Osteoporosis. When we talk about osteoporosis, we have to be familiar with the constituents of bone and what it is formed of.

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1 Osteoporosis When we talk about osteoporosis, we have to be familiar with the constituents of bone and what it is formed of. Osteoblasts by definition are those cells present in the bone and are involved in bone formation. Clastic activity is the opposite where the cells lead to breakdown, metabolism or decrease bone formation or the term also applies to the activity of osteoclasts which increase bone resorption. Bones are the most rigid part of the body, but in osteoporosis, they become fragile. The bone matrix consists of collagen, ground substance and inorganic salts (such as sodium, copper, zinc and calcium) and many other elements. This figure shows normal bone matrix (consisting of osteoblasts, osteoclasts,. etc) versus abnormal bone matrix (osteoporosis). Bone resorption is characterized by overactivity of osteoclasts which will break down bone and release minerals resulting in transfer of calcium from bones to blood. Osteoclastic and osteoblastic activities are in balance, however there are certain situations where one will be in excess to the other, for example during growth in childhood, blastic activity dominates. There are many factors involved such as androgens in males and estrogens in females and the growth hormone is also involved in bone formation.

2 Osteoclastic activity increases in disease states like osteoporosis. So the imbalance within the bone matrix could lead to some sort of disease. Paget's disease is characterized by an imbalance of clastic and blastic activity that leads to abnormal bone formation and deposition in different areas leading to various deformities. The bone is under a continuous process known as bone turnover or bone remodeling, which is the removal of old bone and the replacement by new bone. And so, normally there is no net change in bone mass. Definition of osteoporosis: A reduction in bone mass per unit volume leading to fractures particularly the spine, distal radius and proximal femur (for unknown reasons they are the first bones affected by osteoporosis). The major complaint of people with osteoporosis is back pain. So when a patient above 50 years old complains of back pain, osteoporosis should be considered, especially in postmenopausal females. Osteoporosis is asymptomatic in the early stages and it passes unnoticed by the patient, hence it is known as the "silent thief". Late detection is associated with more complications. Despite treatment, manifestations of osteoporosis remain. Therefore protective measures are important, as old people must be careful while doing any kind of movement as to avoid fractures. Bone formation in old people is very slow as compared to young individuals since everything is decreased in old age including absorption of drugs, excretion and metabolism, therefore they require higher doses. On the other hand, bone fracture in year old individuals would result in even stronger bone than before since bone formation is a continuous process during childhood.

3 Etiology: Hormonal deficiency is responsible for many cases of osteoporosis, estrogen deficiency in females and androgen deficiency in males. As mentioned in a previous lecture, anabolic steroids (androgens) have anabolic effects, growth promoting properties; they build up bone and have a positive nitrogen balance. On the other hand, glucocorticoids increase catabolism and decrease anabolism of proteins, thus affecting the protein matrix of the bones in addition to their effects on calcium. So the major cause of osteoporosis in females is postmenopausal period. While in men, ageing above 60 years leads to more bone resorption and less bone formation, and also androgen deficiency (as in hypogonadism) is one of the main causes of osteoporosis. EXTRA NOTE Osteoporosis in men: It's of two main types: primary and secondary. In cases of primary osteoporosis, either it is caused by age-related bone loss (sometimes called senile osteoporosis) or the cause is unknown (idiopathic osteoporosis). The term idiopathic is used only for men younger than 70; in older men, age-related bone loss is assumed to be the cause. The majority of men with osteoporosis have at least one secondary cause on top of primary. In cases of secondary osteoporosis, the loss of bone mass is caused by certain lifestyle behaviors, diseases, or medications. The most common causes include exposure to glucocorticoid medications, hypogonadism (low levels of testosterone), alcohol abuse, smoking, gastrointestinal disease (malabsorption), hypercalciuria, and immobilization. What happens in postmenopausal period is ovarian failure, which means there is no estrogen and progesterone production. Some ladies develop severe manifestations in addition to osteoporosis such as postmenopausal syndrome which is associated with severe depression, hot flushes, etc. The greatest amount of bone loss occurs in the first 5 years of menopause. Also, the incidence of osteoporosis increases with earlier onset of menopause, for example some ladies lose their ovarian function at the age of 35. By knowing that, women above 40 years should be screened as to

4 initiate therapy early, and that could at least limit progression of the disease or if fracture already occurred, it can limit further fractures. Other causes of osteoporosis: - Thyrotoxicosis - Hyperparathyroidism (increased bone resorption) - Alcohol consumption - Smoking - Caffeine consumption - Low Ca ++ diet (due to not enough exposure to the sun and not eating enough food that contain calcium) - Malabsorption syndrome (hypocalcaemia with secondary hyperparathyroidism) - Drug-induced osteoporosis: o Glucocorticoids (Cushing s syndrome): They are listed under disease-modifying antirheumatic drugs in addition to relieving pain caused by inflammation, and are often used chronically despite their complications. Chronic glucocorticoid therapy could lead to osteoporosis due to their effects on proteins and calcium. o GnRH agonists and superagonists: As mentioned in a previous lecture, prostate cancer is treated with GnRH superagonists which are superior to estrogens, progestin or other antiandrogens like Flutamide. Superagonists are associated with decreased growth of prostate cancer, less pain, and less metastasis, and therefore surgery might not be needed. However they could cause osteoporosis when given chronically, such as Leuprolide Acetate (given subcutaneously in patients with cancer of prostate). o Anticonvulsants o Heparin

