Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 102447009, 18040001, 32369003, 64859006; ICD10CM: M81.0; ICD9CM: 733.0, 733.00, 733.01; DO: 11476;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5q31.1 | {Osteoporosis, susceptibility to} | 166710 | Autosomal dominant | 3 | RIL | 603422 |
| 7q21.3 | {Osteoporosis, postmenopausal, susceptibility} | 166710 | Autosomal dominant | 3 | CALCR | 114131 |
| 7q21.3 | {Osteoporosis, postmenopausal} | 166710 | Autosomal dominant | 3 | COL1A2 | 120160 |
| 11p12 | {Osteoporosis} | 166710 | Autosomal dominant | 2 | BMND8 | 611739 |
| 17q21.33 | {Bone mineral density variation QTL, osteoporosis} | 166710 | Autosomal dominant | 3 | COL1A1 | 120150 |
| 20p12.3 | {Osteoporosis} | 166710 | Autosomal dominant | 2 | BMND7 | 611738 |
A number sign (#) is used with this entry because of evidence that polymorphisms in the COL1A1 gene (120150.0051), the calcitonin receptor gene (CALCR; 114131), and the RIL gene (603422) are associated with osteoporosis. There is evidence that a polymorphism in the ITGB3 gene (173470) is associated with hip fracture.
See BMND1 (601884) for a list of bone mineral density (BMD) quantitative trait loci, some of which have been associated with susceptibility to osteoporosis. Association has been suggested between variation in the ESR1 gene (133430) and BMD.
Using dual-photon absorptiometry, Seeman et al. (1989) demonstrated reduced bone mass in the lumbar spine and perhaps in the femoral neck of premenopausal daughters of postmenopausal women with osteoporotic compression fractures. The findings suggested that genetic factors, expressed as low peak bone mass, may have a role in the development of postmenopausal osteoporosis. Pocock et al. (1987) found in a twin study that the heritability of bone mass was approximately 90% in the lumbar spine and 70% in the femoral neck. Defects in type I collagen of the sort that may lead to osteogenesis imperfecta may produce a picture suggesting idiopathic osteoporosis (see 120150.0038). In studies of vertebral bone density (VBD) in 63 premenopausal women, aged 19 to 40 years, Armamento-Villareal et al. (1992) found a higher proportion of subjects with irregular menses (52% vs 23%, p = 0.03) and a positive family history of osteoporosis (86% vs 61%, p = 0.04) among subjects with low VBD when compared to subjects with normal bone density. They concluded that premenopausal estrogen exposure and possibly genetic predisposition, rather than environmental factors, are the major determinants of peak bone mass before menopause. Seeman et al. (1994) found that the daughters of women with hip fractures show reduced bone density, suggesting that low peak bone density is a leading factor in hip fracture.
Bone Mineral Density QTLs
Styrkarsdottir et al. (2008) performed a quantitative trait analysis of data from 5,861 Icelandic subjects, testing for an association between 301,019 single-nucleotide polymorphisms (SNPs) and bone mineral density of the hip or lumbar spine. The authors then tested for an association between 74 SNPs (most of which were implicated in the discovery set) at 32 loci in replication sets of Icelandic, Danish, and Australian subjects (4165, 2269, and 1491 subjects, respectively). Sequence variants in 5 genomic regions were significantly associated with bone mineral density in the discovery set and were confirmed in the replication sets (combined P values, 1.2 x 10(-7) to 2.0 x 10(-21)). Three regions are close to or within genes previously shown to be important to the biologic characteristics of bone: the receptor activator of nuclear factor-kappa-beta ligand gene (RANKL; 602642) on chromosome 13q14 (BMND9; 612110), the osteoprotegerin gene (OPG; 602643) on chromosome 8q24 (BMND10; 612113), and the estrogen receptor-1 gene (ESR1; 133430) on chromosome 6q25 (BMND11; 612114). The 2 other regions are close to the zinc finger- and BTB domain-containing protein-40 gene (ZBTB40; 612106), located at chromosome 1p36 and previously implicated as a region associated with bone mineral density (BMND3; 606928), and the major histocompatibility complex region at chromosome 6p21. The 1p36, 8q24, and 6p21 loci were also associated with osteoporotic fractures, as were loci at 18q21, close to the receptor activator of the nuclear factor-kappa-beta gene (RANK; 603499), and loci at 2p16 and 11p11. Styrkarsdottir et al. (2008) concluded that they discovered common sequence variants that are consistently associated with bone mineral density and with low-trauma fractures in 3 populations of European descent. They noted that although these variants alone were not considered clinically useful in the prediction of risk to individual persons, they provide insight into the biochemical pathways underlying osteoporosis.
