Safety profile of drugs used in the treatment of osteoporosis: a systematical review of the literature.
Reumatismo. 2013 Oct 31;65(4):143-66. doi: 10.4081/reumatismo.2013.143.
Varenna M, Bertoldo F, Di Monaco M, Giusti A, Martini G, Rossini M, Siommms OB, Sir EB.
Bone Diseases Unit, Department of Rheumatology, Gaetano Pini Institute, Milan. varenna at gpini.it.
The range of osteoporosis treatments is increasingly large and, like any disease, the pharmacological management of patients should involve a risk/benefit evaluation to attain the greatest reduction in risk of fracture with the lowest incidence of adverse events. The aim of this review is to critically appraise the literature about the safety issues of the main pharmacological treatments of osteoporosis. This document is the result of a consensus of experts based on a systematic review of regulatory documents, randomized controlled trials, metaanalyses, pharmacovigilance surveys and case series related to possible adverse drug reactions to osteoporosis treatment with calcium and vitamin D supplements, bisphosphonates, strontium ranelate, selective estrogen receptor modulators, denosumab, and teriparatide. As expected, randomized controlled trials showed only the most common adverse events due to the samples size and the short observation time. Case series and observational studies are able to provide data about uncommon side effects, but in some cases a sure cause-effect relationship needs still to be confirmed. Consistently with methodological limitations, the newer drugs have a tolerance profile that has not been fully explored yet. Osteoporosis treatments showed an overall good tolerance profile with rare serious adverse events that, however, must be well known by the clinician who prescribes these drugs. The concern about possible adverse events should be weighed against the reduction of morbidity and mortality associated with a significant fracture risk reduction.
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Deficits of vitamin D with a lower extent than those causing rickets and osteomalacia are still responsible for a reduced absorption of calcium in the intestinal tract and may represent a pathogenic way of OP, primarily in the elderly. In the last years a number of studies suggested a possible protective role of vitamin D and its metabolites in the pathogenesis of many extra-skeletal diseases, such as muscle, cardiovascular, autoimmune and neoplastic diseases.
The administration of vitamin D at high doses once a year in subjects not deficient was associated with an increased risk of falls and fractures. In a RCT on 2256 women treated with colecalciferol 500,000 IU per os for 3-5 years, the risk of falls (RR 1.15; 95% CI 1.02-1.30, P=0.03) and fractures (RR 1.26; 95% CI 1-1.59, P=0.047) was higher in the treatment group than in the placebo group (39). A previous RCT on 9,440 subjects treated for 3 years with 300,000 IU of intramuscular vitamin D2 had shown a significant increase of risk only for specific types of fractures or in subgroups, without a significantly increased risk of falls (40). Both these studies have relevant methodological limitations among whom the main is, according to the authors (41), the inclusion of subjects with basal 25OH-vitamin D levels in the physiological range. A recent RCT investigating the effects of a supplementation with colecalciferol 150,000 IU every 3 months in subjects not deficient did not show any negative effect on the risk of falls and/or fractures (42). Vice versa, a previous RCT demonstrated favorable effects on falls and fractures of the administration of 100,000 IU of colecalciferol every 4 months for 5 years in 2686 subjects with unknown basal 25OH-vitamin D levels (43). Doses of colecalciferol higher than 600,00 IU were associated with increased levels of markers of bone resorption (44), while this association was not significant from a clinical point of view for boluses of 300,000 IU and absent for doses of 100,000 IU (45).
Monitoring serum 25OH-vitamin D levels during supplementation is suggested only for high doses (>1000 IU/day) or when concomitant diseases can induce extremely elevated serum levels of vitamin D (granulomatosis) or enhance the consequences (primary hyperparathyroidism) (46).
The use of vitamin D metabolites hydroxylated in position 1 (calcitriol and alfacalcidol) is associated with a significantly increased risk of hypercalcemia and hypercalciuria. This effect is well known and documented and it can be easily explained by an overcoming of the metabolic step that is an endogenous regulator of calcitriol synthesis (47,48). However, serious consequences of hypercalcemia are infrequent (49). If the vitamin D metabolite hydroxylated in position 25 (calcifediol) is prescribed, it should be taken into account that doses in micrograms (ug) or in IU did not match with those of colecalciferol. It has been recently suggested that 1ug (40 IU) of calcifediol equals 4-5 ug of colecalciferol (50), but more data are requested in different populations of patients with a long follow-up to exactly define the conversion factor between the two molecules.
Possible adverse effects related to doses of vitamin D higher than or equal to 300,000 IU, administrated once a year in subjects not deficient, have been reported. To maintain an adequate vitamin D status, the use of fractionated doses such as daily, weekly or monthly doses is to be preferred. High doses of vitamin D to be taken in a few weeks are currently recommended in deficient subjects to correct the deficit. A periodic check of serum 25OH-vitamin D levels (e.g. every 2 years) should be performed in subjects supplemented with more than 1000 IU/day. Checks should be more frequent in subjects with granulomatosis or primary hyperparathyroidism. The highest safe dose in long-term treatments is 4000 IU/day. During pregnancy, when supplementation is indicated, boluses (single doses higher than 25,000 IU) have to be avoided. Vitamin D metabolites hydroxylated in position 1 (calcitriol and alfacalcidol) can cause hypercalcemia and hypercalciuria and their administration is not recommended in osteoporosis treatment.
- Overview Toxicity of vitamin D
- Osteoporosis category overview
- European Osteo group recommends 20-50 ng of vitamin D – Jan 2013
- Vitamin D is the first of three ways to make unbreakable bones – Oct 2011
- Overview Fractures and vitamin D
- Is it ethical to not give vitamin D in osteoporosis trials– NEJM Sept 2010
- Overview Osteoporosis and vitamin D contains the following summary
*FACT: Bones need Calcium (this has been known for a very long time)
- FACT: Vitamin D improves Calcium bioavailability (3X ?)
- FACT: Should not take > 750 mg of Calcium if taking lots of vitamin D (Calcium becomes too bio-available)
- FACT: Adding vitamin D via Sun, UV, or supplements increased vitamin D in the blood
- FACT: Vitamin D supplements are very low cost
- FACT: Many trials, studies. reviews, and meta-analysis agree: adding vitamin D reduces osteoporosis
- FACT: Toxic level of vitamin D is about 4X higher than the amount needed to reduce osteoporosis
- FACT: Co-factors help build bones.
- FACT: Vitamin D Receptor can restrict Vitamin D from getting to many tissues, such as bones
- It appears that to TREAT Osteoporosis:
- Calcium OR vitamin D is ok
- Calcium + vitamin D is good
- Calcium + vitamin D + other co-factors is great
- Low-cost Vitamin D Receptor activators sometimes may be helpful
- CONCLUSION: To PREVENT many diseases, including Osteoporosis, as well as TREAT Osteoporosis
- Category Osteoporosis has
- Category Bone Health has
Note: Osteoporosis causes bones to become fragile and prone to fracture
Osteoarthritis is a disease where damage occurs to the joints at the end of the bonesSafety profile of Osteoporosis drugs, including vitamin D – review Nov 2013
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- Category Bone Health has