Chapter 19 Musculoskeletal System
Bisphosphonates (BPs)
MOA (Mechanism of Action)
The structural integrity of bone is determined to a large extent by the balance between the activity of osteoclasts, which break down bone (resorptive), and the activity of osteoblasts, which build bone.
Bisphosphonates (BPs) inhibit osteoclast activity through a variety of mechanisms, some better understood than others (Figure 19-1).
Inside the osteoclast the aminobisphosphonates disrupt the mevalonate pathway, a pathway involved in the posttranslational modification of proteins that are involved in cellular signaling. Disruption of the mevalonate pathway interrupts osteoclast function and leads to apoptosis of the osteoclast.
The non-aminobisphosphonates work by increasing the accumulation of cytotoxic metabolites within osteoclasts, interfering with their function and possibly leading to osteoclast cell death.
The clawlike chemical structure of BPs facilitates their attachment to bone. The multiple oxygen atoms around the perimeter of the BP molecule bind to divalent cations such as Ca2+ within bone matrix. The BPs remain within the matrix until the acids released by the osteoclasts break down the matrix and liberate the BPs. Ironically, the activity of the osteoclasts seals their own fate!
Pharmacokinetics
BPs have very low oral bioavailability (<10%), and their absorption is further reduced by food and by divalent cations such as calcium. It is therefore recommended that BPs be taken on an empty stomach, with plain water.
Contraindications
Side Effects
All
Serious
Esophagitis or esophageal erosion is more commonly seen with the aminobisphosphonates. It may result from a direct irritant effect from tablets lodged in the esophagus or from reflux of gastric acid including the acidic form of the BP. Patients are advised to avoid reclining for at least 30 minutes after taking a BP, reducing the chance of tablet staying in the esophagus or reflux.
Osteonecrosis of the jaw is typically only seen at higher doses. The mechanism has not been established; however, the fact that BPs alter bone turnover is thought to play a role. Jaw bone may have a higher rate of turnover than other areas of the body, perhaps explaining why this side effect is localized to this area.
Important Notes
The non-aminobisphosphonates were the original members of this drug class, whereas the aminobisphosphonates are newer, more potent agents.
BPs have an established history as adjuncts in cancer therapy. They have demonstrated ability to reduce bone pain secondary to metastases and prevent treatment-induced bone loss.
Etidronate can cause bone demineralization; therefore unlike the other BPs, which are typically taken once daily, etidronate is typically administered in 90-day cycles, with 14 days on treatment and 76 days off treatment. During the off-treatment period, calcium tablets are typically administered, and this 90-day treatment cycle (etidronate followed by calcium) is marketed in one kit.
Estrogens appear to have a role in decreasing bone resorption; therefore one of the benefits of hormone replacement therapy in postmenopausal women is to maintain integrity of bone, hopefully leading to fewer fractures.
Evidence
Risedronate versus Placebo or Calcium and Vitamin D or Both in Postmenopausal Osteoporosis
A 2008 Cochrane review (7 trials, N = 14,049 females) found no statistically significant effects for risedronate with respect to primary prevention of vertebral and nonvertebral fractures. For secondary prevention, risedronate demonstrated statistically significant relative risk reductions (RRRs) of vertebral fractures (39%), nonvertebral fractures (20%), and hip fractures (26%). The corresponding absolute risk reductions were small: 5%, 2%, and 1%, respectively. No statistically significant differences were found for adverse events.
Etidronate versus Placebo and/or Calcium and Vitamin D in Postmenopausal Osteoporosis
A 2008 Cochrane review (11 trials, N = 1248 females) found no statistically significant effects of etidronate with respect to primary prevention of any fractures. A statistically significant RRR of 47% was found for secondary prevention of vertebral fractures but not for nonvertebral, hip, or wrist fractures. No statistically significant differences were found for adverse events.
BPs versus Placebo or No Treatment in Myeloma
A 2002 Cochrane review (11 trials, N = 2183 patients) found that BPs prevented pathologic vertebral fractures (number needed to treat [NNT] = 10) and relieved pain (NNT = 11). BPs did not affect mortality, nonvertebral fractures, or hypercalcemia. No significant adverse events were associated with the BPs.
FYI
One of the earliest indications that the BPs had potential in the treatment of bone diseases was the observation that they inhibit the dissolution of hydroxyapatite crystals.
Because of their ability to localize in bone, one of the early uses for BPs was as bone scanning agents, used in the detection of malignancies and other skeletal lesions.