Bone Mineral Density QTL Associations Pending Confirmation
Parsons et al. (2005) used a cross-species strategy to identify genes that regulate BMD. A BMD quantitative trait locus was identified on the mouse X chromosome for postmaturity change in spine BMD in a cross of SAMP6 and AKR/J mice. They genotyped 76 SNPs from the syntenic 10.7-Mb human region on chromosome Xp22 in 2 sets of DNA pools prepared from individuals with lumbar spine-BMD (LS-BMD) values falling into the top and bottom 13th percentiles of a population-based study of 3,100 postmenopausal women. They identified a region of significant association (p less than 0.001) for 2 adjacent SNPs, rs234494 and rs234495, in intron 6 of the PIR gene (300931). Individual genotyping for rs234494 in the BMD pools confirmed the presence of an association for alleles (p = 0.018) and genotypes (p = 0.008). Analysis of rs234494 and rs234495 in 1,053 women derived from the same population who were not selected for BMD values showed an association with LS-BMD for rs234495 (p = 0.01) and for haplotypes defined by both SNPs (p = 0.002).
Zheng et al. (2015) identified novel noncoding genetic variants with large effect on bone mineral density (n total = 53,236) and fracture (n total = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K, a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). Zheng et al. (2015) identified a low-frequency noncoding variant near EN1 (131290), with an effect size 4-fold larger than the mean of previously reported (Estrada et al., 2012) common variants for lumbar spine BMD (rs11692564T, MAF = 1.6%, replication effect size = +0.20 SD, p meta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; p = 2 x 10(-11); n cases = 98,742 and n controls = 409,511).
Prockop (1998) reviewed the search for the genetic basis of osteoporosis. In a review of the genetics of osteoporosis, Giguere and Rousseau (2000) stated that twin studies had shown that genetic factors account for up to 80% of the variance in bone mineral density. They suggested that, considering that the effect of each candidate gene is expected to be modest, discrepancies among the several allelic association studies may have arisen because different populations carry different genetic backgrounds and exposure to environmental factors. They expected that the development of population-specific at-risk profiles for osteoporosis would include genetic and environmental factors, as well as their interactions.
In a review of progress in the elucidation of genetic control of susceptibility to osteoporosis, Ralston (2002) noted that BMD, ultrasound properties of bone, skeletal geometry, bone turnover, and pathogenesis of osteoporotic fracture are determined by the combined effects of several genes and environmental influences, but that occasionally osteoporosis or unusually high bone mass can occur as the result of mutations in a single gene. Examples are the osteoporosis-pseudoglioma syndrome (259770) and the high bone mass syndrome (601884), caused by inactivating and activating mutations, respectively, in the LRP5 gene (603506).
Huang and Kung (2006) reviewed the genes implicated in osteoporosis.
Association with COL1A1
Grant et al. (1996) described a novel G-to-T polymorphism in a regulatory region of the COL1A1 gene (rs1800012; 120150.0051). They found that the polymorphism was significantly related to bone mass and osteoporotic fracture. G/T heterozygotes at the polymorphic Sp1 site (Ss) had significantly lower bone mineral density (BMD) than G/G homozygotes (SS) in 2 populations of British women, 1 from Aberdeen and 1 from London, and BMD was lower still in T/T homozygotes (ss). The unfavorable Ss and ss genotypes were overrepresented in patients with severe osteoporosis and vertebral fractures (54%), as compared with controls (27%), equivalent to a relative risk of 2.97 (95% confidence interval 1.63-9.56) for vertebral fracture in individuals who carried the 's' allele. While the mechanisms that underlie this association remained to be defined, the COL1A1 Sp1 polymorphism appeared to be an important marker for low bone mass and vertebral fracture, raising the possibility that genotyping at this site may be of value in identifying women who are at risk of osteoporosis. The findings of Grant et al. (1996) were confirmed and extended by Uitterlinden et al. (1998).
