Presentation on theme: "Drugs Used for Treatment of Osteoporosis and Rickets/Osteomalacia"— Presentation transcript:
1Drugs Used for Treatment of Osteoporosis and Rickets/Osteomalacia Dr. Kaukab Azim. MBBS, PhD
2What is Osteoporosis“a disease characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in fracture risk.”Osteoporosis is by far the most common metabolic bone disease. One in two white and Asian postmenopausal women and at least one in eight older men and women of other racial backgrounds are likely to have an osteoporotic fracture at some time during their lifetime ( Fig ). Osteoporosis has been better defined by the Consensus Development Conference as
3Incidence of osteopenia and osteoporosis William’s textbook of endocrinologyFigure 28-13 Estimation of the current prevalence of osteoporosis in the United States. On the basis of World Health Organization criteria, more than 9 million women in the United States have osteoporosis; more than half of these women have established osteoporosis with fractures. In addition, 17 million postmenopausal women have osteopenia (low bone mass) and are at risk for development of osteoporosis. (From Melton LJ. How many women have osteoporosis now? J Bone Miner Res 1995;10: )This data is for US. (William’s textbook of Endocrinology)
4Incidence of fractures in osteoporosis Figure 28-14 Age-specific incidence rates for hip, vertebral, and Colles' fractures in Rochester, Minnesota. (From Cooper C, Melton LJ. Epidemiology of osteoporosis. Trends Endocrinol Metab 1992;3:224. Copyright 1992 by Elsevier Science Inc.)
5Normal Calcium Turnover Diet1000 mg300 mg175 mg500 mgGutGutECF Ca++900 mgBoneBone125 mg500 mg9825 mgReabsorbed10,000 mgFiltered / dayFeces825 mgGreenspan’s. Basic and Clinical EndocrinologyCalcium fluxes in a normal individual in a state of zero external mineral balance. The open arrows denote unidirectional calcium fluxes; the solid arrows denote net fluxesUrineKidney175 mgGreenspan’s. Basic and Clinical Endocrinology
13Scanning Electron Micrographs Bone tissue. Coloured scanning electron micrograph (SEM) of cancellous (spongy) bone. This tissue, found in the interior of bones, is characterised by a honeycomb arrangement of trabeculae (columns) and spaces. This honeycomb structure provides
14Bone DensitometryBone densitometry is a safe, painless x-ray technique that compares bone density to the peak bone density that someone of your same sex and ethnicity should have reached at about age when it is at its highest.Bone densitometry allows your doctor to:Detect a potential problem before fracture occurs,Predict chances of future fractures andDetermine your rate of bone loss.All of these factors can then be weighed to determine a course of treatment.
17BisphosphonatesBisphosphonates are agents that prevent the breakdown of bone.PROTOTYPES AND COMMON DRUGSAminobisphosphonatesPrototype: alendronateOthers: risedronate, pamidronateNon-AminobisphosphonatesPrototype: etidronateOthers: clodronate, tiludronate, zoledronate
18Mechanism of ActionThe 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.Inside the osteoclast the aminobisphosphonates disrupt the mevalonate pathway. Disruption of the mevalonate pathway interrupts osteoclast function and leads to apoptosis of the osteoclast.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.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!Osteoclasts contribute further to their demise by devouring the BP molecules after liberating them.BPs have a variety of other cellular effects, inhibiting vitamin D production, intestinal Ca2+ transport, cell growth, metabolic changes in bone cells, and changes in acid and alkaline phosphatases
19The 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 BPs remain within the matrix until the acids released by the osteoclasts break down the matrix and liberate the BPs. The activity of osteoclasts results in their own death.Osteoclasts die after ingesting BP molecules.BPs also inhibit vitamin D production, intestinal Ca2+ transport, and cell growth.
21PharmacokineticsBPs 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.The BPs that are absorbed are highly bound to bone, and are not metabolized, nor do they inhibit or induce metabolizing enzymes. They are eliminated by the kidney.The oral BPs are typically administered once daily. A higher dose of alendronate is also available as a once weekly formulation.
22Indications Osteoporosis Paget's disease of the bone (results in enlarged, deformed bones)Hypercalcemia:▴ Malignancy▴ Primary hyperparathyroidism (continuous parathyroid hormone [PTH] release causes bone demineralization)Bone metastasis causing osteolysis:▴ Multiple myeloma▴ Bone metastases of malignant tumors
23ContraindicationsHypocalcemia: BPs have exhibited decreases in serum calcium, so it is recommended that any deficiencies in calcium be addressed before initiation of therapy.Poor renal function: BPs are eliminated renally, so patients with creatinine clearance <30 mL/min may experience accumulation of these agents.