5 Osteoporosis risk factors: - Family history: genetics are associated with many conditions. - Limited physical activity: physical activity is an essential approach in the management of many conditions. - Low Ca ++ diet - Low vit. D diet or limited exposure to sunlight - Caffeine consumption - Smoking - Alcohol intake - Chronic use of glucocorticoids or anticonvulsants All these can cause osteoporosis especially if they were combined together. Diagnosis of osteoporosis No symptoms during early stages (the "silent thief"), but symptoms will manifest in later stages (advanced osteoporosis). Symptoms and signs: - The most important symptom is low back pain. Prostate cancer should also be considered in elderly males with low back pain. - Fractures of vertebrae, hips or wrist. Bones are fragile so the patient must be careful especially in old age. A slight trauma can cause fractures and especially femoral fractures. Lab tests: - X-ray. Decalcification of bone can be seen. - Blood biochemistry. For example low calcium and low vitamin D (vit. D and vit. B12 deficiencies are common nowadays due to unbalanced nutrition) - Bone mineral density (BMD; densitometry) is the major tool for diagnosing osteoporosis. The densitometer is used to diagnose and assess successful treatment. It is very sensitive, accurate, inexpensive and available. It is also used in drugs clinical trials in advanced phases.

6 Treatment of osteoporosis: Osteoporosis drugs show great outcomes when started early. Resistance to treatment is mainly due to advanced osteoporosis or osteoporosis associated with fracture. Therapy is still provided for advanced disease despite the weak response. o Estrogen replacement therapy (Estrogen + progesterone) Progesterone has no effect on bone, but it is added to protect against uterine cancer as estrogen is known to be a risk factor for certain breast cancers as well as uterine cancer. Although it is usually not preferred to give estrogen replacement therapy, the doctor, personally, highly recommends a small dose of estrogen after menopause as it decreases the incidence of osteoporosis as well as ischemic heart disease. o Androgen therapy can be used in both males and females. Androgen therapy in males is effective and well tolerated. Androgen therapy may also be used in females when estrogen therapy is not tolerated due to its sometimes exaggerated side effects. o Selective estrogen receptor modulators (SERM) e.g.raloxifene. Although it is not an estrogen, it produces estrogenic effects on bones (enhancing bone formation) by acting as an estrogen agonist, and has anti-estrogenic actions on the uterus and breast. So it is effective in the management of certain types of breast cancer (especially those that are estrogen-dependent) and uterine cancer. o Vitamin D + Calcium o Bisphosphonates (such as Etidronate, Alendronate and Residronate) are available, effective orally and are the number one drugs. Etidronate and Alendronate are widely used in the management of many cases of osteoporosis. Since the release of Bisphosphonates, estrogen replacement therapy use has been limited.

7 Bisphosphonates are also effective in Paget's disease because they increase bone formation. Conditions of Paget's disease include demineralization, increase bone resorption and increase bone formation leading to bone deformities and fractures. o Calcitonin is an inhibitor to bone resorption and can be given as intranasal preparations. o Small doses of fluoride. They are believed to be effective in the management of osteoporosis since fluoride ions increase bone formation. There are available dosage forms and slow release dosage forms that provide small doses hence less toxicity since higher doses of fluoride ions usually produce severe toxicity and a severe type of allergy. o Synthetic rpth (Teriparatide). Large doses of parathyroid hormone usually lead to osteoporosis but low doses increase bone formation and hence effective against osteoporosis. o Denosumab: inhibit RANKL (receptor activator of nuclear factor kappa-b ligand). RANKL is a protein present on osteoblasts that causes an increase in the activity of osteoclasts. So inhibiting this ligand will inhibit the protein and hence acting against osteoporosis. Denosumab is also effective in the management of metastasis to the bone due to any type of cancer. Another advantage is that it is given only once every 6 months as subcutaneous injection in cases of osteoporosis and every 4 months for metastasis in cancer. Unfortunately Denosumab is associated with many side effects such as hypocalcemia, serious infections involving the skin, urinary bladder and heart (endocarditis), high blood cholesterol levels, pain in jaws and back (in addition to low back pain caused by osteoporosis). All these cause limitation in the use of Denosumab but their mechanism is very interesting.

8 Postmenopausal osteoporosis R x or prophylaxis: Extensive studies have been searching for the best combination of the afore mentioned drugs as to improve the lifestyle of women with osteoporosis, as these drugs are safe to combine and can each be given alone. - Estrogen + Alendronate + Ca ++ & vit. D + intranasal calcitonin - Raloxifene + Alendronate + Ca ++ & vit. D + calcitonin - Estrogen + Progesterone - Raloxifene + Alendronate - Teriparatide (rpth) (S.C) - Denosumab Done by Ghalia Al-Hammouri