Idiopathic osteoporosis indistinguishable from involutional or postmenopausal osteoporosis beginning at an unusually early age has been described in families on the basis of specific mutations in the COL1A1 gene (120150.0038) on chromosome 17q and the COL1A2 gene (120160.0030) on chromosome 7q.
Jin et al. (2009) showed that the previously reported 5-prime untranslated region (UTR) SNPs in the COL1A1 gene (-1997G-T, rs1107946, 120150.0067; -1663indelT, rs2412298, 120150.0068; +1245G-T, rs1800012) affected COL1A1 transcription. Transcription was 2-fold higher with the osteoporosis-associated G-del-T haplotype compared with the common G-ins-G haplotype. The region surrounding rs2412298 recognized a complex of proteins essential for osteoblast differentiation and function including NMP4 (ZNF384; 609951) and Osterix (SP7; 606633), and the osteoporosis-associated -1663delT allele had increased binding affinity for this complex. Further studies showed that haplotype G-del-T had higher binding affinity for RNA polymerase II, consistent with increased transcription of the G-del-T allele, and there was a significant inverse association between carriage of G-del-T and bone mineral density (BMD) in a cohort of 3,270 Caucasian women. Jin et al. (2009) concluded that common polymorphic variants in the 5-prime UTR of COL1A1 regulate transcription by affecting DNA-protein interactions, and that increased levels of transcription correlated with reduced BMD values in vivo by altering the normal 2:1 ratio between alpha-1(I) and alpha-2(I) chains.
Association with ESR1
BMD, the major determinant of osteoporotic fracture risk, has a strong genetic component. The discovery that inactivation of the ESR1 gene (133430) is associated with low BMD indicated ESR1 as a candidate gene for osteoporosis. Becherini et al. (2000) genotyped 610 postmenopausal women for 3 ESR1 gene polymorphisms (intron 1 RFLPs PvuII and XbaI, and a (TA)n repeat 5-prime upstream of exon 1). Although no significant relationship between intron 1 RFLPs and BMD was observed, a statistically significant correlation between (TA)n-repeat allelic variants and lumbar BMD was observed (P = 0.04, ANCOVA), with subjects having a low number of repeats (TA less than 15) showing the lowest BMD values. The authors observed a statistically significant difference in the mean +/- SD number of (TA)n repeats between 73 analyzed women with a vertebral fracture and the nonfracture group, equivalent to a 2.9-fold increased fracture risk in women with a low number of repeats. Becherini et al. (2000) concluded that in their large sample the (TA)n polymorphism in ESR1 accounts for part of the heritable component of BMD and may prove useful in the prediction of vertebral fracture risk in postmenopausal osteoporosis.
See 601769 for a discussion of contradictory findings concerning a relationship between bone mineral density and polymorphism of the vitamin D receptor.
Colin et al. (2003) studied the combined influence of polymorphisms in the ESR1 and the VDR (601769) genes on the susceptibility to osteoporotic vertebral fractures in 634 women aged 55 years and older. Three VDR haplotypes (1, 2, and 3) of the BsmI, ApaI, and TaqI restriction fragment length polymorphisms and 3 ESR1 haplotypes (1, 2, and 3) of the PvuII and XbaI restriction fragment length polymorphisms were identified. ESR1 haplotype 1 was dose-dependently associated with increased vertebral fracture risk corresponding to an odds ratio of 1.9 (95% confidence interval, 0.9-4.1) per copy of the risk allele. VDR haplotype 1 was overrepresented in vertebral fracture cases. There was a significant interaction (p = 0.01) between ESR1 haplotype 1 and VDR haplotype 1 in determining vertebral fracture risk. The association of ESR1 haplotype 1 with vertebral fracture risk was present only in homozygous carriers of VDR haplotype 1. The risk of fracture was 2.5 for heterozygous and 10.3 for homozygous carriers of ESR1 haplotype 1. These associations were independent of bone mineral density. The authors concluded that interaction between ESR1 and VDR gene polymorphisms leads to increased risk of osteoporotic vertebral fractures in women, largely independent of bone mineral density.
In a study of femoral neck bone loss in 945 postmenopausal Scottish women who had not received hormone replacement therapy, Albagha et al. (2005) found that the ESR1 px haplotype was associated with reduced femoral neck BMD and increased rates of femoral neck bone loss.