24Side Effects Serious Gastrointestinal: nausea, dyspepsia Esophagitis or esophageal erosionOsteonecrosis of the jawAminobisphosphonatesFever, flulike symptomsSIDE EFFECTSAllGastrointestinal: nausea, dyspepsiaSeriousEsophagitis 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.AminobisphosphonatesFever, flulike symptoms are a transient, typically first-dose phenomenon seen with intravenous administration. They are believed to be caused by release of proinflammatory cytokines.IMPORTANT NOTESThe 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.Nonpharmacologic strategies for preventing osteoporosis include smoking cessation and weight-bearing exercise. Smoking is known to reduce bone mineral density (BMD), and weight-bearing exercise has been shown to substantially reduce fracture risk.AdvancedPregnancyThe use of BPs in pregnancy has not been well studied, but they are believed to cross the placenta, based on animal studies. Given their effects on bone, a very careful assessment of risk versus benefit should be performed before these agents are used.EVIDENCERisedronate versus Placebo or Calcium and Vitamin D or Both in Postmenopausal OsteoporosisA 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 OsteoporosisA 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 Myelomapage 293page 294A 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.FYIOne 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.The BPs have a clawlike chemical structure. This is a good way to remember that they attach themselves to bone matrix for long periods of time.The aminobisphosphonates such as alendronate have an amino (NH2-) group.
25Parathyroid hormone TERIPARATIDE This is a recombinant form of naturally occurring PTH.
27Mechanism of ActionPTH 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:Increased serum calciumDecreased serum phosphateIncreased osteoclast activity in boneThe effects on osteoclasts are indirect. PTH increases activity of the RANK (receptor activator of nuclear factor κ) ligand (RANKL). RANKL regulates osteoclast activityPTH increases both bone resorption and formation. High levels of PTH increase bone resorptionPTH 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:▴ Increased serum calcium▴ Decreased serum phosphate▴ Increased osteoclast activity in boneThe 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.In addition to these factors, PTH has several effects on the kidney:▴ Increased reabsorption of Ca2+ and Mg2+▴ Decreased reabsorption of phosphate, amino acids, bicarbonate, Na+, Cl-, and sulfate▴ Stimulation of production of 1,25 dihydroxyvitamin D
28Low levels of intermittent PTH, however, can enhance bone formation Low levels of intermittent PTH, however, can enhance bone formation. The anabolic actions of PTH are mediated through the PTH-1 receptors on osteoblasts. 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.
29In addition to these factors, PTH has several effects on the kidney: Increased reabsorption of Ca2+ and Mg2+Decreased reabsorption of phosphate, amino acids, bicarbonate, Na+, Cl-, and sulfateStimulation of production of 1,25 dihydroxyvitamin D
30PharmacokineticsTeriparatide is administered as a subcutaneous injection once daily.It is both rapidly absorbed and rapidly eliminated, with plasma concentrations reaching their peak at 30 minutes post-injection and falling to undetectable levels after 3 hours.The metabolism of teriparatide is poorly understood, but enzymes are thought to be involved.
31Indications Osteoporosis Typically reserved for severe osteoporosis and/or patients in whom previous therapies, including the BPs, have failedOsteoporosis secondary to corticosteroid use
32Contraindications Children or young adults with open epiphysis HypercalcemiaActive Paget's disease of bone.Skeletal metastases or skeletal malignant conditions: risk of osteosarcomaHistory of radiation to the skeleton: risk of osteosarcoma.Pregnancy and lactationChildren or young adults with open epiphysis: The safety and efficacy of teriparatide has not been studied in pediatrics, and its significant impact on bone remodeling is a concern in this populationHypercalcemia: PTH already raises Ca2+ levels.Active Paget's disease of bone.Skeletal metastases or skeletal malignant conditions: risk of osteosarcoma (see Important Notes).History of radiation to the skeleton: risk of osteosarcoma (see Important Notes).Pregnancy and lactation: The effects of teriparatide have not been studied in pregnancy. Given its significant effects on bone remodeling, deleterious effects on fetal bone development are possible.
