**Abstract**

Calcium homeostasis has a pivotal role in regulating many biological processes. The interplay of calcium-regulating hormones, including parathyroid hormone (PTH), vitamin D, and calcitonin, is crucial in tightly maintaining serum calcium levels. Deregulation of calcium homeostasis has clinical implications resulting in hypercalcemia or hypocalcemia, which can lead to metabolic bone disease (MBD). MBD is a group of multifactorial bone diseases, caused by bone demineralization and characterized by an increased susceptibility to fracture risk. This chapter aims to provide an overview of associated risk factors and diagnostic, prevention, and recent treatment methods for MBD. The diagnosis of MBD is based on the assessment of clinical signs, radiological findings, quantitative ultrasonography, and biochemical evaluation of serum calcium, phosphate, PTH, alkaline phosphatase, and vitamin D. Current pharmacological treatments include antiresorptive and anabolic conventional therapies. Additionally, the efficacy of herbal extracts and nutritional supplements have been evaluated. Recent advances in the MBD management include drugs targeting calcium-sensing receptor and parathyroid hormone-related proteins, leading to the development of cathepsin K and Src tyrosine kinase inhibitors, calcilytics, and monoclonal antibodies against sclerostin or Dickkopf-1. Moreover, new nanomaterials have been used for improving the surgical treatment of vertebral fractures.

**Keywords:** calcium, parathyroid hormone, metabolic bone disease, osteoporosis, vitamin D, anabolic drug, antiresorptive drugs

#### **1. Introduction**

Metabolic bone disease (MBD), the third most prevalent disorder of the endocrine system, involves any disorder that alters the phenomena of mineralization in the normal skeleton. The disorder is primarily caused by abnormalities in the structure of bone or its mass, vitamin D level as well as the presence of certain minerals such as calcium and phosphorus [1].

The concentration of extracellular calcium is crucial for several functions at the cellular level, which needs to be retained in restricted levels. The free concentration of calcium is predominantly negatively regulated by the secretion of the parathyroid hormone (PTH) in response to calcium-sensing receptors. A substantial drop

in the level of free calcium activates the release and synthesis of PTH, which often leads to calcium reabsorption in the renal tubules, enhanced secretion of calcitriol (vitamin D3) promoting calcium absorption from the intestine, and immediate release of calcium from the skeleton, which contains 99% of calcium in the body. Conversely, in regard to rising levels of calcium in the body, PTH level drops that lead to a decline in the above-stated processes. This balance is seen to be disturbed in various pathological circumstances leading to elevated or low calcium levels. High calcium levels, known as hypercalcemia, and low calcium levels, known as hypocalcemia, are observed in conditions such as hypoparathyroidism and vitamin D deficiency.

The most common forms of MBD comprises of osteoporosis, osteomalacia, primary hyperparathyroidism, and fluorosis, while fibrous dysplasia, Paget's disease, osteogenesis imperfecta, and tumor-induced osteomalacia account for its rare forms.

Osteoporosis is a severe MBD that constitutes to be a serious health issue for older people. It represents a decline in the bone mass per unit volume, leading to significant weaknesses in the bone structure, which ultimately leads to bone deformity/fracture. Osteoporosis is categorized as primary when there is no prominent diagnosis of the disease and secondary when an established contributing cause such as steroid treatment is detectable. Type I (postmenopausal) and type II (age-related) are categorized under primary osteoporosis. Type I osteoporosis incorporates bone loss with the expedited bone mass reduction due to the withdrawal of estrogens [2].

Osteomalacia results from curtailed absorption of calcium and phosphate in the intestine due to a deficiency in vitamin D or more rarely due to calcium or phosphate deficiency. Joint pain with fragility in bone and muscular weakness are the common symptoms observed in patients with osteomalacia [3].

Paget's disease leads to skeletal lesions resulting in progressive bone turnover. The finely constructed bone lacks a natural lamellar framework and has poor quality with effects like bone deformity with prominent fractures and related pain [4].

Hyperparathyroidism results due to excess secretion of PTH, which can be categorized as primary hyperparathyroidism or secondary hyperparathyroidism. Primary hyperparathyroidism occurs due to the raised concentration of calcium in the serum. Research reports show hypercalcemia with an abnormally high level of alkaline phosphatase and elevated serum PTH [5].

Fibrous dysplasia is categorized as a rare form of metabolic disorder in which the bones are covered with irregular structures, which appear as a scar-like fibrous tissue. This deposited structure affects bone structure and integrity, making it more fragile and fracture-prone.

This chapter discusses in brief about the associated risk factors and diagnosis of MBD along with the preventive measures and the pharmacological approaches for the treatment of MBD.