Association with IL6
Linkage studies have suggested that variation in the interleukin-6 (IL6; 147620) gene is associated with BMD and osteoporosis.
Association with RIL
Association studies by Omasu et al. (2003) suggested a relationship between susceptibility to osteoporosis and genetic variation in the 5-prime flanking region of the RIL gene (603422.0001).
Association with ITGB3
Tofteng et al. (2007) analyzed the L33P polymorphism in the ITGB3 gene (173470.0006) in 9,233 randomly selected Danish individuals, of whom 267 had a hip fracture during a 25-year follow-up period. Individuals homozygous for L33P had a 2-fold greater risk of hip fracture compared to noncarriers (p = 0.02), with risk confined primarily to postmenopausal women, in whom the hazard ratio was 2.6 after adjustment for age at menopause and use of hormone replacement therapy.
Kyriakidou-Himonas et al. (1999) noted that black women have lower levels of serum 25-hydroxyvitamin D (25OHD) with higher serum parathyroid hormone (PTH; 168450) levels than white women. They hypothesized that correction of these alterations in the vitamin D-endocrine system could lead to less bone loss in postmenopausal women and, consequently, preservation of bone mass. They gave 10 healthy postmenopausal black women 20 microg vitamin D3 daily for 3 months. At the end of the study, mean serum 25OHD levels had increased from 24 to 63 nmol/L. Serum intact PTH and nephrogenous cAMP declined significantly, and there was a 21% drop in the fasting urinary N-telopeptide of type I collagen. The authors concluded that vitamin D3 supplementation raises serum 25OHD levels in postmenopausal black women, decreases secondary hyperparathyroidism, and reduces bone turnover.
Greenspan et al. (2000) investigated whether early changes in serum markers of bone resorption could predict long-term responses in BMD after alendronate therapy in elderly women. One hundred and twenty women (mean age, 70 years) were randomized to alendronate or placebo in a double-blind, placebo-controlled clinical trial for 2.5 years. Outcome measures were hip and spine BMD and biochemical markers of bone resorption, including serum N-telopeptide and C-telopeptide cross-linked collagen type I (NTx and CTx, respectively). Serum NTx and CTx were highly correlated at baseline and remained so throughout the study. After treatment with alendronate, serum NTx decreased 30.4 +/- 16.0% at 6 months, reaching a nadir of -36.7 +/- 18.0% by 24 months. Serum CTx decreased 43.5 +/- 67.0% at 6 months and continued to decrease to 67.3 +/- 19.3% at 2.5 years. Moreover, decreases in serum NTx and CTx at 6 months were correlated with long-term improvements in vertebral BMD at 2.5 years in patients receiving alendronate therapy. The authors concluded that early changes in serum NTx and CTx, markers of bone resorption, predict long-term changes in vertebral BMD in elderly women receiving alendronate therapy and provide a useful tool to assess skeletal health.
Harris et al. (2001) reported a 1-year, double-blind, placebo-controlled study in which 524 postmenopausal women received daily treatment with conjugated equine estrogens (0.625 mg) alone or in combination with risedronate (5 mg). Women who had not undergone hysterectomy received medroxyprogesterone acetate (up to 5 mg, daily or cyclically) at the discretion of the investigator. The primary efficacy end point was the percent change from baseline in mean lumbar spine bone mineral density (BMD) at 1 year. Changes in BMD at the proximal femur and forearm, bone turnover markers, and histology and histomorphometry were also assessed. At 12 months, significant (p less than 0.05) increases from baseline in lumbar spine BMD were observed in both treatment groups (HRT-only, 4.6%; combined risedronate-HRT, 5.2%); the difference between the 2 groups was not statistically significant. Both therapies led to significant increases in BMD at 12 months at the femoral neck (1.8% and 2.7%, respectively), femoral trochanter (3.2% and 3.7%), distal radius (1.7% and 1.6%), and midshaft radius (0.4% and 0.7%). The differences between groups were statistically significant (p less than 0.05) at the femoral neck and midshaft radius. The authors concluded that combined treatment with risedronate and HRT had a favorable effect on BMD, similar to that of HRT alone at the lumbar spine and slightly but significantly greater than that of HRT alone at the femoral neck and midshaft radius. The combined treatment was well tolerated and there were no adverse effects on the skeleton.
