Osteoporosis Meds

What is osteoporosis?

Osteoporosis is a systemic skeletal condition where bone density is reduced and bone tissue loses its intricate structure so that the bones become weak and brittle, which increases risk of fracture.  There are usually no symptoms until a bone is broken or fractured and the condition can develop gradually over many years.  Fractures occur most commonly in the spine, hip and wrist which are painful and vertebral fractures can also result in loss of height.

Although osteoporosis can affect anyone, post-menopausal women are the most susceptible, as reduced levels of oestrogen contribute to the deterioration of bone mass.  Surgical removal of the ovaries also results in low levels of oestrogen.  The incidence of osteoporosis continues to increase with increasing risk of fracture, which causes considerable pain and disability and imposes a considerable financial burden on health services.¹

The diagnosis and management of osteoporosis is guided by international guidelines and includes the use of measurements for bone density, assessment for risk of fracture as well as the use of biological markers of bone metabolism.^{2, 3, 4}

Risk factors for osteoporosis

Bone density is a measure of the amount of bone tissue in a given volume of bone.  Bones reach peak density at the age 30-35 then start to decline with increasing age. 

There are several risk factors for reduced bone density leading to osteoporosis and increased risk of fracture, including:

• long-term treatment with a corticosteroid, an anti-inflammatory steroid,
• family history of osteoporosis
• lifestyle factors such as, inactivity, smoking, high alcohol or caffeine consumption
• low levels of vitamin D, as can result if insufficient exposure to sunlight
• low dietary calcium intake

some medical conditions such as Cushing's syndrome, in which the adrenal glands produce too much cortisol a natural corticosteroid.

Bone turnover

Bone is a complex connective tissue comprised of living bone cells and a matrix in which the cells are suspended.  The matrix comprises a soft component of collagen, a fibrous protein that is found in all connective tissue and provides bone with flexibility to withstand stress; and a hard mineral component hydroxyapatite, which is made up of deposits of calcium and phosphate and provides bone with its strength and rigidity.

There are wo different types of bone cells:

• Osteoblasts that are responsible for bone formation and building the matrix by producing collagen and releasing calcium and phosphate ions in a process called mineralisation to form hydroxyapatite.
• Osteoclasts that are responsible for bone resorption, whereby they dissolve old bone and remove matrix, which releases calcium and phosphate to be reused by the body.

Bone is a dynamic tissue and is constantly undergoing remodelling, a process of bone turnover by which old bone is broken down and replaced with new bone so that bones can grow and repair throughout life.  This process is the result of opposite activities of the osteoblasts and the osteoclasts and is regulated by a range of growth factors, hormones and cytokines.

Maintenance of bone structure and strong bones is dependent on a balance of bone turnover with bone formation matching bone resorption as needed.  An imbalance in the regulation of bone remodelling results in metabolic bone disease such as osteoporosis, when more bone is broken down than new bone is formed; and this shift in balance of bone turnover increases with age, particularly post-menopause.  Also an overall increase in bone turnover is thought to be a major cause of osteoporosis.⁵

Role of calcium metabolism in bone density 

Calcium is an important mineral for many body functions, including blood clotting, nerve transmission and maintaining bone mass, and is found primarily in bone.  It is stored in bone and can be released from bone when needed. Calcium metabolism depends on three mechanisms: intestinal absorption, reabsorption in the kidneys, and bone turnover, and these mechanisms are in turn regulated by Parathyroid Hormone (PTH) and 1,25-dihydroxyvitamin D3, which is the active form of vitamin D. 

The majority of Vitamin D is obtained from synthesis in the skin by the action of natural sunlight and a small proportion is obtained from the diet.  It is then converted to its active form by the action of enzymes in the liver and the kidney.  Vitamin D promotes calcium absorption and also increases bone density by promoting osteoblast differentiation and bone mineralisation.  Conversely, PTH increases the levels of blood calcium by promoting its absorption from the intestines and reabsorption in the kidneys.  PTH also promotes calcium release from bone by triggering bone resorption through binding to osteoblasts which then produce signals activating osteoclast to begin bone resorption. 

Bisphosphonates for osteoporosis management

Bisphosphonates are synthetic chemicals similar to pyrophosphate, the naturally occurring mineral in bone.  Several bisphosphonates have been developed, with different potencies depending on their structure.  They are potent inhibitors of bone resorption and work by binding with high affinity to hydroxyapatite (the scaffolding of bone architecture), specifically at the site of bone resorption and inhibiting the action of osteoclasts.

When taken orally, bisphosphonates have low availability with only around 1% of an oral dose being absorbed and of that dose around 50% ends up binding to bone.

The dose given depends on the potency of the bisphosphonates, which include: alendronate, etidronate, and risedronate.  Alendronate 70 mg once weekly and risedronate 35 mg once weekly are the most commonly used bisphosphonates worldwide and have been shown to significantly reduce risk of fracture in postmenopausal women. ⁴

The bisphosphonates zoledronic has been developed for intravenous infusion and is taken once a year to treat osteoporosis and reduce risk of fracture.  

Other therapies for osteoporosis

The selective estrogen receptor modulators (SERM) raloxifene is used to treat and prevent osteoporosis.  It works by binding to the oestrogen receptor in various tissues and acts as an oestrogen agonist or antagonist, depending on the target tissue.  Raloxifene has beneficial effects on bone by decreasing bone resorption and increasing bone density and mineralisation, restoring the balance in bone turnover and reducing the overall rate of bone remodelling, which has been shown to reduce risk of fracture, particularly vertebral fracture.  However it has anti-oestrogenic effects on the endometrial and breast tissue, and therefore, does not increase risk of oestrogen dependent cancers. ⁶

Calcitriol is the active metabolite of vitamin D that regulates calcium metabolism and also regulates bone remodelling by reducing bone resorption and promoting bone mineralisation.  Calcitriol is also used to treat osteoporosis to reduce risk of vertebral and hip fractures. 

References

1. Reginster JY, Burlet N. Osteoporosis: a still increasing prevalence. Bone. 2006;38 (2 Suppl 1):S4-9.
2. Garnero P. Bone. 2014;66:46-55.  New developments in biological markers of bone metabolism in osteoporosis.
3. Garnero P. Biomarkers for osteoporosis management: utility in diagnosis, fracture risk prediction and therapy monitoring. Mol Diagn Ther. 2008;12:157-70.
4. Kanis JA, McCloskey EV, Johansson H, Cooper C, Rizzoli, R, Reginster JY. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int.2013: 24; 23–57.
5. Garnero P, Sornay-Rendu E, Chapuy  M-C, Delmas  PD.  Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis. J Bone Min Res 1996; 11: 337-349
6. Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial.JAMA1999;282:637-45.