The bisphosphonates are so named because of the two phosphate (P) groups that form the backbone of these molecules.
Vitamin D Replacement
MOA (Mechanism of Action)
Vitamin D is an important regulator of calcium and phosphate homeostasis and bone metabolism. It works in conjunction with PTH. The overall effect of vitamin D is to increase serum calcium concentrations. These effects are mediated via the following:
Vitamin D is lipophilic (it is one of the fat-soluble vitamins—A, D, E, and K) and thus freely crosses the cytoplasmic membrane.
Intracellularly, it binds vitamin D receptors (VDRs) and binds DNA, where it regulates transcription of genes in the intestine, bone, kidney, and parathyroid gland.
Vitamin D also has actions in macrophages and T cells and in proliferation and differentiation of a large number of cells, including cancer cells. Through these actions, it has immunomodulating and potentially, anticancer actions. Also, these actions are the basis of the mechanism whereby it is effective in psoriasis.
Important Notes
Vitamin D is synthesized in the skin, liver, and kidney. Vitamin D supplementation is therefore frequently required in patients with renal failure.
Rickets is a childhood disease characterized by impeded growth and deformity (curvature) of the long bones caused by vitamin D deficiency. The fortification of milk with vitamin D has dramatically reduced the incidence of rickets in developed countries.
Osteomalacia is a condition of bone softening resulting from abnormality in the mineralization of the organic portion of the bone matrix called osteoid. It can be caused by vitamin D deficiency and is like an adult form of rickets. It is characterized by proximal muscle weakness, pain, and bone fragility.
Osteoporosis is characterized by reduced bone mineral density (BMD) and increased bone fragility. It is caused by abnormal osteoblastic and osteoclastic activity. The bone is porous, hence the name of the disease.
Advanced
Common Name | Drug Name | Abbreviation |
---|---|---|
Vitamin D2 | Ergocalciferol | D2 |
1-Hydroxyvitamin D2 | Doxercalciferol | 1(OH)D2 |
Vitamin D3 | Cholecalciferol | D3 |
25-Hydroxyvitamin D3 | Calcifediol | 25(OH)D3 |
1,25-Dihydroxyvitamin D3 | Calcitriol | 1,25(OH)2D3 |
24,25-Dihydroxyvitamin D3 | Secalcifediol | 24,25(OH)2D3 |
Evidence
Vitamin D Plus Calcium and Bone Fractures in the Elderly
The same meta-analysis in 2008 showed that vitamin D plus calcium supplements do reduce hip fractures in the elderly (8 trials, N = 46,658 participants, relative risk [RR] 0.84). Hypercalcemia is significantly more common in people receiving vitamin D or an analogue, with or without calcium (18 trials, N = 11,346 participants, RR 2.35). There is a significant but modest increase in gastrointestinal symptoms (RR 1.04) and a small but significant increase in renal disease (RR 1.16).
FYI
The concept that vitamin D comes from the sun is inaccurate; the inert precursor (7-dehydrocholesterol) is present in the skin, and exposure to ultraviolet light converts it to cholecalciferol, which is then isomerized to vitamin D3. Reduced exposure to sunlight is one cause of vitamin D deficiency.
Parathyroid Hormone
MOA (Mechanism of Action)
PTH is released from the parathyroid gland. It regulates calcium and phosphate flux across cell membranes in bone and kidney. The key effects of PTH are as follows:
The effects on osteoclasts are indirect. PTH increases activity of the RANK (receptor activator of nuclear factor κ) ligand (RANKL). RANKL regulates osteoclast activity (see the discussion of RANKL inhibitors in this chapter). Increasing the activity of RANKL in turn stimulates an increase in the activity and number of osteoclasts.
The stimulation of osteoclasts increases bone remodeling. PTH increases both bone resorption and formation; however, the net effect of excess PTH is to increase bone resorption (Figure 19-3).
Low levels of intermittent PTH, however, can enhance bone formation. The actions of PTH are largely mediated through the PTH-1 receptor. The anabolic effects are mediated by direct effects of PTH on osteoblasts, increasing their number and inhibiting their apoptosis. PTH also stimulates insulin-like growth factor (IGF-1) in osteoblasts, and IGF-1 also has anabolic effects on bone.
It is still not clear why high, sustained PTH has a catabolic effect, whereas low, intermittent administration has an anabolic effect on bone.
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