Bone Strengthening Drugs for Osteoporotic Disease

Osteoporosis is a condition characterized by reduced bone mass and disturbed bone architecture. It can result in spontaneous fractures or fractures from minimal trauma. Osteoporosis is a major reason for the increased the risk of fracture in majority of postmenopausal women and to a certain extent in men, particularly older men. More than 50% of women and about 25% of men suffer from osteoporosis related fractures with advancing age. The body of the vertebrae, radial bone near the wrist joint, and the femur near the hip joint are most commonly fractured bones in osteoporotic individuals. Other bones are also susceptible to fracture in osteoporotic individuals as the bones in general remain easily fragile. The severity of osteoporosis and risk for fractures increase considerably with advancing age.

In osteoporosis there is an imbalance in the bone formation and the bone resorption (breakdown). This is directly related to the imbalance between deposition of calcium in the bones and its removal. The calcium balance is normally maintained by hormones like calcitonin, parathormone and the vitamin D. The treatment of osteoporosis aims at shifting balance in favor of bone formation. Irrespective of the type of osteoporosis, similar therapeutic approaches are useful in minimizing bone loss and increasing bone density.

Types of Medication for Osteoporosis

The currently approved medications for osteoporosis are :

• Bisphosphonates
• Calcitonin
• Parathormone analogue
• Denosumab
• Estrogens
• Selective estrogen receptor modulators

Most drugs approved for osteoporosis are antiresorptive agents (reduces bone resorption) with the exception of teriparatide which enhances bone formation. Some drugs are also used off-label for osteoporosis like fluoride, strontium ranelate and thiazides meaning that osteoporosis is not one of the indications for using these drugs but it has been found to have beneficial effects in osteoporosis. Supplementation of vitamin D (or its analogues) and calcium are generally recommended in all osteoporosis patients.

Bisphosphonates

Bisphosphonates are the most important group of drugs used in osteoporosis. It includes alendronate, risedronate, pamidronate, ibandronate, and zoledronate. The bisphosphonates are grouped into three generations.

• First-generation bisphosphonates (etidronate and tiludronate) are the least effective for osteoporosis.
• Second-generation bisphosphonates (ibandronate, alendronate and pamidronate) are up to 100 times more potent than first-generation agents.
• Third-generation bisphosphonates are nearly 10,000 times more potent than first-generation agents and includes risedronate and zoledronate.

Actions

Bisphosphonates significantly reduce the risk of fractures and increase the bone mineral density (BMD). It improves bone density in various types of osteoporosis in men and women including the postmenopausal osteoporosis. Bisphosphonates have a strong affinity for bone resorptive areas.

• It accumulates in the cells that cause bone resorption (osteoclasts) and inhibit the bone resorption by leading to death of osteoclast cells.
• The newer third generation bisphosphonates also inhibit the cholesterol synthetic pathway by inhibiting an enzyme farnesyl pyrophosphate synthase. This is also believed to reduce bone resorptive activity and increase the bone formation.
• Bisphosphonates also enhance dissolution of hydroxyapatite crystals in the bones and reduce its formation. This may also partially contribute to the beneficial effects of bisphosphonates.

Dosage

Alendronate and risedronate are available as oral drugs. Pamidronate and zoledronate are available only for intravenous use. Ibandronate is available for oral and intravenous use. The treatment schedules can be daily (alendronate 10 mg, risedronate 5 mg, ibandronate 2.5 mg), weekly (alendronate 70 mg or risedronate 35 mg), monthly (ibandronate 150 mg), quarterly (ibandronate 3 mg or pamidronate 30 mg infusion) or annually (zoledronate 5 mg infusion). Oral absorption is reduced by presence of food and therefore biphosphonates are better absorbed when taken in empty stomach and ideally before breakfast.

