Reiner Bartl

Bisphosphonates in Medical Practice

Bisphosphonates in medical practice : , Bisphosphonates in medical practice : , کتابخانه دیجیتال جندی شاپور اهواز

Pharmacological Aspects of Antiresorptive Drugs: Bisphosphonates and Denosumab

Bisphosphonates and denosumab are the most widely used classes of antiresorptive osteotrop drugs worldwide. They are used to treat a variety of bone disorders including osteoporosis, metastatic bone disease and hypercalcemia of malignancy. Bisphosphonates are administered either orally or intravenously, while denosumab is injected subcutaneously. While bisphosphonates are not metabolized and have a strong affinity to the bone and a very long half-life in the bone (months–years), denosumab is an antibody which is metabolized, not specifically stored, in the bone and has a short half-life (weeks). Both substance classes have strong inhibitory effects towards bone resorption and are therefore used for the treatment of osteoporosis and metastatic bone disease as well as other bone disorders with great success. Generally, bisphosphonates and denosumab are well tolerated and have few side effects. However, both substance classes of osteotrop antiresorptives have one side effect in common, namely, osteonecrosis of the jaw.

Management of Osteoporotic Fractures

The main goal of osteoporosis treatment is to prevent fragility fractures. Often, a low-trauma fracture of an elderly patient is the first manifestation of osteoporosis, which was an asymptomatic disease until the fracture event. Low-trauma fractures require orthopaedic trauma management including conservative management with casting or splinting, as well as surgical management with osteosynthesis or joint replacement. In elderly patients with reduced bone mass, surgical stabilisation should allow for early weight-bearing in fractures of the lower extremity, the spine and pelvic ring and for early physiotherapy in fractures of the upper extremity. For these fractures with markedly reduced bone loss, special implants are needed to provide stable fracture fixation to allow bone healing. Early fracture management, rapid mobilisation and active physiotherapy following fracture stabilisation are important to preserve joint function, to prevent joint contractures, to provide muscle strengthening for walking security and to prevent complications due to immobilisation.

Structure and Architecture of Bone

The human skeleton has 204–214 individual bones; it weighs about 10 kg and accounts for about 15 % of the body weight. A rough breakdown differentiates the skeleton of the trunk (trunk or axial skeleton) from the skeleton of the extremities (peripheral skeleton). The skeleton includes the following bones:

Anaemias and Bone Reactions

With the description of facial abnormalities in haemolytic anaemia, Cooley in 1927 first described the relationship of hyperplastic erythropoiesis and increased bone remodelling with malformation of the skeleton. Especially in severe congenital haemolytic anaemias, such as sickle cell anaemia, thalassaemia major and hereditary spherocytosis, there are classic but quite similar osseous abnormalities due to marrow expansion (“haematic dysplasias”). The whole bone may be affected, but the most prominent changes occur in the axial skeleton homing the red marrow (Fig. 86.1). Abnormalities are striking in the skull with widening of the diploic space and thinning of the outer table. Radial spicules of the bone lead to a “hair-on-end appearance” or “brush head” (Fig. 86.2). Osseous expansion also occurs in the face and causes striking facial abnormalities. Also vertebral body deformities are common, with wide marrow cavities and thin cortices. There is, however, no close correlation between the severity of the anaemia and osseous abnormalities on skeletal X-ray. Local lesions are also caused by microvascular occlusions (aseptic necrosis, infarcts and osteomyelitis).

Fractures in Rare Bone Disorders

Typical fractures rarely present diagnostic problems. However, certain special types of fractures are frequently misdiagnosed. This chapter provides background information on various forms of special fractures, pathological fractures and rare bone disorders presenting with fractures.

Peri-implant Bone Loss

Total joint arthroplasty of the hip and knee has become one of the most frequent and rewarding operations in orthopaedic surgery. Worldwide more than one million such prostheses are implanted annually. With the steady rise in life expectancy, long-term complications related to implant loosening and peri-implant fractures are on the rise. Efforts to sustain and improve the clinical survival of total joint implants have thus generated great interest. The main challenge of implant integration by the surrounding bone is an adequate load transmission. Following implantation of a femoral stem, the load transmission is more distal in the femur. Due to the changed biomechanics and the stiffness of the implant, the periprosthetic bone reacts with a proximal periprosthetic osteopaenia (“stress shielding”) (Fig. 104.1). Bone atrophy around the implant components is considered as a potential factor leading to aseptic component loosening limiting the survival of the prosthesis.

Vitamin D and Other Useful Vitamins

The structure of vitamin D was identified in 1900. In the following decades till the end of the century, numerous studies elucidated its metabolism and its effects on calcium-phosphate homeostasis and its correlation to skeletal mineral metabolism. Indeed, some authors have claimed that the bone is an “intracrine organ” for vitamin D metabolism, based on its direct effects on the bone cells and on the fact that the bone cells themselves can convert 25D into 1,25D by means of the 25-hydroxyvitamin D 1-alpha-hydroxylase (CYP27B1), thereby participating in the autocrine and paracrine loops of vitamin D metabolism.

Risk Factors of Osteoporotic Fractures

The primary goal of treating osteoporosis is to reduce the risk of fractures that are associated with tremendous socioeconomic implications. Often a fragility fracture is the first manifestation of the disease osteoporosis, and a high number of patients sustaining a low-trauma fracture do not show densitometric evidence of osteoporosis. Therefore, there is a definitive need to better identify those who are at risk for fracture. Currently, tools combining bone mineral density and clinical risk fractures to assess fracture risk are under investigation.

Bone and Fatty Tissue

The number of overweight or obese people in the USA (69 %) has reached epidemic proportions. Obesity is a national health problem there and in the meantime also recognised as a problem in Europe. Although obesity correlates with a higher bone mass and bone density, studies have shown that the bone quality in adults and children is inferior and in certain regions of the skeleton higher fracture rates have been observed. Osteoblasts and fat cells (adipocytes) derive from a common mesenchymal stem cells (MSC). Factors that increase adipogenesis typically inhibit the differentiation of osteoblastic cells.