33Side EffectsHypercalcemia (mild): This can be managed by reducing Ca2+ and vitamin D intake or by adjusting teriparatide dose from daily to every other day.Leg cramps (may occur)Nausea (may occur)Orthostatic hypotensionSIDE EFFECTSHypercalcemia (mild): PTH increases serum calcium. This can be managed by reducing Ca2+ and vitamin D intake or by adjusting teriparatide dose from daily to every other day.Leg cramps may occur.Nausea may occur.Orthostatic hypotension: PTH infusions have a vasodilatory effect in animals. Hypotension has been observed within 4 hours of infusion in clinical trials.IMPORTANT NOTESpage 296page 297The greatest safety concern associated with teriparatide is osteosarcoma (malignant bone cancer). However, this concern is based on observations in rodents exposed to prolonged high doses and on the ability of teriparatide to stimulate osteoblasts. So far, there does not appear to be an elevated risk of osteosarcoma with teriparatide use in humans.Because of the concerns over osteosarcoma, use of teriparatide is limited to 1.5 to 2 years. The reason for this cutoff is that the safety of teriparatide has not been assessed beyond 2 years in clinical trials.Most of the agents used to manage osteoporosis are antiresorptive and work by inhibiting bone turnover. Teriparatide works by promoting bone turnover; thus there is concern that patients switching from antiresorptive agents, particularly potent agents such as BPs, might experience reduced efficacy with teriparatide. Therefore some clinicians suggest that there should be a washout period when switching from the BPs to teriparatide. The benefits of a washout should be balanced against the risk of no treatment, particularly in patients with severe disease.EVIDENCEBisphosphonates or Teriparatide in Postmenopausal WomenA 2005 systematic review (90 trials) compared all BPs and teriparatide with calcium, calcium plus vitamin D, calcitriol, hormone replacement therapy, exercise, and placebo or no treatment. They found that only teriparatide and risedronate reduced the risk of nonvertebral fracture in women with severe osteoporosis and adequate calcium intake.FYITeriparatide is supplied as prefilled injectable pens, which make it easier for patients to self-administer subcutaneous injections.
34EstrogensThe decline in estrogen levels is a major factor in postmenopausal osteoporosis, and there is evidence that giving hormone replacement therapy (HRT) can ameliorate this condition. But HRT has actions on many systemsThe prevailing hypothesis advanced to explain these observations is that estrogens reduce the bone-resorbing action of PTH. Estrogen administration leads to an increased Vit D level in blood. The increased Vit D levels may result from decreased serum calcium and phosphate and increased PTH.ESTROGENSEstrogens can prevent accelerated bone loss during the immediate postmenopausal period and at least transiently increase bone in the postmenopausal woman.The prevailing hypothesis advanced to explain these observations is that estrogens reduce the bone-resorbing action of PTH. Estrogen administration leads to an increased 1,25(OH)2D level in blood, but estrogens have no direct effect on 1,25(OH)2D production in vitro. The increased 1,25(OH)2D levels in vivo following estrogen treatment may result from decreased serum calcium and phosphate and increased PTH. Estrogen receptors have been found in bone, and estrogen has direct effects on bone remodeling. Recent case reports of men who lack the estrogen receptor or who are unable to produce estrogen because of aromatase deficiency noted marked osteopenia and failure to close epiphyses. This further substantiates the role of estrogen in bone development, even in men. The principal therapeutic application for estrogen administration in disorders of bone mineral homeostasis is the treatment or prevention of postmenopausal osteoporosis. However, long-term use of estrogen is being discouraged because of its deleterious adverse effects. Rather, selective estrogen receptor modulators (SERMs) have been developed to retain the beneficial effects on bone while minimizing these deleterious adverse effects on breast, uterus, and the cardiovascular system (see Newer Therapies for Osteoporosis).
35Estrogen receptors have been found in bone in both males and females, and estrogen has direct effects on bone remodeling. Men who lack the estrogen receptor have marked osteopenia. This further substantiates the role of estrogen in bone development, even in men.The principal therapeutic application for estrogen administration in disorders of bone mineral homeostasis is the treatment or prevention of postmenopausal osteoporosis.
