BTM) are frequently used in clinical trials and to provide valid information about the effectiveness of osteoporosis treatment, reflecting the state of bone metabolism and its response to treatment, although they are not useful alone to estimate bone loss. In this review the behavior of BTM from different clinical trials or different osteoporotic drugs will be addressed.