Ringe et al. (2001) reported the results of a therapeutic trial in men with osteoporosis. This prospective, open-label, active-controlled, randomized clinical study compared the effects of oral alendronate (10 mg daily) and alfacalcidol (1 microg daily) on bone mineral density, safety, and tolerability in 134 males with primary established osteoporosis. All men received supplemental calcium (500 mg daily). After 2 years, alfacalcidol-treated patients showed a mean 2.8% increase in lumbar spine BMD (p less than 0.01) compared with a mean increase of 10.1% in men receiving alendronate (p less than 0.001). The incidence rates of patients with new vertebral fractures were 18.2% and 7.4% for the alfacalcidol and alendronate groups, respectively (p = 0.071). Both therapies were well tolerated. The authors concluded that alendronate may be superior to alfacalcidol in the treatment of men with established primary osteoporosis.
Data obtained by Drake et al. (2003) suggested that among men with osteoporosis it is not possible to identify patients who would be particularly good candidates for therapy with alendronate on the basis of biochemical or hormonal markers. The authors concluded that alendronate therapy appears to benefit osteoporotic males equally, irrespective of baseline serum testosterone, estradiol, IGF1 (147440), or markers of bone turnover.
Both raloxifene (RLX) and alendronate (ALN) can treat and prevent new vertebral fractures, increase BMD, and decrease biochemical markers of bone turnover in postmenopausal women with osteoporosis. Johnell et al. (2002) assessed the effects of combined RLX and ALN in 331 postmenopausal women with osteoporosis. Women received placebo, RLX 60 mg per day, ALN 10 mg per day, or RLX 60 mg per day and ALN 10 mg per day combined (RLX+ALN). At baseline, 6 months, and 12 months, BMD was measured by dual x-ray absorptiometry. The bone turnover markers serum osteocalcin (112260), bone-specific alkaline phosphatase (see 171760), and urinary N- and C-telopeptide corrected for creatinine were measured. All changes in BMD and bone markers at 12 months were different between placebo and each of the active treatment groups and between the RLX and RLX+ALN groups (p less than 0.05). On average, lumbar spine BMD increased by 2.1%, 4.3%, and 5.3% from baseline with RLX, ALN, and RLX+ALN, respectively. The increase in femoral neck BMD in the RLX+ALN group (3.7%) was greater than the 2.7% and 1.7% increases in the ALN (p = 0.02) and RLX (p less than 0.001) groups, respectively. The authors concluded that RLX+ALN reduced bone turnover more than either drug alone, resulting in greater BMD increment, but they did not assess whether this difference reflected better fracture risk reduction.
Hodsman et al. (2003) investigated the efficacy and safety of human parathyroid hormone-(1-84) (full-length PTH; 168450) in the treatment of postmenopausal osteoporosis. PTH treatment induced time- and dose-related increases in lumbar spine BMD. The 100-microgram dose increased BMD significantly at 3 and 12 months. BMD underestimated the anabolic effect of PTH in lumbar spine (bone mineral content, +10.0%) because bone area increased significantly (+2.0%). Dose-related incidences of transient hypercalcemia occurred, but only 1 patient was withdrawn because of repeated hypercalcemia. The authors concluded that full-length PTH was efficacious and safe over 12 months.
The most rapid period of skeletal development occurs over several years in childhood and adolescence, accounting for 40 to 50% of the total accrual of skeletal mass. Maximizing peak bone mass during the first few decades of life is a potentially major strategy in osteoporosis prevention. Cameron et al. (2004) presented the results of a randomized, single-blind, placebo-controlled trial of 51 pairs of premenarcheal female twins (27 monozygotic and 24 dizygotic) in which 1 twin of each pair received a 1,200-mg calcium carbonate supplement. They observed that calcium supplementation increased areal bone mineral density at regional sites over the first 12 to 18 months, but these gains were not maintained to 24 months.
Idris et al. (2005) demonstrated that cannabinoid receptor-1 (CNR1; 114610)-null mice had increased bone mass and were protected from ovariectomy-induced bone loss. Pharmacologic antagonists of CNR1 and CNR2 receptors prevented ovariectomy-induced bone loss in vivo and caused osteoclast inhibition in vitro by promoting osteoclast apoptosis and inhibiting production of several osteoclast survival factors. Idris et al. (2005) concluded that the CNR1 receptor has a role in the regulation of bone mass and ovariectomy-induced bone loss.
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