36Adverse Effects of Estrogens Migraine headachesWater retention (weight gain)Stimulation of reproductive organ tissues:Vaginal bleeding or spotting (because of growth of endometrial tissue)Enlarged fibroidsBreast tendernessGall bladder disease (primarily stones)Thrombosis: (estrogen is a procoagulant)Deep vein thrombosis and pulmonary embolismStrokeCoronary heart diseaseIncreased triglyceridesIMPORTANT NOTESProgesterone is often co-administered with estrogen.Estrogen stimulates endometrial growth and can also stimulate cancers of reproductive tissues.Estrogens do not cause HTN at the doses in which they are currently prescribed but can cause HTN at very high doses.Estrogen is prothrombotic. It increases the probability of clot formation. Bleeding is a potential complication of natural childbirth, and the prothrombotic effects of estrogen are therefore beneficial during this time.The natural progression of sex hormone synthesis is as follows: progestins → androgens → estrogens (Figure 14-10). The similarity to aldosterone probably accounts for the water retention properties of sex hormones.AdvancedThe cause of water retention is not fully understood, but it is possibly mediated by the following:▴ Changes in the thresholds for antidiuretic hormone (ADH) secretion and osmotic thirst, resulting in increased body water▴ Increases in the renin-angiotensin-aldosterone system by estrogen or progesterone▴ Nitric oxide-mediated vasodilation (thus increasing total blood volume) because of estrogenThe mechanism by which estrogens increase the prevalence of migraines is complex, but it probably involves the following:▴ Vasodilation mediated by nitric oxide▴ Neuronal excitability mediated by increased calcium and decreased magnesiumEVIDENCEpage 155page 156page 156page 157(Note that many studies also include progesterone.)Many studies, often with different methodologies, have resulted in many results; summarizing is difficult because of the heterogeneity of studies that exists. Patient differences (age, gravida status, time since menopause) and drug differences (estrogen only versus estrogen with progesterone, dose, duration, estrogen formulation, estrogen delivery method) are some examples of the differences among studies. A very small subset of the evidence is presented here.▴ Endometrial cancer risk: An analysis of 45 RCTs with 38,702 postmenopausal women demonstrated that unopposed estrogen (without any progesterone coadministered) of any dose for a duration of only 1 year increases risk of endometrial hyperplasia (and by extension, endometrial cancer) in patients being treated for menopausal symptoms. This effect increased with increasing dose of estrogen and increasing duration of administration.▴ Cardiovascular risk: A single large double-blind RCT of 10,739 postmenopausal women comparing estrogen with placebo demonstrated no difference in myocardial infarction or cardiac death. However, the hazard ratio for stroke was 1.39, indicating an almost 40% increase in risk for stroke. Average follow-up time was 6.8 years.▴ Bone health (bone density, fractures):An analysis in 2008 of 13 RCTs (two were placebo controlled), provides evidence that combined hormone oral contraceptives does not affect bone health. Depot progesterone alone (depot medroxyprogesterone acetate or DMPA) was associated with decreased bone density. Note that oral contraceptives would be administered to women of childbearing age.A single large double blind RCT of 10,739 postmenopausal women comparing estrogen with placebo demonstrated a hazard ratio of 0.61 for hip fractures (reduction of risk by 40%) and 0.70 for all fractures in the estrogen group. Average follow-up time was 6.8 years.▴ DVT risk: In a 2006 RCT, 10,739 women followed for an average of 7.1 years demonstrated a rate of venous thrombosis of 3.0 per 1000 person-years in the estrogen group versus 2.2 in the placebo group. This represents a statistically significant hazard ratio of 1.47 (47% more likely to get a blood clot if on estrogen). Compared with estrogen plus progesterone, it appears that the risk is greater with combination therapy versus estrogen alone.▴ Cognitive function: A meta-analysis in 2007 of 16 studies with 10,114 women with normal brain function demonstrated no benefit in prevention of cognitive decline over a period of 3 to 5 years compared with placebo. In fact, there was a slight trend toward better function with placebo. It has been previously suggested that estrogen deficiency is associated with decreased cognitive function.▴ Weight gain: An analysis of available literature in 2008 included five RCTs (957 women) comparing hormone with placebo and did not find strong evidence to support an association between weight gain and the use of oral contraceptives; however, most studies were not designed to study this particular outcome.▴ Acne: A meta-analysis in 2009 found 25 trials evaluating combined hormones and acne treatment. Of the 25, seven were placebo controlled, and these studies showed improvement in acne with hormone therapy. The remaining studies compared different hormone combinations and doses. Hormones containing cyproterone acetate might be superior in treating acne, but data are somewhat conflicting.Figure 14-10FYIA state of estrus in mammals (excluding humans) is the time around ovulation when the female is receptive to sexual activity (being in heat); estrogen peaks right before this time in the cycle.Simplified memory tip: Estrogen is like fertilizer for the endometrium. Progesterone is like the lawnmower.Fibroids are benign tumors of the uterus, composed of myometrium.Gravida status refers to the number of previous pregnancies.Dysfunctional uterine bleeding is defined as bleeding outside the normal menstrual period.Menorrhagia is heavy menstrual bleeding.Dysmenorrhea is a condition of having excessively painful menstrual periods.