Contraindications and Side Effects

Use of oral bisphosphonates is contraindicated in patients with reduced kidney function, gastroesophageal reflux disease (GERD) or peptic ulcer disease. Intravenous preparations can be used in GERD patients and peptic ulcer disease patients. Gastric and esophageal irritations are important adverse effects of bisphosphonates. Esophageal irritation may be reduced with adequate intake of water when taking the medication and by avoiding lying down for half an hour after the intake of the drug.

Persistent gastric irritation may require the use of a proton pump inhibitor or change to a weekly or monthly treatment schedule. Osteomalacia is a side effect seen in particular with first-generation bisphosphonates. Pamidronate is associated with fever and muscle pain following initial intravenous dose. Zoledronate is associated with renal toxicity and necessitates monitoring of renal function. Necrosis of the jaw bone is a rare adverse effect seen with high intravenous doses of bisphosphonates.

Calcitonin

Calcitonin is a polypeptide hormone that is normally secreted from the C cells in the thyroid gland in response to  an increase in the blood calcium level. It is obtained from salmon is found to be more potent and has longer lasting effect on the calcium regulation than the human calcitonin. Currently several synthetic or recombinant calcitonin preparations identical to salmon calcitonin are available for clinical use. Calcitonin has been found to produce significant improvement in osteoporosis specifically associated with the vertebral bodies. It is approved for use in postmenopausal women who have been in menopause for more than 5 years with established osteoporosis that cannot be treated with other medications.

Actions

Calcitonin promotes deposition of calcium in the bones (bone formation) and reduces the blood calcium levels. It has been found to increase the bone mass and reduce fractures. Calcitonin also inhibits parathormone mediated bone resorption. Continuous use of calcitonin, however, can result in reduced bone formation. Calcium and vitamin D supplementation can minimize the reduction in bone formation from continuous calcitonin use.

Dosage

Calcitonin is available as nasal spray and as injection for subcutaneous or intramuscular use. Calcitonin 100 IU injection given subcutaneously or intramuscularly on alternate days may be sufficient to provide improvement in osteoporosis of the vertebral bones. The recommended intranasal dose is one spray (200 IU) daily. The nasal spray is ideally administered in alternating nostrils each day. Adequate supplementation of calcium (example calcium carbonate 1.5 gm daily) and vitamin D (400 units) is recommended with use of calcitonin to prevent is loss of bone mass with time.

Side Effects

Gastrointestinal upset (nausea and vomiting), injection site reactions, muscle pain, fatigue, edema, skin rashes etc are some of the side effects associated with calcitionin. In addition to these side effects nasal spray is specifically associated with stuffy-nose, bleeding from nose (epistaxis) and rhinitis. Serious allergic reactions to salmon calcitonin can occur rarely. The beneficial effects of calcitonin can be monitored periodically with lumbar vertebral bone density measurements. It may also be done with biochemical markers of bone resorption.

Parathormone Analogue

Parathormone (parathyroid hormone ~ PTH) is secreted by the parathyroid glands in response to a drop in the blood calcium levels. Teriparatide is a recombinant form of the active part of parathormone. It is approved for use in severe osteoporosis patients with high risk for fractures. It is useful in osteoporosis associated with menopause in women, hypogonadism in men and in osteoporosis associated with glucocorticoid therapy. Teriparatide use is associated with significant reduction in the incidence of fractures and increase in the bone mineral density.

Actions

Parathormone increases the blood calcium levels by mobilizing calcium from the bones (bone resorption). Parathormone also enhance production of active form of vitamin D. The enhanced bone resorption with parathormone is seen only when parathormone level is continuously elevated. Intermittent administration of parathormone paradoxically stimulates bone formation.

Dosage

Teriparatide is administered at a daily dose of 20 mcg subcutaneously over thigh or abdomen. The blood level of teriparatide is undetectable within 3 hours of administration. This underlines the effect of intermittent parathormone administration. Teriparatide is not recommended for use for more than 2 years.