37RaloxifeneMany women fear adverse effects of estrogen therapy, particularly the increased risk of breast cancer from continued estrogen use (the well-demonstrated increased risk of endometrial cancer is prevented by cycling with a progestin) and do not like the persistence of menstrual bleeding that often accompanies this form of therapy.Raloxifene. Selective Estrogen Receptor Modulator (SERM) Reloxifene shares some of the beneficial effects of estrogen on bone without increasing the risk of breast or endometrial cancer (it may actually reduce the risk of breast cancer). Although not as effective as estrogen in increasing bone density, raloxifene has been shown to reduce vertebral fractures.
38Mechanism of Action Actions and mechanism of action Raloxifene produces a dose-dependent increase in osteoblast activity and reduction in osteoclast action.PharmacokineticsIt is well absorbed in the gastrointestinal tract, and undergoes extensive first-pass metabolism in the liver. (Colestyramine, given with it, reduces the enterohepatic cycling of raloxifene by 60%.)Thus bioavailability is only about 2%. It is widely distributed in the tissues, and is converted to an active metabolite in liver, lungs, bone, spleen, uterus and kidneys. Its half-life averages 32 hours. It is excreted mainly in the faeces.
39Unwanted effectsHot flushes and leg cramps are common. In a recent clinical trial, raloxifene was found to be associated with venous thromboembolism; however, other authorities state that there is less risk of this adverse effect in younger patients.
40Strontium ReanelateThis compound, newly introduced for treatment of osteoporosis, is composed of two atoms of strontium combined with organicranelic acid. It inhibits bone resorption and also stimulates bone formation.Mechanism of ActionStrontium is similar to calcium as regards its absorption in the gastrointestinal tract, its incorporation into bone and its renal elimination. Strontium atoms are exchange for calcium in the bone minerals and remain in the bone for many years.PharmacokineticsThe drug is well tolerated; a low incidence of nausea and diarrhoea is reported.STRONTIUM RANELATEThis compound, newly introduced for treatment of osteoporosis, is composed of two atoms of strontium combined with organic ranelic acid, the latter being a carrier for the active strontium component. It inhibits bone resorption and also stimulates bone formation. In recent trials, it has been shown to be effective in preventing vertebral and non-vertebral fractures in older women (see Fogelman & Blake, 2005).The precise mechanism of action is not clear. Strontium is similar to calcium as regards its absorption in the gastrointestinal tract, its incorporation into bone and its renal elimination. Strontium atoms are adsorbed on to the hydroxyapatite crystals, but eventually they exchange for calcium in the bone minerals and remain in the bone for many years.The drug is well tolerated; a low incidence of nausea and diarrhoea is reported.
41CalcitoninThe main preparation available for clinical use is salcatonin (synthetic salmon calcitonin). Synthetic human calcitonin is now also available.Calcitonin is given by subcutaneous or intramuscular injection, and there may be a local inflammatory action at the injection site. It can also be given intranasally. Its plasma half-life is 4-12 minutes, but its action lasts for several hours.Adverse effects include nausea and vomiting, facial flushing, tingling sensation in the hands and an unpleasant taste in the mouth.
43Osteomalacia and Rickets Osteomalacia (referred to as rickets in children) is defined as an excess organic bone matrix secondary to defective or inadequate bone mineralization Predominant age: All ages. It is usually a disease of the older population (50-80). Predominant sex: Female > Male (slightly)
45Vitamin D synthesis and activation Vitamin D is synthesized in the skin in response to ultraviolet radiation and is also absorbed from the diet. It is then transported to the liver, where it undergoes 25-hydroxylation. This metabolite is the major circulating form of vitamin D. The final step in hormone activation, 1-hydroxylation, occurs in the kidney.
46Rickets and Osteomalacia In children, prior to epiphyseal fusion, vitamin D deficiency results in growth retardation associated with an expansion of the growth plate known as rickets.OsteomalaciaIn adults the hypocalcemia and hypophosphatemia that accompany vitamin D deficiency result in impaired mineralization of bone matrix proteins, a condition known as osteomalacia .