Contraindications and Side Effects

Teriparatide use is not indicated in patients at risk of osteosarcoma, like patients with Paget’s disease, as suggested by some animal studies. Increased incidence of kidney stones, increased levels of serum uric acid and calcium, muscle pain and hypotension with initial dose are important side effects of teriparatide.

Denosumab

Denosumab is approved for treatment of postmenopausal osteoporotic women, osteoporotic patients on androgen deprivation therapy for prostate cancer and osteoporotic patients on aromatase inhibitor therapy for breast cancer who are at high risk for fractures. Denosumab therapy is found to reduce the incidence of vertebral and hip fractures in women with postmenopausal osteoporosis. Incidences of vertebral fractures were reduced in prostate cancer and breast cancer patients with osteoporosis resulting from the respective anticancer therapy.

Actions

Denosumab is a human monoclonal antibody targeting the human ‘receptor activator of nuclear factor kappa-B ligand’ (RANKL). It binds to RANKL and prevents its activation. RANKL is essential for the formation, normal functioning, and survival of osteoclasts. This results in reduction of the bone resorption and increase in the bone mass.  Denosumab is administered subcutaneously every 6 months in the upper arm, thigh, or abdomen at a dose of 60 mg. Calcium and vitamin D supplementation is essential along with denosumab therapy.

Side Effects

Most common adverse reactions seen with denosumab are back pain, muscle pain, hypercholesterolemia and cystitis. Serious infections, skin reactions, hypocalcemia and necrosis of the jaw bone are some serious side effects associated with denosumab use.

Estrogens

Reduction in the levels of estrogen is unquestionably considered to be the primary reason behind postmenopausal osteoporosis. Estrogen replacement prevents the enhanced bone loss during the early postmenopausal period. It also marginally increases bone density in postmenopausal woman. The estrogen preparations used for HRT are estradiol, ethinyl estradiol or conjugated estrogens in combination with or without progestins (like norethindrone, medroxyprogesterone).

Actions

Estrogen receptors are present on the bone. These receptors have direct influence on the bone development and its turnover. Estrogens also reduce the bone resorptive effects of parathormone and increase the levels of active vitamin D in blood. Postmenopausal women used to be treated worldwide with estrogen for these reasons. This is popularly known as hormone replacement therapy (HRT). However, the HRT approach is currently discouraged as long term estrogen use was associated with serious adverse outcomes.

Side Effects

The deleterious effects linked to long-term HRT include increased risk of heart disease and breast cancer. Estrogens when used alone for long-term also increase the risk of endometrial cancer. This is prevented by adding progestin to the HRT estrogen cycles. Estrogen therapy is associated with abdominal pain, bloating, nausea, vomiting, breakthrough vaginal bleeding or spotting, peripheral edema, breast tenderness and breast enlargement. Currently HRT use is reserved only for short-term management of the symptoms of menopause. SERMs provide similar benefits like estrogens without causing these harmful effects.

Selective estrogen receptor modulators (SERMs)

Selective estrogen receptor modulators (SERMs) are drugs that produce an estrogen-like effect without having the long-term adverse effects like estrogens. Raloxifene is a SERM which has been approved for oral use in the management of osteoporosis. It is not as effective as estrogen in preventing or treating postmenopausal osteoporosis. Raloxifene effectively provides protection against spine fractures but offers less protection to other bones.

Actions

The effects of SERMs is the same as those discussed above under estrogens.

Dosage

Raloxifene is given at a daily dose of 60 mg.

Side Effects

Raloxifene offers no beneficial effects in preventing hot flashes of menopause. Sometimes raloxifene can worsen the vasomotor symptoms of menopause. In addition to the benefits, raloxifene use is also associated with increased thrombophlebitis risk seen with estrogens. It is contraindicated in patients at risk of deep vein thrombosis or pulmonary embolism. Other adverse effects seen with use of raloxifene include leg cramps, hot flashes, edema, and joint pains.