47CausesVitamin D deficiency (most common) caused by reduced exposure to sunlight, poor nutrition, malabsorption syndromes.Defective metabolism of parent vitamin D to active metabolitesDrug-induced, i.e., anticonvulsants – phenytoin, chronic renal failure, hypophosphatemia, long-term hemodialysisRISK FACTORSPovertyInadequate nutrition and sunlight exposure
55Pseudofractures are pathognomonic for osteomalacia A band of bone material of decreased density may form alongside the surface of the bone. Thickening of the periosteum occurs. The formation of callouses in the affected area is also common. This gives the appearance of a false fracture. Typical sites of involvement are the axillary margins of the scapula, ribs, pubic rami, proximal ends of the femur and ulna. a lucent line about 1 –2 cm wide vertical to the cortex ..all the changes have unclear border.Plain radiograph of pelvis taken at the time of initial presentation and reported as bilateral undisplaced subtrochanteric pseudofractures of femur due to osteomalacia (see notes below)
57Vitamin D replacement consists of vitamin D and its derivatives. Prototype: calcitriolOthers: ergocalciferol (vitamin D2), calcipotriene, doxercalciferol, paricalcitol
58Various forms of Vitamin D Common NameDrug NameAbbreviationVitamin D2ErgocalciferolD21-Hydroxyvitamin D2Doxercalciferol1(OH)D2Vitamin D3CholecalciferolD325-Hydroxyvitamin D3Calcifediol25(OH)D31,25-Dihydroxyvitamin D3Calcitriol1,25(OH)2D324,25-Dihydroxyvitamin D3Secalcifefiol24,25(OH)2D3
59Mechanism of ActionThe two major forms of vitamin D replacements are vitamin D2 and vitamin D3.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:Increased calcium absorption from the intestineRegulation of bone resorption and formationIncreased calcium reabsorption in the distal renal tubulesThe two major forms of vitamin D replacements are vitamin D2 and vitamin D3.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:▴ Increased calcium absorption from the intestine▴ Regulation of bone resorption and formationThis occurs via stimulation of both osteoblastic and osteoclastic processes. Osteoblasts form bone, and osteoclasts dissolve bone.▴ Increased calcium reabsorption in the distal renal tubules (Figure 19-2)Vitamin D results in a negative feedback loop and decreases transcription and secretion of PTH.▴ The overall effect of PTH is to increase serum calcium levels, so increased vitamin D inhibits the actions of PTH so that both mechanisms do not drive up calcium levels too high.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.
60Vitamin D results in a negative feedback loop and decreases transcription and secretion of PTH. The overall effect of PTH is to increase serum calcium levels, so increased vitamin D inhibits the actions of PTH so that both mechanisms do not drive up calcium levels too high.
61Mechanism of ActionVitamin 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.
63PHARMACOKINETICSCalcitriol is available in oral and intravenous formulations. It is a lipid-soluble vitamin and therefore can accumulate and cause toxicityINDICATIONSOsteoporosisHyperparathyroidismOsteomalaciaRicketsCONTRAINDICATIONSNone
64Side EffectsSide effects are related to long-term overadministration of vitamin D supplementation. Symptoms are primarily induced by hypercalcemia, which include gastrointestinal pain, renal stones, and psychiatric disturbances.IMPORTANT NOTESVitamin 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.AdvancedVitamin D supplements are sometimes used in the treatment of psoriasis, a common skin condition involving rapid turnover and inflammation of the skin. The evidence for this use, however, is not strongly conclusive.The various forms of vitamin D are referred to by several different names, summarized in Table 19-1.EVIDENCEVitamin D Alone and Bone Fractures in the ElderlyA meta-analysis in 2008 showed that vitamin D alone in the elderly was unlikely to be effective in preventing hip fractures (9 trials, N = 24,749 participants), vertebral fractures (5 trials, N = 9138 participants), or any new fracture (10 trials, N = 25,016 participants).Vitamin D Plus Calcium and Bone Fractures in the ElderlyThe 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).FYIThe 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.Calcitonin is another hormone secreted by the thyroid gland. It has the opposing action of PTH: it "tones down" (lowers) the serum calcium levels.Vitamin D is a secosteroid: this is a steroid with one of the rings (the B ring) broken. Vitamin D2 is from ergosterol, whereas vitamin D3 is from cholesterol. Ergosterol is not produced in vertebrates, and therefore vitamin D2 is not produced in humans.